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Use of hemoperfusion for treatment of theophylline intoxication
472
despite differing heart rate profiles. The authors conclude that the overall efficacy of the slow calcium channel blocker verapamil compares favorably with that of propranolol but by different mechanisms - propranolol by its negative chronotropic effects and verapamil both by its effects on systemic and coronary arterioles and by its intracellular oxygen sparing effects. [Tom Drake, MD]
? I?DOBUTAMINE. Leier CV, Unverferth DV. Ann Intern Med 1983; 99:490-496.
Presented is a review of the pharmacology and clinical indications for the use of dobutamine, a synthetic catecholamine with a relatively selective positive inotropic effect. The predominant mechanism of action of dobutamine is augmentation of myocardial contractility mediated through /3-adrenergic stimulation with mild stimulation of PI and c~, receptors. There is a linear relationship between dobutamine dose, plasma concentration, and hemodynamic effect. Dobutamine is administered as a continuous intravenous infusion beginning at doses of 2 to 3 pg/kg/min, with 2 to 3 pg/kg/min increments until the desired hemodynamic effects are obtained or undesirable side effects occur. Optimal maintenance doses usually range between 7.5 and 15 pg/kg/min. Side effects include tachycardia, dysrhythmias, headache, anxiety, tremors, and excessive changes in blood pressure. Onset of action with continuous infusion is within two minutes with a maximum effect at ten minutes. The mean plasma half-life is 2.37 ho.70 minutes. Dobutamine is indicated for use as short-term positive inotropic support in the treatment of cardiovascular decompensation secondary to depressed myocardial contractility as found with chronic coronary insufficiency, acute myocardial infarction, and during and after cardiac surgery. Dobutamine has less vasopressor activity than norepinephrine and dopamine and should not be the primary treatment in conditions characterized by marked hypotension [Patricia L. Johnson, MD] or shock. Editor’s Note: This is an excellent, comprehensive review of the pharmacology and clinical indications for dobutamine.
?? CURRENT STATUS OF ERYTHROCYTE SUBSTITUTES. Byrd GP. Can Med Assoc J 1983; 129:237-244.
The Journal of Emergency Medicine
The production of blood substitutes is an area of active research and development. Hemoglobin solutions free of cellular stromal elements and emulsified fluorocarbon mixtures are the two groups of agents that will probably satisfy many of the requirements for stable noncellular oxygen delivery solutions. Stroma-free hemoglobin solution has a short half-life (two to three hours) in plasma and binds oxygen strongly, adversely affecting tissue off-loading. Manipulations of the hemoglobin molecule have produced a longer-lasting compound with reduced oxygen affinity. Further improvements are needed before a clinically useful solution is available. Oxygen-soluble fluorocarbon substitutes can contribute significantly to oxygen supply if hyperbaric oxygen is used to increase arterial PO, well above physiologic levels. Reversible distortion of liver morphology without disturbed hepatocellular function has been observed in animal models. There is little information available comparing these two agents. The hemodynamic effects are similar and both show promise as oxygen-transporting plasma expanders. Fluorocarbons have the added potential for use as agents for oxygen delivery in cases of poisoning with carbon monoxide, sulfide, or cyanide, because unloading of oxygen to and from fluorocarbons is not affected by the abnormal ligands of hemoglobin. [Brian McGowan, MD]
?U ?SE OF HEMOPERFUSION FOR TREATMENT OF THEOPHYLLINE .INTOXICATION. Park GD, Spector R, Roberts RJ, et al. Am JMed
1983; 74:961-966.
