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Hypokalemia, hyperglycemia, and acidosis after intentional theophylline overdose
Hypokalemia, Hyperglycemia, and Acidosis after Intentional Theophylline Overdose WILLIAM T. SAWYER, MS,*t$ E. MARTIN CARAVATI, MD,$j MARK J. ELLISON, PharmD/ KAROL A. KRUEGER, BSt Three cases of intentional theophylline overdose in adult patients are described. Among these, hypokalemia, hyperglycemia, and acidosis were found, and markedly elevated initial serum theophylline concentrations (106, 76.2, and 41.4 pg/ml) were measured. All patients recovered completely with conservative management. The observed biochemical abnormalities rapidly resolved during maintenance fluid therapy and modest potassium supplementation. In addition, seizures, ventricular arrhythmias, and other serious toxic effects were notably absent. (Am J Emerg Med 1985;3:408-411)
The clinical manifestations of theophylline toxicity are well documented.‘-8 Adverse effects observed with serum theophylline concentrations greater than 20 kg/ml include nausea, vomiting, diarrhea, agitation and headache.lm3 Higher serum concentrations have been associated with hyperreflexia, cardiac arrhythmias, seizures, brain damage, and death.? Toxicity secondary to ingestion of massive amounts of oral theophylline products has also been specifically described.4-8 However, the majority of data describing theophylline toxicity have been obtained in patients during therapeutic theophylline administration where toxicity resulted from an acute iatrogenic overdose or gradual toxic accumulation. The clinical presentation and appropriate management of acute theophylline toxicity following intentional suicidal overdose has not been as clearly characterized. Three adult patients in whom intentional theophylline overdose was associated with hypokalemia, hyperglycemia, and acidosis are discussed here. Markedly elevated initial serum theophylline concentrations (106, 76.2, and 41.4 pg/ ml) were also observed in each patient, although none experienced seizures, ventricular arrhythmias, or other serious toxicity during recovery. From the “Charlotte Area Health Education Center, Charlotte, North Carolina, the Schools of tPharmacy and *Medicine, University of North Carolina, Chapel Hill, North Carolina, and the Departments of §Emergency Medicine and IlPharmaceutical Services, Charlotte Memorial Hospital and Medical Center, Charlotte, North Carolina. Manuscript received cember 4, 1984.
October
12, 1984; revision
Address reprint requests to Mr. Sawyer: macy, NC Memorial Hospital, Manning NC 27514. Key 408
Words: Poisoning,
theophylline.
accepted
De-
Department of PharDrive, Chapel Hill,
CASE REPORTS Patient I. A poorly responsive 25-year-old man was brought to the hospital by ambulance. While en route, he spontaneously vomited 25-30 partially digested pink tablet fragments and several whole brown tablets. The patient was lethargic but easily arousable upon arrival in the emergency department. He claimed to have ingested approximately 2’12 quarts of beer, 75- 100 oxtriphylline 400 mg tablets (Choledyl SA 400, equivalent to anhydrous theophylline, 256 mg, Parke-Davis Division of Warner-Lambert Company, Morris Plains, New Jersey), and 25 penicillin-VK 250 mg tablets approximately l-2 hours before hospital presentation. The patient was given ipecac (30 ml) via nasogastric tube and vomited a large amount of fluid and 15-20 partially digested pink tablet fragments. The patient was then given activated charcoal (60 g) and magnesium citrate (300 ml). Results of the physical examination were essentially normal with the exception of an elevated pulse of 102 beats per minute. The patient’s temperature was 37°C. his blood pressure was 120/50 mm Hg, and his respiratory rate was 24 breaths per minute. An electrocardiogram revealed a sinus tachycardia (115 beats per minute) and a prolonged QT interval (0.36 seconds). Arterial blood-gas determination showed a Pcoz of 3 1 mm Hg, a PO1 of 114 mm Hg, and a pH of 7.30. Laboratory test results included: sodium, 141 mEq/ 1; potassium, 2.8 mEq/l; bicarbonate, 14 mEq/l: chloride. 