Fatal overdose from a sustained-release theophylline preparation

CASE REPORT drug, overdose, theophylline; theophylline, overdose, treatment

Fatal Overdose from a Sustained.Release Theophylline Preparation A 26-year-old woman ingested approximately 9 g of theophylline (Theodur®). She exhibited agitation, generalized seizures, hyperglycemia, hypokalemia, hypomagnesemia, hypophosphatemia, and diuresis. Later in her hospital course rhabdomyolysis, myoglobinuria, and acute renal failure occurred. Hemodialysis was performed to correct electrolyte imbalance. She subsequently died of intractable shock and hyperkalemia. This case illustrates the metabolic abnormalities which m a y occur with severe the. ophylline intoxication. [Robertson NJ: Fatal overdose from a sustainedrelease theophylline preparation. Ann Emerg Med February 1985;14:154158.] INTRODUCTION Theophylline is one of the most commonly prescribed medications available today for treatment of asthma. With the addition of sustained release preparations to our armamentarium (Table 1), there are additional therapeutic successesJ Due to prolongea absorption properties and increases in prescribing patterns, these products also provide an increased likelihood for morbidity and mortality when acute ingestions occur, according to a conversation with Michael Smith of Pharmaceutical Data Services, Scottsdale, Arizona {May 5, 1984). The following case represents such a situation.

Nancy J Robertson, PharmD Denver, Colorado From the University of Colorado School of Pharmacy, Denver, Colorado. Received for publication April 19, 1984. Revision received May 24, 1984. Accepted for publication July 30, 1984. Address for reprints: Nancy J Robertson, PharmD, Assistant Professor of Clinical Pharmacy, University of Colorado Health Sciences Center, Box C-238, 4200 East Ninth Avenue, Denver, Colorado 80262.

CASE REPORT A 26-year-old woman was brought to the emergency department at 6:30 PM after ingesting 30 Theodur ® tablets, 300 mg, earlier that afternoon. Her blood pressure was 130/100 m m Hg; heart rate, 100/rain; and respirations, 24/min. She was given ipecac syrup with subsequent vomiting, but. no pill fragments were recovered. The patient was admitted to the ICU after one hour. Further history revealed increased domestic tension and an observed change in her behavior at approximately 5:45 PM. She had the usual childhood illnesses and an episode of pneumonia in 1978. She also had a single asthmatic attack in 1980 for which she had received Theodur ®. She continued to take this product intermittently. Her history also included prior treatment for depression with tricyclic antidepressants, although she denied ingestion of these agents on the day of admission. Physical examination revealed an agitated and vomiting woman in moderate distress. She was oriented to person, place, and time. The remainder of her physical examination was normal except for sinus tachycardia. An intravenous line of dextrose 5% with V2normal saline, 125 mL/h, was inserted, a cardiac monitor was placed, and activated charcoal and magnesium citrate were administered through a nasogastric tube. Diarrhea occurred subsequently. She experienced generalized tonic/clonic seizure activity five hours after admission. The seizure activity continued for 50 minutes and was unresponsive to 1 g phenytoin IV and 60 mg diazepam W. The patient was intubated with difficulty due to continued seizure activity. She received 390 mg phenobarbital IV, and seizures finally dissipated after 100 mg thiopental IV. Sinus bradycardia developed and progressed tO asystole. Cardiopulmonary resuscitation was initiated, and the patient regained a sinus rhythm after administration of 25 mL/h dextrose 5% with V2 normal saline, 125, 250, and 200

