Effect of nitric oxide synthase modulation on resuscitation success in a swine ventricular fibrillation cardiac arrest model

Huang

Academic Emergency Medicine

et al. 2014

Objectives: Intravenous (IV) administration of ascorbic acid during cardiopulmonary resuscitation (CPR) was reported to facilitate defibrillation and improves survival in ventricular fibrillation (VF) cardiac arrest. We investigated whether IV administration of ascorbic acid after return of spontaneous circulation (ROSC) can improve outcomes in VF cardiac arrest in a rat model and its interaction with therapeutic hypothermia.Methods: Ventricular fibrillation-induced cardiac arrest followed by CPR and defibrillation was performed in male Wistar rats. After ROSC, the animals were equally randomized to the normothermia (NormoT), hypothermia (HypoT), ascorbic acid (AA+NormoT), and ascorbic acid plus hypothermia (AA+HypoT) groups. The AA+NormoT and AA+HypoT groups received IV ascorbic acid (100 mg/kg). In the HypoT and AA+HypoT groups, therapeutic hypothermia was maintained at 32°C for 2 hours.Results: There were 12 rats in each group. Within 4 hours after ROSC, the HypoT, AA+NormoT, and AA+HypoT groups had significantly lower myocardial lipid peroxidation than the NormoT group. Within 4 hours following ROSC, the AA+NormoT group had a significantly better systolic function (dp/dt 40 ) than the NormoT group (6887.9 mm Hg/sec, SD AE 1049.7 mm Hg/sec vs. 5953.6 mm Hg/sec, SD AE 1161.9 mm Hg/sec; p < 0.05). The AA+HypoT group also showed a significantly better diastolic function (-dp/dt max ) than the HypoT group (dp/dt 40 : 8524.8, SD AE 1166.7 mm Hg/sec vs. 7399.8 mm Hg/sec, SD AE 1114.5 mmHg/sec; dp/dt max : -8183.4 mm Hg/sec, SD AE 1359.0 mm Hg/sec vs. -6573.7 mm Hg/sec, SD AE 1110.9 mm Hg/sec; p < 0.05) at the fourth hour following ROSC. Also at 4 hours, there was less myocytolysis in the HypoT, AA+NormoT, and AA+HypoT groups than the NormoT group. The HypoT, AA+NormoT, and AA+HypoT groups had significantly better survival rates and neurologic outcomes than the NormoT group. Compared with only five surviving animals in the NormoT group, there were nine, eight, and 10 in the HypoT, AA+NormoT, and AA+HypoT groups, respectively, with good neurologic outcomes at 72 hours.Conclusions: Intravenous ascorbic acid administration after ROSC in normothermia may mitigate myocardial damage and improve systolic function, survival rate, and neurologic outcomes in VF cardiac arrest of rat. Combination of ascorbic acid and hypothermia showed an additive effect in improving both systolic and diastolic functions after ROSC.ACADEMIC EMERGENCY MEDICINE 2014; 21:257-265

mentioning

confidence: 99%

Combination of Intravenous Ascorbic Acid Administration and Hypothermia After Resuscitation Improves Myocardial Function and Survival in a Ventricular Fibrillation Cardiac Arrest Model in the Rat

Huang

Academic Emergency Medicine

et al. 2014

“…Caterine et al [6] demonstrated an elevated blood concentration of ROS after ES in a canine model, with or without the presence of VF. When pretreated with an antioxidant, the free radicals were significantly decreased [9]. Our previous study demonstrated that administering AA eliminated free [10].…”

Section: Discussionmentioning

confidence: 87%

“…In cardiomyocytes, ES causes an elevated diastolic calcium concentration, which is positively correlated with the energy delivered [5]. Reactive oxygen species (ROS) are thought to be involved in ES-related myocardial injury [6,9,10]. Plasma ROS increases in direct proportion to the delivered energy of ES and is significantly attenuated when pre-treated with antioxidants [6,9].…”

