Effects of a novel acetaminophen (APAP) analog on survival time after extremity trauma and moderate or severe conscious hemorrhage in rats

Background: Multiple analgesics are used for acute pain relief following trauma in both the military and civilian settings. However, in addition to their ability to relieve pain, medical providers must also be concerned about secondary effects of the analgesics, especially effects on the cardiovascular and respiratory systems when the pain of trauma is associated with hemorrhage. Kalyra Pharmaceuticals has developed novel analogs of APAP to circumvent liver toxicity and improve analgesic efficacy. These analogs have the potential to replace opioids for severe pain while minimizing adverse effects. The objective of this study is to test a pain-reducing dose of D-112, an APAP analog, for its effects on survival to hemorrhage after extremity trauma (ET). We hypothesize that D-112 will not affect survival after either moderate or severe hemorrhage. Methods: Male Rats (~360 grams) were randomly assigned to receive either 0.9% saline (V) or 50 mg/kg D-112 (D) after either ~37% or ~50% of blood volume hemorrhage. All rats were surgically implanted with a carotid catheter under anesthesia. Carotid catheters were used for blood withdrawal and for injection of V or D. 24 hrs later, rats were briefly (~10 min) anesthetized again and ET consisting of soft tissue injury (crushing of the right gastrocnemius and semimembranosus muscles for 30 sec with forceps) and fibula fracture was performed. After completion of ET, rats were allowed to recover. 90 min after ET, rats underwent a conscious hemorrhage via the indwelling catheter. At the end of hemorrhage, rats received either V or D via the carotid catheter. Rats were observed for a maximum of 4 hrs after the start of the 25 min hemorrhage. Results: Survival after hemorrhage was recorded in the 4 groups: V-37% (n=13), D-37% (n=11), V-50% (n=10), D-50% (n=11). The survival proportions at 240 min were 92.3% for V-37%, 81.8% for D-37%, 60.0% for V-50%, and 18.1% for D-50%. While there was no significant difference in the survival curves of V-37% and D-37%, the survival curves of V-50% and D-50% were significantly different ( p = 0.036). Conclusions: The analgesic dose of D-112 tested decreased survival after ET and severe hemorrhage (~50% of blood volume), but not after ET and moderate hemorrhage (~37%). These results suggest that D-112 may not be an appropriate analgesic following traumatic hemorrhage. Applied Pain Research Program, US Army Clinical and Rehabilitative Medicine/Joint Program Committee 8, and US Army Combat Casualty Care Research Program, US Army Medical Research and Development Command. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.