Review articleEffects of in-hospital low targeted temperature after out of hospital cardiac arrest: A systematic review with meta-analysis of randomized clinical trials☆
Introduction
Out of hospital cardiac arrest (OHCA) is an increasing public-health concern in industrialized countries, with a reported incidence of 38 per 100,000 and a survival to hospital discharge of only 10.7%.1 Long-term survival and clinical outcome after cardiac arrest (CA) improved with years.2 However, many survivors suffer from a poor neurologic outcome, with low quality of life and an extended brain injury.3 After OHCA, post resuscitation care may significantly influence survival and neurologic outcome.4 Although, therapeutic hypothermia (TH) was included in the last guidelines on CA as a treatment for the post resuscitation phase,5 and it has been implemented as the standard of care in many countries, the evidences for its possible beneficial effects after OHCA are still debated.
From a pathophysiological point of view, TH may reduce the excitotoxin exposure and reduce the inflammatory response associated with the post cardiac arrest syndrome.5 On the other hand, TH has been associated with potential adverse side effects including pneumonia, cardiovascular instability and metabolic disturbance, which may further increase morbidity and mortality.6 In OHCA caused by ventricular fibrillation (VF), TH reduced mortality and improved 6-months neurological outcome.7, 8 In contrast, the efficacy of TH in the setting of other causes of cardiac arrest i.e. pulseless electrical activity and asystole, remains unclear.9, 10 A Cochrane review supported the use of TH after OHCA to improve survival and cerebral performance at hospital discharge.11 However, a recent target temperature management (TTM) trial did not show any difference in terms of survival and neurological outcome between OHCA patients treated with two levels of targeted temperature set at 33 and 36 °C.10
The aim of this systematic review and meta-analysis was to evaluate the effectiveness of in-hospital low targeted temperature (<34 °C, low T) compared to controls with both in-hospital not targeted temperature (no target T) and in-hospital targeted temperature (TT) in adult patients after OHCA on mortality and neurologic performance as main outcomes. The TTM study was not the first trial that randomized patients to receive two level of targeted temperature. Bernard et al., and Laurent et al., included a control group with targeted temperature.7, 9, 10 Keeping the patient's temperature stable at an established degree may avoid an uncontrolled increase of body temperature and its side effects.10 Given this, we hypothesized that a low targeted temperature (<34 °C) may have more beneficial effects over a slightly higher targeted temperature (≈36 °C). For this reason, we “a priori” planned a sub-analysis dividing the studies according the temperature management (targeted/not targeted) in different control groups. In addition, studies evaluating hypothermia after OHCA were mainly focused on patients with VF or ventricular tachycardia as initial rhythm.6, 7, 8, 9, 10 According to this, we “a priori” planned a further sub-group analysis of studies including mainly patients with shockable initial rhythm of OHCA.
Section snippets
Data sources and searches
We aimed to identify all randomized control trials (RCTs) assessing mortality at discharge after therapeutic induced hypothermia in adult cardiac arrest patients.
The electronic search strategy applied standard filters for identification of RCTs. Databases searched were the MEDLINE and PUBMED (from inception to April 2014). We applied English language restrictions. Our search included the following keywords: cardiac arrest, out of hospital cardiac arrest, in hospital cardiac arrest, circulatory
Study selection
We identified 1079 references and excluded 1043 after reading titles and abstracts for cardiac arrest, hypothermia, mortality and randomized clinical trials. We analyzed 36 articles in full paper format. Six references fulfilled our search criteria.7, 16, 17 Thirty references, including 3 RCTs evaluating the role of pre-hospital hypothermia, were excluded.18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 3, 43 Fig. 1 shows the study selection
Discussion
In this systematic review and meta-analysis we found that: (1) low T reduced mortality at hospital discharge and at 6 months when compared with no targeted T while there was no reduction in mortality comparing low T with TT; (2) in patients with initial VF/VT rhythm low T reduced short and long-term mortality when compared with no targeted T while not when compared to TT; (3) low T improved neurologic performance at hospital discharge compared with no targeted T.
The results of the present
Limitations
This systematic review and meta-analysis has some limitations, which need to be addressed. We included only full papers in English language and excluding abstracts, but only one of all trials showed overall low risk of bias. We found a substantial heterogeneity (I2 > 50%) according to Cochrane guidelines in 8 out of 17 considered outcomes. We were not able to divide the results according asystole/PEA initial rhythm of OHCA because of the lack of more than one study. Since the overall mortality
Conclusions
In-hospital low targeted temperature (<34 °C) was associated with beneficial effects on short and long-term mortality when compared to in-hospital not targeted temperature. At the same time, we are not able to demonstrate the same results when in-hospital low targeted temperature (<34 °C) was compared with in-hospital slightly higher targeted temperature (≈36 °C). Further studies are needed to establish the best targeted temperature and its potential beneficial effects, and determine how this
Funding
No funding was obtained for this manuscript.