Section: Introductionmentioning

confidence: 99%

“…Reactive oxygen species (ROS) are thought to be involved in ES-related myocardial injury [6,9,10]. Plasma ROS increases in direct proportion to the delivered energy of ES and is significantly attenuated when pre-treated with antioxidants [6,9]. Besides, ROS has been known to be involved in ischemia/reperfusion injury [11][12][13][14][15], reperfusion arrhythmia [11][12][13], and cardiogenic shock [14].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ascorbic acid mitigates the myocardial injury after cardiac arrest and electrical shock

Chen

et al. 2011

Intensive Care Med

Acta Anaesthesiol Scand

“…Other NOS inhibitors such as the non-selective NOS inhibitor N G -monomethyl-L-arginine (L-NAME) [71], N G -nitro-L-arginine (L-NNA) [185] and selective inhibitors such as aminoguanidine (iNOS inhibitor), 1-2 (trifluoromethylphenyl) imidazol (TRIM), a nNOS inhibitor, were also tested in experimental models of cardiac arrest [186,187]. Schleien et al [71] demonstrated that non-specific NOS inhibition with L-NAME attenuated the post-ischemic cerebral and myocardial hyperemia.…”

Section: Methylene Blue In Ca and Cprmentioning

confidence: 99%

Cerebral protection in experimental cardiopulmonary resuscitation (with special reference to the effects of methylene blue)

Miclescu¹

2010

Although survival rates are increasing, brain injury continues to be a leading cause of death after cardiac arrest (CA). Permanent brain damage after CA is determined by limited tolerance to ischemia from CA and cardiopulmonary resuscitation (CPR), as well as the unique cerebral response to reperfusion after return of spontaneous circulation (ROSC). A major pathway leading to neurotoxic cascade and neuronal injury after CA involves the increased presence of reactive oxygen and nitrogen species generated during ischemia and reperfusion. The magnitude of cerebral oxidative injury induced by free radicals increased with the duration of CA (Paper I). Nitric oxide (NO), a free radical responsible for the formation of reactive nitrogen species, is increased during global ischemia from CA and reperfusion (Paper IV). Hypothetically, the administration of a drug that counteracts the overproduction of NO and also acts as a scavenger of oxygen free radicals might be warranted in order to reduce the damage caused by nitrosative and oxidative stress. For these purposes we used methylene blue (MB), an old dye that has been used in medicine for almost half a century, and an experimental pig model of 20 min of ventricular fibrillation (VF) to reflect a clinical scenario of ischemia/reperfusion injury. Administration of MB added to a hypertonic-hyperoncotic solution (MBHSD) that was started during CPR and continued for 50 min after ROSC increased short-term survival by decreasing myocardial damage, as well as cerebral peroxidation and inflammatory injury (Paper II). Immunostaining of cerebral tissue collected at different time points after CA and ROSC (Paper IV) provided experimental evidence that cortical blood-brain barrier (BBB) disruption begins as early as during the initial phase of untreated as well as treated CA. The results indicated that MB administration reduced the neurologic injury and BBB disruption considerably, but did not reverse the ongoing detrimental processes. The demonstrated positive effects of MB were related to a decrease of nitrite/nitrate tissue content, and thus to a decrease of excess NO due to the MB inhibitory effects on NOS isoforms. A mixture of MB in hypertonic sodium lactate (MBL) was investigated to facilitate administration of MB in "the field." Based on findings that MBL cardio-and neuroprotective properties were similar to those of MBHSD, there is reason to believe that the use of MBL might be extended during ongoing CPR and after ROSC (Paper III). It would therefore make sense to try using MB as a pharmacological neuroprotectant during or after clinical CPR in order to expand the temporal therapeutic window before other measures for neuroprotection such as hypothermia are available. Keywords: Cardiac arrest, cardiopulmonary resuscitation, reperfusion injury, methylene blue, nitric oxide, nitric oxide synthases, blood-brain barrier