Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

Abstract

The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB), resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG) by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 ± 8 years, mean weight 75.4 ± 11.9 kg and mean body surface area 1.83 ± 0.19 m 2 ), receiving propranolol before surgery (80-240 mg a day) and postoperatively (10 mg a day). Plasma propranolol levels were measured before and after CPB by highperformance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre-and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9) to 10.6 h (95% CI = 8.2-14.7; P < 0.01) and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3) to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05), while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6) vs 10.7 ml min -1 kg -1 (95% CI = 7.7-26.6; NS) after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Effect of cardiopulmonary bypass on the pharmacokinetics of propranolol and atenolol

“…This risk score takes into account the following variables: a) emergency procedure, b) preoperative serum creatinine levels, c) presence of left ventricular dysfunction, d) preoperative hematocrit, e) age, f) chronic pulmonary disease, g) prior vascular surgery, h) reoperation, and i) mitral valve insufficiency. Partial results concerning patients receiving propranolol have been already reported elsewhere (10). Body surface area (BSA) and lean body mass (LBM) were calculated using standard formulas, as follows: BSA (m²) = ([height (cm) x weight (kg)] / 3600) ½ ; LBM men (kg) = (1.10 x weight (kg)) -128 (weight 2 / (100 x height (m)) 2 ) and LBM women (kg) = (1.07 x weight (kg)) -148 (weight 2 / (100 x height (m)) 2 ).…”

“…Because it is known that the dose of propranolol necessary to obtain an adequate β-blockade effect in the postoperative period, in order to reduce heart rate to <100 beats per minute (bpm), is lower than the preoperative dose, we carried out a clinical study (10) that showed that cardiopulmonary bypass (CPB) alters the kinetic disposition of propranolol in patients undergoing cardiac surgery.…”

Propranolol Plasma Monitoring in Children Submitted to Surgery of Tetralogy of Fallot by a Micromethod Using High Performance Liquid Chromatography

“…However, the recommended period for discontinuation of the drug prior to the surgery is still controversial. Barazzone and co-workers (1988) proposed an interval of 6 to 8 h after the last propranolol dose, whereas other investigators recommend a longer period ranging from 12-18 h up to 24 h (maximum) before the beginning of the surgical procedure 6,17 . For interpretation of the results (Table 5), plasma propranolol concentrations were normalized to measure the effect of hemodilution caused by the CPB during the surgery.…”

“…On the other hand, when CPB is installed and hemodilution occurs, the plasma propranolol concentration decreases by 50%. In addition, fatsoluble drugs such as propranolol are easily sequestered by the circulator, a fact that contributes to a reduction of plasma propranolol levels during CPB 6 . In the present study, surgery was started about 15h after administration of the last preoperative propranolol dose.…”

“…Patients with tetralogy of Fallot should be submitted to surgical correction consisting of the closure of the ventricular septal defect with alleviation of right ventricular flow obstruction 3,4,5 . Administration of propranolol during the preoperative period is advantageous and reduces the incidence of ischemic events, hypertension and secondary tachyarrhythmias 6 . Because cardiopulmonary bypass (CPB) and hypothermia cause changes in plasma propranolol concentrations, drug monitoring during and after surgery becomes important.…”