Conflict of interest statement
BI and PP participate to target temperature management trial (TTM trial). VM SG, SY and RGR have no conflict of interest.
Acknowledgement
The authors would like to thank Professor John G Laffey for his contribution in manuscript editing and review.
References (55)
- et al.
Incidence of EMS-treated out-of hospital cardiac arrest in Europe
Resuscitation
(2005) - et al.
The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest
Resuscitation
(2013) - et al.
Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest
Resuscitation
(2007) - et al.
European resuscitation council guidelines for resuscitation 2010
Resuscitation
(2010) - et al.
High-volume hemofiltration after cardiac out-of-hospital cardiac arrest
J Am Coll Cardiol
(2005) - et al.
Mild hypothermia induced by a helmet device: a clinical feasibility study
Resuscitation
(2001) - et al.
Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest
Ann Emerg Med
(1997) - et al.
Preliminary clinical outcome study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest
Resuscitation
(1998) - et al.
Feasibility of external cranial cooling during out-of hospital cardiac arrest
Resuscitation
(2002) - et al.
Feasibility and safety of combined percutaneous coronary intervention and therapeutic hypothermia following cardiac arrest
Resuscitation
(2010)
Effectiveness of each target body temperature during therapeutic hypothermia after cardiac arrest
Am J Emerg Med
Effectiveness of each target body temperature during therapeutic hypothermia after cardiac arrest
Am J Emerg Med
Usefulness of mild therapeutic hypothermia for hospitalized comatose patients having out-of-hospital cardiac arrest
Am J Cardiol
Survival does not improve when therapeutic hypothermia is added to post-cardiac arrest care
Resuscitation
Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms
Resuscitation
Therapeutic hypothermia is associated with improved neurologic outcome and survival in cardiac arrest survivors of non-shockable rhythms
Resuscitation
Therapeutic hypothermia application vs standard support care in post resuscitated out-of-hospital cardiac arrest patients
Am J Emerg Med
Should we worry about post-rewarming hyperthermia?
Resuscitation
Prevalence and effect of fever on outcome following resuscitation from cardiac arrest
Resuscitation
The influence of rewarming after therapeutic hypothermia on outcome after cardiac arrest
Resuscitation
influence of mild therapeutic hypothermia on the inflammatory response after successful resuscitation from cardiac arrest
J Crit Care
The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33 °C or 36 °C
Resuscitation
Ventilatory target after cardiac arrest
Minerva Anestesiol
Adverse events and their relation to mortality in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia
Crit Care Med
Treatment of comatose patients 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
Target temperature management at 33 °C versus 36 °C after cardiac arrest
N Engl J Med
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Targeted Hypothermia vs Targeted Normothermia in Survivors of Cardiac Arrest: A Systematic Review and Meta-Analysis of Randomized Trials
2022, American Journal of MedicinePerioperative Management of Acute Central Nervous System Injury
2021, Perioperative Medicine: Managing for Outcome, Second EditionPost-cardiac arrest care and targeted temperature management: A consensus of scientific statement from the Taiwan Society of Emergency & Critical Care Medicine, Taiwan Society of Critical Care Medicine and Taiwan Society of Emergency Medicine
2021, Journal of the Formosan Medical AssociationCitation Excerpt :TTM trial showed that the outcome was not different between 33 °C and 36 °C post-cardiac arrest TTM in 2013. The study included the patients with initial shockable and non-shockable rhythms, but excluded the patient of unwitnessed asystole or having ROSC more than 4 h.49 A meta-analysis, which included 6 randomized studies, demonstrated that the outcome was better in the groups with targeted temperature lower than 34 °C compared to those without temperature management.50 Based on these results, we suggest the targeted temperature can be a constant temperature between 32oto 36 °C.
Is there a role for therapeutic hypothermia in critical care?
2019, Evidence-Based Practice of Critical CareTargeted temperature management in the ICU: Guidelines from a French expert panel
2018, Anaesthesia Critical Care and Pain MedicineCitation Excerpt :R1.4 We suggest considering TTM between 32 and 36 °C in order to improve survival with good neurological outcome after CA. Rationale: Two studies with a high level of evidence and consistent results addressed this question [14,26]. One randomized controlled trial included 939 patients and found no significant difference in survival and neurological outcome between TTM at 33 °C versus TTM at 36 °C [26].
Recent developments in the management of patients resuscitated from cardiac arrest
2017, Journal of Critical CareCitation Excerpt :TTM is defined as precise control of body temperature to prevent complications. Therapeutic hypothermia refers to TTM at a low body temperature, typically 32°C to 34°C, but is no longer the preferred terminology [47,48]. The goal of cooling is neuroprotection and prevention of the harmful effects of elevated body temperature after cardiac arrest.
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A Spanish translated version of the abstract of this article appears as Appendix in the final online version at http://dx.doi.org/10.1016/j.resuscitation.2015.02.038.