- Email: [email protected]
Clinical significance of the positive response to the hollander test
Clinical Significance of the Positive Response to the Hollander Test BERNARD W. THOMPSON, MD, FACS, Little Rock, Arkansas RAYMOND C. RE~D, MD, FACS, Little Rock, Arkansas
\ ; a g o t o m y with p y l o r o p h t s t y has become over the past decade the s t a n d a r d o p e r a t i o n for the comp l i c a t i o n s of duodenal ulcer. T h e only w a y to d e t e r mine p o s t o p e r a t i v e l y the c o m p l e t e n e s s of this p r o cedtlre is to pev'forn~ a H o l l a n d e r test [t1. Dragstedt and ( : a m p [21 as well as A u s t e n and Edwards 1.~'! f r o m t h e i r vast e x p e r i e n c e s u g g e s t e d t h a t rec u r r e n t ulcers irl such p a t i e n t s result from i n c o m plete v a g ~ t o m y and couht be predicted b y p o s i t i v e r e s u l t s on a t [ o l l a n d e r test. U n f o r t u n a t e l y , the insulin test is ass~miated w i t h a c e r t a i n m o r b i d i t y and its results are difficult to i n t e r p r e t since the c r i t e r i a are a r h i t r a r y , b e i n g based largely on animal e x p e r i m e n t a t i o n . Recently, Stempien [~], t ' a e h r a c h [51 , Bank, M a r k s , and Louw [61 , a n d o t h e r s have expressed d i s s a t i s f a c t i o n with the limits used to establish p o s i t i v i t y or n e g a t i v i t y as well as the i n c o n s i s t e n c y of the test in man. Ross and Kay I7i indicate t h a t an e a r l y g a s t r i c acid resp,mse to inslllin, coupled with little c h a n g e in m a x i m a l acid OUtl)ut, m a y be m o r e 'valuable in p r e d i c t i n g those p a t i e n t s w h o are liable to rec u r r e n t ulceration t h a n the ehtssic t [ o l l a n d e r test. l',ecat|se of this c o n t r o v e r s y we have reviewed otlr s t u d i e s of the Hotlancter t e s t and have c o r r e l a t e d them ~:jth the clinical tindings in 195 p a t i e n t s w h o had v a g o t o m y and p y l o r o p l a s t y for duodenal ulcer dis~,ase.
Material and Methods During the past seven years vagotomy arid t)ylorop!asty tmve been carried out on 527 patients at the Veteral~ Administration IIospital. Little Rock, Arkansas, for the treatment of duodenal ulcer. Two hundred and six of these patients had ttottander tests carried mit six ~)1" more weeks after s u r g e r y . P~ecatlse of the inherent morbidity associated with the test all patients over sixty years ~f age and those with abnormal litfflings on eh:etrocardiogram were eliminated from the study. A certain number of patients refused t,, submit to the test. The series is not unselected since it inehates all patient~ who had recurrent symptoms. Fm.m the Sta,l~ical Service, Veterans Administration Hospital, and the C)eCa~ln~Pn! 01 Surgery, University of Arkansas School of Medicine, Pr~s~ertte~ at the Twenty-Second
Ar~nual Meeting of the South-
*~e~t~,'n Suf/E~caf Congress. Dallas, Texas, April 20-23, 1970.
66~)
The criteria used to determine a positive response were those of ttollander IX 1. A nasogastric tube was inserted into tile stomach of a fasting patient. Two control samples of gastric: juice were removed at fifteen minute intervals. The mean of these was used as a base line for gauging a rise of the acidity curve. Regular insulin in a dose of 0.2 units per kg of body weight was injected intravenously. Blood and gastric samples were then drawn every tifteen minutes for two hours. A positiw~ r e s p o n s e w a s a rise in the e o n e e n t r a t i o l l of acid over the basal level on two sueeessive specimens {}f 20 m g q ' L unless the basal samples were anacid, in which case "t rise of 10 mEq "I, cm two successive specimens. The test was not cm~sictered to be valid unless i tie blood sugar level fell below 50 mg pc," cent. In this report we have used the time of one hour to separate lhe positive secretory responses into early and late gl'otlps in eontr-tdistinction to the time of forty-live minutes suggested by Ross and Kay 171, All patients except those who had previously been treated for recurrent ulceration were recalled to the surgical clinic aud evaluated clinically within the past three months. The follow-ul) period ranged from zero to sewtn years with a mean of .'3.,I years. Since the rate of operations remained fairly constant over tile years, the length of follow-up is distributed evenly. These patients were ewduated as to ulcer symptoms, weight gain, diarrhea, dumping s.{'ndrome, and ability to work. All of those seen in the clinic with postoperative symptml~s were readmitted to the hospital and re-evaluated by x-ray 1t11(tsecretory studi{~s. The absolute diagnosis of recurrent ulceration after vagotomy anti l)yh)roplasty is dilticult. I f an ulcer was seen on radiologic study or at the time of a second operation, this was considered a proved recurrent ulcer. tf th~ patient had recurrent ulcer symptoms or gave a history of hematemesis or melena, suspected recurrent ulceration was diagnosed. Both grout)s were combined to give the over-all recurrent rate.
Results Two h u n d r e d six p a t i e n t s o p e r a t e d on f o r duodenal ulcer disease at this institution had satisfactory H o l l a n d e r tests p e r f o r m e d in the postope r a t i v e period. O f these, 194 men a n d one woman (94.7 per c e n t ) have been seen because of late surgical complications or evaluated clinically within the last three months. These 195 patients will be the basis for the study. The American Journal of Surgery
Positive Response to Hollander Test
One h u n d r e d a n d fourteen (58.5 p e r cent) had n e g a t i v e r e s u l t s on H o l l a n d e r t e s t and e i g h t y - o n e (,I1.5 per cent) had posit:lye r e s u l t s on the initial study. Only t h r e e p a t i e n t s had positive r e s u l t s in the forty-five to s i x t y m i n u t e range. R e c u r r e n t s y m l ) t o m s h a v e developed in none of tiles(;. We have included t h e s e p a t i e n t s w i t h the f o r t y (20.5 l,~er c e n t ) havinir earb" posit ive results r a t h e r t h a n the f o r t y - o n e ( 2 l p e r c e n t ) w i t h late ( a f t e r one h o u r ) positive r e s p o n s e s . ( T a b l e I.) T h e r e w a s a total of sixteen r e c u r r e n t ulcers in the e n t i r e series. T e n of these o c c u r r e d in the / r o u p whose H o l l a n d e r t e s t s w e r e initially n e g a tive, t h r e e in tlmse w i t h e a r l y l)ositive r e s u l t s and t h r e e in those w i t h late I)ositive responses. T h e five p a t i e n t s in the g r o u p with sust)ected r e c m u ' e n t ulcers developed ulcer s y m p t o m s six m o n t h s to olle year ai'ier surgery.
