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Suicidal overdoses with hypoglycemic agents
CASE REPORT
Suicidal Overdoses with Hypoglycemic Agents William F. Bobzien, Ul, MD Chapel Hill, North Carolina
Suicide attempts using hypoglycemic agents are uncommon but are associated with a high level of morbidity and mortality. Their recognition is sometimes difficult and the duration of hypoglycemic effect is often prolonged. Two cases that illustrate the difficulties encountered in recognition and therapy are described. Effective therapy depends on adequate glucose supplementation to maintain euglycemia. Therapeutic intervention often must be maintained for several days. Glucocorticoids may be useful in difficult cases. Other modes of therapy, including glucagon, are unproven or controversial. Bobzien WF II1: Suicidal overdoses with hypoglycemic agents. JACEP 8: 467-470, November 1979.
drug overdose, hypoglycemics
INTRODUCTION Despite the wide use and accessibility of i n s u l i n and the sulfonylureas, reports on i n t e n t i o n a l overdose with these agents are uncommon. M a r t i n 1 found 21 cases of suicidal i n s u l i n overdose i n a review of the l i t e r a t u r e and reported a n additional four cases of his own. Two other cases have been reported in the forensic literature. 2,3 The overall m o r t a l i t y in these reports is 27%. One p a t i e n t survived with neurologic disability. In a review of drug-induced hypoglycemia, Seltzer 4 found eight cases of attempted suicide with sulfonylureas. Five more cases have since been reported. ~-s Of these 13 patients, four died acutely and one suffered irreversible cerebral damage leading to death six m o n t h s later. These reports probably represent only a fraction of the actual n u m b e r of suicide attempts involving these agents. Two cases, with a discussion of problems related to recognition, pharmacqlogy, a n d t r e a t m e n t , are reported.
CASE REPORTS Case N u m b e r One. A n 18-year-old woman had been u n d e r a psychiatrist's care for depression. Three days prior to admission she slashed her wrists and was seen i n a n o t h e r emergency department. Her wrists were sutured, a n d she was referred to her psychiatrist. On the m o r n i n g of admission, she was found to be unresponsive. She was b r o u g h t to the emergency d e p a r t m e n t via ambulance. On arrival, her blood pressure was 155/70 m m Hg; pulse, 60 beats/min; respiration, 24/min; and t e m p e r a t u r e , 36.56 C (97.8 F.) Her s k i n was cool a n d dry. Pupils were dilated b u t equal a n d reactive to light. The p a t i e n t responded to deep pain with decerebrate posturing. No focal neurologic deficits were noted. Reflexes were hyperreactive and symmetrical; toe responses were flexor. There were multiple sutures in both wrists. The r e m a i n d e r of her e x a m i n a t i o n was normal. From the Department of Medicine, North Carolina Memorial Hospital, and the University of North Carolina, Chapel Hill, North Carolina. Address for reprints: William F. Bobzien, III, MD, Assistant Professor, Department of Medicine, The University of North Carolina at Chapel Hill, Box 2, Medical School Wing C 221H, Chapel Hill, North Carolina 27514. 8:11 (November) 1979
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Her parents, who accompanied her, indicated that promethazine HC1 (Phenergan) and diethylpropion (Tenuate) had been prescribed for her. She was also reported to have access to her mother's medications, which included a m i t r i p t y l i n e , diazepam, m e p r o b a m a t e , brompheniramine maleate (Dimetapp), and mazindol (Sanorex). Venous blood samples were obtained, an a r t e r i a l blood gas was drawn, and 5% dextrose and water was started intraven o u s l y (IV). A f t e r t h e a d m i n i s tration of 50 ml of 50% glucose, she immediately regained consciousness. At that time she told us t h a t approxi m a t e l y 48 hours e a r l i e r she h a d taken several tablets of tolbutamide t h a t h a d been p r e s c r i b e d for h e r diabetic father. There was no other history of drug ingestion. The initial blood glucose was 25 mg/100 ml. No other a b n o r m a l i t i e s were noted on h e r laboratory examination; a toxicologic screen of blood and urine was negative. One hour after admission she b e c a m e d i a p h o r e t i c and a g a i n responded to an infusion of 50 ml of 50% glucose. Over the next 24 hours she was fed orally and maintained on DsW IV. On the following morning, she was alert and asymptomatic with normal vital signs. A blood glucose was 103 mg/100 ml without any IV fluids running. She was discharged to her family's care with arrangements to see her psychiatrist. A subs e q u e n t r e p o r t from h e r f a m i l y physician indicated that there were no sequelae. Case N u m b e r Two. A 34-year-old woman, d i a b e t i c , was t r a n s f e r r e d from another hospital 12 hours after s e l f - a d m i n i s t r a t i o n of about 1,000 units of isophane insulin. She had been diabetic for seven years and had a long history of depression which had required several psychiatric admissions. On the p r e v i o u s evening, she had self-administered 10 injections of 100 units of isophane insulin. She made this known to her family and was immediately taken to a hospital. On arrival there, she was awake and alert. Urine glucose was 3+ and init i a l blood glucose was 230 mg/100 ml. She was treated with an infusion of DsW. Approximately eight hours l a t e r she b e c a m e s o m n o l e n t a n d diaphoretic. A blood glucose was 58 mg/100 ml. She was given 50 ml of 50% glucose and transferred. On a r r i v a l , her blood pressure was 110/70 mm Hg; p u l s e , 100 beats/min; respiration, 18/min; tem-
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perature, 36.89 C (98.4 F) (R). She was oriented but lethargic. Her skin was w a r m a n d dry. E x t r a o c u l a r m o v e m e n t s were sluggish and she had dysconjugate gaze. The gag reflex was absent. No other neurologic deficits were noted. Urine glucose was 2+ and concomitant blood glucose was 160 mg/100 ml. She was started on an IV solution of DloNS at 100 ml/hr and transferred to the intensive care unit. Eleven hours after arrival, the patient became increasingly somnolent and diaphoretic. The blood glucose at t h a t time was 60 mg/100 ml, and she responded to another infusion of 50 ml of 50% glucose. Despite feeding and continuous infusions of D~oW over the ensuing four days, she h a d r e p e a t e d episodes of hypoglyc e m i a r e q u i r i n g b o l u s e s of 50% glucose. Blood glucose on the morning.of her fourth hospital day was 36 mg/100 ml. On the fifth hospital day, her blood glucose stabilized at normal levels. On t h e sixth hospital day, she became hyperglycemic and glucose supplements were discontinued. On the seventh hospital day, small doses of insulin were required. Nine days after admission she was transferred to the psychiatric unit on her u s u a l i n s u l i n dose. She r e m a i n e d t h e r e for two months without evidence of neurologic sequelae.
