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

doi:10.1016/j.resuscitation.2007.10.015

Resuscitation

Volume 77, Issue 2, May 2008, Pages 242-249

https://doi.org/10.1016/j.resuscitation.2007.10.015 Get rights and content

Summary

Background

Therapeutic hypothermia (TH) represents an important method to attenuate post-resuscitation injury after cardiac arrest. Laboratory investigations have suggested that induction of hypothermia before return of spontaneous circulation (ROSC) may confer the greatest benefit. We hypothesized that a short delay in resuscitation to induce hypothermia before ROSC, even at the expense of more prolonged ischemia, may yield both physiological and survival advantages.

Methods

Cardiac arrest was induced in C57BL/6 mice using intravenous potassium chloride; resuscitation was attempted with CPR and fluid administration. Animals were randomized into three groups (n = 15 each): a normothermic control group, in which 8 min of arrest at 37 °C was followed by resuscitation; an early intra-arrest hypothermia group, in which 6.5 min of 37 °C arrest were followed by 90 s of cooling, with resuscitation attempted at 30 °C (8 min total ischemia); and a delayed intra-arrest hypothermia group, with 90 s cooling begun after 8 min of 37 °C ischemia, so that animals underwent resuscitation at 9.5 min.

Results

Animals treated with TH demonstrated improved hemodynamic variables and survival compared to normothermic controls. This was the case even when comparing the delayed intra-arrest hypothermia group with prolonged ischemia time against normothermic controls with shorter ischemia time (7-day survival, 4/15 vs. 0/15, p < 0.001).

Conclusions

Short resuscitation delays to allow establishment of hypothermia before ROSC appear beneficial to both cardiac function and survival. This finding supports the concept that post-resuscitation injury processes begin immediately after ROSC, and that intra-arrest cooling may serve as a useful therapeutic approach to improve survival.

Introduction

Prompt delivery of CPR and early defibrillation to achieve return of spontaneous circulation (ROSC) remain the highest priorities of immediate care for the cardiac arrest victim as elaborated in the 2005 consensus resuscitation guidelines.¹ However, survival from cardiac arrest remains low despite widespread efforts at improved defibrillation and CPR quality, both fundamental strategies to generate rapid reperfusion.2, 3

Therapeutic hypothermia (TH) has been shown to improve both survival and neurological outcomes after cardiac arrest in several clinical trials, and has been endorsed as an evidence-based treatment modality by the International Liaison Committee on Resuscitation.4, 5, 6, 7 Currently TH is applied in the post-resuscitation time period, to minimize reperfusion injury following ischemia and improve neurological outcome after ROSC is achieved.⁸ Earlier animal work by our group and others has suggested that intra-arrest hypothermia may provide additional survival benefit compared to TH after resuscitation.9, 10 Cellular ischemia-reperfusion experiments have observed deleterious oxidant generation as well as apoptotic activation immediately after reperfusion, and intra-ischemia cooling blunts these damaging processes.11, 12, 13 It is unknown to what degree initial cooling should be given priority over reperfusion and ROSC, if at all. This is particularly controversial if the induction of TH requires a delay in circulatory resuscitation and restoration of perfusion. We sought to test the hypothesis that intra-arrest TH, and therefore “cooled reperfusion”, would lead to improved cardiac function and survival in an animal model of cardiac arrest even if resuscitation efforts, and therefore ROSC, were delayed to facilitate cooling before CPR.

Section snippets

Animal preparation

All animal procedures were approved by the Institutional Animal Care and Use Committee of the University of Chicago (IACUC #71041). Animal husbandry was supervised by the Animal Research Center veterinary staff and included routine care for animals surviving cardiac arrest.

As described in our earlier work, we used adult female C57BL/6 mice (25–33 g; Taconic Farms, Germantown, NY). Animals were allowed free access to food and water prior to study. Animals were anesthetized with 80 μg/g of ketamine

Experimental results

A total of 49 mice underwent surgical preparation to yield 45 animals randomized for the three experimental groups. Baseline characteristics (Table 1) including animal weight, temperature, heart rate and left ventricular (LV) pressure before arrest were statistically indistinguishable between groups. During the arrest period, cooling rates did not differ significantly between the two hypothermia groups (Table 1). We observed that animals cooled rapidly to the target temperature within 90 s

Discussion

In the present study we used a mouse model of cardiac arrest to demonstrate that hemodynamic, survival and neurological metrics were significantly improved with intra-arrest cooling even if resuscitation was delayed for 90 s to first induce hypothermia. Specifically, animals undergoing normothermic resuscitation at 8 min fared worse than animals with delayed resuscitation and cooled reperfusion at 9.5 min (with identical 8 min of normothermic arrest time in both groups). This is consistent with the

Conclusion

Delayed intra-arrest cooling may provide significant hemodynamic, neurological and survival benefits compared with earlier reperfusion without cooling, thus the current paradigm that gives priority to prompt ROSC first may need further careful evaluation. Evaluation of the mechanistic effects of this intra-ischemic cooling will allow for a better understanding of how it may be applied in the clinical setting.

