Intra-arrest cooling with delayed reperfusion yields higher survival than earlier normothermic resuscitation in a mouse model of cardiac arrest

Zhao, Danhong; Abella, Benjamin S.; Beiser, David G.; Alvarado, Jason P.; Wang, Huashan; Hamann, Kimm J.; Hoek, Terry L. Vanden; Becker, Lance B.

doi:10.1016/j.resuscitation.2007.10.015

Cited by 103 publications

(83 citation statements)

References 27 publications

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“…Such rapid ROS generation during minutes of reoxygenation could disrupt microvascular integrity and interrupt blood flow (25,38,56) and is likely related to the microvascular dysfunction that appears within the heart minutes after resuscitation (17). In the present study, the substantial loss of HCMVEC barrier integrity after oxidant stress is also consistent with the microvascular dysfunction seen in critical organs such as the heart and brain within hours of resuscitation (1,8,55).…”

Section: Akt Is Critical For Restoration Of H 2 O 2 -Induced Barrier supporting

confidence: 75%

Akt activates NOS3 and separately restores barrier integrity in H₂O₂-stressed human cardiac microvascular endothelium

Dossumbekova¹,

Berdyshev²,

Горшкова³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Dossumbekova A, Berdyshev EV, Gorshkova I, Shao Z, Li C, Long P, Joshi A, Natarajan V, Vanden Hoek TL. Akt activates NOS3 and separately restores barrier integrity in H2O2-stressed human cardiac microvascular endothelium. Am J Physiol Heart Circ Physiol 295: H2417-H2426, 2008. First published October 17, 2008 doi:10.1152/ajpheart.00501.2008.-The integrity of microvascular endothelium is an important regulator of myocardial contractility. Microvascular barrier integrity could be altered by increased reactive oxygen species (ROS) stress seen within minutes after cardiac arrest resuscitation. Akt and its downstream target nitric oxide (NO) synthase (NOS)3 can protect barrier integrity during ROS stress, but little work has studied these oxidant stress responses in human cardiac microvascular endothelial cells (HCMVEC). We, therefore, studied how ROS affects barrier function and NO generation via Akt and its downstream target NOS3 in HCMVEC. HCMVEC exposed to 500 M H2O2 had increased Akt phosphorylation within 10 min at both Ser-473 and Thr-308 sites, an effect blocked by the phosphatidylinositol 3-kinase inhibitor LY-294002. H2O2 also induced NO generation that was associated with NOS3 Ser-1177 site phosphorylation and Thr-495 dephosphorylation, with Ser-1177 effects attenuated by LY-294002 and an Akt inhibitor, Akt/PKB signaling inhibitor-2 (API-2). H2O2 induced significant barrier disruption in HCMVEC within minutes, but recovery started within 30 min and normalized over hours. The NOS inhibitor N -nitro-L-arginine methyl ester (200 M) blocked NO generation but had no effect on H2O2-induced barrier permeability or the recovery of barrier integrity. By contrast, the Akt inhibitor API-2 abrogated HCMVEC barrier restoration. These results suggest that oxidant stress in HCMVEC activates NOS3 via Akt. NOS3/NO are not involved in the regulation of H2O2-affected barrier function in HCMVEC. Independent of NOS3 regulation, Akt proves to be critical for the restoration of barrier integrity in HCMVEC. oxidative stress; nitric oxide synthase 3; Akt/protein kinase B; endothelial cell barrier function; hydrogen peroxide MICROCIRCULATORY DYSFUNCTION is an important etiological component of ischemia-reperfusion injury. A significant percentage of victims of cardiac arrest, despite being initially resuscitated, die of heart-related causes within hours due to recurrent arrhythmias and cardiovascular collapse (4,23,28,47). Recent work suggests that these cardiac arrest events are temporally associated with interruptions in microvascular blood flow to the heart that begin within minutes of cardiopulmonary resuscitation (CPR) and may affect the return of spontaneous circulation (ROSC) (17). Furthermore, serious microvascular dysfunction in critical organs such as the heart and brain is seen within hours of ROSC and is associated with critical organ dysfunction (1, 8).The mechanism of microvascular endothelial dysfunction in the post-cardiac arrest heart is not well known. Our studies in a swine model of cardiac arrest suggest that o...

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Section: Akt Is Critical For Restoration Of H 2 O 2 -Induced Barrier supporting

confidence: 75%

Akt activates NOS3 and separately restores barrier integrity in H₂O₂-stressed human cardiac microvascular endothelium

Dossumbekova¹,

Berdyshev²,

Горшкова³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The intravenous administration of potassium chloride was also shown to induce a very reproducible cardiac arrest in rodents [9,13,14]. It leads to a quasi-immediate cardiac arrest with asystole.…”

Section: Asystole Through Potassium Chloride Administrationmentioning

confidence: 97%

“…On the other hand, spontaneous heart rate is much higher in rodents than in large animals and humans as usual values average 260-450 or 500-600 beats per minute in awake rats and mice, respectively [7,8]. This directly impacts the required chest compression rate in those species as mice should undergo ≈400 compressions per min to be resuscitated [9][10][11][12][13][14]. Magnetic resonance imaging also showed that usual ejection fraction are higher in mice as compared to humans (75% vs 55%) [15].…”