108 mEq/l; serum glucose, 249 mg/dl; and leukocyte count, 20,400/mm3. An ethanol concentration of 59 mg/dl was also reported. The patient was admitted to the intensive care unit where he received chlordiazepoxide HCI. 50 mg intramuscularly every six hours, as needed for agitation and maintenance IV fluid therapy of 5% dextrose in 0.45% saline with 40 mEq/l of potassium chloride. Five serial theophylline serum concentration measurements were made over the next 48 hours (Fig. 1). Theophylline concentration was determined using an EMIT assay.9 Urinalysis results were positive for thiothixene, although the patient denied any use of this drug. The patient’s recovery was uneventful. Electrolyte abnormalities corrected within 24 hours. after which time he was moved from the intensive care unit, and abnormal ECG findings resolved within 72 hours of admission. The patient was discharged on the fourth hospital day in good condition. Patient 2. A 33-year-old woman was brought to the hospital emergency department by ambulance following a reported drug overdose. While en route, she was given ipecac and vomited copious amounts of gastric fluid and tablet fragments. The patient was alert upon arrival in the emergency department and complained of nausea and abdominal pain. She claimed to have ingested 18-19 theophylline 300 mg
SAWYER
tablets (Sustaire, Roerig Division of Pfizer Pharmaceuticals, New York), 8-12 beers, and three or four Percogesic tablets approximately two hours before hospital presentation. Results of the physical examination were essentially normai with the exception of an elevated pulse of 132 beats per minute. The patient’s temperature was 37°C her blood pressure was 120/70 mm Hg, and her respiratory rate was 36 per minute. An electrocardiogram revealed a sinus tachycardia (125 beats per minute) and nonspecific QT segment changes. Arterial blood-gas determination showed a P,,, of 22 mm Hg, a Po, of 67 mm Hg, and a pH of 7.46. Laboratory test results included: sodium, 138 mEq/l; potassium, 2.5 mEq/l; chloride, 109 mEq/l; bicarbonate, 11 mEq/l; serum glucose, 258 mg/dl; and leukocyte count, 8,300/mm3. An ethanol concentration of 80 mgidl was also reported. The patient was admitted to the hospital and received maintenance intravenous fluid therapy of 5% dextrose in 0.45% saline with 20 mEq/l of potassium chloride. A serum theophylline concentration measured two hours after admission was 76.2 pg/ml. Two additional serum theophylline concentrations were measured over the next 30 hours. The results were 39.4 &ml, measured 19 hours later and 10.7 kg/ ml, recorded 28 hours later. The patient’s recovery was uneventful, her symptomatic complaints, tachycardia, and abnormal ECG findings resolved within 36 hours of admission, and she was discharged in good condition. Patient 3. A 24-year-old woman presented to the hospital emergency department and reported having taken 3050 aminophylline 200 mg tablets approximately one hour previously. Upon arrival, she was alert but somewhat agitated, and complained that intermittent vomiting had occurred since ingestion. Activated charcoal (60 g) was administered. Results of the physical examination were essentially normal with the exception of tremors and an elevated pulse of 160 beats per minute. The patient’s temperature was 36.1”C, her blood pressure was 140/70 mm Hg, and her respiratory rate was 32 per minute. An electrocardiogram revealed a sinus tachycardia (160 beats per minute). Arterial blood-gas determination showed a P,,, of 27 mm Hg, a PO2 of 103 mm Hg, and a pH of 7.40. Laboratory test results included: sodium, 144 mEq/l; potassium, 2.7 mEq/l; chloride, 108 mEq/l; bicarbonate, 17 mEq/l; serum glucose, 116
mg/dl; and leukocyte count, 10,400/mm3. The patient was admitted for observation and received maintenance intravenous fluid therapy of 5% dextrose in 0.45% saline with 40 mEq/l of potassium chloride. Serum theophylline concentration measured at the time of presentation to the emergency department was 41.4 wg/ml, and when measured seven hours later, it was 23.1 pg/ml. Over the next 30 hours, her electrolyte values normalized, her tachycardia resolved, and her vomiting ceased. She was discharged in good condition.
