- Email: [email protected]
Tetanus: A team disease
is Clinical A ~ o c i a t e Professor of S u r g e r y at T h e Ohio State University College of Medicine. After receiving his B.A. a n d M . D . from H a r v a r d University, he served as a Medical Officer with a U n i t e d States A r m y Field Hospital from 1943 to 1946 in China. T h e r e , he saw wounde~l Chinese soldiers die of tetanus, an d observed the efficacy of tetanus toxoid in the prevention of tetanus in wounded U.S. personnel. Following his World W a r I I m i l i t a r y tour of d u ty , he completed his surgical traiaing at the Cincinnati General Hospital and T h e Ohio State U n i v e r s i t y Hospital. H e has published on two anaerobic i n f e c t i o n s ~ t e t a n u s and gas g a n g r e n e - - a n d was ,-m invited essayist and participant to the Second and T h i r d International Conferences on T e t a n u s in Bern, Switzerland, and $5o P a u l o , Brazil, in 1966 a nd 1970, respectively. In 1965, Doctor Furste was invited by President J o h n s o n to a t t e n d his W h i t e Ho u s e signing of the C o m m u n i t y H e a l t h Services Extension A m e n d m e n t s Act of 1965. One of the purposes of this Act of 1965 was to m a k e available throughout the nation a d e q u a t e a m o u n t s of tetanus toxoid. Doctor F u r s t e is a m e m b e r of the s u b c o m m i t t e e on Prophylaxis against T e t a n u s in W o u n d M a n a g e m e n t of the C o m m i t t e e on T r a u m a of the American College of Surgeons.
is m e di c a l resident at Riverside Methodist received his B.S. and M . D . degrees from T u l a n e U n i v e r s i t y respectively. He served pital a nd then, following a tour of d u t y in nam. returned for a medical residency.
Hospital in Columbus, Ohio. H e T h e Ohio State University and an internship at his present hos-the United States.,a.rmy in Viet-
A. INTRODUCTION T E T A N U S is a team disease. T h e striking results that have been achieved in the p r e v e n t i o n and treatment of tetanus in developed countries, and which can b e achieved i n developing countries also, are the resuit of the .laboratory ~;¢ork'of the preclinical scientists, namely, the anatomist, the biochemist, the physiologist, the microbiologist, the pathologist, the immunologist, t h e pharmacologist and their co-workers and of the clinical endeavors of: thb" epidemiologist, the family physician, the internist and his subspecialty associates, the pediatrician, the surgeon and his subspecialty c o l l e a g u e s apd the anesthesiologist. S t u d y of the references for this report will reveal that all of the above types of specialists have made and are making specific contributions in making tetanus a disease of only historical si,gnificance_ Tetanus (lockjaw) is .a sevi~re ,,and dreade-d infectious complication of wounds and is caused by the.toxin-producing Clostridium tetani. This disease is characterized, by. tonic spasms of the voluntary muscles, by a ten3
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1 . - I V I I L E S T O N E S I N T H E H I S T O R Y OF T E T A N U S
Aretaeus, lhe Cappadocian, descrilmd tetanus.l:" Carle demonstrated the transmissibility of telanus by inoculaiion into rabbits of pus from a h u m a n cguse.27 Nicolaier described the tetanus bacilhts. H e was, however, unable to isolate the organism in pure culture,14s Kitasato obtained the pure culture of Cl. tetani.,114 yon Behring and K i t a s a t o described antitoxins and their immunizing powers.20(i R a m o n and Zoeller discussed the use of tetanus toxoid in active immunization of humans.J62, 1~;3 T h e United States m i l i t a r y establishment effectively used the emergency medical identification device. Cohn ,and his co-workers fractiona{ed h u m a n p l a s m a so that T I G (H) became available. 40 McComb, Levine, D w y e r and Letharn established 250 units as the routine prophylactic dose for T I G I H ) . 124.1.~2
dency toward episodes of r e s p i r a t o r y a r r e s t and, over the entire world, by a m o r t a l i t y rate of a p p r o x i m a t e l y 50~o. T e t a n u s has been recognized as a terrifying disease for 2,300 years. H i p p o c r a t e s referred to the m a s t e r of a large ship, who s m a s h e d the index finger of his right hand with the anchor, as follows: "Seven days later a s o m e w h a t foul discharge appeared: then trouble with his tongue • . . on the t h i r d day opisthotonos occurred with s w e a t i n g . . . 6 days later he died. ''~m In the second century, Aretaeus, the C a p p a d o c i a n , called the disease a n i n h u m a n calamity, a n u n s e e m l y sight, a spectacle painful even to the beholder (Table 1). H e wrote: " T h e wish of the physician that the p a t i e n t should expire, otherwise irreverent and objectionable, is, in this case well taken. ''12 T h e correct evaluation of various forms of p r o p h y l a x i s and t h e r a p y for all diseases is difficult, but it is p a r t i c u l a r l y difficult for tetanus. T h e following ])arable indicates how the relationship between a cause and an effect m a y be i n t e r p r e t e d incorrectly. 11~; Fido and the S u n r i s e
"One m o r n i n g Fido awoke earlier than usually. F o r u n k n o w n reasons, he barked. T h e sun rose. T h e n Fido discovered that, each m o r n i n g after he barked, the sun appeared. H e had discovered, he thought, a cause and an effect. "One m o r n i n g Fido overslept, and, when he awakened, the sun was in the sky. Fido, to his chagrin, l e a r n e d that his b a r k i n g did not cause the s u n to a p p e a r in the sky."
B. INTERNATIONAL TETANUS CONFERENCES T h e first of three I n t e r n a t i o n a l Conferences on T e t a n u s took place in India in 1963, the second was held in S w i t z e r l a n d in 1967, the third was convened in Brazil in 1970 and the fourth is tentatively p l a n n e d for a country yet to be d e t e r m i n e d about I974.79, 2o,1. 223 Yodh,217 who was P r e s i d e n t of the S t u d y Group of T e t a n u s a n d who was active in organizing the F i r s t I n t e r n a t i o n a l Conference on T e t a n u s , 4
s u m m a r i z e d well the situation in regard to tetanus in the P r e f a c e of the Proceedings of the ]First International Conference on Tetanus as follows: " T h e incidence of t e t a n u s in India and developing countries is quite high whereas, in the West, the disease has been .practically eradicated because of mass i m m u n i z a t i o n during childhood along with other protective vaccines. T e t a n u s has a high m o r b i d i t y and m o r t a l i t y rate, particularly t e t a n u s n e o n a t o r u m . U n f o r t u n a t e l y , in India and other developing countries, it is not recognized to be a vitally i m p o r t a n t public h e a l t h problem, a n d suffers from a lack of interest on the p a r t of public healfl~ authorities and medical practitioners. "]:n order to create such interest a m o n g medical men, the S t u d y G r o u p on T e t a n u s organized in B o m b a y an I n t e r n a t i o n a l Conference on T e t a n u s in November, 1963. A large n u m b e r of I n d i a n and foreign delegates participated, and t h e r e were m a n y useful discussions c u l m i n a t i n g in certain recommendations. T h e necessity for prevention of t e t a n u s and the use of smaller doses of antitoxin in t r e a t m e n t formed a p a r t of the subject for discussion. T h e need for research, p a r t i c u l a r l y on the transmissioa of the toxin to the nervous system, was stressed. A large n u m b e r of specialists who p a r t i c i p a t e d were of the opinion that prevention of t e t a n u s neon a t o r u m through i m m u n i z a t i o n during p r e g n a n c y is possible and should be encouraged." At the T h i r d I n t e r n a t i o n a l Conference on T e t a n u s in S,~o Paulo, Brazil, in 1970, representatives of nations of all p a r t s of the world, such as the United States, the Union of Soviet Socialist l~epublics, J a p a n and Senegal, were present.S3 T h e p a r t i c i p a n t s were from both the preclinical and clinical disciplines. Among those who contributed p a p e r s were J. B e n n e t t (medical epidemiologist from the U S P H S C e n t e r for Disease Control in A t l a n t a ) , E. E r i k s s o n (surgeon from S w e d e n ) , G. Edsall (immunologist from the M a s s a c h u s e t t s D e p a r t m e n t of Public H e a l t h in .Boston and the London School of H y g i e n e a n d Tropical Medicine in London), J. P a t e l (internist from India) and A. Benenson (specialist in c o m m u n i t y medicine from the University of K e n t u c k y ) . T h e Conference organizer and chairm a n was R. Veronesi (internist from Brazil). T h e official language was English, with s i m u l t a n e o u s translation in Portuguese. F o r informal discussions, however, F r e n c h , ]Russian, P o r t u guese, Spanish, J a p a n e s e a n d G e r m a n w e r e used. T h e Conference was s u p p o r t e d by the World H e a l t h Organization and was sponsored by the A c a d e m y of Medicine of S~o Paulo.
C. INCIDENCE AND EPIDEMIOLOGY I. T h E U
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T e t a n u s continues to occur as a complication of lacerations, open fractures, burns, abrasions, h y p o d e r m i c injections, operations on the gastrointestinal tract and birth (infection of t h e umbilical s t u m p in the newborn). Relatively few cases of t e t a n u s occur in the United States. U n d e r the able directorship of D. Sencer, the U S P H S Center for Disease Control weekly reports telegraphic data on t e t a n u s and p r e p a r e s excellent s u m m a r i e s on m a n y aspects of tetanus. 5
TABLE
INCmENCE OF REPORTED CASES OF TETANUS
2,
IN T H E U N I T E D STATES 3! X~UAIBER OF CASE:$
1966-1970
Diphtheria 214
Poliomyeli|is 53
Tetanus .166
442
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138 120
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FzG. l ( t o p ) . - - R e p o r t e d cases of tetanus, United Stat~;, :I950--1970.'-'9 (Courtesy of Cen{er for Dise&se Control.) FzG. 2(bottorn).--Gex~.graphic distribution of tetanus case.~ (excluding neonatal tetanus) and incidence rates, by state, 1968-1(.)69.47 (Courtesy of Center for Disease Control.)
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:FIG. 3 ( t o p ) . - - W w o h u n d r e d n i n e t y - f i v e t e t a n u s cases ( e x c l u d i n g n e o n a t a l telalm.'~), i)y m o n t h of oruset, Unitcnt S t a t e s , 1968--1969.49 ( C o u r t e s y of C e n t e r for I)isem~e C o n t r o l . ) Fro. 4 ( b o t t o m ) . - - T e t a n u s case f a t a l i t y r a t i o s , U n i t e d S t a t e s , ]9~¢3--19(;¢.).47 T h e t e l a n u s case f a t a l i t y r a t i o of a p p r o x i m a t e l y 60~o for two (|evades s h o u l d in(tee~I be .'~ s t i m u l u s for m o r e w i d e s p r e a d a n d m o r e efficient a d m i n i s t r a t i o n of t e t a n u s t o x o i d , p a r t i c u l a r l y in the y o u n g a n d t h e a g e d , in w h i c h two groUps t h e r e has b e e n a h i g h f a t a l i t y r a t i o ~see Pig. 5). Also, StlCb h i g h f a t a l i t y ratios emph,'~,,izeihat t e i a n u s is a m o s t seriou,; (li.,~e,-ase a n d t h a t - - w h e n I n ~ n i b l e - it s h o u l d be t r e a t e d in a c o m p l e t e l y e q u i p p e d h o s p i t a l staffed b y s p e c i a l i s t s w i t h an inl(:rest in t e t a n u s . ( C o u r t e s y of C e n l e r for Dise~.se C o n t r o l . )
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T h e i n t r o d u c t i o n of t e t a n u s t o x o i d a p p r o x i m a t e l y t h r e e d e c a d e s ago, w h i c h w a s f o l l o w e d in m a n y p a r t s of t h e w o r l d by p r o g r a m s of i m m u n i z a tion o f t h e p o p u l a t i o n , c o n t r i b u t e d g r e a t l y to t h e control o f t e t a n u s . N e v e r t h e l e s s , d u r i n g t h e d e c a d e 1 9 5 1 - 1 9 6 0 , t e t a n u s r e m a i n e d an u n s o l v e d p r o b l e m in m a n y a r e a s of t h e world. In a 1966 report, B y t c h e n k o 2 6 s h o w e d : on t h e basis of t h e a v a i l a b l e l i t e r a t u r e a n d W o r l d H e a l t h O r g a n i z a t i o n statistics, t h a t t e t a n u s c a u s e s m o r e t h a n 50,000 d e a t h s e a c h y e a r all over t h e world. I n d e e d , this figure s h o u l d be r e g a r d e d as a n underestimate, s i n c e it o n l y p a r t i a l l y reflects the a c t u a l s i h m i i o n . B y i c h e n k o ' s p a p e r d r a w s a t t e n t i o n to t h e g e o g r a p h i c dis° t r i b u t i o n oi t e t a n u s in t h e w o r l d a n d i n d i c a t e s that e x i s t i n g foci or z o n e s of i n f e c t i o n m a y be a t t r i b u t e d to e n v i r o n m e n t a l c o n d i t i o n s as well as to social, e c o n o m i c a n d c u l t u r a l factors.
D. MICROBIOLOGY In ~m e d i t o r i a l in a 1964 i s s u e of t h e Journal o[ the American ~[edical Association there is the f o l l o w i n g quotationC, a:
" M a n or b o y that w o r k s or p l a y s In the fields or h i g h w a y s ~]ily, w i t h o u t o f f e n s e or h u r t From the soil contact :i dirl:."
~ M n l c Y I,AM~. 1809
8
T h e " d i r t " of the "fields or h i g h w a y s " envisioned in M a r y L a m b ' s poem includes the ciostridial g r o u p of organisms, of which CI. tetani is a promi n e n t m e m b e r . Also, c o m m o n l y the feces of domestic a n i m a l s a n d h u m a n s c o n t a i n Cl. tetani.n9.17,~ T h e s e s t r i c t a n a e r o b e s a r e the c o m m o n and app r o p r i a t e t e n a n t s of the e a r t h , with a role t h a t favors t h e conversion of o r g a n i c w a s t e m a t e r i a l into fertile soil for the g r o w t h of vegetables, g r a i n s a n d t h e b e a u t i e s of n a t u r e . It is said t h a t if it were not for the p r e s e n c e of th e Clostridia, e x c r e m e n t would a c c u m u l a t e a n d m a k e t h e world untenable. A l t h o u g h t e t a n u s h a d b e e n described a n d was k n o w n as a clinical disease since the time of H i p p o c r a t e s , the d e m o n s t r a t i o n of the i n d u c t i o n of t e t a n u s was not m a d e u n t i l the l a t t e r p a r t of the n i n e t e e n t h c e n t u r y . In 1884, Ca r le was able to p r o d u c e t e t a n u s in rabbits by i n o c u l a t i n g t h e m with pus t a k e n from the w o u n d of a h u m a n with tetanus.27 At a p p r o x i m a t e l y the s a m e time t h a t C a r l e r e p o r t e d his work, N i c o l a i e r r e p o r t e d t h e discovery of the t e t a n u s bacillus. H e was, however, u n a b l e to isolate the o r g a n i s m s ira p u r e culture.l-~8 A few y e a r s l a t e r , in 1889, K i t a s a t o was able to o b t a i n a p u r e c u l t u r e of t h e t e t a n u s bacillus.ll,s Cl. tetani is a large, gram-positive, actively motile bacillus, which, in its s p o r e - b e a r i n g form, has a c h a r a c t e r i s t i c " d r u m s t i c k " a p p e a r a n c e . S p o r e s m a y develop a t e i t h e r end of the bacillus, giving a " d u m b b e l l " a p p e a r ance. I t is a s t r i c t a n a e r o b e , a n d spores will not g e r m i n a t e in the p r e s e n c e of even the s m a l l e s t a m o u n t of oxygen.'~;, ~sl A n o x i d a t i o n - r e d u c t i o n pot e n t i a l of +0.01 volt or less at p H 7 is r e q u i r e d if g e r m i n a t i o n is to t a k e place. T h e Clostridium grows well on l a b o r a t o r y m e d i a a t 37 ° C, a n d g r o w t h occurs slowly at 22 ° C. V e g e t a t i v e bacilli a r e killed r e a d i l y by a n t i s e p t i c s a n d by h e a t , b u t spores a r e h i g h l y r e s i s t a n t to a n t i s e p t i c s and, to a c e r t a i n extent, a r e r e s i s t a n t to heat. T o kill most spores, boiling for 1 h o u r is n e c e s s a r y , but the m o s t r e s i s t a n t m a y r e q u i r e boiling for 4 hours. A u t o c l a v i n g for 10 m i n u t e s at 120 ° C, however, m a y be relied on to FIG. 7 (le[t).---~S. K i t a s a t o . w h o o b t a i n e d a p u r e c u l t u r e of CI. tetani in 1889 a n d who, with yon I~ehring, d ~ c r i l ~ d a n t i t o x i n s in 1890. (Igermi~-~ion of S. N o d a , P h o t o g r a p h i c l z d ~ o r a t o r y of t h e I n s t i t u t e of M e d i c a l S c i e n c e of T o k y o U n i v e r s i t y . a n d courte.,~y of I. E b i s a w a , D e p a r t m e n t of M e d i c i n e at t h e s a m e I n s t i t u t e . ) Fro. 8 ( r i g h t ) . ~ ' I ' e l a n u s in a m o u s e . ]-'luid t e t a n u s toxin was i n j e c t e d into t h e left h i n d ext r e m i t y . C o n t r a c t u r e of the b o d y to the left a n d t e t a n i c left hind e x t r e m i t y a r e visible. {Courtesy of I. E b i s a w a . )
9
TABLE
3.~= D E T E R M I N A T I O N OF SERUM: T E T A N U S A N T r r O X l N A. l~iologie assay 1~. In vitro tests 1. Pas,s i~,e hemagg lu tina l ion 2. llevel,'sed passive hemagglutination 3. Quantitative gel dittusion 4. Passive latex agglutination
s t e r i l i z e c o n t a m i n a t e d objects. P r e s u m a b l y , a f t e r c o n t a m i n a l i o n with soil a n d feces of m a n a n d a n i m a l s , s p o r e s c a n be r e c o v e r e d f r o m d u s t a n d c l o t h i n g ; in s u i t a b l e s u r r o u n d i n g s like d r i e d e a r t h , s p o r e s will s u r v i v e for m a n y y e a r s . ~9, 175 Cl. telani p r o d u e e s two e x o t o x i n s , t e t a n o s p a s m i n a n d tetmmlysin,, a n d , of these, t e t a n o s p a s m i n is l h e n e u r o t o x i n t h a t p r o d u c e s t h e t y p i c a l m u s c l e s p a s m s of tetanus.IS1, '.,-I,1 I t is e x t r e m e l y p o t e n t , e a c h m i l l i g r a m of cryst a l l i z e d t o x i n c o n t a i n i n g 50 m i l l i o n to 75 m i l l i o n m o u s e l e t h a l doses. T h i s e x t r e m e t o x i c i t y a l ) p e a r s to be t h e r e a s o n w h y a n a t t a c k of t e t a n u s does n o t c o n f e r i m m u n i t y , as it is p o s t u l a t e d t h a t t h e fatal dose of t e t a n u s t o x i n is less i h a n t h e a m o u n t r e q u i r e d to provoke an i m m u n e r e s p o n s e . T e t a n o l y s i n c a n c a u s e h e m o l y s i s on blood a g a r 1)lntes. A c c o r d i n g to van H e y n i n g e n , 2 0 a t e t a n o l y s i n is c a r d i o t o x i c a n d c a n c a u s e c a r d i a c d a m a g e in tetanus. I n a 1969 rel)ort on t e t a n u s in t h e U n i t e d S t a l e s for t h e 1965-1966 p e r i o d , L a F o : ' c e a n d his co-workers.'20 r e p o r t e d l h a t in o n l y ,'~'~°t,~,..o of 160 c a s e s in w h i c h c u l t u r e s w e r e t a k e n w a s CI. tetani r e c o v e r e d . T h e s i n g l e best e x p l a n a t i o n is t h a t f a s t i d i o u s a n a e r o b i c g r o w t h r e q u i r e m e n t s of this s p e c i e s m a r k e d l y d e c r e a s e t h e c h a n c e for r e c o v e r y u n l e s s special l)re('aulions a r e t a k e n w i t h s p e c i m e n s . B a c t e r i a l o v e r g r o w t h by o t h e r w o u n d i n v a d e r s a n d t h e i n i t i a t i o n of a n t i m i c r o b i a l t h e r a p y also m a y r e d u c e t h e c h a n c e for r e c o v e r y . D e t e r m i n a t i o n of s e r u m t e t a n u s a n t i t o x i n is a m e l h o d of d e t e r m i n i n g t h e effects of toxoid a n d of a n t i t o x i n , a n d s u c h a d e t e r m i n a t i o n i n d i c a t e s w h e t h e r an i n d i v i d u a l h a s p r o t e c t i o n a g a i n s t t e t a n u s . Biologic assays, or in v i t r o tests m a y be m a d e . T o l ) e r f o r m i h e m o u s e biologic a s s a y a n d t h(~ p a s s i v e h e m a g g l u t i n a t i o n a n d r e v e r s e d passive h e m a g g l u t i n a l i o n tests req u i r e s d a y s . so t h e y a r e n o t of w d u e in d e c i d i n g w h e t h e r a l)alient is p r o t e c t e d a g a i n s t t e t a n u s at t h e t i m e of i n j u r y . A l e x a n d e r a n d M o n crieD. 4 h a v e s t u d i e d a q u a n t i t a t i v e gel d i f t u s i o n m e t h o d a n d a p a s s i v e l a t e x a g g l u t i n a t i o n p r o c e d u r e in a n e n d e a v o r to o b t a i n a s e r u m a n t i t o x i n level w i t h i n s e v e r a l h o u r s ( T a b l e 3).
E. ETIOLOGY (WOUNDS) I n c o n t r a s t io gas g a n g r e n e ( c l o s t r i d i a l m y o s i t i s ) , which is a c o m p l i c a tion of tile s e v e r e a n d s o m e t i m e s n e g l e c t e d w o u n d , t e t a n u s n o t only i s a c o m l ; l i c a t i o n of s e v e r e or n e g l e c l e d or old w o u n d s b u t m a y o c c u r also in i n d i v i d u a l s wilt, very m i n o r a n d v e r y s u p e r f i c i a l w o u n d s o r in i~ldividu;,lu w i t h o u t e v e n a d e r n o n s t r a b l e w'ound ~ ( T a b l e 4}. As T a b l e 5 sh.ows, a t t h e K i n g "2 J,o"V~' a r o M e m o r i a l H o s p i t a l in Bonlbay, I n d i a , l h e lylms of w o u n d s r e s p o n s i b l e for t e t a n u s v a r i e d f r o m i n j u r i e s wiih a n i n c i d e n c e of 44.5'~;~ 10
TABLE
4.~CLASSIFICATION
OF INJURIES
ASSOCIATED WITII
TETANUS, UNrrE1) S I Aq LS. 1 3 6 8 - 1 . ) 6 . ) 'l'YPt; OF WOUND
Ca,q~.:s WITH A
",,o / OF
(~IVEN I N J U R Y
'~J'o'I'AI, CA.%I,~'S
l ) u n c t ure L a c e r a tim ~ Miscellaneous Abrasion No wound Injection Crush Surgical 1)enta 1
87 84 42 28 22 20 10 3 l
'1"o'r ,~L
FATAl, CAriES
21L 3 28.3 14.1 9.4 7.4 6.7 3.4 1.0 0.3
297
.;9
1 ()0. o
CASI,i-FATAL~T~" I{A'rlo
55 48 28 l (i ]3 15 5 "2 Q
63.2 57. l ()). ] 57.1 59.1 75.(1 50.0 66.7
fSff
6 I. 3
::'P;xcludes n e o n a t e s , o n e p e r s o n of u n k n o w n a g e , a n d cases w i t h u n k n o w n o u t COllie. .
~
.
.
.
.
.
.
.
.
! A B L L 5.~. ROUTE OF INFECTION OF C L. T E T A N I IN A "LAltGE SERIES OF TETANUS CASES AT TttE K I N G EDWARD M E M ) R I A L HOSPI%~L, BOMBAY, INI)IA~ 5~ 1 ,)raL
%
892 406 29,2 2N~ C;7 32 2(1 15
44.5 20.2 14.5 14.2 3.3 1.6 1.0 ).
Injury Otorrltea Neonatorunt Unknown':: 1~u e r pe ra I Injection V a c c i n a t ion ( ) p e r a ( ion
'::We a s s u m e t h a t P a t e l a n d Mehla15~; inc l u d e d in t h e " U n k n o w n " c a t e g o r y c a s e s in v,-}lich n o s o u r c e of e n i r y w a s fouIld on ~Jxztllli n a i i o n o r was r e t ) o r t e d .
TABLE
6 . m S r r g OF INJ1JRY OF TETANUS CASES IN TIlE UNITED STATES, 1 9 6 5 - 1 9 6 6 ~s
•
Foot J~and Leg Arm t t e a d a n d ne~.'k O t h e r lo,::ations Trunk 4
¢
•
.
(.d~ x o ] o r a L
1 . JOTAL
O,q
t ,.o • JOTAL
CASE" ]['AT ALI 'r Y I£\TIO
138 90 7J 2'9 21 il 3 7
:]7.4 24.4 19.2 7.8 5.7 3.5 J .,9
71.0 66.6 70.4 72.4 57. I 09.2 28.(1
;t6:)
109.0
68.3
11
T A B L E 7.~TETANUS, U N I T E D STATES, 1968 AND 1969, W H E R E I N J U R Y OCCURRED *'t9 LOCATION
TOTAL
Home Other specified locations Farm Garden Factory
147 40 24 21 5
GmXND TOTAL
237
(}o OF TOTAh
62.0 16.9 10.1 8.9 2.1 100.0
::"Excludes neonates, and is based on persons with known age and outcome, and for whom locality at the time of injm'y is known.
TABLE
8. A~E 62 38 69 65 8 3 65 63
T A B L E 9. AGE 28 26 23 26 26 23
POSTOPERATIVE T E T A N U S IN T H E U N I T E D STATES, 1965-19664s SURGICAL PROCEOURE Amputation of gangrenous foot Unknown Amputation of finger Hemorrhoidectom y
Bunionectomy Ruptured appendix Colectomy Incision and drainage of perirectal abscess Wart removal
OUTCOME
Died Recovered Died Died Recovered Recovered Died Died Died
TETANUS CASES RELATED TO ABORTION AND PARTURITION IN THE UNITED STATES, 1965--19664s CLINICAL BACKGROUND
OUTCO3I E
Spontaneous abortion Self-induced abortion A :Normal delivery 10 days prior to onset j Spontaneous deliver~,, with flint-degree perir~-al tear Incomplete abortion Septic abortiori
Died Died Died Died Died Die~t
to e l e c t i v e o p e r a t i o n s w i t h a n i n c i d e n c e of 0.7%. T a b l e s 6 a n d 7 i n d i c a t e t h e l o c a t i o n s of o c c u r r e n c e . T a b l e s 8 a n d 9 s u m m a r i z e cases of t e t a n u s a f t e r s u r g i c a l p r o c e d u r e s a n d i n o b s t e t r i c cases. FQr s u r g e o n s w h o t a k e c a r e of bowel o b s t r u c t i o n s , a case of t e t a n u s foll o w i n g r e s e c t i o n of a g a n g r e n o u s b u t u n p e r f o r a t e d s m a l l i n t e s t i n e , w h i c h w a s i n v o l v e d in a n o b s t r u c t i o n , m a y be of. c o n s i d e r a b l e interest.39 S h e r m a n 1 7 S h a s u r g e d t h a t t e t a n u s p r o p h y l a x i s be p r o v i d e d f o r t h e b u r n case, a n d r e c e n t l y C h e r u b i n 3 4 h a s e m p h a s i z e d t h a t n a r c o t i c a d d i c t s m a y develop tetanus. A n u m b e r of y e a r s ago, R o b i n s o n e t al. 167 p o i n t e d o u t t h a t - - p r i o r to present-day technics operating room dressings, instruments, catgut and d u s t w e r e i n c r i m i n a t e d as s o u r c e s of C1. t e t a n i for t e t a n u s cases. I n a r e c e n t s t u d y to d e t e r m i n e w h e t h e r s h e e p s k i n s u s e d as b e d p a d s in
i2
t h e p r e v e n t i o n of bedsores could be a source of the C1. t e t a n i for t e t a n u s , Cowling, et al..~o concluded t h a t c o m m e r c i a l t a n n i n g m e t h o d s effectively sterilize s h e e p s k i n s so t h a t t h e r e is no risk of t h e i r c o n v e y i n g t e t a n u s spores to hospitals a n d t h a t the sporicida] effect of g l u t a r a l d e h y d e , w h e n used on sheepskins, is confirmed.
F. PATHOGENESIS T h e m e r e fact t h a t C1. t e t a n i is p r e s e n t in a w o u n d does not n e c e s s a r i l y m e a n t h a t the p a t i e n t has t e t a n u s or t h a t h e will develop it:. T h e organisms will p r o l i f e r a t e only in t h e p r e s e n c e of a n o x i d a t i o n - r e d u c t i o n potential far lower t h a n t h a t existing in n o r m a l living tissue. Once Cl. t e t a n i begins to grow, it p r o d u c e s t e t a n o s p a s m i n , w h i c h is t r a n s p o r t e d to the c e n t r a l n e r v o u s system, w h e r e it becomes fixed a n d is responsible for t h e d e v e l o p m e n t of t e t a n u s . As SmithlSl has p o i n t e d out, t h e r e have been differences of o p i n i o n c o n c e r n i n g the site of action of t e t a n o s p a s m i n a n d c o n c e r n i n g the r o u t e by which it spreads, b u t it now seems established t h a t t h e toxin acts in the s p i n a l cord a n d in the b r a i n s t e m a n d t h a t it s p r e a d s c e n t r a l l y along m o t o r nerve t r u n k s a n d u p the s p i n a l cord. T e t a n u s ~411 follow the i n t r a venous injection of toxin into a n i m a l s , b u t the r o u t e by which toxin in t h e blood e n t e r s the n e r v o u s s y s t e m is not clear. T o x i n i n j e c t e d i n t r a m u s c u l a r l y a p p a r e n t l y s p r e a d s not only by passing u p m o t o r nerves but also by a b s o r p t i o n into the blood, a n d it has been suggested t h a t v a s c u l a r s p r e a d is the m o r e i m p o r t a n t route in g e n e r a l i z e d tetanus. I n a s t u d y of 22 a u t o p s y cases of t e t a n u s i n c l u d i n g 3 n e o n a t e s . E b i s a w a a n d M a t s u k u r a 6 3 concluded t h a t : 1. P u l m o n a r y complications are the f r e q u e n t a n d prognostically imp o r t a n t pathologic findings in t e t a n u s p a t i e n t s , p a r t i c u l a r l y w h e n t h e y a r e t r a c h e o s t o m i e d or w h e n t h e y survive m o r e t h a n a week a f t e r a d m i s s i o n to a hospital. 2. D e g e n e r a t i o n of s t r i a t e d muscles, a l t h o u g h of a v a r i a b l e d e g r e e a n d involving d i a p h r a g m , intercostal, psoas, rectus a b d o m i n i s a n d o t h e r m u s cles, m a y be a f r e q u e n t finding in t e t a n u s . T h e m a i n pathologic c h a n g e s in t h e s t r i a t e d muscles consist of bleeding, loss of stripes, r u p t u r e , i n t e n s e s t a i n i n g a n d h o m o g e n i z a t i o n , lysis a n d d i s a p p e a r a n c e of myofibrils. T h e s e c h a n g e s i n c r e a s e in s e v e r i t y with i n c r e a s i n g survival t i m e of t h e p a t i e n t . 3. Tile d e g e n e r a t i v e c h a n g e s in r e s p i r a t o r y m u s c l e s p l a y a s u b s t a n t i a l role in t h e v e n t i l a t o r y failure of the p a t i e n t . T h e y also e x p l a i n t h e m y a s t h e n i c p h e n o m e n a observed in t h e convalescent period of t e t a n u s , such as p o s t - t e t a n i c p a r a l y s i s of r e s p i r a t o r y a n d o t h e r muscles. 4. S o m e of t h e p a t i e n t s die of f u n c t i o n a l r a t h e r t h a n m o r p h o l o g i c a l l y recognizable causes. A f t e r a n e x h a u s t i v e s t u d y of n e o n a t a l t e t a n u s , Pinheiro160 c o n c l u d e d that: 1. T h e l i t e r a t u r e a s s u m p t i o n t h a t the s t u m p of the u m b i l i c a l cord cons t i t u t e s the p r i n c i p a l p o r t a l of e n t r y of t h e t e t a n i c infection is correct. 2. B l o o d - c i r c u l a t i n g t e t a n u s toxin is found rarely. I n most cases of neon a t a l t e t a n u s , t h e t e t a n o s p a s m i n has a l r e a d y b e e n fixed by l h e cells of tlle c e n t r a l n e r v o u s s y s t e m at the t i m e of admission. S u c h a finding is of 13
u t m o s t i m p o r t a n c e for prognosis in t h a t the infant's fate is p r e d e t e r m i n e d even before hospitalization. Therefore, it m a y be a s s u m e d t h a t the m a n a g e m e n t and cure of t e t a n u s in the newborn infant w i t h o u t the use of a n t i t e t a n i c s e r u m is possible and t h a t use of tetanus antitoxin in the course of t r e a t m e n t m a y not be as f u n d a m e n t a l as has been supposed. 3. T h e r e is a s u r p r i s i n g l y low toxin-producing capacity of Cl. t e t a n i in the cord stump, since the sloughing off of the distal cord eliminates the focus of the infection.
O. CLINICAL PICTURE " I n m y clinical experience I have never seen such a t e r r i f y i n g disease as t e t a n u s . " ~ F R A N K GLENN89
1. INCUBATION :PERIOD In a 1968 report, the U S P H S C e n t e r for Disease Control reported t h a t the m e d i a n incubation period for fatal cases and nonfatal cases was 7 and 8 days, respectively. T h e range was from 1 to 54 days. However, 88% of all cases had dates of onset within 14 days or less from the time of injury.4S T h e longer i n c u b a t i o n periods are p a r t i c u l a r l y likely to occur w h e n the p a t i e n t has received p a r t i a l protection from h u m a n , equine or bovine antitoxin or w h e n secondary surgical revision or m a n i p u l a t i o n of wounds especially war w o u n d s ~ i s performed. R a r e l y , w h e n a scar of a wound has of necessity been explored surgically, t e t a n u s has occurred m a n y years after the time of the p r i m a r y wound.76
2. SYMPTOMS AND SIGNS T e t a n u s almost always a p p e a r s in a general form, but occasionally it m a y a p p e a r as local tetanus. Usually, with the l a t t e r form, general symptoms occur sooner or later, but t h e n the disease is likely to be milder a n d responsible for a lower m o r t a l i t y rate t h a n the general type usually seen.76 I n the familiar general form, the earliest indications of infection usually become evident from 1 to 2 weeks after injury. T h e severity of the clinical picture a n d the m o r t a l i t y rate are roughly inversely proportional to the d u r a t i o n of the i n c u b a t i o n period. S o m e patients have p r o d r o m a l s y m p t o m s of restlessness and headaches. In others, the first s y m p t o m s are those s t e m m i n g from the developing muscle rigidity, with vague discomfort in the jaws, neck or l u m b a r region. A t a n early stage, spasm of the muscles of m a s t i c a t i o n causes t r i s m u s and difficulty with chewing, i.e., lockjaw. S u s t a i n e d contraction of the facial muscles produces a distorted grin (risus sardonicus). S p a s m of the p h a r y n g e a l muscles m a k e s swallowing difficult. Stiff neck and opisthotonos also are a m o n g the early signs. Progressively, other muscle groups become involved, with tightness of the chest a n d rigidity of the a b d o m i n a l wall. the back a n d the limbs. Generalized tonic convulsions are f r e q u e n t a n d exhausting. A n y s u d d e n j a r or sound., such as a h y p o d e r m i c injection or the fall of all object onto the floor., will excite such generalized convulsions. In association with these convulsions, there sometimes is 14
r
.
.
2
*
¸7¸i!i~i~
Fro. 9 ( a b o v e ) . ~ A child with e arly tetanus. P a t i e n t e.*:hibits risus sardonicus, trismus, opisthotonos and extended lower extremities. (Courtesy of E. Velasco-Joven.) FIe,. 10 (rigl~t).~Convalescent stage o f tetanus. T h e patient is trying to remain upright. N o t e the traces of risus sardonicus, trismus, rigidity of the neck and stiffness of the body and extremities. (Courtesy of E . Velasco-Joven.)
s p a s m of t h e l a r y n g e a l a n d r e s p i r a t o r y m u s c l e s with, s o m e t i m e s , a resulting, possibly fatal, a c u t e a s p h y x i a . Mercilessly, t h e p a t i e n t is m e n t a l l y c l e a r t h r o u g h o u t t h e course of t he disease, a n d he suffers g r e a t p a i n from t h e m u s c l e spasms. T h e pulse r a t e is e l e v a t e d a n d t h e r e is p r o f u s e p e r s p i r a t i o n . F e v e r m a y or m a y not be p r e s e n t . N e u r o l o g i c e x a m i n a t i o n discloses h y p e r a c t i v e t e n d o n reflexes. often w i t h s u s t a i n e d clonus. T h e r e a r e no s e n s o r y changes. If t h e p a t i e n t survives, the i n t e n s i t y of the m u s c l e c o n t r a c t i o n s m a y begin to d i m i n i s h slowly d u r i n g a b o u t t h e second week. C o m p l e t e recove r y m a y t a k e several m o n t h s . Occasionally, m i l d cases occur in w h i c h t h e r e is only m o d e r a t e m u s c l e r i ~ d i t y w i t h o u t t e t a n u s seizures. I n a p e r s o n w i t h o u t t e t a n u s toxoid prop h y l a x i s p r i o r to i n j u r y , the a d m i n i s t r a t i o n of toxoid m a y forestall tim d e v e l o p m e n t of s e v e r e t e t a n u s a n d m a y r e s u l t in only a mild t e t a n u s or a local t e t a n u s involving only the m u s c l e s a r o u n d t h e site of i n j u r y . E v e n w h e n t r e a t m e n t is " a d e q u a t e , " t h e mortality_ r a t e m a y be u,~n°~o or higher. O lder c h i l d r e n a n d y o u n g e r a d u l t s r e s p o n d b e t t e r t h a n y o u n g e r c h i l d r e n a n d older adults. M o s t d e a t h s occur w i t h i n 10 d a y s of the o n s e t of th e illness. P a t i e n t s who live as long as a week a n d a half h a v e good p r o s p e c t s of c o m p l e t e recovery. W h a t c a n h a p p e n to a m e m b e r of a n u n i m m u n i z e d civilian p o p u l a t i o n exposed to a m i l i t a r y conflict was described vividly by Glenn'S'*, 90 in conn e c t i o n w i t h W o r l d W a r II: 15
" T h e most f r e q u e n t l y observed clinical p i c t u r e was as follows: A p a t i e n t w i t h a w o u n d of c o n s i d e r a b l e e x t e n t in a n e x t r e m i t y would be u n a b l e to o p e n his m o u t h by 5 to 7 d a y s a f t e r i n j u r y . T h e r e would be m a r k e d trism u s a n d stiffness of the neck muscles. A s s o c i a t e d w i t h t h e s e t w o findings t h e r e would exist, or soon follow, mild s p a s m s which fixed the h e a d , body, a n d e x t r e m i t i e s in a s t r a i g h t line orthotonos. W i t h i n a m a t t e r of h o u r s as the s e i z u r e s b e c a m e m o r e p r o n o u n c e d a n d m o r e f r e q u e n t , o p i s t h o t o n o s d e v e lo p e d with g r e a t e r i n v o l v e m e n t of t h e back muscles, so t h a t d u r i n g a s p a s m the back b e c a m e a r c h e d a n d the body was t r u l y s u p p o r t e d by t h e h e a d a n d heels. C o n c o m i t a n t l y , t h e r e would a p p e a r the classical risus s a r d o n i c u s with elevation of t h e e y e b r o w s a n d r e t r a c t i o n of the c o r n e r s of th e m o u t h , p r o d u c i n g a g r i m a c e t h a t exposed t h e locked jaws. O r t h o t o n o s was observed to be followed not only by o p i s t h o t o n o s b u t e m p r o s t h o t o n o s . S p a s m a n d rigidity of the a b d o m i n a l m u s c l e s was a n e a r l y a n d c o m m o n finding t h a t p r e c e d e d g e n e r a l i z e d seizures a n d p e r s i s t e d d u r i n g a n d bet w e e n them. As s p a s m s b e c a m e m o r e i n t e n s e over a period of h o u r s or days, t h e y r e n d e r e d b r e a t h i n g difficult. W i t h t h e muscles of t h e n e c k a n d d i a p h r a ~ n and the i n t e r c o s t a l s in spasm, the a i r e x c h a n g e was so r e d u c e d t h a t ti~e lips and nail beds b e c a m e very cyanotic. D u r i n g the severe s p a s m s , t h e r e was profuse p e r s p i r a t i o n , a n d p a i n was e x c r u c i a t i n g and u n b e a r a b l e . As the disease p r o g r e s s e d a n d t h e s p a s m s i n c r e a s e d in severity a n d f r e q u e n c y , the p a t i e n t b e c a m e p h y s i c a l l y e x h a u s t e d but r e m a i n e d m e n t a l l y clear a n d terrified. An occasional p a t i e n t died d u r i n g a spasm, but t h e m a j o r i t y , following c o m p l e t e e x h a u s t i o n , b e c a m e listless, a n d the d i m i n i s h i n g convulsive s e i z u r e s w e r e followed by d e a t h . " G l e n n r e p o r t e d t h a t in the b a t t l e for M a n i l a in 1945 t h e r e w e r e 473 r e p o r t e d cases of t e t a n u s in a p p r o x i m a t e l y 12,000 w o u n d e d civilians who, so far as is known, h a d not had t e t a n u s toxoid i n o c u l a t i o n s before being injured. T h e incidence of t e t a n u s was a l m o s t 40 per 1,000 w o u n d e d civiltans (3.97[,). T h e m o r t a l i t y in t h e s e 473 eases was 82.1t'~.
3. LABORATORY DATA T h e diagnosis of t e t a n u s m u s t be based on t h e clinical picture, for labo r a t o r y e x a m i n a t i o n s a r e of little assistance. T h e d e m o n s t r a t i o n of CI. t e t a n i in a w o u n d does not prove the diagnosis of t e t a n u s : the failure to d e m o n s t r a t e the bacillus in a w o u n d does not e l i m i n a t e the possibility of tetantls. T h e u r i n e is norrnal unless s e c o n d a r y u r i n a r y t r a c t infection occurs. T e t a n u s itself p r o d u c e s a slight elevation in the leukocyt e count, but s e c o n d a r y infection m a y p r o d u c e g r e a t e r elevation. T h e c e r e b r o s p i n a l fluid often is u n d e r i n c r e a s e d pressure, but o t h e r w i s e it is not r e m a r k -
4. A PATIENT'S PI~OGRI'k¢;SNOTI.~S Vt, ry r;lrely in the surgical l i l e r a t u r e is t h e r e found the p a t i e n t ' s l~rogress noit:s, After giying the clinician's a(,count of successful t r e a i m e n l (~f Ii'|IIIIIIS ill 11 20-y~,ar-~fld a n a l y l i c a l clwmist, (;oh, r,t al. '~'2 s u b m i t t e d the t'~)ll~xving rel~orl ()f the l):ttient: ""I'll(, tirsl sylnl)lolns sl;irted :il)l)roxinlgllely a week ;tfier l lind cul lny 16
finger. T h e y consisted in a s u d d e n t i g h t e n i n g a r o u n d m y t h r o a t causing e x t r e m e difficulty in b r e a t h i n g a n d m a k i n g swallowing virtually impossible. D u r i n g this spasm, coughing or e x p e c t o r a t i o n a d d e d to the difficulty in obtaining air as m y t h r o a t seemed to collapse when I tried to inspire. " S p a s m s of the t h r o a t usually a p p e a r e d at rest a n d lasted a b o u t ten m i n u t e s in the early stages. L a t e r on, t h e y were more prolonged. Two days after admission they seemed continuous, and about this time ray voice became reduced to a w h i s p e r and m y j a w felt stiff. T h e s y m p t o m s from then on are only snatches of m e m o r y . I felt like snarling, m y u p p e r lip i n v o l u n t a r i l y d r a w i n g back over the teeth, and a peculiar twitch was vaguely p r e s e n t in m y limbs. " D u r i n g the whole of the illness I can r e m e m b e r no acute p a i n except for joint cramp. Double vision was p r e s e n t and this could, I suppose, have been an effect of the drug. ,(He saw double for two days before ' T u b a r i n e ' was begun. L.B.C.) " M o v e m e n t . T h e r e was a certain a m o u n t of discomfort owing to lying in one position. T h i s was definitely helped by being t u r n e d ov.er every two hours. K n o w i n g this was to be done b r o u g h t g r e a t relief, and, of course, it was s o m e t h i n g to look forward to, too. G r e a t discomfort was felt, especially at night when awaking. As far as I can r e m e m b e r this was due to hallucinations at the point of time w h e n the d r u g was due to wear off. On the whole, comfort could not have been better. A point I am quite sure about is the position of legs. I gained g r e a t e r comfort w h e n the positions of m y legs were varied . e.g., first two hours both straight, second two hours lower one straight, third two hours both bent with thighs horizontal. "Eyes. A m a j o r concern was the eyes, which definitely functioned peculiarly while I was u n d e r the drug ( T u b a r i n e ) . :Firstly, they crossed themselves, giving double vision. Secondly, large objects seemed to be m u c h c l o s e r ~ e . g . , w h e n I was lying on my back the ceiling seemed some 18 inches from m y nose. T h e m o r a l here is not to be on one's back. E y e s were improved w h e n I was washed; in fact, d a m p eyes felt n o r m a l for a t,ime. " H e a r i n g . T h i s was acute: every sound seemed magnified; I could hear, quite distinctly, the doctors h a v i n g a good old talk. T h i s was helpful as it occupied m y m i n d the worst times were w h e n there was n o t h i n g to hear. Silence was oppressive, a l t h o u g h I realised one couldn't have a continuous noise vibrating t h r o u g h the ward. I ' m grateful for the m a n y passages read to me when w a k i n g after a n i g h t m a r e . T h e radio was also helpful. " T a k e n off the r e s p i r a t o r for suction. A f t e r several days I lost the fear of never being able to b r e a t h e when off the respirator, as it was a l w a y s restored quickly. I only had one really scaring time, when the tube fell out after replacement. I know it felt more secure w h e n the tube from the ventilator was s c r e w e d into the t r a c h e o s t o m y socket a n d not just p u s h e d in. Also when the tube was t a k e n off before the suction a p p a r a t u s was m a d e ready, the time t a k e n was terrifyingly long. " T h i r s t . ~ I enjoyed the 'lime' m o u t h w a s h e s and the ice-water m o u t h washes, especially in the hot weather. T h e y were a brain-wave." Of p a r t i c u l a r interest is the s t a t e m e n t that "I can r e m e m b e r no acuIe l)ain, except for joint cruml)." This l)alient m u s t have been a t i e n d e d carefully. 17
H. DIFFERENTIAL DIAGNOSIS E a r l y or m i l d t e t a n u s m a y resemble c e r t a i n Other conditions, b u t severe t e t a n u s is likely to be confused With few o t h e r diseases.76, 139 A frequent, diagnostic p r o b l e m is differentiation of h e t e r o l o g o u s s e r u m sickness from e a r l y tetanus. If p a t i e n t s with i n j u r i e s a r e given heterologous e q u i n e or bovine t e t a n u s antitoxin; a p p r o x i m a t e l y 5 - 3 0 % s u b s e q u e n t l y will d e v e l o p s e r u m sickness w i t h t e m p o r o m a n d i b u l a r a r t h r a l g i a a n d trismus, a r t h r a l g i a of o t h e r joints, u r t i c a r i a a n d generalized adenitis. T e t a n y is less severe t h a n t e t a n u s , u s u a l l y follows o p e r a t i o n s on t h e thyroid gland a n d affects the u p p e r e x t r e m i t i e s p r i m a r i l y . T h e muscle contractions of t e t a n y are elicited by p r e s s u r e on the nerves leading to the cont r a c t i n g muscles. M e n i n g i t i s a n d e n c e p h a l k i s m u s t be differentiated from t e t a n u s , but it is u n u s u a l for the a l e r t p h y s i c i a n to be seriously misled. R a b i e s ( h y d r o p h o b i a ) is exhibited by the p a t i e n t ' s i n a b i l i t y to swallow as a n e a r l y s y m p t o m , drooling of saliva and s p a s m s of the muscles of deglutition. L a t e r in the course of the disease, it is c h a r a c t e r i z e d by feverl anxiety, e x c i t e m e n t , d e l i r i u m , h y p e r e s t h e s i a a n d convulsions. R a b i e s involves part i c u l a r l y t h e muscles of respiration. A h i s t o r y of a n i m a l bite u s u a l l y is obtainable. T h e clinical p i c t u r e of s t r y c h n i n e poisoning, w i t h . h y p e r e x c i t a b i l i t y of muscles, opisthotonos, risus s a r d o n i c u s a n d tonic convulsions, m a y m i m i c t e t a n u s closely, except t h a t the muscles are relaxed b e t w e e n seizures in s t r y c h n i n e intoxication, w h e r e a s s p a s m tends to persist in tetanus[ Moreover, in s t r y c h n i n e poisoning, the jaws a n d face are not p a r t i c u l a r l y affected. A n a d e q u a t e l y t a k e n h i s t o r y m a y be g r e a t l y helpful in differentiating t e t a n u s from rigidity due to p h e n o t h i a z i n e t r a n q u i l i z e r drugs and in differe n t i a t i n g t e t a n u s from lead e n c e p h a l o p a t h y . A c u t e psychoses m a y be quite difficult' to differentiate from earl,,, or mild t e t a n u s , a n d a v e r y t h o r o u g h psychiatric e v a l u a t i o n a n d a test of time m a y be n e c e s s a r y to m a k e a n exact diagnosis. 176. 196 Local t e t a n u s m a y closely s i m u l a t e the s p a s m s of a localized group of v o l u n t a r y m u s c l e s due to soft tissue or bone injuries. T r i s m u s not d u e to t e t a n u s m a y occur with p e r i t o n s i l l a r a b s c e s s a n d o t h e r local infections of the m o u t h a n d cervical regions, and with den'tor n a n d i b u l a r problems. D y s p h a g i a , suggestive of tetanus, m a y a c t u a l l y be the result of u p p e r r e s p i r a t o r y infections. N e o n a t a l t e t a n u s m a y be confused with meningitis, h y p o c a l c e m i c t e t a n y , sepsis a n d i n t r a c r a n i a l h e m o r r h a g e , a n d m a y r e q u i r e cerebrospinal fluid analyses, blood c h e m i s t r y studies, w o u n d and blood c u l t u r e s and neurosurgical e v a l u a t i o n for a correct diagnosis. ,.
I. C O M P L I C A T I O N S C o m b i n a t i o n s of c o m p | i c a t i o n s t h a t occur m a y be responsible for death.7~, P u l m o n a r y atelectasis m a y be followed by p n e u m o n i a , which is to be dreaded, for it seriously lessens tile c h a n c e s for recovery. T r a u m a t i c glossitis is seen often. Compression fractures of the v e r t e b r a e m a y result from the convulsive seizures.20, 5:3 D e c u b i t a l ulcers a r e likely to occur in p a t i e n t s 18
u n d e r h e a v y sedation. Constipation, fecal i m p a c t i o n a n d u r i n a r y r e t e n t i o n a r e e n c o u n t e r e d often. Cystitis a n d p y e l o n e p h r i t i s m a y develop in p a t i e n t s r e q u i r i n g c a t h e t e r i z a t i o n . One to 3 weeks a f t e r the a d m i n i s t r a t i o n of heterologous e q u i n e or bovine antitoxin, s e r u m sickness m a y occur. If homologous s e r u m [ T I G ( H ) ] is given, such sickness will not occur. Foot drop a n d m u s c l e c o n t r a c t u r e s m a y follow prolonged unconsciousness with the limbs in poor position. A s p h y x i a from r e s p i r a t o r y or l a r y n g e a l m u s c l e s p a s m or from a s p i r a t i o n of secretions, vomitus or food m a y be the i m m e d i a t e cause of death. V a r i o u s drugs a n d a d j u n c t i v e m e a s u r e s are used in t h e m a n a g e m e n t of a p a t i e n t with t e t a n u s ; hence, it m a y be almost imPossible to decide the exact cause of s u b s e q u e n t complications from drugs. I n 1964, H a r r i s o n e t al. 95 stressed the i m p o r t a n c e of following c o m p l e t e blood counts w i t h p r o m p t investigation of the clotting m e c h a n i s m should bleeding occur, a n d discussed 3 cases of t e t a n u s with u n u s u a l bleeding diatheses developing d u r i n g t r e a t m e n t . A 47-year-old w o m a n h a d severe hypop r o t h r o m b i n e m i a , factor V I I a n d X deficiencies a n d a large r e t r o p e r i t o n e a l h e m a t o m a , which r e q u i r e d massive t r a n s f u s i o n a n d p a r e n t e r a i a d m i n i s t r a tion of v i t a m i n K. T h e p r o t h r o m b i n activity r e t u r n e d to n o r m a l a n d she recovered. A 6-year-old boy h a d t h r o m b o c y t o p e n i c p u r p u r a with a p l a t e l e t c o u n t of 8,000; the condition was t r e a t e d w i t h steroids b u t was 3 weeks in resolving. I n t r a v a s c u l a r h e m o l y s i s occurred on two occasions in a 3-year-old boy d u r i n g t r a n s f u s i o n w i t h packed cells. T h e p a t i e n t ' s h e m a t u r i a cleared rapidly without treatment. I n ]969, Okulskil49 r e p o r t e d that, in 25 t e t a n u s p a t i e n t s , low p r o t h r o m b i n levels, i m p a i r e d t h r o m b i n g e n e r a t i o n a n d i n c r e a s e d p l a s m a fibrinolytic activity w e r e observed. Also, blood p l a t e l e t counts a n d p r o t h r o m b i n c o n s u m p tion in s e r u m w e r e slightly decreased. B l e e d i n g times w e r e slightly s h o r t e r t h a n normal. T h e blood a n d recaleified p l a s m a clotting time, p l a s m a t h r o m bin t i m e a n d fibrinogen levels w e r e n o r m a l . T h e observed c h a n g e s w e r e related to the evolution of the disease. Prothrombin" levels w e r e decreased m o s t in e a r l y p h a s e s of the disease, increas: ing g r a d u a l l y in the course of the n e x t few weeks. Blood p l a t e l e t counts a n d s e r u m p r o t h r o m b i n c o n s u m p t i o n also r e t u r n e d to n o r m a l levels. A slight t r a n s i e n t increase in fibrinogen level was a c c o m p a n i e d by decreased fibrinolyric activity. M e a n bleeding time showed n o n c h a r a c t e r i s t i c fluctuations, a n d blood clotting time g r a d u a l l y b e c a m e longer in the course of hospitalization, a t t a i n i n g n o r m a l m e a n values. Differences in the b e h a v i o r of some of these tests w e r e observed b e t w e e n mild a n d severe cases of tetanus. M e a n p r o t h r o m b i n values w e r e lower in severely ill p a t i e n t s a n d fibrinogen levels were higher. I n the g r o u p s of severly ill p a t i e n t s , g r e a t e r i m p a i r m e n t of p r o t h r o m b i n c o n s u m p t i o n in s e r u m a n d longer p l a s m a p r o t h r o m b i n times w e r e observed also. I n t h e long-term e v a l u a t i o n of t h e clinical picture, the neurologic a n d e l e c t r o e n c e p h a l o g r a p h i c s e q u e l a e of t e t a n u s m u s t be considered.10.~ Previously r e p o r t e d s y n a p t i c c h a n g e s in e x p e r i m e n t a l t e t a n u s led Illis a n d Taylor105 to a clinical fol|ow-up of survivors f r o m tetanus. T w e n t y - f i v e were followed for a period r a n g i n g from 3 m o n t h s to 11 y e a r s a f t e r recovery. F e a t u r e s noted in the follow-up included irritability, s | e e p d i s t u r b a n c e , fits, myoclonus, decreased libido, postural h y p o t e n s i o n and e]ectroencephalographic abnormalities. 19
J.
PROPHYLAXIS T h e four bases on w h i c h ~.he p y r a m i d - o f t e t a n u s p r o p h y l a x i s f o r . t h e w o u n d e d is based are (1) t e t a n u s toxoid, ( 2 ) surgical care, (3) a n t i t o x i n a n d (4) e m e r g e n c y m e d i c a l i d e n t i f i c a t i o n devices. F o r centuries, surgical cm'e was the only i m m e d i a t e l y available t y p e of t e t a n u s p r o p h y l a x i s for the victim of t r a u m a . T h e n , at t h e l a t t e r p a r t of the n i n e t e e n t h c e n t u r y , heterologous a n t i t o x i n s w e r e developed; a f t e r Wo'rld W a r I, toxoid b e c a m e available; d u r i n g W o r l d W a r II, e m e r g e n c y m e d i c a l identification devices w e r e used; and, a b o u t the m i d d l e of t h e t w e n t i e t h c e n t u r y , homologous t e t a n u s a n t i t o x i n b e c a m e a realityl F r o m t h e e a r l y p a r t of t h e t w e n t i e t h c e n t u r y , the A m e r i c a n College of Surgeons, t h r o u g h its C o m m i t t e e on T r a u m a , has b e e n active in d e v e l o p i n g t e t a n u s p r o p h y l a x i s a n d in e n d e a v o r i n g to hell) the m e d i c a l , profession in crystallizing its t h i n k i n g c o n c e r n i n g s u c h prophylaxis.S6, 165 A l t h o u g h a significant p e r c e n t a g e of the m a l e p o p u l a t i o n h a s received t e t a n u s toxoid w h e n in m i l i t a r y service, m a n y w o m e n a r e not protected.74 E v e r y i n j u r y p r e s e n t s its own p r o b l e m s to the physician:called on to t r e a t it, b u t active i m m u n i z a t i o n w i t h t e t a n u s t o x o i d ~ a s far as the risk of t e t a n u s is c o n c e r n e d ~ h a s a l m o s t oversimplified t e t a n u s p r o p h y l a x i s in the m a j o r i t y of i n j u r e d persons, in t h a t a small booster dose fisually is given to those previously i m m u n i z e d a n d is m o s t efficacious in p r e v e n t i n g tetanus. A m a j o r problem, however, is t h a t - s o m e t i m e s n e i t h e r the p a t i e n t n o r his p h y s i c i a n c a n be c o m p l e t e l y c e r t a i n of p r i o r protectionl by toxoid unless the p a t i e n t c a r r i e s a n e m e r g e n c y medical identification device i n d i c a t i n g p r o t e c t i o n or sensitivity to toxoid. I n association w i t h the ever-increasing ~ use of t e t a n u s toxoid a n d the s t e a d i l y dec-lining incidence of t e t a n u s , t h e r e possibly has developed a dec r e a s i n g aware~ness b y p h y s i c i a n s t h a t t e t a n u s c a n occur. T h e possibility of t e t a n u s s h o u l d a t least be t h o u g h t of in the individual w i t h u n e x p l a i n e d i r r i t a b i l i t y or convulsions. I n view of these c o n s i d e r a t i o n s a n d in light of r e c e n t d e y e l o p m e n t s in r e g a r d to t e t a n u s p r o p h y l a x i s , r e - e m p h a s i s of c e r t a i n concepts seems w a r r a n t e d at this time. T h a t t e t a n u s c a n b e ' p r e v e n t e d is a m p l y d o c u m e n t e d . T h e incidence of t e t a n u s in a group of w o u n d e d civilians Without t e t a n u s toxoid i m m u n i z a tion d u r i n g W o r l d W a r : I I w a s 900,000% g r e a t e r t h a n in w o u n d e d U n i t e d S t a t e s A r m y p e r s o n n e l w i t h such immunization.SG, sg~ I.~5, 126
1. WOUND PREVENTION F o r t e t a n u s to occur, C1. tetani m u s t gain e n t r a n c e to the body by a w o u n d even t h o u g h the w o u n d m a y be so small t h a t "it is not redognized, a n d t e t a n u s toxin, Which a c t u a l l y is responsib]e.f0r tetanus, m u s t be produced. If w o u n d p r e v e n t i o n p r o g r a m s w e r e corripletely efficacious e v e r y w h e r e , t e t a n u s would not occur. .
INDIVIDUALIZATION OF WOUNDED PATIENTS Wo.unded p a t i e n t s are individuals. S o m e m a y not have h a d all the indicated t e t a n u s toxoid injections, others m a y h a v e h a d too m a n y toxoid injec20
tions a n d a ' s m a l l n u m b e r m a y be h y p e r s e n s i t i v e to t e t a n u s toxoid.(;9, l~,s, 1s4 A few m a y have insig]fificant wounds; o t h e r s m a y have almost: l e t h a l wounds. M a n y m a y n o t have with t h e m a n u p - t o - d a t e e m e r g e n c y medical identification device with significant t e t a n u s toxoid injection information. H e n c e , i n d i v i d u a l i z a t i o n of each p a t i e n t for t e t a n u s p r o p h y l a x i s m u s t be considered.
