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Salicylate intoxication in infants and children
SALICYLATE
INTOXICATION
IN INFANTS
AND
CHILDREN
HENRY L. BAR.NETT,M.D., JOHN 1~. POWEI~S, 1V[.D., JOHN H. BENWARD, M.D., AND AL]~XIS F. HARTMANN, M.D. ST'. Lo.um, Mo~. T H E past eight years there have been seen at St. Louis Children's I NHospital five patients, in whom the diagnosis of salicy]ate poisoning was made. In four of the five cases the intoxication resulted from intensive therapeutic use of the salieylates, which, together with reports in the literature of similar poisonings, 1, 2 indicates the importance of the often repeated warning that the salicyl compounds are not always the harmless household remedy that they are supposed to be. The striking similarity of the clinical pictures in these five cases and the acuteness of the medical emergency which they presented aroused our interest in this subject. The paucity of recent clinical studies in the American pediatric literature prompted us to r e p o r t these cases and to discuss, the treatment which would seem to be indicated in view of our present knowledge concerning this intoxication. The p e r t i n e n t facts concerning the histories and findings of the cases presented are shown injTable I. Salic,ylate Ad~ninistratio,n.--In f o u r of the five cases, the symptoms of intoxication developed i during the therapeutic administration of salicylates. ~The quantities of salieylate taken by these f o u r cases, as shown in Table I, were estimated to be between 0.07 and 0.17 Gin. per kilogram per twenty-four hour% and the symptoms, usually occurred within twenty-four hours after the administration was begun. These figures for the amounts, taken were estimated from the histories, and therefore are not strictly reliable due to possible inaccuracies in the statements of the informants. The figures given in Table I refer to the minimum amount estimated. The usually recommended dose of aspirin during infancy is 1 gr. per year of age, 3 which would be approximately 0.04 Gin. per' kilogram per twenty-four hours if the dose were repeated every f o u r hours. The quantities apparently taken by these patients showing intoxication ran~ed from only two to four times the recommended dosage. I t would appear from ~his, as w e l l as from the fact that comparatively large dosages are, commonly given with no signs of intoxication, that factors in addition to the amount of salieylate ingested influence the occurrence of these symptoms. This will be discussed later. It is noteworthyl however, t h a t in only one of the cases was less than two times the recommended dosage given. F r o m th e D e p a r t m e n t of P e d i a t r i c s , ~ a s h i n g t o n a n d t h e St. L ouis Children's :[-Iospital. 214
U n i v e r s i t y School of ]Yiediclne,
BARNETT
ET
AL.
:
SALICYLATE
215
INTOXICATION
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THE JOURNAL OF PEDIATRICS
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217
SALICYLATE INTOXICATION
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Clinica~ Picture.--The outstanding clinical manifestation in these cases was the intense hyperventiIation which, in all of them, suggested the severest type of acidosis. The presence of this hyperventilation in an infant or child who is not severely dehydrated, and in whose history is found none of the usual causes for acidosis, suggests salicylate intoxication. The diagnosis was tentatively m a d e in two of the f o u r cases receiving the drug therapeutically b e f o r e a n y l a b o r a t o r y data was: obtained, and in one of the f o u r cases on the a p p e a r a n c e of the child alone. De,hyd,ratio n of some degree was noted in every case, but it was usually mild. I t was frequently r e m a r k e d b y the first observer of the case t h a t the dehydration was not in proportion to t h e a p p a r e n t degree of acidosis, and in one case sodium r-lactate was given in a m o r e ' c o n c e n t r a t e d solution than usually employed because of t h e m i l d n e s s of the dehydration. gamiting had occurred in all but one case and was u s u a l l y severe. Stupor, associated with periods of irritability, was present i/t all:five cases. Ge~e,ralize,d co.n~ulsions occurred i n t w o cases. Cyanosis was observed in two of the cases. An acetone odor of: the expired air :was detected in three of the cases. One p a t i e n t complained of abdominal p,ain. I n three of the five cases the t e m p e r a t u r e was not significantly elevated. Fever was present on admission in two instances, but the infections for which the drugs were given were still present. Tinnitus was reported in only one case. Thirst and poly,vria were not mentioned in the histories obtained, possibly because of the age of the patients. Laborato,~ Fi~dings on A c~missio~.