DISCUSSION The three cases presented illustrate two aspects of acute theophylline intoxication following intentional overdose that merit attention. The first is the presence of hypokalemia, hyperglycemia, and acidosis in association with theophylline overdose. AIthough these biochemical changes have been occasionally reported
ET AL H THEOPHYLLINE
OVERDOSE
106.0
1 SION
IO
I I 20 30 TIME (hours)
I 40
1 50
Figure 1. Serum theophylline concentration as a function of time following oral oxtriphylline overdose in Patient I.
as incidental observations in previous case descriptions,7-‘5 their incidence and clinical significance has not been extensively evaluated. In a recent retrospective evaluation of 22 cases of intentional theophylline overdose, however, these abnormalities were observed in over 90% of patients.16 Hypokalemia and hyperglycemia result from hyperinsulinemia and glycogenolysis produced by the action of direct beta agonists, as well as indirect stimulants such as theophylline.‘7-19 These effects have been observed during betamimetic therapy of premature labor,19 as well as after an intentional combination overdose with pseudoephedrine and choline theophyllinate.” The elevated serum concentrations of insulin and glucose promote an intracellular shift of glucose and potassium that results in relative hypokalemia and a lessening of the degree of hyperglycemia.20 However, the hypokalemia does not necessarily represent a total-body potassium deficiency requiring aggressive supplementation, and it rapidly resolved in our patients with routine fluid administration and modest potassium supplementation. The etiology of the observed metabolic acidosis is less certain, although it has been attributed to a lactic acidosis secondary to increased glycolysis.14 Among our patients, the serum lactate concentration was elevated in one (5 mmol/l) and not measured in 409
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the other two. Various degrees of respiratory alkalosis were observed in all three patients, reflecting either a compensatory mechanism or direct stimulatory effects of theophylline on the respiratory center. A second notable feature of these cases was the absence of serious toxicity, specifically seizures, in any patient. Although seizures have frequently been reported in patients with serum theophylline concentrations above 40 p_g/ml, in previous descriptions of theophylline overdose serum concentrations have not been shown to be reliable predictors of toxicity.10-*3 In one series, seizures occurred in all seven patients with serum theophylline concentrations above 47 pg/ ml.iO In contrast, another report described a patient with a serum theophylline concentration of 59 pg/ml in whom seizures did not occur.’ In other cases, patients with serum theophylline levels exceeding 146 pg/ml all experienced seizures.lO-I3 However, the association between specific elevations of serum theophylline concentration and toxic effects has most commonly been described in patients chronically treated with theophylline derivatives. The correlation between toxicity and serum concentration has been more variable in cases of acute suicidal overdose. In one series of six patients with intentional theophylline overdose, seizures occurred in two cases in association with peak theophylline concentrations of 150 and 90 kg!m1.i4 The patient with the higher initial concentration subsequently died, while the second patient manifested a severe residual neurological deficit. Seizures did not occur in the remaining four patients whose (extrapolated) peak serum theophylline concentrations ranged from 71 to 84 pg/ml. However, charcoal hemoperfusion was initiated early in each of the four cases to rapidly reduce the serum drug concentration. Similarly, in the most recent 22-patient series of intentional overdoses,” among which seizures occurred in three cases, charcoal hemoperfusion was used in 16122 patients. Our patients, although hemoperfusion was not employed, recovered without incident and experienced no seizures, other neurological sequelae, or adverse effects. The absence of seizures in the first two cases described in this report, and particularly Patient 1 who presented a serum theophylline concentration of 106 kg/ml, is unusual. However. these cases document the fact that patients may completely recover from a substantial overdose with conservative management. In two of the patients reported here. this included administration of activated charcoal, which has been described as a successful noninvasive means of enhancing theophylline elimination.” Of additional interest is the serum theophylline concentration-time profile observed in Patient 1 (Fig. 1). At levels above 90 kg/ml, the patient’s theophylline elimination rate appeared to be slower than at con410
