Theophylline kinetics in acute pulmonary edema Nine patients with acute cardiogenic pulmonary edema were given theophylline intravenously, and its disposition was observed over the next 24 hr. Compared to that in 19 normal subjects, these patients had prolonged plasma half-lifes (mean, 22.9 from 6.7 hr) and decreased plasma clearances of theophylline (mean, 0.041 from 0.062 L [kg-I] hr- I). The intersubject variation in these parameters was 20-fold in patients with pulmonary edema and 4-fold in normal subjects. Since the peak plasma concentrations attained and the apparent volumes of distribution were not different in the two groups, a suitable initial dose can be calculated. A loading dose of 4.5 to 5 mg Ikg theophylline (6 mglkg aminophylline) given over 20 min appears sale. Because ~f the great variability in the plasma clearance of this drug in patients with heart failure, plasma concentrations and toxicity would be unpredictable after repeated doses or constant infusions.
K. M. Piafsky, M.D., D. S. Sitar, Ph.D.,. R. E. Rangno, M.D., and R. I. Ogilvie, M.D. Montreal, Quebec, Canada Clinical Pharmacology Division, the Montreal General Hospital, and Departments of
Medicine and Pharmacology and Therapeutics, McGill University
Intravenous aminophylline (theophylline ethylenediamine) is widely recommended as an adjunct to the treatment of acute left ventricular failure. Present dosage recommendations are entirely empirical and there is no clear evidence of the need for theophylline treatment. To obtain more complete information on theophylline kinetics and hence dosage requirements, the disposition of single intravenous doses of theophylline was studied in patients with acute left ventricular failure during the initial stage of illness. Supported by grants from the Medical Research Council of Canada (MA-4847) and the Canadian Foundation for the Advancement of Therapeutics. Received for publication Aug. 27, 1976. Accepted for publication Jan. 3, 1977. Reprint requests to: Dr. R. I. Ogilvie, Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec H3G IA4. 'Monat Scholar, McGill University.
310
Methods and materials
Patients with pulmonary edema. Nine patients from the Emergency Department and Medical Wards of the Montreal General Hospital were given theophylline intravenously as part of their therapy for acute left ventricular failure. The diagnosis was made on the basis of a history of acute onset or severe exacerbation of dyspnea in a patient with diffuse bilateral chest rales on auscultation and a chest x-ray exhibiting signs of severe cardiogenic pulmonary edema. The patients received theophylline (2.3 or 4.5 mg/kg) as aminophylline through a Harvard infusion pump over 28 min into the side arm of an intravenous line. The theophylline was administered within 15 min of the attending physician's decision to use the drug. Patients received theophylline within 15 min to 2 hr after clinical presentation and all were consid-
Theophylline kinetics
Volume 21 Number 3
ered to be in severe congestive heart failure when the theophylline was administered. Biventricular heart failure was present in all but Patients 3 and 8. All patients had received intravenous furosemide and 5 had received morphine sulphate subcutaneously or intravenously. Four patients received digoxin acutely and 4 others were already receiving digoxin chronically. Patients 1,2,3, and 8 gave a history of smoking cigarettes prior to admission to hospital. The purpose of the study was explained to all of the patients. * Blood samples (5 ml in sodium oxalate) were taken from an indwelling venous catheter in the arm opposite the infusion. Whenever possible, blood was taken at the following times after the start of the infusion: 0, 10, 20, 30, 45, 60, and 90 min and 2, 3,4,6,8, 12, 18, and 24 hr. All patients were observed for adverse effects, and cardiac rates and rhythms were continuously monitored in the Medical Intensive Care Unit for at least 24 hr after receiving the theophylline. Normal subjects. The controls were 19 men who were either normal volunteers or patients on the medical wards. None had renal, hepatic, or cardiac dysfunction as assessed by clinical examination and laboratory tests. Ten were smokers. Subjects receiving other drugs were excluded. Each subject received theophylline 4.5 mg/kg as aminophylline delivered by Harvard infusion pump over 6 to 28 min. Blood samples were taken according to the schedule described above. Analysis. The blood samples were centrifuged and the plasma separated and frozen. Analysis of theophylline was performed in duplicate using the high-performance liquid chromatographic method of Sitar and coworkers. 12 This method is specific for theophylline and sensitive to 0.1 fLg/ml with a coefficient of variation of