T h e n e x t m o s t c o m m o n late c o m p l i c a t i o n in this s t u d y w a s the d u m p i n g s y n d r o m e w h i c h w a s seen in eleven p a t i e n t s . It~would s e e m as t h o u g h this c o m p l i c a t i o n w a s p r e s e n t only w h e n the s t o m a c h h a s lost its v a g a t fibers since it w a s p r e s e n t in 7.0 to 7.5 p e r cent o f p a t i e n t s w i t h a n e g a t i v e or late p o s i t i v e r e s p o n s e to the insulin t e s t a n d n o t seen its a n y o f those w i t h an e a r l y p o s i t i v e r e s p o n s e to the H o l l a n d e r test. D i a r r h e a w a s seen in only seven p a t i e n t s (3.6 p e r c e n t ) . T h e r e seemed to be little c o r r e l a t i o n w i t h the r e s p o n s e to insulin s t i m u l a t i o n a l t h o u g h it s e e m e d s l i g h t l y m o r e c o m m o n in t h o s e w i t h the n e g a t i v e r e s p o n s e . All of the a s y m p t o m a t i c pat i e n t s e i t h e r m a i n t a i n e d or s u r p a s s e d t h e i r p r e o p e r a t i v e w e i g h t . T h o s e w i t h r e c u r r e n t ulceration, d u m p i n g , o r c[iarrhea f r e q u e n t l y lost weight. T h e r e w a s no c o r r e l a t i o n of w e i g h t g a i n to the r e s p o n s e to the instflin test.
E a c h }las h a d o l l l y a s i n g l e
zieKaiix'e respollse to the insulin test. T h e five palimits ill the ~]'oup w i t h n e g a t i v e results on t-Iol]iil/(l(~l" test and ])roved tl]COl'S ( s e e l t lit s u r g e r y OF ()ll r o e l / l g e l l o g r l t n l ) a r e o|" t ) a r t i e u l a r i n t e r e s t . In l~,~,'t) o | ~ t h e m s y l l l l ) t o l l l s o f r e c u r . l ' e I l t u l c e r devel(q)ed t h r e e and five y e a r s later, r e s p e c t i v e l y , a t w h i c h time results of lhe insulin test when rel)e:tled had c h a n g e d to e a r l y I)ositive, T w o of the, o t h e r t h r e e in t h i s / r o u p h a v e had ne.cative r e s u l t s on two :rod t h r e e insuliH tests, resl)eetively, d e s p i t e the, fin(ling (d' a recurrez)t ulcer at s u r g e r y . T h e fifth in i b i s Eroup h a s both s y m p t o m s a n d radioh,~dc evidence of a duo(lenal ulcer desl)ite n e g a t i v e r e s u l t s ~)n t~Vo l a t e r insulin tests. O f the t h r e e p a t i e n t s in the g r o u p h a v i n g e a r l y p o s i t i v e responses, one had bleeding one y e a r p o s t operatively" and w a s f o u n d to h a v e a r e c u r r e n t ulc e r ai; s u r g e r y . In the second, ulcer s y m p t o m s developed five y e a r s p o s t o p e r a t i v e l y and the p a t i e n t w a s f o u n d to h a v e a r e c u r r e n t u l c e r at; o p e r a t i o n . In the t h i r d ulcer, s y m p t o m s developed a n d r a d i o logic studies revealed a r e c u r r e n t ulcer b u t tile p a t i e n t is w o r k i n g a n d does not desire f u r t h e r operations. In the t h r e e p a t i e n t s in the g r o u p w i t h late p o s i t i v e responses, r e c u r r e n t s y m p t o m s or h e m a t e m e s i s developed t w o to t h r e e ),ears a f t e r s u r g e r y . All t h r e e w e r e t r b a t e d s u r g i c a l l y by t r a n s t h o r a c i c v a g o t o m y . ( T a b l e I.) TABLE I
Comments
Surprisingly, proved recurrent ulceration was seen j u s t as o f t e n in p a t i e n t s w i t h a n e g a t i v e response to H o l l a n d e r t e s t as in those w i t h positive r e s p o n s e s . ]t h a s g e n e r a l l y been a c c e p t e d t h a t patients w i t h a n e g a t i v e r e s p o n s e to the H o l l a n d e r t e s t h a d c o m p l e t e s e v e r a n c e of t h e v a g u s n e r v e s and t h a t duodenal ulcer would not recur. Vice versa, w h e n the H o l l a n d e r t e s t g a v e p o s i t i v e results, v a g o t o m y w a s c o n s i d e r e d i n c o m p l e t e and the p a t i e n t w a s t h o u g h t in d a n g e r of h a v i n g the ulcer recur. One e x p l a n a t i o n f o r the r e d e v e l o p m e n t of p e p t i c disease a f t e r n e g a t i v e r e s p o n s e to the H o l l a n d e r t e s t in the e a r l y p o s t o p e r a t i v e p e r i o d is r e c o v e r y of v a g a t n e r v e f u n c t i o n a f t e r o p e r a t i v e t r a u m a a n d b r u i s i n g or if c o m p l e t e division of the n e r v e w a s not accomplished. T h i s m a y h a v e o c c u r r e d in t w o of o u r p a t i e n t s since w h e n the ulcer r e a p p e a r e d t h r e e and five y e a r s later, respectively, the H o l l a n d e r t e s t r e p e a t e d a t - t h a t t i m e g a v e s t r o n g l y p o s i t i v e r e s u l t s in the first hour. R e c e n t l y , J o n e s and Grifl~th [9], w o r k i n g w i t h rats, h a v e denied t h a t r e s u l t s of t h e H o l l a n d e r test can c o n v e r t f r o m n e g a t i v e to positive. N e v e r theless, Gillespie et al [10] did s h o w this c h a n g e in s e v e n t e e n of t h i r t y - o n e p a t i e n t s followed up f o r
Response to Hollander Test Correlated with Clinical Results in 195 Patients Followed Up for Zero to Seven Years (Mean, 3.4 Years) after Surgery Proved
Suspected
Total Recurrent
Number
Ulcer
Ulcer
Ulceration
Dumping