--The i m p o r t a n t laboratory findings on admission are included in Table I I . The values for the carbon dioxide content of the blood sera in the f o u r cases in which the salicyl compound was given therapeutically and in which the intoxication was well developed on admission varied f r o m 15.4 to 28.9 volumes per cent. I n one case, J. L., the p H Of the serum on admission was 7.34 at a time When the carbon dioxide content was 25 volumes p e r cent, the significance of which will be mentioned later. I n three of the cases in whicl~ serum nonprotein nitrogen determinations were done on admission, the values were 28, 35.2, and 45 rag. p e r cent. Blood sugar determinations on four of the five cases were within normal limits on admission. I n the ease of g . C. the distillate of the protein-free filtrate of the blood serum obtained by heating" before the addition of potassium p e r m a n g a n a t e in the determination of lactic acid gave a h e a v y cloud when caught in Scott-Wilson's reagent, which served as a qnalitative test of marked increase in blo~d acetone. I n e a c h o~..the eases, the urine was acid on admission and gave a strongly positive test o n addition of ferric chloride, which persisted a f t e r acidification and boiling. The tr test f o r acetone was strongly positive, and the distillate of the urine specimen f r o m R. C. gave a h e a v y cloud when tested with Scott-Wilson's reagent. In one case the u r i n a r y sediment showed no formed elements on microscopic examina-
B A R N E T T E T AL. :
SALICYLATE INTOXICATION
'219
tion, a n d in the other f o u r only white blood cells were present in small numbers. I n one case, P. B., in. which a lumbar p u n c t u r e was done, the spinal fluid was crystal clelr, contained no increase in cells, gave a strongly positive test with f~l:riC chloride, and the carbon dioxide content was 19.5 volumes p e r C~nt (blood was 26.6 volumes per cent). DISCUSSION AND T R E A T M E N T
T r e a t m e n t of salicylate intoxication must be generally directed toward correction of the i m p o r t a n t changes, which have. taken place. A description of these changes and of the m e c h a n i s m involved in the production of them has been the subject of numerous investigations and must primarily consider the following factors : 1. The explanation for the intense hyperpnea, which is the outstanding clinical manifestation. 2. The failure to relieve the acidosis, when present, b y the administration of the usual quantity of alkali. 3. The occurrence of symptoms of intoxication in some patients who receive, quantities of salicyl compounds which are easily tolerated by other patients. The data obtained in our cases which relate to these factors can be presented in the following considerations. I n the only case (J. L.) in which a p H m e a s u r e m e n t of the serum was made, it was f o u n d to be 7.34 at a time when the carbon dioxide content of the serum was 25 volumes p e r cent. This corresponds to the t y p e of change in the acid-base balance observed in this l a b o r a t o r y 4 after the administration of large doses of sulfanilamide, ~ and suggests the: occurrence of a carbon dioxide deficit type of alkalosis produced by hyperventilation. The occurrence of p r i m a r y hyperventilation during salicylate administration has been observed by numerous investigators and has been attributed to direct central stimulation of the r e s p i r a t o r y center b y salicyl compounds. 2 and to the changes in t e m p e r a t u r e , the sensation of heat, and the increase in gaseous exchange induced b y the sa]icylates. 1 Whatever the direct cause of the stimulus to respiration, it seems well founded t h a t the intense h y p e r p n e a early in the course of sa!icylate intoxication is. due almost wholly to central stimulation of respiration since it m a y occur before a n y fall in the carbon dioxide content of the serum is observed. 2 L a t e r in the course of the intoxication, when acidosis .does develop, the effect of this specific central stimulation is added to the stimulation of respiration by the acidosis (see below) and the characteristic intense h y p e r p n e a is produced. * i t h a s b e e n s h o w n b y ] ~ e c k m a n a n d his c o - w o r k e r s 5 a n d c o n f i r m e d in t h i s l a b o r a t o r y t h a t p r i m a r y h y p e r v e n t i l a t t o n c a n n o t a c c o u n t f o r all of t h e c h a n g e s in a c i d - b a s e balance following s u l f o n a m i d e a d m i n i s t r a t i o n , since the urine b e c o m e s alkaline before a n i n c r e a s e in a i r e x c h a n g e is o b s e r v e d b y d i r e c t m e a s u r e m e n t . N e i t h e r of t h e c o n f l i c t i n g v i e w s w h i c h h a s b e e n o f f e r e d to e x p l a i n t h e t y p e of a l t e r a t i o n a n d t h e c a u s e of t h i s c h a n g e in t h e a c i d - b a s e b a l a n c e a f t e r s u l f a n i l a m i d e a d m i n i s t r a t i o n is a d e q u a t e , a n d i t is still o u r i m p r e s s i o n f r o m o u r . d a t a t h a t p r i m a r y h y p e r v e n t i l a t i o n from a direct r stimulation to respiration b y sulfanilamide plays an i m p o r t a n t ro~l~.
