Fentanyl impairs but ketamine preserves the microcirculatory response to hemorrhage

Peripheral vasoconstriction is the most critical compensating mechanism following hemorrhage to maintain blood pressure. On the battlefield, ketamine rather than opioids is recommended for pain management in case of hemorrhage, but effects of analgesics on compensatory vasoconstriction are not defined. We hypothesized that fentanyl impairs but ketamine preserves the peripheral vasoconstriction and blood pressure compensation following hemorrhage.

Sprague-Dawley rats (11-13 weeks) were randomly assigned to control (saline vehicle), fentanyl, or ketamine-treated groups with or without hemorrhage (n = 8 or 9 for each group). Rats were anesthetized with Inactin (i.p. 10 mg/100 g), and the spinotrapezius muscles were prepared for microcirculatory observation. Arteriolar arcades were observed with a Nikon microscope, and vessel images and arteriolar diameters were recorded by using Nikon NIS Elements Imaging Software (Nikon Instruments Inc. NY). After baseline perimeters were recorded, the arterioles were topically challenged with saline, fentanyl, or ketamine at concentrations relevant to intravenous analgesic doses to determine direct vasoactive effects. After arteriolar diameters returned to baseline, 30% of total blood volume was removed in 25 minutes. Ten minutes after hemorrhage, rats were intravenously injected with an analgesic dose of fentanyl (0.6 μg/100 g), ketamine (0.3 mg/100 g), or a comparable volume of saline. For each drug or vehicle administration, the total volume injected was 0.1 mL/100 g. Blood pressure, heart rate, and arteriolar responses were monitored for 40 minutes.

Topical fentanyl-induced vasodilation (17 ± 2%), but ketamine caused vasoconstriction (-15 ± 4%, p < 0.01). Following hemorrhage, intravenous ketamine did not affect blood pressure or respiratory rate, while fentanyl induced a slight and transient (<5 minutes, p = 0.03 vs. saline group) decrease in blood pressure, with a profound and prolonged suppression in respiratory rate (>10 minutes, with a peak inhibition of 57 ± 8% of baseline, p < 0.01). The compensatory vasoconstriction observed after hemorrhage was not affected by ketamine treatment. However, after fentanyl injection, although changes in blood pressure were transiently present, arteriolar constriction to hemorrhage was absent and replaced with a sustained vasodilation (78 ± 25% to 36 ± 22% of baseline during the 40 minutes after injection, p < 0.01).

Ketamine affects neither systemic nor microcirculatory compensatory responses to hemorrhage, providing preclinical evidence that ketamine may help attenuate adverse physiological consequences associated with opioids following traumatic hemorrhage. Microcirculatory responses are more sensitive than systemic response for evaluation of hemodynamic stability during procedures associated with pain management.