3. TOXOID P r o p h y l a c t i c m e a s u r e s r e n d e r e d at the time of i n j u r y to nonactively imm u n i z e d persons Cannot be g u a r a n t e e d to offer protection, but, w i t h prior active i m m u n i z a t i o n , a booster dose at the time of i n j u r y offers effective a n d prolonged protection. I n the p r e v i o u s l y i m m u n i z e d , a very small booster dose of toxoid (0.2 Lf) will p r o d u c e a n t i b o d y levels in 3 weeks, w h i c h can be i n t e r p r e t e d as e q u i v a l e n t to a 1,000-100,000-unit dose of heterologous or homologous passive antibody.133. 197 I n addition, it has been d e m o n s t r a t e d in a n i m a l studies with toxin t h a t a n active booster response a p p e a r s e a r l i e r t h a n c a n be e s t i m a t e d by blood a n t i t o x i n levels.106 To give g r e a t e r p r o t e c t i o n a g a i n s t severe, slight a n d u n r e c o g n i z e d wounds, to m a i n t a i n this protection a n d to avoid the e x t r a c a r e a n d cost e n t a i l e d in active-passive i m m u n i z a t i o n , every p r a c t i c i n g p h y s i c i a n , regardless of his specialty, should m a k e every effort to actively i m m u n i z e w i t h t e t a n u s t o x o i d ~ a n d to keel) actively i m m u n i z e d , his p a t i e n t s , t h e i r families, his f a m i l y a n d himself.7.~ I n r e g a r d to himself, he should r e m e m b e r the words of t h e p a r s o n a b o u t w h o m it is w r i t t e n in the P r o l o g u e to Chaucei"'s Canterbury Tales3a: " T h i s noble e n s a m p l e [ e x a m p l e ] to his s h e e p he y a f [gave], T h a t first ~ e w r o u g h t e , a n d a f t e r w a r d he t a u g h t e . " a) DEVELOPZ~IENT BY RA..SION, DEsCOI~$BEY AND ZOELLER.. D u r i n g the y e a r s i m m e d i a t e l y a f t e r World. W a r I, R a m o n , Descom]Sey a n d Zoeller w e r e able to c u l t u r e Cl. tetani, t~) p u r i f y its toxin a d e q u a t e l y , a n d to l)repare a fluid toxoid suitable for a n i m a l a n d clinical trial.56, as2, 1G,~ b) TYPES OF TOXO1D. A t first, only t h e plain or fluid t y p e of t e t a n u s toxoid was available, but t h e n t h e a d s o r b e d or p r e c i p i t a t e d t y p e of toxoid was developed a n d b e c a m e a v a i l a b l e in one of five p r e p a r a t i o n s ( T a b l e 11). F o r some time, fluid toxoid was p r e f e r r e d by some on the basis of fewer reactions, a m o r e r a p i d a n a r n n e s t i c response, a D a n y s z p h e n o m e n o n w i t h s i m u l t a n e o u s active-passive i m m u n i z a t i o n a n d a h i g h e r incidence of anterior poliomyelitis w i t h a d s o r b e d toxoid.S, lz9 S h o r t - t e r m a n d long-term studies, however, have since i n d i c a t e d that. the adsorbed is the p r e f e r r e d type.32, 92, 124, 131, 198 Specii~cally, TrincalgS has d e m o n s t r a t e d well a n adeq u a t e r e s p o n s e w i t h a d s o r b e d toxoid (Fig. 11).
T A B L E 10.
T Y P E S OF ][:hI]~IUNIZATION A G E N T S
A. Active i m n m n i z a t i o n agents: antigens 1. Dead bacteria or viruses; 2. Attenuated bacteria or virtv;es 3. Toxin-antitoxin mixtures 4. Toxoids or anatoxins: tenanus B. Passive immunization agents: antibtxl'ies 1. Antitoxins: tetanus i m m u n e globulin (human) 2. Antisera
2]
TABLE II. PREPARATIONS OF q~ETANUS Toxom TI:IAT HArm BEEN AVAILABLE57 A. F l u i d (plain) toxoid B. Adsorbed (precipitated or " m i l k y " ) toxoid 1. A l u m precipitated 2, A l u m i n u m hydroxide a d s o r b e d 3. A l u m i n u m h y d r o x i d e precipitated 4. A h m a i n u m phosphate a d s o r b e d 5. A l u m i n u m phosphate precipitated
:l~oxoids distributed by different producers have different concentrations, and world-wide standardization of toxoids continues to be investigated constantly so that m a x i m u m effectiveness can be obtained with a m i n i m u m of side reactions w h e n a toxoid injection is given.211 Of course, at all times, quality control m u s t be m a i n t a i n e d in regard to conversion of all toxins to toxoid, in regard to bacterial contamination and in regard to reversion of toxicity of tetanus toxoid.2 At the International T e t a n u s Conferences, concern was expressed that not all toxoids contain the s a m e number of Lf units per ml. and should be standardized. T h e L i m e s flocculation unit (Lf) is a measure of the purity of tetanus toxoid, and is the amount of toxoid that gives the most rapid flocculation w i t h 1 standard unit of antitoxin. In the past, toxoids have contained C) PURITY OF TOXOID.
FIG. l l . - - B o o s t e r response to tetanus toxoid. T h e s e patients h a d b e e n given tetanus toxoid previously. A protective response is obtained with both fluid and adsorbed toxoid. 1,'~s ( C o u r t e s y of d. Trinca.) i00
;E
lO o
/
Z
/ !
//
i/
Z N 0 Z <
F
0. I
t
x---x o--o
BOOSTER
u~ Z <
0.01
F L U I D (30 S U B J E C T S ) ADSORBED (32 S U B f f E C T S )
"Minimum protective level"
0 0
4
DAYS
7
AFTER
22
BOOSTER
14
INJECTION
possibly as m a n y as 40 Lf per ml. of toxoid. Such h i g h - p o t e n c y toxoids have produced very a n n o y i n g side-reactions. M a n y . o f the t e t a n u s toxoids used presently c o n t a i n a p p r o x i m a t e l y 5-7.5 Lf per 0.5 ml. T h e p u r i t y of l e t a n u s toxoid is expressed as Lf per rag. of protein nitrogen. d ) METHODS OF ADMINISTRATION. Toxoid has been a d m i n i s t e r e d by injection s u b c u t a n e o u s l y or intramuscularly.54, ~n In D e n m a r k , t e t a n u s toxoid a l w a y s has been given s u b c u t a n e o u s l y , since the D a n e s have believed t h a i such injections of a l u m i n u m h y d r o x i d e - a d s o r b e d toxoid have produced a satisfactory a n d long-lasting i m m u n i t y with a m i n i m u m of local reactions.~,~ F o r rapid i m m u n i z a t i o n of large groups, a jet injector or " g u n " has become available, a n d can be l o a d e d with m a n y doses of an i m m u n i z i n g agent.54, 55 Recently, the possibility of t e t a n u s toxoid i m m u n i z a t i o n by a n aerosol m e t h o d has been explored.213 Soluble t e t a n u s toxoid given as a n aerosol to h u m a n volunteers led to a n increase in s e r u m a n t i b o d y titers c o m p a r a b l e to t h a t resulting from conventional Subcutaneous a d m i n i s t r a t i o n . N o increase in the titer of nasal a n t i b o d y was d e m o n s t r a t e d . S p u t u m a n t i b o d y titers, however, were found to increase significantly in the persons who received aerosolized vaccine, d e m o n s t r a t i n ~ t h a t secretory a n t i b o d y was p r o d u c e d in response to a n a n t i g e n t h a t n o r m a l l y does not e n t e r the r e s p i r a t o r y tract. In a recent c o m m u n i c a t i o n , VeronesiZ04 s t a t e d t h a t he has succeeded in obtaining s e r u m tetanus, a n t i t o x i n levels by the a d m i n i s t r a t i o n of t e t a n u s toxoid orally. T o obtain such levels with both initial a n d booster doses, he has coated the toxoid to protect it a g a i n s t acid gastric juice. e) EXPERIENCES WITH TETANUS TOXOID.- 1) United States A r m y . During W o r l d W a r I]:, the practically 100% efficiency a n d safety of t e t a n u s toxoid as a p r o p h y l a c t i c a g e n t were proved by the experience of the U n i t e d S t a t e s Army.125, 126 Only 12 cases of t e t a n u s occurred in a series of 2,734,819 hospital admissions for wounds a n d injuries. T h e m o r t a l i t y in these 12 cases was 41.7%. As to i m m u n i z a t i o n status, only 4 of these 12 9 a t i e n t s had had both a n initial i m m u n i z a t i o n of fluid toxoid a n d a booster dose. T h e zero incidence of t e t a n u s in U n i t e d S t a t e s A r m y active d u t y personnel from 1956 to N o v e m b e r of 1971 reinforces w h a t was l e a r n e d a b o u t tetanus toxoid in W o r l d W a r II.I46 2) Pregnant women and neonatal tetanus.. ]Prior to 1965, i m m u n i z a t i o n of p r e g n a n t w o m e n in N e w G u i n e a with 3 injections of p l a i n toxoid had p r e v e n t e d n e o n a t a l tetanus. In a 1965 report, a n t i t o x i n levels i n d u c e d by
TABLE
12,
-INCIDENCE OF T~TANUS IN THE UNITED STATES ARi~ft'72, 96, 125, 126. 146 AD~XlSSm~'S FOR W O U N D S AND I N J U R I E S
Civil War X,Vorld War I 1920-1941" V,rorld XVar II Korean War 1956-Nov. 1971, including lhe Vietnam conflict
280,040 523,158 580,283 2,734,819
CASF~]I00,000 CASF,S OF TETANUS
505 70 14 12 6-8 0
*]nclt~sive.
9.2
AND INJURED
WOUNDS
18.03 13.4 2.4 0.44
TABLE 13.--TETANUS Toxom
IMM:UNIZATION STATUS OF 12 CASES OF TETANUS IN 2,734,819 UNITED STATES ARMY HOSPITAL ADMISSIONS DURING WORLD WAR I1125, 126
No active immunization
Initial immunization (3 irijections of fluid toxoid) accomplished but no emergency stimulating injection given Initial immunization plus emergency booster dose given TOTAL
FATA L CASF~S 2
T O TA L
1
2
2 5
4 12
CASES 6
,.
2 o i l - a d j u v a n t toxoids (1 i n j e c t i o n ) , 1 AIPO,t toxoid (2 injections) a n d 1 p l a i n toxoid (3 injections) w e r e c o m p a r e d w i t h those i n d u c e d by t h e s a m e p l a i n toxoid as used in the e a r l i e r study.127 A t term, t h e r e was no signific a n t difference in the levels for the 5 toxoids, but those for the plain toxoids l a t e r d e c l i n e d rapidly. A 1 P O t - t o x o i d l i t e r s were significantly h i g h e r t h a n t h e t i t e r s for t h e p l a i n toxoids a t t h e end of a y e a r b u t lower t h a n t h e oila d j u v a n t titers, which w e r e t h e highest a n d m o s t persistent. However, una c c e p t a b l e side-effects ( i n d u c e d by s u b s e q u e n t lots of o i l - a d j u v a n t toxoids) p r e c l u d e d t h e i r r o u t i n e use. W h e r e a s previously the incidence of n e o n a t a l t e t a n u s was 80 per 1,000 live births, for the 1.965 r e p o r t t h e r e were no cases of t e t a n u s in 120 babies. T h e r e s u l t s i n d i c a t e t h a t a m a t e r n a l a n t i t o x i n level at delivery of 0.01 u n i t / m l , is protective. A l u m i n u m - c o m p o u n d toxoid r a p i d l y a c h i e v e d liters t h a t w e r e b e t t e r t h a n this for at least a year, with m i n i m a l side-effects. H e n c e , such toxoids are r e c o m m e n d e d for m a t e r n a l i m m u n i z a tion to p r e v e n t n e o n a t a l tetanus.OZ I n a 1966 report, Newel] et aI.147 r e p o r t e d s i m i l a r l y good results. W i t h a view to d e t e r m i n i n g t h e effectiveness of a m e t h o d for the control of t e t a n u s n e o n a t o r u m t h a t would be i n d e p e n d e n t of m e d i c a l e x a m i n a t i o n or care, a double-blind field trial covering 1,618 w o m e n was c o n d u c t e d b e t w e e n ~1961 a n d 1966 i n a r u r a l a r e a of Colombia with a n e s t i m a t e d existing t e t a n u s neon a t o r u m d e a t h r a t e of 11.6 p e r 100 births. T h e s t u d y g r o u p was given 1-3 i n j e c t i o n s of 1 ml. of a n a l u m i n u m p h o s p h a t e - a d s o r b e d t e t a n u s toxoid m o r e t h a n 6 weeks a p a r t a n d the control g r o u p a s i m i l a r n u m b e r of injections of a n influenza virus vaccine. T h e r e was no s t a t i s t i c a l l y significant difference b e t w e e n those in the control a n d s t u d y g r o u p s given 1 injection. T h o s e in t h e control group given 2 or 3 injections had a t e t a n u s n e o n a t o r u m d e a t h r a t e of 7.8 per 100 b i r t h s a n d the c o r r e s p o n d i n g s u b j e c t s in the s t u d y g r o u p had none. T h i s difference is u n l i k e l y to h a v e o c c u r r e d by chance. f) DURATION OF EFFECT OF TETANUS TOXOID.- ....T h e h u m a n body does not " f o r g e t " a dose of t e t a n u s toxoid. T h e first injection sensitizes or triggers t h e body so t h a t it r e s p o n d s to the second a n d reinforcing or booster (loses of t e t a n u s toxoid by p r o d u c i n g c i r c u l a t i n g s e r u m t e t a n u s a n t i t o x i n and probably o t h e r protective mechanisms.J0~; As yet, t h e r e has not })eel2 determ i n e d ~! m i n i m u m period of time a f t e r which t h e r e is not an a n a m n e s t i c response; a n t i t o x i n liters a r e being d e t e r m i n e d f r e q u e n t l y for \Vorld W a r I I v e t e r a n s to d e t e r m i n e w h e t h e r t h e r e is su('h an interval. Edsall points out that a numl)er of i n v e s t i g a t o r s a l r e a d y have shown a n u n e x p e c t e d l y high 24
TABLE
1 4 . ~ R E A C T I O N S OF A M A L E TO T E T A N U S T o x o m ~VITH REPEATED DOSES 2h'PE oF ToxoII)
DATE AND AGE
1949:2 1949:2 1951:4 1952:5 1953:6 1955:8
GIVEN SC.
DPT DPT Pptd. T DPT Pptd. T Pptd. T
RF~.XCTION
REASON
0 0 0 0 0 Redness and induration greater than anticipated Redness and induration 1963:16 Pptd. T Injury of half of upper arm 1964:17 Pptd. T Injury Redness and induration from elbow to shoulder; "almost double in size" (September 1965: serum tetanus antitoxin flier: 3 units per ml. [McComb].) Initial seri~s Initial seri~s Injury Booster Injury Injury
incidence of long-lasting immunity; in their studies, 8 5 - 9 5 % of individuals immunized against tetanus during World W a r II still carried protective antibody levels 15-21 years later.69, 12s W i t h practically no exceptions, these individuals responded well to a booster dose of toxoid. g) N o ANTITOXIN IF ADEQUATE TETANUS TOXOID I?,IMUNIZATION. .....I t should be noted that protection against tetanus by booster toxoid after w o u n d i n g in the U n i t e d States armed forces in World War II was achieved without the simultaneous use of antitoxin w h e n there was a d e q u a t e prior tetanus toxoid immunization. Credit is due to the U n i t e d S t a t e s military forces consultants who r e c o m m e n d e d that antitoxin was not necessary w i t h a d e q u a t e toxoid prophylaxis.15 h) REACTIONS TO TETANUS TCXOID. Significant reactions to t e t a n u s toxold continue to be rare but are occurring more frequently.GS, 6.q,15s, 173,184, ! 9 9 In late 1964 it was reported by Kittler e t al.~ ~5 that: 1. T e t a n u s toxoid hypersensitivity is infrequent, but a p p a r e n t l y the incidence is increasing. 2. Adults react fairly frequently to alum-precipitated tetanus toxoid.
T A B L E 15.~: ,TOTAL NUMBER OF REPORTED SYSTEMIC REACTIONS TO MONOVALENT TETANUS TOXOID IN DENMARK 1951--1970 ( 2 . 5 MILLION INJECTIONS)3"~ N o . OF CASF~;
Deleterious Death Survival with Neurologic ,sequelae G Iomeruloneph ri t is No permanent damage Acute collapse Late allergy Urticaria. arlhralgia, lymphadenitis (8tli day) Urtwaria persisting > ! month Polyrad icul it i,~
25
INJECTION NUMBER
0 1 I
-->4
2
1,1
3 2 1
1,1,1,
2
4
T A B L E 16. ,,DEATHS W I T H I N 3 D A Y S AFTER VACCINE I N J E C T I O N IN RELATION TO TOTAL NUS,IBER OF I N J E C T I O N S , D E N M A R K 37 CO~IPOSITION OF VACCINE
PERIOD
1947-51 1952-60 1961-70
12 Lf Tetanus 12 Lf T e l a n u s 50 Lf Diphtheria No. of Inj. Deaths N o . of Inj. Deaths 68,000 0 570,000 3 620,000 0 2,000,000 0 1,850,000 0 670,000 0
12 Lf Tetanus 12 Lf Diphtheria No. of Inj. Deaths 73.000 0 550,000 0 610,000 0
7 Lf Tetanus 30 Lf Diphtheria 16 X 109 Pertussis Org. No. of Inj. Deaths
2,500,000
10
3. T h i r t e e n persons wi~re found to be sensitive to t e t a n u s toxoid by history a n d skin test a n d 1 p a t i e n t h a d an a n a p h y l a c t i c reaction to toxoid. A t the Silo P a u l o T e t a n u s Conference, ChristensenaZ r e p o r t e d t h a t from 1951 until 1970 m o r e t h a n two a n d a half million injections of adsorbed tetan u s toxoid h a d been given in D e n m a r k with no r e p o r t s of d e a t h a n d only a single case of neurologic complications with s e q u e l a e (Table 15). H e points out, however, t h a t t e t a n u s toxoid reactions seem to increase in i n t e n s i t y a n d f r e q u e n c y w i t h i n c r e a s i n g n u m b e r s of injections. T h e y range from mild inf l a m m a t o r y local reactions to e d e m a t o u s local reactions, a n d include systemic reactions, such as u r t i c a r i a (sometimes persisting for weeks), a r t h r a l gia, n e p h r o s i s a n d a n a p h y l a c t i c shock. Moreover, the addition of d i p h t h e r i a a n d pertussis a n t i g e n s increases the possibility of reactions (Table 16). I n 1966, B l u m s t e i n a n d K r e i t h e n l 9 r e p o r t e d a case of l)eril)heral n e u r o p a t h y following t e t a n u s toxoid a d m i n i s t r a t i o n . B e c a u s e some individuals m a y be sensitive or become sensitive to t e t a n u s toxoid, one m a i n p r i n c i p l e of active tetafius i m m u n i z a t i o n m u s t be to bala n c e the dosage and a d m i n i s t r a t i o n of toxoid a~ainst the side-reactions so as to obtain o p t i m a l p r o t e c t i o n with m i n i m a l risk of complications. i) BASIC I M h I U N I Z A T I O N ; FREQUENCY OF PERIODIC AND WOUND BOOSTERS. ,-. Since t e t a n u s toxoid is a most effective antigen t h a t m a y lSroduce undesirable reactions, r e c o m m e n d a t i o n s continue to be m a d e for less f r e q u e n t use a n d s m a l l e r dosage of t e t a n u s toxoid. In the 30 October 1971 W e e k l y R e p o r t of the C e n t e r for Disease Control of the U n i t e d S t a t e s Public H e a l t h Service of the H e a l t h , E d u c a t i o n , and W e l f a r e D e p a r t m e n t , the following r e c o m m e n d a t i o n of the P u b l i c H e a l t h Service Advisory C o m m i t t e e on I m m u n i z a t i o n P r a c t i c e s was published:~2" R E C O M M E N D A T I O N OF THE P U B L I C H E A L T H SERVICE ADVISORY C O M M I T T E E ON I M M U N I Z A T I O N PRACTICES
Diphtheria and Tetamls Toxoids and Pertussis Vaccine Introduction Routine i m m u n i z a t i o n against diphtheria, tetanus, and perlussis in infancy or childhood has been widely advocated and generally practice d in the United Stales for lh¢ past 25 years, lls effectiveness is reflected in the rnarked dccrcasc in cases and deaths from these three diseases, 26
Tetanus Although its incidence in the United States has declined in recent years, tetanus remains an important health problem. In 1970, 148 cases of tetanus were reported; a l l o c c u r r e d in unimmunized persons or ones whose immunization history was vague. M o r e than half of the reported cases were in persons 50 years of age or older, and more thah 60 percent were fatal. Since there is no natural immunity to the tetanus toxin and since the tetanus organism is ubiquitous, immunization is a universal requirement regardless of age. Tetanus toxoid is an almost ideal immunizing agent. It is highly effec}ive and provides long-lasting protection. Hypersensitivity reactions, though uncommon with primary immunization, occur frequently in persons who have received an excessive number of booster injections.
Preparations Used for Immunization Diphtheria a n d tetanus toxoids are prepared by formaldehyde treatment of the respective toxins. Pertussis vaccine is made from a killed suspension of bacteria or a bacterial fraction. The toxoids are available in both fluid and adsorbed forms. Comparative tests have shown that the adsorbed toxoids are clearly superior in inducing high antitoxin titers and achieving durable protection. T h e p r o m p t n e s s of antibody responses to booster doses of either fluid or adsorbed toxoid is not sufficiently different to be of clinical importance. Therefore, adsorbed t o y oids are the agents of choice for both primary and booster immunization. The toxoids and pertussis vaccine are available in various combinations and concentrations for specific purposes. Three preparations are important for public health use: 1. Diphtheria and Tetanus Toxoids and Pertussis Vaccine ( D T P ) 2. Tetanus and Diphtheria Toxoids, Adult Type ( T d ) 3. T e t a n u s T o x o i d (T) All preparations contain comparable amounts of tetanus toxoid, but the diphtheria component in the adult type of tetanus and diphtheria toxoids ( T d ) is only about 15 to 20 percent of that contained in the standard D T P preparation for infants and young children.
Vaccine Usage Schedule and dose. The concentration of antigens varies in different manufacttlrers" products. The labeling provides specific information on the proper volume of a single dose. Primao' Immunization Children 2 months through 6 years: The manufacturer's recommended dose of D T P given intran~uscularly on four occasions, three doses al 4 to 6 week intervals with a fourth dose approxinlately 1 year after the third injection. Ideally. immunization should begin at 2 to 3 months of age or a! the time of a B-week "check-up" if that is an established routine. 27
Schoolchildren and adults: A series of three doses of Td* given intramuscularly with the second dose 4 to 6 weeks after the first, and the third dose 6 rnonths to 1 year after the second. Booster doses. :.Children 3 through 6 years (preferably at time of school entrance-kindergarten or elememary school): One injection of the recommended dose of D T P intramuscularly. Thereafter am1 /or all other persons: The recommended dose of Td (adult) intramttscularly every 10 years. If a dose is administered sooner as part of wound management (see specifi c ,recommendations), the next booster is not needed for another 10-years. More frequent booster doses are not indicated and may be associated with increased incidence and severity of reactions. Tetanus Prophylaxis in Wound Management The physician is often faced with questions concerning the use of tetanus toxoid, Tetanus Immune Globulin ( H u m a n ) ( T I G ) , or tetanus antitoxin of animal origin as part of his management of a patient with a wound. Available evidence shows that complete primary immunization with tetanus toxoid provides long-lasting protective antitoxin levels. Additionally, protective antitoxin develops rapidly in response to a booster dose in t~ersons who have previously received at least two doses of tetanus toxoid. Therefore, passive protection with T I G or antitoxin need be considered only when the patient has had less than two previous injections of tetanus toxoid or when the wound has been untended for more than 24 hours. A review of tetanus in the United States in recent years fails to reveal documented cases occurring in individuals with adequate primary immunization. Available evidence shows antitoxin persisting at protective levels for at least 5 years after four doses of tetanus toxoid. Ability to react promptly to booster injections persists for a longer" time. In wound management, it is therefore unnecessary to use booster injections more than every 5 years. F o r persons whose immunizations are still incomplete following wound management, the remainder of the recommended series should be given. The following table is a conservative guide to active and passive tetanus immunization at the time of wound cleansing or debridement. It presumes a reliable knowledge of the patient's immunization history. G U I D E TO T E T A N U S PROPHYLAXIS IN W O U N D M A N A G E M E N T HISTORY OF TETANUS IMMUNIZATION (DOSES)
Uncertain 0--1 2 3 or more
CLEAN. MINOR WOUNDS Td TIG
Yes Yes Yes No"
No No No No
ALL OTItER WOUNDS Td TIG
Yes Yes Yes No:~
Yes Yes No 1 No
I. U n l e s s w o u n d m o r e t h a n 24 h o u r s old. 2. U n l e s s m o r e t h a n 10 years since last dose. 3. U n l e s s m o r e t h a n 5 years since last dose. * T d ( a d u l t ) is c o n s i d e r e d the a g e n t of c h o i c e for i m m u n i z a t i o n of s c h o o l - a g e c h i l d r e n on the basis of d a t a r e g a r d i n g its a d e q u a c y in p r i m a r y i m m u n i z a t i o n of older c h i l d r e n a n d a d u l t s a n d b e c a u s e of i n c r e a s i n g f r e q u e n c y o f r e a c t i o n s to ftzll doses o f d i p h t h e r i a t o x o i d with age.
28
If passive i m m u n i z a t i o n is to be used, T I G is p r e f e r a b l e to, a n i m a l antitoxin, it offers ihe a d v a n t a g e s of longer protection a n d f r e e d o m from undesirable reactions. T h e c u r r e n t l y r e c o m m e n d e d p r o p h y l a c t i c dose of T I G is 250 units for ~'ounds of average severity. W h e n tetanus toxoid and globulin are giver~ c o n c u r r e n t l y , s e p a r a t e syringes and separate sites should be used. Should T I G be unavailable, equine or bovine antitoxin m a y be used, but there is a risk that serious antiphylactic or s e r u m sickness reactions will folIow. I t s a d m i n i s t r a t i o n should always be p r e c e d e d by careful screening for sensitivity in a c c o r d a n c e with instructions a c c o m p a n y i n g the antitoxin. T h e usual dose is 3,000 to 5,000 units. Likewise, on 17 October 1971, the C o m m i t t e e on Infectious D i s e a s e s o f the A m e r i c a n A c a d e m y of P e d i a t r i c s r e c o m m e n d e d t h a t c o m b i n e d t e t a n u s a n d d i p h t h e r i a tox0ids ( a d u l t t y p e ) , ifi c o n t r a s t t o d i p h t h e r i a a n d t e t a n u s ( T D ) c o n t a i n i n g a :larger a m o u n t of d i p h t h e r i a antigen, should be given to those over 6 y e a r s of age, a n d also r e c o m m e n d e d that, at the t i m e of i n j u r y , for c l e a n m i n o r wounds, no booster dose of t e t a n u s toxoid is needed b y a f~llly i m m l i n i z e d child unless m o r e t h a n 10 y e a r s have elapsed since the last dose and, for c o n t a m i n a t e d wounds, a booster dose should be given if m o r e t h a n 5 y e a r s h a v e e l a p s e a since t h e last dose.9 Methods" of i m m u n i z a t i o n a g a i n s t t e t a n u s have b e e n o u t l i n e d for D e p a r t m e n t s of the A r m y , the N a v y a n d t h e A i r Force in a M a y 1970 directive as follows a n d have been f u r t h e r described in a J u l y 1.971 c o m m u n i c a t i o n ,~4, ~5: 1. I n i t i a l i m m u n i z a t i o n consists of ~ i n t r a m u s c u l a r or s u b c u t a n e o u s injections, t h e first 2 doses of w h i c h will consist of 0.5 ml. of the c o m b i n e d toxoids p e r injection, a n d the t h i r d Of 0.1 mI. T h e second injection should be given 1 to 2 m o n t h s a f t e r the first a n d the t h i r d (reinforcing) injection, 0.1 ml., a p p r o x i m a t e l y 12 m o n t h s a f t e r the sec6nd. F o r c h i l d r e n u n d e r 12 y e a r s of age, 0.5 ml. should be given as t h e t h i r d dose to a s s u r e a d e q u a t e immunity against diphtheria. 2. T o a s s u r e a c i r c u l a t i n g level of t e t a n u s a n t i t o x i n a d e q u a t e to p r o t e c t a fighting m a n who m i g h t be in a s i t u a t i o n w h e r e a booster:.dose of toxoid is not available at the t i m e of i n j u r y , a booster dose of 0.1 ml. i n t r a m u s c u l a r l y or s u b c u t a n e o u s l y should be given r o u t i n e l y e v e r y 6 y e a r s following completion of the initial series. 3. T h i s schedule will establish a l o n g - l a s t i n g p r o t e c t i v e level of circulat: ing t e t a n u s a n t i t o x i n in the vast m a j o r i t y of subjects. H o w e v e r , to p r o t e c t the occasional p a t i e n t who does not m a i n t a i n such a level a n d who is therefore subject to t h e risk of tetanus, it is still n e c e s s a r y to a d m i n i s t e r emergency booster (%round booster") i n j e c t i o n s of 0.5 ml. of this p r o d u c t to all individuals who (a) h a v e not received a n injection of t e t a n u s toxoid ( e i t h e r as such or as D T P , Td, etc.) w i t h i n the p r e c e d i n g 12 m o n t h s a n d who have e i t h e r (b) i n c u r r e d w o u n d s or severe b u r n s on the battIefield or a r e p a t i e n t s u n d e r g o i n g second o p e r a t i o n s or m a n i p u l a t i o n s of old wounds, (c) i n c u r r e d p u n c t u r e or l a c e r a t e d wounds, severe b u r n s or o t h e r conditions w h i c h m i g h t be c o m p l i c a t e d by the i n t r o d u c t i o n of Clostridium tetani into the tissues. If, in the view of t h e medical officer, t h e p a t i e n t ' s condition is such t h a t a n u n t o w a r d reaction to e i t h e r d i p h t h e r i a or t e t a n u s toxoid 29
would be h a z a r d o u s , a r e d u c e d dose of this p r o d u c t s h o u l d be a d m i n i s t e r e d . T h e d o s e - r e s p o n s e slope for a b o o s t e r i n j e c t i o n is quite flat so t h a t a dose as s m a ll as 0.05 nil. will i n d u c e a sioaificant r e s p o n s e in p a t i e n t s with low antitoxin titers. ( F o r those p e r s o n n e l who h a v e not received 2 or m o r e doses of t e t a n u s toxoid, passive i m m u n i t y m u s t be provided.) (d) Reactions. E r y t h e m a a n d i n d u r a t i o n at the site of injection occur occasionally a n d a p p e a r to be r e l a t e d to pre-existing i m m u n i t y . T h e s e rea c t i o n s a r e seldom severe; the incidence of severe r e a c t i o n s a p p e a r s to be no m o r e t h a n 1 or 2 p e r c e n t in individuals u n d e r 30 or 35 y e a r s of age a n d p e r h a p s s o m e w h a t g r e a t e r in those older. U r t i c a r i a l a n d o t h e r allergic rea c t i o n s occur r a r e l y ; t h e y also a r e g e n e r a l l y , though not i n v a r i a b l y associated with already established hyperimmunity. T h e r e c o m m e n d e d toxoid p r e p a r a t i o n consists of a m i x t u r e of Mump r e c i p i t a t e d , a l u m i n u m p h o s p h a t e - a d s o r b e d or a l u m i n u m h y d r o x i d e - a d sorbed t e t a n u s a n d purified d i p h t h e r i a toxoids in such p r o p o r t i o n s t h a t each 0.5-ml. dose c o n t a i n s 5-15 Lf of t e t a n u s toxoid a n d only 1-2 Lf of d i p h t h e r i a toxoid. At t h e t i m e of writing, we favor the Guide in T a b l e 17, which is based on previous p u b l i c a t i o n s of the C o m m i t t e e on T r a u m a of t h e A m e r i c a n College of Surgeons.43.44 T h i s G u i d e is s o m e w h a t conservative in t h a t ~ i f t h e r e is d o u b t c o n c e r n i n g p r i o r a d m i n i s t r a t i o n of t e t a n u s t o x o i d ~ a dose of t e t a n u s toxoid a n d c o n s i d e r a t i o n of T I G (H) a r e r e c o m m e n d e d . S u c h a conservative a t t i t u d e is based on t h e s e concepts:
TABLE
17.
A GumE TO PROPHYLAXIS IN WOUND MANAGEMENT
AGAINST
TETANUS
GlenERALPRINCIPLES I. The attending physician must determine for each patient with a wound what is required for adequate prophylaxis against tetanus. It. Regardless of the active immunization status of the patient, meticulous surgical care, including removal of all devitalized tissue and foreign bodies, should [m provided immediately for all wounds. Such care is essential ms part of the prophylaxis agabx~t tetanus. IIL Each patient with a wound should receive adsorbed tetanus toxoid::: intt'amuscularly at the time of injury, either as an initial immunizing (lose, or m~ ' a b , ~ t e r for previous immunization, unless he has received a booster or hms completed his initial immunization series within the past 5 years. As the antigen concentration varies in different products. specific information on the volume of a single dose is provided on the |abel of the package. IV. Whether or not to provide pa~ive irnmunization with homologous tetanus immune globulin (human) must be decided individually for each patient. The characteristics of the wound, conditions under which it was incurred, its treatment, ils age, and the previous active immunization status of the patient must be considered. V. T o e v e r y w o u n d e d p a t i e n t give a w r i t t e n record of t h e i m m u n i z a t i o n providc~t, i n s t r u c t i n g h i m to c a r r y t h e record at all times, a n d if i n d i c a t e d , to c o m p l e t e active i m m u n i z a t i o n . F o r precise t e t a n u s p r o p h y l a x i s , an a c c u r a t e a n d i m m e d i a t e l y a v a i l a b l e h i s t o r y r e g a r d i n g p r e v i o u s active i m m u n i z a t i o n a g a i n s t t e t a n u s is r e q u i r e d . VI. B a s i c i m m u n i z a t i o n with a d s o r b e d toxoid r e q u i r e s 3 injections. A booster of a d s o r b e d toxoid is i n d i c a t e d 10 *~-" y e a r s a f t e r t h e t h i r d i n j e c t i o n or, 10"* y e a r s a f t e r a n i n t e r v e n i n g w o u n d booster. AII i n J i v i d u a l s , i n c l u d i n g p r e g n a n t w o m e n , shouht h a v e basic iInmunization a n d i n d i c a t e d booster injections. * T h e P u b l i c H e a l t h S e r v i c e A d v i s o r y C o m m i t t e e on I m m u n i z a t i o n P r a c t i c e s in 1969 recomm e n d e d D T P ( d i p h t h e r i a a n d t e t a n u s toxoids c o m b i n e d with pertussis v a c c i n e ) for b~usic imm u n i z a t i o n in infants a n d c h i l d r e n from 2 m o n t h s t h r o u g h the sixth y e a r of age a n d T d ( c o m b i n e d t e t a n u s a n d d i p h t h e r i a toxoid~_: a d u l t t y p e ) for basic i m n l u n i z a t i o n of those over 6 y e a r s of age. F o r the l a t t e r g r o u p , T d toxoid was r e c o m m e n d e d for r o u t i n e or w o u n d boos'ters; lint if t h e r e is a n y r e a s o n to s u s p e c t h y p e r s e n s i t i v i t y to the d i p h t h e r i a c o m p o n e n t , t e t a n u s toxoid (T) s h o u l d be s u b s t i t u t e d for Td.4.,
30
SPECIFIC MEASURES FOF. PATIENTS "WITH WOUNDS I.
Previously immunized individuals A. W h e n t h e p a t i e n t h a s b e e n a c t i v e l y i m m u n i z e d w i t h i n l h e p a s t 10** yem,~. I. T o t h e great, m a j o r i t y , g i v e 0.5 cc. of a d s o r b e d ~etanus toxoid* as a boc~sicr unh'ss it is certain that the patient has received a booster w i t h i n the pret, ious 5 >'ears. 2. T o t h o s e w i t h s e v e r e , n e g l e c t e d , o r old ( m o r e t h a n 24 h o u r s ) t e t a n u s - p r o n e w o u n d s , g i v e 0.5 ec. of a d s o r b e d toxoid':' unless it is certain tfiat the patient has received o booster w i t h i n the previous year. B. W h e n t h e p a t i e n t h a s b e e n a c t i v e l y i m m u n i z e d n l o r e t h a n 10"::' ye~rs p r e v i o u s l y , 1. T o t h e g r e a t m a j o r i t y , g i v e 0.5 co. of a dsorl~z-d tetanus":: loxoid. 2. T o t h o s e w i t h s e v e r e , n e g l e c t e d , o r old ( m o r e t h a n 2,1 h o u r s ) t e t a n u s - p r o n e w o u n d s , a. G i v e 0.5 cc. of a d s o r b e d to×old,*,**::' ........... b. G i v e 250 u n i"t s ~"~ ....... of t e t a n u s i m m u n e g l o b u l i n ( h u m a n ) , *::~::: c. C o n s i d e r p r o v i d i n g o x y l e t r a c y c l i n e or p e n i c i l l i n . II. I n d i v i d u a l s N O T p r e v i o u s l y i m m u n i z e d A. W i t h c l e a n m i n o r w o u n d s in w h i c h t e t a n u s is m o s t u n l i k e l y , g i v e 0.5 cc. of a d s o r b e d t e t a n u s toxoid* (initial i m n a u n i z i n g d o s e ) . 13. W i t h all o t h e r w o u n d s 1 G i v e 0.5 cc. of a d s o r l m d t e t a n u s t o x o i d * (initial i m m u n i z i n g dcxse) ,*::'* 2. G i v e 250 units:::*::;* of tetantls i m m u n e g l o b u l i n (human),::'":~' 3. Cop_sider p r o v i d i n g o x y t e t r a c y c l i n e or p e n i c i l l i n . *:::Some a u t h o r i t i e s a d v i s e 6 r a t h e r l h a n 10 y e a r s , p a r t i c u l a r l y for p a t i e n t s w i t h severe, n e g l e c t e d , or o l d ( m o r e t h a n 24 h o u r s ) t e t a n u s - p r o n e w o u n d s s u c h as m a y be s u s t a i n e d by m i l i t a r y p e r s o n n e l in cornbat.54, ~5. a 1~ **":"Use d i f f e r e n t s y r i n g e s , n e e d l e s , a n d s i t e s of i n j e c t i o n . **"::",':In severe, n e g l e c t e d , o r o l d ( m o r e t h a n 24 h o u r s ) t e t a n u s - p r o n e w o u n d s , 500 u n i t s of tetanus immune globulin (human) are advisable.
1. In general, surgeons see a more severe and a more unusual wound than the nonsurgical physician. T h e long intervals b e t w e e n wound boosters are for the "usual types" of wounds.158 2. T e t a n u s , in contrast to gas gangrene, m a y occur in individuals who have no demonstrable w o u n d or who have very minor wounds; hence, all individuals should have adequate s e r u m tetanus antitoxin tilers at all times.77 3. P h y s ; c i a n s want none of their patients w h e t h e r they. have special problems or not- -to develop tetanus. 4: T h e A r m y statistics, which include those for the fighting forces in Vietnam, are impressive: no cases of tetanus, have been reported among active duty personnel from 1956 to N o v e m b e r 197114~ (Tables 12 and 18). In contrast to such A r m y statistics, there w e r e reported 120 civilian cases of tetanus in 1971 in the U n i t e d States.a1 5. P a t i e n t s do not have an i m m e d i a t e l y available e m e r g e n c y medical identification device with reliable tetanus data on it. (a) In a survey of patients and their friends during parts of 1970, 1971 and 1972, only 22 of 428 (5.1%) had such data i m m e d i a t e l y available. ( b ) T h e recommendations of the U S P H S and the A A P are based on i m m e d i a t e l y available and accurate records with tetanus data.9, a2 6. For the particularly severe or c o n t a m i n a t e d so-called t e t a n u s - p r o n e ,Jr
TABLE
18.: :VOLUNTARY VERSUS CONTROLLED TETANUS
P R O P I I Y L A X I S 31, 1,16
N o . o r CASES
~ATEGORY
United States Army personnel, 1956-1971 ( N o v e m } m r ) U n i t e d S t a t e s c i v i l i a n s , 1971
31
0 120
9034' DOSES
80-
70-
60I,:>" I.,u
o 50-
n,t.M o,.
40
30-
20NO VACCINE 10-
I"
I'
"62
"63
I
'64
I
'
I
"65 %6 YEAR
l......
"67
I
"68
-I
]
'69
"70
I
'71
Fro. 12.--Diphtheria-tetanus-pertussis immunization, 1-4 age group, United States, 19621971. In the United States, approximately 10% of infants and children 1--4 years of age have not been vaccinated for these three conditions.:~0 (Courtesy of C e n t e r for" Disease Control.)
u n u s u a l injuries, it has been stated t h a t t h e r e is a need for additional booster doses.6], 15s 7. In general, reactions to t e t a n u s toxoid are m i n i m a l in contrast to the grim picture of a person with t e t a n u s and to the average m o r t a l i t y rate of a b o u t 50%. 8. T h e drug-store cost of a booster dose of t e t a n u s toxoid is small comp a r e d to the hospital cost of a case of t e t a n u s ($9,773.80 for a recent case). 9. T h e r e still are a n u m b e r of individuals who do not have a d e q u a t e tetanus toxoid i m m u n i z a t i o n but who m a y e r r o n e o u s l y be considered to have such i m m u n i z a t i o n w h e n they a r e seen as w o u n d e d patients.67,130 In 1970, Mat et al3 37 stated t h a t 0ne-third of a r a n d o m group of children of all ages in H a m b u r g , G e r m a n y , did not have t e t a n u s toxoid i m m u n i z a t i o n . M o r e recently, HorstmannlOO a n d Witte214 have e m p h a s i z e d the lagging i m m u nity of our children. 10. Cases of failure of booster t e t a n u s toxoid injections to p r e v e n t t e t a n u s m a n y years after injections Or cases of modified t e t a n u s after such injections have been reported.144 11. T h e professional l i a b i l i t y responsibilities of the surgeon are g r e a t e r t h a n those of the n o n s u r g e o n physician (cf. section M). 12. S u r g e o n s ~ i n respect to the p r e v e n t i o n of t e t a n u s ~ d o not w a n t to be like the poet, Ovid,in1 who wrote: "Too late I g r a s p m y shield after m y wounds." IN,lURY.--Rapid, active i m m u n i z a t i o n , i.e., 3-5 closes of t e t a n u s toxoid a p p r o x i m a t e l y every o t h e r day, will not. produce active i m m u n i t y rapidly enough i:o protect an j)
I~APID, ACTIVE, BASIC I~I:MUNIZATION AT T I l E TIMI,~ OF
32
i n d i v i d u a l in w h o m s u c h i m m u n i z a t i o n is s t a r t e d j u s t a f t e r a w o u n d has b e e n inflicted.24, 91, 93, 174, 190 k ) O N E - I N J E C T I O N , BASIC IMMUNIZATION.--Single-dose basic i m m u n i z a tion w i t h a n a d s o r b e d toxoid m a y be t h e final a n s w e r in e l i m i n a t i n g t e t a n u s in developing c o u n t r i e s w h e r e p h y s i c i a n s f r e q u e n t l y h a v e only one opport u n i t y to give p r o p h y l a c t i c t e t a n u s toxoid. A t the 1966 B e r n Conference, a s i n g l e - i n j e c t i o n toxoid t h a t would r e q u i r e only a booster dose a t the t i m e of i n j u r y w a s described b y M~rieux.142 H i s results w e r e . e n c o u r a g i n g b u t p e r h a p s i n d i c a t e t h a t only a p a r t of a p o p u l a tion m a y be given a d e q u a t e basic i m m u n i z a t i o n b y s u c h a one-injection technic. I n 1970, Veronesi e t a / . 205 p o i n t e d o u t t h e p o t e n t i a l value of a t e t a n u s vaccine c a p a b l e of i m m u n i z i n g in a single dose in view of t h e high m o r t a l i t y of the disease in developing countries, as well as the l o w e r cost, g r e a t e r a c c e p t a b i l i t y a n d considerable simplification of the a d m i n i s t r a t i o n of m a s s i m m u n i z a t i o n c a m p a i g n s t h a t w o u l d result. T h e y r e p o r t e d on t h e i m m u n e responses to single doses of different toxoids in different c o n c e n t r a t i o n s , w i t h a n d w i t h o u t a d d i t i o n a l a d j u v a n t s . T h e y found that, w i t h h i g h l y conc e n t r a t e d a l u m i n u m h y d r o x i d e - a d s o r b e d toxoids, 100% protective levels h a d b e e n achieved in a small g r o u p w h e n tested 4 weeks a n d 8 m o n t h s a f t e r i m m u n i z a t i o n a n d t h a t the c o n c e n t r a t e d toxoids, with or w i t h o u t a d j u v a n t s , w e r e well tolerated. A t t h e I n t e r n a t i o n a l Congress for Microbiology in Mexico City in 1970, E d s a l l et al. 7o r e p o r t e d as follows on t h e r e s p o n s e to a single dose of t e t a n u s toxoid: " T o d e t e r m i n e the l o n g - t e r m r e s p o n s e to a single dose of h i g h l y p o t e n t t e t a n u s toxoid, 40 females aged 15 to 45 years, w i t h no p r i o r h i s t o r y of active t e t a n u s i m m u n i z a t i o n , w e r e i n j e c t e d i n t r a m u s c u l a r l y with 25 Lf teta n u s toxoid in 3.8 m g A1PO4. S e r u m w a s d r a w n a t 0, 7, 26 a n d a b o u t 400 days p o s t - i n j e c t i o n for t e t a n u s a n t i t o x i n t i t r a t i o n by tile m o u s e n e u t r a l i z a tion technique. S e v e n s u b j e c t s w e r e excluded b e c a u s e of d e m o n s t r a b l e antitoxin titers a t d a y s 0 or 7. Of t h e 29 a v a i l a b l e a n d a c c e p t a b l e subjects a t d a y 26, 27 h a d m e a s u r a b l e a n t i t o x i n levels, a n d 24 w e r e a t or above t h e g e n e r a l l y a c c e p t e d protective level (0.01 u n i t / m l . ) . F o u r t e e n m o n t h s a f t e r inoculation, 18 a v a i l a b l e a n d a c c e p t a b l e subjects w i t h no h i s t o r y of interm e d i a t e injections h a d m e a s u r a b l e titers, 16 h a d p r o t e c t i v e levels, a n d the g e o m e t r i c m e a n t i t e r of t h e 18 subjects w a s 0.045 unit, c o m p a r e d to a m e a n t i t e r of 0.064 for t h e s a m e subjects a t 26 days. T h e m e a n t i t e r s in the teenage girls w e r e 4 to 8 times h i g h e r t h a n in the a d u l t w o m e n . " S u c h findings s u p p o r t t h e belief t h a t in the not too d i s t a n t f u t u r e a n effective single-dose t e t a n u s toxoid can be p r e p a r e d w i t h o u t the n e c e s s i t y for e m p l o y i n g u n u s u a l r e a g e n t s or p r e p a r a t i v e procedures. ]) PROPHYLAXIS AGAINST TETANUS BY T I t E FIRST INJECTION OF TOXOID GIVEN AT THE TIME OF I N J U R Y . - . T h e initial injection of toxoid at the time of an
i n j u r y does not provide i m m u n i t y for t e t a n u s from t h a t i n j u r y . If a n inj u r e d p a t i e n t who has not been given t e t a n u s toxoid p r e v i o u s l y is given tet,~)us toxoid i m m e d i a t e l y a f t e r an i n j u r y , this first dose of t e t a n u s toxoid does not provide i m m u n i t y for the injury.l:)1,219 m) NO ACTIVE IhIMUNITY FROM TETANUS. T h e a m o u n t of the very potent t e t a n u s toxin n e c e s s a r y 1o p r o d u c e clinical t e t a n u s is so small t h a t it will 33
not incite an active a n t i b o d y level high enough to prevent a second a t t a c k of tetanus. Consequently, t e t a n u s is a n o n i m m u n i z i n g disease and, hence, a history of t e t a n u s does not rule out the possibility of a second attack of tetanus. To p r e v e n t such a second attack, w h e n a p a t i e n t is recovering from tetanus and is about 4 weeks after the onset of tetanus, his a t t e n d i n g physician should begin active i m m u n i z a t i o n with t e t a n u s toxoid.64, 15a, 192, 212,215 n ) POSSIBLE CAUSES OF FAILURE OF ANAMNESTIC RESPONSE.--Antitoxin is not necessary in a d e q u a t e l y actively i m m u n i z e d individuals. It provides only the disadvantages of passive prophylaxis w i t h o u t in a n y way improving the active prophylaxis. T h e r e are certain conditions or situations, however, in which the actively i m m u n i z e d individual possibly m a y not have the usual a n a m n e s t i c response to toxoid. If a physician is called to t r e a t a w o u n d e d individual who has been actively i m m u n i z e d but who is included in one of the following four categories and if it is not possible for the physician to be certain of his p a t i e n t ' s s e r u m antitoxin level, consideration should be given to a d m i n i s t e r i n g T I G ( H ) in addition to t e t a n u s toxoid. 1) Agamrnaglobulinemia.. A n t i t o x i n could be of a d v a n t a g e in a case of a g a m m a g l o b u l i n e m i a or h y p o g a m m a g l o b u l i n e m i a , which f o r t u n a t e l y is ext r e m e l y rare a n d in which the body's ability to produce antibodies fails totally or in part.195 F o r practical purposes, this rarity need not be considered. It is much less likely to occur t h a n is a s e r u m reaction from heterologous antitoxin. 2) Exposure to acute doses of radiation from any source.~Eckmann22O has p o i n t e d out t h a t if an i n j u r e d person has been passively exposed to radioactivity, the effect of a booster injection of t e t a n u s toxoid cannot be d e p e n d e d on for at least several days. T h e effect of whole-body i r r a d i a t i o n on a n t i b o d y formation has been investigated extensively.16 S t u d i e s using small l a b o r a t o r y a n i m a l s generally have indicated a m a r k e d depressive effect of i r r a d i a t i o n on response to a p r i m a r y stimulus; response of a previously sensitized a n i m a l to a booster dose was not affected significantly. Since prophylaxis against t e t a n u s depends on routine i m n m n i z a t i o n with toxoid, followed by a booster dose a d m i n i s t e r e d at the time of i n j u r y to evoke a rapid a n d high antitoxin response, B e n e n s o n et al.16 believed t h a t it was necessary to reinvestigate this response should the i n j u r y be associated with whole-body irradiation. T h e y found t h a t whole-body i r r a d i a t i o n of dogs i m m u n i z e d with a n alump r e c i p i t a t e d t e t a n u s toxoid results in a delay in a p p e a r a n c e of antitoxin if the first toxoid is a d m i n i s t e r e d after irradiation. Dogs i r r a d i a t e d 30 days after a first dose of toxoid and receiving a booster injection 24 hours after i r r a d i a t i o n presented a good antitoxin response when m e a s u r e d by the h e m a g g l u t i n a t i o n test. A poor antibody response, however, was found if the antitoxin was m e a s u r e d by the toxin n e u t r a l i z a t i o n technics. K r e m l e v l 1s studied the efficacy of e m e r g e n c y specific prophylaxis against e x p e r i m e n t a l t e t a n u s u n d e r a g g r a v a t e d conditions. T h e a n i m a l s were rabbits. T h e a g g r a v a t e d conditions were burns or radiation. T h e a n i m a l s were actively i m m u n i z e d against t e t a n u s with a double dose of toxoid. F o u r m o n t h s after the second dose of toxoid, and 12 hours after infliction of the b u r n or radiation, plus the injection of one rabbit lethal dose of t e t a n u s spores, the a n i m a l s were given toxoid or antitoxin, or both. M o r t a l i t y was 34
12 of 17 a n i m a l s with toxoid r e i m m u n i z a t i o n , 12 of 17 w i t h a n t i t o x i n prop h y l a x i s a n d 10 of 17 w i t h both toxoid a n d antitoxin. K r e m l e v seems to be on r e a s o n a b l y sound g r o u n d in t h e o r i z i n g t h a t the low efficacy a p p a r e n t l y is d u e to the a g g r a v a t i n g action of b u r n s a n d ionizing radiation. 3) Immunosuppressive drugs.--Reeent e x p o s u r e to i m m u n o s u p l ) r e s s i v e drugs m a y i n t e r f e r e with the a n a m n e s t i c response. C h l o r a m p h e n i e o l is to be i n c l u d e d in this g r o u p t e m p o r a r i l y , for it has been n o t e d t h a t c o m m o n l y e m p l o y e d t h e r a p e u t i c a m o u n t s of c h l o r a m p h e n i c o l to t r e a t infections in m a n h a v e b e e n s h o w n to s u p p r e s s t h e a n a m n e s t i c response to t e t a n u s toxoid.210 It would i n d e e d be a t r a g e d y for a renal or e a r d i a e t r a n s p l a n t p a t i e n t who h a s h a d his i m m u n e m e c h a n i s m s a l t e r e d to p r e v e n t t r a n s p l a n t rejection a n d who h a d suffered a m i n o r w o u n d to develop t e t a n u s a n d to die because an a d m i n i s t e r e d toxoid booster did not p r o d u c e the u s u a l active antitoxin response a n d because the p a t i e n t was not given T I G ( H ) in addition to toxoid! 4) Carcinoma o[ the breast.~Studies by H u m p h r e y et al.lO2 on p a t i e n t s with b r e a s t disease have s h o w n t h a t p a t i e n t s with benign breast disease could r e s p o n d a d e q u a t e l y to injection of t e t a n u s toxoid b u t that, on the o t h e r h a n d , p a t i e n t s w i t h m a m m a r y cancer, i n e l u d i n g those from w h o m t h e regional nodes w e r e r e m o v e d as well as those in w h o m the nodes were left intact, failed to r e s p o n d to i p s i l a t e r a l injections of t e t a n u s toxoid. O) ACTIVE IMS{UNIZATION AGAINST CL. TETANI AND OTHER CLOSTRIDIA.--In
1970, Klose a n d Schallehn117 r e p o r t e d t h a t i m m u n i z a t i o n w i t h Cl. novyi toxoid or c o m b i n e d C1. novyi toxoid a n d t e t a n u s toxoid in g u i n e a pigs provided reliable p r o t e c t i o n a g a i n s t Cl. novyi gas g a n g r e n e or Ct. novyi gas g a n g r e n e plus t e t a n u s for a period of at least 2 years. T h e y were hopeful t h a t their e x p e r i m e n t s m i g h t o p e n the w a y to provide p r o t e c t i o n a g a i n s t both gas g a n g r e n e a n d t e t a n u s in m a n , especially since the combined vaccine does not cause a n y m a r k e d reactions. T h e y r e c o m m e n d e d t h a t such protective i m m u n i z a t i o n be p e r f o r m e d in all school c h i l d r e n in G e r m a n y . S i m i l a r l y , V r a n c h e v a e t a / . 207 h a v e i n v e s t i g a t e d tritoxoid for Ci. per[ringens, C1. oedematiens a n d C1. tetani.2o7 p ) 100°7o TETANUS TOXOID IMIV[UNIZATION.. T h e following w a y s a n d m e a n s of effecting w i d e s p r e a d t e t a n u s toxoid i m m u n i z a t i o n in the civilian p o p u l a t i o n have b e e n proposedS4: 1. E n c o u r a g e all m e m b e r s of the civilian p o p u l a t i o n to o b t a i n basic teta n u s toxoid i m m u n i z a t i o n . P u t d i s p l a y s in the w a i t i n g rooms of p h y s i c i a n s ' offices. H a v e notices in the n e w s p a p e r s from medical o r g a n i z a t i o n s , the city h e a l t h c o m m i s s i o n e r a n d the c o u n t y h e a l t h commissioner. S e n d l i t e r a t u r e to P a r e n t - T e a c h e r Associations, 4-H Clubs, Boy Scout troops, Girl Scout troops a n d s i m i l a r organizations, c h u r c h e s a n d social a n d a t h l e i i c clubs. U r g e factories to r e c o m m e n d s t r o n g l y or to r e q u i r e a d e q u a t e t e t a n u s toxoid i m m u n i z a t i o n at the time of e m p l o y m e n t . R e q u e s t colleges a n d universities to r e c o m m e n d s t r o n g l y or r e q u i r e a d e q u a t e t e t a n u s toxoid i m m u n i z a i i o n at t h e t i m e of s t u d e n t s ' m a t r i c u l a t i o n . R e c o m m e n d to p h y s i c i a n s t h a t t h e y give t e t a n u s toxoid w h e n o t h e r i m m u n i z a t i o n s such as d i p h t h e r i a , perl.ussis a n d a n t e r i o r poliomyelitis a r e given. 2. S t i m u l a t e p h y s i c i a n s lo become actively engaged in the i m m u n i z a t i o n 35
c a m p a i g n . Give talks a t hospital g e n e r a l staff a n d section meetings. P r e s e n t p a p e r s at local, sectional a n d n a t i o n a l meetings. S u b m i t p a p e r s , editorials a n d l e t t e r s to the editors in local, sectional a n d medical j o u r n a l s . D i s p l a y exhibits at s t a t e a n d n a t i o n a l medical meetings. T h e active p a r t i c i p a t i o n of all physicians, t o g e t h e r w i t h c o o p e r a t i o n from t h e civilian p o p u l a t i o n , can e n s u r e n a t i o n w i d e t e t a n u s toxoid i m m u n i z a t i o n c o m p a r a b l e to t h a t a l r e a d y effected in the U n i t e d S t a t e s a r m e d forces. On e h u n d r e d p e r c e n t i m m u n i z a t i o n of all m e m b e r s of the p o p u l a t i o n could be a real c h a l l e n g e for local t r a u m a c o m m i t t e e s of t h e A m e r i c a n College of Surgeons. B y a c h i e v i n g such a p e r c e n t a g e of t e t a n u s toxoid imm u n i z a t i o n , the local t r a u m a c o m m i t t e e s would be p r o t e c t i n g all pote,~tial victims of t r a u m a a g a i n s t t e t a n u s a n d .... t h e r e b y .... would m a k e t h e i r own work e a s i e r in t h e e v e n t s u c h i n d i v i d u a l s a r e b r o u g h t to the e m e r g e n c y room w i t h a severe w o u n d or wounds. I n s u p p o r t of such a n activity, C u r t i s Artz, t h e C h a i r m a n of t h e ACS C o m m i t t e e on T r a u m a , h a s w r i t t e n , " T h e r e a r e m a n y a r e a s . . . t h a t really n e e d some bright, y o u n g fellow to t a k e the bull by t h e h o r n s and i m m u n i z e large c o m m u n i t i e s . " l a
4. SURGICAL WOUND CARE S u r g i c a l p r o p h y l a x i s consists of the removal of Cl. t e t a n i a n d n o n v i a b l e tissue from w o u n d s a n d of t h e best possible r e c o n s t r u c t i o n of aerobic wounds.77 M e t i c u l o u s surgical c a r e of w o u n d s is p e r f o r m e d w h e n t he following a r e c a r r i e d out: 1. T h e w o u n d s a r e t a k e n care of a t t h e e a r l i e s t possible m o m e n t . 2. As e ptic technic, w i t h the use of gloves, gowns, masks, sterile i n s t r u m e n t s a n d t h e a p p l i c a t i o n of p r o p e r solutions to p r e p a r e the skin before t h e n e c e s s a r y o p e r a t i v e p r o c e d u r e s at the i n j u r e d site. 3. D u r i n g skin p r e p a r a t i o n , t h e w o u n d s h o u l d be covered with gauze to prevent further contamination. 4. P r o p e r lighting, so t h a t the s u r g e o n can exactly identify a n d p r o t e c t vital s t r u c t u r e s such as n e r v e s and vessels. 5. A d e q u a t e i n s t r u m e n t s a n d a d e q u a t e help, so t h a t t h e r e is the best possible a n d g e n t l e r e t r a c t i o n of s t r u c t u r e s in wounds. 6. H e m o s t a s i s w i t h delicate i n s t r u m e n t s a n d with fine s u t u r e m a t e r i a l , so t h a t t h e r e is a m i n i m u m of n e c r o t i c tissue left in wounds. 7. G e n t l e h a n d l i n g of tissues a t all times, so t h a t n e c r o t i c tissue is not p ro d u c e d . 8. C o m p l e t e d e b r i d e m e n t with scalpel excision of n e c r o t i c tissue a n d with r e m o v a l of foreigJl bodies, so t h a t no p a b u l u m is left on w h i c h a n y u n r e moved b a c t e r i a c a n p r o p a g a t e . 9. T h e w o u n d is i r r i g a t e d copiously w i t h l a r g e a m o u n t s of physiologic salt solution to w a s h out m i n u t e a v a s c u l a r f r a g m e n t s of tissue a n d to elimi n a t e foreign bodies. 10. If t h e r e is a n y d o u b t c o n c e r n i n g a w o u n d pro~dding a n a e r o b i c conditions so t h a t t h e t e t a n u s bacillus c a n grow a n d p r o d u c e its l e t h a l toxin in it, t h e w o u n d is left wide open, a n d d r a i n a g e is i n s t i t u t e d w h e n necessary. D u r i n g the l a t t e r p a r t of the n i n e t e e n t h c e n t u r y , the p r i n c i p l e s for p r o p e r w o u n d c a r e t h a t h a d been developed by S e m m e l w e i s , Lister, H o i s t e d and 36
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FIG. 1 3 . ~ M o ~ a l i t y of tetanus by age groups (per 10D,000 population) and rate of delivery at medical institutions (per cent) in Japan.~;2 (Courtesy of I. Ebisawa.)
