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Prolonged Toxicity following Massive Ingestion of Sustained-release Theophylline Preparation
Prolonged Toxicity following Massive Ingestion of Sustained-release Theophylline Preparation* Broce C. Corser, M.D.; Charles Youngs, Pharm. D.; and Robert e Baughman, M.D.
Massive ingestion of sustained-release theophylline preparations in three patients was treated with gastric lavage and repeated dosages oforally-administered activated charcoal. Therapy was initiated prompdy; however, two patients had their highest theophylline levels documented six to 12 boon after ingestion, and theophylline levels on arrival at the
hospital were signi&candy lower than the maximal level documented. AU three patients had prolonged elevations of the level, with markecUy delayed half-lives of the drug. Overdosages due to sustained release preparations may lead to prolonged toxicity and require aggressive and continuous therapy.
Recently, we treated three patients with profoundly elevated serum theophylline levels following ingestion of toxic quantities of sustained-release theophylline preparations. 1Wo of these patients had dramatic rises in serum theophylline concentrations at six and nine hours after hospital admission despite immediate treatment with oral activated charcoal. The prolonged absorption of sustained release theophylline preparations may cause delayed elevations in serum levelsafter an overdose. This phenomenon has not been well described and has important clinical implications.
admission to the Emergency Department. His initial theophylline level was46.8 "glml. He was given syrup of Ipecac, followed by 100g activated charcoal, in increments, and one bottle of magnesium citrate. He tolerated the orally administered activated charcoal poorly and vomited some of the doses. He was then transferred to the Medical Intensive Care Unit where he was agitated, tremulous, and nauseated. His ECG results showed supraventricular tachyeardia with a rate of 160 to 180. Figure 1 summarizes his theophylline levels during his three-day hospital stay. His serum theophylline level peaked at 91 "glml nine hours after admission. By 26 hours after admission, his theophylline level was 29 "glml, his symptoms had resolved, and his ECG results showed a normal sinus rhythm. He was discharged in good condition.
CASE REPORTS CASE 1
A 25-year-old alcoholic male smoker presented to the Emergency Department following a suicide attempt by ingesting between 30 and 50 Theo-Dur (Key Pharmaceuticals) 300 mg tablets approximately three hours prior to admission. His initial theophylline level upon admission was 69 "glml. A nasogastric tube was placed and he wasgiven 100 g activated charcoaland 300 mlof magnesium citrate in the Emergency Department, then transferred to the Medical Intensive Care Unit where he was noted to be agitated, tremulous, and vomiting profusely. Electrocardiographic examination showed supraventricular tachycardia with a rate of18O to 200. Six hours after admission, his serum theophylline level was 179.6 "glml. Serum theophylline levels were determined in the clinical toxicology laboratory using high pressure liquid chromatography. Figure 1 demonstrates the patients theophylline levels during his hospital stay. 1Wo additional doses (50 g each) of activated charcoal, followed by magnesium citrate, were administered through the nasogastric tube eight and 12 hours after admission, although portions of these doses were vomited. The nausea, vomiting, and tachycardia diminished, and, by 36 hours after admission, his symptoms had resolved. By the third hospital day, his theophylline level was negligible and he was discharged in good health. CASE 2
A 32-year-old male smoker ingested an unknown quantity of his
mother's Constant-T (300 mg) tablets approximately 45 min prior to *From the Department of Internal Medicine and Pharmacy, University of Cincinnati Medical Center, Cincinnati. Manuscript received April 22; revision accepted May 15. Reprint requests: Dr. Bau~man, Pulmona~etl8e Division, Mail Location 564, Unit>errily OjCincinnati Me Center, Cincinnati
45267-0564
CASE 3