220
THE
JOURNAL
OF
PEDIATRICS
The use of sodium r-lactate in the t r e a t m e n t of acidosis in salicylate intoxication has been reported by Williams and P a n t i n g ~ to bring about r a p i d i m p r o v e m e n t in the clinical condition a n d by Shirreff and Pearlmall ~ to produce no startling results. The results of the t r e a t m e n t of the acidosis with sodium r-lactate in our cases is shown in Table II. The subject has been discussed in full by H a r t l n a n n and his co-workers s-in the case of R. C. which is included in this series and whose course d u r i n g t r e a t m e n t is shoran in Chart 1. As was pointed out b y H a r t m a n n and his associates, the expected rise in the carbon dioxide content of the serum did not occur with sodium r-lactate. However, as is also shown in Chart
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l=~esponse t o t r e a t m e n t of acidosis of salicylate intoxication who had received a saleyl compound accidentally.
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1 b y the curve of serum lactic acid following" the administration of sodium r-lactate, the lactate was n o r m a l l y metabolized. Because of this, and p a r t i c u l a r l y because the expected rise did not follow the intravenous administration of sodium bicarbonate either, it was. concluded t h a t the failure to correct the acidosis was duo to the fact t h a t the a m o u n t of alkali given w a s quantitatively insufficient to offset completely the basefinding effect of the ketone acids. Additional data obtained f r o m the b~ood and urine of case R. C. and the urines of cases P. B. and J. L. conf i r m the belief that the accumulation of ketone acids was unusuall$ per-
B A I ~ N E T T E T AL. :
SALICYLATE INTOXICATION
221
sistent and intense. Ketone acids were demonstrated in large amounts in the blood of the patient R. C., by the method previously mentioned, until Nov. 28, 1933, which, as can be seen from Chart 1, was three and one-half days9 after treatment was begun. The ketone acids persisted in the urine of this patient until Nov. 30, 1933, which was five days after the beginning of treatment. In the. cases of P. B. and J. L., ketone acids persisted for four and three days, respectively. Our data. fail to show evidence of significant nitrogen retention or lactic acid accumulation, so that the acidosis in these cases could not be explained on the basis of renal or cardiac failure. Acidosis, of the type described, due to intense ketosis was present in each of the five cases here reported, and the improvement in the clinical condition of the patients corresponded so closely with the correction of the acidosis9 t h a t we feel that this9 is the most important phase of treat~ ment. Although the earliest change in the acid-base balance is of the carbon dioxide deficit type of alkalosis, this change is :apparently quickly reversed by the development of ketosis, and a t r u e metabolic acidosis develops. In the case of R. C. the p H of the urine, as determined by indicators, rose f r o m about 5 during the acidosis before treatment was started to between 6 and 7 before the carbon dioxide content rose to no~'malP This would indicate that the p r i m a r y stimulation of respiration by the saliey, lares had persisted, since one v~ould have expected the u r i n a r y p i t to remain of maximum acidity un'cil the carbon dioxide content of the serum had become n o r m a l unless p r i m a r y hyperventilation was continuing. 9The ketosis was more intense and particularly more persistent than could be expected merely from starvation due to vomiting for such short periods, under normal circumstances. I t suggested the possibility that there may have been some specific inadequacy of carbohydrate metabolism. This suggestion was strengthened by :the fact that hypogl?]cemiat was actually observed to have occurred in the case shown in Chart 1. In view of the experimental work of Dodd and her co-workers 2 in which they showed an increase in the metabolic rate following salicylate administration, this would suggest that salieylates may specifically cause a rapid depletion in the glycogen reserve of the body. This glycogen depletion would be augmented by low carbohydrate intake d u e to poor appetite d u r i n g the illness f o r which the sa]ieylate is being given and to vomiting, and would allow ketosis to occur with inordinat e rapidity: This: .conception does not account for differences in the susceptibility of *A c a s e of s a l i e y l a t e i n t o x i c a t i o n r e c e n t l y s t u d i e d b y ]:)'ovals a t St. L o u i s 9 Hospital showed this strikingly. O n a d m i s s i o n , t h e p H o f t h e u r i n e w a s 4 . 5 and' the" b l o o d , c a r b o n d i o x i d e c o n t e n t w a s 3 6 v o l u m e s p e r cent. Three hours after the ~ d m i n i s t r a t i o n o f s o d i u m l a c t a t e t h e p a t i e n t Still s h o w e d m a r k e d h y p e r p n c a , b u t the,~urine: p i t - w a s 7 a n d r e m a i n e d t h e r e e v e n t h o u g h s e v e n a n d o n e - h a l f ~ h o u r s l a t e r t h e : c a r b o n :dioxide c o n t e n t of t h e s e r u m h a d r i s e n o n l y ' t o 44 voium~es" Per- cent; 9 9 ~ T h e - . : ~ r a l u e s h o w n in C h a r t : l a s 40 r a g . p e r c e n t f o r t h e b l o d d ~ d g ' a n is- i n ~ e r m s o f a p i ~ a r e n t blo'od s t i g a r ; a s i m u l t a n e o u s d e t e r m i n a t i o n of t r u e blood s u g a r w a s f o u n d to be 25 m g . p e r c e n t .