Conflict of interest

Dr. Abella has received speaking honoraria from Philips Medical Systems, Zoll Corporation and Alsius Corporation, and research funding from Philips Medical Systems and Cardiac Science Corporation. Dr. Becker has received research funding from Alsius Corporation, Philips Medical Systems, and Cardiac Science Corporation. Dr. Vanden Hoek has received grant support from Philips Medical Systems and Medivance Incorporated. Drs. Becker and Vanden Hoek have equity interest in Cold Core Therapeutics, as

Acknowledgements

We would like to thank Raina Merchant, MD, for advice and critique of the current work. We also thank Michael Retzer, Lynne Harnish, and Ameena Al-Amin for their administrative assistance. This work was supported by a grant from the National Institutes of Health (R01-HL71734-01). Dr. Abella is also supported by a Career Development Award from the NIH (1 K23 HL 83082-01).

Contributors: Conception of study was done by BS Abella, LB Becker, TL Vanden Hoek, and D Zhao. Experimental work was carried

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The design of the PRINCESS 2 trial: A randomized trial to study the impact of ultrafast hypothermia on complete neurologic recovery after out-of-hospital cardiac arrest with initial shockable rhythm
2024, American Heart Journal
Delayed hypothermia, initiated after hospital arrival, several hours after cardiac arrest with 8-10 hours to reach the target temperature, is likely to have limited impact on overall survival. However, the effect of ultrafast hypothermia, i.e., delivered intra-arrest or immediately after return of spontaneous circulation (ROSC), on functional neurologic outcome after out-of-hospital cardiac arrest (OHCA) is unclear. In two prior trials, prehospital trans-nasal evaporative intra-arrest cooling was safe, feasible and reduced time to target temperature compared to delayed cooling. Both studies showed trends towards improved neurologic recovery in patients with shockable rhythms. The aim of the PRINCESS2-study is to assess whether cooling, initiated either intra-arrest or immediately after ROSC, followed by in-hospital hypothermia, significantly increases survival with complete neurologic recovery as compared to standard normothermia care, in OHCA patients with shockable rhythms.
In this investigator-initiated, randomized, controlled trial, the emergency medical services (EMS) will randomize patients at the scene of cardiac arrest to either trans-nasal cooling within 20 minutes from EMS arrival with subsequent hypothermia at 33°C for 24 hours after hospital admission (intervention), or to standard of care with no prehospital or in-hospital cooling (control). Fever (>37,7°C) will be avoided for the first 72 hours in both groups. All patients will receive post resuscitation care and withdrawal of life support procedures according to current guidelines. Primary outcome is survival with complete neurologic recovery at 90 days, defined as modified Rankin scale (mRS) 0-1. Key secondary outcomes include survival to hospital discharge, survival at 90 days and mRS 0-3 at 90 days. In total, 1022 patients are required to detect an absolute difference of 9% (from 45 to 54%) in survival with neurologic recovery (80% power and one-sided α=0,025, β=0,2) and assuming 2,5% lost to follow-up. Recruitment starts in Q1 2024 and we expect maximum enrolment to be achieved during Q4 2024 at 20-25 European and US sites.
This trial will assess the impact of ultrafast hypothermia applied on the scene of cardiac arrest, as compared to normothermia, on 90-day survival with complete neurologic recovery in OHCA patients with initial shockable rhythm.
NCT06025123.
Effects of regional body temperature variation during asphyxial cardiac arrest on mortality and brain damage in a rat model
2020, Journal of Thermal Biology
To date, hypothermia has focused on improving rates of resuscitation to increase survival in patients sustaining cardiac arrest (CA). Towards this end, the role of body temperature in neuronal damage or death during CA needs to be determined. However, few studies have investigated the effect of regional temperature variation on survival rate and neurological outcomes. In this study, adult male rats (12 week-old) were used under the following four conditions: (i) whole-body normothermia (37 ± 0.5 °C) plus (+) no asphyxial CA, (ii) whole-body normothermia + CA, (iii) whole-body hypothermia (33 ± 0.5 °C)+CA, (iv) body hypothermia/brain normothermia + CA, and (v) brain hypothermia/body normothermia + CA. The survival rate after resuscitation was significantly elevated in groups exposed to whole-body hypothermia plus CA and body hypothermia/brain normothermia plus CA, but not in groups exposed to whole-body normothermia combined with CA and brain hypothermia/body normothermia plus CA. However, the group exposed to hypothermia/brain normothermia combined with CA exhibited higher neuroprotective effects against asphyxial CA injury, i.e. improved neurological deficit and neuronal death in the hippocampus compared with those involving whole-body normothermia combined with CA. In addition, neurological deficit and neuronal death in the group of rat exposed to brain hypothermia/body normothermia and CA were similar to those in the rats subjected to whole-body normothermia and CA. In brief, only brain hypothermia during CA was not associated with effective survival rate, neurological function or neuronal protection compared with those under body (but not brain) hypothermia during CA. Our present study suggests that regional temperature in patients during CA significantly affects the outcomes associated with survival rate and neurological recovery.