A 5i-year-old female smoker with a history of severe chronic obstructive pulmonary disease and several prior suicide attempts presented to the Emergency Department with the complaint of shortness of breath" and, shortly thereafter, developed a generalized major motor seizure. Her outpatient drug-therapy included Theo-Dur, 300 mg tid. Her serum theophylline level was found to be 91 "glml. She underwent placement of a nasogastric tube and had gastric lavage with 2 L normal saline solution, followed by the administration of 100 g activated charcoal and one bottle of magnesium citrate. In the Medical Intensive Care Unit, she was comatose with a diffuse fine tremor and hyperreflexia. ECG examination demonstrated supraventricular tachycardia with a rate of 160. Her abdomen was quiet and abdominal roentgenographic examination showed a nonobstructive ileus pattern. Her theophylline level remained elevated at 78 "glml eighteen hours after admission. Figure 1shows the slow decline ofher theophylline level. Thirty-five hours after admission, she developed ventricular fibrillation, which converted to sinus rhythm following electrical cardioversion. Her ileus gradually resolved and level of consciousness slowly increased. Forty-two hours after admission, her theophylline level was 4.2 "glml. On the sixth hospital day, she suffered cardiopulmonary arrest and subsequently died. II
DISCUSSION
As demonstrated in Figure 1, two of our three patients experienced dramatic rises in theophylline levels after hospital admission despite prompt treatment with boluses of orally administered activated charcoal. The rise in serum concentration was associated with a marked increase in toxic symptoms. We CHEST I 88 I 5 I NOVEMBER. 1985
748
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FICURE 1. Semilogarithmic plot of serum theophylline levels in
three patients with theophylline toxicity. Where possible (patients 1
and 2), the elimination rate constant (K) was determined by leastsquares linear regression of the logarithm of the serum concentration of theophylline vs time. The serum half life, t Vi, equals 0.693IK. Patient 1 is represented by (~), patient 2 by (x ), and patient 3 by (0).
have found only one other report showing a delayed peak in serum theophylline levels occurring after treatment with orally administered charcoal. 1 The patient described in that report ingested Theo-Dur 300 mg tablets. Initial serum theophylline level was 56 ~g1ml, and a peak level greater than 200 ~g1ml was documented eight hours later: In this report, case 1 ingested Theo-Our 300 mg tablets. The in vivo absorption of this product after the first 15 percent up to the final 15 percent occurs at a relatively constant rate over approximately 12 hours. 2 In single dose studies, Theo-Dur given as a dose of 8 mglkg body weight produced its peak theophylline level after an average time of9.2±1.9 hours following administration. Patient 2 ingested Constant T (300 mg) tablets. In similar single-dose studies at a dosing equivalent of 8 mg/kg body weight, peak theophylline blood levels occurred at 4.6 ± 0.9 hours after administration as 300 mg tablets. Theophylline is an effective bronchodilator drug in the therapeutic serum range oflO to 20 ~g1ml, but the frequency and severity of toxicity increase as levels rise above 20 ...,g1ml. 3 Gastrointestinal dialysis using orallyadministered activated charcoal to increase theophylline clearance is an effective noninvasive treatment for theophylline toxicity- and has been shown to reduce the serum half-lifeof theophylline administered intra-
750
venously or orally," Orally-administered charcoal pro-motes drug elimination by enhancing the diffusion of theophylline from blood across the gut wall into the intestinal lumen." Furthermore, orally-administered charcoal may bind unabsorbed theophylline, preventing continued absorption. The three patients in this report tolerated poorly the orally-administered activated charcoal. The first two patients had recurrent vomiting, which caused them to lose some of the administered activated charcoal and limited the additional doses that could be given. The third patient had a sustained elevation of serum theophylline levels. This was probably related to her intestinal ileus, which may have diminished the efficacy of the oral activated charcoal. Based on a study of the effects of orally-administered activated charcoal on theophylline clearance in normal volunteer subjects; the optimal frequency of administration of charcoal is probably at doses of 10 to 20 g every two hours." In a series of cases of theophylline toxicity, 30 g of activated charcoal was administered orally every two hours fur two to four doses. Ten of the 14 patients in that study tolerated orallyadministered charcoal and demonstrated both an increase in theophylline clearance and amelioration of symptoms. 8 In conclusion, ingestion of an overdose of a slow-release theophylline preparation may cause dramatic late increases in serum theophylline levels. Early treatment with orally-administered activated charcoal enhances theophylline elimination, but may not avert a large delayed elevation in serum levels. ACKNOWLEDGMENTS: The authors wish to thank Dr. Robert G. Loudon fOrhis revie\\', and Naomi Sims for help in preparation of this manuscript.