Diarrhea
114 (58.5%) 40 (20.5%) 41 (21.0%)
5 2 0
5 1 3
10 (8.7%) 3 (7.5%) 3 (.7,5°70)
8 (7.0%) 0 (0,0%) 3 (7.5%)
5 (4.4%) 1 (2,5%) I (2.5%)
Insulin Response
Negative Early positive Late positive
Volume 120, November 1970
66t
T h o m p s o n and Read
t h r e e m o n t h s to f o u r y e a r s . R e c o v e r y or r e g e n e r a tion c a n n o t e x p l a i n r e c u r r e n t ulcer p r o v e d a t ope r a t i o n in o u r t h r e e l ) a t i e n t s s o m e y e a r s a f t e r v a g o t o m y a n d p y l o r o p l a s t y since r e s u l t s of t h e H o l l a n d e r t e s t r e m a i n e d n e g a t i v e e v e n w h e n rep e a t e d . T h e p r e s e n c e of p r o v e d r e c u r r e n t d u o d e n a l u l c e r a t i o n h a s been r e p o r t e d p r e v i o u s l y b y B a c h r a c h and B a c h r a c h [11], K a y [12], a n d J o h n s t o n et al [13]. One m u s t a s s u m e h e r e t h a t r e c u r r e n t u l c e r a t i o n is r e l a t e d to s o m e h o r m o n a l d i s t u r b a n c e or an i n c o r r e c t l y p e r f o r m e d test. I t h a s been p o i n t e d oiit t h a t ideally the n a s o g a s t r i e t u b e should be placed in the s t o m a c h u n d e r fluoroscopic control. T h e p r e s e n t s t u d i e s w e r e c a r r i e d o u t oil the s u r g i c a l w a r d s w i t h o u t t h i s check. T h e p o s s i b i l i t y of s t a s i s o r r e g u r g i t a t i o n of d u o d e n a l c o n t e n t s m a s k i n g a p o s i t i v e r e s p o n s e by n e u t r a l i z a t i o n h a s been c o m m e n t e d u p o n p r e v i o u s l y [8]. O f course, a m o r e s i m p l e e x p l a n a t i o n is t h a t the H o l l a n d e r t e s t m i g h t well h a v e g i v e n p o s i t i v e r e s u l t s in t h e s e p a t i e n t s h a d it been e v a l u a t e d , as h a s b e e n stlggested, by o t h e r p a r a m e t e r s , such as v o l u m e inc r e a s e [l~,] or acid o u t p u t p e r h o u r [11] r a t h e r t h a n by m e r e l y a s i g n i f i c a n t c h a n g e in acid conc e n t r a t i o n a b o v e t h e f a s t i n g level. I t is equally s u r p r i s i n g t h a t of the e i g h t y - o n e p a t i e n t s h a v i n g p o s i t i v e r e s p o n s e to the H o l l a n d e r t e s t only six h a v e h a d a n y difficulty a f t e r o p e r a tion. T h e f o l l o w - u p p e r i o d is, of course, r e l a t i v e l y short and these patients may yet have trouble, but to d a t e m a n y h a v e b e e n f o l l o w e d , u p f o r m o r e t h a n five y e a r s a n d r e m a i n a s y m p t o m a t i c , g a i n i n g w e i g h t , and w o r k i n g . H o l l a n d e r ' s c r i t e r i a m a y be p h y s i o l o g i c a l l y s o u n d b u t clinically too s t r i c t ill t h a t section o f all v a g a l n e r v e s m a y n o t be essential to e n s u r e c u r e of a d u o d e n a l ulcer. Tile r a t e o f 41..5 p e r c e n t p o s i t i v e r e s p o n s e s to tile H o l l a n d e r t e s t seen in t h i s s t u d y w o u l d s e e m to be high. M o s t l a r g e s e r i e s r e p o r t a f i g u r e of a p p r o x i m a t e l y 33 p e r c e n t [6,7,12]. H o w e v e r , in a s e r i e s s i m i l a r to o u r s , i n c l u d i n g a n u m b e r of p a t i e n t s e v a l u a t e d b e c a u s e of r e c u r r e n t s y m p t o m s , J o h n s t o n et al [13] r e p o r t e d p o s i t i v e r e s p o n s e to the H o l l a n d e r t e s t in 46.8 p e r cent. A n o t h e r f a c t o r which elevates our number of positive responses was the veteran population which was almost e n t i r e l y m a l e . S p e n c e r et al [15] h a v e r e c e n t l y p o i n t e d o u t t h a t m e n h a v e h i g h e r p e a k acid o u t p u t s a n d t w i c e the p e r c e n t a g e of p o s i t i v e r e s p o n s e s to the H o l l a n d e r t e s t s t h a n t h o s e of w o m e n . In conehtsion, t h i s s t u d y , a l o n g w i t h o t h e r rec e n t w o r k , e m p h a s i z e s tile l i m i t a t i o n o f tile H o t l a n d e r test. It is n o t w i t h o u t risk ill o l d e r p a t i e n t s a n d t h o s e w i t h m y o c a r d i a l disease. T h e m a j o r i t y of t h o s e w i t h a p o s i t i v e r e s p o n s e s e e m to do as
662
well as t h o s e w i t h n e g a t i v e r e s p o n s e s . A single n e g a t i v e r e s p o n s e does not m e a n t h a t the ulcer will not in stone c a s e s recur. B e c a u s e of t h e s e deftciencies a n u n l b e r of investig.d:ors h a v e s u g g e s t e d m o d i f i c a t i o n s in c r i t e r i a o f t h e insulin t e s t [6] or the use of a n t n n b e r o f n e w a g e n t s [16,17] f o r ceilt r a l v a g a l s t i m u l a t i o n . To d a t e none of t h e s e a p p e a r to be totally s a t i s f a c t o r y . N e v e r t h e l e s s , w i t h all its p r o b l e m s the H o l l a n d e r t e s t is the b e s t m e t h o d a v a i l a b l e to i n d i c a t e w h e t h e r a p r e v i o u s l y p e r f o r m e d v a g o t o m y is c o m p l e t e a n d it is a r o u g h i n d i c a t o r in the d i f f e r e n t i a l d i a g n o s i s in p a t i e n t s havin~r diiliculty a f t e r w~gotomy and pylorot)l'lsty.
