Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs.

OBJECTIVE: Despite the introduction of mild therapeutic hypothermia into postcardiac arrest care, cerebral and myocardial injuries represent the limiting factors for survival after cardiac arrest. Administering xenon may confer an additional neuroprotective effect after successful cardiopulmonary resuscitation due to its ability to stabilize cellular calcium homeostasis via N-methyl-D-aspartate-receptor antagonism. DESIGN: In a porcine model, we evaluated effects of xenon treatment in addition to therapeutic hypothermia on neuropathologic and functional outcomes after cardiopulmonary resuscitation. SETTING: Prospective, randomized, laboratory animal study. SUBJECTS: Fifteen male pigs. INTERVENTIONS: Following 10 mins of cardiac arrest and 6 mins of cardiopulmonary resuscitation, ten pigs were randomized to receive either mild therapeutic hypothermia (33°C for 16 hrs) or mild therapeutic hypothermia 1 xenon (70% for 1 hr). Five animals served as normothermic controls. MEASUREMENTS AND MAIN RESULTS: Gross hemodynamic variables were measured using right-heart catheterization. Neurocognitive performance was evaluated for 5 days after cardiopulmonary resuscitation using a neurologic deficit score before the brains were harvested for histopathological analysis. All animals survived the observation period in the mild therapeutic hypothermia 1 xenon group while one animal in each of the other two groups died. Mild therapeutic hypothermia 1 xenon preserved cardiac output during the induction of mild therapeutic hypothermia significantly better than did mild therapeutic hypothermia alone (4.6 6 0.6 L/min vs. 3.2 6 1.6 L/min, p # .05). Both treatment groups showed significantly fewer necrotic lesions in the cerebral cortex, caudate nucleus, putamen, and in hippocampal sectors CA1 and CA3/4. However, only the combination of mild therapeutic hypothermia and xenon resulted in reduced astrogliosis in the CA1 sector and diminished microgliosis and perivascular inflammation in the putamen. Clinically, only the mild therapeutic hypothermia 1 xenon-treated animals showed significantly improved neurologic deficit scores over time (day 1 = 59.0 6 27.0 vs. day 5 = 4.0 6 5.5, p ø .05) as well as in comparison to the untreated controls on days 3 through 5 after cardiopulmonary resuscitation. CONCLUSIONS: These results demonstrate that even a short exposure to xenon during induction of mild therapeutic hypothermia results in significant improvements in functional recovery and ameliorated myocardial dysfunction.

Hydrogen sulfide does not increase resuscitability in a porcine model of prolonged cardiac arrest.

Treatment options to improve resuscitability and neurological prognosis after cardiac arrest (CA) are limited. Hydrogen sulfide has demonstrated remarkable improvements in outcomes in small animal models of severe hypoxia or hemorrhage. We investigated the influence of sodium sulfide (Na2S), a liquid hydrogen sulfide donor, on resuscitability, postresuscitation hemodynamics, and neurological performance in a porcine model of prolonged CA and cardiopulmonary resuscitation. Twenty-four male pigs were instrumented with arterial and pulmonary artery catheters before 10 min of CA was induced. During resuscitation, animals were randomized to receive either high-dose (1 mg/kg; n = 8) or low-dose (0.3 mg/kg; n = 8) Na2S (IK-1001; Ikaria, Clinton, NJ) or control (saline placebo; n = 8) i.v. injection and consecutive infusion. Cardiopulmonary resuscitation was performed for 6 min before defibrillation was attempted. Hemodynamic variables were taken at baseline and 10, 30, 60, 120, and 240 min after successful resuscitation. Neurological outcome was evaluated on 4 postoperative days before brains and hearts were harvested for histopathologic analysis. No differences in hemodynamic parameters were observed at baseline. Initial resuscitability was not improved by Na2S. Animals exposed to high- and low-dose Na2S showed significantly reduced cardiac output, heart rate, and pulmonary arterial pressure compared with control animals during the early postresuscitation period. Strikingly, two of the high-dose Na2S animals died during the postresuscitation period, whereas all other animals survived. High-dose Na2S significantly decreased microglial activation in striatal areas, although this did not translate into improved neurological outcome. Although animals receiving Na2S developed higher troponin T serum levels, these differences remained insignificant. In this investigation, Na2S did not improve resuscitability but significantly compromised postresuscitation hemodynamics.