REFERENCES 1 Robertson, NJ. Fatal overdose from a sustained-release theophylline preparation. Ann Emerg Med 1985; 14:154-58 2 Hendeles L, Iafrate ~ Weinberger M. A clinical and pharmaeokinetic basisfOrthe selection and use of slow-release theophylline products. Clin Phannakokinetics 1984;9:95-135 3 Hendeles L, Bigbley L, Richardson RH, Hepler CD, Carmichael J. Frequent toxicity from IV aminophylline infusions in criticallyill patients. Drug Intell Clin Phann 1977; 11:12-18 4 Levy G. Gastrointestinal clearance of drugs with activated cbaJ'o coal. N Eng} J Med 1982; 307:676-78 5 Berlinger WG, Spector R, Goldberg MJ, Johnson GF, Quee CI:, Berg MJ. Enhancement of theophylline clearance by oral activated charcoal. Clin Pharmacol Ther 1983; 33:351-54 6 Mahutte CK, 'frue RJ, Michiels TM, Berman JM, Light RW Increased serum theophylline clearance with orally-administered activated charcoal. Am Rev Respir Dis 1983 128:820-22 7 Park GO, Radomski L, Goldberg MJ, Spector R, Johnson GF, Quee CK. Effect of size and frequency of multiple oral charcoal doses on theophylline clearance. Clin Pharmacol Ther 1983; 34:663-66 8 Sessler CN, Glauser FL, Cooper KR. 1reatment of theophylline toxicity with oral activated charcoal. Chest 1985; 87:325-29
Prolonged Toxicityafter MasaNe ingestion of TheophyIUne Pr8pendIon (Cotser, )bunga, Baughman)
Massive ingestion of sustained-release theophylline preparations in three patients was treated with gastric lavage and repeated dosages oforally-administered activated charcoal. Therapy was initiated prompdy; however, two patients had their highest theophylline levels documented six to 12 boon after ingestion, and theophylline levels on arrival at the
hospital were signi&candy lower than the maximal level documented. AU three patients had prolonged elevations of the level, with markecUy delayed half-lives of the drug. Overdosages due to sustained release preparations may lead to prolonged toxicity and require aggressive and continuous therapy.
Recently, we treated three patients with profoundly elevated serum theophylline levels following ingestion of toxic quantities of sustained-release theophylline preparations. 1Wo of these patients had dramatic rises in serum theophylline concentrations at six and nine hours after hospital admission despite immediate treatment with oral activated charcoal. The prolonged absorption of sustained release theophylline preparations may cause delayed elevations in serum levelsafter an overdose. This phenomenon has not been well described and has important clinical implications.
admission to the Emergency Department. His initial theophylline level was46.8 "glml. He was given syrup of Ipecac, followed by 100g activated charcoal, in increments, and one bottle of magnesium citrate. He tolerated the orally administered activated charcoal poorly and vomited some of the doses. He was then transferred to the Medical Intensive Care Unit where he was agitated, tremulous, and nauseated. His ECG results showed supraventricular tachyeardia with a rate of 160 to 180. Figure 1 summarizes his theophylline levels during his three-day hospital stay. His serum theophylline level peaked at 91 "glml nine hours after admission. By 26 hours after admission, his theophylline level was 29 "glml, his symptoms had resolved, and his ECG results showed a normal sinus rhythm. He was discharged in good condition.