The authors retrospectively studied 36 patients with a plasma theophylline concentration of 30 pg/mL or greater seen over a 2%-year period. Twenty-two patients had plasma theophylline concentrations of 37 i 1 pg/mL and experienced no severe toxicity (i.e., ventricular extrasystoles or tachycardia, seizures, cardiovascular collapse, or death); these patients were managed by discontinuation or reduction of the theophylline dose. Six patients had toxic plasma theophylline concentrations (mean 92 * 12 pg/mL) from self-administered overdose; eight patients had iatrogenically induced toxicity with a mean serum concentration of 48 f 6 &mL. Six of these latter 14 patients underwent charcoal hemoperfusion, 1 of whom died. This patient had developed seizures prior to treatment. Three
Abstracts
of the patients not having hemoperfusion had fatal outcomes, two following seizures, one with cardiovascular collapse. The elimination rate of theophylline was increased five fold with hemoperfusion. Only minimal complications were experienced with charcoal hemoperfusion (hypotension, hypocalcemia, and thrombocytopenia) and all were easily managed. The authors conclude that early charcoal hemoperfusion is indicated for the treatment of theophylline toxicity in all patients with theophylline plasma concentrations greater than 60 pg/mL at four hours post ingestion. Hemoperfusion is also indicated in patients with concentrations of < 60 pg/mL but > 30 pg/mL who have three of the four following risk factors: (1) age 60 years or greater, (2) significant liver disease or congestive heart failure, (3) a theophylline half-life of 24 hours or greater, (4) theophylline plasma concentration 50 pg/mL or greater. There is no evidence that lowering the theophylline concentration is of any clinical benefit once seizures [Elizabeth Black, MD] develop. Editor’s Note: The authors present a detailed review of their experience with theophylline toxicity and charcoal hemoperfusion. More importantly, they provide indications for hemoperfusion in severe theophylline toxicity.
ClACUTE ISOPROPYL ALCOHOL INTOXICATION. DIAGNOSIS AND MANAGEMENT. Lacouture PG, Wason S, Abrams A, Lovejoy FH Jr. Am J A4ed 1983; 75:680-86. The authors review 22 cases of isopropyl alcohol intoxication and discuss its pharmacology, toxicology, differential diagnosis, and management. Signs and symptoms of intoxication include abdominal pain and vomiting, ataxia, lethargy, confusion, and coma. The onset of central nervous system effects is usually rapid, occuring within 30 to 60 minutes of ingestion. With large doses, myocardial depression and severe hypotension may result. Patients having both coma and hypotension have the poorest prognosis. The differential characteristics of isopropyl alcohol toxicity compared with other alcohols (methyl, ethyl, and ethylene glycol) are discussed, emphasizing differences in degree of acidosis and ketosis and presence of an anion
473
gap and increased serum osmolality. Management is largely supportive. Indications for hemodialysis include hypotension, coma, and a serum alcohol level of greater than 400 mg/dL. [Elizabeth Mueller, MD]
?? DIAZEPAM LOADING: SIMPLIFIED TREATMENT OF ALCOHOL WITHDRAWAL. Sellers EM, Naranjo CA, Harrison M, et al. Clin Pharmacol Ther 1983; 34:822-826. A simplified treatment protocol for alcohol withdrawal is described. In view of the extended half-life of diazepam and its metabolites, the authors hypothesized that if an adequate oral loading dose of diazepam were given, therapeutic concentrations of diazepam and its active metabolites should be present for longer than the 72 hours usually required for alcohol withdrawal symptoms to subside. In a randomized double-blind trial, 50 patients in moderate-to-severe alcohol withdrawal received supportive care and either 20 mg of oral diazepam or placebo every two hours until they were asymptomatic. Clinical course was assessed using the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A). Patients receiving diazepam had more rapid and greater improvement than those treated with placebo. The median number of diazepam doses needed to treat alcohol withdrawal was three, given over a period of 7.6 hours. Any patient who did not respond to six doses of diazepam or placebo received (unblinded) oral diazepam 20 mg every two hours. On this regimen, all patients eventually improved. Once adequate diazepam loading was accomplished, no patient needed more of the drug. There were no adverse effects from the diazepam. Complications occurred in four patients (two seizures, one hallucination, one arrhythmia), all of whom had initially been treated with placebo. The authors suggest that this delay in benzodiazepine therapy may have been responsible for the appearance of complications in alcohol withdrawal. [James E. Gruber, MD] Editor’s Note: As the authors note, one further benefit of this proposed method of treatment is that patients do not have drug-seeking behavior reinforced, as may be the case when a medication is given on a pm basis.
despite differing heart rate profiles. The authors conclude that the overall efficacy of the slow calcium channel blocker verapamil compares favorably with that of propranolol but by different mechanisms - propranolol by its negative chronotropic effects and verapamil both by its effects on systemic and coronary arterioles and by its intracellular oxygen sparing effects. [Tom Drake, MD]
? I?DOBUTAMINE. Leier CV, Unverferth DV. Ann Intern Med 1983; 99:490-496.