Summary I ) u r i n g the p a s t seven y e a r s , 206 of the 527 pat i e n t s o p e r a t e d upm~ f o r d u o d e n a l ulcer had a H o l l a n d e r t e s t l l e r f o r m e d . Due to the m o r b i d i t y a s s o c i a t e d w i t h lhe t e s t it has been used only in y o u n g e r p a t i e n t s w i t h m l t h e a r t disease, e s p e c i a l l y those w h o r e t u r n w i t h syn!t)torns. One h u n d r e d n i n e t y - f i v e o f t h o s e tested w e r e e v a l u a t e d clinically w i t h i n tile p a s t i h r e e m o n t h s . E i g h t y - o n e (41.5. pel: c e n t ) of the t e s t s initially g a v e p o s i t i v e r e s u l i s u s i n g the e r i t e r i : r <)f g a s t r i c a c i d i t y r i s i n g 10 m E q 'I~ oil t w o c o n s e c u t i v e s a m ples if p r e v i o u s l y a e h l o r h y d r i c , or 20 m E q / L a b o v e tile f a s t i n g level, in f o r t y p a t i e n t s the rise occ u r r e d in t h e first h o u r and an a d d i t i o n a l f o r t y one s h o w e d a rise t)5" the end of two hcmrs. By tile c r i t e r i a of w e i g h t gain, r e c u r r e r i t u l c e r a t i o n , d i a r rhea, or d u m p i n g s y n d r o m e , t h e r e is little differenee b e t w e e n tile p a t i e n t w i t h an e a r l y or late p o s i t i v e r e s p o n s e to the H o l l a n d e r t e s t a n d the others. O u r foltow-ui) d a t a s u g g e s t t h a t a l t h o u g h insulin h y p o g l y c e m i a e v o k e s g a s t r i c s e c r e t i o n , even if a f e w v a g a l fibers r e m a i n , the u l c e r d i a t h e s i s is still c o n t r o l l e d w i t h less t h a n c o m p l e t e v a g o t o m y . T h e H o l l a n d e r t e s t m a y be too sensitive. H o w e v e r , it is tile b e s t a v a i l a b l e to s h o w c o m p l e t e n e s s of w t g a l division, b u t c a n n o t be used to p r e d i c t clinical response of vagotomy and pyloroplasty. References ] . Hollander F: T h e insulin t e s t f o r the presence of intact nerve fibers after vagal operations for peptic ulcer. Gastroenterology 7: 607, 1946. 2. Dragstedt LR, Camp EH: Follow-up of gastric vagotomy alo.ne in the treatment of peptic ulcer. Gastroenterology 11: 460, 1948. 3. Austen WG, Edwards HC: A clinical appraisal of the t r e a t m e n t of chronic duoder;at ulcer by vagotomy and gastric drainage operation. Gut 2: 158, 1961. 4. Stempien SJ: Insulin gastic analysis: technic and interpretations. Amer J Dig Dis 7: 138, 1962. 5. Bachrach WH: Laboratory criteria for completeness of vagotomy. Amer J Dig Dis 7: 1071, 1962.
The American Journal of Surgery
Positive Response to H o l l a n d e r Test 6. Bank S, Marks IN, Louw JH: Histamine and insulinstimulated gastric acid secretion after selective and truncal vagotomy. Gut 8: 36, 1967. 7. Ross B, Kay AW: The insulin test after vagotomy. Gastroenterology 46: 379, 1964. 8. Hollander F. Laboratory procedures in the study of va, g o t o m y (with particular reference to insulin test). Gastroenterology 11: 419, 1948. 9. Jones WM, Griffith CA: On the question of vagal reinnerration of the stomach. It. Tile unchanging secretory and ulcerogenic potential. Ann Surg 171: 369, 1970. 10. Gillespie G, Elder JB, Gillespie IE, Kay AW: The longterm stability of the insulin response after vagotonly. Brit J Surg 56: 705, 1969. 1]. Bachrach WH, Bachrach LB: Re-evaluation of the Hollander test. Ann N Y Acad Sci ]40: 9 ] 5 , ] 9 6 7 .
Volume ]20, November ] 9 7 0
12. Kay AW: Memorial lecture: an evaluation of gastric acid secretion tests. Gastroenterology 53: 834, 1967. 13. Johnston D, Thomas DG, Checketts RG, Duthie HL: An assessment of postoperative testing for completeness of vagotomy. Brit J Sure 54: 831, 1967. 14. Waddell WR: The acid secretory response to histamine and insulin hypoglycemia after various operations on the stomach. Surgery 42: 652, 1957, 15. Spencer J, Burns GP, Cheng FCY, Cox AG, Welbourn RB: Differences between males and females in the Hollander insulin test. Gut 10: 307, ] 9 6 9 . 16. Hirschowitz BI, Sachs G: Vagal gastric secretory stimulation by 2.deoxy-D-glucose. Amer J Physiol 209: 452. 1965. ]7. Venables CW, Johnston IDA: The use of a combined pentagastrin/insulin test to assess the effectiveness of truncat vagotomy. 8 r i t J Surg 56: 701, 1969.