DISCUSSION S y m p t o m a t i c h y p o g l y c e m i a is usually found in adults when blood glucose concentration falls below 40 mg/100 m l 2 Individual response to specific l e v e l s of blood glucose is quite variable, and rapid decline from hyperglycemia to normal blood glucose levels may also be associated with symptoms2 Prolonged hypoglycemia r o u t i n e l y leads to b e h a v i o r d i s t u r b a n c e s , seizures, coma, and death2, ~° The severity of sequelae is generally related to duration of the hypoglycemia. W h i l e suicidal overdoses with hypoglycemic agents are uncommon, the gravity of the sequelae and the availability of specific therapy make prompt recognition and intervention essential. Unfortunately, as in our case number one, the diagnosis may not be apparent. In this case, the patient's parents provided information that was incomplete and, therefore, m i s l e a d i n g . While evidence of increased sympathetic nervous system activity frequently accompanies hypoglycemia, its presence is not invariable. Case number one presented with dry skin and a pulse rate of 60.
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S i m i l a r findings have been described in other reports of sulfonylurea overdoses.5,1~-~3 Severe hypoglycemia can be mistaken for acute intracerebral disease, and focal neurologic deficits s e c o n d a r y to h y p o g l y c e m i a h a v e been reported.S, Ia-15 All these factors e m p h a s i z e t h e n e e d to p r e s u m e h y p o g l y c e m i a in a n y comatose patient until proven otherwise. Intravenous a d m i n i s t r a t i o n of 50 ml of 50% glucose will neither benefit nor h a r m patients with coma from other etiologies; its routine administration to a l l c o m a t o s e p a t i e n t s m a y be lifesaving to those with unsuspected hypoglycemia.
PHARMACOLOGY Insulin Most deliberate overdoses are rel a t e d to lon'g-acting i n s u l i n s : isophane, lente, and ultralente. Their duration of action varies from 13 to 36 hours, z° In spite of the massive doses of insulin often associated with d e l i b e r a t e overdoses, the degree of hypoglycemia induced is sometimes surprisingly mild. 1 The comparable efficacy of low-dose and high-dose insulin therapies for diabetic ketoacidosis suggests t h a t blood glucose response to high levels of plasma insulin m a y be l i m i t e d . TM Conversely, massive doses may substantially prolong their duration of action. 1 In case n u m b e r two, a blood glucose of 36 mg/100 ml was measured 80 hours after administration despite what we t h o u g h t was v i g o r o u s glucose therapy.
Sulfonylureas The sulfonylureas in use in the U n i t e d S t a t e s are: t o l b u t a m i d e (Orinase), acetohexamide (Dymelor), t o l a z a m i d e (Tolinase), a n d chlorp r o p a m i d e (Diabinese). A "second generation" sulfonylurea, glibenclamide, is available in Europe and the United Kingdom. Suicidal overdoses of all these agents except tolazamide have been described.4-s,1' Sulfonylureas act p r i m a r i l y by s t i m u l a t i n g pancreatic secretion of insulin, though the exact mechanism remains uncertain. In addition, they promote glycogen deposition in the liver and other tissues and inhibit release of glucose from the liver. 17 Response to these agents is gene r a l l y considered more q u a l i t a t i v e t h a n q u a n t i t a t i v e , ie, d e g r e e of h y p o g l y c e m i a is not n e c e s s a r i l y p r o p o r t i o n a l to dose administered, e s p e c i a l l y above t h e t h e r a p e u t i c r a n g e . 18 T h e r e is a m a r k e d indi-
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v i d u a l v a r i a t i o n in response even at low d o s a g e levels. A d v a n c i n g age, fasting, a n d r e n a l or h e p a t i c insufficiency are all k n o w n to predispose to h y p o g l y c e m i a in p a t i e n t s r e c e i v i n g t h e s e agents. 4 Tolbutamide has the shortest d u r a t i o n of action. I t h a s a s e r u m half-life of t h r e e to five hours and is m e t a b o l i z e d by t h e l i v e r to an inactive compound, carboxytolbutamide2°, ~v Tolazamide h a s a s i m i l a r s e r u m half-life, b u t some of its hepatic m e t a b o l i t e s r e t a i n h y p o g l y c e m i c activity, giving it a longer d u r a t i o n of action (up to 24 hours). ~7 C h l o r p r o p a m i d e is t h e drug most c o m m o n l y r e p o r t e d 4 in a c c i d e n t a l and suicidal hypoglycemia. It has the l o n g e s t s e r u m h a l f - l i f e (32 to 38 hours) and consequently the longest d u r a t i o n of action. 17 E a r l y r e p o r t s s u g g e s t e d t h a t it was e l i m i n a t e d exc l u s i v e l y b y t h e k i d n e y s . 