others g r a d u a l l y were accepted and, at the beginning of the t w e n t i e t h century, were applied to the problems of m i l i t a r y medicine. After s t u d y i n g an analysis of W o r l d W a r I cases af t e t a n u s in 1915, Bruce,22 who was c h a i r m a n of the World W a r I B r i t i s h W a r Office Comm i t t e e for the S t u d y of T e t a n u s , r e p o r t e d that, if t h o r o u g h surgical treatm e n t is c a r r i e d out on wounds from the b e g i n n i n g so as to e l i m i n a t e necrotic tissue a n d foreign bodies, the n u m b e r of cases of t e t a n u s should sensibly diminish if n o t a l t o g e t h e r d i s a p p e a r . Ebisawafi2 a J a p a n e s e internist, has offered statistical proof of the value of i m m e d i a t e meticulous surgical care of wounds in the p r e v e n t i o n of tetanus. In a s t u d y of obstetric cases, he noted a s h a r p decrease in tetanus, a t t r i b u t i n g this to w o u n d care. In J a p a n , the n e o n a t a l t e t a n u s m o r t a l i t y r a t e in 1947 was 36.1 and in 1961 it was 7.1 per 100,000 live births; the percentage of deliveries at medical institutions for all births in J a p a n for these s a m e y e a r s rose from 2 . 4 ~ to 58~o. As t e t a n u s toxoid had been excluded from the J a p a n e s e i m m u n i z a t i o n programs, as J a p a n e s e physicians were not informed of the availability of t e t a n u s toxoid until recently, as n e i t h e r a n t i t o x i n nor penicillin was used to protect n e o n a t e s from t e t a n u s and as the s h a r p decrease in t e t a n u s m o r t a l i t y occurred, E b i s a w a concluded that the g r e a t l y reduced m o r t a l i t y from t e t a n u s was the result of improving obstetric facilities for the care of tile reproductive tract in the m o t h e r and of the umbilicus and cord in the infant. 37
5. ANTITOXINS a) HETEROLOGOUS A N T I T O X I N S . - ....I r l 1890, yon Behring and Kitasafo206 demonstrated the formation of tetanus antitoxin, which was formed in the blood of mice and rabbits following active immunization. This antitoxin, injected into unvaccinated mice and rabbits, protected them against a subsequent tetanus injection. Other animals also could be treated with these sera with good results. Thus, the practical value of both homologous and heterologous antisera was proved. Few discoveries in the history of medicine have excited scientists and laymen alike as much as this one did, for the ever-present threat of tetanus might now be banished. By the end of the )lineteenth century, despite some skepticism, antitoxin therapy and particularly prophylaxis were widely adopted and approved. The application and dissemination of the practical value of heterologous antitoxin on a large scale became possible in World War I. The British began effectively to use equine tetanus antitoxin about the middle of October, 1914. Bruce22 reported a sudden drop in the incidence of tetanus from 9 cases per 1,000 wounded in September, 1914, to 1.4 per 1.000 in December, 1914. The antitoxin, which has been used commonly, is produced by the active immunization of horses with tetanus toxoid and toxin. Injection of such horse serum may result in sensitization of the patient. A subsequent dose may result in sensitivity reactions, such as local redness and swelling of the injected limb or generalized serum sickness. Equine antitoxin has been of real value, but both fatal anaphylactic shock and serum sickness (5-30~azb) have occurred with the heterologous antitoxins.14, 23, 28, 73, 121, Is0 Moreover, the half-life of the hetero]ogous an/itoxins cannot be predicted in any given individual.129 Recently, because certain parts of the world have not had adequate supplies of TIG(H), interest in bovine antitoxin has been stirnu]ated. Trinca and Reid,200 as recently as January, 1967, put forth evidence that bovine antitoxin, refined by ethanol fractionation, is unlikely to provoke reactions in patients hypersensitive to horse serum. After careful follow-up, only 3 patients (4.3%) were found to have had aller~c responses, and these were minor local reactions. Significantly, an editorial accompanying the Trinca-Reid report on bovine antitoxin states that interest in bo~dne antitoxin must not divert attention from two even more pressing needs in tetanus prophylaxis: (I) the extension of active immunization and (2) the production of adequate supplies of TIG (H), which, unlike bovine antitoxin, is practically nonantigenic in man. As the Hsks of tetanus from a wound may be unpredictably more or less than the risks of complications from heterologous antisera, and since there are at least 5,000 known cases of tetanus following the administration of equine antiserum, participants at the Second International Conference on Tetanus at Bern in 1966 went on record as stating that it is the final rnedico|ega] right and prerogative of an attending physician to decide whether a heterologous serum with its associated dangers should be used.101,177, 22! On the basis of the few existing reports on previous experiments, it has been widely accepted that the absorption of serum into the blood after intramuscular injection is much more rapid and produces a higher concen38
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T A B L E 19:= GENERIC, OFFICIAL OR SCIENTIFIC NAMES FOR TETANUS I M M U N E (JLOBULIN ( H U M A N ) T H A T HAVE B ~ N IN. TtIE WORLD LITERATURE
FOUND
"FIG(human) TIG (H) TIG Human tetanus antitoxin Homologous tetanus antitoxin Immune globulin Hyperimmune globulin Human immune globulin Human hyperimmune globulin Homologous serum Antitetanic gamma globulin Homologes immunglobulin Hyperimmune globulin antitetanus HiG Human serum globulin Human antitetanus globulin Human A.T.G. Antitetanus globulin Htunan t e t a n u s immune globulin Tetanus hyperimmune ganaraa globulin
t r a t i o n of antibodies in the blood t h a n a f t e r s u b c u t a n e o u s injection. This belief was re-examined by Christensen36 in t h r e e different e x p e r i m e n t s : (1) on rabbits injected with purified t e t a n u s antitoxin, (2) on rabbits given native t e t a n u s horse s e r u m a n d (3) on 8 h u m a n s receiving purified t e t a n u s antitoxin. H e found t h a t c o m p a r i s o n of the times at which a given low conc e n t r a t i o n was reached did not show significant differences b e t w e e n the i n t r a m u s c u l a r a n d s u b c u t a n e o u s routes of injection in a n y group, t h a t comparison of the concentrations r e a c h e d after 24 hours showed no significant differences in groups (2) a n d (3), t h a t in group (I) t h e r e m a y have been a m i n o r p r e p o n d e r a n c e of i n t r a m u s c u l a r injections a n d t h a t -in a supplem e n t a r y a n a p h y l a x i s e x p e r i m e n t no definite differences could be demons t r a t e d b e t w e e n the two routes of injection with respect to the shock action on sensitized guinea pigs. b) TETANUS IiV[5[UNE GLOBULIN (HU3[AN). Tetanus immune globulin (human) or TIG(H) has been referred to by numerous scientific and trade names (Tables 19 and 20). The possibility of production of TIG(H) is the result of the work in the 1940s of Cohn and his colleagues, who made feasible large-scale fractiona-
T A B L E 20. TRADE,COI~IMERCIAL OR PROPRIETARY NAMES FOR TETANUS IMMUNE GLOBULIN (HUMAN) FOREIGN Tetabullin (Austria) Tetagam (~rest Germany) Tetuman Berna (Switzerland) Tetaglobuline (France)
U.S.A. Hyper-Tet Hu-Tet. Homo-Tet Gamatet
Immu-Tetanus T-I-Gammagee Pro-Tet Gamulin T
39
tion of s e r u m proteins by p r e c i p i t a t i o n with ethanol u n d e r carefully controlled conditions at low temperatures.lS, 4o T I G ( H ) , a sterile solution c o n t a i n i n g 165 ---+ 15 rag. of g a m m a globulin p e r ml., is p r e p a r e d from h u m a n blood p l a s m a having a high titer of t e t a n u s antitoxin. S u c h plasma is obtained, f am blood of h y p e r i m m u n i z e d volunteers, from blood for g a m m a globulin m a n u f a c t u r e t h a t has been screened for t e t a n u s a n t i t o x i n titers or from placentas from m o t h e r s who h a d received t e t a n u s toxoid booster inoculations a few weeks preceding delivery.l 0 T I G ( H ) is effective p r o p h y l a c t i c a l l y in p a t i e n t s with wounds t h a t m a y be c o n t a m i n a t e d with C1. tetani, and, because it is of h u m a n origin, it is virt u a l l y free from the risk of inducing hypersensitivity. Its use is advised p a r t i c u l a r l y w h e n a h i s t o r y of active i m m u n i z a t i o n with t e t a n u s toxoid c a n n o t be established w i t h reasonable c e r t a i n t y and whe::n the risk of immediate or d e l a y e d reactions to equine antitoxin m u s t be avoided (patients k n o w n to be sensitive to horse serum, those who have h a d prior injections of horse serum or those who have a history of allergy). W h e n a history of previous active i m m u n i z a t i o n can be established, the a d m i n i s t r a t i o n of a booster dose of t e t a n u s toxoid is preferable. Passive i m m u n i z a t i o n with T I G (H) is no s u b s t i t u t e for active i m m u n i z a tion with t e t a n u s toxoid, n o r is it a s u b s t i t u t e for a d e q u a t e surgical care of c o n t a m i n a t e d or p o t e n t i a l l y c o n t a m i n a t e d wounds. T h e half-life of passively acquired t e t a n u s toxin antibodies from T I G (H) is t h o u g h t to be at least 3 weeks and possibly m o r e t h a n 4 weeks.129, ls5 By contrast, t e t a n u s toxin antibodies from heterologous sources (equine or bovine antitoxins) have a relatively brief half-life, which m a y be as short as 2 or 3 days. Studies on the absorption and persistence of T I G (H) indicate t h a t abQut one-half of an i n t r a m u s c u l a r dose a p p e a r s in the plasma. The, injection of 4-5 u n i t s / k g , of body weight ensures a p l a s m a level of 0.02 u n i t s / m l , for as long as 4 weeks: this level probably is a d e q u a t e to protect a g a i n s t any b u t a f u l m i n a t i n g t e t a n u s infection. Unless e x t r a n e o u s c o n t a m i n a t i o n occurs, t h e r e is virtually no likelihood of t r a n s m i t t i n g viral hepatitis by the a d m i n i s t r a t i o n of this agent, T h e possibility t h a t allergic reactions m a y occur is remote.71, ss As with o t h e r g a m m a globulin p r e p a r a t i o n s , however, p a i n a n d redness at the site of injection m a y occur rarely. At the time of i n t r a m u s c u l a r a d m i n i s t r a t i o n , skin sensitivity testing need not be done, but care should be taken to d r a w back on the p l u n g e r of the s y r i n g e in order to be c e r t a i n t h a t the needle is not in a blood vessel. U n d e r no circumstances should the globulin be given intravenously.a07-109, 150. 194 W h e n . T I G ( H ) is given, adsorbed t e t a n u s toxoid also should be a d m i n istered. A different sterile syringe a n d needle are used to inject the toxoid so as to lessen the possibility of some of the antitoxin and some of the toxoid n e u t r a l i z i n g each other. A dose of 250-400 units of T I G (H) does not a p p e a r to interfere ~l)preciably with p r i m a r y active immunization.12J. 129, i:~1.1:~2. J,~;, 1.z0, ~6s, J:0 (Figs. 14-16). Thus, s i m u l t a n e o u s active-passive imm u n i z a t i o n can be accomplished by injecting adsorbed toxoid i n t r a m u s c u larly into one e x t r e m i t y and the "FIG (H) into another, p r e f e r a b l y one deltoid muscle and the c o n t r a l a t e r a l gluteal muscles, By such simult:meous immuniz~ltion, i m m e d i a t e lmssive l)roteciion is conferred and active protection is initiated.
40
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FIG. 14 (le/t).--Mean s e r u m t e t a n u s a n t i t o x i n levels a f t e r a c t i v e - p a s s i v e i m m u n i z a t i o n of n o n i m m u n e persons with fluid o r a l u m toxoid, i n o c u l a t e d s i m u l t a n e o u s l y with T I G ( H ) . T h e c r o ~ h a t c h i n g covers 1 s t a n d a r d e r r o r of t h e m e a n . T h e h o r i z o n t a l d a s h e d line a t 0.01 u n i t p e r nil. r e p r e s e n t s t h e g e n e r a l l y a c c e p t e d m i n i m a l p r o t e c t i v e level. T h e a r r o w a t the 28th d a y i n d i c a t e s a s e c o n d toxoid i n o c u l a t i o n i d e n t i c a l w i t h t h a t on the d a y of immunization.131 ( C o u r t e s y of L. L e v i n e a n d J. M c C o m b . ) Fr~. 15 (right).~Mean s e r u m a n t i t o x i n levels of n o n i m m u n e p e r s o n s r e c e i v i n g a l u m toxoid a n d T I G ( H ) with a n d w i t h o u t a d e l a y (3 or 4 h o u r s ) in a d m i n i s t r a t i o n of t h e globulin. T h e d a s h e d c u r v e r e p r e s e n t s control s u b j e c t s w h o r e c e i v e d T I G ( H ) alone. T h e d a s h e d h o r i z o n t a l line a n d t h e a r r o w a r e ,as in F i g u r e 14.1al ( C o u r t e s y of L. L e v i n e a n d J . M c C o m b . )
S i m u l t a n e o u s active-passive immunization with toxoid and T I G ( H ) should be practiced w h e n necessary, as indicated in Table 17. Possible unusual indications for s i m u l t a n e o u s administration of both toxoid and T I G ( H ) to the wounded, which were indicated previously in the toxoid section (J-3-n), are (1) agammaglobulinemia, (2) recent exposure to radioa c t i v e substances, (3) recent exposure to i m m u n o s u p p r e s s i v e agents a n d (4) m a m m a r y carcinoma. Recently, the r e c o m m e n d e d prophylactic dose of 250 units of T I G ( H ) Fw,. 1 6 . - - M e a n s e r u m a n t i t o x i n levels of n o n i m m u n e p e r s o n s receiving a l u m toxoid alone, a l u m plus simultaneou.s T I G ( H ) a n d T I G ( H ) alone. At t h e 56th d a y . t h e foxoid a l o n e a n d the c o m b i n e d i m m u n i z a t i o n h a v e i d e n t i c a l values. T h e s e m e a n v a l u e s fail to s h o w a n y signific a n t d a m a g e to e i t h e r t h e a n t i t o x i n o r the toxoid.131 ( C o u r t e s y of L. L e v i n e a n d J . M c C o m b . ) ~ r"i-
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TABLE 21. PROPHYLACTIC D O S E S OF T E T A N U S I M H I U N E G L O B U L I N ( H U M A N ) FOR I N F A N T S AND C H I L D R E N $7 AGI~ 10 years or older 5-10 years U n d e r 5 years
DOSE 250 units 125 units 75 unit..,;
for t h e usual, p r o p e r l y surgically t r e a t e d a n d i m m e d i a t e l y cared-for w o u n d in a n a d u l t has been questioned. S u c h q u e s t i o n i n g has been based on w o u n d s t h a t were m o r e t h a n 48 h o u r s old w h e n t h e T I G ( H ) was given, or h a s been considered in r e g a r d to a railroad w o r k e r who could have had a n u n r e c o g n i z e d i n j u r y p r i o r to t h e one for which he was given the T I G ( H ) . 4 8 , 111 T h e careful studies by McComb, D w y e r , Levine, Rubbo, Suri a n d o t h e r s as well as the consensus of the p a r t i c i p a n t s at th e Second a n d T h i r d I n t e r n a t i o n a l C onferences on T e t a n u s i n d i c a t e t h a t w h e n the dose of 250 u n i t s of T I G ( H ) has not been a d e q u a t e p r o p h y l a c t i c a l l y , the following questions should be a n s w e r e d fully12,~. 129, 13l, 132, 136, 140, 168. 170: 1. Did t h e p a t i e n t have an u n r e c o g n i z e d w o u n d t h a t o c c u r r e d prior to the i n j u r y considered to be responsible for t e t a n u s a n d which was the w ound a c t u a l l y responsible for t e t a n u s ? 2. W a s the T I G ( H ) given too late to be effective propt~ylactically? 3. W a s the w o u n d severe or neglected so t h a t a 500-unit dose of T I G (H) was i n d i c a t e d ? 4. W a s the T I G (H) o r d e r e d and not given? 5, W a s some d r u g t h a t was t h o u g h t to be T I G ( H ) given i n s t e a d of TIG(H) ? 6. W a s the T I G (H) a n i n a d e q u a t e p r e p a r a t i o n ? 7. W a s t h e T I G (H) o u t d a t e d ? 8. W a s too m u c h toxoid .... e i t h e r in respect to total volume or in r espect to Lf c o n c e n t r a t i o n a d m i n i s t e r e d ? 9. W e r e t e t a n u s toxoid a n d T I G (H) a d m i n i s t e r e d with the s a m e s y r i n g e and needle? 10. W e r e t e t a n u s toxoid a n d T I G ( H ) a d m i n i s t e r e d at the s a m e site? 11. W a s adsorbed or fluid t e t a n u s toxoid a d m i n i s t e r e d ? 6. ANTIBIOTICS At th e Second I n t e r n a t i o n a l Conference on T e t a n u s in 1966. t he cons e n s u s was t h a t antibiotics, s u c h as penicillin, h a v e been shown to be effective a g a i n s t v e g e t a t i v e t e t a n u s bacilli both in vitro a n d in e x p e r i m e n t a l animals. T h e y h a v e no effect a g a i n s t toxin. T h e effectiveness of antibiotics for p r o p h y l a x i s r e m a i n s u n p r o v e d , and, if used, t h e y should be given over a period of a t / e a s t 5 days.221 T h e following s u p p o r t s such an a t t i t u d e . I n a 1959 r e p o r t c o n c e r n i n g an in vitro i n v e s t i g a t i o n of the sensitivity of different s t r a i n s of CI. t e t a n i to antibiotics, Scheibel a n d A s s a n d r i l ; 2 s t a t e d t h a t v a r i a t i o n s have been d e m o n s t r a t e d in the sensitivity to antibiotics of different s t r a i n s of C1. tetani, these being especially p r o n o u n c e d as r e g a r d s penicillin but also evident to some degree with o x y t e t r a c y c l i n e . S u c h a n observation applies to both t he vegetative p h a s e and the g e r m i n a t i n g spore 42
phase, and both as regards the g r o w t h - i n h i b i t i n g and the bactericidal effect. S t r e p t o m y c i n was found to be almost ineffective. Toxigenic persister organisms have been d e m o n s t r a t e d in cultures with both low and high concentrations of antibiotics. Conversion to toxigenic, resistant L-forms may occur when penicillin is used. On the basis of these findings and because of the occurrence of d e a t h from t e t a n u s in 3 i n j u r e d persons who were given antibiotics only, Scheibel and Assandri concluded (hat justification for reliance on antibiotics for tetanus prophylaxis in nonvaccinated persons m u s t be challenged. In 1964, SmithIS2 reported that the development of t e t a n u s in mice infected with Cl. t e t a n i could be p r e v e n t e d with penicillin only when an adequate serum concentration was m a i n t a i n e d for a period of 3-4 days. If penicillin t r e a t m e n t was d e l a y e d until more t h a n 4 hours a f t e r infection, tetanus could not be prevented, but antitoxin was effective up to 20 hours after infection. Even t h o u g h penicillin effectively prevented tetanus, spores were found to survive in the tissues, and could be reactivated l a t e r to produce a fatal tetanus. Penicillil~ failed to p r e v e n t t e t a n u s in mice injected in the same site with both spores and penicillinase-producing S t a p h y l o c o c c u s (lltrells.
In 1966, 1Regamey el el. 1~;-~pointed out /.hat in the guinea pig the injection of procaine penicillin G (at a dose c o r r e s p o n d i n g to 2 m e g a u n i t s per 50-kg. subject) at the time of insertion of highly tetanogenic silk t h r e a d s does not suppress the d e v e l o p m e n t of lethal tetanus. F u r t h e r , in experim e n t s using a recording biophotometer, they showed t h a t t e t a n u s bacilli develop a b u n d a n t l y in the presence of certain c o n c e n t r a t i o n s of penicillin G but then s u d d e n l y undergo ]ysis. This destruction of the organism is t h o u g h t to liberate the e n d o c y t o p l a s m i c toxin, which can be n e u t r a l i z e d only by antitoxin. Therefore, in viva, w h e r e osmotic tensions are such as to readiIy permit bacterial lysis, penicillin could cause the release of the intracellu]ar toxin load. Hence, if a potentially lytic antibiotic, such as penicillin, and antitoxin are to be a d m i n i s t e r e d , the antitoxin should be given several hours before the antibiotic to n e u t r a l i z e a n y toxin released by the antibiotic. K r e m l e v l I.~ studied a n i m a l s with e x p e r i m e n t a l t e t a n u s infections induced after a single dose of toxoid and after a 2-dose basic series. W i t h administration of a toxoid booster plus antibiotics, all a n i m a l s survived. F o r ,91 of these animals, the booster was the second dose of toxoid; for 9 of the animals, the booster was a legitimate booster after a 2-dose basic series. W i t h only an antibiotic m i x t u r e of crystalline penicillin, b e n z a t h i n e penicillin G and streptomycin, 7 of 9 a n i m a l s survived. Bustle and his colleagues25 studied the action of an antibiotic against tetanus toxin (not spores) in viva and in vitro. T h e y instituted the study despite previous reports indicating no k n o w n activity of antibiotics against t e t a n u s toxin. T h e y observed that 1 rag. of N - ( p y r r o l i d i n o m e t h y l ) t e t r a cycline will inactivate 130 mouse lethal doses of t e t a n u s toxin. T h e inactivated toxin still has good antigenic properties. Case reports, such as those of Cases 1,4 and 6 in Section L, a p p e a r from time to time and represent failures of penicillin prophy]axis.,t¢, 144 In view of the i m m e d i a t e l y preceding observations it can be slated that antibiotics such ;Is penicillin, given l)rOml)tly after injury, m a y have a det e r r e n t action against t e t a n u s infection, especially for a brief 1)eriod, but cannot be used as the only I)rol)hylaxis. T e t a n u s is a m a n i f e s t a t i o n of a fox. 43
emia, not of an invasive infection. Antibiotics m a y be of value in combating a n y Cl. tetani bacilli t h a t have not been or c a n n o t be removed surgically. Antibiotics should not be used as a substitute for active or passive immunization a n d / o r as a substitute for p r o p e r surgical care of the wound, and antibiotics are not necessary to p r e v e n t t e t a n u s in the actively immunized. If used, a convenient method of a d m i n i s t e r i n g penicillin is to give 1.2 million units of long-acting b e n z a t h i n e penicillin G i n t r a m u s c u l a r l y . On the basis of in vitro sensitivity testing of CL t e t a n i strains, oxytetracycline is considered to be one of the best t e t r a c y c l i n e - r e l a t e d drugs. O x y t e t r a e y c l i n e m a y be given by the oral route in a dosage of 1-2 Gm. daily for 1-3 weeks. In the p a t i e n t with a severe o l d wound, antibiotics are used for their effect on organisms other t h a n the t e t a n u s bacillus, such as Cl. per/ringens.Sl If antibiotics are administered, it should not be forgotten t h a t they can cause u n d e s i r e d reactions. T h e incidence of reactions a m o n g 5,107 servicem e n who received 1,200,000 units of b e n z a t h i n e penicillin G was 1.687/o.135 T h e widespread use of an antibiotic, such as penicillin, is thus not without hazard, p a r t i c u l a r l y if the d r u g should be given to h u n d r e d s or thousands or millions of the p o p u l a t i o n at a time of a national disaster.
7. GANGLIOSIDEAND GANGLIOSIDE-CEREBROSIDECOMPLEX M e l l a n b y a n d her co-workers141 have found t h a t ganglioside with or w i t h o u t cerebroside acts as a prophylactic a g e n t in e x p e r i m e n t a l t e t a n u s in mice. T h e y found t h a t the s y m p t o m s of t e t a n u s in mice, resulting from int r a m u s c u l a r injection of either purified t e t a n u s toxin or vegetative Cl. tetani, can be p a r t i a l l y prevented if the mice are injected at the same time, or a few hours before or after, with a p r e p a r a t i o n of mi~:ed gangliosides or with a suspension of ganglioside-cerebroside complex. Injection at the same site as the toxin injection is most effective, a l t h o u g h intravenous injection of ganglioside (but not of the complex) also has some action; 0.5 rag. of ganglioside, w h e n complexed with 1.5 rag. cerebroside, is as effective in protection as 5 nag. ganglioside alone. P r o t e c t i o n by complexes containing different proportions of ganglioside reflects their ability to fix t e t a n u s toxin in • 4tro. M e l l a n b y et al. tentatively suggest t h a t injection of gangliosidecerebroside complex at a site of i n j u r y migh~ be of p r o p h y l a c t i c value for h u m a n tetanus.
8. :EMERGENCYMEDICAL IDENTIFICATI()NDEVICES In the p r e s e n t era of sophisticated chemical and electronic e q u i p m e n t and of complicated and heroic operative procedures, p r o p e r consideration should still be given generally to the p a t i e n t ' s history and more specifically to the emergency medical identification device (the E M I D ) .s5 I n the U n i t e d States, where now more a n d more individuals are actively i m m u n i z e d for tetanus, such devices are becoming more r a t h e r t h a n less i m p o r t a n t . Clinicians in active practice are constantly faced with these questions in the m a n a g e m e n t of the wounded: 1. 2. 3. 4.
H a s the p a t i e n t been actively i m m u n i z e d for t e t a n u s ? If actively i m m u n i z e d for tetanus, when? H a v e there been reactions to t e t a n u s toxoid? Should T I G ( H ) be given? 44
S u c h questions can be a n s w e r e d i m m e d i a t e l y if each individual has on his person a n u p - t o - d a t e E M I D . It is most distressing to he called to take care of w o u n d e d patients who have little or no knowledge of t h e i r i m m u n i z a t i o n status. If in doubt, simultaneous active-passive i m m u n i z a t i o n can be effected, but, in doing so, T I G (H) m a y be wasted. Brooks a n d his co-workers21 and H a r r i s o n 94 stress careful d o c u m e n t a t i o n of the i m m u n i z a t i o n history. If the history is vague a n d poorly d o c u m e n t e d , the p a t i e n t should be given tetanus toxoid as though the dose or doses of to.~oid in question had not been given. P h y s i c i a n s have had patients tell t h e m t h a t they have been given t e t a n u s toxoid injections only to discover on closer search of the history t h a t it was t e t a n u s antitoxin, or d i p h t h e r i a toxoid, or p e r h a p s t y p h o i d vaccine t h a t h a d been given but not t e t a n u s toxoid.67,130 ][n the U n i t e d States, at present, few people have in their i m m e d i a t e possession an emergency medical identification device with tetanus data. T h e following case report is p r e s e n t e d to e m p h a s i z e how a surgeon interested in t e t a n u s p r o p h y l a x i s m a y be lured into a false sense of security c o n c e r n i n g the tetanus p r o p h y l a x i s status of a n i n j u r e d person. At a p p r o x i m a t e l y 6:30 P.]~L, F r i d a y , 8 N o v e m b e r 1968, a y o u n g a d u l t m a l e suffered multiple injuries in an a i r p l a n e crash. At 11:00 P.~L, w h e n he was e x a m i n e d in the hospital, he stated t h a t he h a d been in the U.S. A r m y a n d t h a t he had received a booster dose for tetanus 2 m o n t h s previously. D u r i n g the r e m a i n d e r of the night, n u m e r o u s facial lacerations were debrided and s u t u r e d , a n d a p p r o p r i a t e care rendered for fractures of the base of the skull and of the maxillae, for hemat u r i a and for m u l t i p l e contusions. A t 9 A.~[., S a t u r d a y , 9 November, a careful cheek of the hospital records indicated t h a t the p a t i e n t had not h a d a booster dose of t e t a n u s toxoid 2 m o n t h s previously. Also, it was established t h a t he had been in" the A r m y in 1958. T h e n , a dose of t e t a n u s toxoid was given. B y 9 A.~., S u n d a y , 10 N o v e m b e r , his wife h a d found his A r m y record on which t h e r e were notations for only two injections of t e t a n u s toxoid (27 M a y 1958 a n d 9 J u l y 1958). T I G ( H ) was ordered. At 7 P.M., 10 N o v e m b e r 1968 ( a p p r o x i m a t e l y 48 hours after i n j u r y ) , the T I G ( H ) was a d m i n i s t e r e d . F o r t u n a t e l y , the p a t i e n t had an excellent recovery. H e was, however, an individual who h a d received serious tetanus-conducive injuries in the immediate vicinity of his b r a i n so t h a t any t e t a n u s toxin t h a t h a d been produced in the wound would have had to be t r a n s p o r t e d only a short distance to become fixed in the brain and to produce tetanus. If the p a t i e n t h a d had on his person a n up-to-date E M I D , more i m m e d i a t e and more specific t e t a n u s p r o p h y l a x i s could have been instituted. If every person c a r r i e d some type of e m e r g e n c y medical identification device, history t a k i n g after i n j u r y could be greatly simplified and expedited, t e t a n u s toxoid i m m u n i z a t i o n could be p e r f o r m e d a c c u r a t e l y and scientifically, overdosage and u n n e c e s s a r y injections of t e t a n u s toxoid could be avoided and injections could be avoided in the r~re individua| who is sensitive to t e t a n u s toxoid. 45
T h e A m e r i c a n Medical Association has m a d e available to p h y s i c i a n s at low cost a n e m e r g e n c y medical identification card.60 On this card. t:here is r e p r o d u c e d the A m e r i c a n M e d i c a l Association identification symbol, which was a d o p t e d by the World Medical Associ~,_tion t h r o u g h a n action by its Assembly in 1964 a n d w h i c h was r e c o m m e n d e d for use in the c o u n t r i e s repr e s e n t e d by the W o r l d Medical Association m e m b e r s . S i m i l a r c a r d s or records also a r e available from t h e W o r l d H e a l t h O r g a n i z a t i o n , th e U n i t e d S t a t e s G o v e r n m e n t P r i n t i n g Office, the A m e r i c a n A c a d e m y of P e d i a t r i c s , t h e A m e r i c a n A c a d e m y of G e n e r a l P r a c t i c e , t h e M i c h i g a n S t a t e M e d i c a l Society, t h e K a r o l i n s k a S j u k h u s e t a n d The Columbus [Ohio] Dispatch. At th e 1967 W o r l d Congress of M o t o r i n g M e d i c i n e in Vienna, in a discussion of e m e r g e n c y medical identification devices for motorists, a n asbestos, n o n i n f l a m m a b l e card used in A u s t r i a was described. A b u t t o n m a y be a t t a c h e d to u n d e r c l o t h i n g , to a billfold or to a purse. M e t a l tags are available in a t t r a c t i v e configurations, such as a h e a r t . T a t t o o m a r k s , of course, are a l w a y s on the p a t i e n t , a n d a r e readi l y a p p a r e n t if not d e s t r o y e d by local t r a u m a , such as a burn. T h e use of such m a r k s , however, h a s been questioned. S o m e y e a r s ago, t h e C o m m i t t e e on E m e r gency M e d i c a l I d e n t i f i c a t i o n of the A m e r i c a n M e d i c a l Association cons id e re d tattoos a t some length a n d decided t h a t they were not slfitable for s e v e ra l reasons. T h e p r i m a r y one was the a n t a g o n i s m toward p e r m a n e n t m a r k i n g s h e l d by a g r e a t m a n y n a t i o n a l i t y a n d e t h n i c g r o u p s from the e x p e r i e n c e s t h e y suffered d u r i n g W o r l d W a r s I a n d II. Also, it is difficult to provide a t a t t o o in a place in which it is accessible and at t he s a m e t i m e inconspicuous. T h e tine, a tattoo t y p e of device, has been deve, Ioped for use in connection with tuberculosis. A t t h e 1966 I n t e r n a t i o n a l C o n f e r e n c e on T e t a n u s , Rubbo169 s u g g e s t e d t h a t carbon be i m p r e g n a t e d on t h e tips of a fine with t h e d a t e of a y e a r a n d t h a t the tine t h e n be used to t a t t o o the d a t e of t he l a s t toxoid injection.
K. MANAGEMENT OF THE VICTIM OF TETANUS {TREATMENT) A t t h e t i m e of t h e Civil W a r a n d i m m e d i a t e l y t h e r e a f t e r , little was k n o w n a b o u t tile p r e v e n t i o n a n d t r e a t m e n t of t e t a n u s . B y o u r p r e s e n t - d a y s t a n dards, wound c a r e a t its best was poor, consisting p r i m a r i l y of analgesics, a t t e m p t s a t h e m o s t a s i s , nonspecific o i n t m e n t s a n d a m p u t a t i o n . D u r i n g the Civil W a r , in 280,040 admissions for w o u n d s a n d injuries, t h e r e were 505 cases of t e t a n u s , with 451 d e a t h s (89.3%) (see T a b l e 12). I n the 1.863 h~Ianu a l of M i l i t a r y S u r g e r y for the A r m y of the C o n f e d e r a t e S t a t e s a p p e a r e d this s t a t e m e n t : " T o e n u m e r a t e t h e m e a n s used for the relief of t e t a n u s would r e q u i r e a volume; to record those e n t i t l e d to confidence does not req u i r e a line."lga I n c o n t r a s t to s u c h a s t a t e m e n t of 1863, it now m a y be s t a t e d t h a t the t r e a t m e n t of t e t a n u s is complex b u t successful. I t r e q u i r e s devoted a n d exh a u s t i n g a t t e n t i o n by all echelons of p h y s i c i a n s a n d hospital personnel. It is t r u l y a t e a m effort t h a t can best be c a r r i e d out in a t e t a n u s c e n t e r or hospital in w h i c h m a n y cases of t e t a n u s have been t r e a t e d successfully or in a large g e n e r a l hospital, w h e r e all t h e m o d e r n medical a n d surgical a d v a n c e s c a n be d i r e c t e d t o w a r d o v e r c o m i n g a t e r r i b l e disease associated with horrible p a i n for t h e u n f o r t u n a t e p a t i e n t . 46
P a t e l a n d Joag~5~ of I n d i a have e m p h a s i z e d t h a t if m e t h o d s of t h e r a p y are to be e v a l u a t e d correctly t h e r e should be developed a uniform system of g r a d i n g of tetanus. If such a s y s t e m is not developed, cases of mild t e t a n u s with a low m o r t a l i t y rate m a y be wrongly c o m p a r e d with cases of severe t e t a n u s with a high m o r t a l i t y rate. Adams1 of S o u t h Africa stresses t h a t in t r e a t i n g t e t a n u s -in which death is due to a n u m b e r of f a c t o r s ~ i t is very difficult to know which factor or factors cause d e a t h and hence it is very difficult to know about the effect of a certain form of t h e r a p y . A specific conclusion can be d r a w n concerning the efficiency of a p a r t i c u l a r t y p e of t r e a t m e n t only if all other t r e a t m e n t s are controlled and only if cases in the same stages of t e t a n u s are compared. A d a m s states that the value of different forms of t h e r a p y can be evaluated best by constant comparisons of results in one hospital r a t h e r t h a n in comparisons of results in different hospitals. T h e results of S m y t h e a n d Bowie and those of Ildirim (cf. section K-2-b) in the t r e a t m e n t of n e o n a t a l t e t a n u s are p a r t i c u l a r l y striking. In t r e a t i n g 321 cases of n e o n a t a l t e t a n u s d u r i n g the period from 1956 to 1969, S m y t h e and BowietS'~ were able to decrease the m o r t a l i t y rate for n e o n a t a l t e t a n u s from 100% to consistently below 20% (Fig. 17). S m y t h e ascribes his i m p r o v e d results to three factors: 1. T h e control of i n t e r m i t t e n t positive-pressure r e s p i r a t i o n by monitoring the Pco2.186 2. T h e clarification of the problems of t r a c h e o s t o m y a n d d e t u b a t i o n in the infant.Is7 3. T h e striking i m p r o v e m e n t in control of infection following instillation of penicillin and colistin down the t r a c h e o s t o m y tube.lSs T h e t h e r a p e u t i c r e c o m m e n d a t i o n s t h a t follow are those that have been proved by the experiences of those p a r t i c u l a r l y i n t e r e s t e d in the m a n a g e m e n t of t e t a n u s and which have been discussed in detail at the three I n t e r -
FIG. 1 7 . - - N e o n a t a l tetanus m o r t a l i t y rates, South Africa, 1956-1969.~ .~:~ (Courtesy of P. S m y t h e and M. Bowie.) i00
80
60
40
ZO
!956
!958 1957
1960 1959
1962 1964 1966 1968 196 1 1963 1965 1967 1969
47
n a t i o n a l C o n f e r e n c e s on T e t a n u s . I , 35, 41, 79, s3, 220, 223 T h e i r i n i t i a t i o n is based on the e s t a b l i s h m e n t of a diagnosis of t e t a n u s . T h e y c o n s t i t u t e a guide t h a t is to be a l t e r e d a c c o r d i n g to t h e e x p e r i e n c e and p e r s o n a l judgm e n t of t h e a t t e n d i n g p h y s i c i a n . S o m e of the m e t h o d s of t r e a t m e n t can h a v e a d v e r s e as well as beneficial effects. H e n c e , w h e n a n y t r e a t m e n t is i n i t i a t e d , a q u o t a t i o n of H i p p o c r a t e s s h o u l d be r e m e m b e r e d : " P r i m u m non nocere."97 H i s advice, liberally t r a n s lated, is: "As to diseases, m a k e a h a b i t of two t h i n g s to help, or at l east to do no harm."65 T h e following r e c o m m e n d a t i o n s for m a n a g e m e n t are given in o r d e r of chronologic priority.S1 1) COIVIPLETE HISTORY AND PttYSICAL EXAI~INATIO.N. O b t a i n a c o m p l e t e m e d i c a l a n d surgical h i s t o r y of t h e p a t i e n t , a n d p e r f o r m a c o m p l e t e physical e x a m i n a t i o n . I n p a r t i c u l a r , i n q u i r e a b o u t the d a t e of i n j u r y , th e circums t a n c e s of i n j u r y , the d e p t h of the i n j u r y below the skin a n d allergies. S u c h i n f o r m a t i o n forms a b a s e l i n e for the recognition of such c o m p l i c a t i o n s as atelectasis, p n e u m o n i a , t r a u m a t i c glossitis, f r a c t u r e s of the v e r t e b r a e , decubital ulcers a n d fecal impaction. If rectal probes a r e left in place for cons t a n t recording of t e m p e r a t u r e , t h e y m u s t be checked c a r e f u l l y to p r e v e n t t r a u m a to t h e rectal m u c o s a a n d a n o r e c t a l veins d u r i n g convulsions., 2) ANTITOXIN. a) I n t r a m u s c u l a r i n j e c t i o n . As soon as the diagnosis of t e t a n u s is made, give deeply i n t r a m u s c u l a r l y 3,000-6,000 u n i t s of T I G ( H ) . T I G ( H ) is to be given in the p r o x i m a l portion of t h e e x t r e m i t y in wh ic h is the w o u n d responsible for t e t a n u s , or in t h e gluteal muscl es if th e w o u n d is not in a n e x t r e m i t y , or if the c a u s a t i v e w o u n d c a n n o t be found. T h e exact effective dosage of T I G (H) has not been clearly established.l,~' S i n c e a s e r u m t e t a n u s a n t i t o x i n level o,f 0.01 u n i t p e r ml. will p r e v e n t tetan u s in t h e i n j u r e d , a dosage of 10,000 u n i t s of T I G f H ) is m o r e t h a n adeq u a t e for severe t e t a n u s , and, as was discussed at the Second I n t e r n a t i o n a l C o n f e r e n c e on T e t a n u s in Bern, a dose of p r o b a b l y only 1,500 u n i t s a n d p e r h a p s only 500 u n i t s m a y be t h e r a p e u t i c for less severe t e t a n u s . T h e dose t h a t N a t i o n el al. 14~, selected was on t h e basis of previous exp e r i m e n t a l work, which i n d i c a t e d t h a t levels of 0.08-0.160 per ml. of s e r u m would be achieved with 1,500 u n i t s of T I G ( H ) . T h e y chose to a d m i n i s t e r 3,000-6,000 units to provide blood levels well in excess of t h e s e values. In t h e i r series of cases, the dose r a n g e was from 29 u n i t s to 300 u n i t s p e r kilog r a m of body weight. No difference in effectiveness was noted at t h e extremes. In t h e U n t i e d S t a t e s , w h e r e t h e r e a r e now a d e q u a t e supplies of T I G ( H ) , t h e r e a r e no indications for the a d m i n i s t r a t i o n of h e t e r o l o g o u s e q u i n e and bovine antitoxins, which h a v e been responsible for s e r u m sickness, m y o c a r dial infarction, p e r i p h e r a l n e u r i t i s a n d a n a p h y l a c t i c shock with death.~; Moreover, in the h u m a n being, the life sl)an of the heterologous a n t i t o x i n s ('annot be predicted with c e r t a i n t y . In c o u n t r i e s in which T / G ( H ) is not available heterologous a n t i t o x i n s ~lre still being used. P;ttel and Iris associates1.5(;. )r,; in Bonfi)ay, India, where the incidence of tet;mnus is high, have shed light on the l h e r a l ) e u l i c use of e q u i n e tetantm antitoxin. Ttley found no signific~tnt difference in m o r t M i t y for doses r;ingim~ from 5,000 units (the lowest dose used) Io 60,000 ,niis, and int(,rl~r(,t~,d l;lrg~,r ct~s(,s ;m b(.ing l)rolmbly detrim~,ni;ll. I,'urlhermor(,, they ~'~uld find
48
no t e t a n u s toxin circulating in the blood of 43 patients seriously ill from t e t a n u s on admission and before the a d m i n i s t r a t i o n of antitoxin. Such d a t a agree with w h a t has a l r e a d y been k n o w n r e g a r d i n g the rapid combination of toxin with nerve tissue, and would indicate that, by the time s y m p t o m s are present, s e r u m t r e a t m e n t serves to n e u t r a l i z e only n e w l y p r o d u c e d toxin. V a i s h n a v a et al.,2ol after a blind controlled trial with heterologous antitoxin in 470 patients, concluded t h a t a n t i s e r u m has little value in the treatm e n t of clinical tetanus. Also, Pate] a n d Goodluck154 studied 1,188 p a t i e n t s with n e o n a t a l t e t a n u s a d m i t t e d to the K i n g E d w a r d M e m o r i a l H o s p i t a l d u r i n g the period November 1, 1954, to October 31, 1966, and t r e a t e d t h e m with v a r y i n g a m o u n t s of heterologous antitoxin. One h u n d r e d sixty-three p a t i e n t s did not receive antitoxin. Significant beneficial effect was observed by a d m i n i s t r a t i o n of antitoxin. A small dose of antitoxin (1,500 IU) a p p e a r e d to be as effective as a l a r g e r dose. T h a t s e r u m was n e c e s s a r y was f u r t h e r s u p p o r t e d by t h e i r d e m o n s t r a t i o n of circulating toxin in 5 of 18 samples of blood tested. b) Intrathecal injection o/ a mixtllre o[ antitoxin and p r e d n i s o l o n e . ~ Consider the i n t r a t h e c a l injection of a m i x t u r e of antitoxin and prednisolone.IS,% a18 F o r a n u m b e r of years, i n t r a t h e c a l s e r o t h e r a p y of t e t a n u s has not been performed. T h e r e has been a fear that such t h e r a p y can c o n t r i b u t e to a fatal outcome by causing excitement, s e r u m m e n i n g i t i s and possibly cerebral or m e d u l l a r y edema.191 At the 1970 I n t e r n a t i o n a l Conference on T e t a n u s . however, Ildiriml0,~, 104 of T u r k e y p r e s e n i e d a most s t i m u l a t i n g and provocative p a p e r entitled I n t r a t h e c a l T r e a t m e n t of T e t a n u s with Aniit e t a n u s S e r u m a n d P r e d n i s o l o n e Mixture.104 His report was divided into l a b o r a t o r y studies and clinical trial. In the laboratory, t e t a n u s was produced in pedigreed dogs by the i n t r a venous a d m i n i s t r a t i o n of 5 × LD.~o t e t a n u s toxin. T h e y were studied in four groups, with one used as control. A n i m a l s in the t r e a t m e n t group were given horse antitoxin. All 5 dogs receiving physiologic saline via cisternal, i n t r a v e n o u s and i n t r a m u s c u l a r routes died. Five of 6 dogs receiving only prednisolone cisternally and antitoxin i n t r a v e n o u s l y a n d i n t r a m u s c u l a r l y also died (83°0). Six of 14 dogs receiving antitoxin cisternally, intravenously and i n t r a m u s c u l a r l y died (43%). Only 1 of 14 dogs receiving a mixture of prednisolone and antitoxin cisternally in addition to antitoxin i n t r a v e n o u s l y, a n d i n t r a m u s c u l a r l y died (7.1 ~', ~o ) - T h e difference between the last group and others was found to be statistically significant. In clinical application, 28 neonates and 3 children with t e t a n u s were | r e e l e d with horse aniitoxin and prednisolone m i x t u r e i n i r a t h e c a l l y , antitoxin intr:ivenously and i n t r a m u s c u l a r l y and l)rednisolone orally. T h e y were sedated with sodium phenobarbital and with d i a z e p a m , fed by nasogastric tube and given antibiotics for prophyl~lxis. Only 3 n e o n a t e s died. Others recovered in 15.6 days on the average. T h e f a | a l i t y rate for neonatal te~nnus with the abo~:e-mentioned t r e ~ | m e n t was 10.70;,, in c o n t r a s t to the rale~; shown in F i g u r e 17. N o r m a l values were obtained for growlh ~nd develol)meni in the follow-up studies. Also, in 1966 Smiihl~:~ showed that horse serum nniitoxin given inirn('(,,rebr;llly wrls able 1o IJrotecl mice ngnins| letnnus nt ;l time when nntitoxin given inl r;~venollsly in the same dose w~ls ineffective. W h e n the inl ravenous dose ,)f a n | | t o x i n was ilwreased to 100 times |he n m o u n t given inirncere. 49
- :,
\
FIa. 1 8 . ~ N e o n a t a l t e t a n u s in T u r k e y . O p i s t h o t o n o s , flexion of t h e a r m s , c l e n c h e d fists a n d p l a n t a r flexion of the toes a r e seen in A; t y p i c a l t e t a n u s face ( t r i s m u s a n d risus s a r d o n i c u s ) a n d c l e n c h e d fists a r e visible in B.103 ( C o u r t e s y of I. I l d i r i m . )
brally, tile two routes of t r e a t m e n t were equally effective. Such a finding m a y be due to the fact t h a t antitoxin passes from the blood into the b r a i n with difficulty and it is only when a high serum concentration is produced t h a t appreciable quantities of antitoxin quickly reach the brain. 3) " LABORATORY TESTS. O r d e r the following tests: 1. Complete blood cell count with differential white blood cell count. 2. Urinalysis. 3. Serologic test for syphilis. 4. P r o t h r o m b i n time and partial t h r o m b o p l a s t i n time. 5. Blood c h e m i s t r y tests: urea nitrogen, creatinine, electrolytes, s e r u m protein electrophoresis, bilirubin, calcium, glucose. 6. Arterial blood gases. 7. Chest roentgenogram. 8. E l e c t r o c a r d i o g r a m . 9. E l e c t r o e n c e p h a l o g r a m . 10. W o u n d and if the p a t i e n t is febrile blood cultures. 11. If necessary for diagnosis, cerebrospinal fluid for culture, smear, cells a n d chemistry tests. Provide 24-hour constant n u r s i n g care. A resident or i n t e r n i m m e d i a t e l y available for complications, p a r t i c u l a r l y r e s p i r a t o r y problems such as r e s p i r a t o r y arrest, will g r e a t l y increase the patient's chance for recovery from tetanus. After a detailed study of cases of neon a t a l tetanus, Pinheirol60 stated t h a t even though the m a n a g e m e n t is as yet unsatisfactory, it still ought to be p r e s u m e d t h a t the high m o r t a l i t y rate of t e t a n u s n e o n a t o r u m is m o r e due to the lack of careful medical a n d n u r s i n g care t h a n to the severity of the disease. H e m a i n t a i n e d that continual nursing care, day and night, d u r i n g the acute stage of the illness is still the most i m p o r t a n t m e a s u r e in t e t a n u s of the newborn infant t r e a t m e n t routine. 5) ANALaEmCS.:=::A d m i n i s t e r analgesics, which will relieve the pain associated with the tonic contractions of tetanus but will not cause respiratory depression. Codeine, m e p e r i d i n e (Demerol) and m e p e r i d i n e with p r o m e t h a z i n e {Phenergan) are suitable drugs. 4)
NURSING CARE.
50
6) SEDATIVES AND h{USCLE RELAXANTS.wUse sedatives and muscle relaxants correctly. A most i m p o r t a n t consideration is t h a t the physician know how to use safely the sedatives a n d muscle relaxants t h a t he orders for the p a t i e n t with tetanus. T h e mildest cases of t e t a n u s can be sedated a d e q u a t e l y with phenobarbital, pentobarbital, secobarbital and p a r a l d e h y d e . In the more severe cases, thiopental sodium (Pentothal) m a y be administered i n t r a v e n o u s | y in a very dilute solution (0.5-1.0 Gin. per 1,000 ml.) at a rate of 20-25 drops per m i n u t e in an effort to lower the p a t i e n t ' s threshold of irritabilit~ to external stimuli and to reduce the n u m b e r and severity of seizures and r e s p i r a t o r y arrests.7 Care is taken to avoid overdosage. T h e optimal level of continuous sedation i s ' o b t a i n e d when the p a t i e n t remains sleepy but still can be aroused by m o d e r a t e external stimuli sufficiently to obey commands. Objectively, the best indication of this level is when the rectus muscles of the a b d o m e n lose their h y p e r t o n i c state a n d have only a n o r m a l degree of resistance to palpation. W h e n a severe convulsive seizure occurs, with respiratory arrest, 2--8 ml. of a 2.5% solution of t h i o p e n t a l sodium is injected i n t r a v e n o u s l y i m m e d i a t e l y and as necessary. This u s u a l l y produces muscle relaxation w i t h i n 30-45 seconds and p e r m i t s s p o n t a n e o u s re-establishment of the r e s p i r a t o r y cycle. Some centers have been e n t h u s i a s t i c about the use of m u s c l e - r e l a x a n t drugs to control convulsive seizures.161 Such drugs are difficult to m a n a g e a n d have not prevented d e a t h from r e s p i r a t o r y arrest. D r u g s more comm o n l y suggested for such use are d i a z e p a m (Valium), m e t h o c a r b a m o l (1Robaxin), m e p h e n e s i n (Tolserol), d - t u b o c u r a r i n e and succinylcholine. T h e m a r g i n of safety with these drugs is narrow, a n d they seem best designed for the cases excessively difficult to m a n a g e w a n d then only u n d e r careful observation of an experienced anesthesiologist. M e p r o b a m a t e ( M i | t o w n ) , given i n t r a m u s c u l a r l y , also has been used as a muscle relaxant, u s u a l l y in combination with phenobarbital, a m o b a r b i t a l or methocarbam.ol. 7) SURGICALWOUND CARE.~Carry out meticulous surgical care of wounds as described u n d e r surgical care in the p r o p h y l a x i s section (J-4).77 8) ANTIBIOTICS. Consider the a d m i n i s t r a t i o n of antibiotics for the treatm e n t of the infectious complications of tetanus. In vitro, penicillin is effective a g a i n s t t e t a n u s bacillus. It is not surprising, however, that antibiotic t h e r a p y is clinically d i s a p p o i n t i n g insofar as it is directed against the t e t a n u s disease itself. T e t a n u s is not a bacteremia, for the bacillus r e m a i n s at the place of its entry. By the time antibiotic t h e r a p y is begun, the wound often has been excised, and the toxins are being s p r e a d in the circulation. W h e n the site of infection is not known a n d the antibiotic effect would be p a r t i c u l a r l y desired, t h e r e is little probability t h a t the bacteria are reached by p a r e n t e r a l a d m i n i s t r a t i o n of an antibiotic due to anaerobic conditions in the concealed closed p u n c t u r e wound. D e s p i t e the in vitro effects of penicillin, a noticeable, specific t h e r a p e u t i c reaction cannot be expected.5. 182.209 On the other hand, the antibiotics do play their p a r t in the t h e r a p y p|an. T h e y are irreplaceable in the care of infectious complications of tetanus, especially in combating p n e u m o n i a or secondary, invasive, wound infections. A c o m b i n a t i o n of penicillin (at least 2 million unils every 6 hours) and s t r e p t o m y c i n (0.5 Gin. every 12 hours) m a y be given i n t r a m u s c u l a r l y ; or a n o t h e r antibiotic, with a b r o a d - s p e c t r u m effect, such ns tetracycline (0.5
51
Gm. every 6 h o u r s ) , m a y be a d m i n i s t e r e d intravenously. As a l r e a d y indicated, penicillin and colistin have been injected down the t r a c h e o s t o m y tube with considerable success in neonatal tetanus.lSS T h e possible complications t h a t m a y develop with antibiotic t h e r a p y m u s t be given p a r t i c u l a r a t t e n t i o n in the case of t e t a n u s patients. Especially in the more severe cases, in which n o u r i s h m e n t is accomplished t h r o u g h semiphysiologic methods, there will be a t e n d e n c y t o w a r d gastrointestinal disturbances. If, at the same time, there is an increase in resistant bacteria. e.g., staphylococci, in the intestines, a n enterocolitis can develop readily. 9) TRACHEOSTOMY.. P e r f o r m t r a c h e o s t o m y if personnel and facilities are available to care a d e q u a t e l y for the tracheostomy.gs. 1s7 If the incubation period has been only. a few days so that the p a t i e n t m a y have very severe tetanus, a t r a c h e o s t o m y probably will be necessary and can be p e r f o r m e d u n d e r general anesthesia, if extensive wound debridem e n t is necessary, or with local anesthesia. T h o s e t e t a n u s p a t i e n t s in w h o m a t r a c h e o s t o m y is necessary also will need, in most cases, continuous artificial respiration. Such respiration is facilitated by a t t a c h i n g with a gas-tight a d a p t e r a Portex tracheostomy tube with double inflatable cuffs to an E m e r s o n Volume-Controlled Ventilator or a B e n n e t t R e s p i r a t i o n U n i t Model MA-I. N u r s i n g care of the seriously ill t r a c h e o s t o m y p a t i e n t is not easy. T h e inspired air m u s t be moist. If the p a t i e n t can b r e a t h e spontaneously, moisturizing a p p a r a t u s is set up in the p a t i e n t ' s hospital room; if, however, the p a t i e n t is being given artificial respiration, the r e s p i r a t o r used m u s t be one t h a t continuously moistens the gas mixture. D e h y d r a t i o n of the r e s p i r a t o r y tract can lead to severe h e m o r r h a g i c tracheobronchitis, which can be fatal. E v e n with absolutely correct conditioning of the inspired air, secretions can collect in the airway. A suction m a c b i n e always m u s t be at the patient's bedside. P a t i e n t s with p a r a l y z e d r e s p i r a t o r y muscles must be suctioned every hour. Also of e x t r e m e i m p o r t a n c e is the cleanliness of the tracheostomy tube; d e h y d r a t e d secretions, p s e u d o m e m b r a n e s and crusts can form on the i n n e r m a r g i n of the c a n n u l a and m a y lead to n a r r o w i n g of the res p i r a t o r y airway. T h e tracheostomy tube should be changed w h e n e v e r it c a n n o t be m a d e to function correctly by cleaning and m a n i p u l a t i o n . A n i m p r o p e r l y cared-for t r a c h e o s t o m y m a y be worse t h a n none. T r a c h e o s t o m y m a y be poorly tolerated in the n e w b o r n infant, and dec a n n u l a t i o n m a y be quite difficult. In i n f a n t s ~ p a r t i c u l a r l y those with neonatal t e t a n u s ~ before p e r f o r m i n g a tracheostomy, consider endotracheal intubation by insertion of an e n d o t r a c h e a l tube t h r o u g h the nose or, less preferably, t h r o u g h the mouth.gs 10) PR1YATE, DARK, QUIET ROO~I. Place the p a t i e n t in a private, dark, quiet room. Efforts should be m a d e to reduce as m u c h as possible all external stimuli. Visitors should be limited to the absolute m i n i m u m . It should be pointed out that with a d e q u a t e sedation and muscle relaxation some no longer r e c o m m e n d the dark, quiet room.159 11) INCUaATOR FOR INFANTS.~PIace infants with neonatal t e t a n u s in an incubator in which the oxygen partial pressure, e n v i r o n m e n t a l t e m p e r a t u r e and a nebulized a t m o s p h e r e of distilled w a t e r can be m o n i t o r e d and maintained. 12) I~OENTGENOGRA~IS.. Order indicated roentgenograms. These m a y be for (1) fractures associated with the initial injury, (2) d e t e r m i n a t i o n of 52
p u l m o n a r y problems such as atelectasis and p n e u m o n i a a n d (3) fractures or avulsions of muscle insertions produced by the tonic muscle contractions of tetanus. Compression fractures of the vertebrae m a y be the result of the intense p a r o x y s m s that c h a r a c t e r i z e the disease, and their diagnosis m a y be easily missed w i t h o u t roentgenograms.122 13) PADDED TONGUE DEPRESSOR. L,, , B y insertion of a padded tongue depressor, protect the tongue from being bitten during tonic contractions. 14) ORAL HYGIENE." Clean the lips, teeth, tongue and oral cavity daily to lessen the possibility of growth of pathologic bacteria and viruses. Remove all loose debris from the oral and nasal cavities. I 5 ) NUTRITION.:: Give correct a m o u n t s of n o u r i s h m e n t by oral, nasogastric tube, gastrostomy tube a n d intravenous routes. T h e relaxed p a t i e n t is totally d e p e n d e n t on artificial n o u r i s h m e n t . Initially, tube feedings t h r o u g h a soft nasogastric tube are indicated. If difficulties are encountered with the tube feedings, it m a y be necessary to resort to i n t r a v e n o u s s u p p l e m e n t s . Central venous pressure systems using the subclavian vein provide an excellent route for feeding, including h y p e r a l i m e n t a t i o n . T r a n s f u s i o n s of blood, p l a s m a and h u m a n a l b u m i n can be s u p p l e m e n t e d with electrolyte solutions of glucose, alcohol, fructose and protein hydrolysates. T h e infusions can be f u r t h e r s u p p l e m e n t e d with high doses of vitamins C and B complex. T h e s e r u m protein and electrolytes should be checked repeated|y.99 N o t h i n g is given by m o u t h until i m p r o v e m e n t begins. In choosing a diet, the fact that the p a t i e n t on occasion m a y feel p a i n w h e n he chews should be taken into consideration. 16) ALI~ENTARY TRACT ELIMINATION.~Provide for a d e q u a t e gastrointestinal elimination. S p o n t a n e o u s defecation u s u a l l y is absent. Defecation can be controlled by saline laxatives given orally or into the nasogastric tube and by enemas p.r.n. 17) URINE E L I M I N A T I O N . ~ \ V h e n necessary, provide for elimination of bladder urine by the insertion of a Foley catheter. Remove the. c a t h e t e r at the earliest possible time to prevent u r i n a r y tract infections. 18) INTAKE AND OUTPUT RECORDS. R e c o r d intake and output. 19) PROTECTION OF THE EYES.. Protect the eyes. P a r t i c u l a r a t t e n t i o n m u s t be given to incomplete closure of the eyelids. W i t h o u t p r o p h y l a c t i c measures, exsiccation, keratitis and corneal ulcer can develop. An ophthalmic o i n t m e n t m a y be a p p l i e d and the eyes covered with a moist gauze sponge. 20) PREVENTION OF DECUBITAL ULCERS.~ K e e p the p a t i e n t ' s s k i n dry, and cushion pressure points, to avoid decubital ulcers. 21) BLOOD DYSCRASIAS AND BLEEDING PROBLEMS.~If there is a possibility of blood dyscrasias or bleeding problems, order f r e q u e n t complete blood cell counts and p r o m p t l y investigate the clotting mechanisms.9~. 112,149 22) PREVENTION OF hIUSCLE CONTRACTURES.--As the p a t i e n t improves, prevent muscle contractures with resulting deformities, such as foot drop. Use foam-rubber padding, pillows, sandbags a n d splin{s as indicated. W h e n necessary for muscle imbalance, p h y s i o t h e r a p y should be instituted as soon as possible. 23) ELECTROENCEPHALOGRAMS.~Orderelectroencephalograms when it is technically possib|e to obtain / h e m and when their p r o c u r e m e n t will not interfere with the l)atient's recovery. Such records m a y be of considerable i m p o r i a n c e in the long-range evaluation and care of lhe patient.JT, 10n 53
24) STEROm T H E R A P Y . C o n s i d e r steroid t h e r a p y if there is a possibility of adrenal gland exhaustion. A l t h o u g h not used routinely, steroid t h e r a p y has been emp'~oyed in a few severe cases of t e t a n u s in which the prolonged course of the disease was t h o u g h t to e x h a u s t the a d r e n a l glands. 25) TETANUS TOXOm.--One m o n t h a f t e r the diagnosis of t e t a n u s is made, give 0.5 ml. of adsorbed t e t n n u s toxoid i n t r a m u s c u l a r l y for active i m m u n i zation, and, if the p a t i e n t did not have a dose of t e t a n u s toxoid at the time of injury, he should have a n o t h e r dose in 1 month. A n o t h e r 0.5 mI., which is given 6-12 m o n t h s later, completes the basic active i m m u n i z a t i o n . T h e n , routine t e t a n u s toxoid boosters are given every 6-10 years. Such i m m u n i z a tion is necessary, because an a t t a c k of t e t a n u s does not produce antibodies to p r e v e n t a n o t h e r attack. 26) EM:ERGENCY ,-~IEDICAL IDENTIFICATION DEVICES. A t the time of discharge from the hospital, ~ v e the cured p a t i e n t a completed E M I D a n d instruct him to complete his active i m m u n i z a t i o n with t e t a n u s toxoid to p r e v e n t r e c u r r e n t tetanus. 27) HYPERBARIC OXYGEN. ....H y p e r b a r i c oxygen is not r e c o m m e n d e d in view of the m i n i m a l good effects and in view of the complications of such t r e a t m e n t . T e t a n u s is a toxemic state and is not due to bacteria t h a t are s p r e a d i n g t h r o u g h o u t the body and which m i g h t be acted on by oxygen in the circulating blood. According to a 1964 report, observations in 9 patients with clinical tetanus revealed active regression of s y m p t o m s following h y p e r b a r i c oxygen therapy. 152 T h e progression of the disease was a r r e s t e d and reversed. Seizures were reduced. T h e m e n t a l clarity and cooperation of these patients resulted in better control of r e s p i r a t o r y problems a n d nutritional r e q u i r e m e n t s . T h e need for t e t a n u s antitoxin and t r a c b e o s t o m y was obviated. In contrast, in a 1968 report on 8 cases of severe tetanus, h y p e r b a r i c oxygen did not have a significant effect on the course of the disease.Vt~ T h e addition of 2% CO._, a p p e a r e d to have some effect, if only t e m p o r a r y , on the disease, b u t r e q u i r e d f r e q u e n t estimates of arterial Pco2 a n d some m e a s u r e of control of the p a t i e n t ' s respiration to keep the h a z a r d s of its use within justifiable limits. T h e m o r t a l i t y was 6 of 8 p a t i e n t s (75 %). I n 1968, in a series of e x p e r i m e n t s with guinea pigs, oxygen did not affect the course of clinically developed tetanus.SS 28) HYPOTHERMIA.. ,Just as little e n t h u s i a s m is expressed for h y p e r b a r i c oxygen t h e r a p y , little s u p p o r t is given to h y p o t h e r m i a as a t y p e of therapy. T e t a n u s p e r se does not cause fever, but the complications of t e t a n u s cause fever. Hence, the complications should be treated, not the fever itself. Labo r a t o r y confirmation of this clinical opinion, which was expressed at the I n t e r n a t i o n a l Conferences on T e t a n u s , is found in a 1966 report.lla T h e effect of whole-body h y p o t h e r m i a (30 ° C-32 ° C) was studied in a control group a n d a h y p o t h e r m i c group of a n i m a l s challenged by t e t a n u s toxin. H y p o t h e r m i a did not prolong survival time. 29) PRALIDOXIME 5IETHANESULFONATE...Leonardi 123 ]]as r e c o m m e n d e d oxime t r e a t m e n t in tetanus. H e has shown that, in vitro, t e t a n u s toxin partially inhibits the activity of pure crystalline cholinesterase from nerve tissue. A l t h o u g h this effect is m u c h disputed, he t h o u g h t it w o r t h w h i l e to try cholinesierase-reactivating agents in the t h e r a p y of tetanus. P r e l i m i n a r y work on the guinea pig showed thai pralidoxime m e t h a n e s u l f o n a l e 24 5,1
a n d 48 rag. p e r kg. daily prolonged the i n c u b a t i o n period of t e t a n u s but did not p r e v e n t death. W h e n , in addition, a single dose of 10 units of anti t e t a n u s s e r u m (a dose t h a t h a d no effect when given alone) was a d m i n i s t e r e d , a statistically significant reduction in m o r t a l i t y was obtab~ed. T h e results were confirmed l a t e r in the donkey. Such results p r o m p t e d L e o n a r d i to try the t r e a t m e n t in a p a t i e n t with tetanus, and, according to him, a favorable result was obtained.
