Potentially lethal fentanyl-induced hyperammonemia in hyperthermic rats

Introduction. Excessive growth of intestinal microbiota, acute dysfunction of the gut-blood barrier, and the subsequent endotoxemia are integral to the pathogenesis of critical illness. Heat stress was previously shown to potentiate the lethal effect of fentanyl in rats, accompanied by hyperammonemia. While literature suggests its intestinal origin, this hypothesis remains to be tested.

Objective. To identify the mechanisms of hyperammonemia induced by fentanyl and/or heat stress in rats.

Materials and methods. The study was conducted on outbred male albino rats (191–210 g). The animals were divided into the following groups: 22 °C (intact), Fentanyl + 22 °C (kept at room temperature after fentanyl administration), 40 °C (exposure to 40 °C in a thermal chamber for 40 min), and Fentanyl + 40 °C (exposure to 40 °C for 40 min following fentanyl administration). The first series of experiments evaluated the effects of fentanyl (200 μg/kg) and/or heat stress (40 °C) on 40-minute mortality, body temperature, and blood levels of ammonia, urea, creatinine, and lactate. The second series investigated the impact of these factors on the transperitoneal mass transfer of ammonia, urea, and creatinine. In the third series, the effects of the same factors on intestinal permeability were evaluated in vivo (based on transperitoneal transfer of intragastrically administered methylene blue). Fentanyl was injected at a dose of 200 μg/kg (4 mL/kg) into the lateral tail vein. Transperitoneal mass transfer of nitrogenous metabolites or methylene blue (MB) was calculated based on their accumulation over 40 min in 0.9% sodium chloride solution (30 mL/kg) administered intraperitoneally. Statistical analysis was performed using OriginPro software.

Results. Heat exposure or fentanyl administration alone was non-lethal, while their combination resulted in mortality rates of 44%, 33%, and 36% in the first, second, and third series of experiments, respectively. In response to heat stress, rectal temperature increased from 37.2 °C to 42.2 °C, reaching 43.6 °C under heat stress combined with fentanyl administration. Conversely, fentanyl alone caused a decrease to 32.8 °C. Animal body weight decreased by 4.4% in the 40 °C group and by 2.6% in the Fentanyl + 40 °C group. The combined effect of heat and fentanyl elevated blood ammonia levels from 132 ± 16 μM to 294 ± 24 μM. Blood urea levels under the influence of fentanyl, hyperthermia, or their combination increased from 3.4 ± 0.3 mM to 5.5 ± 0.7 mM, 7.1 ± 0.4 mM, and 6.8 ± 0.3 mM, respectively; creatinine levels increased from 38.8 ± 4.7 μM to 60.4 ± 3.9 μM under isolated hyperthermia and to 62.9 ± 3.5 μM under combined hyperthermia, respectively. Creatinine levels rose from 38.8 ± 4.7 μM to 60.4 ± 3.9 μM under heat stress alone and to 62.9 ± 3.5 μM under heat stress combined with fentanyl administration. The combined effect of heat and fentanyl increased the transperitoneal mass transfer of ammonia from 78 ± 6 to 168 ± 22 nmol/(kg × min) and that of MB from 83.6 ± 26.2 to 167.3 ± 29.2 pmol/(kg × min). Both heat exposure alone and when combined with fentanyl administration resulted in lactacidemia.

Conclusions. Fentanyl administration followed by heat exposure induced azotemia and lactic acidosis in rats. This combination also caused a synergistic increase in mortality, body temperature, blood ammonia levels, and transperitoneal ammonia transport from the intestine. The primary mechanisms underlying this potentially lethal hyperammonemia include fentanyl-induced enhancement of intestinal ammoniogenesis and heat stress-mediated increase in intestinal permeability.

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