ACCORDING to anesthesia lore, we killed more sailors with thiopental than the Japanese did with bombs after the attack on Pearl Harbor.1The story is apocryphal,2but it makes a vivid teaching point that the potency of intravenous anesthetics is greatly increased during hemorrhagic shock, which is probably why we drill this story into our residents to this day.
Since that time we have learned to resuscitate trauma patients aggressively with fluid, usually crystalloid, before induction of anesthesia. In this issue of Anesthesiology, Johnson et al. demonstrate that aggressive fluid resuscitation after massive hemorrhage in a pig model fails to completely reverse the profound increase in propofol potency induced by hemorrhage3even though hemodynamics were nearly restored to baseline levels. Figure 5 of this paper tells the entire story: a 4 mg/kg bolus of propofol drops the bispectral index of control animals to 50. However, the same dose drives the bispectral index to 0 (isoelectricity) in animals after severe hemorrhage, even though they have been aggressively fluid resuscitated.
This manuscript is the most recent installment in a series of papers from this laboratory, documenting the influence of shock on the clinical pharmacology of fentanyl,4remifentanil,5etomidate,6and propofol.7These articles tell a consistent story. Shock decreased the size of the central compartment and systemic clearance for fentanyl4and remifentanil,5resulting in increased concentrations. Shock decreased the central and peripheral volumes of etomidate, increasing the blood levels by about 20%.6In the case of propofol, shock decreased the intercompartmental clearance of propofol, significantly raising concentrations and resulting in increased propofol potency.7
Compartmental models of pharmacokinetics are an attempt to provide physiologic insight into the mathematical relationship between dose and concentration. With the probable exception of systemic clearance, there is little physiologic or anatomical “truth” to the volumes and clearances identified in pharmacokinetic models. In all likelihood, the reported changes in volumes and clearances for propofol, etomidate, fentanyl, and remifentanil tell the same story, regardless of the specific details: in shock the body becomes a blood-brain circuit, at the expense of circulation to the gut, liver, and muscles. This results in higher brain concentrations, more rapid onset, and more profound effect.
Propofol, however, has another dimension to the increased potency in shock. Hemorrhagic shock has little effect on intrinsic brain sensitivity to etomidate6or remifentanil.5Only for propofol does the brain become more sensitive in shock.3,7,8This may reflect the complex relationship propofol has with its lipid vehicle9,10and blood proteins.11However, propofol's combination of higher brain concentrations and increased brain sensitivity in hemorrhage is profound and dangerous.
In a series of simulations using the pharmacokinetics from these series of manuscripts, I calculated the reduction in dose to achieve the same effect with a bolus or a 10-min infusion. The results are shown in figure 1. With propofol, the dose should be reduced by 80 to 90% for a patient (or at least a pig) in hemorrhagic shock. The reduction is the same, whether anesthesia is induced by a bolus or a 10-min infusion. I will repeat this for emphasis: a patient in hemorrhagic shock should receive only 10–20% of the propofol dose that a healthy patient would receive. Even after vigorous fluid resuscitation, the propofol dose should be about half of what a healthy patient would receive.
The real surprise is etomidate. There is virtually no change in etomidate dose requirement with hemorrhage. Etomidate is often thought of as the drug of choice for hemodynamically compromised patients. However, I never expected its pharmacokinetic and pharmacodynamic profile to be so resistant to hemorrhage-induced alteration.
Figure 1suggests that perhaps etomidate could be combined with 50% of the typical fentanyl dose. Although these articles indicate that no more than half of a typical fentanyl dose should be used in trauma, it might need to be reduced even further. To date Johnson et al. have not explored drug interactions in massive hemorrhage. The interaction between opioids and hypnotics may be more profound in hemorrhagic shock than in control patients. This would be a logical next study in this line of research. It would also be very interesting to know why etomidate does not show the pharmacokinetic changes expected from the physiologic alterations that accompany shock. Surely it does not undo the physiologic shunting of cardiac output to a blood-brain circuit: that would be catastrophic. Similarly, why does brain sensitivity increase to propofol, but not to etomidate, when both work at the GABAAreceptor?
The “take home” message to the clinician is that propofol is a particularly poor choice for induction of anesthesia in patients with shock even after adequate fluid resuscitation. Even with adequate fluid resuscitation, propofol remains substantially more potent in patients with hemorrhage. In marked contrast, the potency of etomidate is nearly unchanged in shock. Thus, etomidate may be the drug of choice for anesthetic induction in patients with recent hemorrhage, even after adequate fluid resuscitation.
Stanford University School of Medicine, Stanford, California, and University of California at San Francisco, San Francisco, California. steven.shafer@stanford.edu