222
THE
JOURNAL
OF P E D I A T R I C S
patients to the original primary hyperventilation. It may explain, however, the sporadic occurrence of salieylate intoxication on the basis that susceptibility may depend on the adequacy of glycogen reserve when salieyl compounds are given. Dodd and her co-workers~ have emphasized the importance of treating dehydration and hyperpyrexia in cases of salicylate intoxication. Since neither of these findings was prominent in our cases, we should feel that the treatment of them becomes of secondary importance. On the basis of our observations, the most important phases in the prevention and treatment of salieylate intoxication would appear to be: 1. Avoidance of the therapeutic administration of quantities of salieyl compounds above the recommended dosage and the provision of adequate carbohydrate intake during the period of administration would appear to be most important in prevention. 2. Treatment of the acidosis with adequate amounts of alkali, repeated as often as necessary, would seem from our data to be the most important phase of treatment. Alkali can be safely and preferably given in the form of sodium r-lactate, ~ since it has been shown to be metabolized in the presence of salieylate intoxication. If it is not possible by frequent examinations of the carbon dioxide content of the serum to determine the amount required, it would have to be judged on clinical response, but one should be prepared to give many times the usual amount. I f the dehydration is very mild, one-third molar solutions of sodium r-lactate may be preferable to the usual one-sixth molar. 3. The administration of large quantities of carbohydrate seems indicated. Because of the frequent and severe vomiting, this is best given in the form of intravenous dextrose. The sodium lactate will also serve to supply available carbohydrate. 4. Steps 2 and 3 would also relieve dehydration and would hasten elimination of the drug. 5. Measures directed toward reduction of hyperpyrexia, if present, would be desirable, as suggested by Dodd and her co-workers. 6. Treatment of the infection for which the salicylates were given should not be neglected. SU]Y[MAR,Y
1. Five cases Of salicylate intoxication are presented. 2. In four of the five cases the intoxication occurred during thera, peutie administration of the salieyl compound. 3. Unusually large quantities of alkali may be required to correct the acidosis of saliey!ate intoxication because of the intense and persistent ketosis. 4 . The importance of glycogen depletion specifically associated with the increased metabolic activity due to salieylates in the development of ketosiS and acidosis is suggested, and the effect of this on prevention and treatment of the intoxication is discussed.
:BARNETT ET AL. :
SALICYLATE INTOXICATION
223
REFERENCEIS
L Odin, M.: Acta reed. Scandinav. 50 (Supp.): 177, 1932. 2. Dodd, K., Minor, A. S., and Arena, J. M.: Am. J. Dis. Child. 53: 1435, 1937. 3. Marriott, W. M., and Jeans, P. C. : I n f a n t l~utrition, St. Louis, ]941, The C. V. Mosby Company, p. 453. 4. /-Iartmann, A. E., Perley, A. M., and Barnett, It. L.: J. Clin. Investigation 17: 465, 1938. 5. Beckman, W. W., Rossmeisel, E. C., PettengiI, R. ]3., and Bauer, W. : J. Clin. Investigation 19: 635, 1940. 6. Williams, S. W., and Panting, R. M.: Brit. M. J. 1: 550, ]937. 7. Shirreff, W. T., and Pearlman, L. N.: Canad. M. A. J. 43: 264, ]940. 8. Doval, J. : Personal communication. 9. H a r t m a n n , A. 1% Perley, A. M., Basman, J., Nelson, M. V., and Asher, C.: J. PE1)IAT. 13: 692, 1938. 10. Hartmann, A. F.: Arch. Int. Med. 56: 413, 1935.
