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Abstract

Introduction: A significant cause of mortality and morbidity across economic and age groups is hemorrhagic shock resulting from traumatic injury. Centhaquin, a cardiovascular active agent, has shown efficacy as a resuscitative agent in studies of controlled hemorrhagic shock without tissue injury. To better simulate a true clinical scenario, these effects should be explored in a rabbit model of uncontrolled hemorrhage with tissue injury. Therefore, the objective of this study was to determine the resuscitative efficacy of centhaquin in a rabbit model of uncontrolled hemorrhagic shock with tissue injury. Methods: Male New Zealand rabbits were placed under anesthesia with ketamine and xylazine and a laparotomy was performed with running sutures placed for later closure. Hemorrhage was induced via a single puncture injury to the infrarenal aorta with a 20G needle and the abdomen was immediately closed. After a 15-minute period to simulate arrival of emergency medical services, resuscitation was initiated and continued for 60 minutes. Animals were randomly assigned to one of three groups: Group 1: No resuscitation (control) (n=9), Group 2: normal saline resuscitation to MAP = 45 mmHg (n=13), Group 3: Centhaquin 0.05 mg/kg in normal saline resuscitation to MAP = 45 mmHg (n=11). Maximum infusion rate was set to 5 ml/min and infusion fluid volume was recorded. Animals were observed for an additional hour. The abdomen was re-opened to measure blood loss and animals were sacrificed by exsanguination. Cardiovascular parameters and arterial blood gas analysis was obtained before, following hemorrhage and various times after resuscitation. Results: Blood lactate increased significantly from baseline value of 1.52 ± 0.27 to 13.53 ± 0.75 mmol/L following hemorrhage; this increase was similar in all groups. Animals that were not resuscitated did not survive to more than 5 min, while saline and centhaquin resuscitated animals survived for 2 hours after which they were sacrificed. Resuscitation significantly decreased lactate levels to 6.65 ± 1.34 and 6.14 ± 0.86 mmol/L in saline and centhaquin treated rats, respectively. The volume of fluid required for resuscitation in centhaquin (133.60 ± 11.91 ml) treated rats was significantly less (p=0.0011) compared to that required in saline (207.82 ± 9.08 ml) treated rats. The blood loss was 44.37 ± 6.55, 40.60 ± 3.12 and 38.34 ± 2.21 ml in no resuscitation, saline and centhaquin resuscitation, respectively. Centhaquin treated rats had less loss of blood compared to no resuscitation group. MAP and body temperature were similar in saline and centhaquin treated groups. Conclusions: We have successfully developed a rabbit model of uncontrolled hemorrhagic shock with tissue injury in our laboratory and this model can be used to study effect and mechanism of action of various resuscitation procedures and agents. In the present study, centhaquin citrate demonstrated significant efficacy as a resuscitative agent. Acknowledgements: Centhaquin citrate was synthesized and provided by Pharmazz India Private Limited, Greater Noida, India; courtesy Dr. Manish Lavhale.