L. CASE REPORTS E i g h t cases are described. T h e first case is reviewed in detail to e m p h a size a g a i n the t e a m aspect of tetanus. T h e last 7 cases are s u m m a r i z e d briefly to p r e s e n t specific considerations of clinical tetanus. CASE 1. A.
Severe h a n d injury, 23-year-old farmer.
FIRST HOSPITALIZATION
1. Chief complaint: "I can't open m y m o u t h . " 2. Present illness: On 5 M a r c h 1971, this 23-year-old male caugh~ his right t h u m b in a feed grinder. A t the local hospital e m e r g e n c y room, to which he was t a k e n i m m e d i a t e l y , the w o u n d was debrided and closed prim a r i l y and he was given a dose of t e t a n u s toxoid and a p r e s c r i p t i o n for oral penicillin. About 7 M a r c h , the p a t i e n t began to take C o m p o c i l l i n - V K 250 ms. every 8 hours; on 8 March, he d i s c o n t i n u e d the oral a d m i n i a t r a t i o n of Compocillin-VK a n d was i n s t r u c t e d to take V i b r a m y c i n 100 rag. daily by a n o t h e r physician, who also c h a n g e d the dressing. On 11 M a r c h , the p a t i e n t was seen a g a i n by the second physician, who referred h i m for hospital admission. On this day, the p a t i e n t noted d r a i n a g e from the t h u m b dressing (Fig. 19) a n d spasm of his face when a t t e m p t i n g unsuccessfully to d r i n k cold water. 3. Past history: T h e p a t i e n t stated t h a t possibly he h a d h a d a reaction to penicillin a t some time. H e denied severe illnesses, injuries or operations. Fro. 1 9 . - - I n j u r e d right t h u m b of patient in Case 1. Note generalized cellulitis, where skin has been removed, and absence of thumbnail.
55
4. Physical examination: At 8:00 P.M., 11 M a r c h , the p a t i e n t was a welldeveloped a n d well-nourished, a l e r t y o u n g m a n who t a l k e d w i t h clenched teeth. Vital signs w e r e w i t h i n n o r m a l limits. H e could s e p a r a t e his incisor t e e t h by only 1 cm. a n d exhibited m a r k e d s p a s m of the m a s s e t e r muscles. T h e right t h u m b was swollen, e d e m a t o u s a n d h a d p u r u l e n t d r a i n a g e from m u l t i p l e l a c e r a t i o n s t h a t h a d b e e n s u t u r e d b u t from w h i c h the s u t u r e s had b e e n removed. T h e r e was a 2-cm.-diameter, freely movable node in t h e a p e x of the right axilla. T h e r e was no s p a s m or t r e m o r of the extremities, and d e e p t e n d o n reflexes w e r e 2 plus a n d s y m m e t r i c . 5. A n t i t o x i n prophylaxis and therapy: O n 11 M a r c h , at the t i m e of hospit¢d admission, 3,000 u n i t s of T I G ( H ) was a d m i n i s t e r e d in the right deltoid muscle. On 12 M a r c h , a n o t h e r 3,000 u n i t s was i n j e c t e d into the gluteus m a x i m u s muscle. 6. Initial laboratory data: / n i t i a l l a b o r a t o r y studies w e r e as follows: h e m o g l o b i n 12.0 G m . / 1 0 0 ml., h e m a t o c r i t 36.2 v/o, total l e u k o c y t e c o u n t 8,300 with 8 5 ~ n e u t r o p h i l s , 12% ] y m p h o c y t e s a n d 3 ~ monocytes. U r i n a l y sis a n d n u m e r o u s o t h e r l a b o r a t o r y studies done at a d m i s s i o n w e r e noncontributory. 7. Hospital course: By 8:00 A.M., 12 M a r c h , the d a y a f t e r hospital admission a n d 7 d a y s a f t e r i n j u r y , the p a t i e n t h a d developed opisthotonos a n d risus sardonicus, a n d was t r a n s f e r r e d to the I C U (Fig. 20). T h e slightest stimuli p r o d u c e d generalized tonic convulsions. After tetanic seizures, his Fxc,. 20 (le/t).--Patient in C a s e I a n d his n u r s e n e a r t h e e n d of his s t a y in the I C U . At lhe r i g h t is t h e r e s p i r a t i o n u n i t . T h e p a t i e n t is b e i n g g i v e n u l r a s o n i c m i s t o x y g e n o v e r his doublecuffed P o r t e x t r a c h e o s t o m y tube. I n t r a v e n o u s f e e d i n g is b y t h e r i g h t s u b c l a v i a n c e n t r a l vellou~ p r e s s u r e c a t h e t e r . "I~abe f e e d i n g s are b e i n g a d m i n i s t e r e d by a n a s o g a s t r i c tube. T h e F o l e y c a t h e t e r is c o n n e c t e d to a s t r a i g h t d r a i n a g e bag. E l b o w s h e e p s k i n p a d s a r e p r e v e n t i n g p r e s s u r e necrosis, a n d t h e f o o t b o a r d p r e v e n t s foot d r o p . Chest E C G leads g i v e c o n t i n u o u s c a r d i a c t r a c i n g s on t h e o s c i l l o s c o p e a b o v e t h e bed, a n d also a r e c e n t r a l l y m o n i t o r e d in t h e n u r s i n g s t a t i o n . T h e wall s u c t i o n a n d o x y g e n o u t l e t s a r e seen a b o v e t h e b e d s i d e s t a n d . Fro. 21 (right).~Patient in C a s e I a f t e r r e m o v a l of t r a c h e o s t o m y tube. At t h e t i m e of t u b e r e m o v a l , t h e p a t i e n t c o u l d s e p a r a t e his t e e t h at least 1 c m . , a d i s t a n c e sufficient to p r o v i d e e j e c t i o n of v o m i t u s a n d to p r e v e n t a s p i r a t i o n .
56
t e m p e r a t u r e rose on the evening of 13 M a r c h , r e a c h i n g a p e a k of 105.4 ° (R). On 24 M a r c h , he began to show objective i m p r o v e m e n t in t h a t he would raise a n d lower both u p p e r eyelids on c o m m a n d . On 10 April, he was able to sit up in a chair. By 14 April, he was able to s e p a r a t e the incisor teeth 1 cm. (Fig. 21). B y 15 April, he was showing definite i n t e r e s t in his surroundings but did not r e m e m b e r his wife's name. On 18 April, after 38 days in the ICU, he was t r a n s f e r r e d to an acute medical bed. By 1 May, he was able to completely care for himself, he was having no problems in e a t i n g and he was discharged. 8. Analgesics: At the beginning of hospitalization, i n t r a v e n o u s D i l a u d i d , 0.5-1 rag., was a d m i n i s t e r e d p.r.n, for generalized distress a n d pain. 9. Sedation and muscle relaxation: At the time of admission, d i a z e p a m (Valium) was a d m i n i s t e r e d intravenously. T h r o u g h o u t the p a t i e n t ' s hospital stay, d i a z e p a m was used as the basic sedative, with dosage being a d j u s t e d as necessary from a m i n i m u m of 40 mg. per 24 h o u r s to a maxim u m of 144 rng. per 24 hours, with 3 mg. being given i n t r a v e n o u s l y every half hour and oftener if necessary. By 13 M a r c h , it was evident t h a t convulsions were not being controlled with d i a z e p a m intravenously. T h e r e f o r e , at 11:00 P.M., 13 M a r c h , 0.1% thiopentaI ( P e n t o t h a l ) in dextrose solution was t i t r a t e d intravenously. B y the m o r n i n g o$ 14 M a r c h , convulsions were occurring only w h e n tracheal a s p i r a t i o n was performed, but, by the a f t e r n o o n of 14 M a r c h , the concentration of thiopental had been increased to 0.2/o a~ in an e n d e a v o r to control the p a t i e n t ' s opisthotonos. By !8 March, seizures were s o m e w h a t controlled, but periods of a p n e a were occurring. F o r better control, . therefore, a B e n n e t t R e s p i r a t i o n U n i t Model M A - I was a t t a c h e d to the t r a c h e o s t o m y tube; the t h i o p e n t a l was discontinued and d - t u b o c u r a r i n e was given. Initially, 21 mg. of d-tubocurarine was injected; then m a i n t e n a n c e doses of 3-6 rag. were a d m i n i s t e r e d every 30 m i n u t e s or oftener, if necessary for control of seizures. On 30 M a r c h . the d - t u b o c u r a r i n e , which had been a l t e r n a t e d every 15 m i n u t e s at a dosage of 3 rag. with d i a z e p a m 3 rag., was discontinued; t h e last dose was given as the d i a z e p a m was g r a d u a l l y decreased both in respect to frequency and a m o u n t of dosage, with the last injection of d i a z e p a m being given on 8 April. F o r a d e q u a t e u t i l i z a t i o n of the respiration unit and for evaluation of the r e s p i r a t o r y tract, arterial .blood gas d e t e r m i n a t i o n s were m a d e daily. 10. Surgical care o / w o u n d : On 5 M a r c h , the d a y of i n j u r y , the wound was debrided and closed primarily. On 11 March, the sutures were removed. F r o m then on, w h e n e v e r necrotic tissue was evident in the thumb, such tissue was removed. On 16 M a r c h , .the distal p h a l a n x of the t h u m b was removed by guillotine aml)utation. Initially, saline compresses were at)plied to the t h u m b and a d j a c e n t a r e a s of the hand. As the p a t i e n t iml)roved, the snline dressings were rep/ace(l g r a d u a l l y with 1)elro/atum or lanolin dressings until they were no longer necessary. l I. Antibiotics: A( the time of admission on 11 h'Iar('h, antibiotic thernl)y ('onsisting of n,queous penicillin 2,000,000, unils intraw,nously ew:ry 6 hours and strel~lomy('in 0.5 Gm.'intrarnus('ularly ev(-ry 12 hours w~s initiated, By 16 Mar('ll, E. eoli nnd E n t e r o b a c t e r sensitive to ;ttnpieillin were ob. 57
rained from the s p u t u m specimens. Therefore, the penicillin and s t r e p t o m y cin were discontinued and ampicillin 500 rag. intravenously every 4 hours was ordered and continued t h r o u g h 23 March. On 20 M a r c h , a g r a m - n e g a t i v e organ.~sm was persistently p r e s e n t on the tracheal cultures. In an effort to control such organisms, g e n t a m i c i n was initiated, with 40 mg. being injected i n t r a m u s c u l a r l y every 8 hours until 29 March, when it was discontinued. Although a n u m b e r of specimens were t a k e n from the w o u n d of the thumb, Cl. tetani was not d e m o n s t r a t e d ; however, Cl. per[ringens was isolated from the wound. In addition to the antibiotics a l r e a d y m e n t i o n e d , n i t r o f u r a n t o i n 100 rag. t h r e e times a day was given orally d u r i n g the l a t t e r p a r t of the p a t i e n t ' s hospital stay for a 100,000 colony count of Staphylococcus albus c u l t u r e d from the urine. N y s t a t i n oral suspension, 1 ml., was a d m i n i s t e r e d three times a day for superinfection of Candida albicans. 12. Tracheostomy: On 12 March, e m e r g e n c y t r a c h e o s t o m y was performed in the ICU. W i t h 2% lidocaine infiltration anesthesia a n d t h r o u g h a n incision in the t h i r d tracheal ring, a # 3 6 F r e n c h Portex, double-cuff t r a c h e o s t o m y tube was inserted. An ultrasonic nebulizer was used for supp l e m e n t a l oxygen and hmnidification. On 14 April, the t r a c h e o s t o m y tube was closed with a plug, and on 16 April, the tube was removed. 13. Private, dark room: On the night of admission, the p a t i e n t was placed in a private, dark room. Such s u r r o u n d i n g s were provided p.r.n, for the p a t i e n t ' s comfort. 14. Roentgenograms: Chest r o e n t g e n o g r a m s were ordered as necessary for evaluation of potential cardiac and r e s p i r a t o r y problems. Vertebral films on 19 April indicated compression fractures of the end plates of the second, third, fourth a n d fifth thoracic vertebrae. 15. Nutrition: Initially, the p a t i e n t was fed by p e r i p h e r a l i n t r a v e n o u s solutions. T h e n , on 18 M a r c h , a central venous pressure c a t h e t e r was placed in the left subclavian vein; when this would no longer accept fluid on 25 M a r c h , a n o t h e r was inserted into the right subclavian vein a n d left in place until 12 April. At first, 5°o glucose solutions with balanced electrolyte concentrations a n d vitamins were given; later, these were replaced by similar p r e p a r a t i o n s with 900 calories per liter. I n addition, s e r u m a l b u m i n was ~ v e n w h e n necessary. D e s p i t e meticulous a t t e n t i o n to nutrition, the patient's weight fell from a n admission weight of 155 lb. to 127 lb. 16. Control of gastrointestinal hemorrhage: On 23 M a r c h , 12 days after admission, n u m e r o u s b r i g h t red blood clots were observed in the feces, and the hemoglobin a n d h e m a t o c r i t decreased to 9.0 Gm./100 ml. and 17.6 v/o, respectively. At first, the possibility of stress ulcer in the u p p e r gastrointestinal tract or a p s e u d o m e m b r a n o u s enterocolitis was considered, but the final decision was t h a t i r r i t a t i o n of the rectum by the c o n s t a n t l y p r e s e n t rectal t h e r m o m e t e r probe was responsible for the bleeding. W h e n a Levin tube was inserted into the s t o m a c h on 23 March, no blood was obtained. This tube was left in place initially for feeding with an ulcer milk regimen and then later, on 29 March, changed to Gerber's F o r m u l a #l. D u r i n g the rectal bleeding, which lasted .for several days, the hemoglobin 58
a n d h e m a t o c r i t were m a i n t a i n e d at n o r m a l levels with a total r e p l a c e m e n t of 3,000 ml. of whole blood. D u r i n g t h e l a t t e r p a r t of the hospitalization, a slight residual a n e m i a was corrected w i t h Feosol 1 teaspoonful t.i.d, at first a n d t h e n ferrous sulfate 325 rag. t.i.d. 17. Urinary tract catheter: At 5:00 P.~., 13 M a r c h , the p a t i e n t was unable to void, a n d a F o l e y c a t h e t e r w a s i n s e r t e d into the u r i n a r y bladder. On 14 April, the c a t h e t e r was removed, and, on t h e following day, the p a t i e n t was b e g i n n i n g to have control of micturition. 18. Care o[ skin: D u e to the efforts of the n u r s e s to keep this p a t i e n t ' s skin dry, to avoid p r e s s u r e a r e a s a n d to c h a n g e his position f r e q u e n t l y , he did not develop d e c u b i t a l ulcers. S u c h a result a t t e s t s to the efficiency of a n I C U in the care of the p a t i e n t w i t h tetanus. 19. Prevention of muscle contractures: F r o m the time of admission, p r o p e r s u p p o r t s w i t h p a d d i n g w e r e placed u n d e r the soles of the feet to p r e v e n t foot drop. I n addition, w h e n t h e p a t i e n t ' s muscles were relaxed, passive exercises and, later, active exercises- .were c a r r i e d out to p r e v e n t deformities. 20. Tetanus toxoid prophylaxis: T h e p a t i e n t h a d not been given his " b a b y shots" because "his m o t h e r did not believe in injections." In 1960, the p a t i e n t possibly m a y have b e e n given t e t a n u s toxoid. In 1965, he was given a dose of t e t a n u s toxoid ( p r o b a b l y fluid) for a laceration of his left little finger. At the t i m e Of i n j u r y on 5 M a r c h 1971, he was given a dose of fluid t e t a n u s toxoid. O n 26 April, 0.5 ml. a l u m i n u m phosp h a t e - a d s o r b e d t e t a n u s toxoid was injected in the left deltoid muscle. 21. Orthopedic consultation: On 27 April, the o r t h o p e d i c c o n s u l t a n t s t a t e d t h a t no t r e a t m e n t was n e c e s s a r y for t h e v e r t e b r a l c o m p r e s s i o n fractures. 22. Speech therapy consultation: O n 30 April, formal testing of l a n g u a g e i n d i c a t e d a severe a u d i t o r y p e r c e p t i v e disturbance. T h e p a t i e n t h a d difficulty with all tasks r e q u i r i n g a u d i t o r y stimuli. I n reading, be was able to read words in isolation but h a d difficulty as m o r e words w e r e ' i n c l u d e d . H i s c o m p r e h e n s i o n for r e a d i n g was poor. W r i t i n g tasks i n d i c a t e d ability to rep r o d u c e m a t e r i a l b u t not to i n i t i a t e it. 23. Final diagnoses: (a) feed g r i n d e r i n j u r y of right t h u m b , (b) severe tetanus, (c) p n e u m o n i t i s , (d) u r i n a r y t r a c t infection, (e) rectal bleeding w i t h a n e m i a , (f) c o m p r e s s i o n f r a c t u r e s of thoracic v e r t e b r a e , (g) h y p o x i c encephalopathy. B. SECOND HOSPITALIZATION
1. Chief complaint: "I f a i n t e d . " 2. Present illness: At r e a d m i s s i o n on 29 October 1971, the p a t i e n t ' s wife s t a t e d t h a t for several weeks he h a d b e e n biting his t o n g u e d u r i n g his sleep. Moreover, d u r i n g the 3 d a y s p r i o r to admission, h e h a d been p l a y i n g cards at night, a n d h a d h a d only a few h o u r s of sleep each night. J u s t before being b r o u g h t to the h o s p i t a l on 29 October, he "felt tight all over" a n d fainted. 3. Physical examination: T h e r i g h t t h u m b was well h e a l e d a t the interp h a l a n g e a l joint. T h e r e a p p e a r e d to be some difficulty in c o n c e n t r a t i o n a n d in e x p r e s s i n g himself. T h e r e was a slight decrease in s t r e n g t h of t h e right extremities; t h e r e w a s a d e c r e a s e d ability to p e r f o r m repetitive a l t e r n a t i n g m o v e m e n t s of the right e x t r e m i t i e s rapidly; t h e r e was slow p r o n a t i o n of the right u p p e r e x t r e m i t y ; t h e r e was a decrease in position sense of the right extremities; a n d t h e r e was decreased v i b r a t o r y sense of the right side. 59
4. Laboratory data: E l e c t r o e n c e p h a l o g r a m indicated a resolving encephalitic involvement and a possible secondary epileptogenJcity. T h e p a t i e n t was t r e a t e d with p h e n o b a r b i t a l 15 rag. and M e s a n t o i n 100 rag. p.o.t.i.d. W i t h such a regimen, he had a n uneventful course a n d was discharged on 5 November. C. FOLLOW-UP EXAMINATION On 6 J a n u a r y 1972, w h e n the p a t i e n t was last seen, he a p p e a r e d to be in good condition w i t h o u t gross a b n o r m a l i t i e s on general physical a n d neurologic examinations. This case has been r e p o r t e d to e m p h a s i z e the n u m e r o u s problems t h a t m a y develop d u r i n g a case of t e t a n u s a n d to give details of the a t t e m p t s to solve such problems by cooperation of all types of preclinical and clinical specialists. T h e m e n t a l difficulties both acute and chronic were of p a r t i c u l a r interest. T h e most probable e x p l a n a t i o n for them is a posthypoxic encephalopathy. Certainly, the unavoidable p u l m o n a r y complications and the convulsions, which occurred despite continuous t i t r a t i o n with anticonvulsants, could have been responsible for i n a d e q u a t e delivery of oxygen to the brain a n d a resulting e n c e p h a l o p a t h y . A consulting p s y c h i a t r i s t a n d neurologist who reviewed the case could not find a n y evidence on a psychiatric basis for the m e n t a l and neurologic abnormalities. CASE 2 . . . S p l i n t e r u n d e r toenail. One d a y prior to hospitalization, a 4year-old girl complained of a "stomach ache" and then developed stiffness from her neck to h e r toes. She exhibited typical convulsions of tetanus, risus sardonicus a n d trismus. S h e had not h a d prior t e t a n u s toxoid immunization. T h e only d e m o n s t r a b l e wounds were several abrasions on the arms a n d legs and one associated with a large splinter b e n e a t h the left great toenail. T h e toenail a n d the splinter were removed. A c u l t u r e of the splinter a r e a was negative for C1. tetani. W i t h intensive care in the hospital, the p a t i e n t recovered from t e t a n u s (Fig. 22). T h e tetanus in this little girl, who lived less t h a n a mile from the hospital in which she was treated, could have been p r e v e n t e d by p r o p e r prophylaxis with t e t a n u s tox6id. N o t e t h a t the p r e s u m e d cause was a m i n o r wound a s p l i n t e r u n d e r a toenail. CASE 3. P u n c t u r e w o u n d of h y p o d e r m i c injection in a d r u g addict. A 40year-old male who had been addicted to heroin for a n u m b e r of years was a d m i t t e d to the hospital because of inability to eat for 3 days a n d for an abscess of the s u p e r o l a t e r a l aspect of the right u p p e r arm. T h e abscess was at the site of a h y p o d e r m i c injection. W i t h i n several days, he developed signs typical of tetanus. W i t h s u p p o r t i v e m e a s u r e s and d r a i n a g e of the abscess, he slowly but steadily responded. M u c h improved, he left the hospital a g a i n s t advice 21 days after the onset of his symptoms. This ease is proof t h a t t e t a n u s m a y develop---as Cherubin34 has e m p h a s i z e d in the d r u g addict who has not h a d toxoid i m m u n i z a t i o n . In view of the e x p a n d i n g problem of d r u g addiction in the United States, t e t a n u s a n d d r u g addiction m u s t be considered in the p a t i e n t with u n e x p l a i n e d irritability or convulsions. CASE 4. P u n c t u r e wound of the foot in a diabetic. On 8 M a y 1969, a 45year-old diabetic male was a d m i t t e d to the o u t p a t i e n t clinic of a hospital in G u a m comphfining of a nail p u n c t u r e wound, i n c u r r e d 3 hours earlier, on his left foot. T h e w o u n d was cleaned and he was given t e t a n u s toxoid and 60
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30
FIG. 2 2 . ~ C h a r t of patient in Case 2. This child was also given the benefit of Seconal, phenobarbital, diazepam and methocarbamol. (Courtesy of R. Haynes.)
penicillin a n d discharged. H e h a d no h i s t o r y of previous t e t a n u s toxoid i m m u n i z a t i o n . On 13 M a y , he was a d m i t t e d to the hospital because of a tickling sensation of the wound, neck stiffness a n d coughing. His neck was stiff but not rigid, b r e a t h i n g was shallow a n d reflexes were normal. T h e left heel was swollen, but no i n d u r a t i o n or c r e p i t u s was noted. H e was given t e t a n u s a n t i t o x i n in divided doses of 170,000 units daily, i n t r a v e n o u s a n d oral penicillin, chlorpromazine, a muscle r e l a x a n t a n d tetracycline. On 14 M a y , 24 hours after admission, the neck stiffness was worse and difficulty in b r e a t h i n g was noted. On 15 M a y , a b d o m i n a l rigidity developed. T h e p a t i e n t was given 500 units of T I G (H). A t noon t h a t day, tiis vital signs were n o r m a l , but 1 hour later he convulsed a n d died. In this case, C1. tetani was d e m o n s t r a t e d in a n a u t o p s y c u l t u r e of w o u n d tissue; the bacillus was recovered in only 32% of a series of 160 cases r e p o r t e d in 1969.120 This case stresses the need to a s c e r t a i n carefully t e t a n u s i m m u n i z a t i o n history at the time of i n j u r y and to give p r o p h y l a c t i c t r e a t m e n t as indicated by the imm u n i z a t i o n status { T I G ( H ) and toxoid for persons whose i m m u n i z a t i o ~ s t a t u s is not a d e q u a t e according to present recommendations).4G CASE 5 . M i n o r wound, according to patient. A 46-year-old w o m a n fell off the steps of h e r home into:a ~ose bush. S h e was seen i m m e d i a t e l y at the hospital, w h e r e it was beliekced that she had s p r a i n e d a n d contused her back. Six days after the i n j u r y .that is, on the d a y of admission to the h o s p i t a l - the p a t i e n t had shooting pains in h e r left lower extremity, back and neck, a n d exhibited i n t e r m i t t e n t contractions of h e r left leg. S h e h a d a d r a i n i n g w o u n d on her left buttock, w h e r e a rose bush t h o r n h a d p e n e t r a t e d . D e s p i t e intensive t h e r a p y , the p a t i e n t died 8 days later. T h i s case is recorded to e m p h a s i z e the possibility of t e t a n u s developing a f t e r a p e n e t r a t i n g wound t h a t was not considered to be significant by the p a t i e n t at the time of injury. T h i s p a t i e n t h a d not h a d t e t a n u s toxoid i m n m n i z a t i o n a n d she did not have t e t a n u s a n t i t o x i n at the time of injury. CASE 6. P u n c t u r e w o u n d of the foot in a W o r l d W a r II veteran. A 4761
year-old m a l e was a d m i t t e d to the hospital on 22 A u g u s t 1969 with a history of increasing trismus for 48 hours, rigidity, d y s p h a g i a , d y s p n e a and painful spasms, p a r t i c u l a r l y involving the right leg, for 24 hours. H e h a d served in the R o y a l A u s t r a l i a n Air F o r c e in W o r l d W a r II~ a n d had received full i m m u n i z a t i o n a g a i n s t tetanus. H e h a d not received a n y booster injections until 13 A u g u s t 1969. On that day, he sustained a p e n e t r a t i n g i n j u r y of the right foot w h e n he stood on a stake in his garden. H e w e n t to his local doctor w i t h i n 1 h o u r of the i n j u r y a n d was given a booster dose of t e t a n u s toxoid a n d 2,000,000 units of procaine penicillin; the penicillin t h e r a p y was continued twice daily until he was referred to the hospital, w h e r e it was c o n t i n u e d as penicillin G in a dosage of 1,000,000 units every 4 hours. On his admission to the hospital, he was treated intensively for tetanus, but died on the 6th d a y after admission. P r e s u m a b l y this case represents a failure with t e t a n u s toxoid given d u r i n g W o r l d W a r II and in 1969 and a failu re of p r o p h y l a x i s with penicillin. 14.t CASE 7.- Bowel obstruction a n d resection. A 61-year-old male with gangrene of the small intestine s e c o n d a r y to obstruction by postoperative adhesions developed t e t a n u s in the i m m e d i a t e postoperative period. T e t a n u s organisms were recovered from a culture specimen of the malodorous peritoneal fluid found at operation to s u r r o u n d the grossly u n p e r f o r a t e d intestine. A t r a c h e o s t o m y was performed, a n d the p a t i e n t recovered on a regim e n of nasogastric feedings, sedation, d a r k e n e d environment, antibiotics a n d t e t a n u s antitoxin. This case is reported to indicate that t e t a n u s m a y develop after the resection of g a n g r e n o u s bowel a n d to emphasize the advisability of active i m m u n i z a t i o n of all persons against tetanus.39 CASE 8 . ~ F a c e lacerations. On 9 N o v e m b e r 1967, a 71-year-old male suffered a l a c e r a t i o n of his nose a n d a n o t h e r of his left cheek. H e h a d not h a d prior t e t a n u s toxoid i m m u n i z a t i o n . H e was t r e a t e d in an e m e r g e n c y room by having the face wounds debrided and closed p r i m a r i l y a n d by receiving a dose of t e t a n u s toxoid. On 17 November, he h a d initial s y m p t o m s of tetanus, a n d on 19 N o v e m b e r he was a d m i t t e d to the hospital. D e s p i t e intensive care, he died of t e t a n u s on 23 November. This last case r e p o r t emphasizes t h a t a n initial dose of t e t a n u s toxoid at the time of i n j u r y will not p r e v e n t tetanus, t h a t all i n d i v i d u a l s ~ i n c l u d i n g all our senior citizens should h a v e a d e q u a t e basic t e t a n u s toxoid i m m u n i z a t i o n and t h a t a c c u r a t e e m e r g e n c y medical identification devices should be available for the victims of t r a u m a .
M. MEDICOLEGAL ASPECTS T h e legal aspects of medical practice in the m o r e and m o r e consideration. To e m p h a s i z e s t a t e m e n t was mailed, in the form of a news general a n d specialty medical publications and v e m b e r 1970:
U n i t e d States are receiving the problem, the following release, to science writers, the wire services on 12 No-
" T h e R e g e n t s of the A m e r i c a n College of Surgeons feel obligated to inform the public t h a t the rising n u m b e r of lawsuits against physicians is seriously t h r e a t e n i n g the quality of surgical care and increasing its cost to patients.'U66 62
I..PROBLEMS OF IMMUNIZATION Specific a t t e n t i o n was given to d r u g c o m p a n y liability in i m m u n i z a t i o n p r o g r a m s in a p a p e r by Curran,52 in which he r e p o r t e d the following: " A n e x t r e m e l y i m p o r t a n t decision, T i n n e r h o l m v. P a r k e , Davis & Co.. has recently been passed down by the prestigious Second Circuit ( F e d e r a l ) Court of A p p e a l s in N e w York affirming a decision of the District Court against the d r u g firm concerning Quadrigen, a vaccine combining diphtheria, tetanus, pertussis a n d i n a c t i v a t e d poliovirus antigens. T h e trialcourt decision, with a d a m a g e s a w a r d of $651,783, had caused a g r e a t deal of concern in d r u g - c o m p a n y a n d p u b l i c - h e a l t h circles, w h e r e it was t h o u g h t t h a t the proof offered of a causal relation between the t a k i n g of Q u a d r i g e n and severe i n j u r y a n d disability in a t w o - m o n t h - o l d i n f a n t was not warr a n t e d scientifically." In discussing such an award, C u r r a n stated: " M a n y public-health officials a n d scientists i n t e r e s t e d in i m m u n i z a t i o n p r o g r a m s a r e concerned about decisions such as T i n n e r h o l m a n d the earlier case of Davis v. W y e t h Laboratories, which involved a n alleged paralysis due to the S a b i n T y p e 3 polio vaccine. Both cases involved very serious injuries and c o n s e q u e n t l y large verdicts. Both were u p h e l d by F e d e r a l Circuit Courts. T h e trend of the law is thus becoming firmly established. It is difficult for the d r u g companies to defend in these cases, since they are t r y i n g to prove a negative t h a t is, t h a t the d r u g did n o t cause the devastating i n j u r y a n d disability t h a t was clearly s u s t a i n e d by the plaintiff from s o m e cause. T h e fear of public-health people is t h a t these claims will drive the drug companies a w a y from this field, or will so a l a r m the public as to cripple i m m u n i z a t i o n p r o g r a m s altogether. " T h e d i l e m m a for the law is also clear. T h e courts m u s t e n t e r t a i n the just claims of i n j u r e d people. T h e loss m u s t fall somewhere. T h e problem of legal proof versus scientific proof has not been solved. P e r h a p s this problem the problem of a c c o m m o d a t i n g the needs of the law a n d the m e t h o d s of proof in medical science - should receive m u c h m o r e a t t e n t i o n . " 2. SPECIFIC MEDICOLEGAL PROBLEMS FOR TETANUS PROPHYLAXIS AND THERAPY
In the case cited by C u r r a n , t e t a n u s toxoid was not the p r i m e consideration. In the following cases, however, some p a r t i c u l a r aspect or aspects of t e t a n u s p r o p h y l a x i s and t h e r a p y were of importance.TS a) DENTAL EXTRACTION. According to hospital records s u b m i t t e d to one of us for medicolegal evaluation, a d e n t i s t e x t r a c t e d 9 u p p e r t e e t h from a 40-year-old woman. S e v e n days later, the p a t i e n t developed tetanus, and 9 days after the e x t r a c t i o n she died. T h e d e n t i s t was sued for m a l p r a c t i c e . b) HETEROLOGOUS TETANUS ANTITOXIN., ~In a lawsuit for which one of us was consulted, the responsible physician was being sued because his p a t i e n t (an a d u l t w o m a n ) after a negative skin test p r e s u m a b l y developed a reactior{ to a dose of heterologous horse antitoxin. C) WRINGER INJURY OF HAND., I n a n o t h e r l a w s u i t for which one of us was consulted in 1952, a 2-year-old male suffered a w r i n g e r i n j u r y of his 63
h a n d a n d developed tetanus. :In 1968, the a t t e n d i n g surgeon was sued for a six-figure sum.
3. ATTORNEYS AND PHYSICIANS T h r e e missions of the cooperation of a t t o r n e y s and p h y s i c i a n s are to give the best possible care to the patient, to protect the p a t i e n t medicolegally a n d to protect the physician medicolegally. In a n e n d e a v o r to protect the rights a n d privileges of their clients, however, a t t o r n e y s have been instrum e n t a l in o b t a i n i n g a g a i n s t physicians a w a r d s t h a t are not just financially e m b a r r a s s i n g but are even financially crippling to the physicians. Physicians cannot fail to note such awards. Consequently, knowingly or u n k n o w ingly, in an e n d e a v o r to protect themselves legally, they m a y p u r s u e a plan of p r o p h y l a x i s or t h e r a p y t h a t m a y not be the best in a scientific sense but which is a safer course legally. M o r e specifically, it is m u c h easier for a physician to give an extra, u n n e c e s s a r y dose of toxoid and a s s u m e the risk of a not too significant reaction to the toxoid t h a n to keep exact records, take careful histories and give toxoid only w h e n indicated. In a similar fashion, it is m u c h s i m p l e r to a d m i n i s t e r T I G ( H ) , which is practically free of reactions, t h a n it is to keep a c c u r a t e toxoid records, to require*patients to c a r r y e m e r g e n c y medical identification devices and to obtain an a d e q u a t e history at the time of an injury. In the U n i t e d States, a financial n e w s p a p e r has pointed out t h a t c e r t a i n medicolegal considerations are becoming a t h r e a t to medical care with the following headlines on its first page20S: SUING THE DOCTOR Chances for success in m a l p r a c t i c e suits are rising, experts say. Courts, la~5,ers m a k e it easier to circumvent lack of physicians' testimony. A t h r e a t to medical care? If p h y s i c i a n s continue to be involved in such suits as those s u m m a r i z e d above, t h e i r a t t i t u d e to p a t i e n t s and to t r e a t m e n t inevitably m u s t be altered. P h y s i c i a n s will be t h i n k i n g of which t e t a n u s p r o p h y l a x i s a n d t h e r a p y will have the least medicolegal liability r a t h e r t h a n which scientific course is best for the patient.
N. COST Effective t e t a n u s p r o p h y l a x i s is one of the least expensive types of prophylaxis. As has been discussed in the prophylaxis secti¢,fl (J), a few injections of t e t a n u s toxoid will p r e v e n t tetanus. According to the a m o u n t of toxoid p u r c h a s e d and to the vial or ready-forinjection s y r i n g e in which t e t a n u s toxoid is sold, the p h a r m a c y cost for the p a t i e n t of l dose of t e t a n u s toxoid is s o m e w h a t less or s o m e w h a t m o r e t h a n a dollar. T h e hospital cost of one case of t e t a n u s in the U n i t e d S t a t e s in 1971 was $9,773.80. T h e t r e a t m e n t of a d a n g e r o u s l y ill patient, such as one with tetanus, in West G e r m a n y in 1967 was e s t i m a t e d to be up to 20,000 D M ($5,000 in U.S. c u r r e n c y ) . 1:',-~ In view of the cost of t e t a n u s toxoid and of the cost of the t r e a t m e n t of 64
a case of t e t a n u s , n e e d a n y m o r e be said a b o u t t e t a n u s toxoid p r o p h y l a x i s being a n economic t r i u m p h ?
O. POLITICAL CONSIDERATIONS In 1971, the following note was received from a p h y s i c i a n in a c o u n t r y m a n y c e n t u r i e s old: " I n o u r c o u n t r y we h a v e no good d o c u m e n t a t i o n s of previous t e t a n u s toxoid injections in individuals. F o r this r e a s o n we a r e i n j e c t i n g 3000 u. T A T a n d t e t a n u s toxoid. S o m e t i m e s we do n o t h a v e t e t a n u s toxoid, a n d t h e n we a r e giving only T A T . W e h a v e no T I G ( h u m a n ) in o u r c o u n t r y . " Millions a n d millions of U.S. dollars a r e b e i n g s p e n t to develop a p e r p e t u a l peace. S h o u l d a m i n u t e f r a c t i o n of such e x p e n d i t u r e s be d i v e r t e d for t h e p u r c h a s e a n d d i s t r i b u t i o n of t e t a n u s toxoid, T I G ( H ) , a n d e m e r g e n c y m e d i c a l identification devices to o t h e r c o u n t r i e s of the w o r l d to prove t h a t t h e U n i t e d S t a t e s is r e a l l y i n t e r e s t e d in citizens of o t h e r c o u n t r i e s a n d in their health?
P. CONCLUSION A b o u t a decade ago, P r e s i d e n t K e n n e d y p r e d i c t e d t h a t m a n w o u l d be on t h e m o o n w i t h i n 10 y e a r s ; his p r e d i c t i o n w a s confirmed. H o p e f u l l y , with t h e m e a n s a v a i l a b l e in the U n i t e d States, by 1980 t e t a n u s will no l o n g e r occ~.r in the U n i t e d States, a n d will have become a disease of only historical significance.S2 F o r t e t a n u s p r o p h y l a x i s , let us n o t be too l a t e w i t h too little, like the R o m a n poet Ovid, who, as m e n t i o n e d previously, wrote: " T o o late I g r a s p m y shield a f t e r m y wounds."151
ACKNOWLEDGMENTS A p p r e c i a t i o n is expressed to O s c a r P. H a m p t o n , Jr., a n d P a u l A. S k u d d e r for countless ideas, e v a l u a t i o n s a n d r e c o m m e n d a t i o n s in r e g a r d to all a s p e c t s of t e t a n u s ; to M a r y A. Magill, S e n i o r E d i t o r , C h e m i c a l A b s t r a c t s Service, C o l u m b u s , Ohio, for c a r e f u l l y p r o o f r e a d i n g t h e m a n u s c r i p t a n d for m e t i c u l o u s l y c h e c k i n g a n d c o r r e c t i n g the references; to Oscar F. :Rosenow a n d O w e n E. J o h n s o n for p e r m i s s i o n to p r e s e n t Case 1, w h i c h h a d b e e n r e f e r r e d to t h e m for care; to the following for s u p p l y i n g a n d giving p e r m i s sion to use the i n d i c a t e d figures: D. F r a s e r , J. B e n n e t t , B. D u l l a n d D. Sencer of the U S P H S C e n t e r for D i s e a s e Control (Figs. 1-6 a n d 12), S. N o d a a n d I. E b i s a w a of T o k y o U n i v e r s i t y (Figs. 7, 8 a n d 13), E. V e l a s c o - J o v e n of S a n L a z a r o H o s p i t a l , M a n i l a (Figs. 9 a n d 10), J. T r i n c a of C o m m o n w e a l t h S e r u m L a b o r a t o r i e s of A u s t r a l i a (Fig. 11), L. L e v i n e a n d J. McC o m b of the M a s s a c h u s e t t s D e p a r t m e n t of P u b l i c H e a l t h S t a t e L a b o r a t o r y I n s t i t u t e (Figs. 14-16), P. S m y t h e a n d M. Bowie of the R e d Cross Child r e n ' s H o s p i t a l of S o u t h Africa (Fig. 17), I. I l d i r i m of A t a t i i r k U n i v e r s i t y E r z u r u m M e d i c a l School (Fig. 18), R. H a y n e s of C h i l d r e n ' s H o s p i t a l , Columbus, Ohio (Fig. 22); to S u z a n n e F. O'Neill, H o m e r F o r d a n d T h o m a s P. S h e r r i n of R i v e r s i d e M e t h o d i s t H o s p i t a l , Columbus, Ohio, for i m p o r t a n t b i b l i o g r a p h i c s u p p o r t , for v a l u a b l e p h o t o g r a p h s a n d glossy p r i n t s a n d p h a r m a c o l o g i c data, respectively; a n d especially to M a r s h a S. B i e r | y for h e r excellent s e c r e t a r i a l h e l p in n u m e r o u s revisions of the t y p e s c r i p t . 65
REFERENCES Periodicals and Chapters in Books 1. 2.
Adan~s, E.: T h e prognosis and prevention of tetanus. South African M. J. 42: 739, 1968. Akama, K., Ira, A., Yamamoto, A., and Sadahiro, S.: Reversion of toxicity of tetanus toxoid, Jap. J. M. Sc. & Biol. 24: 181, 1971. 3. Alexander, J., and Moncrief, ft.: Use of a double-diffusion technic in agar gel for the quantitation of tetanus antiloxin levels, J. T r a u m a 6: 539, 1966. 4. Alexander, J . , and Moncrief, J.: In vitro deter~nination of tetanus i m m u n i t y , J. T r a u m a 7: 288, 1967. 5. Altemeier, W.: Penicillin in tetanus, J.A.M.A. 130:67, 1946. 6. Altemeier, W., and Furste, W.: Studies ia virulence of Clostridium welchii, Surgery 25:12, 1949. 7. Altemeier, W., and H u m m e l , R.: T r e a t m e n t of tetant~s, Surgery 60: 495, 1966. 8. American A c a d e m y of Pediatrics: Report of the Committee on the Control of Infectious Diseases, p. 2 (Evanston, Ill.: T h e Academy, 1966). (1966 Red Book.) 9. American A c a d e m y of Pediatrics: Report of the C o m m i t t e e on the Control of Infectious Diseases, p. 5, revision of 17 October 1971 (Evanston, Ill.: T h e Academy, 1970). (1970 Red Book. ) 10. A.M.A. Council on Drugs: A.M.A. Drug Evaluation, pp. 643-647 and N 183-184, 1971. 11. Anwar, A., and Turner, T.: Antibiotics in experimental tetanus: In vitro and in viva studies, Bull. J o h n s Hopkins Hasp. 98: 85, 1956. 12. Aretaeus, the Cappadocian: On tetanus, in The E x t a n t Works, Adams, F. (eel.), London, pp. 246-249, 400--404, 1856. 13. Artz, C.: Letter, dated 4 October 1971, Charleston, South Carolina. 14. Bardenwerper, H.: Serum neuritis from tetanus antitoxin, J . A . M . A . 179:763, 1962. 15. Barr, M., and Sachs, C.: T h e investigation into the prevention of tetanus in the British army, Army Pathology Advisory Comm., W.O., Code No. 11262. The War Office, London, S.W. 1. October 1955. 16. Benenson, A., Shively, J., and Vicuna, S.: Effect of irradiation mad test system on development of tetanus antibodies, Proc. Sac. Exper. Biol. & Med. 112: 527, 1963. 17. Bertoye, A., M a s t e r , P., Garin, g., Humbert, G., and Vincent, P.: Surveillance 61ectroenc~phalographique des t~tanos t r a i l , s par le N e m b u t a l ~. doses massives, J . m~d. Lyon 46:1967, 1965. 18. Billaudelle, H., Lundblad, G., Falksveden, L., and Ullberg-Olsson, K.: Fractionation of h u m a n i m m u n e serum anti tetanus by gel filtration, Ztschr. Immunit~itsforsch. 131: 170, 1966. 19. Blurastein, G., and Kreithen, H.: Peripheral n e u r o p a t h y following tetanus toxoid administration, J . A . M . A . 198:166, 1966. 20. Bohrer, S.: Spinal fractures in tetanus, Radiology 85: 1111, 1965. 21. Brooks, G., Buchanan, T., and Bennett, J.: Tetanus toxoid i m m u n i z a t i o n of a d u l t s - - a continuing need, Ann. Int. Med. 73: 603, 1970. 22. Bruce, D.: Tetanus. Analysis of 1458 cases, which occurred in home military hospitals during the years 1914-1918, J. Hyg. 19: 1, 1920. 23. Buff, B.: Fatal anaphylactic shock following intradermal skin test with dilute horse serum tetanus antitoxin, J . A . M . A . 174: 1200, 1960. 24. Burkhardt, G., Starke, G., and Seifart, W.: tiber die Anwendung yon H u m a n - i m m u n globulin beim Tetanus, Zentralbl. Chir. 95: 180, 1970. 25. Busila, V., Petrica, L., and Alexandrescu, R.: Zur Wirkung yon Pyrrolidino-MethylTetracyclin auf das Tetanustoxin, Ztschr. Immunit~itsforsch. 130: 242, 1966. 26. Bytchenko, B.: Geographical distribution of tetanus in the world, 1951-1960, Bull. W H O 34: 71, 1966. 27. Carle, A., a n d 1Rattone, G.: Studio experimentale sull' eziologia del tetano, Gior. Accad. reed. Torino 3 ser. 32: 174, 1884. 28. Catalano, T.: Myocardial infarction after serum sickness from tetanus antitoxin, J . A . M . A . 188: 1154, 1964. 29. Center for Disease Control, Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Annual Supplement. Morbidity and Mortality Weekly Report 19: 53, 1971. 30. Center for Disease Control, Public Health Service, U,S. D e p a r t m e n t of Health, Education, and Welfare: Cases of specified notifiable diseases: United States. Morbidity and Mortality Weekly Report 20: 436, 1971. 31. Center for Disease Control, Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Cases of specified notifiable diseases: United States. Morbidity and Mortality Weekly Report 20: 467, 1971. 32. Center for Disease Control. Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: R e c o m m e n d a t i o n of the Public Health Service Advisory Committee on I m m u n i z a t i o n Practices. Morbidity and Mortality Weekly Report 20: 396, 1971. 33. Chaucer (The Complete Works of Geoffrey Chaucer) : Canterbury Tales, Prologue, lines 496-497, Robinson, F. N. (ed.) (Boston: Houghton Mifflin Company, 1933). 34. Cherubin, C.: Infectious disease problems of narcotic addicts, Arch. Int. Med. 128:309, 1971.
65
35.
Christelmen, N.: T r e a t m e n t of the patient wiih severe tetanus, S. Clin. N o r t h America 49: 1189, 1969. 36. Christensen, P.: Comparative studies on the rate of absorption after subcuta,mous and intramuscular injection of tetanus antitoxin, Acia path. et microbiol, scandinav. "H:262, 1952. 37. Christensen, P.: Side reactions to tetanus toxoid. 1Report, T h i r d International Conference on Tetanus, Silo Paulo, Brazil, 1970. 38. Christensen, P.: Letter dated 28 December /971, Statens Seruminstitut, Copenhagen, Denmark. 39. Clay, R., and Bolton, J.: Tetanus arising from gangrenous unperforated small intestine, ff.A.M.A. 187: 856, 1964. 40. Cohn, E., Strong, L., Hughes, W., Jr., Mulford, D., Ashworth, J., Melin, M., and Taylor, H.: Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids, ft. Am. Chem. Soc. 68: 459, 1946. 41. Cole, L., and Youngman, H.: T r e a t m e n t of tetanus, Lancet 1: 1017, 1969. 42. Cole, L., ¥ o u n g m a n . H., and Gandy, A.: An attack of tetanus, Lancet 2:567, 1968. 43. Committee on Trauma, American College of Surgeons (Hampton, O., Jr., Chron.): Prophylaxis against tetanus in wound management, Bull. Am. Coll. Surgeons 52: 230, 1967. 44. Committee on Trauma, American College of Surgeons (Artz, C., Chron.): A guide to prophylaxis again~st tetanus in wound m a n a g e m e n t , Bull. Am. Coll. Surgeons 56: 22, 1971. 45. Communicable Disease Center, Public H e a l t h Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Collected recommendations of the Public Health Service Advisory Commit[ee on I m m u n i z a t i o n Practices. Morbidity and M o r t a l i t y Weekly ]Report 18 (supp.) : 4, 1969. 46. Communicable Disease Center, Public H e a l t h Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Tetanus. M o r b i d i t y and Mortality Weekly Report 18:310, 1969. 47. Communicable Disease Center, Public Health Service. U.S. D e p a r t m e n t of Health, Education, and Welfare: Tetanus. Morbidity and Mortality Weekly Report 19:162, 1970. 48. Communicable Disease Center, Public H e a l t h Service, U.S. D e p a r t m e n t of Health, Education, and ~¥elfare: T e t a n u s surveillance. Report No. 1, February 1, 1968. 49. Communicable Disease Center, Public H e a l t h Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: T e t a n u s surveillance. Report No. 3, March 31, 1970. 50. Cowling, D., Gray, A., and Pressley, T.: Sheepskins and tetanus, Brit. M. J. 1:52, 1969. 51. Crozier, D.: T h e physician and biological warfare, New E n g l a n d J . Med. 284: 1008, 1971. 52. CreTan, W.: D r u g - c o m p a n y liability in i m m u n i z a t i o n programs, N e w .England J. Med. 281: 1057, 1969. 53. Davis, P., and Rowland, H.: Vertebral fractures in West Africans suffering from tetanus, J. Bone & J o i n t Surg. 47-B: 61, 1965. 54. D e p a r t m e n t s of the Army, the N a v y and the Air Force: Immunization. TI3 Med 114, N A V M E D P-5052-15A and A F P 161-9 (25 M a y 1970). 55. Departments of the Army, the Navy, Air Force and Transportation:" I m m u n i z a t i o n requirements and procedures. AR 40-562, B U M E D I N S T 6230.1F, A F R 161-13 and CG C O M D T I N S T 6230.4A (30 J u l y 1971). 56. Descombey, P.: L ' a n a t o x i n e t6tanique, Compt. rend. Soc. biol. 91:239, 1924. 57. Division of Biologics Standards, National Institutes of Health, Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Biological products. Public Health Service Publication No. 50:29, 1968. 58. Dostal, J . , V ~ n o l a , F., Boschetty, V., and Seveik, V.: Tile influence of hyperbaric oxygen on tetanus in guinea pigs, Anaesthesist 17: 324, 1968. 59. Dubovsky, B., and Meyer, K.: The occurrence of B. tetani in soil and on vegetables, J. infect. Dis. 31:614, 1922. 60. Dukelow, D.: T h e A M A ' s continuing interest in immunization, Arch. Environ. Health 15: 515, 1967. 61. Dull, H.: Athletic injuries on artificial turf and tetanus immunization, J . A . M . A . 216: 338, 1971. 62. Ebisawa, I.: ~qortality of T e t a n u s in Japan; an U n i n t e n t i o n a l Control Observation, in E c k m a n n , L. (ed.), Principles on Tetanus (Bern: Hans Huber, 1967), p. 71. 6~. Ebisawa, I., and Matsukura, M.: P u l m o n a r y and muscular changes in tetanus, Jap. J. Exper. Med. 38:27, 1968. 64. Ebisawa, I., Sawai, Y., Makino, M., Kawamura, Z., and Ogonuki, T.: Relapse or reinfection in tetanus and diphtheria, and reenvenomation in m a m u s h i and habu snake bites. Problems associated ~vith reinjection of horse serum antitoxin or antivenom in nmn, Jap. J. Exper. Med. 34: 125, 1964. 65. Editorial Staff: First of all do no harm. New E n g l a n d J. Meal. 285: 1258, 1971. 66. Editorial Staff: T e t a n u s can be prevented, J . A . M . A . 187:3(~'J,1964. 67. Edsall, G.: Modified tetanus, New E n g l a n d J. Med. 267:520, 1962. 68. Edsall, G.: T h e current status of teianus immunization, Hosp. Practice 6:57, 1971.
67
69.
Edsall, G., Elliott, M., Peebles, T., Levine, L., and Eldred, M.: Excessive use of tetanus toxoid boosters. J.A.]VI.A. 202: 17, 1967. 70. Edsall, G., MacLennan, R.. Levine, L., and Belsey, M.: Response to a single dose of tetanus toxoid. Report, International Congress for Microbiology, Mexico City, Mexico, 1970. 71. Ellis, E., and Henney, C.: Adverse reactions following administration of h u m a n g a m m a globulin, J. Allergy 43: 45, 1969. 72. Engert, R.: Letter, date
68
106.