INTOXICATION
IN INFANTS
AND
CHILDREN
HENRY L. BAR.NETT,M.D., JOHN 1~. POWEI~S, 1V[.D., JOHN H. BENWARD, M.D., AND AL]~XIS F. HARTMANN, M.D. ST'. Lo.um, Mo~. T H E past eight years there have been seen at St. Louis Children's I NHospital five patients, in whom the diagnosis of salicy]ate poisoning was made. In four of the five cases the intoxication resulted from intensive therapeutic use of the salieylates, which, together with reports in the literature of similar poisonings, 1, 2 indicates the importance of the often repeated warning that the salicyl compounds are not always the harmless household remedy that they are supposed to be. The striking similarity of the clinical pictures in these five cases and the acuteness of the medical emergency which they presented aroused our interest in this subject. The paucity of recent clinical studies in the American pediatric literature prompted us to r e p o r t these cases and to discuss, the treatment which would seem to be indicated in view of our present knowledge concerning this intoxication. The p e r t i n e n t facts concerning the histories and findings of the cases presented are shown injTable I. Salic,ylate Ad~ninistratio,n.--In f o u r of the five cases, the symptoms of intoxication developed i during the therapeutic administration of salicylates. ~The quantities of salieylate taken by these f o u r cases, as shown in Table I, were estimated to be between 0.07 and 0.17 Gin. per kilogram per twenty-four hour% and the symptoms, usually occurred within twenty-four hours after the administration was begun. These figures for the amounts, taken were estimated from the histories, and therefore are not strictly reliable due to possible inaccuracies in the statements of the informants. The figures given in Table I refer to the minimum amount estimated. The usually recommended dose of aspirin during infancy is 1 gr. per year of age, 3 which would be approximately 0.04 Gin. per' kilogram per twenty-four hours if the dose were repeated every f o u r hours. The quantities apparently taken by these patients showing intoxication ran~ed from only two to four times the recommended dosage. I t would appear from ~his, as w e l l as from the fact that comparatively large dosages are, commonly given with no signs of intoxication, that factors in addition to the amount of salieylate ingested influence the occurrence of these symptoms. This will be discussed later. It is noteworthyl however, t h a t in only one of the cases was less than two times the recommended dosage given. F r o m th e D e p a r t m e n t of P e d i a t r i c s , ~ a s h i n g t o n a n d t h e St. L ouis Children's :[-Iospital. 214
U n i v e r s i t y School of ]Yiediclne,
BARNETT
ET
AL.
:
SALICYLATE
215
INTOXICATION
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q~HE JOURNAL OF PEDIATRICS
Clinica~ Picture.--The outstanding clinical manifestation in these cases was the intense hyperventiIation which, in all of them, suggested the severest type of acidosis. The presence of this hyperventilation in an infant or child who is not severely dehydrated, and in whose history is found none of the usual causes for acidosis, suggests salicylate intoxication. The diagnosis was tentatively m a d e in two of the f o u r cases receiving the drug therapeutically b e f o r e a n y l a b o r a t o r y data was: obtained, and in one of the f o u r cases on the a p p e a r a n c e of the child alone. De,hyd,ratio n of some degree was noted in every case, but it was usually mild. I t was frequently r e m a r k e d b y the first observer of the case t h a t the dehydration was not in proportion to t h e a p p a r e n t degree of acidosis, and in one case sodium r-lactate was given in a m o r e ' c o n c e n t r a t e d solution than usually employed because of t h e m i l d n e s s of the dehydration. gamiting had occurred in all but one case and was u s u a l l y severe. Stupor, associated with periods of irritability, was present i/t all:five cases. Ge~e,ralize,d co.n~ulsions occurred i n t w o cases. Cyanosis was observed in two of the cases. An acetone odor of: the expired air :was detected in three of the cases. One p a t i e n t complained of abdominal p,ain. I n three of the five cases the t e m p e r a t u r e was not significantly elevated. Fever was present on admission in two instances, but the infections for which the drugs were given were still present. Tinnitus was reported in only one case. Thirst and poly,vria were not mentioned in the histories obtained, possibly because of the age of the patients. Laborato,~ Fi~dings on A c~missio~.