663
\ ; a g o t o m y with p y l o r o p h t s t y has become over the past decade the s t a n d a r d o p e r a t i o n for the comp l i c a t i o n s of duodenal ulcer. T h e only w a y to d e t e r mine p o s t o p e r a t i v e l y the c o m p l e t e n e s s of this p r o cedtlre is to pev'forn~ a H o l l a n d e r test [t1. Dragstedt and ( : a m p [21 as well as A u s t e n and Edwards 1.~'! f r o m t h e i r vast e x p e r i e n c e s u g g e s t e d t h a t rec u r r e n t ulcers irl such p a t i e n t s result from i n c o m plete v a g ~ t o m y and couht be predicted b y p o s i t i v e r e s u l t s on a t [ o l l a n d e r test. U n f o r t u n a t e l y , the insulin test is ass~miated w i t h a c e r t a i n m o r b i d i t y and its results are difficult to i n t e r p r e t since the c r i t e r i a are a r h i t r a r y , b e i n g based largely on animal e x p e r i m e n t a t i o n . Recently, Stempien [~], t ' a e h r a c h [51 , Bank, M a r k s , and Louw [61 , a n d o t h e r s have expressed d i s s a t i s f a c t i o n with the limits used to establish p o s i t i v i t y or n e g a t i v i t y as well as the i n c o n s i s t e n c y of the test in man. Ross and Kay I7i indicate t h a t an e a r l y g a s t r i c acid resp,mse to inslllin, coupled with little c h a n g e in m a x i m a l acid OUtl)ut, m a y be m o r e 'valuable in p r e d i c t i n g those p a t i e n t s w h o are liable to rec u r r e n t ulceration t h a n the ehtssic t [ o l l a n d e r test. l',ecat|se of this c o n t r o v e r s y we have reviewed otlr s t u d i e s of the Hotlancter t e s t and have c o r r e l a t e d them ~:jth the clinical tindings in 195 p a t i e n t s w h o had v a g o t o m y and p y l o r o p l a s t y for duodenal ulcer dis~,ase.
Material and Methods During the past seven years vagotomy arid t)ylorop!asty tmve been carried out on 527 patients at the Veteral~ Administration IIospital. Little Rock, Arkansas, for the treatment of duodenal ulcer. Two hundred and six of these patients had ttottander tests carried mit six ~)1" more weeks after s u r g e r y . P~ecatlse of the inherent morbidity associated with the test all patients over sixty years ~f age and those with abnormal litfflings on eh:etrocardiogram were eliminated from the study. A certain number of patients refused t,, submit to the test. The series is not unselected since it inehates all patient~ who had recurrent symptoms. Fm.m the Sta,l~ical Service, Veterans Administration Hospital, and the C)eCa~ln~Pn! 01 Surgery, University of Arkansas School of Medicine, Pr~s~ertte~ at the Twenty-Second
Ar~nual Meeting of the South-
*~e~t~,'n Suf/E~caf Congress. Dallas, Texas, April 20-23, 1970.
66~)
The criteria used to determine a positive response were those of ttollander IX 1. A nasogastric tube was inserted into tile stomach of a fasting patient. Two control samples of gastric: juice were removed at fifteen minute intervals. The mean of these was used as a base line for gauging a rise of the acidity curve. Regular insulin in a dose of 0.2 units per kg of body weight was injected intravenously. Blood and gastric samples were then drawn every tifteen minutes for two hours. A positiw~ r e s p o n s e w a s a rise in the e o n e e n t r a t i o l l of acid over the basal level on two sueeessive specimens {}f 20 m g q ' L unless the basal samples were anacid, in which case "t rise of 10 mEq "I, cm two successive specimens. The test was not cm~sictered to be valid unless i tie blood sugar level fell below 50 mg pc," cent. In this report we have used the time of one hour to separate lhe positive secretory responses into early and late gl'otlps in eontr-tdistinction to the time of forty-live minutes suggested by Ross and Kay 171, All patients except those who had previously been treated for recurrent ulceration were recalled to the surgical clinic aud evaluated clinically within the past three months. The follow-ul) period ranged from zero to sewtn years with a mean of .'3.,I years. Since the rate of operations remained fairly constant over tile years, the length of follow-up is distributed evenly. These patients were ewduated as to ulcer symptoms, weight gain, diarrhea, dumping s.{'ndrome, and ability to work. All of those seen in the clinic with postoperative symptml~s were readmitted to the hospital and re-evaluated by x-ray 1t11(tsecretory studi{~s. The absolute diagnosis of recurrent ulceration after vagotomy anti l)yh)roplasty is dilticult. I f an ulcer was seen on radiologic study or at the time of a second operation, this was considered a proved recurrent ulcer. tf th~ patient had recurrent ulcer symptoms or gave a history of hematemesis or melena, suspected recurrent ulceration was diagnosed. Both grout)s were combined to give the over-all recurrent rate.
Results Two h u n d r e d six p a t i e n t s o p e r a t e d on f o r duodenal ulcer disease at this institution had satisfactory H o l l a n d e r tests p e r f o r m e d in the postope r a t i v e period. O f these, 194 men a n d one woman (94.7 per c e n t ) have been seen because of late surgical complications or evaluated clinically within the last three months. These 195 patients will be the basis for the study. The American Journal of Surgery
Positive Response to Hollander Test
One h u n d r e d a n d fourteen (58.5 p e r cent) had n e g a t i v e r e s u l t s on H o l l a n d e r t e s t and e i g h t y - o n e (,I1.5 per cent) had posit:lye r e s u l t s on the initial study. Only t h r e e p a t i e n t s had positive r e s u l t s in the forty-five to s i x t y m i n u t e range. R e c u r r e n t s y m l ) t o m s h a v e developed in none of tiles(;. We have included t h e s e p a t i e n t s w i t h the f o r t y (20.5 l,~er c e n t ) havinir earb" posit ive results r a t h e r t h a n the f o r t y - o n e ( 2 l p e r c e n t ) w i t h late ( a f t e r one h o u r ) positive r e s p o n s e s . ( T a b l e I.) T h e r e w a s a total of sixteen r e c u r r e n t ulcers in the e n t i r e series. T e n of these o c c u r r e d in the / r o u p whose H o l l a n d e r t e s t s w e r e initially n e g a tive, t h r e e in tlmse w i t h e a r l y l)ositive r e s u l t s and t h r e e in those w i t h late I)ositive responses. T h e five p a t i e n t s in the g r o u p with sust)ected r e c m u ' e n t ulcers developed ulcer s y m p t o m s six m o n t h s to olle year ai'ier surgery.