5 w September
1985
centrations below 60 pg/ml. The observed serum concentrations could reflect laboratory artifact, prolonged, delayed, or interrupted drug absorption, or elimination enhanced by charcoal administration. The observed elimination pattern may also represent saturation of hepatic biotransformational systems at high serum theophylline concentrations. While reports of dose-dependent theophylline elimination kinetics are uncommon and confined to observations in pediatric patients,5*6 the data observed in this patient suggest that additional evaluation of theophylline disposition at high concentrations is desirable. CONCLUSION Three cases are presented to demonstrate two aspects of intentional theophylline overdose that should be considered in clinical management. Hypokalemia and hyperglycemia may frequently be observed as part of the initial patient presentation, and these represent logical extensions of the drug’s pharmacological action. A mild metabolic acidosis may also be present. However, these biochemical abnormalities are amenable to conservative management and rapidly resolve with fluid replacement and modest potassium supplementation. In addition, patients may fully recover from a substantial overdose that produces markedly elevated serum theophylline concentrations without serious toxicity or residual effects. Although this observation should not discourage the use of charcoal hemoperfusion or similar techniques for rapid reduction of drug serum concentration, it may be particularly relevant to situations where they are not available. Serious toxicity may also be less likely to occur in otherwise healthy young adult patients, as those presented in this report. REFERENCES 1. Mountain RD, Neff TA. Oral theophylline intoxication. Arch Int Med 1984;144:724-727. 2. Hendeles L, Weinberger M. Johnson G. Theophylline. In Evans WE, Schentag JJ, Jusko WJ (eds). Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. San Francisco: Applied Therapeutics, Inc., 1980:95-138. 3. Hendeles L, Brighley L, Richardson RH, et al. Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intel1 Clin Pharm 1977;11:12-18. 4. lberti TJ, Hammond RS. Massive oral theophylline poisoning. South Med J 1978;71:965-966. 5. Haddad ZH, Sakai R. Massive accidental theophylline ingestion: Linear first-order elimination kinetics in an infant. Ann Allergy 1982;48:178-179. 6. Kadlec GJ, Jarboe CH, Pollard SJ, et al. Acute theophylline intoxication: Biphasic first order elimination kinetics in a child. Ann Allergy 1978;41:337-339. 7. Vaucher Y, Lightner ES, Walson PD. Theophylline poisoning. J Pediatr 1977;90:827-830, 8. Helliwell M, Berry D. Theophylline poisoning in adults. Br Med J 1979;2:1114.
SAWYER
9. Chang JY, Bastiani RJ. Performance evaluation of the EMIT theophylline assay: Clinical Study No. 41 summary report. Palo Alto, California: Syva Corporation, 1977. 10. Zwillich CW, Sutton FD, Neff TA, et al. Theophylline-induced seizures in adults: Correlation with serum concentrations. Ann Intern Med 1975;82:784-787. 11. Rose C. Theophylline toxicity. West J Med 1979;130:466467. 12. Ehlers SM, Zaske DE, Sawchuk RJ. Massive theophylline overdose: Rapid elimination by charcoal hemoperfusion. JAMA 19?8;240:474-475. 13. Jefferys DB, Raper SM, Helliwell M, et al. Hemoperfusion for theophylline overdose. Br Med J 1980;280:1767. 14. Park KD, Spector A, Roberts RJ, et al. Use of hemoperfusion for treatment of theophylline intoxication. Am J Med 1983;74:961-966. 15. Aranda JV. Metabolic effect of theophylline in premature neonate. J Pediatr 1976;89:833-834.
ET AL a THEOPHYLLINE
OVERDOSE
16. Hail KW, Dobson KE, Dalton JG, et al. Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med 1984;101:457-462. 17. Brown MJ, Brown DC, Murphy MB. Hypokalemia from betaw-receptor stimulation by circulating epinephrine. N Engl J Med 1983;309:1414-1419. 18. Bengtsson B, Fagerstrom P. Extrapulmonary effects of terbutaline during prolonged administration. Clin Pharmacol Ther 1982;31:726-732. 19. Hastwell G, Lambert BE. The effect of oral salbutamol on serum potassium and blood sugar. Br J Obstet Gynecol 1978;85:767-769. 20. McCleave DJ, Phillips PJ, Vedig AE. Compartmental shift of potassium-A result of sympathomimetic overdose. Aust N i! J Med 1978;8:180-183. 21. Gal P, Miller A, McCue JD. Oral activated charcoal to enhance theophylline elimination in an acute overdose. JAMA 1984;251:3130-3131.