--The i m p o r t a n t laboratory findings on admission are included in Table I I . The values for the carbon dioxide content of the blood sera in the f o u r cases in which the salicyl compound was given therapeutically and in which the intoxication was well developed on admission varied f r o m 15.4 to 28.9 volumes per cent. I n one case, J. L., the p H Of the serum on admission was 7.34 at a time When the carbon dioxide content was 25 volumes p e r cent, the significance of which will be mentioned later. I n three of the cases in whicl~ serum nonprotein nitrogen determinations were done on admission, the values were 28, 35.2, and 45 rag. p e r cent. Blood sugar determinations on four of the five cases were within normal limits on admission. I n the ease of g . C. the distillate of the protein-free filtrate of the blood serum obtained by heating" before the addition of potassium p e r m a n g a n a t e in the determination of lactic acid gave a h e a v y cloud when caught in Scott-Wilson's reagent, which served as a qnalitative test of marked increase in blo~d acetone. I n e a c h o~..the eases, the urine was acid on admission and gave a strongly positive test o n addition of ferric chloride, which persisted a f t e r acidification and boiling. The tr test f o r acetone was strongly positive, and the distillate of the urine specimen f r o m R. C. gave a h e a v y cloud when tested with Scott-Wilson's reagent. In one case the u r i n a r y sediment showed no formed elements on microscopic examina-
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tion, a n d in the other f o u r only white blood cells were present in small numbers. I n one case, P. B., in. which a lumbar p u n c t u r e was done, the spinal fluid was crystal clelr, contained no increase in cells, gave a strongly positive test with f~l:riC chloride, and the carbon dioxide content was 19.5 volumes p e r C~nt (blood was 26.6 volumes per cent). DISCUSSION AND T R E A T M E N T
T r e a t m e n t of salicylate intoxication must be generally directed toward correction of the i m p o r t a n t changes, which have. taken place. A description of these changes and of the m e c h a n i s m involved in the production of them has been the subject of numerous investigations and must primarily consider the following factors : 1. The explanation for the intense hyperpnea, which is the outstanding clinical manifestation. 2. The failure to relieve the acidosis, when present, b y the administration of the usual quantity of alkali. 3. The occurrence of symptoms of intoxication in some patients who receive, quantities of salicyl compounds which are easily tolerated by other patients. The data obtained in our cases which relate to these factors can be presented in the following considerations. I n the only case (J. L.) in which a p H m e a s u r e m e n t of the serum was made, it was f o u n d to be 7.34 at a time when the carbon dioxide content of the serum was 25 volumes p e r cent. This corresponds to the t y p e of change in the acid-base balance observed in this l a b o r a t o r y 4 after the administration of large doses of sulfanilamide, ~ and suggests the: occurrence of a carbon dioxide deficit type of alkalosis produced by hyperventilation. The occurrence of p r i m a r y hyperventilation during salicylate administration has been observed by numerous investigators and has been attributed to direct central stimulation of the r e s p i r a t o r y center b y salicyl compounds. 2 and to the changes in t e m p e r a t u r e , the sensation of heat, and the increase in gaseous exchange induced b y the sa]icylates. 1 Whatever the direct cause of the stimulus to respiration, it seems well founded t h a t the intense h y p e r p n e a early in the course of sa!icylate intoxication is. due almost wholly to central stimulation of respiration since it m a y occur before a n y fall in the carbon dioxide content of the serum is observed. 2 L a t e r in the course of the intoxication, when acidosis .does develop, the effect of this specific central stimulation is added to the stimulation of respiration by the acidosis (see below) and the characteristic intense h y p e r p n e a is produced. * i t h a s b e e n s h o w n b y ] ~ e c k m a n a n d his c o - w o r k e r s 5 a n d c o n f i r m e d in t h i s l a b o r a t o r y t h a t p r i m a r y h y p e r v e n t i l a t t o n c a n n o t a c c o u n t f o r all of t h e c h a n g e s in a c i d - b a s e balance following s u l f o n a m i d e a d m i n i s t r a t i o n , since the urine b e c o m e s alkaline before a n i n c r e a s e in a i r e x c h a n g e is o b s e r v e d b y d i r e c t m e a s u r e m e n t . N e i t h e r of t h e c o n f l i c t i n g v i e w s w h i c h h a s b e e n o f f e r e d to e x p l a i n t h e t y p e of a l t e r a t i o n a n d t h e c a u s e of t h i s c h a n g e in t h e a c i d - b a s e b a l a n c e a f t e r s u l f a n i l a m i d e a d m i n i s t r a t i o n is a d e q u a t e , a n d i t is still o u r i m p r e s s i o n f r o m o u r . d a t a t h a t p r i m a r y h y p e r v e n t i l a t i o n from a direct r stimulation to respiration b y sulfanilamide plays an i m p o r t a n t ro~l~.