T h e n e x t m o s t c o m m o n late c o m p l i c a t i o n in this s t u d y w a s the d u m p i n g s y n d r o m e w h i c h w a s seen in eleven p a t i e n t s . It~would s e e m as t h o u g h this c o m p l i c a t i o n w a s p r e s e n t only w h e n the s t o m a c h h a s lost its v a g a t fibers since it w a s p r e s e n t in 7.0 to 7.5 p e r cent o f p a t i e n t s w i t h a n e g a t i v e or late p o s i t i v e r e s p o n s e to the insulin t e s t a n d n o t seen its a n y o f those w i t h an e a r l y p o s i t i v e r e s p o n s e to the H o l l a n d e r test. D i a r r h e a w a s seen in only seven p a t i e n t s (3.6 p e r c e n t ) . T h e r e seemed to be little c o r r e l a t i o n w i t h the r e s p o n s e to insulin s t i m u l a t i o n a l t h o u g h it s e e m e d s l i g h t l y m o r e c o m m o n in t h o s e w i t h the n e g a t i v e r e s p o n s e . All of the a s y m p t o m a t i c pat i e n t s e i t h e r m a i n t a i n e d or s u r p a s s e d t h e i r p r e o p e r a t i v e w e i g h t . T h o s e w i t h r e c u r r e n t ulceration, d u m p i n g , o r c[iarrhea f r e q u e n t l y lost weight. T h e r e w a s no c o r r e l a t i o n of w e i g h t g a i n to the r e s p o n s e to the instflin test.
E a c h }las h a d o l l l y a s i n g l e
zieKaiix'e respollse to the insulin test. T h e five palimits ill the ~]'oup w i t h n e g a t i v e results on t-Iol]iil/(l(~l" test and ])roved tl]COl'S ( s e e l t lit s u r g e r y OF ()ll r o e l / l g e l l o g r l t n l ) a r e o|" t ) a r t i e u l a r i n t e r e s t . In l~,~,'t) o | ~ t h e m s y l l l l ) t o l l l s o f r e c u r . l ' e I l t u l c e r devel(q)ed t h r e e and five y e a r s later, r e s p e c t i v e l y , a t w h i c h time results of lhe insulin test when rel)e:tled had c h a n g e d to e a r l y I)ositive, T w o of the, o t h e r t h r e e in t h i s / r o u p h a v e had ne.cative r e s u l t s on two :rod t h r e e insuliH tests, resl)eetively, d e s p i t e the, fin(ling (d' a recurrez)t ulcer at s u r g e r y . T h e fifth in i b i s Eroup h a s both s y m p t o m s a n d radioh,~dc evidence of a duo(lenal ulcer desl)ite n e g a t i v e r e s u l t s ~)n t~Vo l a t e r insulin tests. O f the t h r e e p a t i e n t s in the g r o u p h a v i n g e a r l y p o s i t i v e responses, one had bleeding one y e a r p o s t operatively" and w a s f o u n d to h a v e a r e c u r r e n t ulc e r ai; s u r g e r y . In the second, ulcer s y m p t o m s developed five y e a r s p o s t o p e r a t i v e l y and the p a t i e n t w a s f o u n d to h a v e a r e c u r r e n t u l c e r at; o p e r a t i o n . In the t h i r d ulcer, s y m p t o m s developed a n d r a d i o logic studies revealed a r e c u r r e n t ulcer b u t tile p a t i e n t is w o r k i n g a n d does not desire f u r t h e r operations. In the t h r e e p a t i e n t s in the g r o u p w i t h late p o s i t i v e responses, r e c u r r e n t s y m p t o m s or h e m a t e m e s i s developed t w o to t h r e e ),ears a f t e r s u r g e r y . All t h r e e w e r e t r b a t e d s u r g i c a l l y by t r a n s t h o r a c i c v a g o t o m y . ( T a b l e I.) TABLE I
Comments
Surprisingly, proved recurrent ulceration was seen j u s t as o f t e n in p a t i e n t s w i t h a n e g a t i v e response to H o l l a n d e r t e s t as in those w i t h positive r e s p o n s e s . ]t h a s g e n e r a l l y been a c c e p t e d t h a t patients w i t h a n e g a t i v e r e s p o n s e to the H o l l a n d e r t e s t h a d c o m p l e t e s e v e r a n c e of t h e v a g u s n e r v e s and t h a t duodenal ulcer would not recur. Vice versa, w h e n the H o l l a n d e r t e s t g a v e p o s i t i v e results, v a g o t o m y w a s c o n s i d e r e d i n c o m p l e t e and the p a t i e n t w a s t h o u g h t in d a n g e r of h a v i n g the ulcer recur. One e x p l a n a t i o n f o r the r e d e v e l o p m e n t of p e p t i c disease a f t e r n e g a t i v e r e s p o n s e to the H o l l a n d e r t e s t in the e a r l y p o s t o p e r a t i v e p e r i o d is r e c o v e r y of v a g a t n e r v e f u n c t i o n a f t e r o p e r a t i v e t r a u m a a n d b r u i s i n g or if c o m p l e t e division of the n e r v e w a s not accomplished. T h i s m a y h a v e o c c u r r e d in t w o of o u r p a t i e n t s since w h e n the ulcer r e a p p e a r e d t h r e e and five y e a r s later, respectively, the H o l l a n d e r t e s t r e p e a t e d a t - t h a t t i m e g a v e s t r o n g l y p o s i t i v e r e s u l t s in the first hour. R e c e n t l y , J o n e s and Grifl~th [9], w o r k i n g w i t h rats, h a v e denied t h a t r e s u l t s of t h e H o l l a n d e r test can c o n v e r t f r o m n e g a t i v e to positive. N e v e r theless, Gillespie et al [10] did s h o w this c h a n g e in s e v e n t e e n of t h i r t y - o n e p a t i e n t s followed up f o r
Response to Hollander Test Correlated with Clinical Results in 195 Patients Followed Up for Zero to Seven Years (Mean, 3.4 Years) after Surgery Proved
Suspected
Total Recurrent
Number
Ulcer
Ulcer
Ulceration
Dumping