411
The clinical manifestations of theophylline toxicity are well documented.‘-8 Adverse effects observed with serum theophylline concentrations greater than 20 kg/ml include nausea, vomiting, diarrhea, agitation and headache.lm3 Higher serum concentrations have been associated with hyperreflexia, cardiac arrhythmias, seizures, brain damage, and death.? Toxicity secondary to ingestion of massive amounts of oral theophylline products has also been specifically described.4-8 However, the majority of data describing theophylline toxicity have been obtained in patients during therapeutic theophylline administration where toxicity resulted from an acute iatrogenic overdose or gradual toxic accumulation. The clinical presentation and appropriate management of acute theophylline toxicity following intentional suicidal overdose has not been as clearly characterized. Three adult patients in whom intentional theophylline overdose was associated with hypokalemia, hyperglycemia, and acidosis are discussed here. Markedly elevated initial serum theophylline concentrations (106, 76.2, and 41.4 pg/ ml) were also observed in each patient, although none experienced seizures, ventricular arrhythmias, or other serious toxicity during recovery. From the “Charlotte Area Health Education Center, Charlotte, North Carolina, the Schools of tPharmacy and *Medicine, University of North Carolina, Chapel Hill, North Carolina, and the Departments of §Emergency Medicine and IlPharmaceutical Services, Charlotte Memorial Hospital and Medical Center, Charlotte, North Carolina. Manuscript received cember 4, 1984.
October
12, 1984; revision
Address reprint requests to Mr. Sawyer: macy, NC Memorial Hospital, Manning NC 27514. Key 408
Words: Poisoning,
theophylline.
accepted
De-
Department of PharDrive, Chapel Hill,
CASE REPORTS Patient I. A poorly responsive 25-year-old man was brought to the hospital by ambulance. While en route, he spontaneously vomited 25-30 partially digested pink tablet fragments and several whole brown tablets. The patient was lethargic but easily arousable upon arrival in the emergency department. He claimed to have ingested approximately 2’12 quarts of beer, 75- 100 oxtriphylline 400 mg tablets (Choledyl SA 400, equivalent to anhydrous theophylline, 256 mg, Parke-Davis Division of Warner-Lambert Company, Morris Plains, New Jersey), and 25 penicillin-VK 250 mg tablets approximately l-2 hours before hospital presentation. The patient was given ipecac (30 ml) via nasogastric tube and vomited a large amount of fluid and 15-20 partially digested pink tablet fragments. The patient was then given activated charcoal (60 g) and magnesium citrate (300 ml). Results of the physical examination were essentially normal with the exception of an elevated pulse of 102 beats per minute. The patient’s temperature was 37°C. his blood pressure was 120/50 mm Hg, and his respiratory rate was 24 breaths per minute. An electrocardiogram revealed a sinus tachycardia (115 beats per minute) and a prolonged QT interval (0.36 seconds). Arterial blood-gas determination showed a Pcoz of 3 1 mm Hg, a PO1 of 114 mm Hg, and a pH of 7.30. Laboratory test results included: sodium, 141 mEq/ 1; potassium, 2.8 mEq/l; bicarbonate, 14 mEq/l: chloride. 