Therapeutic hypothermia applicable to cardiac surgery
2015, Veterinary Anaesthesia and Analgesia
To review the beneficial and adverse effects of therapeutic hypothermia (TH) applicable to cardiac surgery with cardiopulmonary bypass (CPB) in the contexts of various temperature levels and techniques for achieving TH.
Multiple electronic literature searches were performed using PubMed and Google for articles published from June 2012 to December 2014. Relevant terms (e.g. ‘hypothermia’, ‘cardiopulmonary bypass’, ‘cardiac surgery’, ‘neuroprotection’) were used to search for original articles, letters and reviews without species limitation. Reviews were included despite potential publication bias. References from the studies identified were also searched to find other potentially relevant citations. Abstracts, case reports, conference presentations, editorials and expert opinions were excluded.
Therapeutic hypothermia is an essential measure of neuroprotection during cardiac surgery that may be achieved most effectively by intravascular cooling using hypothermic CPB. For most cardiac surgical procedures, mild to modest (32–36 °C) TH will be sufficient to assure neuroprotection and will avoid most of the adverse effects of hypothermia that occur at lower body core temperatures.
The efficacy and safety of prehospital therapeutic hypothermia in patients with out-of-hospital cardiac arrest: A systematic review and meta-analysis
2015, Resuscitation
The benefit of therapeutic hypothermia (TH) to patients suffering out-of-hospital cardiac arrest (OHCA) has been well established. However, the effect of prehospital cooling remains unclear. We aimed to investigate the efficacy and safety of prehospital TH for OHCA patients by conducting a systematic review of randomised controlled trials (RCTs).
The MEDLINE, EMbase and CENTRAL databases were searched for publications from inception to April 2015. RCTs that compared cooling with no cooling in a prehospital setting among adults with OHCA were eligible for inclusion. Random- and fixed-effect models were used depending on inter-study heterogeneity.
Eight trials that recruited 2379 participants met the inclusion criteria. Prehospital TH was significantly associated with a lower temperature at admission (mean difference (MD) −0.94; 95% confidence interval (CI) −1.06 to −0.82). However, survival upon admission (Risk ratio (RR) 1.01, 95%CI 0.98–1.04), survival at discharge (RR 1.02, 95%CI 0.91–1.14), in-hospital survival (RR 1.05, 95%CI 0.92–1.19) and good neurological function recovery (RR 1.06, 95% CI 0.91–1.23) did not differ between the TH-treated and non-treated groups. Prehospital cooling increased the incidence of recurrent arrest (RR 1.23, 95%CI 1.02–1.48) and decreased the PH at admission (MD −0.04, 95%CI −0.07 to −0.02). Pulmonary oedema did not differ between the arms (RR 1.02, 95%CI 0.67–1.57). None of the potentially controversial issues (cooling methods, time of inducing TH, the proportion of continuing cooling in hospital, actual prehospital infusion volume and primary cardiac rhythms) affected the efficacy.
Evidence does not support the administration of prehospital TH to patients with OHCA.
Temperature Control After Cardiac Arrest: A Narrative Review
2023, Advances in Therapy
A ventricular fibrillation cardiac arrest model with extracorporeal cardiopulmonary resuscitation in rats: 8 minutes arrest time leads to increased myocardial damage but does not increase neuronal damage compared to 6 minutes
2023, Frontiers in Veterinary Science

View all citing articles on Scopus

^☆: A Spanish translated version of the summary of this article appears as Appendix in the online version at doi:10.1016/j.resuscitation.2007.10.015.

¹: The first two authors contributed equally to this work.

View full text

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

Summary

Background

Methods

Results

Conclusions

Introduction

Section snippets

Animal preparation

Experimental results

Discussion

Conclusion

Conflict of interest

Acknowledgements

Ann Emerg Med

Resuscitation

Resuscitation

J Mol Cell Cardiol

Resuscitation

Resuscitation

Resuscitation

Mol Brain Res

Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia

N Engl J Med

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

N Engl J Med

Therapeutic hypothermia after cardiac arrest: an advisory statement by the advanced life support task force of the International Liaison Committee on Resuscitation

Circulation

Hypothermia for neuroprotection after cardiac arrest: systematic review and individual patient data meta-analysis

Crit Care Med

Mild cerebral hypothermia during and after cardiac arrest improves neurologic outcome in dogs

J Cereb Blood Flow Metab

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