Diarrhea
114 (58.5%) 40 (20.5%) 41 (21.0%)
5 2 0
5 1 3
10 (8.7%) 3 (7.5%) 3 (.7,5°70)
8 (7.0%) 0 (0,0%) 3 (7.5%)
5 (4.4%) 1 (2,5%) I (2.5%)
Insulin Response
Negative Early positive Late positive
Volume 120, November 1970
66t
T h o m p s o n and Read
t h r e e m o n t h s to f o u r y e a r s . R e c o v e r y or r e g e n e r a tion c a n n o t e x p l a i n r e c u r r e n t ulcer p r o v e d a t ope r a t i o n in o u r t h r e e l ) a t i e n t s s o m e y e a r s a f t e r v a g o t o m y a n d p y l o r o p l a s t y since r e s u l t s of t h e H o l l a n d e r t e s t r e m a i n e d n e g a t i v e e v e n w h e n rep e a t e d . T h e p r e s e n c e of p r o v e d r e c u r r e n t d u o d e n a l u l c e r a t i o n h a s been r e p o r t e d p r e v i o u s l y b y B a c h r a c h and B a c h r a c h [11], K a y [12], a n d J o h n s t o n et al [13]. One m u s t a s s u m e h e r e t h a t r e c u r r e n t u l c e r a t i o n is r e l a t e d to s o m e h o r m o n a l d i s t u r b a n c e or an i n c o r r e c t l y p e r f o r m e d test. I t h a s been p o i n t e d oiit t h a t ideally the n a s o g a s t r i e t u b e should be placed in the s t o m a c h u n d e r fluoroscopic control. T h e p r e s e n t s t u d i e s w e r e c a r r i e d o u t oil the s u r g i c a l w a r d s w i t h o u t t h i s check. T h e p o s s i b i l i t y of s t a s i s o r r e g u r g i t a t i o n of d u o d e n a l c o n t e n t s m a s k i n g a p o s i t i v e r e s p o n s e by n e u t r a l i z a t i o n h a s been c o m m e n t e d u p o n p r e v i o u s l y [8]. O f course, a m o r e s i m p l e e x p l a n a t i o n is t h a t the H o l l a n d e r t e s t m i g h t well h a v e g i v e n p o s i t i v e r e s u l t s in t h e s e p a t i e n t s h a d it been e v a l u a t e d , as h a s b e e n stlggested, by o t h e r p a r a m e t e r s , such as v o l u m e inc r e a s e [l~,] or acid o u t p u t p e r h o u r [11] r a t h e r t h a n by m e r e l y a s i g n i f i c a n t c h a n g e in acid conc e n t r a t i o n a b o v e t h e f a s t i n g level. I t is equally s u r p r i s i n g t h a t of the e i g h t y - o n e p a t i e n t s h a v i n g p o s i t i v e r e s p o n s e to the H o l l a n d e r t e s t only six h a v e h a d a n y difficulty a f t e r o p e r a tion. T h e f o l l o w - u p p e r i o d is, of course, r e l a t i v e l y short and these patients may yet have trouble, but to d a t e m a n y h a v e b e e n f o l l o w e d , u p f o r m o r e t h a n five y e a r s a n d r e m a i n a s y m p t o m a t i c , g a i n i n g w e i g h t , and w o r k i n g . H o l l a n d e r ' s c r i t e r i a m a y be p h y s i o l o g i c a l l y s o u n d b u t clinically too s t r i c t ill t h a t section o f all v a g a l n e r v e s m a y n o t be essential to e n s u r e c u r e of a d u o d e n a l ulcer. Tile r a t e o f 41..5 p e r c e n t p o s i t i v e r e s p o n s e s to tile H o l l a n d e r t e s t seen in t h i s s t u d y w o u l d s e e m to be high. M o s t l a r g e s e r i e s r e p o r t a f i g u r e of a p p r o x i m a t e l y 33 p e r c e n t [6,7,12]. H o w e v e r , in a s e r i e s s i m i l a r to o u r s , i n c l u d i n g a n u m b e r of p a t i e n t s e v a l u a t e d b e c a u s e of r e c u r r e n t s y m p t o m s , J o h n s t o n et al [13] r e p o r t e d p o s i t i v e r e s p o n s e to the H o l l a n d e r t e s t in 46.8 p e r cent. A n o t h e r f a c t o r which elevates our number of positive responses was the veteran population which was almost e n t i r e l y m a l e . S p e n c e r et al [15] h a v e r e c e n t l y p o i n t e d o u t t h a t m e n h a v e h i g h e r p e a k acid o u t p u t s a n d t w i c e the p e r c e n t a g e of p o s i t i v e r e s p o n s e s to the H o l l a n d e r t e s t s t h a n t h o s e of w o m e n . In conehtsion, t h i s s t u d y , a l o n g w i t h o t h e r rec e n t w o r k , e m p h a s i z e s tile l i m i t a t i o n o f tile H o t l a n d e r test. It is n o t w i t h o u t risk ill o l d e r p a t i e n t s a n d t h o s e w i t h m y o c a r d i a l disease. T h e m a j o r i t y of t h o s e w i t h a p o s i t i v e r e s p o n s e s e e m to do as
662
well as t h o s e w i t h n e g a t i v e r e s p o n s e s . A single n e g a t i v e r e s p o n s e does not m e a n t h a t the ulcer will not in stone c a s e s recur. B e c a u s e of t h e s e deftciencies a n u n l b e r of investig.d:ors h a v e s u g g e s t e d m o d i f i c a t i o n s in c r i t e r i a o f t h e insulin t e s t [6] or the use of a n t n n b e r o f n e w a g e n t s [16,17] f o r ceilt r a l v a g a l s t i m u l a t i o n . To d a t e none of t h e s e a p p e a r to be totally s a t i s f a c t o r y . N e v e r t h e l e s s , w i t h all its p r o b l e m s the H o l l a n d e r t e s t is the b e s t m e t h o d a v a i l a b l e to i n d i c a t e w h e t h e r a p r e v i o u s l y p e r f o r m e d v a g o t o m y is c o m p l e t e a n d it is a r o u g h i n d i c a t o r in the d i f f e r e n t i a l d i a g n o s i s in p a t i e n t s havin~r diiliculty a f t e r w~gotomy and pylorot)l'lsty.