Ipsen0 J.: Changes in i m m u n i t y and antitoxin level i m m e d i a t e l y after secondary stimulus with tetanus toxoid in rabbifis, J. Immunol. 86: 50, 1961. 107. Janeway, C.: Clinical use of products of h u m a n plasma fractionation. I. Allmmin in shock and hypoproteinemia. II. G a m m a globulin in measles, J . A . M . A . 126: 674, 1944. 108. Janeway, C., Merler, E., Rosen, F., Salmon, S., and Crain. J.: lnlravenous g a m m a globulin. Metabolism of g a m m a globulin fragments in normal and agammaglol)ulinemia persons, New E n g l a n d J. Med. 278: 919, 1968. 1{)9. Janeway, C., and Rosen, F.: T h e g a m m a globulirL~. IV. Therapeutic use.s of g a m m a globulin, New E n g l a n d J. Med. 275: 826. 1966. 110. Jennings, H., Jr.: Letter, dated 1 August 1969, D e p a r t m e n t of the United States Alzny. 111. Johnson, D.: Fatal telanus after prophylaxis with h u m a n tetanus i m n m n e globulin. J . A . M . A . 207: 1519, 1969. 112. Johnson, IX{., Swartz, H., and Donati, R.: Hematologic alterations produced by nitrous oxide, Anesthesiology 34: 42, 1971. 113. King, YC, and Lempke, R.: T h e effect of hypothermia on tetanus, J. T r a u m a 6:563, 1966. 114. Kitasato, S.: Ober den Tetanusbacillus, Ztschr. Hyg. 7:225, 1889. 115. Kittler, F., Smith. P., Jr., Hefley, B., and Cazorf, A.: Reactions to tetanus toxoid, South. M. J. 59: 149, 1966. 116. Kloetzel. K.: Personal conmmnication, Second International Conference on Tetanus, Bern, Switzerland, 1966. 117. Klose, F., and Schallehn, G.: Aktive und passive Schutzimpfung gegen Wundstarrkramp[ und C l o s t r i d i u m - n o v y i Gas6dem, Deutsche reed. Wchrkschr. 95: 510, 1970. 118. Kremlev, G.: Efficacy of e m e r g e n c y specific prophylaxis against experimental tetanus under aggravated conditions, Zh. Mikrobiol. 40: 94, 1963. 119. Kremlev, G.: E m e r g e n c y prophylaxis o[ tetanus with antibiotics in conjunction with toxoid revaecination in experiments in animals. Zh. Mikrobiol. 41: 39, 1964. 120. LaForce, F., Young, L., and Bennett, J.: T e t a n u s in the United Stales (196,.5-1966). Epidemiotogic and clinical features, New E n g l a n d J. Med. 280: 569, 1969. 121. Laurent, L., and Parish, H.: Serum reactions and sertun sensitivity test.s, Brit. M. J. 1: 1294, 1952. 122. I~Chevallier, P., Lamisse, F., and Bertrand, M.: ~ para-osteo-arthropathies au tours du tetanos. X propos de huit cas personnels, Rev. ]Rhum. 37: 485, 1970. 123. Leonardi, G.: Oxime treatment in lelanus, Lancet 2: 658, 1971. 124. Levine, L., MeComb, J., 1)wyer, R., and Latham, W,: Active-pas,sive tetanus immunization. Choice of toxoid, dose of tetanus i m m u n e globulin and timing of injections, New England J. Med. 274: 186, 1966. 125. Ixmg, A.: T h e A r m y I m m u n i z a t i o n Program. Vol. III. Preventive Medicine in World War II, Medical Department, U n i t e d States A r m y (Washington. D.C.: United States Government Printing Office, 1955), p. 287. 126. Long, A., and Sartwell, P.: T e t a n u s in the U.S. Army in World War I[, Bull. U.S. Army Med. Dept. 7: 371, 1947. 127. MacLennan, R., Schotieki, F., P i t t m a n , M., Hardegree, M., and 'Battle. M.: Immunization against neonatal tetanus in New Guinea; antiloxin response of pregnant women to adjuvant and plain toxoids, Bull. W H O 32: 683, 1965. 128. McCarroll, J., Abrahams, I., and Skudder, P.: Antibody response to tetanus toxoid 15 years after initial immunization, Am. J. Pub. H e a l t h 52:1669, 1962. 129. McComb, J.: T h e prophylactic dose of homologous tetanus antitoxin, New E n g l a n d J. Med. 270: 175, 1964. lo0. McComb, J.: Tetanus in previously i m m u n i z e d persons, New Engi,-md J. Med. 273: 452, 1965. 131. McComb, J.: T h e Combined Use of i:Iomologous T e t a n u s I m m u n e Globulin and Toxokl in Man, in Ec'kmann, L. ted.), Principles on T e t a n u s (Bern: Hans Huber, 1967), p. 359. 132. McComb, J., and Dwyer, R.: Passive-active irmnunization with tetanus i m m u n e globulin (htunan), New E n g l a n d J. Med. 268: 857, 1963. 133. McComb, g., and Levine, L.: Adult immunization. II. Dosage reduction as a solution to increasing reactions to tetanus toxoid, New E n g l a n d g. Med. 265: 1152, 1961. 134. McCracken, G., Jr., Dowell, D., and Marshall, F.: Double-blind trial of eqtfine antitoxin and h u m a n i m m u n e globulin in tetanus neonatorum, Lancet 1: 1146. 1971. 135. McFarland, R., Colvin, V., anti Seal, J.: Mass prophylaxis of epidemic streptococcal infectior~s with benzathine penicillin G. It. Experience at Naval Training Center during winter of 1956-1957,.New E n g l a n d J. Med. 258: 1277, 1958. 136. Mahoney, L., Apri]e, M., a n d Moloney, P.: Combined active-passive immunization against tetanus in m,-m, Canad. M . A . J . 96: 1401, 1967. 137. Mat, K., Bartelheimer, H., anti 1Rosin, H.: tJher den Stand und die Dauer ties hnpfs c h u t z ~ gegen Tetantt,; bet Kindern, Deutsche reed. Wchnschr. 95: 1044, 1970. 138. Manz, R., Beer, R., anti Boldt, V.: Complicatior~ antl cause of death in tetanus, Ztschr. prak. Anas. 3: 357, 1968. 139. ]Vtanz, R., anti Drost, R.: Heutiger Stand yon Verh/itung und Behandlung ties Wundstarrkrampfes, Anaesthesist 18: 101, 1969, 140. Matveev, K., Dzhavrova, I., Petrov, P., Ka,sparova, E., Kashintseva, N.. anti Popova,
69
K.: Effectivene.~ of active-passive prophylaxis of tetanus in man, Zh. Mikrobio]. 46: 72, 1969. 141. Mellanby, J., Mellanby,/ H., Pope, D., and van Heyningen. ~V.: Ganglioside as a prophylactic agent in experimental tetanus in mice, J. Gen. Microbiol. 54: 161, 1968. 142. MSrieux, C.: Single Shot Primovaccinalion agairL,~t Tetanus by Needleless Injectors, in Eckmann, L. ted.), Principles on Tetanus (Bern: Hans Huber, 1967), p. 423. 143. Milledge, J.: Hyperbaric oxygen lherapy in tetanus, J.A.iVLA. 203: 875, 1968. 144. M u r p h y , K.: Fat,~d tetanus with brain-stem involvement and myocarditis in a n exserviceman, M. J. Australia 2: 542. 1970. 145. Nation, N., Pierce, N., Adler, S., Chinnock, R., and V~ehrle, P.: T e t a n u s ~ t h e use of h u m a n h y p e r i m m u n e globulin in treatment. California Med. 98: 305, 1963. 146. Neel, S.: I.~tter, dated 10 November 1971, D e p a r t m e n t of the United States Army. 147. •NeweIl, K., Lehmann, A., Leblanc, D., m~d Osorio, N.: T h e use of toxoid for the prevention of tetanus neonatorum. Final report of a double-blind controlled field trial. Bull. W H O 35: 863, 1966. 148. Nicolaier, A.: tiber infectiosen Tetanus, Deutsche reed. Wchnschr. 10: 842, 1884. 149. Okulski, J.: T h e blood coagulation system in tetanus patients, Acta meal. pol. 10:291, 1,969. 150. 0 r d m a n , C.. Jennings, C., Jr., and Janeway, C.: Chemical, clinical, and immunological studies on the products of h u m a n plasma fractionation. X I L T h e use of concentrated normal h u m a n serum g a m m a globulin (human i m m u n e serum globulin) in prevention and attenuation of measles, J. Clin. Invest. 23: 541, 1944. 151. Ovid: Tristia I. 3.35. 152. Pascale, L., Wallyn, R., Goldfein, S.. and Gumbiner, S.: T r e a t m e n t of tetanus by hyperbaric oxygenation, J . A . M . A . 189: 408, 1964. 153. Patel, J . : Relapse after tetanus, L~mcet 2: 902, 1969. 154. Patel, J., and Goodluck, R.: Serum therapy in neonatal tetanus, Am. J. Dis. Chile/. 114: 131, 1967. 155. Patei, J., and Joag, G.: Grading of tetanus to evaluate prognosis. Indian J. M. Sc. 13: 834, 1959. 156. Patel, J . , and Mehta, B.: Tet,~nus: A s t u d y of 2007 cases, I n d i a n J. M. Sc. 17: 791, 1963. 157. Patel, J., Mehta. B., Nanavati, B., Hazra, A., Rao, S., and Swaminathan, C.: Role of sertun therapy in tetanus, Lancet 1: 740, 1963. 158. Peebles, T., Levine, L., Eldred, M., and Edsall, G.: Tetanus loxoid emergency boosters. A reappraisal, New E n g l a n d J. Med. 280: 575, 1969. 159. Perlstein, M.: T r e a t m e n t of tetanus, J.A.M.A. 208:1024, 1969. 160. Pinheiro, D.: Tetanus neonatorum: Report of an experimental trial, Rev. Brasil. pescluisas reed. e biol. 3: 69, 1970. 161. Prys-Roberts, C., Kerr, d., Corbett, d., Smith, A., and Spalding, J.: T r e a t m e n t of sympathetic overactivity in tetanus, Lancet 1: 542. 1969. 162. Ramon, G., and Zoeller, C.: L'anatoxin t~tanique et l ' i m m u n i s a t i o n active de l ' h o m m e vis-a-vis du teianos, Ann. Inst. Pasteur 41: 803, 1927. 163. Ramon, G., a n d Zoeller, C.: Sur la valeur et la dttr~e de l ' i m m u n i t 6 conferee par l'anatoxine t~tanique dans la vaccination de t ' h o m m e contre le t~tanus, Compt. rend. Soc. biol. 112: 347, 1933. 164. tRegamey, 1R., Gindrat, J., and Wantz, M.: Quelques aspects de la toxinogen~se t6tanique, Path. et Microbiol. 29: 523, 1966. 165. Regents, American College of Surgeons: Policy on tetanus immunization, Bull. Am. Coll. Surgeons 49: back cover, 1964. 166. :Regents, American College of Surgeons: Professional liability insurance, Bull. Am. Coll. Surgeons 56: 31, 1971. 167. Robinson, D., McLeod, J., and Downie, A.: Dust in surgical theaters as a possible source of postoperative tetanus, Lancet 1:152, 1946. 168. Rubbo, S.: New approaches to tetanus prophylaxis, Lancet 2: 449, 1966. 169. Rubbo, S.: Prophylaxis against Tetanus, in E c k m a n n , L. ~ed.), Principles on Tetanus (Bern: Hans Huber, 1967), p. 345. 170. 1Rubbo, S., and Suri, J.: Combined active-passive i m m u n i z a t i o n against tetanus with h u m a n i m m u n e globulin, M. J. Australia 2:109, 1965. 171. Rubinstein, H.: Studies on h u m a n tetanus antitoxin, Am. J. Hyg. 76:276, 1962. 172. Scheibel, I., and Assandri, J.: In vitro investigation into the sensitivity of different strains of Cl. tetani to antibiotics, Acta path. et microbiol, scandinav. 47: 435, 1959. 173. Schneider, C.: Reactions to tetanus toxoid: A report of five cases, M. J . Australia 2:303, 1964. 174. Schumann, H., and Hache, H.: E i n Tetanus-Todesfall nach aktiver Schnellimmtmisierung, Deutsche Gesundh. 22: 1935, 1967. 175. Sergeeva, T., and Matveev, K.: Geographical Distribution of Clostridiura tetani in the Soil of the USSR, in E c k m a n n , L. ted.), Principles on Tetanus (Bern: Hans Hub~r, 1967}, p. 77. 176. Shaw, E.: Tetanus mimicking a psychophysiologic reaction, J.A.M.A. 201:981, 1967. 177. Sherman, R.: Tetanus after antitoxin prophylaxis. Am. J. Surg. 108:36, 1964,
70
Sherm,-m, R.: T h e prevention and treatment of tetanus in tile burn patient, S. Clin. N o r t h America 50: 1277, 1970. 179. Skudder, P., ,-rod McCarroll, J.: Current status of tetanus control, J . A . M . A . 188: 625, 1964. 180. Skudder, P., IV/cCarroll, J., Ecker, R., and Cahow, E.: T h e incidence of reactions following administration of tetanus antitoxin. J. T r a u m a 1: 41, 1961. 181; Smith, A.: Tetanus, in Beeson, P. B.. and McDermott. W. (eds.), C~cil-l_,oeb Textbooh of Medicine (13th ed.; Philadelphia: W. B. Saunders Company, 1971). p. r~6. 182. Smith, J.: Penicillin in the prevention of tetanus, Brit. M. J. 2: 1293, 1964. 183. Smith, J.: Intracerebral antitoxin in experimental tetanus, Brit. J. Exper. Path. 47: 17. 1966. 184. Smith, J.: Diphtheria and tetantrs toxoids, Brit. M. Bull. 25: 177, 196"9. 185. Smolens, J., VogL A., Crawford, M., and Stokes, J,, Jr.: T h e persistence in the h u m a n circulation of horse and h u m a n antitoxins, J. Pedlar. 59: 899. 1961. 186. Smythe, P.: Studies on neonatal tetanus, and on p u h n o n a r y compliance of tim totally relaxed infant, Brit. M. J. 1: 565, 1963. 187. Smythe, P.: T h e problem of detubating an infant with a tracheostomy, J. Pedlar. 65: 446, 1964. 188. Smythe, P.: T r e a t m e n t of tetanus in neonates, l~mcet I: 335, 1967. 189. Smythe, P., and Bowie, M.: In press. 190. Snyder, H., :Edsall, G., and Levine, L.: T e t a n u s immunization, J. T r a u n m 6: 529. 1,96(;. 191. Spaeth, R.: A clinical study of tetanus, Am. J . Dis. Child. 60:130, 1940. 192. Spenney. J., Lamb, R., and Cobbs. C.: Recurrent tetanus, South. M. J. 64:859, 1971. 193. Stark, R.: Surgeons and surgical care of the Confederate States Am~y, Virginia M. M o n t h l y 87: 230, 1960. 194. Stokes, J., Jr., Marts, E., and Gellis, S.: Chemical, clinical, and immunological s t u d i ~ on the prodvcts of h u m a n plasma fractionation. XI. The use of concentrated normal htanan serum g a m m a globulin (human i m m u n e serum globulin) in prophylaxis and treatment of measles. J. Clin. Invest. 23: 531, 1944. 195. T e n n e n b a u m , J.: Immunologic deficiency states. A review, Ohio M. J. 62: 1157, ]966. 196. Treadway, C., and Prange, A., Jr.: Tetanus mimicking psychophysiologic reaction: Occurrence after dental extraction, J . A . M . A . 200: 891, 1967. 197. Trinca, d.: Active tetanus immunization: ~ffect of a reduced reinforcing dose of adsorbed toxoid on the partly immunized reactive patient, M. d. Australia 2: 389, 196:t. 198. Trinca, ft.: Active i m m u n i z a t i o n against tet,~us- T h e need for a single all-purpose foxold. M. d. Australia 2: 116, 1965. 199. Trinca, J.: Problems in tetanus prophylaxis: T h e i m m u n e patient, M. J. Australia 2: 153, 1967. 200. Trinca, J'., a n d 1Reid, J'.: Prevention of tetanus by antitoxin of bovine origin, l a n c e t 1: 76, 1967. 201. Vaishnava. H., Goyal, R., Neogy, C., and Mathur, G.: A controlled trial of antiserum in the treatment of tetanus, Lancet 2: 1371, 1966. 202. van Heyningen, W.: Tetanus, Scient. Am. 218: 69, 1968. 203. van Heyningen, W.: Pathogenicity and Virulence of Microorganisms. IV. Bacterial Toxins, in Lord Florey ted.), General Pathology (4th ed.; London: Lloyd-Luke, 1970), p. 879. 204. Veronesi, 1R.: Oral tetanus toxoid. Letter dated 24 J a n u a r y 1972, $5o Pau[o, Brazil. 205. Veronesi, It., Correa, A., and Alterio, D.: Single dose i m m u n i z a t i o n against tetanus. :Promising results Jn h u m a n trials, 1Rev. Inst. reed. trop. Stio P a u l o 12:46, 1970. 206. yon Behring, E., and Kitasato, S.: Ober das Z u s t a n d e l k o m m e n der l b i p h t h e r i e q m m u n i ttit und der Tetanus-Immunit~it bet T h i e r e n , Deutsc~'le reed. Wchnschr. 16: 1113, 1890. 207. Vrancheva, S., Denchev, V., and Yomtov, M.: Active i m m u n i z a t i o n with tritoxoid (perfringens, oedematiens and tetanus) in experimental conditions, Med. Fiscult. 8:91, 1962. 208. IVall Street Journal: Suing the doctor, p. 1, :New York, 28 F e b r u a r y 1969. 2O9. \Veinstein, L., and Wesselhoeft, C.: Penicillin in the treatment of tetanus. Iteport of two cases, New E n g l a n d J. ~(Ied. 233: 681, 1945. 210. x,Veisberger, A.: Mechanisnts of action of chloramphenicol, J . A . M . A . 209: 97, 1 ~ 9 . 211. W H O Expert C o m m i t t e e on Biological Standardization: Twenty-second report, W H O Teeh. 1Rep. Ser. 444: 17, 1970. 212. Wichramasinghe, S., and Fernando, M.: Recurrent tetanus, Brit. M. J. 4:.530. 1967. 213. ~,Vigley, F., l,Vood. S., and ~,VaIdman, R.: Aerosol immunization of humao_s with tet~mtt~ toxoid, J. I m m u n o l . 103:1096, 1969. 214. Witte, J.: Status of i m m u n i z a t i o n of one-four year olds, N e w E n g l a n d J. Meal. 286: 2~3, 1972. 215. Woziwodzki, G., and Graesser. R.: D e r Antitoxintiter im menschlichen Blut nach iibers t a n d e n e m W u n d s t a r r k r a m p f sowie nach aktiver .F~rhutzimpfung, Chirurg 37: 97, 19(;6. 216. Wright, G.: Neurotoxins of Clcstridium botulinum anti Clostridmm tctani, Pharmacol. Rev. 7: 413, 1955. 217. Yodh. B.: Preface, Proceedings o / t h e First International Con'e ence on Tetanus, Patel, J. ted.) IBombay: Associated Advertisers and Printers, 1965), p. v. 218. Zuber, L.: Beitrag zur B e h a n d l u n g des manifesten Tetantt,~ m i t Prednisoton intralumbal, ZentralbI. Clair. 93:1045, 1968. 178.
71
Monographs and Books
219. 220. 221. 222. 223. 224.
Adams, E., Laurence, D., and Smith, J.: Tetanus (Oxford and Edinburgh: Blackwell Scientific Publications, 1969), p. 64. E c k m a n n , L.: Tetanus: Prophylaxis and Therapy, translate
Audio-Visual Presentations
225. 226. 227. 228.
Christensen, N.: Tetanus and its prevention, Mayo Clinic, Rochester, Minnesota, 1963. Furste, W.: A new look at tetanus prophylaxis, Douglms Film Indttstries, Chicago, :I965. Institut M6rieux: Tetanus {French and English sound tracks), Compagnie Lyonnaise de Cinema Lyon, France, 197{}. Rubbo, S.. and Trinca, J.: Tetanus and its prevention, Australian Instruction Films Proprietary Limited, Sydney, New South Wales, 1966.
Audio Presentations
229. 230.
Furste, W.: Tetanus prophylaxis, Ikon Enterprises, Sacramento, California, 1965. Furste, W.: Past, present and future concepts for tetanus prophylaxis, Orthopaedic Audio-Synopsis Foundation, Los Angeles, Cali[ornia, 1970.
72
is m e di c a l resident at Riverside Methodist received his B.S. and M . D . degrees from T u l a n e U n i v e r s i t y respectively. He served pital a nd then, following a tour of d u t y in nam. returned for a medical residency.
Hospital in Columbus, Ohio. H e T h e Ohio State University and an internship at his present hos-the United States.,a.rmy in Viet-
A. INTRODUCTION T E T A N U S is a team disease. T h e striking results that have been achieved in the p r e v e n t i o n and treatment of tetanus in developed countries, and which can b e achieved i n developing countries also, are the resuit of the .laboratory ~;¢ork'of the preclinical scientists, namely, the anatomist, the biochemist, the physiologist, the microbiologist, the pathologist, the immunologist, t h e pharmacologist and their co-workers and of the clinical endeavors of: thb" epidemiologist, the family physician, the internist and his subspecialty associates, the pediatrician, the surgeon and his subspecialty c o l l e a g u e s apd the anesthesiologist. S t u d y of the references for this report will reveal that all of the above types of specialists have made and are making specific contributions in making tetanus a disease of only historical si,gnificance_ Tetanus (lockjaw) is .a sevi~re ,,and dreade-d infectious complication of wounds and is caused by the.toxin-producing Clostridium tetani. This disease is characterized, by. tonic spasms of the voluntary muscles, by a ten3
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TABLE A.D. 2d C e n t u r y 1884 1884 1889 1890 1927 and 1933 1942 1946 1966
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1 . - I V I I L E S T O N E S I N T H E H I S T O R Y OF T E T A N U S
Aretaeus, lhe Cappadocian, descrilmd tetanus.l:" Carle demonstrated the transmissibility of telanus by inoculaiion into rabbits of pus from a h u m a n cguse.27 Nicolaier described the tetanus bacilhts. H e was, however, unable to isolate the organism in pure culture,14s Kitasato obtained the pure culture of Cl. tetani.,114 yon Behring and K i t a s a t o described antitoxins and their immunizing powers.20(i R a m o n and Zoeller discussed the use of tetanus toxoid in active immunization of humans.J62, 1~;3 T h e United States m i l i t a r y establishment effectively used the emergency medical identification device. Cohn ,and his co-workers fractiona{ed h u m a n p l a s m a so that T I G (H) became available. 40 McComb, Levine, D w y e r and Letharn established 250 units as the routine prophylactic dose for T I G I H ) . 124.1.~2
dency toward episodes of r e s p i r a t o r y a r r e s t and, over the entire world, by a m o r t a l i t y rate of a p p r o x i m a t e l y 50~o. T e t a n u s has been recognized as a terrifying disease for 2,300 years. H i p p o c r a t e s referred to the m a s t e r of a large ship, who s m a s h e d the index finger of his right hand with the anchor, as follows: "Seven days later a s o m e w h a t foul discharge appeared: then trouble with his tongue • . . on the t h i r d day opisthotonos occurred with s w e a t i n g . . . 6 days later he died. ''~m In the second century, Aretaeus, the C a p p a d o c i a n , called the disease a n i n h u m a n calamity, a n u n s e e m l y sight, a spectacle painful even to the beholder (Table 1). H e wrote: " T h e wish of the physician that the p a t i e n t should expire, otherwise irreverent and objectionable, is, in this case well taken. ''12 T h e correct evaluation of various forms of p r o p h y l a x i s and t h e r a p y for all diseases is difficult, but it is p a r t i c u l a r l y difficult for tetanus. T h e following ])arable indicates how the relationship between a cause and an effect m a y be i n t e r p r e t e d incorrectly. 11~; Fido and the S u n r i s e
"One m o r n i n g Fido awoke earlier than usually. F o r u n k n o w n reasons, he barked. T h e sun rose. T h e n Fido discovered that, each m o r n i n g after he barked, the sun appeared. H e had discovered, he thought, a cause and an effect. "One m o r n i n g Fido overslept, and, when he awakened, the sun was in the sky. Fido, to his chagrin, l e a r n e d that his b a r k i n g did not cause the s u n to a p p e a r in the sky."
B. INTERNATIONAL TETANUS CONFERENCES T h e first of three I n t e r n a t i o n a l Conferences on T e t a n u s took place in India in 1963, the second was held in S w i t z e r l a n d in 1967, the third was convened in Brazil in 1970 and the fourth is tentatively p l a n n e d for a country yet to be d e t e r m i n e d about I974.79, 2o,1. 223 Yodh,217 who was P r e s i d e n t of the S t u d y Group of T e t a n u s a n d who was active in organizing the F i r s t I n t e r n a t i o n a l Conference on T e t a n u s , 4
s u m m a r i z e d well the situation in regard to tetanus in the P r e f a c e of the Proceedings of the ]First International Conference on Tetanus as follows: " T h e incidence of t e t a n u s in India and developing countries is quite high whereas, in the West, the disease has been .practically eradicated because of mass i m m u n i z a t i o n during childhood along with other protective vaccines. T e t a n u s has a high m o r b i d i t y and m o r t a l i t y rate, particularly t e t a n u s n e o n a t o r u m . U n f o r t u n a t e l y , in India and other developing countries, it is not recognized to be a vitally i m p o r t a n t public h e a l t h problem, a n d suffers from a lack of interest on the p a r t of public healfl~ authorities and medical practitioners. "]:n order to create such interest a m o n g medical men, the S t u d y G r o u p on T e t a n u s organized in B o m b a y an I n t e r n a t i o n a l Conference on T e t a n u s in November, 1963. A large n u m b e r of I n d i a n and foreign delegates participated, and t h e r e were m a n y useful discussions c u l m i n a t i n g in certain recommendations. T h e necessity for prevention of t e t a n u s and the use of smaller doses of antitoxin in t r e a t m e n t formed a p a r t of the subject for discussion. T h e need for research, p a r t i c u l a r l y on the transmissioa of the toxin to the nervous system, was stressed. A large n u m b e r of specialists who p a r t i c i p a t e d were of the opinion that prevention of t e t a n u s neon a t o r u m through i m m u n i z a t i o n during p r e g n a n c y is possible and should be encouraged." At the T h i r d I n t e r n a t i o n a l Conference on T e t a n u s in S,~o Paulo, Brazil, in 1970, representatives of nations of all p a r t s of the world, such as the United States, the Union of Soviet Socialist l~epublics, J a p a n and Senegal, were present.S3 T h e p a r t i c i p a n t s were from both the preclinical and clinical disciplines. Among those who contributed p a p e r s were J. B e n n e t t (medical epidemiologist from the U S P H S C e n t e r for Disease Control in A t l a n t a ) , E. E r i k s s o n (surgeon from S w e d e n ) , G. Edsall (immunologist from the M a s s a c h u s e t t s D e p a r t m e n t of Public H e a l t h in .Boston and the London School of H y g i e n e a n d Tropical Medicine in London), J. P a t e l (internist from India) and A. Benenson (specialist in c o m m u n i t y medicine from the University of K e n t u c k y ) . T h e Conference organizer and chairm a n was R. Veronesi (internist from Brazil). T h e official language was English, with s i m u l t a n e o u s translation in Portuguese. F o r informal discussions, however, F r e n c h , ]Russian, P o r t u guese, Spanish, J a p a n e s e a n d G e r m a n w e r e used. T h e Conference was s u p p o r t e d by the World H e a l t h Organization and was sponsored by the A c a d e m y of Medicine of S~o Paulo.
C. INCIDENCE AND EPIDEMIOLOGY I. T h E U
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T e t a n u s continues to occur as a complication of lacerations, open fractures, burns, abrasions, h y p o d e r m i c injections, operations on the gastrointestinal tract and birth (infection of t h e umbilical s t u m p in the newborn). Relatively few cases of t e t a n u s occur in the United States. U n d e r the able directorship of D. Sencer, the U S P H S Center for Disease Control weekly reports telegraphic data on t e t a n u s and p r e p a r e s excellent s u m m a r i e s on m a n y aspects of tetanus. 5
TABLE
INCmENCE OF REPORTED CASES OF TETANUS
2,
IN T H E U N I T E D STATES 3! X~UAIBER OF CASE:$
1966-1970
Diphtheria 214
Poliomyeli|is 53
Tetanus .166
442
30 12
138 120
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202
FzG. l ( t o p ) . - - R e p o r t e d cases of tetanus, United Stat~;, :I950--1970.'-'9 (Courtesy of Cen{er for Dise&se Control.) FzG. 2(bottorn).--Gex~.graphic distribution of tetanus case.~ (excluding neonatal tetanus) and incidence rates, by state, 1968-1(.)69.47 (Courtesy of Center for Disease Control.)
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:FIG. 3 ( t o p ) . - - W w o h u n d r e d n i n e t y - f i v e t e t a n u s cases ( e x c l u d i n g n e o n a t a l telalm.'~), i)y m o n t h of oruset, Unitcnt S t a t e s , 1968--1969.49 ( C o u r t e s y of C e n t e r for I)isem~e C o n t r o l . ) Fro. 4 ( b o t t o m ) . - - T e t a n u s case f a t a l i t y r a t i o s , U n i t e d S t a t e s , ]9~¢3--19(;¢.).47 T h e t e l a n u s case f a t a l i t y r a t i o of a p p r o x i m a t e l y 60~o for two (|evades s h o u l d in(tee~I be .'~ s t i m u l u s for m o r e w i d e s p r e a d a n d m o r e efficient a d m i n i s t r a t i o n of t e t a n u s t o x o i d , p a r t i c u l a r l y in the y o u n g a n d t h e a g e d , in w h i c h two groUps t h e r e has b e e n a h i g h f a t a l i t y r a t i o ~see Pig. 5). Also, StlCb h i g h f a t a l i t y ratios emph,'~,,izeihat t e i a n u s is a m o s t seriou,; (li.,~e,-ase a n d t h a t - - w h e n I n ~ n i b l e - it s h o u l d be t r e a t e d in a c o m p l e t e l y e q u i p p e d h o s p i t a l staffed b y s p e c i a l i s t s w i t h an inl(:rest in t e t a n u s . ( C o u r t e s y of C e n l e r for Dise~.se C o n t r o l . )
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DEVELOPING
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T h e i n t r o d u c t i o n of t e t a n u s t o x o i d a p p r o x i m a t e l y t h r e e d e c a d e s ago, w h i c h w a s f o l l o w e d in m a n y p a r t s of t h e w o r l d by p r o g r a m s of i m m u n i z a tion o f t h e p o p u l a t i o n , c o n t r i b u t e d g r e a t l y to t h e control o f t e t a n u s . N e v e r t h e l e s s , d u r i n g t h e d e c a d e 1 9 5 1 - 1 9 6 0 , t e t a n u s r e m a i n e d an u n s o l v e d p r o b l e m in m a n y a r e a s of t h e world. In a 1966 report, B y t c h e n k o 2 6 s h o w e d : on t h e basis of t h e a v a i l a b l e l i t e r a t u r e a n d W o r l d H e a l t h O r g a n i z a t i o n statistics, t h a t t e t a n u s c a u s e s m o r e t h a n 50,000 d e a t h s e a c h y e a r all over t h e world. I n d e e d , this figure s h o u l d be r e g a r d e d as a n underestimate, s i n c e it o n l y p a r t i a l l y reflects the a c t u a l s i h m i i o n . B y i c h e n k o ' s p a p e r d r a w s a t t e n t i o n to t h e g e o g r a p h i c dis° t r i b u t i o n oi t e t a n u s in t h e w o r l d a n d i n d i c a t e s that e x i s t i n g foci or z o n e s of i n f e c t i o n m a y be a t t r i b u t e d to e n v i r o n m e n t a l c o n d i t i o n s as well as to social, e c o n o m i c a n d c u l t u r a l factors.
D. MICROBIOLOGY In ~m e d i t o r i a l in a 1964 i s s u e of t h e Journal o[ the American ~[edical Association there is the f o l l o w i n g quotationC, a:
" M a n or b o y that w o r k s or p l a y s In the fields or h i g h w a y s ~]ily, w i t h o u t o f f e n s e or h u r t From the soil contact :i dirl:."
~ M n l c Y I,AM~. 1809
8
T h e " d i r t " of the "fields or h i g h w a y s " envisioned in M a r y L a m b ' s poem includes the ciostridial g r o u p of organisms, of which CI. tetani is a promi n e n t m e m b e r . Also, c o m m o n l y the feces of domestic a n i m a l s a n d h u m a n s c o n t a i n Cl. tetani.n9.17,~ T h e s e s t r i c t a n a e r o b e s a r e the c o m m o n and app r o p r i a t e t e n a n t s of the e a r t h , with a role t h a t favors t h e conversion of o r g a n i c w a s t e m a t e r i a l into fertile soil for the g r o w t h of vegetables, g r a i n s a n d t h e b e a u t i e s of n a t u r e . It is said t h a t if it were not for the p r e s e n c e of th e Clostridia, e x c r e m e n t would a c c u m u l a t e a n d m a k e t h e world untenable. A l t h o u g h t e t a n u s h a d b e e n described a n d was k n o w n as a clinical disease since the time of H i p p o c r a t e s , the d e m o n s t r a t i o n of the i n d u c t i o n of t e t a n u s was not m a d e u n t i l the l a t t e r p a r t of the n i n e t e e n t h c e n t u r y . In 1884, Ca r le was able to p r o d u c e t e t a n u s in rabbits by i n o c u l a t i n g t h e m with pus t a k e n from the w o u n d of a h u m a n with tetanus.27 At a p p r o x i m a t e l y the s a m e time t h a t C a r l e r e p o r t e d his work, N i c o l a i e r r e p o r t e d t h e discovery of the t e t a n u s bacillus. H e was, however, u n a b l e to isolate the o r g a n i s m s ira p u r e culture.l-~8 A few y e a r s l a t e r , in 1889, K i t a s a t o was able to o b t a i n a p u r e c u l t u r e of t h e t e t a n u s bacillus.ll,s Cl. tetani is a large, gram-positive, actively motile bacillus, which, in its s p o r e - b e a r i n g form, has a c h a r a c t e r i s t i c " d r u m s t i c k " a p p e a r a n c e . S p o r e s m a y develop a t e i t h e r end of the bacillus, giving a " d u m b b e l l " a p p e a r ance. I t is a s t r i c t a n a e r o b e , a n d spores will not g e r m i n a t e in the p r e s e n c e of even the s m a l l e s t a m o u n t of oxygen.'~;, ~sl A n o x i d a t i o n - r e d u c t i o n pot e n t i a l of +0.01 volt or less at p H 7 is r e q u i r e d if g e r m i n a t i o n is to t a k e place. T h e Clostridium grows well on l a b o r a t o r y m e d i a a t 37 ° C, a n d g r o w t h occurs slowly at 22 ° C. V e g e t a t i v e bacilli a r e killed r e a d i l y by a n t i s e p t i c s a n d by h e a t , b u t spores a r e h i g h l y r e s i s t a n t to a n t i s e p t i c s and, to a c e r t a i n extent, a r e r e s i s t a n t to heat. T o kill most spores, boiling for 1 h o u r is n e c e s s a r y , but the m o s t r e s i s t a n t m a y r e q u i r e boiling for 4 hours. A u t o c l a v i n g for 10 m i n u t e s at 120 ° C, however, m a y be relied on to FIG. 7 (le[t).---~S. K i t a s a t o . w h o o b t a i n e d a p u r e c u l t u r e of CI. tetani in 1889 a n d who, with yon I~ehring, d ~ c r i l ~ d a n t i t o x i n s in 1890. (Igermi~-~ion of S. N o d a , P h o t o g r a p h i c l z d ~ o r a t o r y of t h e I n s t i t u t e of M e d i c a l S c i e n c e of T o k y o U n i v e r s i t y . a n d courte.,~y of I. E b i s a w a , D e p a r t m e n t of M e d i c i n e at t h e s a m e I n s t i t u t e . ) Fro. 8 ( r i g h t ) . ~ ' I ' e l a n u s in a m o u s e . ]-'luid t e t a n u s toxin was i n j e c t e d into t h e left h i n d ext r e m i t y . C o n t r a c t u r e of the b o d y to the left a n d t e t a n i c left hind e x t r e m i t y a r e visible. {Courtesy of I. E b i s a w a . )
9
TABLE
3.~= D E T E R M I N A T I O N OF SERUM: T E T A N U S A N T r r O X l N A. l~iologie assay 1~. In vitro tests 1. Pas,s i~,e hemagg lu tina l ion 2. llevel,'sed passive hemagglutination 3. Quantitative gel dittusion 4. Passive latex agglutination
s t e r i l i z e c o n t a m i n a t e d objects. P r e s u m a b l y , a f t e r c o n t a m i n a l i o n with soil a n d feces of m a n a n d a n i m a l s , s p o r e s c a n be r e c o v e r e d f r o m d u s t a n d c l o t h i n g ; in s u i t a b l e s u r r o u n d i n g s like d r i e d e a r t h , s p o r e s will s u r v i v e for m a n y y e a r s . ~9, 175 Cl. telani p r o d u e e s two e x o t o x i n s , t e t a n o s p a s m i n a n d tetmmlysin,, a n d , of these, t e t a n o s p a s m i n is l h e n e u r o t o x i n t h a t p r o d u c e s t h e t y p i c a l m u s c l e s p a s m s of tetanus.IS1, '.,-I,1 I t is e x t r e m e l y p o t e n t , e a c h m i l l i g r a m of cryst a l l i z e d t o x i n c o n t a i n i n g 50 m i l l i o n to 75 m i l l i o n m o u s e l e t h a l doses. T h i s e x t r e m e t o x i c i t y a l ) p e a r s to be t h e r e a s o n w h y a n a t t a c k of t e t a n u s does n o t c o n f e r i m m u n i t y , as it is p o s t u l a t e d t h a t t h e fatal dose of t e t a n u s t o x i n is less i h a n t h e a m o u n t r e q u i r e d to provoke an i m m u n e r e s p o n s e . T e t a n o l y s i n c a n c a u s e h e m o l y s i s on blood a g a r 1)lntes. A c c o r d i n g to van H e y n i n g e n , 2 0 a t e t a n o l y s i n is c a r d i o t o x i c a n d c a n c a u s e c a r d i a c d a m a g e in tetanus. I n a 1969 rel)ort on t e t a n u s in t h e U n i t e d S t a l e s for t h e 1965-1966 p e r i o d , L a F o : ' c e a n d his co-workers.'20 r e p o r t e d l h a t in o n l y ,'~'~°t,~,..o of 160 c a s e s in w h i c h c u l t u r e s w e r e t a k e n w a s CI. tetani r e c o v e r e d . T h e s i n g l e best e x p l a n a t i o n is t h a t f a s t i d i o u s a n a e r o b i c g r o w t h r e q u i r e m e n t s of this s p e c i e s m a r k e d l y d e c r e a s e t h e c h a n c e for r e c o v e r y u n l e s s special l)re('aulions a r e t a k e n w i t h s p e c i m e n s . B a c t e r i a l o v e r g r o w t h by o t h e r w o u n d i n v a d e r s a n d t h e i n i t i a t i o n of a n t i m i c r o b i a l t h e r a p y also m a y r e d u c e t h e c h a n c e for r e c o v e r y . D e t e r m i n a t i o n of s e r u m t e t a n u s a n t i t o x i n is a m e l h o d of d e t e r m i n i n g t h e effects of toxoid a n d of a n t i t o x i n , a n d s u c h a d e t e r m i n a t i o n i n d i c a t e s w h e t h e r an i n d i v i d u a l h a s p r o t e c t i o n a g a i n s t t e t a n u s . Biologic assays, or in v i t r o tests m a y be m a d e . T o l ) e r f o r m i h e m o u s e biologic a s s a y a n d t h(~ p a s s i v e h e m a g g l u t i n a t i o n a n d r e v e r s e d passive h e m a g g l u t i n a l i o n tests req u i r e s d a y s . so t h e y a r e n o t of w d u e in d e c i d i n g w h e t h e r a l)alient is p r o t e c t e d a g a i n s t t e t a n u s at t h e t i m e of i n j u r y . A l e x a n d e r a n d M o n crieD. 4 h a v e s t u d i e d a q u a n t i t a t i v e gel d i f t u s i o n m e t h o d a n d a p a s s i v e l a t e x a g g l u t i n a t i o n p r o c e d u r e in a n e n d e a v o r to o b t a i n a s e r u m a n t i t o x i n level w i t h i n s e v e r a l h o u r s ( T a b l e 3).
E. ETIOLOGY (WOUNDS) I n c o n t r a s t io gas g a n g r e n e ( c l o s t r i d i a l m y o s i t i s ) , which is a c o m p l i c a tion of tile s e v e r e a n d s o m e t i m e s n e g l e c t e d w o u n d , t e t a n u s n o t only i s a c o m l ; l i c a t i o n of s e v e r e or n e g l e c l e d or old w o u n d s b u t m a y o c c u r also in i n d i v i d u a l s wilt, very m i n o r a n d v e r y s u p e r f i c i a l w o u n d s o r in i~ldividu;,lu w i t h o u t e v e n a d e r n o n s t r a b l e w'ound ~ ( T a b l e 4}. As T a b l e 5 sh.ows, a t t h e K i n g "2 J,o"V~' a r o M e m o r i a l H o s p i t a l in Bonlbay, I n d i a , l h e lylms of w o u n d s r e s p o n s i b l e for t e t a n u s v a r i e d f r o m i n j u r i e s wiih a n i n c i d e n c e of 44.5'~;~ 10
TABLE
4.~CLASSIFICATION
OF INJURIES
ASSOCIATED WITII
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(~IVEN I N J U R Y
'~J'o'I'AI, CA.%I,~'S
l ) u n c t ure L a c e r a tim ~ Miscellaneous Abrasion No wound Injection Crush Surgical 1)enta 1
87 84 42 28 22 20 10 3 l
'1"o'r ,~L
FATAl, CAriES
21L 3 28.3 14.1 9.4 7.4 6.7 3.4 1.0 0.3
297
.;9
1 ()0. o
CASI,i-FATAL~T~" I{A'rlo
55 48 28 l (i ]3 15 5 "2 Q
63.2 57. l ()). ] 57.1 59.1 75.(1 50.0 66.7
fSff
6 I. 3
::'P;xcludes n e o n a t e s , o n e p e r s o n of u n k n o w n a g e , a n d cases w i t h u n k n o w n o u t COllie. .
~
.
.
.
.
.
.
.
.
! A B L L 5.~. ROUTE OF INFECTION OF C L. T E T A N I IN A "LAltGE SERIES OF TETANUS CASES AT TttE K I N G EDWARD M E M ) R I A L HOSPI%~L, BOMBAY, INI)IA~ 5~ 1 ,)raL
%
892 406 29,2 2N~ C;7 32 2(1 15
44.5 20.2 14.5 14.2 3.3 1.6 1.0 ).
Injury Otorrltea Neonatorunt Unknown':: 1~u e r pe ra I Injection V a c c i n a t ion ( ) p e r a ( ion
'::We a s s u m e t h a t P a t e l a n d Mehla15~; inc l u d e d in t h e " U n k n o w n " c a t e g o r y c a s e s in v,-}lich n o s o u r c e of e n i r y w a s fouIld on ~Jxztllli n a i i o n o r was r e t ) o r t e d .
TABLE
6 . m S r r g OF INJ1JRY OF TETANUS CASES IN TIlE UNITED STATES, 1 9 6 5 - 1 9 6 6 ~s
•
Foot J~and Leg Arm t t e a d a n d ne~.'k O t h e r lo,::ations Trunk 4
¢
•
.
(.d~ x o ] o r a L
1 . JOTAL
O,q
t ,.o • JOTAL
CASE" ]['AT ALI 'r Y I£\TIO
138 90 7J 2'9 21 il 3 7
:]7.4 24.4 19.2 7.8 5.7 3.5 J .,9
71.0 66.6 70.4 72.4 57. I 09.2 28.(1
;t6:)
109.0
68.3
11
T A B L E 7.~TETANUS, U N I T E D STATES, 1968 AND 1969, W H E R E I N J U R Y OCCURRED *'t9 LOCATION
TOTAL
Home Other specified locations Farm Garden Factory
147 40 24 21 5
GmXND TOTAL
237
(}o OF TOTAh
62.0 16.9 10.1 8.9 2.1 100.0
::"Excludes neonates, and is based on persons with known age and outcome, and for whom locality at the time of injm'y is known.
TABLE
8. A~E 62 38 69 65 8 3 65 63
T A B L E 9. AGE 28 26 23 26 26 23
POSTOPERATIVE T E T A N U S IN T H E U N I T E D STATES, 1965-19664s SURGICAL PROCEOURE Amputation of gangrenous foot Unknown Amputation of finger Hemorrhoidectom y
Bunionectomy Ruptured appendix Colectomy Incision and drainage of perirectal abscess Wart removal
OUTCOME
Died Recovered Died Died Recovered Recovered Died Died Died
TETANUS CASES RELATED TO ABORTION AND PARTURITION IN THE UNITED STATES, 1965--19664s CLINICAL BACKGROUND
OUTCO3I E
Spontaneous abortion Self-induced abortion A :Normal delivery 10 days prior to onset j Spontaneous deliver~,, with flint-degree perir~-al tear Incomplete abortion Septic abortiori
Died Died Died Died Died Die~t
to e l e c t i v e o p e r a t i o n s w i t h a n i n c i d e n c e of 0.7%. T a b l e s 6 a n d 7 i n d i c a t e t h e l o c a t i o n s of o c c u r r e n c e . T a b l e s 8 a n d 9 s u m m a r i z e cases of t e t a n u s a f t e r s u r g i c a l p r o c e d u r e s a n d i n o b s t e t r i c cases. FQr s u r g e o n s w h o t a k e c a r e of bowel o b s t r u c t i o n s , a case of t e t a n u s foll o w i n g r e s e c t i o n of a g a n g r e n o u s b u t u n p e r f o r a t e d s m a l l i n t e s t i n e , w h i c h w a s i n v o l v e d in a n o b s t r u c t i o n , m a y be of. c o n s i d e r a b l e interest.39 S h e r m a n 1 7 S h a s u r g e d t h a t t e t a n u s p r o p h y l a x i s be p r o v i d e d f o r t h e b u r n case, a n d r e c e n t l y C h e r u b i n 3 4 h a s e m p h a s i z e d t h a t n a r c o t i c a d d i c t s m a y develop tetanus. A n u m b e r of y e a r s ago, R o b i n s o n e t al. 167 p o i n t e d o u t t h a t - - p r i o r to present-day technics operating room dressings, instruments, catgut and d u s t w e r e i n c r i m i n a t e d as s o u r c e s of C1. t e t a n i for t e t a n u s cases. I n a r e c e n t s t u d y to d e t e r m i n e w h e t h e r s h e e p s k i n s u s e d as b e d p a d s in
i2
t h e p r e v e n t i o n of bedsores could be a source of the C1. t e t a n i for t e t a n u s , Cowling, et al..~o concluded t h a t c o m m e r c i a l t a n n i n g m e t h o d s effectively sterilize s h e e p s k i n s so t h a t t h e r e is no risk of t h e i r c o n v e y i n g t e t a n u s spores to hospitals a n d t h a t the sporicida] effect of g l u t a r a l d e h y d e , w h e n used on sheepskins, is confirmed.
F. PATHOGENESIS T h e m e r e fact t h a t C1. t e t a n i is p r e s e n t in a w o u n d does not n e c e s s a r i l y m e a n t h a t the p a t i e n t has t e t a n u s or t h a t h e will develop it:. T h e organisms will p r o l i f e r a t e only in t h e p r e s e n c e of a n o x i d a t i o n - r e d u c t i o n potential far lower t h a n t h a t existing in n o r m a l living tissue. Once Cl. t e t a n i begins to grow, it p r o d u c e s t e t a n o s p a s m i n , w h i c h is t r a n s p o r t e d to the c e n t r a l n e r v o u s system, w h e r e it becomes fixed a n d is responsible for t h e d e v e l o p m e n t of t e t a n u s . As SmithlSl has p o i n t e d out, t h e r e have been differences of o p i n i o n c o n c e r n i n g the site of action of t e t a n o s p a s m i n a n d c o n c e r n i n g the r o u t e by which it spreads, b u t it now seems established t h a t t h e toxin acts in the s p i n a l cord a n d in the b r a i n s t e m a n d t h a t it s p r e a d s c e n t r a l l y along m o t o r nerve t r u n k s a n d u p the s p i n a l cord. T e t a n u s ~411 follow the i n t r a venous injection of toxin into a n i m a l s , b u t the r o u t e by which toxin in t h e blood e n t e r s the n e r v o u s s y s t e m is not clear. T o x i n i n j e c t e d i n t r a m u s c u l a r l y a p p a r e n t l y s p r e a d s not only by passing u p m o t o r nerves but also by a b s o r p t i o n into the blood, a n d it has been suggested t h a t v a s c u l a r s p r e a d is the m o r e i m p o r t a n t route in g e n e r a l i z e d tetanus. I n a s t u d y of 22 a u t o p s y cases of t e t a n u s i n c l u d i n g 3 n e o n a t e s . E b i s a w a a n d M a t s u k u r a 6 3 concluded t h a t : 1. P u l m o n a r y complications are the f r e q u e n t a n d prognostically imp o r t a n t pathologic findings in t e t a n u s p a t i e n t s , p a r t i c u l a r l y w h e n t h e y a r e t r a c h e o s t o m i e d or w h e n t h e y survive m o r e t h a n a week a f t e r a d m i s s i o n to a hospital. 2. D e g e n e r a t i o n of s t r i a t e d muscles, a l t h o u g h of a v a r i a b l e d e g r e e a n d involving d i a p h r a g m , intercostal, psoas, rectus a b d o m i n i s a n d o t h e r m u s cles, m a y be a f r e q u e n t finding in t e t a n u s . T h e m a i n pathologic c h a n g e s in t h e s t r i a t e d muscles consist of bleeding, loss of stripes, r u p t u r e , i n t e n s e s t a i n i n g a n d h o m o g e n i z a t i o n , lysis a n d d i s a p p e a r a n c e of myofibrils. T h e s e c h a n g e s i n c r e a s e in s e v e r i t y with i n c r e a s i n g survival t i m e of t h e p a t i e n t . 3. Tile d e g e n e r a t i v e c h a n g e s in r e s p i r a t o r y m u s c l e s p l a y a s u b s t a n t i a l role in t h e v e n t i l a t o r y failure of the p a t i e n t . T h e y also e x p l a i n t h e m y a s t h e n i c p h e n o m e n a observed in t h e convalescent period of t e t a n u s , such as p o s t - t e t a n i c p a r a l y s i s of r e s p i r a t o r y a n d o t h e r muscles. 4. S o m e of t h e p a t i e n t s die of f u n c t i o n a l r a t h e r t h a n m o r p h o l o g i c a l l y recognizable causes. A f t e r a n e x h a u s t i v e s t u d y of n e o n a t a l t e t a n u s , Pinheiro160 c o n c l u d e d that: 1. T h e l i t e r a t u r e a s s u m p t i o n t h a t the s t u m p of the u m b i l i c a l cord cons t i t u t e s the p r i n c i p a l p o r t a l of e n t r y of t h e t e t a n i c infection is correct. 2. B l o o d - c i r c u l a t i n g t e t a n u s toxin is found rarely. I n most cases of neon a t a l t e t a n u s , t h e t e t a n o s p a s m i n has a l r e a d y b e e n fixed by l h e cells of tlle c e n t r a l n e r v o u s s y s t e m at the t i m e of admission. S u c h a finding is of 13
u t m o s t i m p o r t a n c e for prognosis in t h a t the infant's fate is p r e d e t e r m i n e d even before hospitalization. Therefore, it m a y be a s s u m e d t h a t the m a n a g e m e n t and cure of t e t a n u s in the newborn infant w i t h o u t the use of a n t i t e t a n i c s e r u m is possible and t h a t use of tetanus antitoxin in the course of t r e a t m e n t m a y not be as f u n d a m e n t a l as has been supposed. 3. T h e r e is a s u r p r i s i n g l y low toxin-producing capacity of Cl. t e t a n i in the cord stump, since the sloughing off of the distal cord eliminates the focus of the infection.
O. CLINICAL PICTURE " I n m y clinical experience I have never seen such a t e r r i f y i n g disease as t e t a n u s . " ~ F R A N K GLENN89
1. INCUBATION :PERIOD In a 1968 report, the U S P H S C e n t e r for Disease Control reported t h a t the m e d i a n incubation period for fatal cases and nonfatal cases was 7 and 8 days, respectively. T h e range was from 1 to 54 days. However, 88% of all cases had dates of onset within 14 days or less from the time of injury.4S T h e longer i n c u b a t i o n periods are p a r t i c u l a r l y likely to occur w h e n the p a t i e n t has received p a r t i a l protection from h u m a n , equine or bovine antitoxin or w h e n secondary surgical revision or m a n i p u l a t i o n of wounds especially war w o u n d s ~ i s performed. R a r e l y , w h e n a scar of a wound has of necessity been explored surgically, t e t a n u s has occurred m a n y years after the time of the p r i m a r y wound.76
2. SYMPTOMS AND SIGNS T e t a n u s almost always a p p e a r s in a general form, but occasionally it m a y a p p e a r as local tetanus. Usually, with the l a t t e r form, general symptoms occur sooner or later, but t h e n the disease is likely to be milder a n d responsible for a lower m o r t a l i t y rate t h a n the general type usually seen.76 I n the familiar general form, the earliest indications of infection usually become evident from 1 to 2 weeks after injury. T h e severity of the clinical picture a n d the m o r t a l i t y rate are roughly inversely proportional to the d u r a t i o n of the i n c u b a t i o n period. S o m e patients have p r o d r o m a l s y m p t o m s of restlessness and headaches. In others, the first s y m p t o m s are those s t e m m i n g from the developing muscle rigidity, with vague discomfort in the jaws, neck or l u m b a r region. A t a n early stage, spasm of the muscles of m a s t i c a t i o n causes t r i s m u s and difficulty with chewing, i.e., lockjaw. S u s t a i n e d contraction of the facial muscles produces a distorted grin (risus sardonicus). S p a s m of the p h a r y n g e a l muscles m a k e s swallowing difficult. Stiff neck and opisthotonos also are a m o n g the early signs. Progressively, other muscle groups become involved, with tightness of the chest a n d rigidity of the a b d o m i n a l wall. the back a n d the limbs. Generalized tonic convulsions are f r e q u e n t a n d exhausting. A n y s u d d e n j a r or sound., such as a h y p o d e r m i c injection or the fall of all object onto the floor., will excite such generalized convulsions. In association with these convulsions, there sometimes is 14
r
.
.
2
*
¸7¸i!i~i~
Fro. 9 ( a b o v e ) . ~ A child with e arly tetanus. P a t i e n t e.*:hibits risus sardonicus, trismus, opisthotonos and extended lower extremities. (Courtesy of E. Velasco-Joven.) FIe,. 10 (rigl~t).~Convalescent stage o f tetanus. T h e patient is trying to remain upright. N o t e the traces of risus sardonicus, trismus, rigidity of the neck and stiffness of the body and extremities. (Courtesy of E . Velasco-Joven.)
s p a s m of t h e l a r y n g e a l a n d r e s p i r a t o r y m u s c l e s with, s o m e t i m e s , a resulting, possibly fatal, a c u t e a s p h y x i a . Mercilessly, t h e p a t i e n t is m e n t a l l y c l e a r t h r o u g h o u t t h e course of t he disease, a n d he suffers g r e a t p a i n from t h e m u s c l e spasms. T h e pulse r a t e is e l e v a t e d a n d t h e r e is p r o f u s e p e r s p i r a t i o n . F e v e r m a y or m a y not be p r e s e n t . N e u r o l o g i c e x a m i n a t i o n discloses h y p e r a c t i v e t e n d o n reflexes. often w i t h s u s t a i n e d clonus. T h e r e a r e no s e n s o r y changes. If t h e p a t i e n t survives, the i n t e n s i t y of the m u s c l e c o n t r a c t i o n s m a y begin to d i m i n i s h slowly d u r i n g a b o u t t h e second week. C o m p l e t e recove r y m a y t a k e several m o n t h s . Occasionally, m i l d cases occur in w h i c h t h e r e is only m o d e r a t e m u s c l e r i ~ d i t y w i t h o u t t e t a n u s seizures. I n a p e r s o n w i t h o u t t e t a n u s toxoid prop h y l a x i s p r i o r to i n j u r y , the a d m i n i s t r a t i o n of toxoid m a y forestall tim d e v e l o p m e n t of s e v e r e t e t a n u s a n d m a y r e s u l t in only a mild t e t a n u s or a local t e t a n u s involving only the m u s c l e s a r o u n d t h e site of i n j u r y . E v e n w h e n t r e a t m e n t is " a d e q u a t e , " t h e mortality_ r a t e m a y be u,~n°~o or higher. O lder c h i l d r e n a n d y o u n g e r a d u l t s r e s p o n d b e t t e r t h a n y o u n g e r c h i l d r e n a n d older adults. M o s t d e a t h s occur w i t h i n 10 d a y s of the o n s e t of th e illness. P a t i e n t s who live as long as a week a n d a half h a v e good p r o s p e c t s of c o m p l e t e recovery. W h a t c a n h a p p e n to a m e m b e r of a n u n i m m u n i z e d civilian p o p u l a t i o n exposed to a m i l i t a r y conflict was described vividly by Glenn'S'*, 90 in conn e c t i o n w i t h W o r l d W a r II: 15
" T h e most f r e q u e n t l y observed clinical p i c t u r e was as follows: A p a t i e n t w i t h a w o u n d of c o n s i d e r a b l e e x t e n t in a n e x t r e m i t y would be u n a b l e to o p e n his m o u t h by 5 to 7 d a y s a f t e r i n j u r y . T h e r e would be m a r k e d trism u s a n d stiffness of the neck muscles. A s s o c i a t e d w i t h t h e s e t w o findings t h e r e would exist, or soon follow, mild s p a s m s which fixed the h e a d , body, a n d e x t r e m i t i e s in a s t r a i g h t line orthotonos. W i t h i n a m a t t e r of h o u r s as the s e i z u r e s b e c a m e m o r e p r o n o u n c e d a n d m o r e f r e q u e n t , o p i s t h o t o n o s d e v e lo p e d with g r e a t e r i n v o l v e m e n t of t h e back muscles, so t h a t d u r i n g a s p a s m the back b e c a m e a r c h e d a n d the body was t r u l y s u p p o r t e d by t h e h e a d a n d heels. C o n c o m i t a n t l y , t h e r e would a p p e a r the classical risus s a r d o n i c u s with elevation of t h e e y e b r o w s a n d r e t r a c t i o n of the c o r n e r s of th e m o u t h , p r o d u c i n g a g r i m a c e t h a t exposed t h e locked jaws. O r t h o t o n o s was observed to be followed not only by o p i s t h o t o n o s b u t e m p r o s t h o t o n o s . S p a s m a n d rigidity of the a b d o m i n a l m u s c l e s was a n e a r l y a n d c o m m o n finding t h a t p r e c e d e d g e n e r a l i z e d seizures a n d p e r s i s t e d d u r i n g a n d bet w e e n them. As s p a s m s b e c a m e m o r e i n t e n s e over a period of h o u r s or days, t h e y r e n d e r e d b r e a t h i n g difficult. W i t h t h e muscles of t h e n e c k a n d d i a p h r a ~ n and the i n t e r c o s t a l s in spasm, the a i r e x c h a n g e was so r e d u c e d t h a t ti~e lips and nail beds b e c a m e very cyanotic. D u r i n g the severe s p a s m s , t h e r e was profuse p e r s p i r a t i o n , a n d p a i n was e x c r u c i a t i n g and u n b e a r a b l e . As the disease p r o g r e s s e d a n d t h e s p a s m s i n c r e a s e d in severity a n d f r e q u e n c y , the p a t i e n t b e c a m e p h y s i c a l l y e x h a u s t e d but r e m a i n e d m e n t a l l y clear a n d terrified. An occasional p a t i e n t died d u r i n g a spasm, but t h e m a j o r i t y , following c o m p l e t e e x h a u s t i o n , b e c a m e listless, a n d the d i m i n i s h i n g convulsive s e i z u r e s w e r e followed by d e a t h . " G l e n n r e p o r t e d t h a t in the b a t t l e for M a n i l a in 1945 t h e r e w e r e 473 r e p o r t e d cases of t e t a n u s in a p p r o x i m a t e l y 12,000 w o u n d e d civilians who, so far as is known, h a d not had t e t a n u s toxoid i n o c u l a t i o n s before being injured. T h e incidence of t e t a n u s was a l m o s t 40 per 1,000 w o u n d e d civiltans (3.97[,). T h e m o r t a l i t y in t h e s e 473 eases was 82.1t'~.
3. LABORATORY DATA T h e diagnosis of t e t a n u s m u s t be based on t h e clinical picture, for labo r a t o r y e x a m i n a t i o n s a r e of little assistance. T h e d e m o n s t r a t i o n of CI. t e t a n i in a w o u n d does not prove the diagnosis of t e t a n u s : the failure to d e m o n s t r a t e the bacillus in a w o u n d does not e l i m i n a t e the possibility of tetantls. T h e u r i n e is norrnal unless s e c o n d a r y u r i n a r y t r a c t infection occurs. T e t a n u s itself p r o d u c e s a slight elevation in the leukocyt e count, but s e c o n d a r y infection m a y p r o d u c e g r e a t e r elevation. T h e c e r e b r o s p i n a l fluid often is u n d e r i n c r e a s e d pressure, but o t h e r w i s e it is not r e m a r k -
4. A PATIENT'S PI~OGRI'k¢;SNOTI.~S Vt, ry r;lrely in the surgical l i l e r a t u r e is t h e r e found the p a t i e n t ' s l~rogress noit:s, After giying the clinician's a(,count of successful t r e a i m e n l (~f Ii'|IIIIIIS ill 11 20-y~,ar-~fld a n a l y l i c a l clwmist, (;oh, r,t al. '~'2 s u b m i t t e d the t'~)ll~xving rel~orl ()f the l):ttient: ""I'll(, tirsl sylnl)lolns sl;irted :il)l)roxinlgllely a week ;tfier l lind cul lny 16
finger. T h e y consisted in a s u d d e n t i g h t e n i n g a r o u n d m y t h r o a t causing e x t r e m e difficulty in b r e a t h i n g a n d m a k i n g swallowing virtually impossible. D u r i n g this spasm, coughing or e x p e c t o r a t i o n a d d e d to the difficulty in obtaining air as m y t h r o a t seemed to collapse when I tried to inspire. " S p a s m s of the t h r o a t usually a p p e a r e d at rest a n d lasted a b o u t ten m i n u t e s in the early stages. L a t e r on, t h e y were more prolonged. Two days after admission they seemed continuous, and about this time ray voice became reduced to a w h i s p e r and m y j a w felt stiff. T h e s y m p t o m s from then on are only snatches of m e m o r y . I felt like snarling, m y u p p e r lip i n v o l u n t a r i l y d r a w i n g back over the teeth, and a peculiar twitch was vaguely p r e s e n t in m y limbs. " D u r i n g the whole of the illness I can r e m e m b e r no acute p a i n except for joint cramp. Double vision was p r e s e n t and this could, I suppose, have been an effect of the drug. ,(He saw double for two days before ' T u b a r i n e ' was begun. L.B.C.) " M o v e m e n t . T h e r e was a certain a m o u n t of discomfort owing to lying in one position. T h i s was definitely helped by being t u r n e d ov.er every two hours. K n o w i n g this was to be done b r o u g h t g r e a t relief, and, of course, it was s o m e t h i n g to look forward to, too. G r e a t discomfort was felt, especially at night when awaking. As far as I can r e m e m b e r this was due to hallucinations at the point of time w h e n the d r u g was due to wear off. On the whole, comfort could not have been better. A point I am quite sure about is the position of legs. I gained g r e a t e r comfort w h e n the positions of m y legs were varied . e.g., first two hours both straight, second two hours lower one straight, third two hours both bent with thighs horizontal. "Eyes. A m a j o r concern was the eyes, which definitely functioned peculiarly while I was u n d e r the drug ( T u b a r i n e ) . :Firstly, they crossed themselves, giving double vision. Secondly, large objects seemed to be m u c h c l o s e r ~ e . g . , w h e n I was lying on my back the ceiling seemed some 18 inches from m y nose. T h e m o r a l here is not to be on one's back. E y e s were improved w h e n I was washed; in fact, d a m p eyes felt n o r m a l for a t,ime. " H e a r i n g . T h i s was acute: every sound seemed magnified; I could hear, quite distinctly, the doctors h a v i n g a good old talk. T h i s was helpful as it occupied m y m i n d the worst times were w h e n there was n o t h i n g to hear. Silence was oppressive, a l t h o u g h I realised one couldn't have a continuous noise vibrating t h r o u g h the ward. I ' m grateful for the m a n y passages read to me when w a k i n g after a n i g h t m a r e . T h e radio was also helpful. " T a k e n off the r e s p i r a t o r for suction. A f t e r several days I lost the fear of never being able to b r e a t h e when off the respirator, as it was a l w a y s restored quickly. I only had one really scaring time, when the tube fell out after replacement. I know it felt more secure w h e n the tube from the ventilator was s c r e w e d into the t r a c h e o s t o m y socket a n d not just p u s h e d in. Also when the tube was t a k e n off before the suction a p p a r a t u s was m a d e ready, the time t a k e n was terrifyingly long. " T h i r s t . ~ I enjoyed the 'lime' m o u t h w a s h e s and the ice-water m o u t h washes, especially in the hot weather. T h e y were a brain-wave." Of p a r t i c u l a r interest is the s t a t e m e n t that "I can r e m e m b e r no acuIe l)ain, except for joint cruml)." This l)alient m u s t have been a t i e n d e d carefully. 17
H. DIFFERENTIAL DIAGNOSIS E a r l y or m i l d t e t a n u s m a y resemble c e r t a i n Other conditions, b u t severe t e t a n u s is likely to be confused With few o t h e r diseases.76, 139 A frequent, diagnostic p r o b l e m is differentiation of h e t e r o l o g o u s s e r u m sickness from e a r l y tetanus. If p a t i e n t s with i n j u r i e s a r e given heterologous e q u i n e or bovine t e t a n u s antitoxin; a p p r o x i m a t e l y 5 - 3 0 % s u b s e q u e n t l y will d e v e l o p s e r u m sickness w i t h t e m p o r o m a n d i b u l a r a r t h r a l g i a a n d trismus, a r t h r a l g i a of o t h e r joints, u r t i c a r i a a n d generalized adenitis. T e t a n y is less severe t h a n t e t a n u s , u s u a l l y follows o p e r a t i o n s on t h e thyroid gland a n d affects the u p p e r e x t r e m i t i e s p r i m a r i l y . T h e muscle contractions of t e t a n y are elicited by p r e s s u r e on the nerves leading to the cont r a c t i n g muscles. M e n i n g i t i s a n d e n c e p h a l k i s m u s t be differentiated from t e t a n u s , but it is u n u s u a l for the a l e r t p h y s i c i a n to be seriously misled. R a b i e s ( h y d r o p h o b i a ) is exhibited by the p a t i e n t ' s i n a b i l i t y to swallow as a n e a r l y s y m p t o m , drooling of saliva and s p a s m s of the muscles of deglutition. L a t e r in the course of the disease, it is c h a r a c t e r i z e d by feverl anxiety, e x c i t e m e n t , d e l i r i u m , h y p e r e s t h e s i a a n d convulsions. R a b i e s involves part i c u l a r l y t h e muscles of respiration. A h i s t o r y of a n i m a l bite u s u a l l y is obtainable. T h e clinical p i c t u r e of s t r y c h n i n e poisoning, w i t h . h y p e r e x c i t a b i l i t y of muscles, opisthotonos, risus s a r d o n i c u s a n d tonic convulsions, m a y m i m i c t e t a n u s closely, except t h a t the muscles are relaxed b e t w e e n seizures in s t r y c h n i n e intoxication, w h e r e a s s p a s m tends to persist in tetanus[ Moreover, in s t r y c h n i n e poisoning, the jaws a n d face are not p a r t i c u l a r l y affected. A n a d e q u a t e l y t a k e n h i s t o r y m a y be g r e a t l y helpful in differentiating t e t a n u s from rigidity due to p h e n o t h i a z i n e t r a n q u i l i z e r drugs and in differe n t i a t i n g t e t a n u s from lead e n c e p h a l o p a t h y . A c u t e psychoses m a y be quite difficult' to differentiate from earl,,, or mild t e t a n u s , a n d a v e r y t h o r o u g h psychiatric e v a l u a t i o n a n d a test of time m a y be n e c e s s a r y to m a k e a n exact diagnosis. 176. 196 Local t e t a n u s m a y closely s i m u l a t e the s p a s m s of a localized group of v o l u n t a r y m u s c l e s due to soft tissue or bone injuries. T r i s m u s not d u e to t e t a n u s m a y occur with p e r i t o n s i l l a r a b s c e s s a n d o t h e r local infections of the m o u t h a n d cervical regions, and with den'tor n a n d i b u l a r problems. D y s p h a g i a , suggestive of tetanus, m a y a c t u a l l y be the result of u p p e r r e s p i r a t o r y infections. N e o n a t a l t e t a n u s m a y be confused with meningitis, h y p o c a l c e m i c t e t a n y , sepsis a n d i n t r a c r a n i a l h e m o r r h a g e , a n d m a y r e q u i r e cerebrospinal fluid analyses, blood c h e m i s t r y studies, w o u n d and blood c u l t u r e s and neurosurgical e v a l u a t i o n for a correct diagnosis. ,.