CASE REPORTS CASE 1
A 25-year-old alcoholic male smoker presented to the Emergency Department following a suicide attempt by ingesting between 30 and 50 Theo-Dur (Key Pharmaceuticals) 300 mg tablets approximately three hours prior to admission. His initial theophylline level upon admission was 69 "glml. A nasogastric tube was placed and he wasgiven 100 g activated charcoaland 300 mlof magnesium citrate in the Emergency Department, then transferred to the Medical Intensive Care Unit where he was noted to be agitated, tremulous, and vomiting profusely. Electrocardiographic examination showed supraventricular tachycardia with a rate of18O to 200. Six hours after admission, his serum theophylline level was 179.6 "glml. Serum theophylline levels were determined in the clinical toxicology laboratory using high pressure liquid chromatography. Figure 1 demonstrates the patients theophylline levels during his hospital stay. 1Wo additional doses (50 g each) of activated charcoal, followed by magnesium citrate, were administered through the nasogastric tube eight and 12 hours after admission, although portions of these doses were vomited. The nausea, vomiting, and tachycardia diminished, and, by 36 hours after admission, his symptoms had resolved. By the third hospital day, his theophylline level was negligible and he was discharged in good health. CASE 2
A 32-year-old male smoker ingested an unknown quantity of his
mother's Constant-T (300 mg) tablets approximately 45 min prior to *From the Department of Internal Medicine and Pharmacy, University of Cincinnati Medical Center, Cincinnati. Manuscript received April 22; revision accepted May 15. Reprint requests: Dr. Bau~man, Pulmona~etl8e Division, Mail Location 564, Unit>errily OjCincinnati Me Center, Cincinnati
45267-0564
CASE 3
A 5i-year-old female smoker with a history of severe chronic obstructive pulmonary disease and several prior suicide attempts presented to the Emergency Department with the complaint of shortness of breath" and, shortly thereafter, developed a generalized major motor seizure. Her outpatient drug-therapy included Theo-Dur, 300 mg tid. Her serum theophylline level was found to be 91 "glml. She underwent placement of a nasogastric tube and had gastric lavage with 2 L normal saline solution, followed by the administration of 100 g activated charcoal and one bottle of magnesium citrate. In the Medical Intensive Care Unit, she was comatose with a diffuse fine tremor and hyperreflexia. ECG examination demonstrated supraventricular tachycardia with a rate of 160. Her abdomen was quiet and abdominal roentgenographic examination showed a nonobstructive ileus pattern. Her theophylline level remained elevated at 78 "glml eighteen hours after admission. Figure 1shows the slow decline ofher theophylline level. Thirty-five hours after admission, she developed ventricular fibrillation, which converted to sinus rhythm following electrical cardioversion. Her ileus gradually resolved and level of consciousness slowly increased. Forty-two hours after admission, her theophylline level was 4.2 "glml. On the sixth hospital day, she suffered cardiopulmonary arrest and subsequently died. II
DISCUSSION
As demonstrated in Figure 1, two of our three patients experienced dramatic rises in theophylline levels after hospital admission despite prompt treatment with boluses of orally administered activated charcoal. The rise in serum concentration was associated with a marked increase in toxic symptoms. We CHEST I 88 I 5 I NOVEMBER. 1985
748
200
'" E .......
C)
~
'" c 0
;:
...e
«S ~
Q) (J
e 0
0
CD
:§ ~
s:
Q.
0
CD
20
s:
~
10
5
10 15 20 25 30 35 40 45 50 55 Time (hrs)
FICURE 1. Semilogarithmic plot of serum theophylline levels in
three patients with theophylline toxicity. Where possible (patients 1
and 2), the elimination rate constant (K) was determined by leastsquares linear regression of the logarithm of the serum concentration of theophylline vs time. The serum half life, t Vi, equals 0.693IK. Patient 1 is represented by (~), patient 2 by (x ), and patient 3 by (0).