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mL/h over several hours; dextrose 5% with lactated Ringer's solution, 1 mg epinephrine, 0.5 mg atropine, norepinephrine (no dosage indicated), and 10 to 20 mg/kg/h dopamine. A blood pressure of 60 to 80 m m Hg by palpation was maintained only with continued use of d0pamine, which was tapered over the next three hours. Further seizure a c t i v i t y t h a t responded tO IV thiopental occurred 12 hours postadmission. The patient was acidotic {pH, 6.94; PO 2 >100; PCOz, 57) and hyperthermic (39.6 C) at this time. Her blood pressure was maintained at 70 to 80 mm Hg with a fluid challenge of 500 mL dextrose 5% with Y2 normal saline with 20 mEq KC1, and four amps of Sodium bicarbonate were given to restore a normal pH. Serum theophylline level on admission was 56 ~g/mL. A second sample obtained eight hours after admission was > 200 I~g/mL. Discussions with the local poison center indicated that she might be a candidate for charcoal h e m o p e r f u s i o n . Seventeen hours postadmission the patient was transferred to the referral hospital for evaluation. On arrival at the referral hospital she was variably responsive to pain and loud verbal stimuli. Her blood pressure was 85/40 mm Hg on a dopamine infusion. Physical examination showed little change except for the absence of bowel sounds, occasional h o r i z o n t a l n y s t a g m u s , and conjunctival edema. She had no myoclonus or pathologic reflexes. Admission laboratory data at the referral hospital were as follows: pH, 7.38; PO2, 177; PCO2, 22; bicarbonate, 13; Na, 152 mEq/L; K, 2.1 mEq/L; C1, 122 mEq/L; CO2, cp 19 mEq/L; Ca, 7.3 mg/dL; Phos, 0.5 mg/dL; Mg, 1.2 mEq/ L; BUN, 16 mg/dL; glucose, 626 mg/ dL; creatinine, 1.9 mg/dL; CPK, 3,739 IU/L; WBC, 26,000; and Hgb, 11.7. The theophylline level fell from 158.2 #g/mL 18 hours after admission to 105.6 #g/mL 22 hours after admission. Charcoal hemoperfusion was not performed due to the absence of seizure activity, decreasing theophylline levels~ and electrolyte disturbances. A drug screen done on admission confirmed that the patient had received phenobarbital, phenytoin, and acetaminophen therapeutically and it also showed caffeine. It failed to show evidence of tricyclic antidepressants or other toxins. Her urine output remained approx120/155

TABLE 1. Available forms of theophylline

Generic Name Theophylline

Trade N a m e Immediate Release

Trade Name - Sustained Release

Aerolate Aquaphyllin Bronkodyl

Aerolate

Elixophyllin Elixicon

Bronkodyl SR Constant T Elixophyllin SR LaBID

Lanophyllon Quibron T Slophyllin SomophyHin T

Theoclear Theolair Theon Theophyl

Lod rane Quibron T SR Respbid Slophyllin Gyrocaps SIobid Gyrocaps Somophyllin CRT Sustaire Theobid duracaps Theobron SR Theoclear LA Cenules Theodur Theolair SR Theophyl SR Theospan SR

Theostat Theovent Aminophylline (theophylline ethylenediamine)

Amoline Lixaminol Somophyllin Truphylline Aminodur Phyllocontin

Oxtriphylline (choline theophyllinate) Theophylline sodium glycinate

Choledyl Synophylate

imately 2,000 mL per hour. She received 1/2 normal saline to match her urine output plus Y2 normal saline with 80 mEq/L potassium phosphate at 250 mL per hour; magnesium sulfate, 2 g IV; and 1 g calcium chloride IV. Three to 15 units of insulin were given intravenously over the next three days to control her serum glucose, which was as high as 800 mg/dL. Activated charcoal was withheld due to the absence of bowel sounds. Approximately 28 hours postadmission the patient's urine output decreased. Despite a fluid challenge and removal of potassium from her IV fluidsi she became anuric and her serum potassium rose to 8.1 mEq/L. Blood gases were as follows: pH, 7.41; POz, 89; PCO2, 23; and bicarbonate, 14. Seven grams of intravenous calcium was administered until emergency hemodialysis could be initiated. Her serum theophylline level was 80.9 Annals of Emergency Medicine