108 mEq/l; serum glucose, 249 mg/dl; and leukocyte count, 20,400/mm3. An ethanol concentration of 59 mg/dl was also reported. The patient was admitted to the intensive care unit where he received chlordiazepoxide HCI. 50 mg intramuscularly every six hours, as needed for agitation and maintenance IV fluid therapy of 5% dextrose in 0.45% saline with 40 mEq/l of potassium chloride. Five serial theophylline serum concentration measurements were made over the next 48 hours (Fig. 1). Theophylline concentration was determined using an EMIT assay.9 Urinalysis results were positive for thiothixene, although the patient denied any use of this drug. The patient’s recovery was uneventful. Electrolyte abnormalities corrected within 24 hours. after which time he was moved from the intensive care unit, and abnormal ECG findings resolved within 72 hours of admission. The patient was discharged on the fourth hospital day in good condition. Patient 2. A 33-year-old woman was brought to the hospital emergency department by ambulance following a reported drug overdose. While en route, she was given ipecac and vomited copious amounts of gastric fluid and tablet fragments. The patient was alert upon arrival in the emergency department and complained of nausea and abdominal pain. She claimed to have ingested 18-19 theophylline 300 mg
SAWYER
tablets (Sustaire, Roerig Division of Pfizer Pharmaceuticals, New York), 8-12 beers, and three or four Percogesic tablets approximately two hours before hospital presentation. Results of the physical examination were essentially normai with the exception of an elevated pulse of 132 beats per minute. The patient’s temperature was 37°C her blood pressure was 120/70 mm Hg, and her respiratory rate was 36 per minute. An electrocardiogram revealed a sinus tachycardia (125 beats per minute) and nonspecific QT segment changes. Arterial blood-gas determination showed a P,,, of 22 mm Hg, a Po, of 67 mm Hg, and a pH of 7.46. Laboratory test results included: sodium, 138 mEq/l; potassium, 2.5 mEq/l; chloride, 109 mEq/l; bicarbonate, 11 mEq/l; serum glucose, 258 mg/dl; and leukocyte count, 8,300/mm3. An ethanol concentration of 80 mgidl was also reported. The patient was admitted to the hospital and received maintenance intravenous fluid therapy of 5% dextrose in 0.45% saline with 20 mEq/l of potassium chloride. A serum theophylline concentration measured two hours after admission was 76.2 pg/ml. Two additional serum theophylline concentrations were measured over the next 30 hours. The results were 39.4 &ml, measured 19 hours later and 10.7 kg/ ml, recorded 28 hours later. The patient’s recovery was uneventful, her symptomatic complaints, tachycardia, and abnormal ECG findings resolved within 36 hours of admission, and she was discharged in good condition. Patient 3. A 24-year-old woman presented to the hospital emergency department and reported having taken 3050 aminophylline 200 mg tablets approximately one hour previously. Upon arrival, she was alert but somewhat agitated, and complained that intermittent vomiting had occurred since ingestion. Activated charcoal (60 g) was administered. Results of the physical examination were essentially normal with the exception of tremors and an elevated pulse of 160 beats per minute. The patient’s temperature was 36.1”C, her blood pressure was 140/70 mm Hg, and her respiratory rate was 32 per minute. An electrocardiogram revealed a sinus tachycardia (160 beats per minute). Arterial blood-gas determination showed a P,,, of 27 mm Hg, a PO2 of 103 mm Hg, and a pH of 7.40. Laboratory test results included: sodium, 144 mEq/l; potassium, 2.7 mEq/l; chloride, 108 mEq/l; bicarbonate, 17 mEq/l; serum glucose, 116
mg/dl; and leukocyte count, 10,400/mm3. The patient was admitted for observation and received maintenance intravenous fluid therapy of 5% dextrose in 0.45% saline with 40 mEq/l of potassium chloride. Serum theophylline concentration measured at the time of presentation to the emergency department was 41.4 wg/ml, and when measured seven hours later, it was 23.1 pg/ml. Over the next 30 hours, her electrolyte values normalized, her tachycardia resolved, and her vomiting ceased. She was discharged in good condition.
