Effect of cardiopulmonary bypass on vancomycin and netilmicin disposition

Abstract

The effect of cardiopulmonary bypass (CPB) on the disposition of vancomycin (15 mg/kg) and of netilmicin (3 mg/kg) was studied in 10 adults. The concentration-time profile of the drug in serum and renal clearance were characterized pre-CPB, during CPB, and post-CPB. Vancomycin and netilmicin exhibited initial decreases in mean concentrations in serum of 4.0 mg/liter (16.8%) and 2.2 mg/liter (29.1%), respectively, upon initiation of CPB. Netilmicin concentrations in serum rebounded to a mean of 0.6 mg/liter (15.4%) within 90 min on CPB and then continuously decreased. Vancomycin concentrations in serum demonstrated a rebound increase of 2.3 mg/liter (23.5%) at the end of CPB when the aorta was unclamped. Mean renal clearance throughout CPB was decreased for vancomycin (58.4 to 43.4 ml/min per mi2) and netilmicin (53.4 to 31.5 ml/min per m2). The rebound in vancomycin concentration in serum strongly correlated with the length of time between unclamping the aorta and coming off CPB (r = 0.94), as well as with the increase in temperature upon rewarming (r = 0.92).Antimicrobial prophylaxis for cardiopulmonary bypass (CPB) surgery is routinely prescribed to prevent endocarditis or sternal and costochondral infections (7, 26). Selection of an appropriate antibiotic is directed against Staphylococcus aureus and Staphylococcus epidermidis, which account for the majority of bacterial infections, and also against the gram-negative bacilli (2, 3, 7, 26). The increasing incidence of methicillin-resistant staphylococci has led to the recommendation that vancomycin be administered prophylactically for cardiothoracic surgery in hospitals in which methicillin-resistant staphylococci are prevalent (3,15,16). Aminoglycosides have been recommended for prophylaxis against the gram-negative pathogens on the cardiac valves and the sternum and for some prophylactic effect against staphylococci (16).Many physiologic changes occur in patients placed on CPB. These changes, including decreased cardiac output and organ perfusion, can alter drug absorption, distribution, metabolism, and excretion (13,14). Studies with prophylactic vancomycin and netilmicin in CPB surgery are very limited. Only two reports have examined vancomycin concentrations in serum during CPB surgery, and both sought to determine appropriate dosing, rather than drug disposition (4, 10).One published report of aminoglycoside prophylaxis in open-heart surgery has addressed netilmicin concentrations in pericardial fluid, atrial appendage, and serum but only in the intraoperative phase of CPB (27). Therefore, this study was designed to investigate what effect CPB surgery has on the disposition of two renally excreted prophylactic antibiotics, vancomycin and netilmicin, before, during, and after CPB. MATERIALS AND METHODSA total of 10 adult patients scheduled for elective coronary artery bypass grafting or cardiac valve replacement surgery requiring CPB were studied. All patients gave written informed consent to participate in this protocol, which was * Corresponding author....

Ceftriaxone disposition in open-heart surgery patients

“…However, this can be explained by the dose-dependent characteristics of ceftriaxone where higher free concentrations (as in this study) give rise to higher clearances based on total drug (31). Physiologically, though, renal and liver functions are adversely affected by hypothermia and CPB (14,15,27). The CLCR and clearances based on free drug are consistent with the physiologic changes known to occur and other reports of reduced drug clearance (11) during CPB.…”

“…Renal clearances (CLR) of vancomycin and netilmicin de-* Corresponding author. crease during CPB (14). Decreased hepatic elimination has also been demonstrated for fentanyl (15).…”

“…Blood flow is decreased during CPB, and hypothermia causes shunting of blood away from peripheral organs, leading to decreased liver and kidney clearing ability (14,15,27,35). Hemodilution and concomitant drug administration may also alter protein binding in plasma and interstitial fluid and may influence overall drug distribution (22,36).…”

Penetration of vancomycin into mediastinal and cardiac tissues in humans

“…After aortic unclamping, an increase (although nonsignificant) in plasma vancomycin levels was observed at T6 and T7. This was probably explained by the fact that upon rewarming and increased blood circulation, vancomycin returned to the intravascular volume from peripheral tissues, as well as from tissues which were isolated from the CPB circuit (10). This increase in plasma vancomycin levels in group 1 patients probably explained why the concentrations in tissue were not different between the two groups at the end of surgery.…”

“…Many physiological changes occur in patients placed on CBP, and this technique is known to alter drug levels in plasma (8,15). At least two factors can explain this result: a rapid increase in the volume of distribution because of the additional volume in the priming pump (11) and drug sequestration within the CPB circuit, which has been demonstrated for fentanyl (8) and nitroglycerin (5) but is only suspected for vancomycin (10). Whatever the mechanism, plasma vancomycin concentrations decrease when the patient is placed on CPB.…”