Beneficial effects of nitric oxide on outcomes after cardiac arrest and cardiopulmonary resuscitation in hypothermia-treated mice.
BACKGROUND
Therapeutic hypothermia (TH) improves neurological outcomes after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Although nitric oxide prevents organ injury induced by ischemia and reperfusion, role of nitric oxide during TH after CPR remains unclear. In this article, the authors examined the impact of endogenous nitric oxide synthesis on the beneficial effects of hypothermia after CA/CPR. The authors also examined whether or not inhaled nitric oxide during hypothermia further improves outcomes after CA/CPR in mice treated with TH.


METHODS
Wild-type mice and mice deficient for nitric oxide synthase 3 (NOS3(−/−)) were subjected to CA at 37 °C and then resuscitated with chest compression. Body temperature was maintained at 37 °C (normothermia) or reduced to 33 °C (TH) for 24 h after resuscitation. Mice breathed air or air mixed with nitric oxide at 10, 20, 40, 60, or 80 ppm during hypothermia. To evaluate brain injury and cerebral blood flow, magnetic resonance imaging was performed in wild-type mice after CA/CPR.


RESULTS
Hypothermia up-regulated the NOS3-dependent signaling in the brain (n = 6 to 7). Deficiency of NOS3 abolished the beneficial effects of hypothermia after CA/CPR (n = 5 to 6). Breathing nitric oxide at 40 ppm improved survival rate in hypothermia-treated NOS3(−/−) mice (n = 6) after CA/CPR compared with NOS3(−/−) mice that were treated with hypothermia alone (n = 6; P < 0.05). Breathing nitric oxide at 40 (n = 9) or 60 (n = 9) ppm markedly improved survival rates in TH-treated wild-type mice (n = 51) (both P < 0.05 vs. TH-treated wild-type mice). Inhaled nitric oxide during TH (n = 7) prevented brain injury compared with TH alone (n = 7) without affecting cerebral blood flow after CA/CPR (n = 6).


CONCLUSIONS
NOS3 is required for the beneficial effects of TH. Inhaled nitric oxide during TH remains beneficial and further improves outcomes after CA/CPR. Nitric oxide breathing exerts protective effects after CA/CPR even when TH is ineffective due to impaired endogenous nitric oxide production.
From the Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine (K.K., K.S., B.Y., K.D.B., and F.I.); Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology (J.B.M.), Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.
Kotaro
K
Kida
Kazuhiro
K
Shirozu
Binglan
B
Yu
Joseph B
JB
Mandeville
Kenneth D
KD
Bloch
Fumito
F
Ichinose
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D016887:Cardiopulmonary Resuscitation / Q000379:methods*; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006323:Heart Arrest / Q000503:physiopathology* / Q000628:therapy*; D007036:Hypothermia, Induced / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000494:pharmacology*; D015996:Survival Rate; D016896:Treatment Outcome
D016166:Free Radical Scavengers; D009569:Nitric Oxide