19 Subsequently, it has been shown t h a t 80% of chlorpropamide is metabolized in the l i v e r by p a t h w a y s s i m i l a r to the o t h e r sulfonylureas, w h i l e 20% is exc r e t e d u n c h a n g e d in t h e u r i n e . 2° Renal insufficiency r e m a i n s an imp o r t a n t p r e d i s p o s i n g factor for prot r a c t e d hypoglycemia. 2~ The metabolism of g l i b e n c l a m i d e is s i m i l a r to t h a t of chlorpropamide. 2~ Acetohexamide has a short s e r u m h a l f - l i f e (1.6 h o u r s ) b u t is metabolized by the liver to an active compound, h y d r o x y h e x a m i d e . 22 This m e t a b o l i c p r o d u c t is e l i m i n a t e d by the kidneys, and r e n a l insufficiency has t h e s a m e i m p l i c a t i o n s for this d r u g as for c h l o r p r o p a m i d e . ~ A l l t h e s e a g e n t s a r e h i g h l y b o u n d to p l a s m a proteins, g e n e r a l l y in excess of 90%.23, 24 The b i g u a n i d e , phenform i n , is c o n s i d e r e d a n e u g l y c e m i c agent and has a negligible hypoglycemic p o t e n t i a l in the n o r m a l individual, t h o u g h r a r e cases of hypoglycemia h a v e been described. 4 P h e n formin is no longer a v a i l a b l e for use in the U n i t e d States. O t h e r drugs a r e known to h a v e hypoglycemic effects or the c a p a c i t y to p o t e n t i a t e t h e e f f e c t s of s u l fonylureas. The most i m p o r t a n t and common of t h e s e a g e n t s is e t h a n o l which, in addition to depleting liver glycogen stores, is a direct i n h i b i t o r of gluconeogenesis. 9 Salicylates have been r e p o r t e d to h a v e i n h e r e n t h y p o g l y c e m i c a c t i v i t y a n d to r a i s e blood levels and prolong the half-life of sulfonylureas.4, 21 Phenylbutazone, dicumerol, and certain a n t i b a c t e r i a l sulfonylureas m a y p o t e n t i a t e the hyPoglycemic effects of s u l f o n y l u r e a s , and p r o p r a n o l o l i n t e r f e r e s w i t h
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counter-regulatory mechanisms that respond to hypoglycemia.21,25, 2~ Conc o m i t a n t use of these agents, even in t h e r a p e u t i c doses, should a l e r t the p h y s i c i a n to expect more severe and prolonged hypoglycemia. In our cases, t h e r e a p p e a r e d to be a considerable delay between ingestion and the onset of severe hypoglycemia. This d e l a y h a s not been observed p r e v i o u s l y with t o l b u t a m i d e o v e r d o s e s b u t h a s been s e e n w i t h c h l o r p r o p a m i d e ingestions.% 2v The e x p l a n a t i o n for t h i s o b s e r v a t i o n is unclear. Physicians should be a w a r e t h a t the onset of s y m p t o m s following i n g e s t i o n m a y be delayed up to 24 h o u r s , 27 a n d p a t i e n t s s h o u l d be closely observed d u r i n g this period.
THERAPY The t h e r a p y for suicide a t t e m p t s with i n s u l i n or oral hypoglycemics is straightforward: adequate glucose a d m i n i s t r a t i o n to m a i n t a i n n o r m a l blood glucose levels. The pitfalls of therapy are insufficient glucose q u a n t i t i e s a n d p r e m a t u r e cessation of therapy. The oral hypoglycemics, w i t h the exception of tolazamide, are r a p i d l y absorbed from the gastroint e s t i n a l tract. ~7 Induction of emesis or g a s t r i c l a v a g e is of l i m i t e d usefulness but m a y be a t t e m p t e d if the pat i e n t is s e e n p r i o r to t h e o n s e t of hypoglycemic symptoms. The r o u t i n e a d m i n i s t r a t i o n of 50% glucose is r e c o m m e n d e d by us in all comatose patients. If a hypoglycemic overdose is suspected or confirmed, this should be followed by an infusion of DloW at a r a t e sufficient to m a i n t a i n blood glucose in excess of 100 mg/100 ml. W h e n the i n i t i a l response to glucose is unsatisfactory, t h e a d d i t i o n of glucocorticoids m a y be useful. TM T h e p a t i e n t s h o u l d be a d m i t t e d for close o b s e r v a t i o n . Rep e a t e d boluses of 50% glucose m a y be r e q u i r e d . T h e r a p y s h o u l d be continued until sustained euglycemia h a s been achieved. In retrospect, the d i s c h a r g e of t h e p a t i e n t in c a s e n u m b e r one was p r e m a t u r e . F o r t u n a t e l y , she did not h a v e r e c u r r e n t hypoglycemic symptoms. These patients are not candid a t e s for d i s c h a r g e fl'om t h e emerg e n c y d e p a r t m e n t . The onset of hypog l y c e m i a m a y be d e l a y e d and the dur a t i o n of h y p o g l y c e m i a protracted, esp e c i a l l y with chlorpropamide.~,7,27, 2s P h y s i c i a n s e n c o u n t e r i n g t h e s e pat i e n t s m u s t also be a t t u n e d to t h e factors t h a t m a y enhance the effect of t h e h y p o g l y c e m i c a g e n t , includi n g f a s t i n g , r e n a l or h e p a t i c insufficiency, and other drugs.