I. C O M P L I C A T I O N S C o m b i n a t i o n s of c o m p | i c a t i o n s t h a t occur m a y be responsible for death.7~, P u l m o n a r y atelectasis m a y be followed by p n e u m o n i a , which is to be dreaded, for it seriously lessens tile c h a n c e s for recovery. T r a u m a t i c glossitis is seen often. Compression fractures of the v e r t e b r a e m a y result from the convulsive seizures.20, 5:3 D e c u b i t a l ulcers a r e likely to occur in p a t i e n t s 18
u n d e r h e a v y sedation. Constipation, fecal i m p a c t i o n a n d u r i n a r y r e t e n t i o n a r e e n c o u n t e r e d often. Cystitis a n d p y e l o n e p h r i t i s m a y develop in p a t i e n t s r e q u i r i n g c a t h e t e r i z a t i o n . One to 3 weeks a f t e r the a d m i n i s t r a t i o n of heterologous e q u i n e or bovine antitoxin, s e r u m sickness m a y occur. If homologous s e r u m [ T I G ( H ) ] is given, such sickness will not occur. Foot drop a n d m u s c l e c o n t r a c t u r e s m a y follow prolonged unconsciousness with the limbs in poor position. A s p h y x i a from r e s p i r a t o r y or l a r y n g e a l m u s c l e s p a s m or from a s p i r a t i o n of secretions, vomitus or food m a y be the i m m e d i a t e cause of death. V a r i o u s drugs a n d a d j u n c t i v e m e a s u r e s are used in t h e m a n a g e m e n t of a p a t i e n t with t e t a n u s ; hence, it m a y be almost imPossible to decide the exact cause of s u b s e q u e n t complications from drugs. I n 1964, H a r r i s o n e t al. 95 stressed the i m p o r t a n c e of following c o m p l e t e blood counts w i t h p r o m p t investigation of the clotting m e c h a n i s m should bleeding occur, a n d discussed 3 cases of t e t a n u s with u n u s u a l bleeding diatheses developing d u r i n g t r e a t m e n t . A 47-year-old w o m a n h a d severe hypop r o t h r o m b i n e m i a , factor V I I a n d X deficiencies a n d a large r e t r o p e r i t o n e a l h e m a t o m a , which r e q u i r e d massive t r a n s f u s i o n a n d p a r e n t e r a i a d m i n i s t r a tion of v i t a m i n K. T h e p r o t h r o m b i n activity r e t u r n e d to n o r m a l a n d she recovered. A 6-year-old boy h a d t h r o m b o c y t o p e n i c p u r p u r a with a p l a t e l e t c o u n t of 8,000; the condition was t r e a t e d w i t h steroids b u t was 3 weeks in resolving. I n t r a v a s c u l a r h e m o l y s i s occurred on two occasions in a 3-year-old boy d u r i n g t r a n s f u s i o n w i t h packed cells. T h e p a t i e n t ' s h e m a t u r i a cleared rapidly without treatment. I n ]969, Okulskil49 r e p o r t e d that, in 25 t e t a n u s p a t i e n t s , low p r o t h r o m b i n levels, i m p a i r e d t h r o m b i n g e n e r a t i o n a n d i n c r e a s e d p l a s m a fibrinolytic activity w e r e observed. Also, blood p l a t e l e t counts a n d p r o t h r o m b i n c o n s u m p tion in s e r u m w e r e slightly decreased. B l e e d i n g times w e r e slightly s h o r t e r t h a n normal. T h e blood a n d recaleified p l a s m a clotting time, p l a s m a t h r o m bin t i m e a n d fibrinogen levels w e r e n o r m a l . T h e observed c h a n g e s w e r e related to the evolution of the disease. Prothrombin" levels w e r e decreased m o s t in e a r l y p h a s e s of the disease, increas: ing g r a d u a l l y in the course of the n e x t few weeks. Blood p l a t e l e t counts a n d s e r u m p r o t h r o m b i n c o n s u m p t i o n also r e t u r n e d to n o r m a l levels. A slight t r a n s i e n t increase in fibrinogen level was a c c o m p a n i e d by decreased fibrinolyric activity. M e a n bleeding time showed n o n c h a r a c t e r i s t i c fluctuations, a n d blood clotting time g r a d u a l l y b e c a m e longer in the course of hospitalization, a t t a i n i n g n o r m a l m e a n values. Differences in the b e h a v i o r of some of these tests w e r e observed b e t w e e n mild a n d severe cases of tetanus. M e a n p r o t h r o m b i n values w e r e lower in severely ill p a t i e n t s a n d fibrinogen levels were higher. I n the g r o u p s of severly ill p a t i e n t s , g r e a t e r i m p a i r m e n t of p r o t h r o m b i n c o n s u m p t i o n in s e r u m a n d longer p l a s m a p r o t h r o m b i n times w e r e observed also. I n t h e long-term e v a l u a t i o n of t h e clinical picture, the neurologic a n d e l e c t r o e n c e p h a l o g r a p h i c s e q u e l a e of t e t a n u s m u s t be considered.10.~ Previously r e p o r t e d s y n a p t i c c h a n g e s in e x p e r i m e n t a l t e t a n u s led Illis a n d Taylor105 to a clinical fol|ow-up of survivors f r o m tetanus. T w e n t y - f i v e were followed for a period r a n g i n g from 3 m o n t h s to 11 y e a r s a f t e r recovery. F e a t u r e s noted in the follow-up included irritability, s | e e p d i s t u r b a n c e , fits, myoclonus, decreased libido, postural h y p o t e n s i o n and e]ectroencephalographic abnormalities. 19
J.
PROPHYLAXIS T h e four bases on w h i c h ~.he p y r a m i d - o f t e t a n u s p r o p h y l a x i s f o r . t h e w o u n d e d is based are (1) t e t a n u s toxoid, ( 2 ) surgical care, (3) a n t i t o x i n a n d (4) e m e r g e n c y m e d i c a l i d e n t i f i c a t i o n devices. F o r centuries, surgical cm'e was the only i m m e d i a t e l y available t y p e of t e t a n u s p r o p h y l a x i s for the victim of t r a u m a . T h e n , at t h e l a t t e r p a r t of the n i n e t e e n t h c e n t u r y , heterologous a n t i t o x i n s w e r e developed; a f t e r Wo'rld W a r I, toxoid b e c a m e available; d u r i n g W o r l d W a r II, e m e r g e n c y m e d i c a l identification devices w e r e used; and, a b o u t the m i d d l e of t h e t w e n t i e t h c e n t u r y , homologous t e t a n u s a n t i t o x i n b e c a m e a realityl F r o m t h e e a r l y p a r t of t h e t w e n t i e t h c e n t u r y , the A m e r i c a n College of Surgeons, t h r o u g h its C o m m i t t e e on T r a u m a , has b e e n active in d e v e l o p i n g t e t a n u s p r o p h y l a x i s a n d in e n d e a v o r i n g to hell) the m e d i c a l , profession in crystallizing its t h i n k i n g c o n c e r n i n g s u c h prophylaxis.S6, 165 A l t h o u g h a significant p e r c e n t a g e of the m a l e p o p u l a t i o n h a s received t e t a n u s toxoid w h e n in m i l i t a r y service, m a n y w o m e n a r e not protected.74 E v e r y i n j u r y p r e s e n t s its own p r o b l e m s to the physician:called on to t r e a t it, b u t active i m m u n i z a t i o n w i t h t e t a n u s t o x o i d ~ a s far as the risk of t e t a n u s is c o n c e r n e d ~ h a s a l m o s t oversimplified t e t a n u s p r o p h y l a x i s in the m a j o r i t y of i n j u r e d persons, in t h a t a small booster dose fisually is given to those previously i m m u n i z e d a n d is m o s t efficacious in p r e v e n t i n g tetanus. A m a j o r problem, however, is t h a t - s o m e t i m e s n e i t h e r the p a t i e n t n o r his p h y s i c i a n c a n be c o m p l e t e l y c e r t a i n of p r i o r protectionl by toxoid unless the p a t i e n t c a r r i e s a n e m e r g e n c y medical identification device i n d i c a t i n g p r o t e c t i o n or sensitivity to toxoid. I n association w i t h the ever-increasing ~ use of t e t a n u s toxoid a n d the s t e a d i l y dec-lining incidence of t e t a n u s , t h e r e possibly has developed a dec r e a s i n g aware~ness b y p h y s i c i a n s t h a t t e t a n u s c a n occur. T h e possibility of t e t a n u s s h o u l d a t least be t h o u g h t of in the individual w i t h u n e x p l a i n e d i r r i t a b i l i t y or convulsions. I n view of these c o n s i d e r a t i o n s a n d in light of r e c e n t d e y e l o p m e n t s in r e g a r d to t e t a n u s p r o p h y l a x i s , r e - e m p h a s i s of c e r t a i n concepts seems w a r r a n t e d at this time. T h a t t e t a n u s c a n b e ' p r e v e n t e d is a m p l y d o c u m e n t e d . T h e incidence of t e t a n u s in a group of w o u n d e d civilians Without t e t a n u s toxoid i m m u n i z a tion d u r i n g W o r l d W a r : I I w a s 900,000% g r e a t e r t h a n in w o u n d e d U n i t e d S t a t e s A r m y p e r s o n n e l w i t h such immunization.SG, sg~ I.~5, 126
1. WOUND PREVENTION F o r t e t a n u s to occur, C1. tetani m u s t gain e n t r a n c e to the body by a w o u n d even t h o u g h the w o u n d m a y be so small t h a t "it is not redognized, a n d t e t a n u s toxin, Which a c t u a l l y is responsib]e.f0r tetanus, m u s t be produced. If w o u n d p r e v e n t i o n p r o g r a m s w e r e corripletely efficacious e v e r y w h e r e , t e t a n u s would not occur. .
INDIVIDUALIZATION OF WOUNDED PATIENTS Wo.unded p a t i e n t s are individuals. S o m e m a y not have h a d all the indicated t e t a n u s toxoid injections, others m a y h a v e h a d too m a n y toxoid injec20
tions a n d a ' s m a l l n u m b e r m a y be h y p e r s e n s i t i v e to t e t a n u s toxoid.(;9, l~,s, 1s4 A few m a y have insig]fificant wounds; o t h e r s m a y have almost: l e t h a l wounds. M a n y m a y n o t have with t h e m a n u p - t o - d a t e e m e r g e n c y medical identification device with significant t e t a n u s toxoid injection information. H e n c e , i n d i v i d u a l i z a t i o n of each p a t i e n t for t e t a n u s p r o p h y l a x i s m u s t be considered.
3. TOXOID P r o p h y l a c t i c m e a s u r e s r e n d e r e d at the time of i n j u r y to nonactively imm u n i z e d persons Cannot be g u a r a n t e e d to offer protection, but, w i t h prior active i m m u n i z a t i o n , a booster dose at the time of i n j u r y offers effective a n d prolonged protection. I n the p r e v i o u s l y i m m u n i z e d , a very small booster dose of toxoid (0.2 Lf) will p r o d u c e a n t i b o d y levels in 3 weeks, w h i c h can be i n t e r p r e t e d as e q u i v a l e n t to a 1,000-100,000-unit dose of heterologous or homologous passive antibody.133. 197 I n addition, it has been d e m o n s t r a t e d in a n i m a l studies with toxin t h a t a n active booster response a p p e a r s e a r l i e r t h a n c a n be e s t i m a t e d by blood a n t i t o x i n levels.106 To give g r e a t e r p r o t e c t i o n a g a i n s t severe, slight a n d u n r e c o g n i z e d wounds, to m a i n t a i n this protection a n d to avoid the e x t r a c a r e a n d cost e n t a i l e d in active-passive i m m u n i z a t i o n , every p r a c t i c i n g p h y s i c i a n , regardless of his specialty, should m a k e every effort to actively i m m u n i z e w i t h t e t a n u s t o x o i d ~ a n d to keel) actively i m m u n i z e d , his p a t i e n t s , t h e i r families, his f a m i l y a n d himself.7.~ I n r e g a r d to himself, he should r e m e m b e r the words of t h e p a r s o n a b o u t w h o m it is w r i t t e n in the P r o l o g u e to Chaucei"'s Canterbury Tales3a: " T h i s noble e n s a m p l e [ e x a m p l e ] to his s h e e p he y a f [gave], T h a t first ~ e w r o u g h t e , a n d a f t e r w a r d he t a u g h t e . " a) DEVELOPZ~IENT BY RA..SION, DEsCOI~$BEY AND ZOELLER.. D u r i n g the y e a r s i m m e d i a t e l y a f t e r World. W a r I, R a m o n , Descom]Sey a n d Zoeller w e r e able to c u l t u r e Cl. tetani, t~) p u r i f y its toxin a d e q u a t e l y , a n d to l)repare a fluid toxoid suitable for a n i m a l a n d clinical trial.56, as2, 1G,~ b) TYPES OF TOXO1D. A t first, only t h e plain or fluid t y p e of t e t a n u s toxoid was available, but t h e n t h e a d s o r b e d or p r e c i p i t a t e d t y p e of toxoid was developed a n d b e c a m e a v a i l a b l e in one of five p r e p a r a t i o n s ( T a b l e 11). F o r some time, fluid toxoid was p r e f e r r e d by some on the basis of fewer reactions, a m o r e r a p i d a n a r n n e s t i c response, a D a n y s z p h e n o m e n o n w i t h s i m u l t a n e o u s active-passive i m m u n i z a t i o n a n d a h i g h e r incidence of anterior poliomyelitis w i t h a d s o r b e d toxoid.S, lz9 S h o r t - t e r m a n d long-term studies, however, have since i n d i c a t e d that. the adsorbed is the p r e f e r r e d type.32, 92, 124, 131, 198 Specii~cally, TrincalgS has d e m o n s t r a t e d well a n adeq u a t e r e s p o n s e w i t h a d s o r b e d toxoid (Fig. 11).
T A B L E 10.
T Y P E S OF ][:hI]~IUNIZATION A G E N T S
A. Active i m n m n i z a t i o n agents: antigens 1. Dead bacteria or viruses; 2. Attenuated bacteria or virtv;es 3. Toxin-antitoxin mixtures 4. Toxoids or anatoxins: tenanus B. Passive immunization agents: antibtxl'ies 1. Antitoxins: tetanus i m m u n e globulin (human) 2. Antisera
2]
TABLE II. PREPARATIONS OF q~ETANUS Toxom TI:IAT HArm BEEN AVAILABLE57 A. F l u i d (plain) toxoid B. Adsorbed (precipitated or " m i l k y " ) toxoid 1. A l u m precipitated 2, A l u m i n u m hydroxide a d s o r b e d 3. A l u m i n u m h y d r o x i d e precipitated 4. A h m a i n u m phosphate a d s o r b e d 5. A l u m i n u m phosphate precipitated
:l~oxoids distributed by different producers have different concentrations, and world-wide standardization of toxoids continues to be investigated constantly so that m a x i m u m effectiveness can be obtained with a m i n i m u m of side reactions w h e n a toxoid injection is given.211 Of course, at all times, quality control m u s t be m a i n t a i n e d in regard to conversion of all toxins to toxoid, in regard to bacterial contamination and in regard to reversion of toxicity of tetanus toxoid.2 At the International T e t a n u s Conferences, concern was expressed that not all toxoids contain the s a m e number of Lf units per ml. and should be standardized. T h e L i m e s flocculation unit (Lf) is a measure of the purity of tetanus toxoid, and is the amount of toxoid that gives the most rapid flocculation w i t h 1 standard unit of antitoxin. In the past, toxoids have contained C) PURITY OF TOXOID.
FIG. l l . - - B o o s t e r response to tetanus toxoid. T h e s e patients h a d b e e n given tetanus toxoid previously. A protective response is obtained with both fluid and adsorbed toxoid. 1,'~s ( C o u r t e s y of d. Trinca.) i00
;E
lO o
/
Z
/ !
//
i/
Z N 0 Z <
F
0. I
t
x---x o--o
BOOSTER
u~ Z <
0.01
F L U I D (30 S U B J E C T S ) ADSORBED (32 S U B f f E C T S )
"Minimum protective level"
0 0
4
DAYS
7
AFTER
22
BOOSTER
14
INJECTION
possibly as m a n y as 40 Lf per ml. of toxoid. Such h i g h - p o t e n c y toxoids have produced very a n n o y i n g side-reactions. M a n y . o f the t e t a n u s toxoids used presently c o n t a i n a p p r o x i m a t e l y 5-7.5 Lf per 0.5 ml. T h e p u r i t y of l e t a n u s toxoid is expressed as Lf per rag. of protein nitrogen. d ) METHODS OF ADMINISTRATION. Toxoid has been a d m i n i s t e r e d by injection s u b c u t a n e o u s l y or intramuscularly.54, ~n In D e n m a r k , t e t a n u s toxoid a l w a y s has been given s u b c u t a n e o u s l y , since the D a n e s have believed t h a i such injections of a l u m i n u m h y d r o x i d e - a d s o r b e d toxoid have produced a satisfactory a n d long-lasting i m m u n i t y with a m i n i m u m of local reactions.~,~ F o r rapid i m m u n i z a t i o n of large groups, a jet injector or " g u n " has become available, a n d can be l o a d e d with m a n y doses of an i m m u n i z i n g agent.54, 55 Recently, the possibility of t e t a n u s toxoid i m m u n i z a t i o n by a n aerosol m e t h o d has been explored.213 Soluble t e t a n u s toxoid given as a n aerosol to h u m a n volunteers led to a n increase in s e r u m a n t i b o d y titers c o m p a r a b l e to t h a t resulting from conventional Subcutaneous a d m i n i s t r a t i o n . N o increase in the titer of nasal a n t i b o d y was d e m o n s t r a t e d . S p u t u m a n t i b o d y titers, however, were found to increase significantly in the persons who received aerosolized vaccine, d e m o n s t r a t i n ~ t h a t secretory a n t i b o d y was p r o d u c e d in response to a n a n t i g e n t h a t n o r m a l l y does not e n t e r the r e s p i r a t o r y tract. In a recent c o m m u n i c a t i o n , VeronesiZ04 s t a t e d t h a t he has succeeded in obtaining s e r u m tetanus, a n t i t o x i n levels by the a d m i n i s t r a t i o n of t e t a n u s toxoid orally. T o obtain such levels with both initial a n d booster doses, he has coated the toxoid to protect it a g a i n s t acid gastric juice. e) EXPERIENCES WITH TETANUS TOXOID.- 1) United States A r m y . During W o r l d W a r I]:, the practically 100% efficiency a n d safety of t e t a n u s toxoid as a p r o p h y l a c t i c a g e n t were proved by the experience of the U n i t e d S t a t e s Army.125, 126 Only 12 cases of t e t a n u s occurred in a series of 2,734,819 hospital admissions for wounds a n d injuries. T h e m o r t a l i t y in these 12 cases was 41.7%. As to i m m u n i z a t i o n status, only 4 of these 12 9 a t i e n t s had had both a n initial i m m u n i z a t i o n of fluid toxoid a n d a booster dose. T h e zero incidence of t e t a n u s in U n i t e d S t a t e s A r m y active d u t y personnel from 1956 to N o v e m b e r of 1971 reinforces w h a t was l e a r n e d a b o u t tetanus toxoid in W o r l d W a r II.I46 2) Pregnant women and neonatal tetanus.. ]Prior to 1965, i m m u n i z a t i o n of p r e g n a n t w o m e n in N e w G u i n e a with 3 injections of p l a i n toxoid had p r e v e n t e d n e o n a t a l tetanus. In a 1965 report, a n t i t o x i n levels i n d u c e d by
TABLE
12,
-INCIDENCE OF T~TANUS IN THE UNITED STATES ARi~ft'72, 96, 125, 126. 146 AD~XlSSm~'S FOR W O U N D S AND I N J U R I E S
Civil War X,Vorld War I 1920-1941" V,rorld XVar II Korean War 1956-Nov. 1971, including lhe Vietnam conflict
280,040 523,158 580,283 2,734,819
CASF~]I00,000 CASF,S OF TETANUS
505 70 14 12 6-8 0
*]nclt~sive.
9.2
AND INJURED
WOUNDS
18.03 13.4 2.4 0.44
TABLE 13.--TETANUS Toxom
IMM:UNIZATION STATUS OF 12 CASES OF TETANUS IN 2,734,819 UNITED STATES ARMY HOSPITAL ADMISSIONS DURING WORLD WAR I1125, 126
No active immunization
Initial immunization (3 irijections of fluid toxoid) accomplished but no emergency stimulating injection given Initial immunization plus emergency booster dose given TOTAL
FATA L CASF~S 2
T O TA L
1
2
2 5
4 12
CASES 6
,.
2 o i l - a d j u v a n t toxoids (1 i n j e c t i o n ) , 1 AIPO,t toxoid (2 injections) a n d 1 p l a i n toxoid (3 injections) w e r e c o m p a r e d w i t h those i n d u c e d by t h e s a m e p l a i n toxoid as used in the e a r l i e r study.127 A t term, t h e r e was no signific a n t difference in the levels for the 5 toxoids, but those for the plain toxoids l a t e r d e c l i n e d rapidly. A 1 P O t - t o x o i d l i t e r s were significantly h i g h e r t h a n t h e t i t e r s for t h e p l a i n toxoids a t t h e end of a y e a r b u t lower t h a n t h e oila d j u v a n t titers, which w e r e t h e highest a n d m o s t persistent. However, una c c e p t a b l e side-effects ( i n d u c e d by s u b s e q u e n t lots of o i l - a d j u v a n t toxoids) p r e c l u d e d t h e i r r o u t i n e use. W h e r e a s previously the incidence of n e o n a t a l t e t a n u s was 80 per 1,000 live births, for the 1.965 r e p o r t t h e r e were no cases of t e t a n u s in 120 babies. T h e r e s u l t s i n d i c a t e t h a t a m a t e r n a l a n t i t o x i n level at delivery of 0.01 u n i t / m l , is protective. A l u m i n u m - c o m p o u n d toxoid r a p i d l y a c h i e v e d liters t h a t w e r e b e t t e r t h a n this for at least a year, with m i n i m a l side-effects. H e n c e , such toxoids are r e c o m m e n d e d for m a t e r n a l i m m u n i z a tion to p r e v e n t n e o n a t a l tetanus.OZ I n a 1966 report, Newel] et aI.147 r e p o r t e d s i m i l a r l y good results. W i t h a view to d e t e r m i n i n g t h e effectiveness of a m e t h o d for the control of t e t a n u s n e o n a t o r u m t h a t would be i n d e p e n d e n t of m e d i c a l e x a m i n a t i o n or care, a double-blind field trial covering 1,618 w o m e n was c o n d u c t e d b e t w e e n ~1961 a n d 1966 i n a r u r a l a r e a of Colombia with a n e s t i m a t e d existing t e t a n u s neon a t o r u m d e a t h r a t e of 11.6 p e r 100 births. T h e s t u d y g r o u p was given 1-3 i n j e c t i o n s of 1 ml. of a n a l u m i n u m p h o s p h a t e - a d s o r b e d t e t a n u s toxoid m o r e t h a n 6 weeks a p a r t a n d the control g r o u p a s i m i l a r n u m b e r of injections of a n influenza virus vaccine. T h e r e was no s t a t i s t i c a l l y significant difference b e t w e e n those in the control a n d s t u d y g r o u p s given 1 injection. T h o s e in t h e control group given 2 or 3 injections had a t e t a n u s n e o n a t o r u m d e a t h r a t e of 7.8 per 100 b i r t h s a n d the c o r r e s p o n d i n g s u b j e c t s in the s t u d y g r o u p had none. T h i s difference is u n l i k e l y to h a v e o c c u r r e d by chance. f) DURATION OF EFFECT OF TETANUS TOXOID.- ....T h e h u m a n body does not " f o r g e t " a dose of t e t a n u s toxoid. T h e first injection sensitizes or triggers t h e body so t h a t it r e s p o n d s to the second a n d reinforcing or booster (loses of t e t a n u s toxoid by p r o d u c i n g c i r c u l a t i n g s e r u m t e t a n u s a n t i t o x i n and probably o t h e r protective mechanisms.J0~; As yet, t h e r e has not })eel2 determ i n e d ~! m i n i m u m period of time a f t e r which t h e r e is not an a n a m n e s t i c response; a n t i t o x i n liters a r e being d e t e r m i n e d f r e q u e n t l y for \Vorld W a r I I v e t e r a n s to d e t e r m i n e w h e t h e r t h e r e is su('h an interval. Edsall points out that a numl)er of i n v e s t i g a t o r s a l r e a d y have shown a n u n e x p e c t e d l y high 24
TABLE
1 4 . ~ R E A C T I O N S OF A M A L E TO T E T A N U S T o x o m ~VITH REPEATED DOSES 2h'PE oF ToxoII)
DATE AND AGE
1949:2 1949:2 1951:4 1952:5 1953:6 1955:8
GIVEN SC.
DPT DPT Pptd. T DPT Pptd. T Pptd. T
RF~.XCTION
REASON
0 0 0 0 0 Redness and induration greater than anticipated Redness and induration 1963:16 Pptd. T Injury of half of upper arm 1964:17 Pptd. T Injury Redness and induration from elbow to shoulder; "almost double in size" (September 1965: serum tetanus antitoxin flier: 3 units per ml. [McComb].) Initial seri~s Initial seri~s Injury Booster Injury Injury
incidence of long-lasting immunity; in their studies, 8 5 - 9 5 % of individuals immunized against tetanus during World W a r II still carried protective antibody levels 15-21 years later.69, 12s W i t h practically no exceptions, these individuals responded well to a booster dose of toxoid. g) N o ANTITOXIN IF ADEQUATE TETANUS TOXOID I?,IMUNIZATION. .....I t should be noted that protection against tetanus by booster toxoid after w o u n d i n g in the U n i t e d States armed forces in World War II was achieved without the simultaneous use of antitoxin w h e n there was a d e q u a t e prior tetanus toxoid immunization. Credit is due to the U n i t e d S t a t e s military forces consultants who r e c o m m e n d e d that antitoxin was not necessary w i t h a d e q u a t e toxoid prophylaxis.15 h) REACTIONS TO TETANUS TCXOID. Significant reactions to t e t a n u s toxold continue to be rare but are occurring more frequently.GS, 6.q,15s, 173,184, ! 9 9 In late 1964 it was reported by Kittler e t al.~ ~5 that: 1. T e t a n u s toxoid hypersensitivity is infrequent, but a p p a r e n t l y the incidence is increasing. 2. Adults react fairly frequently to alum-precipitated tetanus toxoid.
T A B L E 15.~: ,TOTAL NUMBER OF REPORTED SYSTEMIC REACTIONS TO MONOVALENT TETANUS TOXOID IN DENMARK 1951--1970 ( 2 . 5 MILLION INJECTIONS)3"~ N o . OF CASF~;
Deleterious Death Survival with Neurologic ,sequelae G Iomeruloneph ri t is No permanent damage Acute collapse Late allergy Urticaria. arlhralgia, lymphadenitis (8tli day) Urtwaria persisting > ! month Polyrad icul it i,~
25
INJECTION NUMBER
0 1 I
-->4
2
1,1
3 2 1
1,1,1,
2
4
T A B L E 16. ,,DEATHS W I T H I N 3 D A Y S AFTER VACCINE I N J E C T I O N IN RELATION TO TOTAL NUS,IBER OF I N J E C T I O N S , D E N M A R K 37 CO~IPOSITION OF VACCINE
PERIOD
1947-51 1952-60 1961-70
12 Lf Tetanus 12 Lf T e l a n u s 50 Lf Diphtheria No. of Inj. Deaths N o . of Inj. Deaths 68,000 0 570,000 3 620,000 0 2,000,000 0 1,850,000 0 670,000 0
12 Lf Tetanus 12 Lf Diphtheria No. of Inj. Deaths 73.000 0 550,000 0 610,000 0
7 Lf Tetanus 30 Lf Diphtheria 16 X 109 Pertussis Org. No. of Inj. Deaths
2,500,000
10
3. T h i r t e e n persons wi~re found to be sensitive to t e t a n u s toxoid by history a n d skin test a n d 1 p a t i e n t h a d an a n a p h y l a c t i c reaction to toxoid. A t the Silo P a u l o T e t a n u s Conference, ChristensenaZ r e p o r t e d t h a t from 1951 until 1970 m o r e t h a n two a n d a half million injections of adsorbed tetan u s toxoid h a d been given in D e n m a r k with no r e p o r t s of d e a t h a n d only a single case of neurologic complications with s e q u e l a e (Table 15). H e points out, however, t h a t t e t a n u s toxoid reactions seem to increase in i n t e n s i t y a n d f r e q u e n c y w i t h i n c r e a s i n g n u m b e r s of injections. T h e y range from mild inf l a m m a t o r y local reactions to e d e m a t o u s local reactions, a n d include systemic reactions, such as u r t i c a r i a (sometimes persisting for weeks), a r t h r a l gia, n e p h r o s i s a n d a n a p h y l a c t i c shock. Moreover, the addition of d i p h t h e r i a a n d pertussis a n t i g e n s increases the possibility of reactions (Table 16). I n 1966, B l u m s t e i n a n d K r e i t h e n l 9 r e p o r t e d a case of l)eril)heral n e u r o p a t h y following t e t a n u s toxoid a d m i n i s t r a t i o n . B e c a u s e some individuals m a y be sensitive or become sensitive to t e t a n u s toxoid, one m a i n p r i n c i p l e of active tetafius i m m u n i z a t i o n m u s t be to bala n c e the dosage and a d m i n i s t r a t i o n of toxoid a~ainst the side-reactions so as to obtain o p t i m a l p r o t e c t i o n with m i n i m a l risk of complications. i) BASIC I M h I U N I Z A T I O N ; FREQUENCY OF PERIODIC AND WOUND BOOSTERS. ,-. Since t e t a n u s toxoid is a most effective antigen t h a t m a y lSroduce undesirable reactions, r e c o m m e n d a t i o n s continue to be m a d e for less f r e q u e n t use a n d s m a l l e r dosage of t e t a n u s toxoid. In the 30 October 1971 W e e k l y R e p o r t of the C e n t e r for Disease Control of the U n i t e d S t a t e s Public H e a l t h Service of the H e a l t h , E d u c a t i o n , and W e l f a r e D e p a r t m e n t , the following r e c o m m e n d a t i o n of the P u b l i c H e a l t h Service Advisory C o m m i t t e e on I m m u n i z a t i o n P r a c t i c e s was published:~2" R E C O M M E N D A T I O N OF THE P U B L I C H E A L T H SERVICE ADVISORY C O M M I T T E E ON I M M U N I Z A T I O N PRACTICES
Diphtheria and Tetamls Toxoids and Pertussis Vaccine Introduction Routine i m m u n i z a t i o n against diphtheria, tetanus, and perlussis in infancy or childhood has been widely advocated and generally practice d in the United Stales for lh¢ past 25 years, lls effectiveness is reflected in the rnarked dccrcasc in cases and deaths from these three diseases, 26
Tetanus Although its incidence in the United States has declined in recent years, tetanus remains an important health problem. In 1970, 148 cases of tetanus were reported; a l l o c c u r r e d in unimmunized persons or ones whose immunization history was vague. M o r e than half of the reported cases were in persons 50 years of age or older, and more thah 60 percent were fatal. Since there is no natural immunity to the tetanus toxin and since the tetanus organism is ubiquitous, immunization is a universal requirement regardless of age. Tetanus toxoid is an almost ideal immunizing agent. It is highly effec}ive and provides long-lasting protection. Hypersensitivity reactions, though uncommon with primary immunization, occur frequently in persons who have received an excessive number of booster injections.
Preparations Used for Immunization Diphtheria a n d tetanus toxoids are prepared by formaldehyde treatment of the respective toxins. Pertussis vaccine is made from a killed suspension of bacteria or a bacterial fraction. The toxoids are available in both fluid and adsorbed forms. Comparative tests have shown that the adsorbed toxoids are clearly superior in inducing high antitoxin titers and achieving durable protection. T h e p r o m p t n e s s of antibody responses to booster doses of either fluid or adsorbed toxoid is not sufficiently different to be of clinical importance. Therefore, adsorbed t o y oids are the agents of choice for both primary and booster immunization. The toxoids and pertussis vaccine are available in various combinations and concentrations for specific purposes. Three preparations are important for public health use: 1. Diphtheria and Tetanus Toxoids and Pertussis Vaccine ( D T P ) 2. Tetanus and Diphtheria Toxoids, Adult Type ( T d ) 3. T e t a n u s T o x o i d (T) All preparations contain comparable amounts of tetanus toxoid, but the diphtheria component in the adult type of tetanus and diphtheria toxoids ( T d ) is only about 15 to 20 percent of that contained in the standard D T P preparation for infants and young children.
Vaccine Usage Schedule and dose. The concentration of antigens varies in different manufacttlrers" products. The labeling provides specific information on the proper volume of a single dose. Primao' Immunization Children 2 months through 6 years: The manufacturer's recommended dose of D T P given intran~uscularly on four occasions, three doses al 4 to 6 week intervals with a fourth dose approxinlately 1 year after the third injection. Ideally. immunization should begin at 2 to 3 months of age or a! the time of a B-week "check-up" if that is an established routine. 27
Schoolchildren and adults: A series of three doses of Td* given intramuscularly with the second dose 4 to 6 weeks after the first, and the third dose 6 rnonths to 1 year after the second. Booster doses. :.Children 3 through 6 years (preferably at time of school entrance-kindergarten or elememary school): One injection of the recommended dose of D T P intramuscularly. Thereafter am1 /or all other persons: The recommended dose of Td (adult) intramttscularly every 10 years. If a dose is administered sooner as part of wound management (see specifi c ,recommendations), the next booster is not needed for another 10-years. More frequent booster doses are not indicated and may be associated with increased incidence and severity of reactions. Tetanus Prophylaxis in Wound Management The physician is often faced with questions concerning the use of tetanus toxoid, Tetanus Immune Globulin ( H u m a n ) ( T I G ) , or tetanus antitoxin of animal origin as part of his management of a patient with a wound. Available evidence shows that complete primary immunization with tetanus toxoid provides long-lasting protective antitoxin levels. Additionally, protective antitoxin develops rapidly in response to a booster dose in t~ersons who have previously received at least two doses of tetanus toxoid. Therefore, passive protection with T I G or antitoxin need be considered only when the patient has had less than two previous injections of tetanus toxoid or when the wound has been untended for more than 24 hours. A review of tetanus in the United States in recent years fails to reveal documented cases occurring in individuals with adequate primary immunization. Available evidence shows antitoxin persisting at protective levels for at least 5 years after four doses of tetanus toxoid. Ability to react promptly to booster injections persists for a longer" time. In wound management, it is therefore unnecessary to use booster injections more than every 5 years. F o r persons whose immunizations are still incomplete following wound management, the remainder of the recommended series should be given. The following table is a conservative guide to active and passive tetanus immunization at the time of wound cleansing or debridement. It presumes a reliable knowledge of the patient's immunization history. G U I D E TO T E T A N U S PROPHYLAXIS IN W O U N D M A N A G E M E N T HISTORY OF TETANUS IMMUNIZATION (DOSES)
Uncertain 0--1 2 3 or more
CLEAN. MINOR WOUNDS Td TIG
Yes Yes Yes No"
No No No No
ALL OTItER WOUNDS Td TIG
Yes Yes Yes No:~
Yes Yes No 1 No
I. U n l e s s w o u n d m o r e t h a n 24 h o u r s old. 2. U n l e s s m o r e t h a n 10 years since last dose. 3. U n l e s s m o r e t h a n 5 years since last dose. * T d ( a d u l t ) is c o n s i d e r e d the a g e n t of c h o i c e for i m m u n i z a t i o n of s c h o o l - a g e c h i l d r e n on the basis of d a t a r e g a r d i n g its a d e q u a c y in p r i m a r y i m m u n i z a t i o n of older c h i l d r e n a n d a d u l t s a n d b e c a u s e of i n c r e a s i n g f r e q u e n c y o f r e a c t i o n s to ftzll doses o f d i p h t h e r i a t o x o i d with age.
28
If passive i m m u n i z a t i o n is to be used, T I G is p r e f e r a b l e to, a n i m a l antitoxin, it offers ihe a d v a n t a g e s of longer protection a n d f r e e d o m from undesirable reactions. T h e c u r r e n t l y r e c o m m e n d e d p r o p h y l a c t i c dose of T I G is 250 units for ~'ounds of average severity. W h e n tetanus toxoid and globulin are giver~ c o n c u r r e n t l y , s e p a r a t e syringes and separate sites should be used. Should T I G be unavailable, equine or bovine antitoxin m a y be used, but there is a risk that serious antiphylactic or s e r u m sickness reactions will folIow. I t s a d m i n i s t r a t i o n should always be p r e c e d e d by careful screening for sensitivity in a c c o r d a n c e with instructions a c c o m p a n y i n g the antitoxin. T h e usual dose is 3,000 to 5,000 units. Likewise, on 17 October 1971, the C o m m i t t e e on Infectious D i s e a s e s o f the A m e r i c a n A c a d e m y of P e d i a t r i c s r e c o m m e n d e d t h a t c o m b i n e d t e t a n u s a n d d i p h t h e r i a tox0ids ( a d u l t t y p e ) , ifi c o n t r a s t t o d i p h t h e r i a a n d t e t a n u s ( T D ) c o n t a i n i n g a :larger a m o u n t of d i p h t h e r i a antigen, should be given to those over 6 y e a r s of age, a n d also r e c o m m e n d e d that, at the t i m e of i n j u r y , for c l e a n m i n o r wounds, no booster dose of t e t a n u s toxoid is needed b y a f~llly i m m l i n i z e d child unless m o r e t h a n 10 y e a r s have elapsed since the last dose and, for c o n t a m i n a t e d wounds, a booster dose should be given if m o r e t h a n 5 y e a r s h a v e e l a p s e a since t h e last dose.9 Methods" of i m m u n i z a t i o n a g a i n s t t e t a n u s have b e e n o u t l i n e d for D e p a r t m e n t s of the A r m y , the N a v y a n d t h e A i r Force in a M a y 1970 directive as follows a n d have been f u r t h e r described in a J u l y 1.971 c o m m u n i c a t i o n ,~4, ~5: 1. I n i t i a l i m m u n i z a t i o n consists of ~ i n t r a m u s c u l a r or s u b c u t a n e o u s injections, t h e first 2 doses of w h i c h will consist of 0.5 ml. of the c o m b i n e d toxoids p e r injection, a n d the t h i r d Of 0.1 mI. T h e second injection should be given 1 to 2 m o n t h s a f t e r the first a n d the t h i r d (reinforcing) injection, 0.1 ml., a p p r o x i m a t e l y 12 m o n t h s a f t e r the sec6nd. F o r c h i l d r e n u n d e r 12 y e a r s of age, 0.5 ml. should be given as t h e t h i r d dose to a s s u r e a d e q u a t e immunity against diphtheria. 2. T o a s s u r e a c i r c u l a t i n g level of t e t a n u s a n t i t o x i n a d e q u a t e to p r o t e c t a fighting m a n who m i g h t be in a s i t u a t i o n w h e r e a booster:.dose of toxoid is not available at the t i m e of i n j u r y , a booster dose of 0.1 ml. i n t r a m u s c u l a r l y or s u b c u t a n e o u s l y should be given r o u t i n e l y e v e r y 6 y e a r s following completion of the initial series. 3. T h i s schedule will establish a l o n g - l a s t i n g p r o t e c t i v e level of circulat: ing t e t a n u s a n t i t o x i n in the vast m a j o r i t y of subjects. H o w e v e r , to p r o t e c t the occasional p a t i e n t who does not m a i n t a i n such a level a n d who is therefore subject to t h e risk of tetanus, it is still n e c e s s a r y to a d m i n i s t e r emergency booster (%round booster") i n j e c t i o n s of 0.5 ml. of this p r o d u c t to all individuals who (a) h a v e not received a n injection of t e t a n u s toxoid ( e i t h e r as such or as D T P , Td, etc.) w i t h i n the p r e c e d i n g 12 m o n t h s a n d who have e i t h e r (b) i n c u r r e d w o u n d s or severe b u r n s on the battIefield or a r e p a t i e n t s u n d e r g o i n g second o p e r a t i o n s or m a n i p u l a t i o n s of old wounds, (c) i n c u r r e d p u n c t u r e or l a c e r a t e d wounds, severe b u r n s or o t h e r conditions w h i c h m i g h t be c o m p l i c a t e d by the i n t r o d u c t i o n of Clostridium tetani into the tissues. If, in the view of t h e medical officer, t h e p a t i e n t ' s condition is such t h a t a n u n t o w a r d reaction to e i t h e r d i p h t h e r i a or t e t a n u s toxoid 29
would be h a z a r d o u s , a r e d u c e d dose of this p r o d u c t s h o u l d be a d m i n i s t e r e d . T h e d o s e - r e s p o n s e slope for a b o o s t e r i n j e c t i o n is quite flat so t h a t a dose as s m a ll as 0.05 nil. will i n d u c e a sioaificant r e s p o n s e in p a t i e n t s with low antitoxin titers. ( F o r those p e r s o n n e l who h a v e not received 2 or m o r e doses of t e t a n u s toxoid, passive i m m u n i t y m u s t be provided.) (d) Reactions. E r y t h e m a a n d i n d u r a t i o n at the site of injection occur occasionally a n d a p p e a r to be r e l a t e d to pre-existing i m m u n i t y . T h e s e rea c t i o n s a r e seldom severe; the incidence of severe r e a c t i o n s a p p e a r s to be no m o r e t h a n 1 or 2 p e r c e n t in individuals u n d e r 30 or 35 y e a r s of age a n d p e r h a p s s o m e w h a t g r e a t e r in those older. U r t i c a r i a l a n d o t h e r allergic rea c t i o n s occur r a r e l y ; t h e y also a r e g e n e r a l l y , though not i n v a r i a b l y associated with already established hyperimmunity. T h e r e c o m m e n d e d toxoid p r e p a r a t i o n consists of a m i x t u r e of Mump r e c i p i t a t e d , a l u m i n u m p h o s p h a t e - a d s o r b e d or a l u m i n u m h y d r o x i d e - a d sorbed t e t a n u s a n d purified d i p h t h e r i a toxoids in such p r o p o r t i o n s t h a t each 0.5-ml. dose c o n t a i n s 5-15 Lf of t e t a n u s toxoid a n d only 1-2 Lf of d i p h t h e r i a toxoid. At t h e t i m e of writing, we favor the Guide in T a b l e 17, which is based on previous p u b l i c a t i o n s of the C o m m i t t e e on T r a u m a of t h e A m e r i c a n College of Surgeons.43.44 T h i s G u i d e is s o m e w h a t conservative in t h a t ~ i f t h e r e is d o u b t c o n c e r n i n g p r i o r a d m i n i s t r a t i o n of t e t a n u s t o x o i d ~ a dose of t e t a n u s toxoid a n d c o n s i d e r a t i o n of T I G (H) a r e r e c o m m e n d e d . S u c h a conservative a t t i t u d e is based on t h e s e concepts:
TABLE
17.
A GumE TO PROPHYLAXIS IN WOUND MANAGEMENT
AGAINST
TETANUS
GlenERALPRINCIPLES I. The attending physician must determine for each patient with a wound what is required for adequate prophylaxis against tetanus. It. Regardless of the active immunization status of the patient, meticulous surgical care, including removal of all devitalized tissue and foreign bodies, should [m provided immediately for all wounds. Such care is essential ms part of the prophylaxis agabx~t tetanus. IIL Each patient with a wound should receive adsorbed tetanus toxoid::: intt'amuscularly at the time of injury, either as an initial immunizing (lose, or m~ ' a b , ~ t e r for previous immunization, unless he has received a booster or hms completed his initial immunization series within the past 5 years. As the antigen concentration varies in different products. specific information on the volume of a single dose is provided on the |abel of the package. IV. Whether or not to provide pa~ive irnmunization with homologous tetanus immune globulin (human) must be decided individually for each patient. The characteristics of the wound, conditions under which it was incurred, its treatment, ils age, and the previous active immunization status of the patient must be considered. V. T o e v e r y w o u n d e d p a t i e n t give a w r i t t e n record of t h e i m m u n i z a t i o n providc~t, i n s t r u c t i n g h i m to c a r r y t h e record at all times, a n d if i n d i c a t e d , to c o m p l e t e active i m m u n i z a t i o n . F o r precise t e t a n u s p r o p h y l a x i s , an a c c u r a t e a n d i m m e d i a t e l y a v a i l a b l e h i s t o r y r e g a r d i n g p r e v i o u s active i m m u n i z a t i o n a g a i n s t t e t a n u s is r e q u i r e d . VI. B a s i c i m m u n i z a t i o n with a d s o r b e d toxoid r e q u i r e s 3 injections. A booster of a d s o r b e d toxoid is i n d i c a t e d 10 *~-" y e a r s a f t e r t h e t h i r d i n j e c t i o n or, 10"* y e a r s a f t e r a n i n t e r v e n i n g w o u n d booster. AII i n J i v i d u a l s , i n c l u d i n g p r e g n a n t w o m e n , shouht h a v e basic iInmunization a n d i n d i c a t e d booster injections. * T h e P u b l i c H e a l t h S e r v i c e A d v i s o r y C o m m i t t e e on I m m u n i z a t i o n P r a c t i c e s in 1969 recomm e n d e d D T P ( d i p h t h e r i a a n d t e t a n u s toxoids c o m b i n e d with pertussis v a c c i n e ) for b~usic imm u n i z a t i o n in infants a n d c h i l d r e n from 2 m o n t h s t h r o u g h the sixth y e a r of age a n d T d ( c o m b i n e d t e t a n u s a n d d i p h t h e r i a toxoid~_: a d u l t t y p e ) for basic i m n l u n i z a t i o n of those over 6 y e a r s of age. F o r the l a t t e r g r o u p , T d toxoid was r e c o m m e n d e d for r o u t i n e or w o u n d boos'ters; lint if t h e r e is a n y r e a s o n to s u s p e c t h y p e r s e n s i t i v i t y to the d i p h t h e r i a c o m p o n e n t , t e t a n u s toxoid (T) s h o u l d be s u b s t i t u t e d for Td.4.,
30
SPECIFIC MEASURES FOF. PATIENTS "WITH WOUNDS I.
Previously immunized individuals A. W h e n t h e p a t i e n t h a s b e e n a c t i v e l y i m m u n i z e d w i t h i n l h e p a s t 10** yem,~. I. T o t h e great, m a j o r i t y , g i v e 0.5 cc. of a d s o r b e d ~etanus toxoid* as a boc~sicr unh'ss it is certain that the patient has received a booster w i t h i n the pret, ious 5 >'ears. 2. T o t h o s e w i t h s e v e r e , n e g l e c t e d , o r old ( m o r e t h a n 24 h o u r s ) t e t a n u s - p r o n e w o u n d s , g i v e 0.5 ec. of a d s o r b e d toxoid':' unless it is certain tfiat the patient has received o booster w i t h i n the previous year. B. W h e n t h e p a t i e n t h a s b e e n a c t i v e l y i m m u n i z e d n l o r e t h a n 10"::' ye~rs p r e v i o u s l y , 1. T o t h e g r e a t m a j o r i t y , g i v e 0.5 co. of a dsorl~z-d tetanus":: loxoid. 2. T o t h o s e w i t h s e v e r e , n e g l e c t e d , o r old ( m o r e t h a n 2,1 h o u r s ) t e t a n u s - p r o n e w o u n d s , a. G i v e 0.5 cc. of a d s o r b e d to×old,*,**::' ........... b. G i v e 250 u n i"t s ~"~ ....... of t e t a n u s i m m u n e g l o b u l i n ( h u m a n ) , *::~::: c. C o n s i d e r p r o v i d i n g o x y l e t r a c y c l i n e or p e n i c i l l i n . II. I n d i v i d u a l s N O T p r e v i o u s l y i m m u n i z e d A. W i t h c l e a n m i n o r w o u n d s in w h i c h t e t a n u s is m o s t u n l i k e l y , g i v e 0.5 cc. of a d s o r b e d t e t a n u s toxoid* (initial i m n a u n i z i n g d o s e ) . 13. W i t h all o t h e r w o u n d s 1 G i v e 0.5 cc. of a d s o r l m d t e t a n u s t o x o i d * (initial i m m u n i z i n g dcxse) ,*::'* 2. G i v e 250 units:::*::;* of tetantls i m m u n e g l o b u l i n (human),::'":~' 3. Cop_sider p r o v i d i n g o x y t e t r a c y c l i n e or p e n i c i l l i n . *:::Some a u t h o r i t i e s a d v i s e 6 r a t h e r l h a n 10 y e a r s , p a r t i c u l a r l y for p a t i e n t s w i t h severe, n e g l e c t e d , or o l d ( m o r e t h a n 24 h o u r s ) t e t a n u s - p r o n e w o u n d s s u c h as m a y be s u s t a i n e d by m i l i t a r y p e r s o n n e l in cornbat.54, ~5. a 1~ **":"Use d i f f e r e n t s y r i n g e s , n e e d l e s , a n d s i t e s of i n j e c t i o n . **"::",':In severe, n e g l e c t e d , o r o l d ( m o r e t h a n 24 h o u r s ) t e t a n u s - p r o n e w o u n d s , 500 u n i t s of tetanus immune globulin (human) are advisable.
1. In general, surgeons see a more severe and a more unusual wound than the nonsurgical physician. T h e long intervals b e t w e e n wound boosters are for the "usual types" of wounds.158 2. T e t a n u s , in contrast to gas gangrene, m a y occur in individuals who have no demonstrable w o u n d or who have very minor wounds; hence, all individuals should have adequate s e r u m tetanus antitoxin tilers at all times.77 3. P h y s ; c i a n s want none of their patients w h e t h e r they. have special problems or not- -to develop tetanus. 4: T h e A r m y statistics, which include those for the fighting forces in Vietnam, are impressive: no cases of tetanus, have been reported among active duty personnel from 1956 to N o v e m b e r 197114~ (Tables 12 and 18). In contrast to such A r m y statistics, there w e r e reported 120 civilian cases of tetanus in 1971 in the U n i t e d States.a1 5. P a t i e n t s do not have an i m m e d i a t e l y available e m e r g e n c y medical identification device with reliable tetanus data on it. (a) In a survey of patients and their friends during parts of 1970, 1971 and 1972, only 22 of 428 (5.1%) had such data i m m e d i a t e l y available. ( b ) T h e recommendations of the U S P H S and the A A P are based on i m m e d i a t e l y available and accurate records with tetanus data.9, a2 6. For the particularly severe or c o n t a m i n a t e d so-called t e t a n u s - p r o n e ,Jr
TABLE
18.: :VOLUNTARY VERSUS CONTROLLED TETANUS
P R O P I I Y L A X I S 31, 1,16
N o . o r CASES
~ATEGORY
United States Army personnel, 1956-1971 ( N o v e m } m r ) U n i t e d S t a t e s c i v i l i a n s , 1971
31
0 120
9034' DOSES
80-
70-
60I,:>" I.,u
o 50-
n,t.M o,.
40
30-
20NO VACCINE 10-
I"
I'
"62
"63
I
'64
I
'
I
"65 %6 YEAR
l......
"67
I
"68
-I
]
'69
"70
I
'71
Fro. 12.--Diphtheria-tetanus-pertussis immunization, 1-4 age group, United States, 19621971. In the United States, approximately 10% of infants and children 1--4 years of age have not been vaccinated for these three conditions.:~0 (Courtesy of C e n t e r for" Disease Control.)
u n u s u a l injuries, it has been stated t h a t t h e r e is a need for additional booster doses.6], 15s 7. In general, reactions to t e t a n u s toxoid are m i n i m a l in contrast to the grim picture of a person with t e t a n u s and to the average m o r t a l i t y rate of a b o u t 50%. 8. T h e drug-store cost of a booster dose of t e t a n u s toxoid is small comp a r e d to the hospital cost of a case of t e t a n u s ($9,773.80 for a recent case). 9. T h e r e still are a n u m b e r of individuals who do not have a d e q u a t e tetanus toxoid i m m u n i z a t i o n but who m a y e r r o n e o u s l y be considered to have such i m m u n i z a t i o n w h e n they a r e seen as w o u n d e d patients.67,130 In 1970, Mat et al3 37 stated t h a t 0ne-third of a r a n d o m group of children of all ages in H a m b u r g , G e r m a n y , did not have t e t a n u s toxoid i m m u n i z a t i o n . M o r e recently, HorstmannlOO a n d Witte214 have e m p h a s i z e d the lagging i m m u nity of our children. 10. Cases of failure of booster t e t a n u s toxoid injections to p r e v e n t t e t a n u s m a n y years after injections Or cases of modified t e t a n u s after such injections have been reported.144 11. T h e professional l i a b i l i t y responsibilities of the surgeon are g r e a t e r t h a n those of the n o n s u r g e o n physician (cf. section M). 12. S u r g e o n s ~ i n respect to the p r e v e n t i o n of t e t a n u s ~ d o not w a n t to be like the poet, Ovid,in1 who wrote: "Too late I g r a s p m y shield after m y wounds." IN,lURY.--Rapid, active i m m u n i z a t i o n , i.e., 3-5 closes of t e t a n u s toxoid a p p r o x i m a t e l y every o t h e r day, will not. produce active i m m u n i t y rapidly enough i:o protect an j)
I~APID, ACTIVE, BASIC I~I:MUNIZATION AT T I l E TIMI,~ OF
32
i n d i v i d u a l in w h o m s u c h i m m u n i z a t i o n is s t a r t e d j u s t a f t e r a w o u n d has b e e n inflicted.24, 91, 93, 174, 190 k ) O N E - I N J E C T I O N , BASIC IMMUNIZATION.--Single-dose basic i m m u n i z a tion w i t h a n a d s o r b e d toxoid m a y be t h e final a n s w e r in e l i m i n a t i n g t e t a n u s in developing c o u n t r i e s w h e r e p h y s i c i a n s f r e q u e n t l y h a v e only one opport u n i t y to give p r o p h y l a c t i c t e t a n u s toxoid. A t the 1966 B e r n Conference, a s i n g l e - i n j e c t i o n toxoid t h a t would r e q u i r e only a booster dose a t the t i m e of i n j u r y w a s described b y M~rieux.142 H i s results w e r e . e n c o u r a g i n g b u t p e r h a p s i n d i c a t e t h a t only a p a r t of a p o p u l a tion m a y be given a d e q u a t e basic i m m u n i z a t i o n b y s u c h a one-injection technic. I n 1970, Veronesi e t a / . 205 p o i n t e d o u t t h e p o t e n t i a l value of a t e t a n u s vaccine c a p a b l e of i m m u n i z i n g in a single dose in view of t h e high m o r t a l i t y of the disease in developing countries, as well as the l o w e r cost, g r e a t e r a c c e p t a b i l i t y a n d considerable simplification of the a d m i n i s t r a t i o n of m a s s i m m u n i z a t i o n c a m p a i g n s t h a t w o u l d result. T h e y r e p o r t e d on t h e i m m u n e responses to single doses of different toxoids in different c o n c e n t r a t i o n s , w i t h a n d w i t h o u t a d d i t i o n a l a d j u v a n t s . T h e y found that, w i t h h i g h l y conc e n t r a t e d a l u m i n u m h y d r o x i d e - a d s o r b e d toxoids, 100% protective levels h a d b e e n achieved in a small g r o u p w h e n tested 4 weeks a n d 8 m o n t h s a f t e r i m m u n i z a t i o n a n d t h a t the c o n c e n t r a t e d toxoids, with or w i t h o u t a d j u v a n t s , w e r e well tolerated. A t t h e I n t e r n a t i o n a l Congress for Microbiology in Mexico City in 1970, E d s a l l et al. 7o r e p o r t e d as follows on t h e r e s p o n s e to a single dose of t e t a n u s toxoid: " T o d e t e r m i n e the l o n g - t e r m r e s p o n s e to a single dose of h i g h l y p o t e n t t e t a n u s toxoid, 40 females aged 15 to 45 years, w i t h no p r i o r h i s t o r y of active t e t a n u s i m m u n i z a t i o n , w e r e i n j e c t e d i n t r a m u s c u l a r l y with 25 Lf teta n u s toxoid in 3.8 m g A1PO4. S e r u m w a s d r a w n a t 0, 7, 26 a n d a b o u t 400 days p o s t - i n j e c t i o n for t e t a n u s a n t i t o x i n t i t r a t i o n by tile m o u s e n e u t r a l i z a tion technique. S e v e n s u b j e c t s w e r e excluded b e c a u s e of d e m o n s t r a b l e antitoxin titers a t d a y s 0 or 7. Of t h e 29 a v a i l a b l e a n d a c c e p t a b l e subjects a t d a y 26, 27 h a d m e a s u r a b l e a n t i t o x i n levels, a n d 24 w e r e a t or above t h e g e n e r a l l y a c c e p t e d protective level (0.01 u n i t / m l . ) . F o u r t e e n m o n t h s a f t e r inoculation, 18 a v a i l a b l e a n d a c c e p t a b l e subjects w i t h no h i s t o r y of interm e d i a t e injections h a d m e a s u r a b l e titers, 16 h a d p r o t e c t i v e levels, a n d the g e o m e t r i c m e a n t i t e r of t h e 18 subjects w a s 0.045 unit, c o m p a r e d to a m e a n t i t e r of 0.064 for t h e s a m e subjects a t 26 days. T h e m e a n t i t e r s in the teenage girls w e r e 4 to 8 times h i g h e r t h a n in the a d u l t w o m e n . " S u c h findings s u p p o r t t h e belief t h a t in the not too d i s t a n t f u t u r e a n effective single-dose t e t a n u s toxoid can be p r e p a r e d w i t h o u t the n e c e s s i t y for e m p l o y i n g u n u s u a l r e a g e n t s or p r e p a r a t i v e procedures. ]) PROPHYLAXIS AGAINST TETANUS BY T I t E FIRST INJECTION OF TOXOID GIVEN AT THE TIME OF I N J U R Y . - . T h e initial injection of toxoid at the time of an
i n j u r y does not provide i m m u n i t y for t e t a n u s from t h a t i n j u r y . If a n inj u r e d p a t i e n t who has not been given t e t a n u s toxoid p r e v i o u s l y is given tet,~)us toxoid i m m e d i a t e l y a f t e r an i n j u r y , this first dose of t e t a n u s toxoid does not provide i m m u n i t y for the injury.l:)1,219 m) NO ACTIVE IhIMUNITY FROM TETANUS. T h e a m o u n t of the very potent t e t a n u s toxin n e c e s s a r y 1o p r o d u c e clinical t e t a n u s is so small t h a t it will 33
not incite an active a n t i b o d y level high enough to prevent a second a t t a c k of tetanus. Consequently, t e t a n u s is a n o n i m m u n i z i n g disease and, hence, a history of t e t a n u s does not rule out the possibility of a second attack of tetanus. To p r e v e n t such a second attack, w h e n a p a t i e n t is recovering from tetanus and is about 4 weeks after the onset of tetanus, his a t t e n d i n g physician should begin active i m m u n i z a t i o n with t e t a n u s toxoid.64, 15a, 192, 212,215 n ) POSSIBLE CAUSES OF FAILURE OF ANAMNESTIC RESPONSE.--Antitoxin is not necessary in a d e q u a t e l y actively i m m u n i z e d individuals. It provides only the disadvantages of passive prophylaxis w i t h o u t in a n y way improving the active prophylaxis. T h e r e are certain conditions or situations, however, in which the actively i m m u n i z e d individual possibly m a y not have the usual a n a m n e s t i c response to toxoid. If a physician is called to t r e a t a w o u n d e d individual who has been actively i m m u n i z e d but who is included in one of the following four categories and if it is not possible for the physician to be certain of his p a t i e n t ' s s e r u m antitoxin level, consideration should be given to a d m i n i s t e r i n g T I G ( H ) in addition to t e t a n u s toxoid. 1) Agamrnaglobulinemia.. A n t i t o x i n could be of a d v a n t a g e in a case of a g a m m a g l o b u l i n e m i a or h y p o g a m m a g l o b u l i n e m i a , which f o r t u n a t e l y is ext r e m e l y rare a n d in which the body's ability to produce antibodies fails totally or in part.195 F o r practical purposes, this rarity need not be considered. It is much less likely to occur t h a n is a s e r u m reaction from heterologous antitoxin. 2) Exposure to acute doses of radiation from any source.~Eckmann22O has p o i n t e d out t h a t if an i n j u r e d person has been passively exposed to radioactivity, the effect of a booster injection of t e t a n u s toxoid cannot be d e p e n d e d on for at least several days. T h e effect of whole-body i r r a d i a t i o n on a n t i b o d y formation has been investigated extensively.16 S t u d i e s using small l a b o r a t o r y a n i m a l s generally have indicated a m a r k e d depressive effect of i r r a d i a t i o n on response to a p r i m a r y stimulus; response of a previously sensitized a n i m a l to a booster dose was not affected significantly. Since prophylaxis against t e t a n u s depends on routine i m n m n i z a t i o n with toxoid, followed by a booster dose a d m i n i s t e r e d at the time of i n j u r y to evoke a rapid a n d high antitoxin response, B e n e n s o n et al.16 believed t h a t it was necessary to reinvestigate this response should the i n j u r y be associated with whole-body irradiation. T h e y found t h a t whole-body i r r a d i a t i o n of dogs i m m u n i z e d with a n alump r e c i p i t a t e d t e t a n u s toxoid results in a delay in a p p e a r a n c e of antitoxin if the first toxoid is a d m i n i s t e r e d after irradiation. Dogs i r r a d i a t e d 30 days after a first dose of toxoid and receiving a booster injection 24 hours after i r r a d i a t i o n presented a good antitoxin response when m e a s u r e d by the h e m a g g l u t i n a t i o n test. A poor antibody response, however, was found if the antitoxin was m e a s u r e d by the toxin n e u t r a l i z a t i o n technics. K r e m l e v l 1s studied the efficacy of e m e r g e n c y specific prophylaxis against e x p e r i m e n t a l t e t a n u s u n d e r a g g r a v a t e d conditions. T h e a n i m a l s were rabbits. T h e a g g r a v a t e d conditions were burns or radiation. T h e a n i m a l s were actively i m m u n i z e d against t e t a n u s with a double dose of toxoid. F o u r m o n t h s after the second dose of toxoid, and 12 hours after infliction of the b u r n or radiation, plus the injection of one rabbit lethal dose of t e t a n u s spores, the a n i m a l s were given toxoid or antitoxin, or both. M o r t a l i t y was 34
12 of 17 a n i m a l s with toxoid r e i m m u n i z a t i o n , 12 of 17 w i t h a n t i t o x i n prop h y l a x i s a n d 10 of 17 w i t h both toxoid a n d antitoxin. K r e m l e v seems to be on r e a s o n a b l y sound g r o u n d in t h e o r i z i n g t h a t the low efficacy a p p a r e n t l y is d u e to the a g g r a v a t i n g action of b u r n s a n d ionizing radiation. 3) Immunosuppressive drugs.--Reeent e x p o s u r e to i m m u n o s u p l ) r e s s i v e drugs m a y i n t e r f e r e with the a n a m n e s t i c response. C h l o r a m p h e n i e o l is to be i n c l u d e d in this g r o u p t e m p o r a r i l y , for it has been n o t e d t h a t c o m m o n l y e m p l o y e d t h e r a p e u t i c a m o u n t s of c h l o r a m p h e n i c o l to t r e a t infections in m a n h a v e b e e n s h o w n to s u p p r e s s t h e a n a m n e s t i c response to t e t a n u s toxoid.210 It would i n d e e d be a t r a g e d y for a renal or e a r d i a e t r a n s p l a n t p a t i e n t who h a s h a d his i m m u n e m e c h a n i s m s a l t e r e d to p r e v e n t t r a n s p l a n t rejection a n d who h a d suffered a m i n o r w o u n d to develop t e t a n u s a n d to die because an a d m i n i s t e r e d toxoid booster did not p r o d u c e the u s u a l active antitoxin response a n d because the p a t i e n t was not given T I G ( H ) in addition to toxoid! 4) Carcinoma o[ the breast.~Studies by H u m p h r e y et al.lO2 on p a t i e n t s with b r e a s t disease have s h o w n t h a t p a t i e n t s with benign breast disease could r e s p o n d a d e q u a t e l y to injection of t e t a n u s toxoid b u t that, on the o t h e r h a n d , p a t i e n t s w i t h m a m m a r y cancer, i n e l u d i n g those from w h o m t h e regional nodes w e r e r e m o v e d as well as those in w h o m the nodes were left intact, failed to r e s p o n d to i p s i l a t e r a l injections of t e t a n u s toxoid. O) ACTIVE IMS{UNIZATION AGAINST CL. TETANI AND OTHER CLOSTRIDIA.--In
1970, Klose a n d Schallehn117 r e p o r t e d t h a t i m m u n i z a t i o n w i t h Cl. novyi toxoid or c o m b i n e d C1. novyi toxoid a n d t e t a n u s toxoid in g u i n e a pigs provided reliable p r o t e c t i o n a g a i n s t Cl. novyi gas g a n g r e n e or Ct. novyi gas g a n g r e n e plus t e t a n u s for a period of at least 2 years. T h e y were hopeful t h a t their e x p e r i m e n t s m i g h t o p e n the w a y to provide p r o t e c t i o n a g a i n s t both gas g a n g r e n e a n d t e t a n u s in m a n , especially since the combined vaccine does not cause a n y m a r k e d reactions. T h e y r e c o m m e n d e d t h a t such protective i m m u n i z a t i o n be p e r f o r m e d in all school c h i l d r e n in G e r m a n y . S i m i l a r l y , V r a n c h e v a e t a / . 207 h a v e i n v e s t i g a t e d tritoxoid for Ci. per[ringens, C1. oedematiens a n d C1. tetani.2o7 p ) 100°7o TETANUS TOXOID IMIV[UNIZATION.. T h e following w a y s a n d m e a n s of effecting w i d e s p r e a d t e t a n u s toxoid i m m u n i z a t i o n in the civilian p o p u l a t i o n have b e e n proposedS4: 1. E n c o u r a g e all m e m b e r s of the civilian p o p u l a t i o n to o b t a i n basic teta n u s toxoid i m m u n i z a t i o n . P u t d i s p l a y s in the w a i t i n g rooms of p h y s i c i a n s ' offices. H a v e notices in the n e w s p a p e r s from medical o r g a n i z a t i o n s , the city h e a l t h c o m m i s s i o n e r a n d the c o u n t y h e a l t h commissioner. S e n d l i t e r a t u r e to P a r e n t - T e a c h e r Associations, 4-H Clubs, Boy Scout troops, Girl Scout troops a n d s i m i l a r organizations, c h u r c h e s a n d social a n d a t h l e i i c clubs. U r g e factories to r e c o m m e n d s t r o n g l y or to r e q u i r e a d e q u a t e t e t a n u s toxoid i m m u n i z a t i o n at the time of e m p l o y m e n t . R e q u e s t colleges a n d universities to r e c o m m e n d s t r o n g l y or r e q u i r e a d e q u a t e t e t a n u s toxoid i m m u n i z a i i o n at t h e t i m e of s t u d e n t s ' m a t r i c u l a t i o n . R e c o m m e n d to p h y s i c i a n s t h a t t h e y give t e t a n u s toxoid w h e n o t h e r i m m u n i z a t i o n s such as d i p h t h e r i a , perl.ussis a n d a n t e r i o r poliomyelitis a r e given. 2. S t i m u l a t e p h y s i c i a n s lo become actively engaged in the i m m u n i z a t i o n 35
c a m p a i g n . Give talks a t hospital g e n e r a l staff a n d section meetings. P r e s e n t p a p e r s at local, sectional a n d n a t i o n a l meetings. S u b m i t p a p e r s , editorials a n d l e t t e r s to the editors in local, sectional a n d medical j o u r n a l s . D i s p l a y exhibits at s t a t e a n d n a t i o n a l medical meetings. T h e active p a r t i c i p a t i o n of all physicians, t o g e t h e r w i t h c o o p e r a t i o n from t h e civilian p o p u l a t i o n , can e n s u r e n a t i o n w i d e t e t a n u s toxoid i m m u n i z a t i o n c o m p a r a b l e to t h a t a l r e a d y effected in the U n i t e d S t a t e s a r m e d forces. On e h u n d r e d p e r c e n t i m m u n i z a t i o n of all m e m b e r s of the p o p u l a t i o n could be a real c h a l l e n g e for local t r a u m a c o m m i t t e e s of t h e A m e r i c a n College of Surgeons. B y a c h i e v i n g such a p e r c e n t a g e of t e t a n u s toxoid imm u n i z a t i o n , the local t r a u m a c o m m i t t e e s would be p r o t e c t i n g all pote,~tial victims of t r a u m a a g a i n s t t e t a n u s a n d .... t h e r e b y .... would m a k e t h e i r own work e a s i e r in t h e e v e n t s u c h i n d i v i d u a l s a r e b r o u g h t to the e m e r g e n c y room w i t h a severe w o u n d or wounds. I n s u p p o r t of such a n activity, C u r t i s Artz, t h e C h a i r m a n of t h e ACS C o m m i t t e e on T r a u m a , h a s w r i t t e n , " T h e r e a r e m a n y a r e a s . . . t h a t really n e e d some bright, y o u n g fellow to t a k e the bull by t h e h o r n s and i m m u n i z e large c o m m u n i t i e s . " l a
4. SURGICAL WOUND CARE S u r g i c a l p r o p h y l a x i s consists of the removal of Cl. t e t a n i a n d n o n v i a b l e tissue from w o u n d s a n d of t h e best possible r e c o n s t r u c t i o n of aerobic wounds.77 M e t i c u l o u s surgical c a r e of w o u n d s is p e r f o r m e d w h e n t he following a r e c a r r i e d out: 1. T h e w o u n d s a r e t a k e n care of a t t h e e a r l i e s t possible m o m e n t . 2. As e ptic technic, w i t h the use of gloves, gowns, masks, sterile i n s t r u m e n t s a n d t h e a p p l i c a t i o n of p r o p e r solutions to p r e p a r e the skin before t h e n e c e s s a r y o p e r a t i v e p r o c e d u r e s at the i n j u r e d site. 3. D u r i n g skin p r e p a r a t i o n , t h e w o u n d s h o u l d be covered with gauze to prevent further contamination. 4. P r o p e r lighting, so t h a t the s u r g e o n can exactly identify a n d p r o t e c t vital s t r u c t u r e s such as n e r v e s and vessels. 5. A d e q u a t e i n s t r u m e n t s a n d a d e q u a t e help, so t h a t t h e r e is the best possible a n d g e n t l e r e t r a c t i o n of s t r u c t u r e s in wounds. 6. H e m o s t a s i s w i t h delicate i n s t r u m e n t s a n d with fine s u t u r e m a t e r i a l , so t h a t t h e r e is a m i n i m u m of n e c r o t i c tissue left in wounds. 7. G e n t l e h a n d l i n g of tissues a t all times, so t h a t n e c r o t i c tissue is not p ro d u c e d . 8. C o m p l e t e d e b r i d e m e n t with scalpel excision of n e c r o t i c tissue a n d with r e m o v a l of foreigJl bodies, so t h a t no p a b u l u m is left on w h i c h a n y u n r e moved b a c t e r i a c a n p r o p a g a t e . 9. T h e w o u n d is i r r i g a t e d copiously w i t h l a r g e a m o u n t s of physiologic salt solution to w a s h out m i n u t e a v a s c u l a r f r a g m e n t s of tissue a n d to elimi n a t e foreign bodies. 10. If t h e r e is a n y d o u b t c o n c e r n i n g a w o u n d pro~dding a n a e r o b i c conditions so t h a t t h e t e t a n u s bacillus c a n grow a n d p r o d u c e its l e t h a l toxin in it, t h e w o u n d is left wide open, a n d d r a i n a g e is i n s t i t u t e d w h e n necessary. D u r i n g the l a t t e r p a r t of the n i n e t e e n t h c e n t u r y , the p r i n c i p l e s for p r o p e r w o u n d c a r e t h a t h a d been developed by S e m m e l w e i s , Lister, H o i s t e d and 36
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FIG. 1 3 . ~ M o ~ a l i t y of tetanus by age groups (per 10D,000 population) and rate of delivery at medical institutions (per cent) in Japan.~;2 (Courtesy of I. Ebisawa.)