~g/mL prior to hemodialysis and 58.4 ~g/mL one hour after hemodialysis. A Swan-Ganz catheter was placed to evaluate fluid status. Measurements revealed a pulmonary capillary wedge pressure of 18 to 20 m m Hg and a cardiac output of 5.2 L/min. She began spiking temperatures to 38.9 C rectally. Cultures of blood and sputum were obtained because aspiration pneumonia was suspected. Gram stain Of the sputum revealed Gram-positive diplococci for which treatment with penicillin G arid tobramycin in the following doses was initiated: loading dose of 60 mg post dialysis; 75 mg postdialysis; loading dose of 60 mg; 25 mg by IV every eight hours until patient's death. The patient received hemodialysis for hyperkalemia, after which her theophylline level was 19.2 ~g/mL 50 hours after admission. Her CPK had risen to 88,836 IU/L 60 hours after admission. A Tenckhoff 14:2 February 1985

TABLE 2. Signs and symptoms of theophylline toxicity System Gastrointestinal

Symptoms Nausea, vomiting, diarrhea, hematemesis, abdominal pain

Cardiovascular

Central nervous

Sinus tachycardia, supraventricular tachyarrhythmias, ventricuiar arrhythmias, bradycardia asystole, hypotension Agitation, nervousness, hyperreflexia, opisthotonus, seizures, insomnia, tremulousness, irritability,

Respiratory

Tachypnea

Central nervous system stimulation

Renal

Diuresis

Metabolic

Hyperglycemia, acidosis, hypokalemia, hypophosphatemia, hypocalcemia, hypomagnesemia, ketosis Rhabdomyolysis

Inhibition of tubular sodium reabsorption Increased cardiac output, renal blood flow, and glomerular filtration rate Adrenergic stimulation Altered tissue perfusion diuresis Electrolyte shift due to adrenergic stimulation

Skeletal muscle

catheter was placed for continuous peritoneal dialysis to treat recurrent hyperkalemia. During the next two days, her neurologic and renal status continued to deteriorate. She was thought to have suffered anoxic brain damage from her sustained seizure activity with renal damage due to tissue anoxia, rhabdomyolysis , and resultant myoglobinufla. She continued to exhibit marked peripheral vasodilation with a fall in blood pressure. The patient developed peritonitis and could no longer be dialyzed by this route. She died four days after a d m i s s i o n w i t h hyperkalemia and intractable shock. DISCUSSION This case illustrates m a n y of the manifestations o f severe theophylline toxicity (Table 2) and problems with its m a n a g e m e n t . The sustained-release products cause m a n a g e m e n t concerns beyond those related to the 14:2 February 1985

Mechanism Local irritation CNS stimulation of CTZ Increased cAMP levels to stimulate adrenergic nervous system Increased gastric secretions Beta adrenergic stimulation from cAMP excess Acidosis

Direct CNS stimulation Acidosis Fluid and electrolyte disturbances

Sustained seizure activity

direct pharmacologic effects of these agents, for continued absorption may occur for 12 or more hours after ingestion3 Frequently the chemica ! properties of tablets taken in mass quant i t i e s l e n d t h e m s e l v e s to b o l u s formation. 2 This will result in slower and more prolonged release of the toxic agent unless removal is facilitated with ipecac syrup, activated charcoal , and a cathartic. The absence of agitation of the contents in the gastroi n t e s t i n a l tract m a y decrease the amount of drug exposed to the intestinal wall for absorption. 3 Oral pulse charcoal therapy recently has been shown to reduce the halfqife of the e ophylline given intravenously and orally, and thus should be emphasized in the m a n a g e m e n t Of acute overdoses. 4 The majority of symptoms noted in theophylline intoxication can be attributed to beta adrenergic and direct central nervous system (CNS) stimAnnals of Emergency Medicine

