The Increase in Total and Unbound Propofol Concentrations During Accidental Hemorrhagic Shock in Patients Undergoing Liver Transplantation

Abstract

To the Editor: Hemorrhagic shock increases the sedative effects of propofol (1,2), so that a patient in hemorrhagic shock should receive only 10%–20% of the propofol dose that a healthy patient would receive (3). However, the mechanism of increase of end-organ sensitivity remains unclear. We demonstrate increases in total and unbound propofol in four patients with advanced cirrhosis who became hemodynamically unstable as a result of massive blood loss during surgery. After IRB approval and with written informed consent from patient, we induced anesthesia with vecuronium 0.1 mg/kg, and propofol 2 mg/kg and maintained anesthesia with 60% air, 0.5%–1.5% isoflurane in oxygen, fentanyl 30 g/kg, and propofol infusion of 2 mg/kg/h. After propofol injection, we collected arterial blood samples to measure blood propofol concentration. We used high-performance liquid chromatography to measure total and unbound propofol concentrations, as reported previously (4). Table 1 shows systolic arterial blood pressure, heart rate, total propofol, fraction unbound, and unbound propofol. After hemorrhagic shock, all patients were infused with lactated Ringer’s solution and mannitol adenine phosphate or were administered dopamine. All patients were adequately resuscitated within 60 min. Total propofol concentrations increased two-fold during hemorrhagic shock, as did the unbound fraction of propofol. The unbound propofol concentrations increased four-fold during hemorrhagic shock.Table 1: Hemodynamic Data and Propofol ConcentrationsThe total propofol concentration likely increased because of the physiological response to shock in our patients. Specifically, shock likely resulted in substantial reductions in hepatic and renal blood flow. Because the clearance of propofol is highly sensitive to liver and renal blood flow (4,5), the propofol clearance decreased during shock, increasing the concentrations during the infusion. This is consistent with effects of experimental hemorrhagic shock on total propofol concentrations in an animal study (1,2,6). However, relatively little attention has been given to hemorrhagic shock’s effect on unbound propofol concentrations. Propofol is a drug with a large distribution volume, high total body clearance (7), and a high degree of binding to plasma albumin, erythrocytes and lipoproteins (8,9) (unbound fraction of <3%). Therefore, the change of unbound fraction is clinically important as we reported previously (3,10). The unbound drug concentration is responsible for a drug’s pharmacological effects, as it is the unbound concentration that equilibrates between the blood and tissues. As the unbound propofol increased four-fold in our patients, this implies that the propofol dose requirements for these patients could be decreased by about 75%, consistent with Shafer’s analysis (3). Daisuke Takizawa, MD Department of Anesthesiology Saitama Cardiovascular and Pulmonary Center Osato-gun, Saitama 360-0105, Japan Department of Anesthesiology Gunma University Graduate School of Medicine 3-39-22 Showa-machi, Maebashi 371-8511, Japan [email protected] Eri Takizawa, MD Department of Anesthesiology Gunma University Graduate School of Medicine 3-39-22 Showa-machi, Maebashi 371-8511, Japan Sohtaro Miyoshi, PhD Fuminori Kawahara, PhD Haruhiko Hiraoka, PhD Department of Anesthesiology Saitama Cardiovascular and Pulmonary Center Osato-gun, Saitama 360-0105, Japan