We evaluated changes in propranolol plasma levels before, during, and after ... propranolol and had received their last oral dose 10 to 15 hr before surgery.
Plasma propranolol before, during, and after
cardiopulmonary bypass propranolol plasma levels before, during, and after cardiopulmonary bypass (CPB). Two groups of patients were studied, all of whom had been on long-term propranolol and had received their last oral dose 10 to 15 hr before surgery. Approximately 100 min belbre CPB began group I patients (n = 7) received 0.1 mg /kg propranolol intravenously while group II patients (n = 7) received a placebo. Before CPB the plasma propranolol levels fell in accordance with published descriptions for nonsurgical patients receiving oral and intravenous propranolol. Thereafter, the changes in the plasma levels were much the same in both groups. With the onset of CPB, the plasma levels decreased by approximately 50%. There was an insignificant fall in plasma levels during CPB, but the most interesting observation was made after: in each patient, the plasma levels obtained 5, 60, 120, and 240 min after CPB were higher than the last level during CPB. Mean plasma levels did not decline in either group during the 4-hr period. Although the reason for the sustained rise in the propranolol levels after CPB is not known, we suggest that it is due to the redistribution of propranolol from the lungs to the plasma coupled with reduction in hepatic elimination. We evaluated changes in
John R. Plachetka, Pharm.D., Neal W. Salomon, M.D., and Jack G. Copeland, M.D. Tucson, Ariz.
Department of Pharmacy Practice, College of Pharmacy, and Division of Cardiovascular and Thoracic Surgery, College of Medicine, University of Arizona Health Sciences Center
Contrary to the early experience of Viljoen,26 continuing propranolol therapy to within 2 to 24 hr of coronary bypass surgery has been shown to be beneficial for most patients.8, 16, 24, 27 Compared to patients in whom propranolol therapy is stopped before surgery, those maintained on the drug have lower myocardial oxygen consumption" throughout the perioperative Presented, in part, at the Eighty-second Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, New Orleans, La., March 19-21, 1981. Received for publication June 17, 1981. Accepted for publication Aug. 29, 1981. Reprint requests to: Jack G. Copeland, M.D., College of Medicine, University of Arizona Health Sciences Center, Tucson, AZ 85724.
period. Intravenous propranolol has been used for the treatment of arrhythmias during anesthesia" and for the prevention of arrhythmias that are common in the early postoperative period. 16' " Although propranolol kinetics under normal conditions are described,7' 25 there is little information on its disposition before, during, and immediately after cardiopulmonary bypass (CPB). McAllister et al.12 have shown that propranolol plasma levels rise during hypothermic CPB, and in that and a subsequent report" hypothermia was shown to inhibit the hepatic metabolism of propranolol and to reduce its volume of distribution. The handling of propranolol
0009-9236/81/120745+07$00.70/0 © 1981 The C. V. Mosby Co.
745
746
din. Pharmacol.
Ther. December 1981
Plachetka et al.
Table I. Patient characteristics Group I Age (yr) Weight (kg) Daily propranolol dose (mg) Time since last oral dose Pre-CPB Cl (//min/m2) (hr) Flow during CPB (//min/m2) Lowest ToC during CPB Total perfusion time (min) Pump prime (m1) Heparin dose (units) Protamine dose (mg)
59.3 ± 1.8 87.5 -± 5.7 213.3 ±- 39.6 11.5 ± 0.9 2.23 -± 0.10 1.50 ± 0.05 31.3 -±- 0.4 85.3 ± 13.8 1842
±-
129
27500 ± 1204 418 ± 15
immediately before and after CPB, however, has only been briefly described."' 28 We undertook this study because of increased interest in the use of propranolol during the perioperative period and to better understand the fate of propranolol after oral and intravenous use before, during, and after hypothermic CPB. Methods
Our subjects were 14 patients undergoing coronary artery bypass surgery (Table I). All patients were maintained preoperatively on long-term oral propranolol and received their last propranolol dose 10 to 15 hr before surgery. Patients were randomly assigned to one of two groups: group I patients (n = 7) received an intravenous dose of propranolol, 0.1 mg/kg over 15 min, before induction of anesthesia and those in group II (n = 7) received a placebo injection. Both injections were made approximately 100 min before CPB began. No patient in group I suffered any adverse reaction. One patient in group I was found to have taken an oral dose of propranolol 2 hr before surgery and, since continued drug absorption may have occurred during the study period, was eliminated from our data analysis. Assigning the time of intravenous propranolol or placebo dosing as time 0, blood samples were obtained at -15, 0, 5, 15, 30, and 60 min, immediately before CPB (Pre-CPB), 5, 20 and 40 min after beginning CPB, and 5 min before discontinuing (end-CPB) and 5, 60, 120, and 240 min after discontinuing CPB. After time 0, no additional
Group II -± 3.9 78.4 ± 2.9 377.1 -±- 62.2 11.9 ± 0.9 2.07 -± 0.10 1.57 -± 0.05 31.0 -± 0.5 80.9 -± 9.75
57.1
1786
±-
101
25286 ± 896 401
±
18
NS NS
0.06 NS NS NS NS NS NS NS NS
propranolol was given. Plasma propranolol concentrations were determined by the modified" fluorometric method of Shand,23 which is specific for propranolol. Cardiac index (cardiac output ± body surface area) was measured by thermodilution before anesthesia (morphine and nitrous oxide) was induced. The pump prime consisted of a solution of mannitol (12.5 gm), calcium chloride (1 gm), sodium bicarbonate (44.5 mEq), heparin (4,000 units), and 1.5-1 lactated Ringer's solution. Additional heparin (300 units/kg) was injected approximately 15 min before and moderate hypothermia (31°) and low flow (40 to 50 ml/kg/min) were used during CPB. Protamine sulfate was given soon after the bypass was discontinued. Pertinent CPB data are listed in Table I. Unless otherwise stated, data are expressed as mean ± 1 SEM. Differences between groups were tested by a two-tailed Student t test for unpaired samples. Differences between mean plasma propranolol levels from different sampling times within the same group were tested by the two-tailed Student t test for paired samples. The pre-CPB propranolol half-life (t1/2) for patients in group II was obtained by applying linear regression analysis to the pre-CPB plasma levels. Results
Group I. A semilogarithmic plot of plasma propranolol levels versus time for subjects in group I is shown in Fig. 1. The intravenous administration of 0.1 mg/kg propranolol increased
Volume 30 Number 6
Plasma propranolol and cardiopulmonary bypass
Oral & I.V. Propranolol
400
747
400 300
300
200
200
p < 0.05 vs Previous Level
"p
