Pharmacokinetics of high-dose insulin therapy in cardiac surgery

Abstract

Objectives: Elimination half-life and metabolic clearance of intravenously administered insulin at physiological concentrations are approximately 5min and 800–1000mL/min, respectively. However, when insulin is given in high dosages after cardiac surgery, patients require extended glucose infusions even after discontinuation of insulin therapy (IT). We investigated the kinetics of our high-dose insulin protocol and assessed its influence on serum glucose levels. Material and Methods: We included 10 patients with a preoperative EF<40% undergoing CABG with cardioplegic arrest. IT was started at arrival in the ICU (2IU/kg/h for 6h). Rates of glucose and potassium infusion were adjusted hourly. We measured serum levels of insulin in central venous, peripheral venous, peripheral arterial blood and urine. Pharmacokinetic parameters were assessed by Kinetica 4.1. Results: A total of 1030±187IU were infused over the six hours therapy period. Insulin concentration at the end of IT was 14585±5122µU/mL (1000-fold over physiological range). Elimination half-life of insulin after IT was prolonged to 2.95±1.21h. Plasma-clearance was 246±81mL/min. Pulmonary extraction was 23.6±20.2%. Extraction in peripheral tissues was 9.00±10.1%. Urine insulin levels of insulin after IT were 958±2168µU/ml. Serum glucose levels were 132±18.8mg/dL during therapy. Conclusions: Application of supraphysiological dosages of insulin resulted in a significant prolongation of the elimination half-life which was mainly due to an unexpected impairment of plasma clearance. Consideration of these changes allows proper timing and safe application of IT.