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The use of glucagon as an adj u n c t to t h e r a p y r e m a i n s controversial. Glucagon promotes the release of glucose from t h e liver and other sites of glycogen storage. 17 Its effect is limited in s t a t e s associated w i t h g l y c o g e n d e p l e t i o n , s u c h as prol o n g e d f a s t i n g , p r o l o n g e d hypoglycemia, and chronic ethanol ingestion. D a v i e s '2 r e c o m m e n d e d t h e r o u t i n e a d m i n i s t r a t i o n of glucagon with glucose in the t h e r a p y of s u l f o n y l u r e a overdoses. The response to glucagon, however, was noted to be v a r i a b l e in t h a t and in subsequent reports.6,s, 12 The exact role of glucagon and the n e c e s s i t y for its a d m i n i s t r a t i o n is u n c l e a r . F e w cases will fail to respond to glucose even when the addition of glucocorticoids is required. In addition, glucagon's ketogenic prope r t i e s m a k e it p o t e n t i a l l y h a z a r d ous. ~° While we would not g e n e r a l l y r e c o m m e n d t h e use of glucagon, it m a y be indicated in p a r t i c u l a r l y res i s t a n t cases. If glucagon is used, the u s u a l dose is 1 mg, a n d r e p e a t e d doses m a y be necessary27 T h e h i g h d e g r e e of a l b u m i n b i n d i n g of s u l f o n y l u r e a s w o u l d s u g g e s t dialysis is of limited usefulness. D i a l y s i s was u n s u c c e s s f u l in t h e only r e p o r t of its use in this setting. 2s Forced diuresis is also ineffective for the s a m e reasons, s There are no r e p o r t s o f t h e u s e of c h a r c o a l hemoperfusion in overdoses of hypoglycemic agents. The a l b u m i n binding of sulfonylureas m i g h t l i m i t this p r o c e d u r e as well. P l a s m a p h e r e s i s c o u l d b e e x p e c t e d to h a s t e n t h e e l i m i n a t i o n of s u l f o n y l u r e a s in sev e r e cases; h o w e v e r , t h e r e a r e no d a t a on this mode of t h e r a p y , and the t e c h n i q u e is often u n a v a i l a b l e . The u s e of c h a r c o a l h e m o p e r f u s i o n or p l a s m a p h e r e s i s r e m a i n s speculative a n d u n s u p p o r t e d at this time.
CONCLUSION Suicidal overdoses with hypoglycemic agents are uncommon and often difficult to recognize. E m e r g e n cy p h y s i c i a n s m u s t h a v e a high index of suspicion of h y p o g l y c e m i a in all comatose p a t i e n t s a n d when a hist o r y of d r u g ingestion is present. The hypoglycemia induced by these a g e n t s m a y be severe and prolonged. P r o m p t i n t e r v e n t i o n w i t h vigorous g l u c o s e t h e r a p y is m a n d a t o r y . T h e r a p y m u s t be c o n t i n u e d u n t i l s u s t a i n e d e u g l y c e m i a is a c h i e v e d . Glucocorticoids m a y be a useful adj u n c t to t h e r a p y . The use of glucagon a n d o t h e r modes of t h e r a p y a r e of u n c e r t a i n value at this time.
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REFERENCES 1. Martin FIR, Hansen N, Warne GL: Atempted suicide by insulin overdose in insulin requiring diabetics. Med J A u s t 1:58-60, 1977. 2. Sturner WQ, Putnam RS: Suicidal insulin poisoning with nine day survival: recovery in bile at autopsy by radioimmunoassay. J Forensic Sci 17:514-521, 1972. 3. Dickson SJ, Cairns ER, Blazey ND: The isolation and quantitation of insulin in postmortem specimens - - a case report. Forensic Sci 9:37-42, 1977. 4. Seltzer HS: Drug induced hypoglycemia - - a review based on 473 cases. Diabetes 21:955-966, 1972. 5. Kullavanijaya P: Recovery from overdose of glibenclamide. B r M e d J 4:53-54, 1970. 6. Forrest JAH: Chlorpropamide over~ dosages: delayed and prolonged hypoglycemia. Clin Toxicol 7:19-23, 1974. 7. Forman BH, Feeney E, Boas L: Drug induced hypoglycemia. J A M A 229:522, 1974. 8. Dowell RC, Imrie AH: Chlorpropamide poisoning in non-diabetics. Sco~ M e d J 17:305-309, 1972. 9. Baruh S, Sherman L, Kolodny HD, et al: Fasting hypoglycemia. Med Clin North A m 57:1441-1462, 1973. 10. Williams RH, Porte D Jr: The pan-
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creas, in Williams RH (ed): Textbook o[ Endocrinology. Philadelphia, W. B. Saunders Co, 1974, pp 591-597 and 627-659. 11. Cowen DL, Burtis B, Youmans J: Prolonged coma after acetohexamide ingestion. J A M A 201:155-156, 1967. 12. Davies DM, MacIntyre A, Millar EJ, et al: Need for glucagon in severe hypoglycemia induced by sulfonylurea drugs. Lancet 1:363-364, 1967. 13. Sillence DO, Court JM: Glibenclamide induced hypoglycemia. B r M e d J 3:490-491, 1975. 14. Rothfield EL: Severe hypoglycemia. Arch Int Med 115:468-469, 1965. 15. Dall JLC, Conway H, McAlpine SG: Hypoglycemia due to chlorpropamide. Scot Med J 12:403-404, 1967. 16. Soler NG, Wright AD, Fitzgerald MM, et al: Comparative study of different insulin regimens in m a n a g e m e n t of diabetic ketoacidosis. Lancet 2:1221-1224, 1975. 17. Larner J, Haynes RC Jr: Insulin and oral hypoglycemic drugs; glucagon, in Goodman LS, Gilman A (eds): The Pharmacologic B a s i s o f Therapeutics. New York, Macmillan Publishing Co, 1975, pp 150%1533. 18. Cosnett JE: Tolbutamide overdosage and irreversible cerebral damage. South A f r Med J 35:43-44, 1961. 19. Johnson PC, Hennes AR, Driscoll T, et al: Metabolic fate of chlorpropamide in
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man. A n n N Y Acad Sci 74:459-472, 1959.
