4-Phenylbutyric acid extends the gold time of uncontrolled hemorrhagic shock at high altitude by alleviating vital organ injury.

BACKGROUND

Uncontrolled hemorrhagic shock (UHS) is prevalent in military operations, disaster relief, and traffic accidents at high altitudes. Due to reduced tolerance to resuscitation fluids and prolonged evacuation times, its management poses substantial challenges. Whether 4-phenylbutyric acid (PBA) can protect vital organ function and extend the golden period for UHS at high altitudes remains unclear.

METHODS

Rats airlifted from Chongqing to Lhasa were used to establish a UHS model. The experiment consisted of three parts: Part 1 investigated PBA's effect on extending the golden period (prehospital treatment window). Specifically, using a high-altitude rat model of UHS, we observe the duration that PBA + LR maintains mean arterial pressure (MAP) at 50-60 mmHg without definitive hemostasis; Parts 2 and 3 involve hypotensive maintenance of MAP at 50-60 mmHg for 1 and 2 h, respectively, prior to definitive hemostasis, simulating 1-h and 2-h prehospital phases. After hypotensive maintenance, definitive hemostasis is performed. Parameters including vital organ injury markers, blood gas profiles, and survival rates were assessed.

RESULTS

In Part 1, PBA (20 mg/kg) reduced blood loss by 13.3% (from 53.6 ± 2.4% to 45.28 ± 3.4%) and resuscitation fluid volume by 28% compared to LR alone. PBA (20 mg/kg) prolonged the duration of sustained hypotensive resuscitation by 243% (from 39 ± 4.6 min to 134 ± 10.6 min) compared to LR, stabilized hemodynamics, and improved 2-h survival from 12.5% to 62.5%. In Part 2, 20 mg/kg PBA attenuated vital organ damage, increased 72-h survival from 18.7% (LR group) to 50% (20 mg/kg PBA group), and meanwhile reduced blood loss by 7.7% and resuscitation fluid volume by 16.3% compared to LR alone. In Part 3, despite extending hypotensive resuscitation to 2 h, PBA still significantly ameliorated organ function, reduced blood loss, decreased fluid administration, and enhanced 72-h survival in rats from 0% (LR group) to 31.25% (20 mg/kg PBA group).

CONCLUSION

PBA administration during hypotensive resuscitation protects vital organs (heart, liver, kidney), reduces pulmonary and cerebral edema incidence, and significantly extends the golden period for UHS at high altitudes.