have found only one other report showing a delayed peak in serum theophylline levels occurring after treatment with orally administered charcoal. 1 The patient described in that report ingested Theo-Dur 300 mg tablets. Initial serum theophylline level was 56 ~g1ml, and a peak level greater than 200 ~g1ml was documented eight hours later: In this report, case 1 ingested Theo-Our 300 mg tablets. The in vivo absorption of this product after the first 15 percent up to the final 15 percent occurs at a relatively constant rate over approximately 12 hours. 2 In single dose studies, Theo-Dur given as a dose of 8 mglkg body weight produced its peak theophylline level after an average time of9.2±1.9 hours following administration. Patient 2 ingested Constant T (300 mg) tablets. In similar single-dose studies at a dosing equivalent of 8 mg/kg body weight, peak theophylline blood levels occurred at 4.6 ± 0.9 hours after administration as 300 mg tablets. Theophylline is an effective bronchodilator drug in the therapeutic serum range oflO to 20 ~g1ml, but the frequency and severity of toxicity increase as levels rise above 20 ...,g1ml. 3 Gastrointestinal dialysis using orallyadministered activated charcoal to increase theophylline clearance is an effective noninvasive treatment for theophylline toxicity- and has been shown to reduce the serum half-lifeof theophylline administered intra-
750
venously or orally," Orally-administered charcoal pro-motes drug elimination by enhancing the diffusion of theophylline from blood across the gut wall into the intestinal lumen." Furthermore, orally-administered charcoal may bind unabsorbed theophylline, preventing continued absorption. The three patients in this report tolerated poorly the orally-administered activated charcoal. The first two patients had recurrent vomiting, which caused them to lose some of the administered activated charcoal and limited the additional doses that could be given. The third patient had a sustained elevation of serum theophylline levels. This was probably related to her intestinal ileus, which may have diminished the efficacy of the oral activated charcoal. Based on a study of the effects of orally-administered activated charcoal on theophylline clearance in normal volunteer subjects; the optimal frequency of administration of charcoal is probably at doses of 10 to 20 g every two hours." In a series of cases of theophylline toxicity, 30 g of activated charcoal was administered orally every two hours fur two to four doses. Ten of the 14 patients in that study tolerated orallyadministered charcoal and demonstrated both an increase in theophylline clearance and amelioration of symptoms. 8 In conclusion, ingestion of an overdose of a slow-release theophylline preparation may cause dramatic late increases in serum theophylline levels. Early treatment with orally-administered activated charcoal enhances theophylline elimination, but may not avert a large delayed elevation in serum levels. ACKNOWLEDGMENTS: The authors wish to thank Dr. Robert G. Loudon fOrhis revie\\', and Naomi Sims for help in preparation of this manuscript.
REFERENCES 1 Robertson, NJ. Fatal overdose from a sustained-release theophylline preparation. Ann Emerg Med 1985; 14:154-58 2 Hendeles L, Iafrate ~ Weinberger M. A clinical and pharmaeokinetic basisfOrthe selection and use of slow-release theophylline products. Clin Phannakokinetics 1984;9:95-135 3 Hendeles L, Bigbley L, Richardson RH, Hepler CD, Carmichael J. Frequent toxicity from IV aminophylline infusions in criticallyill patients. Drug Intell Clin Phann 1977; 11:12-18 4 Levy G. Gastrointestinal clearance of drugs with activated cbaJ'o coal. N Eng} J Med 1982; 307:676-78 5 Berlinger WG, Spector R, Goldberg MJ, Johnson GF, Quee CI:, Berg MJ. Enhancement of theophylline clearance by oral activated charcoal. Clin Pharmacol Ther 1983; 33:351-54 6 Mahutte CK, 'frue RJ, Michiels TM, Berman JM, Light RW Increased serum theophylline clearance with orally-administered activated charcoal. Am Rev Respir Dis 1983 128:820-22 7 Park GO, Radomski L, Goldberg MJ, Spector R, Johnson GF, Quee CK. Effect of size and frequency of multiple oral charcoal doses on theophylline clearance. Clin Pharmacol Ther 1983; 34:663-66 8 Sessler CN, Glauser FL, Cooper KR. 1reatment of theophylline toxicity with oral activated charcoal. Chest 1985; 87:325-29
Prolonged Toxicityafter MasaNe ingestion of TheophyIUne Pr8pendIon (Cotser, )bunga, Baughman)