20. Brotherton PM, Grieveson P, McMartin C: A study of the metabolic fate of chlorpropamide in man. Clin Pharmacol Therap 10-505-514, 1969. 21. Karam JH, Shaikh BM, Forsham PH: Antidiabetic .drugs after the university group diabetes program (UGDP). A n n Rev Pharmacol 15:351-366, 1975. 22. Galloway JA, McMahon RE, Culp HW, et al: Metabolism, blood levels and rate of ex cr et i o n of acetohexamide in h u m an subjects. D i a b e t e s 16:118-127, 1967. 23. Wishinsky H, Glasser EJ, Perkal S: Protein interactions of sulfonylurea compounds. Diabetes 2(suppl):18-25, 1962. 24. Judis J: Binding of sulfonylureas to serum albumin. J Pharmacol Sci 61:8993, 1972. 25. Hussar DA: The hypog|ycemic agents - - their interactions. J A m P h a r m Assoc NS10:619-624, 1970. 26. Hansten ED: Drug Interactions (3rd ed). Philadelphia, Lea and Febiger, 1975, pp 11-12 and 56-69. 27. Greenberg B, Weihl C, Hug G: Chlorpropamide poisoning. Pediatrics 41:145. 147, 1968. 28. Graw RG, Clarke RR: Chlorpropamide intoxication - - treatment with peri= toneal dialysis. Pediatrics 45:106-109, 1970.
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Suicidal Overdoses with Hypoglycemic Agents William F. Bobzien, Ul, MD Chapel Hill, North Carolina
Suicide attempts using hypoglycemic agents are uncommon but are associated with a high level of morbidity and mortality. Their recognition is sometimes difficult and the duration of hypoglycemic effect is often prolonged. Two cases that illustrate the difficulties encountered in recognition and therapy are described. Effective therapy depends on adequate glucose supplementation to maintain euglycemia. Therapeutic intervention often must be maintained for several days. Glucocorticoids may be useful in difficult cases. Other modes of therapy, including glucagon, are unproven or controversial. Bobzien WF II1: Suicidal overdoses with hypoglycemic agents. JACEP 8: 467-470, November 1979.
drug overdose, hypoglycemics
INTRODUCTION Despite the wide use and accessibility of i n s u l i n and the sulfonylureas, reports on i n t e n t i o n a l overdose with these agents are uncommon. M a r t i n 1 found 21 cases of suicidal i n s u l i n overdose i n a review of the l i t e r a t u r e and reported a n additional four cases of his own. Two other cases have been reported in the forensic literature. 2,3 The overall m o r t a l i t y in these reports is 27%. One p a t i e n t survived with neurologic disability. In a review of drug-induced hypoglycemia, Seltzer 4 found eight cases of attempted suicide with sulfonylureas. Five more cases have since been reported. ~-s Of these 13 patients, four died acutely and one suffered irreversible cerebral damage leading to death six m o n t h s later. These reports probably represent only a fraction of the actual n u m b e r of suicide attempts involving these agents. Two cases, with a discussion of problems related to recognition, pharmacqlogy, a n d t r e a t m e n t , are reported.
CASE REPORTS Case N u m b e r One. A n 18-year-old woman had been u n d e r a psychiatrist's care for depression. Three days prior to admission she slashed her wrists and was seen i n a n o t h e r emergency department. Her wrists were sutured, a n d she was referred to her psychiatrist. On the m o r n i n g of admission, she was found to be unresponsive. She was b r o u g h t to the emergency d e p a r t m e n t via ambulance. On arrival, her blood pressure was 155/70 m m Hg; pulse, 60 beats/min; respiration, 24/min; and t e m p e r a t u r e , 36.56 C (97.8 F.) Her s k i n was cool a n d dry. Pupils were dilated b u t equal a n d reactive to light. The p a t i e n t responded to deep pain with decerebrate posturing. No focal neurologic deficits were noted. Reflexes were hyperreactive and symmetrical; toe responses were flexor. There were multiple sutures in both wrists. The r e m a i n d e r of her e x a m i n a t i o n was normal. From the Department of Medicine, North Carolina Memorial Hospital, and the University of North Carolina, Chapel Hill, North Carolina. Address for reprints: William F. Bobzien, III, MD, Assistant Professor, Department of Medicine, The University of North Carolina at Chapel Hill, Box 2, Medical School Wing C 221H, Chapel Hill, North Carolina 27514. 8:11 (November) 1979
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Her parents, who accompanied her, indicated that promethazine HC1 (Phenergan) and diethylpropion (Tenuate) had been prescribed for her. She was also reported to have access to her mother's medications, which included a m i t r i p t y l i n e , diazepam, m e p r o b a m a t e , brompheniramine maleate (Dimetapp), and mazindol (Sanorex). Venous blood samples were obtained, an a r t e r i a l blood gas was drawn, and 5% dextrose and water was started intraven o u s l y (IV). A f t e r t h e a d m i n i s tration of 50 ml of 50% glucose, she immediately regained consciousness. At that time she told us t h a t approxi m a t e l y 48 hours e a r l i e r she h a d taken several tablets of tolbutamide t h a t h a d been p r e s c r i b e d for h e r diabetic father. There was no other history of drug ingestion. The initial blood glucose was 25 mg/100 ml. No other a b n o r m a l i t i e s were noted on h e r laboratory examination; a toxicologic screen of blood and urine was negative. One hour after admission she b e c a m e d i a p h o r e t i c and