others g r a d u a l l y were accepted and, at the beginning of the t w e n t i e t h century, were applied to the problems of m i l i t a r y medicine. After s t u d y i n g an analysis of W o r l d W a r I cases af t e t a n u s in 1915, Bruce,22 who was c h a i r m a n of the World W a r I B r i t i s h W a r Office Comm i t t e e for the S t u d y of T e t a n u s , r e p o r t e d that, if t h o r o u g h surgical treatm e n t is c a r r i e d out on wounds from the b e g i n n i n g so as to e l i m i n a t e necrotic tissue a n d foreign bodies, the n u m b e r of cases of t e t a n u s should sensibly diminish if n o t a l t o g e t h e r d i s a p p e a r . Ebisawafi2 a J a p a n e s e internist, has offered statistical proof of the value of i m m e d i a t e meticulous surgical care of wounds in the p r e v e n t i o n of tetanus. In a s t u d y of obstetric cases, he noted a s h a r p decrease in tetanus, a t t r i b u t i n g this to w o u n d care. In J a p a n , the n e o n a t a l t e t a n u s m o r t a l i t y r a t e in 1947 was 36.1 and in 1961 it was 7.1 per 100,000 live births; the percentage of deliveries at medical institutions for all births in J a p a n for these s a m e y e a r s rose from 2 . 4 ~ to 58~o. As t e t a n u s toxoid had been excluded from the J a p a n e s e i m m u n i z a t i o n programs, as J a p a n e s e physicians were not informed of the availability of t e t a n u s toxoid until recently, as n e i t h e r a n t i t o x i n nor penicillin was used to protect n e o n a t e s from t e t a n u s and as the s h a r p decrease in t e t a n u s m o r t a l i t y occurred, E b i s a w a concluded that the g r e a t l y reduced m o r t a l i t y from t e t a n u s was the result of improving obstetric facilities for the care of tile reproductive tract in the m o t h e r and of the umbilicus and cord in the infant. 37
5. ANTITOXINS a) HETEROLOGOUS A N T I T O X I N S . - ....I r l 1890, yon Behring and Kitasafo206 demonstrated the formation of tetanus antitoxin, which was formed in the blood of mice and rabbits following active immunization. This antitoxin, injected into unvaccinated mice and rabbits, protected them against a subsequent tetanus injection. Other animals also could be treated with these sera with good results. Thus, the practical value of both homologous and heterologous antisera was proved. Few discoveries in the history of medicine have excited scientists and laymen alike as much as this one did, for the ever-present threat of tetanus might now be banished. By the end of the )lineteenth century, despite some skepticism, antitoxin therapy and particularly prophylaxis were widely adopted and approved. The application and dissemination of the practical value of heterologous antitoxin on a large scale became possible in World War I. The British began effectively to use equine tetanus antitoxin about the middle of October, 1914. Bruce22 reported a sudden drop in the incidence of tetanus from 9 cases per 1,000 wounded in September, 1914, to 1.4 per 1.000 in December, 1914. The antitoxin, which has been used commonly, is produced by the active immunization of horses with tetanus toxoid and toxin. Injection of such horse serum may result in sensitization of the patient. A subsequent dose may result in sensitivity reactions, such as local redness and swelling of the injected limb or generalized serum sickness. Equine antitoxin has been of real value, but both fatal anaphylactic shock and serum sickness (5-30~azb) have occurred with the heterologous antitoxins.14, 23, 28, 73, 121, Is0 Moreover, the half-life of the hetero]ogous an/itoxins cannot be predicted in any given individual.129 Recently, because certain parts of the world have not had adequate supplies of TIG(H), interest in bovine antitoxin has been stirnu]ated. Trinca and Reid,200 as recently as January, 1967, put forth evidence that bovine antitoxin, refined by ethanol fractionation, is unlikely to provoke reactions in patients hypersensitive to horse serum. After careful follow-up, only 3 patients (4.3%) were found to have had aller~c responses, and these were minor local reactions. Significantly, an editorial accompanying the Trinca-Reid report on bovine antitoxin states that interest in bo~dne antitoxin must not divert attention from two even more pressing needs in tetanus prophylaxis: (I) the extension of active immunization and (2) the production of adequate supplies of TIG (H), which, unlike bovine antitoxin, is practically nonantigenic in man. As the Hsks of tetanus from a wound may be unpredictably more or less than the risks of complications from heterologous antisera, and since there are at least 5,000 known cases of tetanus following the administration of equine antiserum, participants at the Second International Conference on Tetanus at Bern in 1966 went on record as stating that it is the final rnedico|ega] right and prerogative of an attending physician to decide whether a heterologous serum with its associated dangers should be used.101,177, 22! On the basis of the few existing reports on previous experiments, it has been widely accepted that the absorption of serum into the blood after intramuscular injection is much more rapid and produces a higher concen38
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T A B L E 19:= GENERIC, OFFICIAL OR SCIENTIFIC NAMES FOR TETANUS I M M U N E (JLOBULIN ( H U M A N ) T H A T HAVE B ~ N IN. TtIE WORLD LITERATURE
FOUND
"FIG(human) TIG (H) TIG Human tetanus antitoxin Homologous tetanus antitoxin Immune globulin Hyperimmune globulin Human immune globulin Human hyperimmune globulin Homologous serum Antitetanic gamma globulin Homologes immunglobulin Hyperimmune globulin antitetanus HiG Human serum globulin Human antitetanus globulin Human A.T.G. Antitetanus globulin Htunan t e t a n u s immune globulin Tetanus hyperimmune ganaraa globulin
t r a t i o n of antibodies in the blood t h a n a f t e r s u b c u t a n e o u s injection. This belief was re-examined by Christensen36 in t h r e e different e x p e r i m e n t s : (1) on rabbits injected with purified t e t a n u s antitoxin, (2) on rabbits given native t e t a n u s horse s e r u m a n d (3) on 8 h u m a n s receiving purified t e t a n u s antitoxin. H e found t h a t c o m p a r i s o n of the times at which a given low conc e n t r a t i o n was reached did not show significant differences b e t w e e n the i n t r a m u s c u l a r a n d s u b c u t a n e o u s routes of injection in a n y group, t h a t comparison of the concentrations r e a c h e d after 24 hours showed no significant differences in groups (2) a n d (3), t h a t in group (I) t h e r e m a y have been a m i n o r p r e p o n d e r a n c e of i n t r a m u s c u l a r injections a n d t h a t -in a supplem e n t a r y a n a p h y l a x i s e x p e r i m e n t no definite differences could be demons t r a t e d b e t w e e n the two routes of injection with respect to the shock action on sensitized guinea pigs. b) TETANUS IiV[5[UNE GLOBULIN (HU3[AN). Tetanus immune globulin (human) or TIG(H) has been referred to by numerous scientific and trade names (Tables 19 and 20). The possibility of production of TIG(H) is the result of the work in the 1940s of Cohn and his colleagues, who made feasible large-scale fractiona-
T A B L E 20. TRADE,COI~IMERCIAL OR PROPRIETARY NAMES FOR TETANUS IMMUNE GLOBULIN (HUMAN) FOREIGN Tetabullin (Austria) Tetagam (~rest Germany) Tetuman Berna (Switzerland) Tetaglobuline (France)
U.S.A. Hyper-Tet Hu-Tet. Homo-Tet Gamatet
Immu-Tetanus T-I-Gammagee Pro-Tet Gamulin T
39
tion of s e r u m proteins by p r e c i p i t a t i o n with ethanol u n d e r carefully controlled conditions at low temperatures.lS, 4o T I G ( H ) , a sterile solution c o n t a i n i n g 165 ---+ 15 rag. of g a m m a globulin p e r ml., is p r e p a r e d from h u m a n blood p l a s m a having a high titer of t e t a n u s antitoxin. S u c h plasma is obtained, f am blood of h y p e r i m m u n i z e d volunteers, from blood for g a m m a globulin m a n u f a c t u r e t h a t has been screened for t e t a n u s a n t i t o x i n titers or from placentas from m o t h e r s who h a d received t e t a n u s toxoid booster inoculations a few weeks preceding delivery.l 0 T I G ( H ) is effective p r o p h y l a c t i c a l l y in p a t i e n t s with wounds t h a t m a y be c o n t a m i n a t e d with C1. tetani, and, because it is of h u m a n origin, it is virt u a l l y free from the risk of inducing hypersensitivity. Its use is advised p a r t i c u l a r l y w h e n a h i s t o r y of active i m m u n i z a t i o n with t e t a n u s toxoid c a n n o t be established w i t h reasonable c e r t a i n t y and whe::n the risk of immediate or d e l a y e d reactions to equine antitoxin m u s t be avoided (patients k n o w n to be sensitive to horse serum, those who have h a d prior injections of horse serum or those who have a history of allergy). W h e n a history of previous active i m m u n i z a t i o n can be established, the a d m i n i s t r a t i o n of a booster dose of t e t a n u s toxoid is preferable. Passive i m m u n i z a t i o n with T I G (H) is no s u b s t i t u t e for active i m m u n i z a tion with t e t a n u s toxoid, n o r is it a s u b s t i t u t e for a d e q u a t e surgical care of c o n t a m i n a t e d or p o t e n t i a l l y c o n t a m i n a t e d wounds. T h e half-life of passively acquired t e t a n u s toxin antibodies from T I G (H) is t h o u g h t to be at least 3 weeks and possibly m o r e t h a n 4 weeks.129, ls5 By contrast, t e t a n u s toxin antibodies from heterologous sources (equine or bovine antitoxins) have a relatively brief half-life, which m a y be as short as 2 or 3 days. Studies on the absorption and persistence of T I G (H) indicate t h a t abQut one-half of an i n t r a m u s c u l a r dose a p p e a r s in the plasma. The, injection of 4-5 u n i t s / k g , of body weight ensures a p l a s m a level of 0.02 u n i t s / m l , for as long as 4 weeks: this level probably is a d e q u a t e to protect a g a i n s t any b u t a f u l m i n a t i n g t e t a n u s infection. Unless e x t r a n e o u s c o n t a m i n a t i o n occurs, t h e r e is virtually no likelihood of t r a n s m i t t i n g viral hepatitis by the a d m i n i s t r a t i o n of this agent, T h e possibility t h a t allergic reactions m a y occur is remote.71, ss As with o t h e r g a m m a globulin p r e p a r a t i o n s , however, p a i n a n d redness at the site of injection m a y occur rarely. At the time of i n t r a m u s c u l a r a d m i n i s t r a t i o n , skin sensitivity testing need not be done, but care should be taken to d r a w back on the p l u n g e r of the s y r i n g e in order to be c e r t a i n t h a t the needle is not in a blood vessel. U n d e r no circumstances should the globulin be given intravenously.a07-109, 150. 194 W h e n . T I G ( H ) is given, adsorbed t e t a n u s toxoid also should be a d m i n istered. A different sterile syringe a n d needle are used to inject the toxoid so as to lessen the possibility of some of the antitoxin and some of the toxoid n e u t r a l i z i n g each other. A dose of 250-400 units of T I G (H) does not a p p e a r to interfere ~l)preciably with p r i m a r y active immunization.12J. 129, i:~1.1:~2. J,~;, 1.z0, ~6s, J:0 (Figs. 14-16). Thus, s i m u l t a n e o u s active-passive imm u n i z a t i o n can be accomplished by injecting adsorbed toxoid i n t r a m u s c u larly into one e x t r e m i t y and the "FIG (H) into another, p r e f e r a b l y one deltoid muscle and the c o n t r a l a t e r a l gluteal muscles, By such simult:meous immuniz~ltion, i m m e d i a t e lmssive l)roteciion is conferred and active protection is initiated.
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FIG. 14 (le/t).--Mean s e r u m t e t a n u s a n t i t o x i n levels a f t e r a c t i v e - p a s s i v e i m m u n i z a t i o n of n o n i m m u n e persons with fluid o r a l u m toxoid, i n o c u l a t e d s i m u l t a n e o u s l y with T I G ( H ) . T h e c r o ~ h a t c h i n g covers 1 s t a n d a r d e r r o r of t h e m e a n . T h e h o r i z o n t a l d a s h e d line a t 0.01 u n i t p e r nil. r e p r e s e n t s t h e g e n e r a l l y a c c e p t e d m i n i m a l p r o t e c t i v e level. T h e a r r o w a t the 28th d a y i n d i c a t e s a s e c o n d toxoid i n o c u l a t i o n i d e n t i c a l w i t h t h a t on the d a y of immunization.131 ( C o u r t e s y of L. L e v i n e a n d J. M c C o m b . ) Fr~. 15 (right).~Mean s e r u m a n t i t o x i n levels of n o n i m m u n e p e r s o n s r e c e i v i n g a l u m toxoid a n d T I G ( H ) with a n d w i t h o u t a d e l a y (3 or 4 h o u r s ) in a d m i n i s t r a t i o n of t h e globulin. T h e d a s h e d c u r v e r e p r e s e n t s control s u b j e c t s w h o r e c e i v e d T I G ( H ) alone. T h e d a s h e d h o r i z o n t a l line a n d t h e a r r o w a r e ,as in F i g u r e 14.1al ( C o u r t e s y of L. L e v i n e a n d J . M c C o m b . )
S i m u l t a n e o u s active-passive immunization with toxoid and T I G ( H ) should be practiced w h e n necessary, as indicated in Table 17. Possible unusual indications for s i m u l t a n e o u s administration of both toxoid and T I G ( H ) to the wounded, which were indicated previously in the toxoid section (J-3-n), are (1) agammaglobulinemia, (2) recent exposure to radioa c t i v e substances, (3) recent exposure to i m m u n o s u p p r e s s i v e agents a n d (4) m a m m a r y carcinoma. Recently, the r e c o m m e n d e d prophylactic dose of 250 units of T I G ( H ) Fw,. 1 6 . - - M e a n s e r u m a n t i t o x i n levels of n o n i m m u n e p e r s o n s receiving a l u m toxoid alone, a l u m plus simultaneou.s T I G ( H ) a n d T I G ( H ) alone. At t h e 56th d a y . t h e foxoid a l o n e a n d the c o m b i n e d i m m u n i z a t i o n h a v e i d e n t i c a l values. T h e s e m e a n v a l u e s fail to s h o w a n y signific a n t d a m a g e to e i t h e r t h e a n t i t o x i n o r the toxoid.131 ( C o u r t e s y of L. L e v i n e a n d J . M c C o m b . ) ~ r"i-
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TABLE 21. PROPHYLACTIC D O S E S OF T E T A N U S I M H I U N E G L O B U L I N ( H U M A N ) FOR I N F A N T S AND C H I L D R E N $7 AGI~ 10 years or older 5-10 years U n d e r 5 years
DOSE 250 units 125 units 75 unit..,;
for t h e usual, p r o p e r l y surgically t r e a t e d a n d i m m e d i a t e l y cared-for w o u n d in a n a d u l t has been questioned. S u c h q u e s t i o n i n g has been based on w o u n d s t h a t were m o r e t h a n 48 h o u r s old w h e n t h e T I G ( H ) was given, or h a s been considered in r e g a r d to a railroad w o r k e r who could have had a n u n r e c o g n i z e d i n j u r y p r i o r to t h e one for which he was given the T I G ( H ) . 4 8 , 111 T h e careful studies by McComb, D w y e r , Levine, Rubbo, Suri a n d o t h e r s as well as the consensus of the p a r t i c i p a n t s at th e Second a n d T h i r d I n t e r n a t i o n a l C onferences on T e t a n u s i n d i c a t e t h a t w h e n the dose of 250 u n i t s of T I G ( H ) has not been a d e q u a t e p r o p h y l a c t i c a l l y , the following questions should be a n s w e r e d fully12,~. 129, 13l, 132, 136, 140, 168. 170: 1. Did t h e p a t i e n t have an u n r e c o g n i z e d w o u n d t h a t o c c u r r e d prior to the i n j u r y considered to be responsible for t e t a n u s a n d which was the w ound a c t u a l l y responsible for t e t a n u s ? 2. W a s the T I G ( H ) given too late to be effective propt~ylactically? 3. W a s the w o u n d severe or neglected so t h a t a 500-unit dose of T I G (H) was i n d i c a t e d ? 4. W a s the T I G (H) o r d e r e d and not given? 5, W a s some d r u g t h a t was t h o u g h t to be T I G ( H ) given i n s t e a d of TIG(H) ? 6. W a s the T I G (H) a n i n a d e q u a t e p r e p a r a t i o n ? 7. W a s t h e T I G (H) o u t d a t e d ? 8. W a s too m u c h toxoid .... e i t h e r in respect to total volume or in r espect to Lf c o n c e n t r a t i o n a d m i n i s t e r e d ? 9. W e r e t e t a n u s toxoid a n d T I G (H) a d m i n i s t e r e d with the s a m e s y r i n g e and needle? 10. W e r e t e t a n u s toxoid a n d T I G ( H ) a d m i n i s t e r e d at the s a m e site? 11. W a s adsorbed or fluid t e t a n u s toxoid a d m i n i s t e r e d ? 6. ANTIBIOTICS At th e Second I n t e r n a t i o n a l Conference on T e t a n u s in 1966. t he cons e n s u s was t h a t antibiotics, s u c h as penicillin, h a v e been shown to be effective a g a i n s t v e g e t a t i v e t e t a n u s bacilli both in vitro a n d in e x p e r i m e n t a l animals. T h e y h a v e no effect a g a i n s t toxin. T h e effectiveness of antibiotics for p r o p h y l a x i s r e m a i n s u n p r o v e d , and, if used, t h e y should be given over a period of a t / e a s t 5 days.221 T h e following s u p p o r t s such an a t t i t u d e . I n a 1959 r e p o r t c o n c e r n i n g an in vitro i n v e s t i g a t i o n of the sensitivity of different s t r a i n s of CI. t e t a n i to antibiotics, Scheibel a n d A s s a n d r i l ; 2 s t a t e d t h a t v a r i a t i o n s have been d e m o n s t r a t e d in the sensitivity to antibiotics of different s t r a i n s of C1. tetani, these being especially p r o n o u n c e d as r e g a r d s penicillin but also evident to some degree with o x y t e t r a c y c l i n e . S u c h a n observation applies to both t he vegetative p h a s e and the g e r m i n a t i n g spore 42
phase, and both as regards the g r o w t h - i n h i b i t i n g and the bactericidal effect. S t r e p t o m y c i n was found to be almost ineffective. Toxigenic persister organisms have been d e m o n s t r a t e d in cultures with both low and high concentrations of antibiotics. Conversion to toxigenic, resistant L-forms may occur when penicillin is used. On the basis of these findings and because of the occurrence of d e a t h from t e t a n u s in 3 i n j u r e d persons who were given antibiotics only, Scheibel and Assandri concluded (hat justification for reliance on antibiotics for tetanus prophylaxis in nonvaccinated persons m u s t be challenged. In 1964, SmithIS2 reported that the development of t e t a n u s in mice infected with Cl. t e t a n i could be p r e v e n t e d with penicillin only when an adequate serum concentration was m a i n t a i n e d for a period of 3-4 days. If penicillin t r e a t m e n t was d e l a y e d until more t h a n 4 hours a f t e r infection, tetanus could not be prevented, but antitoxin was effective up to 20 hours after infection. Even t h o u g h penicillin effectively prevented tetanus, spores were found to survive in the tissues, and could be reactivated l a t e r to produce a fatal tetanus. Penicillil~ failed to p r e v e n t t e t a n u s in mice injected in the same site with both spores and penicillinase-producing S t a p h y l o c o c c u s (lltrells.
In 1966, 1Regamey el el. 1~;-~pointed out /.hat in the guinea pig the injection of procaine penicillin G (at a dose c o r r e s p o n d i n g to 2 m e g a u n i t s per 50-kg. subject) at the time of insertion of highly tetanogenic silk t h r e a d s does not suppress the d e v e l o p m e n t of lethal tetanus. F u r t h e r , in experim e n t s using a recording biophotometer, they showed t h a t t e t a n u s bacilli develop a b u n d a n t l y in the presence of certain c o n c e n t r a t i o n s of penicillin G but then s u d d e n l y undergo ]ysis. This destruction of the organism is t h o u g h t to liberate the e n d o c y t o p l a s m i c toxin, which can be n e u t r a l i z e d only by antitoxin. Therefore, in viva, w h e r e osmotic tensions are such as to readiIy permit bacterial lysis, penicillin could cause the release of the intracellu]ar toxin load. Hence, if a potentially lytic antibiotic, such as penicillin, and antitoxin are to be a d m i n i s t e r e d , the antitoxin should be given several hours before the antibiotic to n e u t r a l i z e a n y toxin released by the antibiotic. K r e m l e v l I.~ studied a n i m a l s with e x p e r i m e n t a l t e t a n u s infections induced after a single dose of toxoid and after a 2-dose basic series. W i t h administration of a toxoid booster plus antibiotics, all a n i m a l s survived. F o r ,91 of these animals, the booster was the second dose of toxoid; for 9 of the animals, the booster was a legitimate booster after a 2-dose basic series. W i t h only an antibiotic m i x t u r e of crystalline penicillin, b e n z a t h i n e penicillin G and streptomycin, 7 of 9 a n i m a l s survived. Bustle and his colleagues25 studied the action of an antibiotic against tetanus toxin (not spores) in viva and in vitro. T h e y instituted the study despite previous reports indicating no k n o w n activity of antibiotics against t e t a n u s toxin. T h e y observed that 1 rag. of N - ( p y r r o l i d i n o m e t h y l ) t e t r a cycline will inactivate 130 mouse lethal doses of t e t a n u s toxin. T h e inactivated toxin still has good antigenic properties. Case reports, such as those of Cases 1,4 and 6 in Section L, a p p e a r from time to time and represent failures of penicillin prophy]axis.,t¢, 144 In view of the i m m e d i a t e l y preceding observations it can be slated that antibiotics such ;Is penicillin, given l)rOml)tly after injury, m a y have a det e r r e n t action against t e t a n u s infection, especially for a brief 1)eriod, but cannot be used as the only I)rol)hylaxis. T e t a n u s is a m a n i f e s t a t i o n of a fox. 43
emia, not of an invasive infection. Antibiotics m a y be of value in combating a n y Cl. tetani bacilli t h a t have not been or c a n n o t be removed surgically. Antibiotics should not be used as a substitute for active or passive immunization a n d / o r as a substitute for p r o p e r surgical care of the wound, and antibiotics are not necessary to p r e v e n t t e t a n u s in the actively immunized. If used, a convenient method of a d m i n i s t e r i n g penicillin is to give 1.2 million units of long-acting b e n z a t h i n e penicillin G i n t r a m u s c u l a r l y . On the basis of in vitro sensitivity testing of CL t e t a n i strains, oxytetracycline is considered to be one of the best t e t r a c y c l i n e - r e l a t e d drugs. O x y t e t r a e y c l i n e m a y be given by the oral route in a dosage of 1-2 Gm. daily for 1-3 weeks. In the p a t i e n t with a severe o l d wound, antibiotics are used for their effect on organisms other t h a n the t e t a n u s bacillus, such as Cl. per/ringens.Sl If antibiotics are administered, it should not be forgotten t h a t they can cause u n d e s i r e d reactions. T h e incidence of reactions a m o n g 5,107 servicem e n who received 1,200,000 units of b e n z a t h i n e penicillin G was 1.687/o.135 T h e widespread use of an antibiotic, such as penicillin, is thus not without hazard, p a r t i c u l a r l y if the d r u g should be given to h u n d r e d s or thousands or millions of the p o p u l a t i o n at a time of a national disaster.
7. GANGLIOSIDEAND GANGLIOSIDE-CEREBROSIDECOMPLEX M e l l a n b y a n d her co-workers141 have found t h a t ganglioside with or w i t h o u t cerebroside acts as a prophylactic a g e n t in e x p e r i m e n t a l t e t a n u s in mice. T h e y found t h a t the s y m p t o m s of t e t a n u s in mice, resulting from int r a m u s c u l a r injection of either purified t e t a n u s toxin or vegetative Cl. tetani, can be p a r t i a l l y prevented if the mice are injected at the same time, or a few hours before or after, with a p r e p a r a t i o n of mi~:ed gangliosides or with a suspension of ganglioside-cerebroside complex. Injection at the same site as the toxin injection is most effective, a l t h o u g h intravenous injection of ganglioside (but not of the complex) also has some action; 0.5 rag. of ganglioside, w h e n complexed with 1.5 rag. cerebroside, is as effective in protection as 5 nag. ganglioside alone. P r o t e c t i o n by complexes containing different proportions of ganglioside reflects their ability to fix t e t a n u s toxin in • 4tro. M e l l a n b y et al. tentatively suggest t h a t injection of gangliosidecerebroside complex at a site of i n j u r y migh~ be of p r o p h y l a c t i c value for h u m a n tetanus.
8. :EMERGENCYMEDICAL IDENTIFICATI()NDEVICES In the p r e s e n t era of sophisticated chemical and electronic e q u i p m e n t and of complicated and heroic operative procedures, p r o p e r consideration should still be given generally to the p a t i e n t ' s history and more specifically to the emergency medical identification device (the E M I D ) .s5 I n the U n i t e d States, where now more a n d more individuals are actively i m m u n i z e d for tetanus, such devices are becoming more r a t h e r t h a n less i m p o r t a n t . Clinicians in active practice are constantly faced with these questions in the m a n a g e m e n t of the wounded: 1. 2. 3. 4.
H a s the p a t i e n t been actively i m m u n i z e d for t e t a n u s ? If actively i m m u n i z e d for tetanus, when? H a v e there been reactions to t e t a n u s toxoid? Should T I G ( H ) be given? 44
S u c h questions can be a n s w e r e d i m m e d i a t e l y if each individual has on his person a n u p - t o - d a t e E M I D . It is most distressing to he called to take care of w o u n d e d patients who have little or no knowledge of t h e i r i m m u n i z a t i o n status. If in doubt, simultaneous active-passive i m m u n i z a t i o n can be effected, but, in doing so, T I G (H) m a y be wasted. Brooks a n d his co-workers21 and H a r r i s o n 94 stress careful d o c u m e n t a t i o n of the i m m u n i z a t i o n history. If the history is vague a n d poorly d o c u m e n t e d , the p a t i e n t should be given tetanus toxoid as though the dose or doses of to.~oid in question had not been given. P h y s i c i a n s have had patients tell t h e m t h a t they have been given t e t a n u s toxoid injections only to discover on closer search of the history t h a t it was t e t a n u s antitoxin, or d i p h t h e r i a toxoid, or p e r h a p s t y p h o i d vaccine t h a t h a d been given but not t e t a n u s toxoid.67,130 ][n the U n i t e d States, at present, few people have in their i m m e d i a t e possession an emergency medical identification device with tetanus data. T h e following case report is p r e s e n t e d to e m p h a s i z e how a surgeon interested in t e t a n u s p r o p h y l a x i s m a y be lured into a false sense of security c o n c e r n i n g the tetanus p r o p h y l a x i s status of a n i n j u r e d person. At a p p r o x i m a t e l y 6:30 P.]~L, F r i d a y , 8 N o v e m b e r 1968, a y o u n g a d u l t m a l e suffered multiple injuries in an a i r p l a n e crash. At 11:00 P.~L, w h e n he was e x a m i n e d in the hospital, he stated t h a t he h a d been in the U.S. A r m y a n d t h a t he had received a booster dose for tetanus 2 m o n t h s previously. D u r i n g the r e m a i n d e r of the night, n u m e r o u s facial lacerations were debrided and s u t u r e d , a n d a p p r o p r i a t e care rendered for fractures of the base of the skull and of the maxillae, for hemat u r i a and for m u l t i p l e contusions. A t 9 A.~[., S a t u r d a y , 9 November, a careful cheek of the hospital records indicated t h a t the p a t i e n t had not h a d a booster dose of t e t a n u s toxoid 2 m o n t h s previously. Also, it was established t h a t he had been in" the A r m y in 1958. T h e n , a dose of t e t a n u s toxoid was given. B y 9 A.~., S u n d a y , 10 N o v e m b e r , his wife h a d found his A r m y record on which t h e r e were notations for only two injections of t e t a n u s toxoid (27 M a y 1958 a n d 9 J u l y 1958). T I G ( H ) was ordered. At 7 P.M., 10 N o v e m b e r 1968 ( a p p r o x i m a t e l y 48 hours after i n j u r y ) , the T I G ( H ) was a d m i n i s t e r e d . F o r t u n a t e l y , the p a t i e n t had an excellent recovery. H e was, however, an individual who h a d received serious tetanus-conducive injuries in the immediate vicinity of his b r a i n so t h a t any t e t a n u s toxin t h a t h a d been produced in the wound would have had to be t r a n s p o r t e d only a short distance to become fixed in the brain and to produce tetanus. If the p a t i e n t h a d had on his person a n up-to-date E M I D , more i m m e d i a t e and more specific t e t a n u s p r o p h y l a x i s could have been instituted. If every person c a r r i e d some type of e m e r g e n c y medical identification device, history t a k i n g after i n j u r y could be greatly simplified and expedited, t e t a n u s toxoid i m m u n i z a t i o n could be p e r f o r m e d a c c u r a t e l y and scientifically, overdosage and u n n e c e s s a r y injections of t e t a n u s toxoid could be avoided and injections could be avoided in the r~re individua| who is sensitive to t e t a n u s toxoid. 45
T h e A m e r i c a n Medical Association has m a d e available to p h y s i c i a n s at low cost a n e m e r g e n c y medical identification card.60 On this card. t:here is r e p r o d u c e d the A m e r i c a n M e d i c a l Association identification symbol, which was a d o p t e d by the World Medical Associ~,_tion t h r o u g h a n action by its Assembly in 1964 a n d w h i c h was r e c o m m e n d e d for use in the c o u n t r i e s repr e s e n t e d by the W o r l d Medical Association m e m b e r s . S i m i l a r c a r d s or records also a r e available from t h e W o r l d H e a l t h O r g a n i z a t i o n , th e U n i t e d S t a t e s G o v e r n m e n t P r i n t i n g Office, the A m e r i c a n A c a d e m y of P e d i a t r i c s , t h e A m e r i c a n A c a d e m y of G e n e r a l P r a c t i c e , t h e M i c h i g a n S t a t e M e d i c a l Society, t h e K a r o l i n s k a S j u k h u s e t a n d The Columbus [Ohio] Dispatch. At th e 1967 W o r l d Congress of M o t o r i n g M e d i c i n e in Vienna, in a discussion of e m e r g e n c y medical identification devices for motorists, a n asbestos, n o n i n f l a m m a b l e card used in A u s t r i a was described. A b u t t o n m a y be a t t a c h e d to u n d e r c l o t h i n g , to a billfold or to a purse. M e t a l tags are available in a t t r a c t i v e configurations, such as a h e a r t . T a t t o o m a r k s , of course, are a l w a y s on the p a t i e n t , a n d a r e readi l y a p p a r e n t if not d e s t r o y e d by local t r a u m a , such as a burn. T h e use of such m a r k s , however, h a s been questioned. S o m e y e a r s ago, t h e C o m m i t t e e on E m e r gency M e d i c a l I d e n t i f i c a t i o n of the A m e r i c a n M e d i c a l Association cons id e re d tattoos a t some length a n d decided t h a t they were not slfitable for s e v e ra l reasons. T h e p r i m a r y one was the a n t a g o n i s m toward p e r m a n e n t m a r k i n g s h e l d by a g r e a t m a n y n a t i o n a l i t y a n d e t h n i c g r o u p s from the e x p e r i e n c e s t h e y suffered d u r i n g W o r l d W a r s I a n d II. Also, it is difficult to provide a t a t t o o in a place in which it is accessible and at t he s a m e t i m e inconspicuous. T h e tine, a tattoo t y p e of device, has been deve, Ioped for use in connection with tuberculosis. A t t h e 1966 I n t e r n a t i o n a l C o n f e r e n c e on T e t a n u s , Rubbo169 s u g g e s t e d t h a t carbon be i m p r e g n a t e d on t h e tips of a fine with t h e d a t e of a y e a r a n d t h a t the tine t h e n be used to t a t t o o the d a t e of t he l a s t toxoid injection.
K. MANAGEMENT OF THE VICTIM OF TETANUS {TREATMENT) A t t h e t i m e of t h e Civil W a r a n d i m m e d i a t e l y t h e r e a f t e r , little was k n o w n a b o u t tile p r e v e n t i o n a n d t r e a t m e n t of t e t a n u s . B y o u r p r e s e n t - d a y s t a n dards, wound c a r e a t its best was poor, consisting p r i m a r i l y of analgesics, a t t e m p t s a t h e m o s t a s i s , nonspecific o i n t m e n t s a n d a m p u t a t i o n . D u r i n g the Civil W a r , in 280,040 admissions for w o u n d s a n d injuries, t h e r e were 505 cases of t e t a n u s , with 451 d e a t h s (89.3%) (see T a b l e 12). I n the 1.863 h~Ianu a l of M i l i t a r y S u r g e r y for the A r m y of the C o n f e d e r a t e S t a t e s a p p e a r e d this s t a t e m e n t : " T o e n u m e r a t e t h e m e a n s used for the relief of t e t a n u s would r e q u i r e a volume; to record those e n t i t l e d to confidence does not req u i r e a line."lga I n c o n t r a s t to s u c h a s t a t e m e n t of 1863, it now m a y be s t a t e d t h a t the t r e a t m e n t of t e t a n u s is complex b u t successful. I t r e q u i r e s devoted a n d exh a u s t i n g a t t e n t i o n by all echelons of p h y s i c i a n s a n d hospital personnel. It is t r u l y a t e a m effort t h a t can best be c a r r i e d out in a t e t a n u s c e n t e r or hospital in w h i c h m a n y cases of t e t a n u s have been t r e a t e d successfully or in a large g e n e r a l hospital, w h e r e all t h e m o d e r n medical a n d surgical a d v a n c e s c a n be d i r e c t e d t o w a r d o v e r c o m i n g a t e r r i b l e disease associated with horrible p a i n for t h e u n f o r t u n a t e p a t i e n t . 46
P a t e l a n d Joag~5~ of I n d i a have e m p h a s i z e d t h a t if m e t h o d s of t h e r a p y are to be e v a l u a t e d correctly t h e r e should be developed a uniform system of g r a d i n g of tetanus. If such a s y s t e m is not developed, cases of mild t e t a n u s with a low m o r t a l i t y rate m a y be wrongly c o m p a r e d with cases of severe t e t a n u s with a high m o r t a l i t y rate. Adams1 of S o u t h Africa stresses t h a t in t r e a t i n g t e t a n u s -in which death is due to a n u m b e r of f a c t o r s ~ i t is very difficult to know which factor or factors cause d e a t h and hence it is very difficult to know about the effect of a certain form of t h e r a p y . A specific conclusion can be d r a w n concerning the efficiency of a p a r t i c u l a r t y p e of t r e a t m e n t only if all other t r e a t m e n t s are controlled and only if cases in the same stages of t e t a n u s are compared. A d a m s states that the value of different forms of t h e r a p y can be evaluated best by constant comparisons of results in one hospital r a t h e r t h a n in comparisons of results in different hospitals. T h e results of S m y t h e a n d Bowie and those of Ildirim (cf. section K-2-b) in the t r e a t m e n t of n e o n a t a l t e t a n u s are p a r t i c u l a r l y striking. In t r e a t i n g 321 cases of n e o n a t a l t e t a n u s d u r i n g the period from 1956 to 1969, S m y t h e and BowietS'~ were able to decrease the m o r t a l i t y rate for n e o n a t a l t e t a n u s from 100% to consistently below 20% (Fig. 17). S m y t h e ascribes his i m p r o v e d results to three factors: 1. T h e control of i n t e r m i t t e n t positive-pressure r e s p i r a t i o n by monitoring the Pco2.186 2. T h e clarification of the problems of t r a c h e o s t o m y a n d d e t u b a t i o n in the infant.Is7 3. T h e striking i m p r o v e m e n t in control of infection following instillation of penicillin and colistin down the t r a c h e o s t o m y tube.lSs T h e t h e r a p e u t i c r e c o m m e n d a t i o n s t h a t follow are those that have been proved by the experiences of those p a r t i c u l a r l y i n t e r e s t e d in the m a n a g e m e n t of t e t a n u s and which have been discussed in detail at the three I n t e r -
FIG. 1 7 . - - N e o n a t a l tetanus m o r t a l i t y rates, South Africa, 1956-1969.~ .~:~ (Courtesy of P. S m y t h e and M. Bowie.) i00
80
60
40
ZO
!956
!958 1957
1960 1959
1962 1964 1966 1968 196 1 1963 1965 1967 1969
47
n a t i o n a l C o n f e r e n c e s on T e t a n u s . I , 35, 41, 79, s3, 220, 223 T h e i r i n i t i a t i o n is based on the e s t a b l i s h m e n t of a diagnosis of t e t a n u s . T h e y c o n s t i t u t e a guide t h a t is to be a l t e r e d a c c o r d i n g to t h e e x p e r i e n c e and p e r s o n a l judgm e n t of t h e a t t e n d i n g p h y s i c i a n . S o m e of the m e t h o d s of t r e a t m e n t can h a v e a d v e r s e as well as beneficial effects. H e n c e , w h e n a n y t r e a t m e n t is i n i t i a t e d , a q u o t a t i o n of H i p p o c r a t e s s h o u l d be r e m e m b e r e d : " P r i m u m non nocere."97 H i s advice, liberally t r a n s lated, is: "As to diseases, m a k e a h a b i t of two t h i n g s to help, or at l east to do no harm."65 T h e following r e c o m m e n d a t i o n s for m a n a g e m e n t are given in o r d e r of chronologic priority.S1 1) COIVIPLETE HISTORY AND PttYSICAL EXAI~INATIO.N. O b t a i n a c o m p l e t e m e d i c a l a n d surgical h i s t o r y of t h e p a t i e n t , a n d p e r f o r m a c o m p l e t e physical e x a m i n a t i o n . I n p a r t i c u l a r , i n q u i r e a b o u t the d a t e of i n j u r y , th e circums t a n c e s of i n j u r y , the d e p t h of the i n j u r y below the skin a n d allergies. S u c h i n f o r m a t i o n forms a b a s e l i n e for the recognition of such c o m p l i c a t i o n s as atelectasis, p n e u m o n i a , t r a u m a t i c glossitis, f r a c t u r e s of the v e r t e b r a e , decubital ulcers a n d fecal impaction. If rectal probes a r e left in place for cons t a n t recording of t e m p e r a t u r e , t h e y m u s t be checked c a r e f u l l y to p r e v e n t t r a u m a to t h e rectal m u c o s a a n d a n o r e c t a l veins d u r i n g convulsions., 2) ANTITOXIN. a) I n t r a m u s c u l a r i n j e c t i o n . As soon as the diagnosis of t e t a n u s is made, give deeply i n t r a m u s c u l a r l y 3,000-6,000 u n i t s of T I G ( H ) . T I G ( H ) is to be given in the p r o x i m a l portion of t h e e x t r e m i t y in wh ic h is the w o u n d responsible for t e t a n u s , or in t h e gluteal muscl es if th e w o u n d is not in a n e x t r e m i t y , or if the c a u s a t i v e w o u n d c a n n o t be found. T h e exact effective dosage of T I G (H) has not been clearly established.l,~' S i n c e a s e r u m t e t a n u s a n t i t o x i n level o,f 0.01 u n i t p e r ml. will p r e v e n t tetan u s in t h e i n j u r e d , a dosage of 10,000 u n i t s of T I G f H ) is m o r e t h a n adeq u a t e for severe t e t a n u s , and, as was discussed at the Second I n t e r n a t i o n a l C o n f e r e n c e on T e t a n u s in Bern, a dose of p r o b a b l y only 1,500 u n i t s a n d p e r h a p s only 500 u n i t s m a y be t h e r a p e u t i c for less severe t e t a n u s . T h e dose t h a t N a t i o n el al. 14~, selected was on t h e basis of previous exp e r i m e n t a l work, which i n d i c a t e d t h a t levels of 0.08-0.160 per ml. of s e r u m would be achieved with 1,500 u n i t s of T I G ( H ) . T h e y chose to a d m i n i s t e r 3,000-6,000 units to provide blood levels well in excess of t h e s e values. In t h e i r series of cases, the dose r a n g e was from 29 u n i t s to 300 u n i t s p e r kilog r a m of body weight. No difference in effectiveness was noted at t h e extremes. In t h e U n t i e d S t a t e s , w h e r e t h e r e a r e now a d e q u a t e supplies of T I G ( H ) , t h e r e a r e no indications for the a d m i n i s t r a t i o n of h e t e r o l o g o u s e q u i n e and bovine antitoxins, which h a v e been responsible for s e r u m sickness, m y o c a r dial infarction, p e r i p h e r a l n e u r i t i s a n d a n a p h y l a c t i c shock with death.~; Moreover, in the h u m a n being, the life sl)an of the heterologous a n t i t o x i n s ('annot be predicted with c e r t a i n t y . In c o u n t r i e s in which T / G ( H ) is not available heterologous a n t i t o x i n s ~lre still being used. P;ttel and Iris associates1.5(;. )r,; in Bonfi)ay, India, where the incidence of tet;mnus is high, have shed light on the l h e r a l ) e u l i c use of e q u i n e tetantm antitoxin. Ttley found no signific~tnt difference in m o r t M i t y for doses r;ingim~ from 5,000 units (the lowest dose used) Io 60,000 ,niis, and int(,rl~r(,t~,d l;lrg~,r ct~s(,s ;m b(.ing l)rolmbly detrim~,ni;ll. I,'urlhermor(,, they ~'~uld find
48
no t e t a n u s toxin circulating in the blood of 43 patients seriously ill from t e t a n u s on admission and before the a d m i n i s t r a t i o n of antitoxin. Such d a t a agree with w h a t has a l r e a d y been k n o w n r e g a r d i n g the rapid combination of toxin with nerve tissue, and would indicate that, by the time s y m p t o m s are present, s e r u m t r e a t m e n t serves to n e u t r a l i z e only n e w l y p r o d u c e d toxin. V a i s h n a v a et al.,2ol after a blind controlled trial with heterologous antitoxin in 470 patients, concluded t h a t a n t i s e r u m has little value in the treatm e n t of clinical tetanus. Also, Pate] a n d Goodluck154 studied 1,188 p a t i e n t s with n e o n a t a l t e t a n u s a d m i t t e d to the K i n g E d w a r d M e m o r i a l H o s p i t a l d u r i n g the period November 1, 1954, to October 31, 1966, and t r e a t e d t h e m with v a r y i n g a m o u n t s of heterologous antitoxin. One h u n d r e d sixty-three p a t i e n t s did not receive antitoxin. Significant beneficial effect was observed by a d m i n i s t r a t i o n of antitoxin. A small dose of antitoxin (1,500 IU) a p p e a r e d to be as effective as a l a r g e r dose. T h a t s e r u m was n e c e s s a r y was f u r t h e r s u p p o r t e d by t h e i r d e m o n s t r a t i o n of circulating toxin in 5 of 18 samples of blood tested. b) Intrathecal injection o/ a mixtllre o[ antitoxin and p r e d n i s o l o n e . ~ Consider the i n t r a t h e c a l injection of a m i x t u r e of antitoxin and prednisolone.IS,% a18 F o r a n u m b e r of years, i n t r a t h e c a l s e r o t h e r a p y of t e t a n u s has not been performed. T h e r e has been a fear that such t h e r a p y can c o n t r i b u t e to a fatal outcome by causing excitement, s e r u m m e n i n g i t i s and possibly cerebral or m e d u l l a r y edema.191 At the 1970 I n t e r n a t i o n a l Conference on T e t a n u s . however, Ildiriml0,~, 104 of T u r k e y p r e s e n i e d a most s t i m u l a t i n g and provocative p a p e r entitled I n t r a t h e c a l T r e a t m e n t of T e t a n u s with Aniit e t a n u s S e r u m a n d P r e d n i s o l o n e Mixture.104 His report was divided into l a b o r a t o r y studies and clinical trial. In the laboratory, t e t a n u s was produced in pedigreed dogs by the i n t r a venous a d m i n i s t r a t i o n of 5 × LD.~o t e t a n u s toxin. T h e y were studied in four groups, with one used as control. A n i m a l s in the t r e a t m e n t group were given horse antitoxin. All 5 dogs receiving physiologic saline via cisternal, i n t r a v e n o u s and i n t r a m u s c u l a r routes died. Five of 6 dogs receiving only prednisolone cisternally and antitoxin i n t r a v e n o u s l y a n d i n t r a m u s c u l a r l y also died (83°0). Six of 14 dogs receiving antitoxin cisternally, intravenously and i n t r a m u s c u l a r l y died (43%). Only 1 of 14 dogs receiving a mixture of prednisolone and antitoxin cisternally in addition to antitoxin i n t r a v e n o u s l y, a n d i n t r a m u s c u l a r l y died (7.1 ~', ~o ) - T h e difference between the last group and others was found to be statistically significant. In clinical application, 28 neonates and 3 children with t e t a n u s were | r e e l e d with horse aniitoxin and prednisolone m i x t u r e i n i r a t h e c a l l y , antitoxin intr:ivenously and i n t r a m u s c u l a r l y and l)rednisolone orally. T h e y were sedated with sodium phenobarbital and with d i a z e p a m , fed by nasogastric tube and given antibiotics for prophyl~lxis. Only 3 n e o n a t e s died. Others recovered in 15.6 days on the average. T h e f a | a l i t y rate for neonatal te~nnus with the abo~:e-mentioned t r e ~ | m e n t was 10.70;,, in c o n t r a s t to the rale~; shown in F i g u r e 17. N o r m a l values were obtained for growlh ~nd develol)meni in the follow-up studies. Also, in 1966 Smiihl~:~ showed that horse serum nniitoxin given inirn('(,,rebr;llly wrls able 1o IJrotecl mice ngnins| letnnus nt ;l time when nntitoxin given inl r;~venollsly in the same dose w~ls ineffective. W h e n the inl ravenous dose ,)f a n | | t o x i n was ilwreased to 100 times |he n m o u n t given inirncere. 49
- :,
\
FIa. 1 8 . ~ N e o n a t a l t e t a n u s in T u r k e y . O p i s t h o t o n o s , flexion of t h e a r m s , c l e n c h e d fists a n d p l a n t a r flexion of the toes a r e seen in A; t y p i c a l t e t a n u s face ( t r i s m u s a n d risus s a r d o n i c u s ) a n d c l e n c h e d fists a r e visible in B.103 ( C o u r t e s y of I. I l d i r i m . )
brally, tile two routes of t r e a t m e n t were equally effective. Such a finding m a y be due to the fact t h a t antitoxin passes from the blood into the b r a i n with difficulty and it is only when a high serum concentration is produced t h a t appreciable quantities of antitoxin quickly reach the brain. 3) " LABORATORY TESTS. O r d e r the following tests: 1. Complete blood cell count with differential white blood cell count. 2. Urinalysis. 3. Serologic test for syphilis. 4. P r o t h r o m b i n time and partial t h r o m b o p l a s t i n time. 5. Blood c h e m i s t r y tests: urea nitrogen, creatinine, electrolytes, s e r u m protein electrophoresis, bilirubin, calcium, glucose. 6. Arterial blood gases. 7. Chest roentgenogram. 8. E l e c t r o c a r d i o g r a m . 9. E l e c t r o e n c e p h a l o g r a m . 10. W o u n d and if the p a t i e n t is febrile blood cultures. 11. If necessary for diagnosis, cerebrospinal fluid for culture, smear, cells a n d chemistry tests. Provide 24-hour constant n u r s i n g care. A resident or i n t e r n i m m e d i a t e l y available for complications, p a r t i c u l a r l y r e s p i r a t o r y problems such as r e s p i r a t o r y arrest, will g r e a t l y increase the patient's chance for recovery from tetanus. After a detailed study of cases of neon a t a l tetanus, Pinheirol60 stated t h a t even though the m a n a g e m e n t is as yet unsatisfactory, it still ought to be p r e s u m e d t h a t the high m o r t a l i t y rate of t e t a n u s n e o n a t o r u m is m o r e due to the lack of careful medical a n d n u r s i n g care t h a n to the severity of the disease. H e m a i n t a i n e d that continual nursing care, day and night, d u r i n g the acute stage of the illness is still the most i m p o r t a n t m e a s u r e in t e t a n u s of the newborn infant t r e a t m e n t routine. 5) ANALaEmCS.:=::A d m i n i s t e r analgesics, which will relieve the pain associated with the tonic contractions of tetanus but will not cause respiratory depression. Codeine, m e p e r i d i n e (Demerol) and m e p e r i d i n e with p r o m e t h a z i n e {Phenergan) are suitable drugs. 4)
NURSING CARE.