ulation.S Theophylline is capable of i n h i b i t i n g p h o s p h o d i e s t e r a s e , an enzyme responsible for the breakdown of cyclic AMP (cAMP) to AMP. Because many beta adrenergic receptors are thought to be adenyl cyclase, 5 the result of theophylline excess may mimic beta adrenergic override. Classically gastrointestinal (GI) upset manifested by nausea, vomiting, and diarrhea is the first sign of theophylline toxicity.5, 6 Although direct GI irritation and CNS m e c h a n i s m s are generally held responsible, some authors attribute the diarrhea to elevations of cAMP in the intestinal tissue.6, 7 The cardiovascular effects include increased cardiac output transiently and a wide variety of arrhythmias. 5 Once again, beta adrenergic stimulation would appear to be responsible for these effects. The most commonly noted arrhythmia w i t h theophylline therapy is sinus tachycardia, although supraventricular tachycardias and premature ventricular contractions occur frequently in intoxication. 8 More serious ventricular a r r h y t h m i a s also have been d o c u m e n t e d , a l t h o u g h these may occur due to concurrent clinical conditions including acidosis, hypoxia, or electrolyte abnormalities. Theophylline has been shown to alter the ventricular fibrillation threshold in a dog model.9 The presence of hypoxia, hypercarbia, and acidosis enhanced the theophylline-induced reductiOn of the ventricular fibrillation threshold7 Agitation and excitation have been reportedlO with therapeutic levels of theophylline (10-20 p,g/mL) in some patients. Generally the more serious CNS toxicities are preceded by gastrointestinal upset and abnormal postures or hyperreflexia, although many patients m a y manifest no warning signs, n-15 T h e m o r t a l i t y in theophylline overdose appears to rise markedly after seizure activity has been noted. Mortality figures of 50% or greater have been reported. 11 Mechanisms suggested for this toxic effect include direct stimulation through increased cAMP levels within the CNS, and decreased perfusion of the brain due to local vasoconstrictor effects of theophylline without changes in the c e r e b r a l m e t a b o l i c r a t e . 12 A m i nophylline has been shown in animal models to be epileptogenic when applied corticallyjO Decreased perfusion of the brain without a concomitant 156/121

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decrease in metabolic rate m a y result in relative hypoxia, w h i c h m a y predispose to seizure activity. 12 T h e o p h y l l i n e causes decreased tubular sodium reabsorption as well as transient increases in renal blood flow, glomerular filtration rate, and cardiac output that results in diuresis. 18 Metabolic changes, including hyperglycemia, also m a y result in osmotic diuresis. Acute renal failure, as noted in this patient, was more likely due to myoglobinuria and tissue hypoxia than to direct effects of theophylline on the renal parenchyma. The m e t a b o l i c abnormalities seen in our p a t i e n t are less clearly documented in the medical literature.tS, lz-19 On admission, her laboratory and clinical picture closely resembled hyperosmolar nonketotic c o m a w i t h a s e r u m g l u c o s e of 626 mg/dL, potassium of 2.9 mEq/L, magnesium of 1.2 mEq/L, and phosphate of 0.5 mg/dL, altered m e n t a l status, and u r i n e o u t p u t Of a p p r o x i m a t e l y 2,000 mL/h. Some also have noted urinary and s e r u m ketones in p a t i e n t s w i t h t h e o p h y l l i n e toxicityA 4 Hyperglycemia is l i k e l y a result of increased t h e o p h y l l i n e levels w i t h release of glucose from g l y c o g e n stores.S, lS,~8 The resultant hyperosmolar state m a y have contributed to the diuresis and multiple electrolyte abnormalities. Sustained Seizure activity and respirat o r y i n s u f f i c i e n c y m a y have c a u s e d her acidosis. Subsequently renal failure m a y have contributed to the acidosis. This patient exhibited rhabd o m y o l y s i s w i t h a s e r u m CPK level reaching 88,836 IU/L. Her prolonged seizure activity in the presence of hypokalemia is the m o s t likely contributing factor. 2o The subsequent elevation of h e r s e r u m potassium, BUN, and creatinine are sequelae of acute r e n a l f a i l u r e s e c o n d a r y to r h a b d o myolysis. 2o Enhancement of elimination of theophylline through h e m o d i a l y s i s and/ or c h a r c o a l h e m o p e r f u s i o n r e m a i n s controversial. 21-31 Some suggest that serum concentrations in excess o f 40 fxg/mL are indications for charcoal hemoperfusion.ZO,2S T h i s is n o t supported by the isolated reports of patients w i t h serum levels in excess of 50 ~g/mL who survive w i t h o u t neurologic sequelae while receiving solely supportive therapy.22, ~3