a g a i n responded to an infusion of 50 ml of 50% glucose. Over the next 24 hours she was fed orally and maintained on DsW IV. On the following morning, she was alert and asymptomatic with normal vital signs. A blood glucose was 103 mg/100 ml without any IV fluids running. She was discharged to her family's care with arrangements to see her psychiatrist. A subs e q u e n t r e p o r t from h e r f a m i l y physician indicated that there were no sequelae. Case N u m b e r Two. A 34-year-old woman, d i a b e t i c , was t r a n s f e r r e d from another hospital 12 hours after s e l f - a d m i n i s t r a t i o n of about 1,000 units of isophane insulin. She had been diabetic for seven years and had a long history of depression which had required several psychiatric admissions. On the p r e v i o u s evening, she had self-administered 10 injections of 100 units of isophane insulin. She made this known to her family and was immediately taken to a hospital. On arrival there, she was awake and alert. Urine glucose was 3+ and init i a l blood glucose was 230 mg/100 ml. She was treated with an infusion of DsW. Approximately eight hours l a t e r she b e c a m e s o m n o l e n t a n d diaphoretic. A blood glucose was 58 mg/100 ml. She was given 50 ml of 50% glucose and transferred. On a r r i v a l , her blood pressure was 110/70 mm Hg; p u l s e , 100 beats/min; respiration, 18/min; tem-
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perature, 36.89 C (98.4 F) (R). She was oriented but lethargic. Her skin was w a r m a n d dry. E x t r a o c u l a r m o v e m e n t s were sluggish and she had dysconjugate gaze. The gag reflex was absent. No other neurologic deficits were noted. Urine glucose was 2+ and concomitant blood glucose was 160 mg/100 ml. She was started on an IV solution of DloNS at 100 ml/hr and transferred to the intensive care unit. Eleven hours after arrival, the patient became increasingly somnolent and diaphoretic. The blood glucose at t h a t time was 60 mg/100 ml, and she responded to another infusion of 50 ml of 50% glucose. Despite feeding and continuous infusions of D~oW over the ensuing four days, she h a d r e p e a t e d episodes of hypoglyc e m i a r e q u i r i n g b o l u s e s of 50% glucose. Blood glucose on the morning.of her fourth hospital day was 36 mg/100 ml. On the fifth hospital day, her blood glucose stabilized at normal levels. On t h e sixth hospital day, she became hyperglycemic and glucose supplements were discontinued. On the seventh hospital day, small doses of insulin were required. Nine days after admission she was transferred to the psychiatric unit on her u s u a l i n s u l i n dose. She r e m a i n e d t h e r e for two months without evidence of neurologic sequelae.
DISCUSSION S y m p t o m a t i c h y p o g l y c e m i a is usually found in adults when blood glucose concentration falls below 40 mg/100 m l 2 Individual response to specific l e v e l s of blood glucose is quite variable, and rapid decline from hyperglycemia to normal blood glucose levels may also be associated with symptoms2 Prolonged hypoglycemia r o u t i n e l y leads to b e h a v i o r d i s t u r b a n c e s , seizures, coma, and death2, ~° The severity of sequelae is generally related to duration of the hypoglycemia. W h i l e suicidal overdoses with hypoglycemic agents are uncommon, the gravity of the sequelae and the availability of specific therapy make prompt recognition and intervention essential. Unfortunately, as in our case number one, the diagnosis may not be apparent. In this case, the patient's parents provided information that was incomplete and, therefore, m i s l e a d i n g . While evidence of increased sympathetic nervous system activity frequently accompanies hypoglycemia, its presence is not invariable. Case number one presented with dry skin and a pulse rate of 60.
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S i m i l a r findings have been described in other reports of sulfonylurea overdoses.5,1~-~3 Severe hypoglycemia can be mistaken for acute intracerebral disease, and focal neurologic deficits s e c o n d a r y to h y p o g l y c e m i a h a v e been reported.S, Ia-15 All these factors e m p h a s i z e t h e n e e d to p r e s u m e h y p o g l y c e m i a in a n y comatose patient until proven otherwise. Intravenous a d m i n i s t r a t i o n of 50 ml of 50% glucose will neither benefit nor h a r m patients with coma from other etiologies; its routine administration to a l l c o m a t o s e p a t i e n t s m a y be lifesaving to those with unsuspected hypoglycemia.
PHARMACOLOGY Insulin Most deliberate overdoses are rel a t e d to lon'g-acting i n s u l i n s : isophane, lente, and ultralente. Their duration of action varies from 13 to 36 hours, z° In spite of the massive doses of insulin often associated with d e l i b e r a t e overdoses, the degree of hypoglycemia induced is sometimes surprisingly mild. 1 The comparable efficacy of low-dose and high-dose insulin therapies for diabetic ketoacidosis suggests t h a t blood glucose response to high levels of plasma insulin m a y be l i m i t e d . TM Conversely, massive doses may substantially prolong their duration of action. 1 In case n u m b e r two, a blood glucose of 36 mg/100 ml was measured 80 hours after administration despite what we t h o u g h t was v i g o r o u s glucose therapy.