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The use of sodium r-lactate in the t r e a t m e n t of acidosis in salicylate intoxication has been reported by Williams and P a n t i n g ~ to bring about r a p i d i m p r o v e m e n t in the clinical condition a n d by Shirreff and Pearlmall ~ to produce no startling results. The results of the t r e a t m e n t of the acidosis with sodium r-lactate in our cases is shown in Table II. The subject has been discussed in full by H a r t l n a n n and his co-workers s-in the case of R. C. which is included in this series and whose course d u r i n g t r e a t m e n t is shoran in Chart 1. As was pointed out b y H a r t m a n n and his associates, the expected rise in the carbon dioxide content of the serum did not occur with sodium r-lactate. However, as is also shown in Chart
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1 b y the curve of serum lactic acid following" the administration of sodium r-lactate, the lactate was n o r m a l l y metabolized. Because of this, and p a r t i c u l a r l y because the expected rise did not follow the intravenous administration of sodium bicarbonate either, it was. concluded t h a t the failure to correct the acidosis was duo to the fact t h a t the a m o u n t of alkali given w a s quantitatively insufficient to offset completely the basefinding effect of the ketone acids. Additional data obtained f r o m the b~ood and urine of case R. C. and the urines of cases P. B. and J. L. conf i r m the belief that the accumulation of ketone acids was unusuall$ per-
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sistent and intense. Ketone acids were demonstrated in large amounts in the blood of the patient R. C., by the method previously mentioned, until Nov. 28, 1933, which, as can be seen from Chart 1, was three and one-half days9 after treatment was begun. The ketone acids persisted in the urine of this patient until Nov. 30, 1933, which was five days after the beginning of treatment. In the. cases of P. B. and J. L., ketone acids persisted for four and three days, respectively. Our data. fail to show evidence of significant nitrogen retention or lactic acid accumulation, so that the acidosis in these cases could not be explained on the basis of renal or cardiac failure. Acidosis, of the type described, due to intense ketosis was present in each of the five cases here reported, and the improvement in the clinical condition of the patients corresponded so closely with the correction of the acidosis9 t h a t we feel that this9 is the most important phase of treat~ ment. Although the earliest change in the acid-base balance is of the carbon dioxide deficit type of alkalosis, this change is :apparently quickly reversed by the development of ketosis, and a t r u e metabolic acidosis develops. In the case of R. C. the p H of the urine, as determined by indicators, rose f r o m about 5 during the acidosis before treatment was started to between 6 and 7 before the carbon dioxide content rose to no~'malP This would indicate that the p r i m a r y stimulation of respiration by the saliey, lares had persisted, since one v~ould have expected the u r i n a r y p i t to remain of maximum acidity un'cil the carbon dioxide content of the serum had become n o r m a l unless p r i m a r y hyperventilation was continuing. 9The ketosis was more intense and particularly more persistent than could be expected merely from starvation due to vomiting for such short periods, under normal circumstances. I t suggested the possibility that there may have been some specific inadequacy of carbohydrate metabolism. This suggestion was strengthened by :the fact that hypogl?]cemiat was actually observed to have occurred in the case shown in Chart 1. In view of the experimental work of Dodd and her co-workers 2 in which they showed an increase in the metabolic rate following salicylate administration, this would suggest that salieylates may specifically cause a rapid depletion in the glycogen reserve of the body. This glycogen depletion would be augmented by low carbohydrate intake d u e to poor appetite d u r i n g the illness f o r which the sa]ieylate is being given and to vomiting, and would allow ketosis to occur with inordinat e rapidity: This: .conception does not account for differences in the susceptibility of *A c a s e of s a l i e y l a t e i n t o x i c a t i o n r e c e n t l y s t u d i e d b y ]:)'ovals a t St. L o u i s 9 Hospital showed this strikingly. O n a d m i s s i o n , t h e p H o f t h e u r i n e w a s 4 . 5 and' the" b l o o d , c a r b o n d i o x i d e c o n t e n t w a s 3 6 v o l u m e s p e r cent. Three hours after the ~ d m i n i s t r a t i o n o f s o d i u m l a c t a t e t h e p a t i e n t Still s h o w e d m a r k e d h y p e r p n c a , b u t the,~urine: p i t - w a s 7 a n d r e m a i n e d t h e r e e v e n t h o u g h s e v e n a n d o n e - h a l f ~ h o u r s l a t e r t h e : c a r b o n :dioxide c o n t e n t of t h e s e r u m h a d r i s e n o n l y ' t o 44 voium~es" Per- cent; 9 9 ~ T h e - . : ~ r a l u e s h o w n in C h a r t : l a s 40 r a g . p e r c e n t f o r t h e b l o d d ~ d g ' a n is- i n ~ e r m s o f a p i ~ a r e n t blo'od s t i g a r ; a s i m u l t a n e o u s d e t e r m i n a t i o n of t r u e blood s u g a r w a s f o u n d to be 25 m g . p e r c e n t .
