[The effects of administration of valproic acid on organ function and outcome in a canine lethal hemorrhagic shock model].

ABSTRACT

OBJECTIVE: To investigate the effects of valproic acid (histone deacetylase inhibitor) on visceral function and outcome in a canine lethal hemorrhage model. METHODS: Twenty male Beagle canines were subjected to an about 42% of total blood volume loss to reproduce a lethal hemorrhage shock model. Animals were randomly divided into shock control group (SC group) and valproic acid treatment group (VPA group), each group n=10. Canines in SC group and VPA group were intravenously injected either 20 ml saline or valproic acid (100 mg/kg) in 20 ml saline 1.5 hours after hemorrhage. Canines in each group were given delayed intravenous fluid resuscitation 24 hours after bleeding. The mean arterial pressure (MAP) was measured at 0 hour and at different time points without anesthesia, and the plasma levels of alanine aminotransferase (ALT), creatinine (Cr) and isoenzyme of creatine kinase (CK-MB) were measured before hemorrhage (0 hour), and at different time points after hemorrhage. Urinary output and survival rate 72 hours after hemorrhage were also recorded. RESULTS: The levels of MAP in both groups were significantly lowered from 2 hours after bleeding. The level of MAP (mm Hg, 1 mm Hg=0.133 kPa) in VPA group recovered rapidly and exceeded with statistically significant difference compared with those of SC group after hemorrhage (4 hours 58.4±7.6 vs. 40.3±5.0, 8 hours 84.4±8.0 vs. 56.4±4.4, 24 hours 92.6±10.3 vs. 72.6±8.9, P<0.05 or P<0.01). The amount of urinary output of VPA group was significantly higher than that of SC group during the period of 0-8 hours, 8-24 hours, 24-48 hours, and 48-72 hours, but it was still lower than that before hemorrhage (0 hour). The plasma parameters for visceral function in both groups were significantly elevated compared with 0 hour. The plasma levels of ALT, Cr and CK-MB in VPA group were obviously lower than those in SC group from 4 hours after hemorrhage [at 4 hours after bleeding, ALT (U/L) 80.1±9.8 vs. 112.2±10.1, Cr (µmol/L) 74.5±8.3 vs. 88.0±7.6, CK-MB (kU/L) 10.39± 1.10 vs. 13.67±1.46, P<0.05 or P<0.01], but the visceral functional parameters at 72 hours after hemorrhage in VPA group were obviously higher than those at 0 hour [ALT (U/L)79.5±7.1 vs. 40.5±4.4; Cr (µmol/L) 85.6±7.1 vs. 46.6±4.8; CK-MB (kU/L) 7.63±0.86 vs. 1.66±0.21, all P<0.01]. The survival rate of VPA group 72 hours after bleeding was significantly higher than that of SC group [70% (7/10) vs. 20% (2/10), P<0.05]. CONCLUSION: The results indicate that intravenous injection of VPA promote MAP, increase urinary output, alleviate visceral injury and improve the survival rate at 72 hours in canines suffering from 42% blood volume loss, it might be an effective drug for hypovolemic shock, especially in war or other site of mass casualties in an austere environment.