Presented is a review of the pharmacology and clinical indications for the use of dobutamine, a synthetic catecholamine with a relatively selective positive inotropic effect. The predominant mechanism of action of dobutamine is augmentation of myocardial contractility mediated through /3-adrenergic stimulation with mild stimulation of PI and c~, receptors. There is a linear relationship between dobutamine dose, plasma concentration, and hemodynamic effect. Dobutamine is administered as a continuous intravenous infusion beginning at doses of 2 to 3 pg/kg/min, with 2 to 3 pg/kg/min increments until the desired hemodynamic effects are obtained or undesirable side effects occur. Optimal maintenance doses usually range between 7.5 and 15 pg/kg/min. Side effects include tachycardia, dysrhythmias, headache, anxiety, tremors, and excessive changes in blood pressure. Onset of action with continuous infusion is within two minutes with a maximum effect at ten minutes. The mean plasma half-life is 2.37 ho.70 minutes. Dobutamine is indicated for use as short-term positive inotropic support in the treatment of cardiovascular decompensation secondary to depressed myocardial contractility as found with chronic coronary insufficiency, acute myocardial infarction, and during and after cardiac surgery. Dobutamine has less vasopressor activity than norepinephrine and dopamine and should not be the primary treatment in conditions characterized by marked hypotension [Patricia L. Johnson, MD] or shock. Editor’s Note: This is an excellent, comprehensive review of the pharmacology and clinical indications for dobutamine.
?? CURRENT STATUS OF ERYTHROCYTE SUBSTITUTES. Byrd GP. Can Med Assoc J 1983; 129:237-244.
The Journal of Emergency Medicine
The production of blood substitutes is an area of active research and development. Hemoglobin solutions free of cellular stromal elements and emulsified fluorocarbon mixtures are the two groups of agents that will probably satisfy many of the requirements for stable noncellular oxygen delivery solutions. Stroma-free hemoglobin solution has a short half-life (two to three hours) in plasma and binds oxygen strongly, adversely affecting tissue off-loading. Manipulations of the hemoglobin molecule have produced a longer-lasting compound with reduced oxygen affinity. Further improvements are needed before a clinically useful solution is available. Oxygen-soluble fluorocarbon substitutes can contribute significantly to oxygen supply if hyperbaric oxygen is used to increase arterial PO, well above physiologic levels. Reversible distortion of liver morphology without disturbed hepatocellular function has been observed in animal models. There is little information available comparing these two agents. The hemodynamic effects are similar and both show promise as oxygen-transporting plasma expanders. Fluorocarbons have the added potential for use as agents for oxygen delivery in cases of poisoning with carbon monoxide, sulfide, or cyanide, because unloading of oxygen to and from fluorocarbons is not affected by the abnormal ligands of hemoglobin. [Brian McGowan, MD]
?U ?SE OF HEMOPERFUSION FOR TREATMENT OF THEOPHYLLINE .INTOXICATION. Park GD, Spector R, Roberts RJ, et al. Am JMed
1983; 74:961-966.