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patients to the original primary hyperventilation. It may explain, however, the sporadic occurrence of salieylate intoxication on the basis that susceptibility may depend on the adequacy of glycogen reserve when salieyl compounds are given. Dodd and her co-workers~ have emphasized the importance of treating dehydration and hyperpyrexia in cases of salicylate intoxication. Since neither of these findings was prominent in our cases, we should feel that the treatment of them becomes of secondary importance. On the basis of our observations, the most important phases in the prevention and treatment of salieylate intoxication would appear to be: 1. Avoidance of the therapeutic administration of quantities of salieyl compounds above the recommended dosage and the provision of adequate carbohydrate intake during the period of administration would appear to be most important in prevention. 2. Treatment of the acidosis with adequate amounts of alkali, repeated as often as necessary, would seem from our data to be the most important phase of treatment. Alkali can be safely and preferably given in the form of sodium r-lactate, ~ since it has been shown to be metabolized in the presence of salieylate intoxication. If it is not possible by frequent examinations of the carbon dioxide content of the serum to determine the amount required, it would have to be judged on clinical response, but one should be prepared to give many times the usual amount. I f the dehydration is very mild, one-third molar solutions of sodium r-lactate may be preferable to the usual one-sixth molar. 3. The administration of large quantities of carbohydrate seems indicated. Because of the frequent and severe vomiting, this is best given in the form of intravenous dextrose. The sodium lactate will also serve to supply available carbohydrate. 4. Steps 2 and 3 would also relieve dehydration and would hasten elimination of the drug. 5. Measures directed toward reduction of hyperpyrexia, if present, would be desirable, as suggested by Dodd and her co-workers. 6. Treatment of the infection for which the salicylates were given should not be neglected. SU]Y[MAR,Y
1. Five cases Of salicylate intoxication are presented. 2. In four of the five cases the intoxication occurred during thera, peutie administration of the salieyl compound. 3. Unusually large quantities of alkali may be required to correct the acidosis of saliey!ate intoxication because of the intense and persistent ketosis. 4 . The importance of glycogen depletion specifically associated with the increased metabolic activity due to salieylates in the development of ketosiS and acidosis is suggested, and the effect of this on prevention and treatment of the intoxication is discussed.
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REFERENCEIS
L Odin, M.: Acta reed. Scandinav. 50 (Supp.): 177, 1932. 2. Dodd, K., Minor, A. S., and Arena, J. M.: Am. J. Dis. Child. 53: 1435, 1937. 3. Marriott, W. M., and Jeans, P. C. : I n f a n t l~utrition, St. Louis, ]941, The C. V. Mosby Company, p. 453. 4. /-Iartmann, A. E., Perley, A. M., and Barnett, It. L.: J. Clin. Investigation 17: 465, 1938. 5. Beckman, W. W., Rossmeisel, E. C., PettengiI, R. ]3., and Bauer, W. : J. Clin. Investigation 19: 635, 1940. 6. Williams, S. W., and Panting, R. M.: Brit. M. J. 1: 550, ]937. 7. Shirreff, W. T., and Pearlman, L. N.: Canad. M. A. J. 43: 264, ]940. 8. Doval, J. : Personal communication. 9. H a r t m a n n , A. 1% Perley, A. M., Basman, J., Nelson, M. V., and Asher, C.: J. PE1)IAT. 13: 692, 1938. 10. Hartmann, A. F.: Arch. Int. Med. 56: 413, 1935.