SUMMARY Due to the increasing popularity of 122~57

s u s t a i n e d - r e l e a s e p r e p a r a t i o n s , theophylline toxicity appears to be an increasing concern. In treating these patients, the clinician must consider several factors, including dose, route and type of preparation, t i m e since ingestion, clinical status (particularly related to CNS toxicity) at the time of p r e s e n t a t i o n , and s e r u m c o n c e n t r a tion of theophylline. Intensive supportive care, pulse charcoal therapy, and p o s s i b l y h e m o p e r f u s i o n are e m p h a sized in the treatment of this intoxication.

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adults: C o r r e l a t i o n w i t h serum concentrations. Ann Intern Med 1975;82: 784-787. 12. Yarnell PR, Chu N: Focal seizures and aminophylline. Neurology 1975;25:819822. 13. Gal P, Roop C, Robinson H, et al: Theophylline-induced seizures in accidentally overdosed neonates. Pediatrics 1980;65: 547-549. 14. McDonald JM, Ladenson JH: Washington University case conference: Theophylline toxicity. Clin Chem 1978;24: 1603-1608. 15. Vaucher Y, Lightner ES, Watson PD: Theophylline poisoning. J Pediatr 1977; 90:827-830. 16. Nobel PA, Light GS: Theophylline induced diuresis in the neonate. J Pediatr 1977;90:825-826. 17. B e n o w i t z NL, O s t e r l o h J, Goldschlager N, et al: Massive catecholamine release from caffeine poisoning. JAMA 1982;248:1097-1098. 18. Penhos JC, Castillo L, Ezekiel M, et al: Insulin-resistant hyperglycemia produced by aminophylline. Endocrinology 1972;90:131-137. 19. Burgan THS, Gupta I, Bate CM: Fatal overdose of theophylline simulating acute pancreatitis. Br Med J 1982;284:939-940. 20. N e p h r o l o g y forum: A c u t e r e n a l failure and r h a b d o m y o l y s i s . Kid Int 1983;23:888-898. 21. Chang TMS, Espinosa-Melendez E, Franceour TE, et al: Albumin-collodion activated charcoal hemoperfusion in the treatment of severe theophylline intoxication in a 3-year-old patient. Pediatrics 1980;65:811-814. 22. Dean LS, Brown JW: Massive theophylline overdose survival without hemoperfusion. JAMA 1982;248:1742. 23. Sahney S, Abarzua J, Sessums L: Hemoperfusion in theophylline neurotoxicity. Pediatrics 1983;71:615-619. 24. Russo ME: M a n a g e m e n t of theophylline intoxication with charcoal-colu m n h e m o p e r f u s i o n . N Engl J Med 1979;300:24-26. 25. Ehlers SM, Zaske DE, Sawchuck RJ: Massive theophylline overdose: Rapid elimination by charcoal hemoperfusion. JAMA 1978;240:474-475. 26. Jeffreys DB, Raper SM, Helliwell M, et al: Haemoperfusion for theophylline overdose. Br Med J 1980;280:1167. 27. Connell JMC, McGeachie JF, Knepil J, et al: Self-poisoning with sustained release aminophylline: Secondary rise in serum theophylline concentration after charcoal hemoperfusion. Br Med J 1982; 284:943. 14:2 February 1985

28. Park GD, Spector R, Roberts RJ, et al: Use of hemoperfusion for treatment of theophylline intoxication. A m J Med 1983;74:961-966. 29. Weinberger M, Hendeles L: Role of di-

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