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October 14, 2006
1:45 PM - 3:15 PM
Room N426a
The Influence of Hemorrhagic Shock on Ketamine: A Pharmacokinetic Analysis
Ian H. Black, M.D., Kurt W. Grathwohl, M.D., Irasema B. Terrazas, M.S., Wenjun Z. Martini, Ph.D., Ken B. Johnson, M.D.
Anesthesiology, US Army Institute of Surgical Research, San Antonio, Texas
Background: Recently, several studies have explored the influence of hemorrhagic shock (HS) on the pharmacokinetics (PKs) of commonly used anesthetic drugs. This work demonstrates that severe blood loss may result in elevated drug plasma levels and prolonged drug clearance with subsequent adverse hemodynamic effects. While some early work highlighted the survival and hemodynamic benefits of ketamine during HS, the influence of moderate to severe blood loss on ketamine's PK behavior has not been explored. Ironically ketamine is a first line induction agent when managing patients suffering from HS. In this study, we quantified the influence of a severe isobaric bleed on ketamine's PKs in a swine model to test the hypothesis that severe blood loss would alter ketamine's PKs.

Methods: After approval from the Animal Care Committee, 12 pigs were randomly assigned to control and shock groups. Pigs were anesthetized with isoflurane, and mechanically ventilated. All animals were instrumented with a femoral artery catheter bilaterally, a pulmonary artery catheter, and an ear vein catheter. Pigs randomized to the shock group were bled to a MAP of 40 mmHg until decompensation as defined by infusion of shed blood or blood lactate; an average of 39 mL/kg was removed. Ketamine 500 mcg/kg/min was infused for 10 minutes to both groups. Twenty arterial samples from each animal were collected at frequent intervals for 250 minutes after the infusion began and analyzed to determine drug concentration. The PK parameters were estimated using a two stage approach with a three compartment model in NONMEM. A P value less than 0.0083 was considered significant as six simultaneous comparisons were made.

Results: All swine completed the experiment. The raw data demonstrated plasma ketamine levels that were slightly higher in the bled animals during the continuous infusion of ketamine (Figure 1). The mean peak plasma ketamine levels were 12.4 and 7.6 mcg/mL in the shock and control animals respectively. Following the infusion, the difference in plasma levels between groups diminished. The compartmental analysis revealed a statistically significant smaller central compartment and a decreasing trend in central clearance in the shock group (Table 1).

Conclusions: Severe isobaric HS minimally altered ketamine PKs. The extent of PK changes in the presence of blood loss appears to be much smaller when compared to propofol and more similar to etomidate. These findings suggest, from a PK perspective, that moderate to severe blood loss has little clinical impact on ketamine dosing.[table1][figure1]

Anesthesiology 2006; 105: A203
Table 1- PK Parameters (Mean Cp ± SEM)
ShockControlP value
Vc (L)2.2 ± 0.44.9 ± 0.60.008*
V2 (L)4.5 ± 0.46.4 ± 0.80.095
V3 (L)42.2 ± 4.046.0 ± 3.10.406
CL1 (L/min)0.8 ± 0.11.1 ± 0.10.026
CL2 (L/min)0.8 ± 0.11.08 ± 0.10.339
CL3 (L/min)0.8 ± 0.10.9 ± 0.10.65
Figure 1