DISCUSSION The three cases presented illustrate two aspects of acute theophylline intoxication following intentional overdose that merit attention. The first is the presence of hypokalemia, hyperglycemia, and acidosis in association with theophylline overdose. AIthough these biochemical changes have been occasionally reported
ET AL H THEOPHYLLINE
OVERDOSE
106.0
1 SION
IO
I I 20 30 TIME (hours)
I 40
1 50
Figure 1. Serum theophylline concentration as a function of time following oral oxtriphylline overdose in Patient I.
as incidental observations in previous case descriptions,7-‘5 their incidence and clinical significance has not been extensively evaluated. In a recent retrospective evaluation of 22 cases of intentional theophylline overdose, however, these abnormalities were observed in over 90% of patients.16 Hypokalemia and hyperglycemia result from hyperinsulinemia and glycogenolysis produced by the action of direct beta agonists, as well as indirect stimulants such as theophylline.‘7-19 These effects have been observed during betamimetic therapy of premature labor,19 as well as after an intentional combination overdose with pseudoephedrine and choline theophyllinate.” The elevated serum concentrations of insulin and glucose promote an intracellular shift of glucose and potassium that results in relative hypokalemia and a lessening of the degree of hyperglycemia.20 However, the hypokalemia does not necessarily represent a total-body potassium deficiency requiring aggressive supplementation, and it rapidly resolved in our patients with routine fluid administration and modest potassium supplementation. The etiology of the observed metabolic acidosis is less certain, although it has been attributed to a lactic acidosis secondary to increased glycolysis.14 Among our patients, the serum lactate concentration was elevated in one (5 mmol/l) and not measured in 409
AMERICAN
JOURNAL
OF EMERGENCY
MEDICINE
n Volume
3, Number
the other two. Various degrees of respiratory alkalosis were observed in all three patients, reflecting either a compensatory mechanism or direct stimulatory effects of theophylline on the respiratory center. A second notable feature of these cases was the absence of serious toxicity, specifically seizures, in any patient. Although seizures have frequently been reported in patients with serum theophylline concentrations above 40 p_g/ml, in previous descriptions of theophylline overdose serum concentrations have not been shown to be reliable predictors of toxicity.10-*3 In one series, seizures occurred in all seven patients with serum theophylline concentrations above 47 pg/ ml.iO In contrast, another report described a patient with a serum theophylline concentration of 59 pg/ml in whom seizures did not occur.’ In other cases, patients with serum theophylline levels exceeding 146 pg/ml all experienced seizures.lO-I3 However, the association between specific elevations of serum theophylline concentration and toxic effects has most commonly been described in patients chronically treated with theophylline derivatives. The correlation between toxicity and serum concentration has been more variable in cases of acute suicidal overdose. In one series of six patients with intentional theophylline overdose, seizures occurred in two cases in association with peak theophylline concentrations of 150 and 90 kg!m1.i4 The patient with the higher initial concentration subsequently died, while the second patient manifested a severe residual neurological deficit. Seizures did not occur in the remaining four patients whose (extrapolated) peak serum theophylline concentrations ranged from 71 to 84 pg/ml. However, charcoal hemoperfusion was initiated early in each of the four cases to rapidly reduce the serum drug concentration. Similarly, in the most recent 22-patient series of intentional overdoses,” among which seizures occurred in three cases, charcoal hemoperfusion was used in 16122 patients. Our patients, although hemoperfusion was not employed, recovered without incident and experienced no seizures, other neurological sequelae, or adverse effects. The absence of seizures in the first two cases described in this report, and particularly Patient 1 who presented a serum theophylline concentration of 106 kg/ml, is unusual. However. these cases document the fact that patients may completely recover from a substantial overdose with conservative management. In two of the patients reported here. this included administration of activated charcoal, which has been described as a successful noninvasive means of enhancing theophylline elimination.” Of additional interest is the serum theophylline concentration-time profile observed in Patient 1 (Fig. 1). At levels above 90 kg/ml, the patient’s theophylline elimination rate appeared to be slower than at con410