50
6) SEDATIVES AND h{USCLE RELAXANTS.wUse sedatives and muscle relaxants correctly. A most i m p o r t a n t consideration is t h a t the physician know how to use safely the sedatives a n d muscle relaxants t h a t he orders for the p a t i e n t with tetanus. T h e mildest cases of t e t a n u s can be sedated a d e q u a t e l y with phenobarbital, pentobarbital, secobarbital and p a r a l d e h y d e . In the more severe cases, thiopental sodium (Pentothal) m a y be administered i n t r a v e n o u s | y in a very dilute solution (0.5-1.0 Gin. per 1,000 ml.) at a rate of 20-25 drops per m i n u t e in an effort to lower the p a t i e n t ' s threshold of irritabilit~ to external stimuli and to reduce the n u m b e r and severity of seizures and r e s p i r a t o r y arrests.7 Care is taken to avoid overdosage. T h e optimal level of continuous sedation i s ' o b t a i n e d when the p a t i e n t remains sleepy but still can be aroused by m o d e r a t e external stimuli sufficiently to obey commands. Objectively, the best indication of this level is when the rectus muscles of the a b d o m e n lose their h y p e r t o n i c state a n d have only a n o r m a l degree of resistance to palpation. W h e n a severe convulsive seizure occurs, with respiratory arrest, 2--8 ml. of a 2.5% solution of t h i o p e n t a l sodium is injected i n t r a v e n o u s l y i m m e d i a t e l y and as necessary. This u s u a l l y produces muscle relaxation w i t h i n 30-45 seconds and p e r m i t s s p o n t a n e o u s re-establishment of the r e s p i r a t o r y cycle. Some centers have been e n t h u s i a s t i c about the use of m u s c l e - r e l a x a n t drugs to control convulsive seizures.161 Such drugs are difficult to m a n a g e a n d have not prevented d e a t h from r e s p i r a t o r y arrest. D r u g s more comm o n l y suggested for such use are d i a z e p a m (Valium), m e t h o c a r b a m o l (1Robaxin), m e p h e n e s i n (Tolserol), d - t u b o c u r a r i n e and succinylcholine. T h e m a r g i n of safety with these drugs is narrow, a n d they seem best designed for the cases excessively difficult to m a n a g e w a n d then only u n d e r careful observation of an experienced anesthesiologist. M e p r o b a m a t e ( M i | t o w n ) , given i n t r a m u s c u l a r l y , also has been used as a muscle relaxant, u s u a l l y in combination with phenobarbital, a m o b a r b i t a l or methocarbam.ol. 7) SURGICALWOUND CARE.~Carry out meticulous surgical care of wounds as described u n d e r surgical care in the p r o p h y l a x i s section (J-4).77 8) ANTIBIOTICS. Consider the a d m i n i s t r a t i o n of antibiotics for the treatm e n t of the infectious complications of tetanus. In vitro, penicillin is effective a g a i n s t t e t a n u s bacillus. It is not surprising, however, that antibiotic t h e r a p y is clinically d i s a p p o i n t i n g insofar as it is directed against the t e t a n u s disease itself. T e t a n u s is not a bacteremia, for the bacillus r e m a i n s at the place of its entry. By the time antibiotic t h e r a p y is begun, the wound often has been excised, and the toxins are being s p r e a d in the circulation. W h e n the site of infection is not known a n d the antibiotic effect would be p a r t i c u l a r l y desired, t h e r e is little probability t h a t the bacteria are reached by p a r e n t e r a l a d m i n i s t r a t i o n of an antibiotic due to anaerobic conditions in the concealed closed p u n c t u r e wound. D e s p i t e the in vitro effects of penicillin, a noticeable, specific t h e r a p e u t i c reaction cannot be expected.5. 182.209 On the other hand, the antibiotics do play their p a r t in the t h e r a p y p|an. T h e y are irreplaceable in the care of infectious complications of tetanus, especially in combating p n e u m o n i a or secondary, invasive, wound infections. A c o m b i n a t i o n of penicillin (at least 2 million unils every 6 hours) and s t r e p t o m y c i n (0.5 Gin. every 12 hours) m a y be given i n t r a m u s c u l a r l y ; or a n o t h e r antibiotic, with a b r o a d - s p e c t r u m effect, such ns tetracycline (0.5
51
Gm. every 6 h o u r s ) , m a y be a d m i n i s t e r e d intravenously. As a l r e a d y indicated, penicillin and colistin have been injected down the t r a c h e o s t o m y tube with considerable success in neonatal tetanus.lSS T h e possible complications t h a t m a y develop with antibiotic t h e r a p y m u s t be given p a r t i c u l a r a t t e n t i o n in the case of t e t a n u s patients. Especially in the more severe cases, in which n o u r i s h m e n t is accomplished t h r o u g h semiphysiologic methods, there will be a t e n d e n c y t o w a r d gastrointestinal disturbances. If, at the same time, there is an increase in resistant bacteria. e.g., staphylococci, in the intestines, a n enterocolitis can develop readily. 9) TRACHEOSTOMY.. P e r f o r m t r a c h e o s t o m y if personnel and facilities are available to care a d e q u a t e l y for the tracheostomy.gs. 1s7 If the incubation period has been only. a few days so that the p a t i e n t m a y have very severe tetanus, a t r a c h e o s t o m y probably will be necessary and can be p e r f o r m e d u n d e r general anesthesia, if extensive wound debridem e n t is necessary, or with local anesthesia. T h o s e t e t a n u s p a t i e n t s in w h o m a t r a c h e o s t o m y is necessary also will need, in most cases, continuous artificial respiration. Such respiration is facilitated by a t t a c h i n g with a gas-tight a d a p t e r a Portex tracheostomy tube with double inflatable cuffs to an E m e r s o n Volume-Controlled Ventilator or a B e n n e t t R e s p i r a t i o n U n i t Model MA-I. N u r s i n g care of the seriously ill t r a c h e o s t o m y p a t i e n t is not easy. T h e inspired air m u s t be moist. If the p a t i e n t can b r e a t h e spontaneously, moisturizing a p p a r a t u s is set up in the p a t i e n t ' s hospital room; if, however, the p a t i e n t is being given artificial respiration, the r e s p i r a t o r used m u s t be one t h a t continuously moistens the gas mixture. D e h y d r a t i o n of the r e s p i r a t o r y tract can lead to severe h e m o r r h a g i c tracheobronchitis, which can be fatal. E v e n with absolutely correct conditioning of the inspired air, secretions can collect in the airway. A suction m a c b i n e always m u s t be at the patient's bedside. P a t i e n t s with p a r a l y z e d r e s p i r a t o r y muscles must be suctioned every hour. Also of e x t r e m e i m p o r t a n c e is the cleanliness of the tracheostomy tube; d e h y d r a t e d secretions, p s e u d o m e m b r a n e s and crusts can form on the i n n e r m a r g i n of the c a n n u l a and m a y lead to n a r r o w i n g of the res p i r a t o r y airway. T h e tracheostomy tube should be changed w h e n e v e r it c a n n o t be m a d e to function correctly by cleaning and m a n i p u l a t i o n . A n i m p r o p e r l y cared-for t r a c h e o s t o m y m a y be worse t h a n none. T r a c h e o s t o m y m a y be poorly tolerated in the n e w b o r n infant, and dec a n n u l a t i o n m a y be quite difficult. In i n f a n t s ~ p a r t i c u l a r l y those with neonatal t e t a n u s ~ before p e r f o r m i n g a tracheostomy, consider endotracheal intubation by insertion of an e n d o t r a c h e a l tube t h r o u g h the nose or, less preferably, t h r o u g h the mouth.gs 10) PR1YATE, DARK, QUIET ROO~I. Place the p a t i e n t in a private, dark, quiet room. Efforts should be m a d e to reduce as m u c h as possible all external stimuli. Visitors should be limited to the absolute m i n i m u m . It should be pointed out that with a d e q u a t e sedation and muscle relaxation some no longer r e c o m m e n d the dark, quiet room.159 11) INCUaATOR FOR INFANTS.~PIace infants with neonatal t e t a n u s in an incubator in which the oxygen partial pressure, e n v i r o n m e n t a l t e m p e r a t u r e and a nebulized a t m o s p h e r e of distilled w a t e r can be m o n i t o r e d and maintained. 12) I~OENTGENOGRA~IS.. Order indicated roentgenograms. These m a y be for (1) fractures associated with the initial injury, (2) d e t e r m i n a t i o n of 52
p u l m o n a r y problems such as atelectasis and p n e u m o n i a a n d (3) fractures or avulsions of muscle insertions produced by the tonic muscle contractions of tetanus. Compression fractures of the vertebrae m a y be the result of the intense p a r o x y s m s that c h a r a c t e r i z e the disease, and their diagnosis m a y be easily missed w i t h o u t roentgenograms.122 13) PADDED TONGUE DEPRESSOR. L,, , B y insertion of a padded tongue depressor, protect the tongue from being bitten during tonic contractions. 14) ORAL HYGIENE." Clean the lips, teeth, tongue and oral cavity daily to lessen the possibility of growth of pathologic bacteria and viruses. Remove all loose debris from the oral and nasal cavities. I 5 ) NUTRITION.:: Give correct a m o u n t s of n o u r i s h m e n t by oral, nasogastric tube, gastrostomy tube a n d intravenous routes. T h e relaxed p a t i e n t is totally d e p e n d e n t on artificial n o u r i s h m e n t . Initially, tube feedings t h r o u g h a soft nasogastric tube are indicated. If difficulties are encountered with the tube feedings, it m a y be necessary to resort to i n t r a v e n o u s s u p p l e m e n t s . Central venous pressure systems using the subclavian vein provide an excellent route for feeding, including h y p e r a l i m e n t a t i o n . T r a n s f u s i o n s of blood, p l a s m a and h u m a n a l b u m i n can be s u p p l e m e n t e d with electrolyte solutions of glucose, alcohol, fructose and protein hydrolysates. T h e infusions can be f u r t h e r s u p p l e m e n t e d with high doses of vitamins C and B complex. T h e s e r u m protein and electrolytes should be checked repeated|y.99 N o t h i n g is given by m o u t h until i m p r o v e m e n t begins. In choosing a diet, the fact that the p a t i e n t on occasion m a y feel p a i n w h e n he chews should be taken into consideration. 16) ALI~ENTARY TRACT ELIMINATION.~Provide for a d e q u a t e gastrointestinal elimination. S p o n t a n e o u s defecation u s u a l l y is absent. Defecation can be controlled by saline laxatives given orally or into the nasogastric tube and by enemas p.r.n. 17) URINE E L I M I N A T I O N . ~ \ V h e n necessary, provide for elimination of bladder urine by the insertion of a Foley catheter. Remove the. c a t h e t e r at the earliest possible time to prevent u r i n a r y tract infections. 18) INTAKE AND OUTPUT RECORDS. R e c o r d intake and output. 19) PROTECTION OF THE EYES.. Protect the eyes. P a r t i c u l a r a t t e n t i o n m u s t be given to incomplete closure of the eyelids. W i t h o u t p r o p h y l a c t i c measures, exsiccation, keratitis and corneal ulcer can develop. An ophthalmic o i n t m e n t m a y be a p p l i e d and the eyes covered with a moist gauze sponge. 20) PREVENTION OF DECUBITAL ULCERS.~ K e e p the p a t i e n t ' s s k i n dry, and cushion pressure points, to avoid decubital ulcers. 21) BLOOD DYSCRASIAS AND BLEEDING PROBLEMS.~If there is a possibility of blood dyscrasias or bleeding problems, order f r e q u e n t complete blood cell counts and p r o m p t l y investigate the clotting mechanisms.9~. 112,149 22) PREVENTION OF hIUSCLE CONTRACTURES.--As the p a t i e n t improves, prevent muscle contractures with resulting deformities, such as foot drop. Use foam-rubber padding, pillows, sandbags a n d splin{s as indicated. W h e n necessary for muscle imbalance, p h y s i o t h e r a p y should be instituted as soon as possible. 23) ELECTROENCEPHALOGRAMS.~Orderelectroencephalograms when it is technically possib|e to obtain / h e m and when their p r o c u r e m e n t will not interfere with the l)atient's recovery. Such records m a y be of considerable i m p o r i a n c e in the long-range evaluation and care of lhe patient.JT, 10n 53
24) STEROm T H E R A P Y . C o n s i d e r steroid t h e r a p y if there is a possibility of adrenal gland exhaustion. A l t h o u g h not used routinely, steroid t h e r a p y has been emp'~oyed in a few severe cases of t e t a n u s in which the prolonged course of the disease was t h o u g h t to e x h a u s t the a d r e n a l glands. 25) TETANUS TOXOm.--One m o n t h a f t e r the diagnosis of t e t a n u s is made, give 0.5 ml. of adsorbed t e t n n u s toxoid i n t r a m u s c u l a r l y for active i m m u n i zation, and, if the p a t i e n t did not have a dose of t e t a n u s toxoid at the time of injury, he should have a n o t h e r dose in 1 month. A n o t h e r 0.5 mI., which is given 6-12 m o n t h s later, completes the basic active i m m u n i z a t i o n . T h e n , routine t e t a n u s toxoid boosters are given every 6-10 years. Such i m m u n i z a tion is necessary, because an a t t a c k of t e t a n u s does not produce antibodies to p r e v e n t a n o t h e r attack. 26) EM:ERGENCY ,-~IEDICAL IDENTIFICATION DEVICES. A t the time of discharge from the hospital, ~ v e the cured p a t i e n t a completed E M I D a n d instruct him to complete his active i m m u n i z a t i o n with t e t a n u s toxoid to p r e v e n t r e c u r r e n t tetanus. 27) HYPERBARIC OXYGEN. ....H y p e r b a r i c oxygen is not r e c o m m e n d e d in view of the m i n i m a l good effects and in view of the complications of such t r e a t m e n t . T e t a n u s is a toxemic state and is not due to bacteria t h a t are s p r e a d i n g t h r o u g h o u t the body and which m i g h t be acted on by oxygen in the circulating blood. According to a 1964 report, observations in 9 patients with clinical tetanus revealed active regression of s y m p t o m s following h y p e r b a r i c oxygen therapy. 152 T h e progression of the disease was a r r e s t e d and reversed. Seizures were reduced. T h e m e n t a l clarity and cooperation of these patients resulted in better control of r e s p i r a t o r y problems a n d nutritional r e q u i r e m e n t s . T h e need for t e t a n u s antitoxin and t r a c b e o s t o m y was obviated. In contrast, in a 1968 report on 8 cases of severe tetanus, h y p e r b a r i c oxygen did not have a significant effect on the course of the disease.Vt~ T h e addition of 2% CO._, a p p e a r e d to have some effect, if only t e m p o r a r y , on the disease, b u t r e q u i r e d f r e q u e n t estimates of arterial Pco2 a n d some m e a s u r e of control of the p a t i e n t ' s respiration to keep the h a z a r d s of its use within justifiable limits. T h e m o r t a l i t y was 6 of 8 p a t i e n t s (75 %). I n 1968, in a series of e x p e r i m e n t s with guinea pigs, oxygen did not affect the course of clinically developed tetanus.SS 28) HYPOTHERMIA.. ,Just as little e n t h u s i a s m is expressed for h y p e r b a r i c oxygen t h e r a p y , little s u p p o r t is given to h y p o t h e r m i a as a t y p e of therapy. T e t a n u s p e r se does not cause fever, but the complications of t e t a n u s cause fever. Hence, the complications should be treated, not the fever itself. Labo r a t o r y confirmation of this clinical opinion, which was expressed at the I n t e r n a t i o n a l Conferences on T e t a n u s , is found in a 1966 report.lla T h e effect of whole-body h y p o t h e r m i a (30 ° C-32 ° C) was studied in a control group a n d a h y p o t h e r m i c group of a n i m a l s challenged by t e t a n u s toxin. H y p o t h e r m i a did not prolong survival time. 29) PRALIDOXIME 5IETHANESULFONATE...Leonardi 123 ]]as r e c o m m e n d e d oxime t r e a t m e n t in tetanus. H e has shown that, in vitro, t e t a n u s toxin partially inhibits the activity of pure crystalline cholinesterase from nerve tissue. A l t h o u g h this effect is m u c h disputed, he t h o u g h t it w o r t h w h i l e to try cholinesierase-reactivating agents in the t h e r a p y of tetanus. P r e l i m i n a r y work on the guinea pig showed thai pralidoxime m e t h a n e s u l f o n a l e 24 5,1
a n d 48 rag. p e r kg. daily prolonged the i n c u b a t i o n period of t e t a n u s but did not p r e v e n t death. W h e n , in addition, a single dose of 10 units of anti t e t a n u s s e r u m (a dose t h a t h a d no effect when given alone) was a d m i n i s t e r e d , a statistically significant reduction in m o r t a l i t y was obtab~ed. T h e results were confirmed l a t e r in the donkey. Such results p r o m p t e d L e o n a r d i to try the t r e a t m e n t in a p a t i e n t with tetanus, and, according to him, a favorable result was obtained.
L. CASE REPORTS E i g h t cases are described. T h e first case is reviewed in detail to e m p h a size a g a i n the t e a m aspect of tetanus. T h e last 7 cases are s u m m a r i z e d briefly to p r e s e n t specific considerations of clinical tetanus. CASE 1. A.
Severe h a n d injury, 23-year-old farmer.
FIRST HOSPITALIZATION
1. Chief complaint: "I can't open m y m o u t h . " 2. Present illness: On 5 M a r c h 1971, this 23-year-old male caugh~ his right t h u m b in a feed grinder. A t the local hospital e m e r g e n c y room, to which he was t a k e n i m m e d i a t e l y , the w o u n d was debrided and closed prim a r i l y and he was given a dose of t e t a n u s toxoid and a p r e s c r i p t i o n for oral penicillin. About 7 M a r c h , the p a t i e n t began to take C o m p o c i l l i n - V K 250 ms. every 8 hours; on 8 March, he d i s c o n t i n u e d the oral a d m i n i a t r a t i o n of Compocillin-VK a n d was i n s t r u c t e d to take V i b r a m y c i n 100 rag. daily by a n o t h e r physician, who also c h a n g e d the dressing. On 11 M a r c h , the p a t i e n t was seen a g a i n by the second physician, who referred h i m for hospital admission. On this day, the p a t i e n t noted d r a i n a g e from the t h u m b dressing (Fig. 19) a n d spasm of his face when a t t e m p t i n g unsuccessfully to d r i n k cold water. 3. Past history: T h e p a t i e n t stated t h a t possibly he h a d h a d a reaction to penicillin a t some time. H e denied severe illnesses, injuries or operations. Fro. 1 9 . - - I n j u r e d right t h u m b of patient in Case 1. Note generalized cellulitis, where skin has been removed, and absence of thumbnail.
55
4. Physical examination: At 8:00 P.M., 11 M a r c h , the p a t i e n t was a welldeveloped a n d well-nourished, a l e r t y o u n g m a n who t a l k e d w i t h clenched teeth. Vital signs w e r e w i t h i n n o r m a l limits. H e could s e p a r a t e his incisor t e e t h by only 1 cm. a n d exhibited m a r k e d s p a s m of the m a s s e t e r muscles. T h e right t h u m b was swollen, e d e m a t o u s a n d h a d p u r u l e n t d r a i n a g e from m u l t i p l e l a c e r a t i o n s t h a t h a d b e e n s u t u r e d b u t from w h i c h the s u t u r e s had b e e n removed. T h e r e was a 2-cm.-diameter, freely movable node in t h e a p e x of the right axilla. T h e r e was no s p a s m or t r e m o r of the extremities, and d e e p t e n d o n reflexes w e r e 2 plus a n d s y m m e t r i c . 5. A n t i t o x i n prophylaxis and therapy: O n 11 M a r c h , at the t i m e of hospit¢d admission, 3,000 u n i t s of T I G ( H ) was a d m i n i s t e r e d in the right deltoid muscle. On 12 M a r c h , a n o t h e r 3,000 u n i t s was i n j e c t e d into the gluteus m a x i m u s muscle. 6. Initial laboratory data: / n i t i a l l a b o r a t o r y studies w e r e as follows: h e m o g l o b i n 12.0 G m . / 1 0 0 ml., h e m a t o c r i t 36.2 v/o, total l e u k o c y t e c o u n t 8,300 with 8 5 ~ n e u t r o p h i l s , 12% ] y m p h o c y t e s a n d 3 ~ monocytes. U r i n a l y sis a n d n u m e r o u s o t h e r l a b o r a t o r y studies done at a d m i s s i o n w e r e noncontributory. 7. Hospital course: By 8:00 A.M., 12 M a r c h , the d a y a f t e r hospital admission a n d 7 d a y s a f t e r i n j u r y , the p a t i e n t h a d developed opisthotonos a n d risus sardonicus, a n d was t r a n s f e r r e d to the I C U (Fig. 20). T h e slightest stimuli p r o d u c e d generalized tonic convulsions. After tetanic seizures, his Fxc,. 20 (le/t).--Patient in C a s e I a n d his n u r s e n e a r t h e e n d of his s t a y in the I C U . At lhe r i g h t is t h e r e s p i r a t i o n u n i t . T h e p a t i e n t is b e i n g g i v e n u l r a s o n i c m i s t o x y g e n o v e r his doublecuffed P o r t e x t r a c h e o s t o m y tube. I n t r a v e n o u s f e e d i n g is b y t h e r i g h t s u b c l a v i a n c e n t r a l vellou~ p r e s s u r e c a t h e t e r . "I~abe f e e d i n g s are b e i n g a d m i n i s t e r e d by a n a s o g a s t r i c tube. T h e F o l e y c a t h e t e r is c o n n e c t e d to a s t r a i g h t d r a i n a g e bag. E l b o w s h e e p s k i n p a d s a r e p r e v e n t i n g p r e s s u r e necrosis, a n d t h e f o o t b o a r d p r e v e n t s foot d r o p . Chest E C G leads g i v e c o n t i n u o u s c a r d i a c t r a c i n g s on t h e o s c i l l o s c o p e a b o v e t h e bed, a n d also a r e c e n t r a l l y m o n i t o r e d in t h e n u r s i n g s t a t i o n . T h e wall s u c t i o n a n d o x y g e n o u t l e t s a r e seen a b o v e t h e b e d s i d e s t a n d . Fro. 21 (right).~Patient in C a s e I a f t e r r e m o v a l of t r a c h e o s t o m y tube. At t h e t i m e of t u b e r e m o v a l , t h e p a t i e n t c o u l d s e p a r a t e his t e e t h at least 1 c m . , a d i s t a n c e sufficient to p r o v i d e e j e c t i o n of v o m i t u s a n d to p r e v e n t a s p i r a t i o n .
56
t e m p e r a t u r e rose on the evening of 13 M a r c h , r e a c h i n g a p e a k of 105.4 ° (R). On 24 M a r c h , he began to show objective i m p r o v e m e n t in t h a t he would raise a n d lower both u p p e r eyelids on c o m m a n d . On 10 April, he was able to sit up in a chair. By 14 April, he was able to s e p a r a t e the incisor teeth 1 cm. (Fig. 21). B y 15 April, he was showing definite i n t e r e s t in his surroundings but did not r e m e m b e r his wife's name. On 18 April, after 38 days in the ICU, he was t r a n s f e r r e d to an acute medical bed. By 1 May, he was able to completely care for himself, he was having no problems in e a t i n g and he was discharged. 8. Analgesics: At the beginning of hospitalization, i n t r a v e n o u s D i l a u d i d , 0.5-1 rag., was a d m i n i s t e r e d p.r.n, for generalized distress a n d pain. 9. Sedation and muscle relaxation: At the time of admission, d i a z e p a m (Valium) was a d m i n i s t e r e d intravenously. T h r o u g h o u t the p a t i e n t ' s hospital stay, d i a z e p a m was used as the basic sedative, with dosage being a d j u s t e d as necessary from a m i n i m u m of 40 mg. per 24 h o u r s to a maxim u m of 144 rng. per 24 hours, with 3 mg. being given i n t r a v e n o u s l y every half hour and oftener if necessary. By 13 M a r c h , it was evident t h a t convulsions were not being controlled with d i a z e p a m intravenously. T h e r e f o r e , at 11:00 P.M., 13 M a r c h , 0.1% thiopentaI ( P e n t o t h a l ) in dextrose solution was t i t r a t e d intravenously. B y the m o r n i n g o$ 14 M a r c h , convulsions were occurring only w h e n tracheal a s p i r a t i o n was performed, but, by the a f t e r n o o n of 14 M a r c h , the concentration of thiopental had been increased to 0.2/o a~ in an e n d e a v o r to control the p a t i e n t ' s opisthotonos. By !8 March, seizures were s o m e w h a t controlled, but periods of a p n e a were occurring. F o r better control, . therefore, a B e n n e t t R e s p i r a t i o n U n i t Model M A - I was a t t a c h e d to the t r a c h e o s t o m y tube; the t h i o p e n t a l was discontinued and d - t u b o c u r a r i n e was given. Initially, 21 mg. of d-tubocurarine was injected; then m a i n t e n a n c e doses of 3-6 rag. were a d m i n i s t e r e d every 30 m i n u t e s or oftener, if necessary for control of seizures. On 30 M a r c h . the d - t u b o c u r a r i n e , which had been a l t e r n a t e d every 15 m i n u t e s at a dosage of 3 rag. with d i a z e p a m 3 rag., was discontinued; t h e last dose was given as the d i a z e p a m was g r a d u a l l y decreased both in respect to frequency and a m o u n t of dosage, with the last injection of d i a z e p a m being given on 8 April. F o r a d e q u a t e u t i l i z a t i o n of the respiration unit and for evaluation of the r e s p i r a t o r y tract, arterial .blood gas d e t e r m i n a t i o n s were m a d e daily. 10. Surgical care o / w o u n d : On 5 M a r c h , the d a y of i n j u r y , the wound was debrided and closed primarily. On 11 March, the sutures were removed. F r o m then on, w h e n e v e r necrotic tissue was evident in the thumb, such tissue was removed. On 16 M a r c h , .the distal p h a l a n x of the t h u m b was removed by guillotine aml)utation. Initially, saline compresses were at)plied to the t h u m b and a d j a c e n t a r e a s of the hand. As the p a t i e n t iml)roved, the snline dressings were rep/ace(l g r a d u a l l y with 1)elro/atum or lanolin dressings until they were no longer necessary. l I. Antibiotics: A( the time of admission on 11 h'Iar('h, antibiotic thernl)y ('onsisting of n,queous penicillin 2,000,000, unils intraw,nously ew:ry 6 hours and strel~lomy('in 0.5 Gm.'intrarnus('ularly ev(-ry 12 hours w~s initiated, By 16 Mar('ll, E. eoli nnd E n t e r o b a c t e r sensitive to ;ttnpieillin were ob. 57
rained from the s p u t u m specimens. Therefore, the penicillin and s t r e p t o m y cin were discontinued and ampicillin 500 rag. intravenously every 4 hours was ordered and continued t h r o u g h 23 March. On 20 M a r c h , a g r a m - n e g a t i v e organ.~sm was persistently p r e s e n t on the tracheal cultures. In an effort to control such organisms, g e n t a m i c i n was initiated, with 40 mg. being injected i n t r a m u s c u l a r l y every 8 hours until 29 March, when it was discontinued. Although a n u m b e r of specimens were t a k e n from the w o u n d of the thumb, Cl. tetani was not d e m o n s t r a t e d ; however, Cl. per[ringens was isolated from the wound. In addition to the antibiotics a l r e a d y m e n t i o n e d , n i t r o f u r a n t o i n 100 rag. t h r e e times a day was given orally d u r i n g the l a t t e r p a r t of the p a t i e n t ' s hospital stay for a 100,000 colony count of Staphylococcus albus c u l t u r e d from the urine. N y s t a t i n oral suspension, 1 ml., was a d m i n i s t e r e d three times a day for superinfection of Candida albicans. 12. Tracheostomy: On 12 March, e m e r g e n c y t r a c h e o s t o m y was performed in the ICU. W i t h 2% lidocaine infiltration anesthesia a n d t h r o u g h a n incision in the t h i r d tracheal ring, a # 3 6 F r e n c h Portex, double-cuff t r a c h e o s t o m y tube was inserted. An ultrasonic nebulizer was used for supp l e m e n t a l oxygen and hmnidification. On 14 April, the t r a c h e o s t o m y tube was closed with a plug, and on 16 April, the tube was removed. 13. Private, dark room: On the night of admission, the p a t i e n t was placed in a private, dark room. Such s u r r o u n d i n g s were provided p.r.n, for the p a t i e n t ' s comfort. 14. Roentgenograms: Chest r o e n t g e n o g r a m s were ordered as necessary for evaluation of potential cardiac and r e s p i r a t o r y problems. Vertebral films on 19 April indicated compression fractures of the end plates of the second, third, fourth a n d fifth thoracic vertebrae. 15. Nutrition: Initially, the p a t i e n t was fed by p e r i p h e r a l i n t r a v e n o u s solutions. T h e n , on 18 M a r c h , a central venous pressure c a t h e t e r was placed in the left subclavian vein; when this would no longer accept fluid on 25 M a r c h , a n o t h e r was inserted into the right subclavian vein a n d left in place until 12 April. At first, 5°o glucose solutions with balanced electrolyte concentrations a n d vitamins were given; later, these were replaced by similar p r e p a r a t i o n s with 900 calories per liter. I n addition, s e r u m a l b u m i n was ~ v e n w h e n necessary. D e s p i t e meticulous a t t e n t i o n to nutrition, the patient's weight fell from a n admission weight of 155 lb. to 127 lb. 16. Control of gastrointestinal hemorrhage: On 23 M a r c h , 12 days after admission, n u m e r o u s b r i g h t red blood clots were observed in the feces, and the hemoglobin a n d h e m a t o c r i t decreased to 9.0 Gm./100 ml. and 17.6 v/o, respectively. At first, the possibility of stress ulcer in the u p p e r gastrointestinal tract or a p s e u d o m e m b r a n o u s enterocolitis was considered, but the final decision was t h a t i r r i t a t i o n of the rectum by the c o n s t a n t l y p r e s e n t rectal t h e r m o m e t e r probe was responsible for the bleeding. W h e n a Levin tube was inserted into the s t o m a c h on 23 March, no blood was obtained. This tube was left in place initially for feeding with an ulcer milk regimen and then later, on 29 March, changed to Gerber's F o r m u l a #l. D u r i n g the rectal bleeding, which lasted .for several days, the hemoglobin 58
a n d h e m a t o c r i t were m a i n t a i n e d at n o r m a l levels with a total r e p l a c e m e n t of 3,000 ml. of whole blood. D u r i n g t h e l a t t e r p a r t of the hospitalization, a slight residual a n e m i a was corrected w i t h Feosol 1 teaspoonful t.i.d, at first a n d t h e n ferrous sulfate 325 rag. t.i.d. 17. Urinary tract catheter: At 5:00 P.~., 13 M a r c h , the p a t i e n t was unable to void, a n d a F o l e y c a t h e t e r w a s i n s e r t e d into the u r i n a r y bladder. On 14 April, the c a t h e t e r was removed, and, on t h e following day, the p a t i e n t was b e g i n n i n g to have control of micturition. 18. Care o[ skin: D u e to the efforts of the n u r s e s to keep this p a t i e n t ' s skin dry, to avoid p r e s s u r e a r e a s a n d to c h a n g e his position f r e q u e n t l y , he did not develop d e c u b i t a l ulcers. S u c h a result a t t e s t s to the efficiency of a n I C U in the care of the p a t i e n t w i t h tetanus. 19. Prevention of muscle contractures: F r o m the time of admission, p r o p e r s u p p o r t s w i t h p a d d i n g w e r e placed u n d e r the soles of the feet to p r e v e n t foot drop. I n addition, w h e n t h e p a t i e n t ' s muscles were relaxed, passive exercises and, later, active exercises- .were c a r r i e d out to p r e v e n t deformities. 20. Tetanus toxoid prophylaxis: T h e p a t i e n t h a d not been given his " b a b y shots" because "his m o t h e r did not believe in injections." In 1960, the p a t i e n t possibly m a y have b e e n given t e t a n u s toxoid. In 1965, he was given a dose of t e t a n u s toxoid ( p r o b a b l y fluid) for a laceration of his left little finger. At the t i m e Of i n j u r y on 5 M a r c h 1971, he was given a dose of fluid t e t a n u s toxoid. O n 26 April, 0.5 ml. a l u m i n u m phosp h a t e - a d s o r b e d t e t a n u s toxoid was injected in the left deltoid muscle. 21. Orthopedic consultation: On 27 April, the o r t h o p e d i c c o n s u l t a n t s t a t e d t h a t no t r e a t m e n t was n e c e s s a r y for t h e v e r t e b r a l c o m p r e s s i o n fractures. 22. Speech therapy consultation: O n 30 April, formal testing of l a n g u a g e i n d i c a t e d a severe a u d i t o r y p e r c e p t i v e disturbance. T h e p a t i e n t h a d difficulty with all tasks r e q u i r i n g a u d i t o r y stimuli. I n reading, be was able to read words in isolation but h a d difficulty as m o r e words w e r e ' i n c l u d e d . H i s c o m p r e h e n s i o n for r e a d i n g was poor. W r i t i n g tasks i n d i c a t e d ability to rep r o d u c e m a t e r i a l b u t not to i n i t i a t e it. 23. Final diagnoses: (a) feed g r i n d e r i n j u r y of right t h u m b , (b) severe tetanus, (c) p n e u m o n i t i s , (d) u r i n a r y t r a c t infection, (e) rectal bleeding w i t h a n e m i a , (f) c o m p r e s s i o n f r a c t u r e s of thoracic v e r t e b r a e , (g) h y p o x i c encephalopathy. B. SECOND HOSPITALIZATION
1. Chief complaint: "I f a i n t e d . " 2. Present illness: At r e a d m i s s i o n on 29 October 1971, the p a t i e n t ' s wife s t a t e d t h a t for several weeks he h a d b e e n biting his t o n g u e d u r i n g his sleep. Moreover, d u r i n g the 3 d a y s p r i o r to admission, h e h a d been p l a y i n g cards at night, a n d h a d h a d only a few h o u r s of sleep each night. J u s t before being b r o u g h t to the h o s p i t a l on 29 October, he "felt tight all over" a n d fainted. 3. Physical examination: T h e r i g h t t h u m b was well h e a l e d a t the interp h a l a n g e a l joint. T h e r e a p p e a r e d to be some difficulty in c o n c e n t r a t i o n a n d in e x p r e s s i n g himself. T h e r e was a slight decrease in s t r e n g t h of t h e right extremities; t h e r e w a s a d e c r e a s e d ability to p e r f o r m repetitive a l t e r n a t i n g m o v e m e n t s of the right e x t r e m i t i e s rapidly; t h e r e was slow p r o n a t i o n of the right u p p e r e x t r e m i t y ; t h e r e was a decrease in position sense of the right extremities; a n d t h e r e was decreased v i b r a t o r y sense of the right side. 59
4. Laboratory data: E l e c t r o e n c e p h a l o g r a m indicated a resolving encephalitic involvement and a possible secondary epileptogenJcity. T h e p a t i e n t was t r e a t e d with p h e n o b a r b i t a l 15 rag. and M e s a n t o i n 100 rag. p.o.t.i.d. W i t h such a regimen, he had a n uneventful course a n d was discharged on 5 November. C. FOLLOW-UP EXAMINATION On 6 J a n u a r y 1972, w h e n the p a t i e n t was last seen, he a p p e a r e d to be in good condition w i t h o u t gross a b n o r m a l i t i e s on general physical a n d neurologic examinations. This case has been r e p o r t e d to e m p h a s i z e the n u m e r o u s problems t h a t m a y develop d u r i n g a case of t e t a n u s a n d to give details of the a t t e m p t s to solve such problems by cooperation of all types of preclinical and clinical specialists. T h e m e n t a l difficulties both acute and chronic were of p a r t i c u l a r interest. T h e most probable e x p l a n a t i o n for them is a posthypoxic encephalopathy. Certainly, the unavoidable p u l m o n a r y complications and the convulsions, which occurred despite continuous t i t r a t i o n with anticonvulsants, could have been responsible for i n a d e q u a t e delivery of oxygen to the brain a n d a resulting e n c e p h a l o p a t h y . A consulting p s y c h i a t r i s t a n d neurologist who reviewed the case could not find a n y evidence on a psychiatric basis for the m e n t a l and neurologic abnormalities. CASE 2 . . . S p l i n t e r u n d e r toenail. One d a y prior to hospitalization, a 4year-old girl complained of a "stomach ache" and then developed stiffness from her neck to h e r toes. She exhibited typical convulsions of tetanus, risus sardonicus a n d trismus. S h e had not h a d prior t e t a n u s toxoid immunization. T h e only d e m o n s t r a b l e wounds were several abrasions on the arms a n d legs and one associated with a large splinter b e n e a t h the left great toenail. T h e toenail a n d the splinter were removed. A c u l t u r e of the splinter a r e a was negative for C1. tetani. W i t h intensive care in the hospital, the p a t i e n t recovered from t e t a n u s (Fig. 22). T h e tetanus in this little girl, who lived less t h a n a mile from the hospital in which she was treated, could have been p r e v e n t e d by p r o p e r prophylaxis with t e t a n u s tox6id. N o t e t h a t the p r e s u m e d cause was a m i n o r wound a s p l i n t e r u n d e r a toenail. CASE 3. P u n c t u r e w o u n d of h y p o d e r m i c injection in a d r u g addict. A 40year-old male who had been addicted to heroin for a n u m b e r of years was a d m i t t e d to the hospital because of inability to eat for 3 days a n d for an abscess of the s u p e r o l a t e r a l aspect of the right u p p e r arm. T h e abscess was at the site of a h y p o d e r m i c injection. W i t h i n several days, he developed signs typical of tetanus. W i t h s u p p o r t i v e m e a s u r e s and d r a i n a g e of the abscess, he slowly but steadily responded. M u c h improved, he left the hospital a g a i n s t advice 21 days after the onset of his symptoms. This ease is proof t h a t t e t a n u s m a y develop---as Cherubin34 has e m p h a s i z e d in the d r u g addict who has not h a d toxoid i m m u n i z a t i o n . In view of the e x p a n d i n g problem of d r u g addiction in the United States, t e t a n u s a n d d r u g addiction m u s t be considered in the p a t i e n t with u n e x p l a i n e d irritability or convulsions. CASE 4. P u n c t u r e wound of the foot in a diabetic. On 8 M a y 1969, a 45year-old diabetic male was a d m i t t e d to the o u t p a t i e n t clinic of a hospital in G u a m comphfining of a nail p u n c t u r e wound, i n c u r r e d 3 hours earlier, on his left foot. T h e w o u n d was cleaned and he was given t e t a n u s toxoid and 60
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FIG. 2 2 . ~ C h a r t of patient in Case 2. This child was also given the benefit of Seconal, phenobarbital, diazepam and methocarbamol. (Courtesy of R. Haynes.)
penicillin a n d discharged. H e h a d no h i s t o r y of previous t e t a n u s toxoid i m m u n i z a t i o n . On 13 M a y , he was a d m i t t e d to the hospital because of a tickling sensation of the wound, neck stiffness a n d coughing. His neck was stiff but not rigid, b r e a t h i n g was shallow a n d reflexes were normal. T h e left heel was swollen, but no i n d u r a t i o n or c r e p i t u s was noted. H e was given t e t a n u s a n t i t o x i n in divided doses of 170,000 units daily, i n t r a v e n o u s a n d oral penicillin, chlorpromazine, a muscle r e l a x a n t a n d tetracycline. On 14 M a y , 24 hours after admission, the neck stiffness was worse and difficulty in b r e a t h i n g was noted. On 15 M a y , a b d o m i n a l rigidity developed. T h e p a t i e n t was given 500 units of T I G (H). A t noon t h a t day, tiis vital signs were n o r m a l , but 1 hour later he convulsed a n d died. In this case, C1. tetani was d e m o n s t r a t e d in a n a u t o p s y c u l t u r e of w o u n d tissue; the bacillus was recovered in only 32% of a series of 160 cases r e p o r t e d in 1969.120 This case stresses the need to a s c e r t a i n carefully t e t a n u s i m m u n i z a t i o n history at the time of i n j u r y and to give p r o p h y l a c t i c t r e a t m e n t as indicated by the imm u n i z a t i o n status { T I G ( H ) and toxoid for persons whose i m m u n i z a t i o ~ s t a t u s is not a d e q u a t e according to present recommendations).4G CASE 5 . M i n o r wound, according to patient. A 46-year-old w o m a n fell off the steps of h e r home into:a ~ose bush. S h e was seen i m m e d i a t e l y at the hospital, w h e r e it was beliekced that she had s p r a i n e d a n d contused her back. Six days after the i n j u r y .that is, on the d a y of admission to the h o s p i t a l - the p a t i e n t had shooting pains in h e r left lower extremity, back and neck, a n d exhibited i n t e r m i t t e n t contractions of h e r left leg. S h e h a d a d r a i n i n g w o u n d on her left buttock, w h e r e a rose bush t h o r n h a d p e n e t r a t e d . D e s p i t e intensive t h e r a p y , the p a t i e n t died 8 days later. T h i s case is recorded to e m p h a s i z e the possibility of t e t a n u s developing a f t e r a p e n e t r a t i n g wound t h a t was not considered to be significant by the p a t i e n t at the time of injury. T h i s p a t i e n t h a d not h a d t e t a n u s toxoid i m n m n i z a t i o n a n d she did not have t e t a n u s a n t i t o x i n at the time of injury. CASE 6. P u n c t u r e w o u n d of the foot in a W o r l d W a r II veteran. A 4761
year-old m a l e was a d m i t t e d to the hospital on 22 A u g u s t 1969 with a history of increasing trismus for 48 hours, rigidity, d y s p h a g i a , d y s p n e a and painful spasms, p a r t i c u l a r l y involving the right leg, for 24 hours. H e h a d served in the R o y a l A u s t r a l i a n Air F o r c e in W o r l d W a r II~ a n d had received full i m m u n i z a t i o n a g a i n s t tetanus. H e h a d not received a n y booster injections until 13 A u g u s t 1969. On that day, he sustained a p e n e t r a t i n g i n j u r y of the right foot w h e n he stood on a stake in his garden. H e w e n t to his local doctor w i t h i n 1 h o u r of the i n j u r y a n d was given a booster dose of t e t a n u s toxoid a n d 2,000,000 units of procaine penicillin; the penicillin t h e r a p y was continued twice daily until he was referred to the hospital, w h e r e it was c o n t i n u e d as penicillin G in a dosage of 1,000,000 units every 4 hours. On his admission to the hospital, he was treated intensively for tetanus, but died on the 6th d a y after admission. P r e s u m a b l y this case represents a failure with t e t a n u s toxoid given d u r i n g W o r l d W a r II and in 1969 and a failu re of p r o p h y l a x i s with penicillin. 14.t CASE 7.- Bowel obstruction a n d resection. A 61-year-old male with gangrene of the small intestine s e c o n d a r y to obstruction by postoperative adhesions developed t e t a n u s in the i m m e d i a t e postoperative period. T e t a n u s organisms were recovered from a culture specimen of the malodorous peritoneal fluid found at operation to s u r r o u n d the grossly u n p e r f o r a t e d intestine. A t r a c h e o s t o m y was performed, a n d the p a t i e n t recovered on a regim e n of nasogastric feedings, sedation, d a r k e n e d environment, antibiotics a n d t e t a n u s antitoxin. This case is reported to indicate that t e t a n u s m a y develop after the resection of g a n g r e n o u s bowel a n d to emphasize the advisability of active i m m u n i z a t i o n of all persons against tetanus.39 CASE 8 . ~ F a c e lacerations. On 9 N o v e m b e r 1967, a 71-year-old male suffered a l a c e r a t i o n of his nose a n d a n o t h e r of his left cheek. H e h a d not h a d prior t e t a n u s toxoid i m m u n i z a t i o n . H e was t r e a t e d in an e m e r g e n c y room by having the face wounds debrided and closed p r i m a r i l y a n d by receiving a dose of t e t a n u s toxoid. On 17 November, he h a d initial s y m p t o m s of tetanus, a n d on 19 N o v e m b e r he was a d m i t t e d to the hospital. D e s p i t e intensive care, he died of t e t a n u s on 23 November. This last case r e p o r t emphasizes t h a t a n initial dose of t e t a n u s toxoid at the time of i n j u r y will not p r e v e n t tetanus, t h a t all i n d i v i d u a l s ~ i n c l u d i n g all our senior citizens should h a v e a d e q u a t e basic t e t a n u s toxoid i m m u n i z a t i o n and t h a t a c c u r a t e e m e r g e n c y medical identification devices should be available for the victims of t r a u m a .
M. MEDICOLEGAL ASPECTS T h e legal aspects of medical practice in the m o r e and m o r e consideration. To e m p h a s i z e s t a t e m e n t was mailed, in the form of a news general a n d specialty medical publications and v e m b e r 1970:
U n i t e d States are receiving the problem, the following release, to science writers, the wire services on 12 No-
" T h e R e g e n t s of the A m e r i c a n College of Surgeons feel obligated to inform the public t h a t the rising n u m b e r of lawsuits against physicians is seriously t h r e a t e n i n g the quality of surgical care and increasing its cost to patients.'U66 62
I..PROBLEMS OF IMMUNIZATION Specific a t t e n t i o n was given to d r u g c o m p a n y liability in i m m u n i z a t i o n p r o g r a m s in a p a p e r by Curran,52 in which he r e p o r t e d the following: " A n e x t r e m e l y i m p o r t a n t decision, T i n n e r h o l m v. P a r k e , Davis & Co.. has recently been passed down by the prestigious Second Circuit ( F e d e r a l ) Court of A p p e a l s in N e w York affirming a decision of the District Court against the d r u g firm concerning Quadrigen, a vaccine combining diphtheria, tetanus, pertussis a n d i n a c t i v a t e d poliovirus antigens. T h e trialcourt decision, with a d a m a g e s a w a r d of $651,783, had caused a g r e a t deal of concern in d r u g - c o m p a n y a n d p u b l i c - h e a l t h circles, w h e r e it was t h o u g h t t h a t the proof offered of a causal relation between the t a k i n g of Q u a d r i g e n and severe i n j u r y a n d disability in a t w o - m o n t h - o l d i n f a n t was not warr a n t e d scientifically." In discussing such an award, C u r r a n stated: " M a n y public-health officials a n d scientists i n t e r e s t e d in i m m u n i z a t i o n p r o g r a m s a r e concerned about decisions such as T i n n e r h o l m a n d the earlier case of Davis v. W y e t h Laboratories, which involved a n alleged paralysis due to the S a b i n T y p e 3 polio vaccine. Both cases involved very serious injuries and c o n s e q u e n t l y large verdicts. Both were u p h e l d by F e d e r a l Circuit Courts. T h e trend of the law is thus becoming firmly established. It is difficult for the d r u g companies to defend in these cases, since they are t r y i n g to prove a negative t h a t is, t h a t the d r u g did n o t cause the devastating i n j u r y a n d disability t h a t was clearly s u s t a i n e d by the plaintiff from s o m e cause. T h e fear of public-health people is t h a t these claims will drive the drug companies a w a y from this field, or will so a l a r m the public as to cripple i m m u n i z a t i o n p r o g r a m s altogether. " T h e d i l e m m a for the law is also clear. T h e courts m u s t e n t e r t a i n the just claims of i n j u r e d people. T h e loss m u s t fall somewhere. T h e problem of legal proof versus scientific proof has not been solved. P e r h a p s this problem the problem of a c c o m m o d a t i n g the needs of the law a n d the m e t h o d s of proof in medical science - should receive m u c h m o r e a t t e n t i o n . " 2. SPECIFIC MEDICOLEGAL PROBLEMS FOR TETANUS PROPHYLAXIS AND THERAPY
In the case cited by C u r r a n , t e t a n u s toxoid was not the p r i m e consideration. In the following cases, however, some p a r t i c u l a r aspect or aspects of t e t a n u s p r o p h y l a x i s and t h e r a p y were of importance.TS a) DENTAL EXTRACTION. According to hospital records s u b m i t t e d to one of us for medicolegal evaluation, a d e n t i s t e x t r a c t e d 9 u p p e r t e e t h from a 40-year-old woman. S e v e n days later, the p a t i e n t developed tetanus, and 9 days after the e x t r a c t i o n she died. T h e d e n t i s t was sued for m a l p r a c t i c e . b) HETEROLOGOUS TETANUS ANTITOXIN., ~In a lawsuit for which one of us was consulted, the responsible physician was being sued because his p a t i e n t (an a d u l t w o m a n ) after a negative skin test p r e s u m a b l y developed a reactior{ to a dose of heterologous horse antitoxin. C) WRINGER INJURY OF HAND., I n a n o t h e r l a w s u i t for which one of us was consulted in 1952, a 2-year-old male suffered a w r i n g e r i n j u r y of his 63
h a n d a n d developed tetanus. :In 1968, the a t t e n d i n g surgeon was sued for a six-figure sum.
3. ATTORNEYS AND PHYSICIANS T h r e e missions of the cooperation of a t t o r n e y s and p h y s i c i a n s are to give the best possible care to the patient, to protect the p a t i e n t medicolegally a n d to protect the physician medicolegally. In a n e n d e a v o r to protect the rights a n d privileges of their clients, however, a t t o r n e y s have been instrum e n t a l in o b t a i n i n g a g a i n s t physicians a w a r d s t h a t are not just financially e m b a r r a s s i n g but are even financially crippling to the physicians. Physicians cannot fail to note such awards. Consequently, knowingly or u n k n o w ingly, in an e n d e a v o r to protect themselves legally, they m a y p u r s u e a plan of p r o p h y l a x i s or t h e r a p y t h a t m a y not be the best in a scientific sense but which is a safer course legally. M o r e specifically, it is m u c h easier for a physician to give an extra, u n n e c e s s a r y dose of toxoid and a s s u m e the risk of a not too significant reaction to the toxoid t h a n to keep exact records, take careful histories and give toxoid only w h e n indicated. In a similar fashion, it is m u c h s i m p l e r to a d m i n i s t e r T I G ( H ) , which is practically free of reactions, t h a n it is to keep a c c u r a t e toxoid records, to require*patients to c a r r y e m e r g e n c y medical identification devices and to obtain an a d e q u a t e history at the time of an injury. In the U n i t e d States, a financial n e w s p a p e r has pointed out t h a t c e r t a i n medicolegal considerations are becoming a t h r e a t to medical care with the following headlines on its first page20S: SUING THE DOCTOR Chances for success in m a l p r a c t i c e suits are rising, experts say. Courts, la~5,ers m a k e it easier to circumvent lack of physicians' testimony. A t h r e a t to medical care? If p h y s i c i a n s continue to be involved in such suits as those s u m m a r i z e d above, t h e i r a t t i t u d e to p a t i e n t s and to t r e a t m e n t inevitably m u s t be altered. P h y s i c i a n s will be t h i n k i n g of which t e t a n u s p r o p h y l a x i s a n d t h e r a p y will have the least medicolegal liability r a t h e r t h a n which scientific course is best for the patient.
N. COST Effective t e t a n u s p r o p h y l a x i s is one of the least expensive types of prophylaxis. As has been discussed in the prophylaxis secti¢,fl (J), a few injections of t e t a n u s toxoid will p r e v e n t tetanus. According to the a m o u n t of toxoid p u r c h a s e d and to the vial or ready-forinjection s y r i n g e in which t e t a n u s toxoid is sold, the p h a r m a c y cost for the p a t i e n t of l dose of t e t a n u s toxoid is s o m e w h a t less or s o m e w h a t m o r e t h a n a dollar. T h e hospital cost of one case of t e t a n u s in the U n i t e d S t a t e s in 1971 was $9,773.80. T h e t r e a t m e n t of a d a n g e r o u s l y ill patient, such as one with tetanus, in West G e r m a n y in 1967 was e s t i m a t e d to be up to 20,000 D M ($5,000 in U.S. c u r r e n c y ) . 1:',-~ In view of the cost of t e t a n u s toxoid and of the cost of the t r e a t m e n t of 64
a case of t e t a n u s , n e e d a n y m o r e be said a b o u t t e t a n u s toxoid p r o p h y l a x i s being a n economic t r i u m p h ?
O. POLITICAL CONSIDERATIONS In 1971, the following note was received from a p h y s i c i a n in a c o u n t r y m a n y c e n t u r i e s old: " I n o u r c o u n t r y we h a v e no good d o c u m e n t a t i o n s of previous t e t a n u s toxoid injections in individuals. F o r this r e a s o n we a r e i n j e c t i n g 3000 u. T A T a n d t e t a n u s toxoid. S o m e t i m e s we do n o t h a v e t e t a n u s toxoid, a n d t h e n we a r e giving only T A T . W e h a v e no T I G ( h u m a n ) in o u r c o u n t r y . " Millions a n d millions of U.S. dollars a r e b e i n g s p e n t to develop a p e r p e t u a l peace. S h o u l d a m i n u t e f r a c t i o n of such e x p e n d i t u r e s be d i v e r t e d for t h e p u r c h a s e a n d d i s t r i b u t i o n of t e t a n u s toxoid, T I G ( H ) , a n d e m e r g e n c y m e d i c a l identification devices to o t h e r c o u n t r i e s of the w o r l d to prove t h a t t h e U n i t e d S t a t e s is r e a l l y i n t e r e s t e d in citizens of o t h e r c o u n t r i e s a n d in their health?
P. CONCLUSION A b o u t a decade ago, P r e s i d e n t K e n n e d y p r e d i c t e d t h a t m a n w o u l d be on t h e m o o n w i t h i n 10 y e a r s ; his p r e d i c t i o n w a s confirmed. H o p e f u l l y , with t h e m e a n s a v a i l a b l e in the U n i t e d States, by 1980 t e t a n u s will no l o n g e r occ~.r in the U n i t e d States, a n d will have become a disease of only historical significance.S2 F o r t e t a n u s p r o p h y l a x i s , let us n o t be too l a t e w i t h too little, like the R o m a n poet Ovid, who, as m e n t i o n e d previously, wrote: " T o o late I g r a s p m y shield a f t e r m y wounds."151
ACKNOWLEDGMENTS A p p r e c i a t i o n is expressed to O s c a r P. H a m p t o n , Jr., a n d P a u l A. S k u d d e r for countless ideas, e v a l u a t i o n s a n d r e c o m m e n d a t i o n s in r e g a r d to all a s p e c t s of t e t a n u s ; to M a r y A. Magill, S e n i o r E d i t o r , C h e m i c a l A b s t r a c t s Service, C o l u m b u s , Ohio, for c a r e f u l l y p r o o f r e a d i n g t h e m a n u s c r i p t a n d for m e t i c u l o u s l y c h e c k i n g a n d c o r r e c t i n g the references; to Oscar F. :Rosenow a n d O w e n E. J o h n s o n for p e r m i s s i o n to p r e s e n t Case 1, w h i c h h a d b e e n r e f e r r e d to t h e m for care; to the following for s u p p l y i n g a n d giving p e r m i s sion to use the i n d i c a t e d figures: D. F r a s e r , J. B e n n e t t , B. D u l l a n d D. Sencer of the U S P H S C e n t e r for D i s e a s e Control (Figs. 1-6 a n d 12), S. N o d a a n d I. E b i s a w a of T o k y o U n i v e r s i t y (Figs. 7, 8 a n d 13), E. V e l a s c o - J o v e n of S a n L a z a r o H o s p i t a l , M a n i l a (Figs. 9 a n d 10), J. T r i n c a of C o m m o n w e a l t h S e r u m L a b o r a t o r i e s of A u s t r a l i a (Fig. 11), L. L e v i n e a n d J. McC o m b of the M a s s a c h u s e t t s D e p a r t m e n t of P u b l i c H e a l t h S t a t e L a b o r a t o r y I n s t i t u t e (Figs. 14-16), P. S m y t h e a n d M. Bowie of the R e d Cross Child r e n ' s H o s p i t a l of S o u t h Africa (Fig. 17), I. I l d i r i m of A t a t i i r k U n i v e r s i t y E r z u r u m M e d i c a l School (Fig. 18), R. H a y n e s of C h i l d r e n ' s H o s p i t a l , Columbus, Ohio (Fig. 22); to S u z a n n e F. O'Neill, H o m e r F o r d a n d T h o m a s P. S h e r r i n of R i v e r s i d e M e t h o d i s t H o s p i t a l , Columbus, Ohio, for i m p o r t a n t b i b l i o g r a p h i c s u p p o r t , for v a l u a b l e p h o t o g r a p h s a n d glossy p r i n t s a n d p h a r m a c o l o g i c data, respectively; a n d especially to M a r s h a S. B i e r | y for h e r excellent s e c r e t a r i a l h e l p in n u m e r o u s revisions of the t y p e s c r i p t . 65
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Adan~s, E.: T h e prognosis and prevention of tetanus. South African M. J. 42: 739, 1968. Akama, K., Ira, A., Yamamoto, A., and Sadahiro, S.: Reversion of toxicity of tetanus toxoid, Jap. J. M. Sc. & Biol. 24: 181, 1971. 3. Alexander, J., and Moncrief, ft.: Use of a double-diffusion technic in agar gel for the quantitation of tetanus antiloxin levels, J. T r a u m a 6: 539, 1966. 4. Alexander, J . , and Moncrief, J.: In vitro deter~nination of tetanus i m m u n i t y , J. T r a u m a 7: 288, 1967. 5. Altemeier, W.: Penicillin in tetanus, J.A.M.A. 130:67, 1946. 6. Altemeier, W., and Furste, W.: Studies ia virulence of Clostridium welchii, Surgery 25:12, 1949. 7. Altemeier, W., and H u m m e l , R.: T r e a t m e n t of tetant~s, Surgery 60: 495, 1966. 8. American A c a d e m y of Pediatrics: Report of the Committee on the Control of Infectious Diseases, p. 2 (Evanston, Ill.: T h e Academy, 1966). (1966 Red Book.) 9. American A c a d e m y of Pediatrics: Report of the C o m m i t t e e on the Control of Infectious Diseases, p. 5, revision of 17 October 1971 (Evanston, Ill.: T h e Academy, 1970). (1970 Red Book. ) 10. A.M.A. Council on Drugs: A.M.A. Drug Evaluation, pp. 643-647 and N 183-184, 1971. 11. Anwar, A., and Turner, T.: Antibiotics in experimental tetanus: In vitro and in viva studies, Bull. J o h n s Hopkins Hasp. 98: 85, 1956. 12. Aretaeus, the Cappadocian: On tetanus, in The E x t a n t Works, Adams, F. (eel.), London, pp. 246-249, 400--404, 1856. 13. Artz, C.: Letter, dated 4 October 1971, Charleston, South Carolina. 14. Bardenwerper, H.: Serum neuritis from tetanus antitoxin, J . A . M . A . 179:763, 1962. 15. Barr, M., and Sachs, C.: T h e investigation into the prevention of tetanus in the British army, Army Pathology Advisory Comm., W.O., Code No. 11262. The War Office, London, S.W. 1. October 1955. 16. Benenson, A., Shively, J., and Vicuna, S.: Effect of irradiation mad test system on development of tetanus antibodies, Proc. Sac. Exper. Biol. & Med. 112: 527, 1963. 17. Bertoye, A., M a s t e r , P., Garin, g., Humbert, G., and Vincent, P.: Surveillance 61ectroenc~phalographique des t~tanos t r a i l , s par le N e m b u t a l ~. doses massives, J . m~d. Lyon 46:1967, 1965. 18. Billaudelle, H., Lundblad, G., Falksveden, L., and Ullberg-Olsson, K.: Fractionation of h u m a n i m m u n e serum anti tetanus by gel filtration, Ztschr. Immunit~itsforsch. 131: 170, 1966. 19. Blurastein, G., and Kreithen, H.: Peripheral n e u r o p a t h y following tetanus toxoid administration, J . A . M . A . 198:166, 1966. 20. Bohrer, S.: Spinal fractures in tetanus, Radiology 85: 1111, 1965. 21. Brooks, G., Buchanan, T., and Bennett, J.: Tetanus toxoid i m m u n i z a t i o n of a d u l t s - - a continuing need, Ann. Int. Med. 73: 603, 1970. 22. Bruce, D.: Tetanus. Analysis of 1458 cases, which occurred in home military hospitals during the years 1914-1918, J. Hyg. 19: 1, 1920. 23. Buff, B.: Fatal anaphylactic shock following intradermal skin test with dilute horse serum tetanus antitoxin, J . A . M . A . 174: 1200, 1960. 24. Burkhardt, G., Starke, G., and Seifart, W.: tiber die Anwendung yon H u m a n - i m m u n globulin beim Tetanus, Zentralbl. Chir. 95: 180, 1970. 25. Busila, V., Petrica, L., and Alexandrescu, R.: Zur Wirkung yon Pyrrolidino-MethylTetracyclin auf das Tetanustoxin, Ztschr. Immunit~itsforsch. 130: 242, 1966. 26. Bytchenko, B.: Geographical distribution of tetanus in the world, 1951-1960, Bull. W H O 34: 71, 1966. 27. Carle, A., a n d 1Rattone, G.: Studio experimentale sull' eziologia del tetano, Gior. Accad. reed. Torino 3 ser. 32: 174, 1884. 28. Catalano, T.: Myocardial infarction after serum sickness from tetanus antitoxin, J . A . M . A . 188: 1154, 1964. 29. Center for Disease Control, Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Annual Supplement. Morbidity and Mortality Weekly Report 19: 53, 1971. 30. Center for Disease Control, Public Health Service, U,S. D e p a r t m e n t of Health, Education, and Welfare: Cases of specified notifiable diseases: United States. Morbidity and Mortality Weekly Report 20: 436, 1971. 31. Center for Disease Control, Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Cases of specified notifiable diseases: United States. Morbidity and Mortality Weekly Report 20: 467, 1971. 32. Center for Disease Control. Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: R e c o m m e n d a t i o n of the Public Health Service Advisory Committee on I m m u n i z a t i o n Practices. Morbidity and Mortality Weekly Report 20: 396, 1971. 33. Chaucer (The Complete Works of Geoffrey Chaucer) : Canterbury Tales, Prologue, lines 496-497, Robinson, F. N. (ed.) (Boston: Houghton Mifflin Company, 1933). 34. Cherubin, C.: Infectious disease problems of narcotic addicts, Arch. Int. Med. 128:309, 1971.
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Cole, L., and Youngman, H.: T r e a t m e n t of tetanus, Lancet 1: 1017, 1969. 42. Cole, L., ¥ o u n g m a n . H., and Gandy, A.: An attack of tetanus, Lancet 2:567, 1968. 43. Committee on Trauma, American College of Surgeons (Hampton, O., Jr., Chron.): Prophylaxis against tetanus in wound management, Bull. Am. Coll. Surgeons 52: 230, 1967. 44. Committee on Trauma, American College of Surgeons (Artz, C., Chron.): A guide to prophylaxis again~st tetanus in wound m a n a g e m e n t , Bull. Am. Coll. Surgeons 56: 22, 1971. 45. Communicable Disease Center, Public H e a l t h Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Collected recommendations of the Public Health Service Advisory Commit[ee on I m m u n i z a t i o n Practices. Morbidity and M o r t a l i t y Weekly ]Report 18 (supp.) : 4, 1969. 46. Communicable Disease Center, Public H e a l t h Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Tetanus. 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Davis, P., and Rowland, H.: Vertebral fractures in West Africans suffering from tetanus, J. Bone & J o i n t Surg. 47-B: 61, 1965. 54. D e p a r t m e n t s of the Army, the N a v y and the Air Force: Immunization. TI3 Med 114, N A V M E D P-5052-15A and A F P 161-9 (25 M a y 1970). 55. Departments of the Army, the Navy, Air Force and Transportation:" I m m u n i z a t i o n requirements and procedures. AR 40-562, B U M E D I N S T 6230.1F, A F R 161-13 and CG C O M D T I N S T 6230.4A (30 J u l y 1971). 56. Descombey, P.: L ' a n a t o x i n e t6tanique, Compt. rend. Soc. biol. 91:239, 1924. 57. Division of Biologics Standards, National Institutes of Health, Public Health Service, U.S. D e p a r t m e n t of Health, Education, and Welfare: Biological products. Public Health Service Publication No. 50:29, 1968. 58. Dostal, J . , V ~ n o l a , F., Boschetty, V., and Seveik, V.: Tile influence of hyperbaric oxygen on tetanus in guinea pigs, Anaesthesist 17: 324, 1968. 59. Dubovsky, B., and Meyer, K.: The occurrence of B. tetani in soil and on vegetables, J. infect. Dis. 31:614, 1922. 60. Dukelow, D.: T h e A M A ' s continuing interest in immunization, Arch. Environ. Health 15: 515, 1967. 61. Dull, H.: Athletic injuries on artificial turf and tetanus immunization, J . A . M . A . 216: 338, 1971. 62. Ebisawa, I.: ~qortality of T e t a n u s in Japan; an U n i n t e n t i o n a l Control Observation, in E c k m a n n , L. (ed.), Principles on Tetanus (Bern: Hans Huber, 1967), p. 71. 6~. Ebisawa, I., and Matsukura, M.: P u l m o n a r y and muscular changes in tetanus, Jap. J. Exper. Med. 38:27, 1968. 64. Ebisawa, I., Sawai, Y., Makino, M., Kawamura, Z., and Ogonuki, T.: Relapse or reinfection in tetanus and diphtheria, and reenvenomation in m a m u s h i and habu snake bites. Problems associated ~vith reinjection of horse serum antitoxin or antivenom in nmn, Jap. J. Exper. Med. 34: 125, 1964. 65. Editorial Staff: First of all do no harm. 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Edsall, G., Elliott, M., Peebles, T., Levine, L., and Eldred, M.: Excessive use of tetanus toxoid boosters. J.A.]VI.A. 202: 17, 1967. 70. Edsall, G., MacLennan, R.. Levine, L., and Belsey, M.: Response to a single dose of tetanus toxoid. Report, International Congress for Microbiology, Mexico City, Mexico, 1970. 71. Ellis, E., and Henney, C.: Adverse reactions following administration of h u m a n g a m m a globulin, J. Allergy 43: 45, 1969. 72. Engert, R.: Letter, date
68
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Monographs and Books
219. 220. 221. 222. 223. 224.
Adams, E., Laurence, D., and Smith, J.: Tetanus (Oxford and Edinburgh: Blackwell Scientific Publications, 1969), p. 64. E c k m a n n , L.: Tetanus: Prophylaxis and Therapy, translate
Audio-Visual Presentations
225. 226. 227. 228.
Christensen, N.: Tetanus and its prevention, Mayo Clinic, Rochester, Minnesota, 1963. Furste, W.: A new look at tetanus prophylaxis, Douglms Film Indttstries, Chicago, :I965. Institut M6rieux: Tetanus {French and English sound tracks), Compagnie Lyonnaise de Cinema Lyon, France, 197{}. Rubbo, S.. and Trinca, J.: Tetanus and its prevention, Australian Instruction Films Proprietary Limited, Sydney, New South Wales, 1966.
Audio Presentations
229. 230.
Furste, W.: Tetanus prophylaxis, Ikon Enterprises, Sacramento, California, 1965. Furste, W.: Past, present and future concepts for tetanus prophylaxis, Orthopaedic Audio-Synopsis Foundation, Los Angeles, Cali[ornia, 1970.
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