Sulfonylureas The sulfonylureas in use in the U n i t e d S t a t e s are: t o l b u t a m i d e (Orinase), acetohexamide (Dymelor), t o l a z a m i d e (Tolinase), a n d chlorp r o p a m i d e (Diabinese). A "second generation" sulfonylurea, glibenclamide, is available in Europe and the United Kingdom. Suicidal overdoses of all these agents except tolazamide have been described.4-s,1' Sulfonylureas act p r i m a r i l y by s t i m u l a t i n g pancreatic secretion of insulin, though the exact mechanism remains uncertain. In addition, they promote glycogen deposition in the liver and other tissues and inhibit release of glucose from the liver. 17 Response to these agents is gene r a l l y considered more q u a l i t a t i v e t h a n q u a n t i t a t i v e , ie, d e g r e e of h y p o g l y c e m i a is not n e c e s s a r i l y p r o p o r t i o n a l to dose administered, e s p e c i a l l y above t h e t h e r a p e u t i c r a n g e . 18 T h e r e is a m a r k e d indi-
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v i d u a l v a r i a t i o n in response even at low d o s a g e levels. A d v a n c i n g age, fasting, a n d r e n a l or h e p a t i c insufficiency are all k n o w n to predispose to h y p o g l y c e m i a in p a t i e n t s r e c e i v i n g t h e s e agents. 4 Tolbutamide has the shortest d u r a t i o n of action. I t h a s a s e r u m half-life of t h r e e to five hours and is m e t a b o l i z e d by t h e l i v e r to an inactive compound, carboxytolbutamide2°, ~v Tolazamide h a s a s i m i l a r s e r u m half-life, b u t some of its hepatic m e t a b o l i t e s r e t a i n h y p o g l y c e m i c activity, giving it a longer d u r a t i o n of action (up to 24 hours). ~7 C h l o r p r o p a m i d e is t h e drug most c o m m o n l y r e p o r t e d 4 in a c c i d e n t a l and suicidal hypoglycemia. It has the l o n g e s t s e r u m h a l f - l i f e (32 to 38 hours) and consequently the longest d u r a t i o n of action. 17 E a r l y r e p o r t s s u g g e s t e d t h a t it was e l i m i n a t e d exc l u s i v e l y b y t h e k i d n e y s . 19 Subsequently, it has been shown t h a t 80% of chlorpropamide is metabolized in the l i v e r by p a t h w a y s s i m i l a r to the o t h e r sulfonylureas, w h i l e 20% is exc r e t e d u n c h a n g e d in t h e u r i n e . 2° Renal insufficiency r e m a i n s an imp o r t a n t p r e d i s p o s i n g factor for prot r a c t e d hypoglycemia. 2~ The metabolism of g l i b e n c l a m i d e is s i m i l a r to t h a t of chlorpropamide. 2~ Acetohexamide has a short s e r u m h a l f - l i f e (1.6 h o u r s ) b u t is metabolized by the liver to an active compound, h y d r o x y h e x a m i d e . 22 This m e t a b o l i c p r o d u c t is e l i m i n a t e d by the kidneys, and r e n a l insufficiency has t h e s a m e i m p l i c a t i o n s for this d r u g as for c h l o r p r o p a m i d e . ~ A l l t h e s e a g e n t s a r e h i g h l y b o u n d to p l a s m a proteins, g e n e r a l l y in excess of 90%.23, 24 The b i g u a n i d e , phenform i n , is c o n s i d e r e d a n e u g l y c e m i c agent and has a negligible hypoglycemic p o t e n t i a l in the n o r m a l individual, t h o u g h r a r e cases of hypoglycemia h a v e been described. 4 P h e n formin is no longer a v a i l a b l e for use in the U n i t e d States. O t h e r drugs a r e known to h a v e hypoglycemic effects or the c a p a c i t y to p o t e n t i a t e t h e e f f e c t s of s u l fonylureas. The most i m p o r t a n t and common of t h e s e a g e n t s is e t h a n o l which, in addition to depleting liver glycogen stores, is a direct i n h i b i t o r of gluconeogenesis. 9 Salicylates have been r e p o r t e d to h a v e i n h e r e n t h y p o g l y c e m i c a c t i v i t y a n d to r a i s e blood levels and prolong the half-life of sulfonylureas.4, 21 Phenylbutazone, dicumerol, and certain a n t i b a c t e r i a l sulfonylureas m a y p o t e n t i a t e the hyPoglycemic effects of s u l f o n y l u r e a s , and p r o p r a n o l o l i n t e r f e r e s w i t h
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counter-regulatory mechanisms that respond to hypoglycemia.21,25, 2~ Conc o m i t a n t use of these agents, even in t h e r a p e u t i c doses, should a l e r t the p h y s i c i a n to expect more severe and prolonged hypoglycemia. In our cases, t h e r e a p p e a r e d to be a considerable delay between ingestion and the onset of severe hypoglycemia. This d e l a y h a s not been observed p r e v i o u s l y with t o l b u t a m i d e o v e r d o s e s b u t h a s been s e e n w i t h c h l o r p r o p a m i d e ingestions.% 2v The e x p l a n a t i o n for t h i s o b s e r v a t i o n is unclear. Physicians should be a w a r e t h a t the onset of s y m p t o m s following i n g e s t i o n m a y be delayed up to 24 h o u r s , 27 a n d p a t i e n t s s h o u l d be closely observed d u r i n g this period.