5 w September
1985
centrations below 60 pg/ml. The observed serum concentrations could reflect laboratory artifact, prolonged, delayed, or interrupted drug absorption, or elimination enhanced by charcoal administration. The observed elimination pattern may also represent saturation of hepatic biotransformational systems at high serum theophylline concentrations. While reports of dose-dependent theophylline elimination kinetics are uncommon and confined to observations in pediatric patients,5*6 the data observed in this patient suggest that additional evaluation of theophylline disposition at high concentrations is desirable. CONCLUSION Three cases are presented to demonstrate two aspects of intentional theophylline overdose that should be considered in clinical management. Hypokalemia and hyperglycemia may frequently be observed as part of the initial patient presentation, and these represent logical extensions of the drug’s pharmacological action. A mild metabolic acidosis may also be present. However, these biochemical abnormalities are amenable to conservative management and rapidly resolve with fluid replacement and modest potassium supplementation. In addition, patients may fully recover from a substantial overdose that produces markedly elevated serum theophylline concentrations without serious toxicity or residual effects. Although this observation should not discourage the use of charcoal hemoperfusion or similar techniques for rapid reduction of drug serum concentration, it may be particularly relevant to situations where they are not available. Serious toxicity may also be less likely to occur in otherwise healthy young adult patients, as those presented in this report. REFERENCES 1. Mountain RD, Neff TA. Oral theophylline intoxication. Arch Int Med 1984;144:724-727. 2. Hendeles L, Weinberger M. Johnson G. Theophylline. In Evans WE, Schentag JJ, Jusko WJ (eds). Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring. San Francisco: Applied Therapeutics, Inc., 1980:95-138. 3. Hendeles L, Brighley L, Richardson RH, et al. Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intel1 Clin Pharm 1977;11:12-18. 4. lberti TJ, Hammond RS. Massive oral theophylline poisoning. South Med J 1978;71:965-966. 5. Haddad ZH, Sakai R. Massive accidental theophylline ingestion: Linear first-order elimination kinetics in an infant. Ann Allergy 1982;48:178-179. 6. Kadlec GJ, Jarboe CH, Pollard SJ, et al. Acute theophylline intoxication: Biphasic first order elimination kinetics in a child. Ann Allergy 1978;41:337-339. 7. Vaucher Y, Lightner ES, Walson PD. Theophylline poisoning. J Pediatr 1977;90:827-830, 8. Helliwell M, Berry D. Theophylline poisoning in adults. Br Med J 1979;2:1114.
SAWYER
9. Chang JY, Bastiani RJ. Performance evaluation of the EMIT theophylline assay: Clinical Study No. 41 summary report. Palo Alto, California: Syva Corporation, 1977. 10. Zwillich CW, Sutton FD, Neff TA, et al. Theophylline-induced seizures in adults: Correlation with serum concentrations. Ann Intern Med 1975;82:784-787. 11. Rose C. Theophylline toxicity. West J Med 1979;130:466467. 12. Ehlers SM, Zaske DE, Sawchuk RJ. Massive theophylline overdose: Rapid elimination by charcoal hemoperfusion. JAMA 19?8;240:474-475. 13. Jefferys DB, Raper SM, Helliwell M, et al. Hemoperfusion for theophylline overdose. Br Med J 1980;280:1767. 14. Park KD, Spector A, Roberts RJ, et al. Use of hemoperfusion for treatment of theophylline intoxication. Am J Med 1983;74:961-966. 15. Aranda JV. Metabolic effect of theophylline in premature neonate. J Pediatr 1976;89:833-834.
ET AL a THEOPHYLLINE
OVERDOSE
16. Hail KW, Dobson KE, Dalton JG, et al. Metabolic abnormalities associated with intentional theophylline overdose. Ann Intern Med 1984;101:457-462. 17. Brown MJ, Brown DC, Murphy MB. Hypokalemia from betaw-receptor stimulation by circulating epinephrine. N Engl J Med 1983;309:1414-1419. 18. Bengtsson B, Fagerstrom P. Extrapulmonary effects of terbutaline during prolonged administration. Clin Pharmacol Ther 1982;31:726-732. 19. Hastwell G, Lambert BE. The effect of oral salbutamol on serum potassium and blood sugar. Br J Obstet Gynecol 1978;85:767-769. 20. McCleave DJ, Phillips PJ, Vedig AE. Compartmental shift of potassium-A result of sympathomimetic overdose. Aust N i! J Med 1978;8:180-183. 21. Gal P, Miller A, McCue JD. Oral activated charcoal to enhance theophylline elimination in an acute overdose. JAMA 1984;251:3130-3131.
411