Summary I ) u r i n g the p a s t seven y e a r s , 206 of the 527 pat i e n t s o p e r a t e d upm~ f o r d u o d e n a l ulcer had a H o l l a n d e r t e s t l l e r f o r m e d . Due to the m o r b i d i t y a s s o c i a t e d w i t h lhe t e s t it has been used only in y o u n g e r p a t i e n t s w i t h m l t h e a r t disease, e s p e c i a l l y those w h o r e t u r n w i t h syn!t)torns. One h u n d r e d n i n e t y - f i v e o f t h o s e tested w e r e e v a l u a t e d clinically w i t h i n tile p a s t i h r e e m o n t h s . E i g h t y - o n e (41.5. pel: c e n t ) of the t e s t s initially g a v e p o s i t i v e r e s u l i s u s i n g the e r i t e r i : r <)f g a s t r i c a c i d i t y r i s i n g 10 m E q 'I~ oil t w o c o n s e c u t i v e s a m ples if p r e v i o u s l y a e h l o r h y d r i c , or 20 m E q / L a b o v e tile f a s t i n g level, in f o r t y p a t i e n t s the rise occ u r r e d in t h e first h o u r and an a d d i t i o n a l f o r t y one s h o w e d a rise t)5" the end of two hcmrs. By tile c r i t e r i a of w e i g h t gain, r e c u r r e r i t u l c e r a t i o n , d i a r rhea, or d u m p i n g s y n d r o m e , t h e r e is little differenee b e t w e e n tile p a t i e n t w i t h an e a r l y or late p o s i t i v e r e s p o n s e to the H o l l a n d e r t e s t a n d the others. O u r foltow-ui) d a t a s u g g e s t t h a t a l t h o u g h insulin h y p o g l y c e m i a e v o k e s g a s t r i c s e c r e t i o n , even if a f e w v a g a l fibers r e m a i n , the u l c e r d i a t h e s i s is still c o n t r o l l e d w i t h less t h a n c o m p l e t e v a g o t o m y . T h e H o l l a n d e r t e s t m a y be too sensitive. H o w e v e r , it is tile b e s t a v a i l a b l e to s h o w c o m p l e t e n e s s of w t g a l division, b u t c a n n o t be used to p r e d i c t clinical response of vagotomy and pyloroplasty. References ] . Hollander F: T h e insulin t e s t f o r the presence of intact nerve fibers after vagal operations for peptic ulcer. Gastroenterology 7: 607, 1946. 2. Dragstedt LR, Camp EH: Follow-up of gastric vagotomy alo.ne in the treatment of peptic ulcer. Gastroenterology 11: 460, 1948. 3. Austen WG, Edwards HC: A clinical appraisal of the t r e a t m e n t of chronic duoder;at ulcer by vagotomy and gastric drainage operation. Gut 2: 158, 1961. 4. Stempien SJ: Insulin gastic analysis: technic and interpretations. Amer J Dig Dis 7: 138, 1962. 5. Bachrach WH: Laboratory criteria for completeness of vagotomy. Amer J Dig Dis 7: 1071, 1962.
The American Journal of Surgery
Positive Response to H o l l a n d e r Test 6. Bank S, Marks IN, Louw JH: Histamine and insulinstimulated gastric acid secretion after selective and truncal vagotomy. Gut 8: 36, 1967. 7. Ross B, Kay AW: The insulin test after vagotomy. Gastroenterology 46: 379, 1964. 8. Hollander F. Laboratory procedures in the study of va, g o t o m y (with particular reference to insulin test). Gastroenterology 11: 419, 1948. 9. Jones WM, Griffith CA: On the question of vagal reinnerration of the stomach. It. Tile unchanging secretory and ulcerogenic potential. Ann Surg 171: 369, 1970. 10. Gillespie G, Elder JB, Gillespie IE, Kay AW: The longterm stability of the insulin response after vagotonly. Brit J Surg 56: 705, 1969. 1]. Bachrach WH, Bachrach LB: Re-evaluation of the Hollander test. Ann N Y Acad Sci ]40: 9 ] 5 , ] 9 6 7 .
Volume ]20, November ] 9 7 0
12. Kay AW: Memorial lecture: an evaluation of gastric acid secretion tests. Gastroenterology 53: 834, 1967. 13. Johnston D, Thomas DG, Checketts RG, Duthie HL: An assessment of postoperative testing for completeness of vagotomy. Brit J Sure 54: 831, 1967. 14. Waddell WR: The acid secretory response to histamine and insulin hypoglycemia after various operations on the stomach. Surgery 42: 652, 1957, 15. Spencer J, Burns GP, Cheng FCY, Cox AG, Welbourn RB: Differences between males and females in the Hollander insulin test. Gut 10: 307, ] 9 6 9 . 16. Hirschowitz BI, Sachs G: Vagal gastric secretory stimulation by 2.deoxy-D-glucose. Amer J Physiol 209: 452. 1965. ]7. Venables CW, Johnston IDA: The use of a combined pentagastrin/insulin test to assess the effectiveness of truncat vagotomy. 8 r i t J Surg 56: 701, 1969.
663