Min Ji Lee

Effect of therapeutic hypothermia according to severity of sepsis in a septic rat model.

AIM OF STUDY The effects of therapeutic hypothermia (HT) during experimental sepsis may be influenced by disease severity. We experimentally investigated the effect of therapeutic HT on varying disease severity in a septic rat model. MATERIALS AND METHODS An adult male Sprague-Dawley rat model of intra-abdominal sepsis was used. To modify the disease severity, we used two different models; a moderate severe sepsis model (MSSM) and a severe septic shock model (SSSM). All rats were randomized to a hypothermia group (HT, 30-32°C) or a normothermia group (NT, 36-38°C) 1h after sepsis induction in each model. HT was maintained for 4h and rewarming was conducted for 2h. Survival time was recorded for up to 12h in the SSSM group and 24h in the MSSM group. Acute lung and liver injury, cytokine, and malondialdehyde (MDA) levels were investigated 7h after sepsis induction. Hemodynamic profiles were also evaluated. RESULTS In the SSSM, there were survival benefits and reduced acute lung and liver injury with therapeutic HT. Therapeutic HT was also associated with significantly reduced levels of plasma interleukin-6 and tissue malondialdehyde (MDA) levels in the liver and lung compared with the NT group in the SSSM. There was a tendency for the mean arterial pressure to be higher in the HT group compared to the NT group in the SSSM. In MSSM, however, there was no such beneficial effect. CONCLUSION In this rat model of severe septic shock, therapeutic HT showed beneficial effects. In contrast, therapeutic HT did not show protective effect in the moderate sepsis model.

Blood pressure-targeted stepwise resuscitation for hemorrhagic shock in rats.

BACKGROUND Generation of reactive oxygen species (ROS) is an important mechanism of ischemia-reperfusion injury. Abrupt reoxygenation compared with slow reoxygenation has been known to increase ROS generation. Thus, slow and stepwise reperfusion can reduce ROS generation and subsequent ischemia-reperfusion injury. This study investigated the effect of slow reperfusion by blood pressure–targeted stepwise resuscitation (PSR) in hemorrhagic shock. METHODS Pressure-controlled hemorrhagic shock was induced in male Sprague-Dawley rats for 1 hour. Rats were then allocated to one of three groups (no-resuscitation group, n = 14; PSR group, n = 15; rapid normalization of blood pressure (RR) group, n = 15). Survival time and hemodynamic changes were recorded and compared. Blood samples and liver tissue were harvested after 6 hours of resuscitation in surviving rats. RESULTS All of the rats in the no-resuscitation group were expired before the end of the 6-hour observation period. Survival times were significantly longer in the PSR group than in the RR group (survival rates, 11 of 15 vs. 5 of 15, log rank p = 0.032). Plasma amino alanine transferase, histologic liver injury, and ROS generation in the liver tissue were significantly lower in the PSR group than in the RR group (all findings significant, p < 0.05). In addition, PSR significantly decreased plasma nitric oxide, liver interleukin 1&bgr;, and liver interleukin 6 compared with rapid resuscitation in addition to augmenting Akt survival pathways (all p < 0.05). CONCLUSION Slow reperfusion by PSR decreased mortality, ROS generation, and liver injury in rats undergoing hemorrhagic shock. Stepwise resuscitation also decreased inflammatory cytokine production and augmented Akt survival pathways.

Effect of valproic acid combined with therapeutic hypothermia on neurologic outcome in asphyxial cardiac arrest model of rats

BACKGROUNDS Valproic acid (VPA) has been reported to have survival and neuroprotective effects in a cardiac arrest rat model. This study was designed to investigate the effect of VPA combined with therapeutic hypothermia (HT) in an asphyxial cardiac arrest rat model. METHODS Rats were subjected to 6 minutes of asphyxial cardiac arrest. Cardiopulmonary resuscitation was performed and then the randomly allocated to 1 of 4 groups (normal saline [NS]/normothermia [NT], VPA/NT, NS/HT, and VPA/HT). Hypothermia (32.5°C ± 0.5°C, 4 hours of HT and 2 hours of rewarming) or NT (37°C ± 0.5°C for 6 hours) was applied, and VPA (300 mg/kg) or NS was administered immediately after the return of spontaneous circulation. Neurologic deficit score was measured, and a tape removal test was performed for 3 days. Histologic injury of hippocampus was evaluated. RESULTS Valproic acid significantly improved neurologic deficit score at 48 and 72 hours in the NT-treated rats and at 72 hours in the HT-treated rats (all P < .05). Although the latency and success rate were not significantly different between the VPA/NT and NS/NT groups, the VPA/HT group showed significantly lower latency and higher success rates compared to the NS/HT group (P < .05). The histologic injury score in the hippocampal CA1 sector was significantly lower in the VPA/NT group than the NS/NT group (P < .05) and showed a tendency to be decreased in the VPA/HT group compared with the NS/HT group (P = .06). CONCLUSION In an asphyxial cardiac arrest rat model, administration of VPA improved neurologic outcomes and added a neuroprotective effect to HT.

Effect of valproic acid on survival and neurologic outcomes in an asphyxial cardiac arrest model of rats

AIM OF THE STUDY Valproic acid (VPA) has been known to reduce neuronal injury, has anti-inflammatory and anti-apoptotic effects as a histone deacetylase (HDAC) inhibitor. Thus, this study was performed to investigate the effects of VPA on survival and neurological outcomes in an asphyxial cardiac arrest model of rats. METHODS Male Sprague-Dawley rats were subjected to asphyxial cardiac arrest. For survival study, rats were subjected to 450s of asphyxial cardiac arrest. Cardiopulmonary resuscitation (CPR) was performed and then rats were blindly allocated to one of two groups (control group, n=10; VPA group, n=10). Valproic acid (300mgkg(-1)) or vehicle (normal saline) was administered via tail vein immediately after return of spontaneous circulation (ROSC) and observed for 72h. For neurological outcome study, rats (n=7 for each group) were subjected to same experimental procedures except duration of cardiac arrest of 360s. Neurological deficit scale (NDS) score was measured every 24h after ROSC for 72h and was ranged from 0 (brain dead) to 80 (normal). Brain tissues were harvested at 72h for evaluation of apoptotic injury and acetylation status of histone H3. RESULTS In survival study, 2 rats in VPA group were excluded because cardiac arrest was not achieved in predetermined time. Thus, 10 rats were allocated to control group and 8 rats were allocated to VPA group. The survival rates at 72h after cardiac arrest were significantly higher in VPA group than in control group (6/8 in VPA group, 3/10 rats in control group; log rank test, p<0.05). In neurological outcome study, all rats survived for 72h and NDS at 72h were significantly higher in VPA group than in control group (p<0.05). In brain tissues, expressions of acetylated histone H3 were not significantly different. However, expressions of cleaved caspase-3 were significantly lower in VPA group than in control group (p<0.05). CONCLUSION VPA increased survival rates and improved neurologic outcome in asphyxial cardiac arrest model of rats while decreasing expressions of cleaved caspase-3.