Section: Cardiac Arrest In Rodentsmentioning

confidence: 99%

How Can we Study Cardiopulmonary Resuscitation and Cardiac Arrest in Animals: a Review

Blondel¹,

Kohlhauer²,

Zilberstein³

et al. 2016

JDVAR

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Animal research is essential to propose new therapeutic approaches limiting the sequels of cardiac arrest in human and veterinary medicine. The ultimate goal is to improve the long term prognosis and neurological recovery. For such investigations, the use of animal models seems unavoidable as cardiac arrest provokes multiple visceral consequences as well as inflammatory response and coagulopathy. These models allow not only a better understanding of the pathophysiology but also the investigation of new treatment strategies to improve basic life support efficiency or prevent multi-organ failure. In this review, we are summarizing the characteristics of the main animal models used in resuscitation sciences. The choice of the species and methods of evaluation of cardiac arrest is crucial. These studies often concern human medicine but they can also address fundamental questions for veterinary research as they are mostly based on animal research.

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“…4,5 The optimal timing of therapeutic cooling remains unclear. Animal models have demonstrated that immediate and faster cooling yields improved outcomes, [6][7][8] but other studies have suggested that no benefit exists in short-term survival with rapid cooling, even when compared to normothermic postresuscitation care. 8 Observational human studies, although limited by their design, have also yielded conflicting results, with rapid cooling reported to be associated with improved, neutral, and negative effects on neurologic status and mortality.…”

Section: Ré Sumémentioning

confidence: 99%

Effect of prehospital initiation of therapeutic hypothermia in adults with cardiac arrest on time-to-target temperature

Schenfeld

Studnek²,

Heffner

et al. 2015

CJEM

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Objective: Despite growing adoption, the impact of prehospital initiation of therapeutic hypothermia on outcomes of cardiac arrest patients is unknown. The objective of this study was to determine if prehospital administration of cold intravenous fluids improved the time-to-target temperature. Methods: All patients enrolled in an institutional postcardiac arrest treatment pathway were prospectively registered into a quality assurance database. Patients undergoing cooling induction on hospital arrival were compared to those receiving a new treatment protocol initiated during the study period involving prehospital cooling with 4uC (39.2uF) normal saline. The primary outcome was the time-to-target temperature. Secondary outcomes included emergency medicine system transport time metrics, mortality, and neurologic status at discharge and 1 year. Results: One hundred thirty-two patients were enrolled during the study period. The initial rhythm was ventricular fibrillation/tachycardia in 63% and asystole/pulseless electrical activity in 36%. Eighty patients received prehospital cooling and 52 patients did not and comprised the historical control group. Time-to-target temperatures were not significantly different between prehospital and hospital cooled groups (256 v. 271 minutes, respectively, p 5 0.64), nor was there any improvement in hospital survival (54% v. 50%, p 5 0.67), good neurologic outcome (49% v. 44%, p 5 0.61), or 1-year survival (49% v. 42%, p 5 0.46) between the two groups. Transport times were longer in the prehospital cooled group. Conclusions: Out-of-hospital cardiac arrest patients treated with prehospital cooling before arrival at our urban hospital did not have faster time-to-target temperature or improvement in outcomes compared to patients cooled immediately on emergency department arrival. Further research is needed to determine if any benefits exist from prehospital cooling prior to its widespread adoption. RÉ SUMÉObjectif: Bien que l'amorce de l'hypothermie thé rapeutique en phase pré hospitaliè re soit de plus en plus ré pandue, on n'en connaît pas l'effet sur les ré sultats, chez les patients victimes d'un arrê t cardiaque. L'é tude visait à dé terminer si l'administration intraveineuse de liquides froids, en phase pré hospitaliè re, permettait d'atteindre plus rapidement la tempé rature cible. Mé thode: Tous les patients soumis à un parcours de traitement, en é tablissement, pour un arrê t cardiaque ont é té inscrits de maniè re prospective dans une base de donné es sur l'assurance de la qualité. Les patients soumis au refroidissement à leur arrivé e à l'hô pital ont é té comparé s avec ceux soumis au nouveau protocole de traitement mis en oeuvre durant la pé riode à l'é tude, comportant un refroidissement pré hospitalier à l'aide de l'administration d'une solution physiologique salé e maintenue à 4uC (39.2uF). Le principal critè re d'é valuation é tait le temps né cessaire à l'atteinte de la tempé rature cible. Les critè res d'é valuation secondaires comprenaient les mesures du tem...

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Intra-arrest cooling with delayed reperfusion yields higher survival than earlier normothermic resuscitation in a mouse model of cardiac arrest

Cited by 103 publications

References 27 publications

Akt activates NOS3 and separately restores barrier integrity in H₂O₂-stressed human cardiac microvascular endothelium

Akt activates NOS3 and separately restores barrier integrity in H₂O₂-stressed human cardiac microvascular endothelium

How Can we Study Cardiopulmonary Resuscitation and Cardiac Arrest in Animals: a Review

Effect of prehospital initiation of therapeutic hypothermia in adults with cardiac arrest on time-to-target temperature

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