THERAPY The t h e r a p y for suicide a t t e m p t s with i n s u l i n or oral hypoglycemics is straightforward: adequate glucose a d m i n i s t r a t i o n to m a i n t a i n n o r m a l blood glucose levels. The pitfalls of therapy are insufficient glucose q u a n t i t i e s a n d p r e m a t u r e cessation of therapy. The oral hypoglycemics, w i t h the exception of tolazamide, are r a p i d l y absorbed from the gastroint e s t i n a l tract. ~7 Induction of emesis or g a s t r i c l a v a g e is of l i m i t e d usefulness but m a y be a t t e m p t e d if the pat i e n t is s e e n p r i o r to t h e o n s e t of hypoglycemic symptoms. The r o u t i n e a d m i n i s t r a t i o n of 50% glucose is r e c o m m e n d e d by us in all comatose patients. If a hypoglycemic overdose is suspected or confirmed, this should be followed by an infusion of DloW at a r a t e sufficient to m a i n t a i n blood glucose in excess of 100 mg/100 ml. W h e n the i n i t i a l response to glucose is unsatisfactory, t h e a d d i t i o n of glucocorticoids m a y be useful. TM T h e p a t i e n t s h o u l d be a d m i t t e d for close o b s e r v a t i o n . Rep e a t e d boluses of 50% glucose m a y be r e q u i r e d . T h e r a p y s h o u l d be continued until sustained euglycemia h a s been achieved. In retrospect, the d i s c h a r g e of t h e p a t i e n t in c a s e n u m b e r one was p r e m a t u r e . F o r t u n a t e l y , she did not h a v e r e c u r r e n t hypoglycemic symptoms. These patients are not candid a t e s for d i s c h a r g e fl'om t h e emerg e n c y d e p a r t m e n t . The onset of hypog l y c e m i a m a y be d e l a y e d and the dur a t i o n of h y p o g l y c e m i a protracted, esp e c i a l l y with chlorpropamide.~,7,27, 2s P h y s i c i a n s e n c o u n t e r i n g t h e s e pat i e n t s m u s t also be a t t u n e d to t h e factors t h a t m a y enhance the effect of t h e h y p o g l y c e m i c a g e n t , includi n g f a s t i n g , r e n a l or h e p a t i c insufficiency, and other drugs.
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The use of glucagon as an adj u n c t to t h e r a p y r e m a i n s controversial. Glucagon promotes the release of glucose from t h e liver and other sites of glycogen storage. 17 Its effect is limited in s t a t e s associated w i t h g l y c o g e n d e p l e t i o n , s u c h as prol o n g e d f a s t i n g , p r o l o n g e d hypoglycemia, and chronic ethanol ingestion. D a v i e s '2 r e c o m m e n d e d t h e r o u t i n e a d m i n i s t r a t i o n of glucagon with glucose in the t h e r a p y of s u l f o n y l u r e a overdoses. The response to glucagon, however, was noted to be v a r i a b l e in t h a t and in subsequent reports.6,s, 12 The exact role of glucagon and the n e c e s s i t y for its a d m i n i s t r a t i o n is u n c l e a r . F e w cases will fail to respond to glucose even when the addition of glucocorticoids is required. In addition, glucagon's ketogenic prope r t i e s m a k e it p o t e n t i a l l y h a z a r d ous. ~° While we would not g e n e r a l l y r e c o m m e n d t h e use of glucagon, it m a y be indicated in p a r t i c u l a r l y res i s t a n t cases. If glucagon is used, the u s u a l dose is 1 mg, a n d r e p e a t e d doses m a y be necessary27 T h e h i g h d e g r e e of a l b u m i n b i n d i n g of s u l f o n y l u r e a s w o u l d s u g g e s t dialysis is of limited usefulness. D i a l y s i s was u n s u c c e s s f u l in t h e only r e p o r t of its use in this setting. 2s Forced diuresis is also ineffective for the s a m e reasons, s There are no r e p o r t s o f t h e u s e of c h a r c o a l hemoperfusion in overdoses of hypoglycemic agents. The a l b u m i n binding of sulfonylureas m i g h t l i m i t this p r o c e d u r e as well. P l a s m a p h e r e s i s c o u l d b e e x p e c t e d to h a s t e n t h e e l i m i n a t i o n of s u l f o n y l u r e a s in sev e r e cases; h o w e v e r , t h e r e a r e no d a t a on this mode of t h e r a p y , and the t e c h n i q u e is often u n a v a i l a b l e . The u s e of c h a r c o a l h e m o p e r f u s i o n or p l a s m a p h e r e s i s r e m a i n s speculative a n d u n s u p p o r t e d at this time.
CONCLUSION Suicidal overdoses with hypoglycemic agents are uncommon and often difficult to recognize. E m e r g e n cy p h y s i c i a n s m u s t h a v e a high index of suspicion of h y p o g l y c e m i a in all comatose p a t i e n t s a n d when a hist o r y of d r u g ingestion is present. The hypoglycemia induced by these a g e n t s m a y be severe and prolonged. P r o m p t i n t e r v e n t i o n w i t h vigorous g l u c o s e t h e r a p y is m a n d a t o r y . T h e r a p y m u s t be c o n t i n u e d u n t i l s u s t a i n e d e u g l y c e m i a is a c h i e v e d . Glucocorticoids m a y be a useful adj u n c t to t h e r a p y . The use of glucagon a n d o t h e r modes of t h e r a p y a r e of u n c e r t a i n value at this time.
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20. Brotherton PM, Grieveson P, McMartin C: A study of the metabolic fate of chlorpropamide in man. Clin Pharmacol Therap 10-505-514, 1969. 21. Karam JH, Shaikh BM, Forsham PH: Antidiabetic .drugs after the university group diabetes program (UGDP). A n n Rev Pharmacol 15:351-366, 1975. 22. Galloway JA, McMahon RE, Culp HW, et al: Metabolism, blood levels and rate of ex cr et i o n of acetohexamide in h u m an subjects. D i a b e t e s 16:118-127, 1967. 23. Wishinsky H, Glasser EJ, Perkal S: Protein interactions of sulfonylurea compounds. Diabetes 2(suppl):18-25, 1962. 24. Judis J: Binding of sulfonylureas to serum albumin. J Pharmacol Sci 61:8993, 1972. 25. Hussar DA: The hypog|ycemic agents - - their interactions. J A m P h a r m Assoc NS10:619-624, 1970. 26. Hansten ED: Drug Interactions (3rd ed). Philadelphia, Lea and Febiger, 1975, pp 11-12 and 56-69. 27. Greenberg B, Weihl C, Hug G: Chlorpropamide poisoning. Pediatrics 41:145. 147, 1968. 28. Graw RG, Clarke RR: Chlorpropamide intoxication - - treatment with peri= toneal dialysis. Pediatrics 45:106-109, 1970.
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