K. M. Piafsky, M.D., D. S. Sitar, Ph.D.,. R. E. Rangno, M.D., and R. I. Ogilvie, M.D. Montreal, Quebec, Canada Clinical Pharmacology Division, the Montreal General Hospital, and Departments of
Medicine and Pharmacology and Therapeutics, McGill University
Intravenous aminophylline (theophylline ethylenediamine) is widely recommended as an adjunct to the treatment of acute left ventricular failure. Present dosage recommendations are entirely empirical and there is no clear evidence of the need for theophylline treatment. To obtain more complete information on theophylline kinetics and hence dosage requirements, the disposition of single intravenous doses of theophylline was studied in patients with acute left ventricular failure during the initial stage of illness. Supported by grants from the Medical Research Council of Canada (MA-4847) and the Canadian Foundation for the Advancement of Therapeutics. Received for publication Aug. 27, 1976. Accepted for publication Jan. 3, 1977. Reprint requests to: Dr. R. I. Ogilvie, Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec H3G IA4. 'Monat Scholar, McGill University.
310
Methods and materials
Patients with pulmonary edema. Nine patients from the Emergency Department and Medical Wards of the Montreal General Hospital were given theophylline intravenously as part of their therapy for acute left ventricular failure. The diagnosis was made on the basis of a history of acute onset or severe exacerbation of dyspnea in a patient with diffuse bilateral chest rales on auscultation and a chest x-ray exhibiting signs of severe cardiogenic pulmonary edema. The patients received theophylline (2.3 or 4.5 mg/kg) as aminophylline through a Harvard infusion pump over 28 min into the side arm of an intravenous line. The theophylline was administered within 15 min of the attending physician's decision to use the drug. Patients received theophylline within 15 min to 2 hr after clinical presentation and all were consid-
Theophylline kinetics
Volume 21 Number 3
ered to be in severe congestive heart failure when the theophylline was administered. Biventricular heart failure was present in all but Patients 3 and 8. All patients had received intravenous furosemide and 5 had received morphine sulphate subcutaneously or intravenously. Four patients received digoxin acutely and 4 others were already receiving digoxin chronically. Patients 1,2,3, and 8 gave a history of smoking cigarettes prior to admission to hospital. The purpose of the study was explained to all of the patients. * Blood samples (5 ml in sodium oxalate) were taken from an indwelling venous catheter in the arm opposite the infusion. Whenever possible, blood was taken at the following times after the start of the infusion: 0, 10, 20, 30, 45, 60, and 90 min and 2, 3,4,6,8, 12, 18, and 24 hr. All patients were observed for adverse effects, and cardiac rates and rhythms were continuously monitored in the Medical Intensive Care Unit for at least 24 hr after receiving the theophylline. Normal subjects. The controls were 19 men who were either normal volunteers or patients on the medical wards. None had renal, hepatic, or cardiac dysfunction as assessed by clinical examination and laboratory tests. Ten were smokers. Subjects receiving other drugs were excluded. Each subject received theophylline 4.5 mg/kg as aminophylline delivered by Harvard infusion pump over 6 to 28 min. Blood samples were taken according to the schedule described above. Analysis. The blood samples were centrifuged and the plasma separated and frozen. Analysis of theophylline was performed in duplicate using the high-performance liquid chromatographic method of Sitar and coworkers. 12 This method is specific for theophylline and sensitive to 0.1 fLg/ml with a coefficient of variation of