The authors retrospectively studied 36 patients with a plasma theophylline concentration of 30 pg/mL or greater seen over a 2%-year period. Twenty-two patients had plasma theophylline concentrations of 37 i 1 pg/mL and experienced no severe toxicity (i.e., ventricular extrasystoles or tachycardia, seizures, cardiovascular collapse, or death); these patients were managed by discontinuation or reduction of the theophylline dose. Six patients had toxic plasma theophylline concentrations (mean 92 * 12 pg/mL) from self-administered overdose; eight patients had iatrogenically induced toxicity with a mean serum concentration of 48 f 6 &mL. Six of these latter 14 patients underwent charcoal hemoperfusion, 1 of whom died. This patient had developed seizures prior to treatment. Three
Abstracts
of the patients not having hemoperfusion had fatal outcomes, two following seizures, one with cardiovascular collapse. The elimination rate of theophylline was increased five fold with hemoperfusion. Only minimal complications were experienced with charcoal hemoperfusion (hypotension, hypocalcemia, and thrombocytopenia) and all were easily managed. The authors conclude that early charcoal hemoperfusion is indicated for the treatment of theophylline toxicity in all patients with theophylline plasma concentrations greater than 60 pg/mL at four hours post ingestion. Hemoperfusion is also indicated in patients with concentrations of < 60 pg/mL but > 30 pg/mL who have three of the four following risk factors: (1) age 60 years or greater, (2) significant liver disease or congestive heart failure, (3) a theophylline half-life of 24 hours or greater, (4) theophylline plasma concentration 50 pg/mL or greater. There is no evidence that lowering the theophylline concentration is of any clinical benefit once seizures [Elizabeth Black, MD] develop. Editor’s Note: The authors present a detailed review of their experience with theophylline toxicity and charcoal hemoperfusion. More importantly, they provide indications for hemoperfusion in severe theophylline toxicity.
ClACUTE ISOPROPYL ALCOHOL INTOXICATION. DIAGNOSIS AND MANAGEMENT. Lacouture PG, Wason S, Abrams A, Lovejoy FH Jr. Am J A4ed 1983; 75:680-86. The authors review 22 cases of isopropyl alcohol intoxication and discuss its pharmacology, toxicology, differential diagnosis, and management. Signs and symptoms of intoxication include abdominal pain and vomiting, ataxia, lethargy, confusion, and coma. The onset of central nervous system effects is usually rapid, occuring within 30 to 60 minutes of ingestion. With large doses, myocardial depression and severe hypotension may result. Patients having both coma and hypotension have the poorest prognosis. The differential characteristics of isopropyl alcohol toxicity compared with other alcohols (methyl, ethyl, and ethylene glycol) are discussed, emphasizing differences in degree of acidosis and ketosis and presence of an anion
473
gap and increased serum osmolality. Management is largely supportive. Indications for hemodialysis include hypotension, coma, and a serum alcohol level of greater than 400 mg/dL. [Elizabeth Mueller, MD]
?? DIAZEPAM LOADING: SIMPLIFIED TREATMENT OF ALCOHOL WITHDRAWAL. Sellers EM, Naranjo CA, Harrison M, et al. Clin Pharmacol Ther 1983; 34:822-826. A simplified treatment protocol for alcohol withdrawal is described. In view of the extended half-life of diazepam and its metabolites, the authors hypothesized that if an adequate oral loading dose of diazepam were given, therapeutic concentrations of diazepam and its active metabolites should be present for longer than the 72 hours usually required for alcohol withdrawal symptoms to subside. In a randomized double-blind trial, 50 patients in moderate-to-severe alcohol withdrawal received supportive care and either 20 mg of oral diazepam or placebo every two hours until they were asymptomatic. Clinical course was assessed using the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A). Patients receiving diazepam had more rapid and greater improvement than those treated with placebo. The median number of diazepam doses needed to treat alcohol withdrawal was three, given over a period of 7.6 hours. Any patient who did not respond to six doses of diazepam or placebo received (unblinded) oral diazepam 20 mg every two hours. On this regimen, all patients eventually improved. Once adequate diazepam loading was accomplished, no patient needed more of the drug. There were no adverse effects from the diazepam. Complications occurred in four patients (two seizures, one hallucination, one arrhythmia), all of whom had initially been treated with placebo. The authors suggest that this delay in benzodiazepine therapy may have been responsible for the appearance of complications in alcohol withdrawal. [James E. Gruber, MD] Editor’s Note: As the authors note, one further benefit of this proposed method of treatment is that patients do not have drug-seeking behavior reinforced, as may be the case when a medication is given on a pm basis.