Review articleTherapeutic hypothermia after cardiac arrest: A systematic review/meta-analysis exploring the impact of expanded criteria and targeted temperature☆
Introduction
The use of cooling as therapeutic agent was initially utilized for the treatment of head wounds, and was first described in the Edwin Smith papyrus over 5000 years ago.1 First reports of the use of therapeutic hypothermia (TH) during resuscitative efforts date back to 1803 when patients where covered in snow as way to facilitate resuscitation.2 Subsequently, the use of TH after cardiopulmonary arrest was described 50 years ago in a case series limited to patients with in-hospital cardiac arrest.3, 4 Due to a consistent benefit of hypothermia on brain cell ischemia in experimental models,5 these earlier studies targeted much lower temperatures than those recommended in current guidelines.6 Despite demonstration of benefit, generalization of results was often hampered by the high incidence of adverse events associated with TH at the time.7 Therapeutic hypothermia became a more accepted therapeutic intervention after two landmark trials in the early 2000’s demonstrated significant survival benefit and improved neurological outcomes associated with TH after out-hospital cardiac arrest (OHCA).8, 9, 10
TH is strongly recommended in unconscious survivors of OHCA stemming from ventricular fibrillation (Class Ib).6 Outside of this cohort of patients, there is a great degree of uncertainty and variation in practice. There is a significant paucity of data for the use of TH in all cases of cardiac arrest due to small size of study subjects, substantial differences in cooling protocols and strict inclusion criteria.10 Due to this lack of data, most of the recommendations on the specifics of TH are based on observational studies and expert opinion. Current guidelines support cooling of comatose survivor of cardiac arrests stemming from non-shockable rhythms and in-hospital settings (Class IIb).8, 9, 11, 12 These recommendations have significantly modified clinical practice, and have expanded the use of TH beyond the inclusion criteria of initial trials.13 Nonetheless, the data showing the benefits of TH when applied to a broader spectrum of patients remain scattered at best.
Since the publication of the first TH trials, efforts have been made to define an ideal cooling temperature.14, 15, 16, 17 But after almost two decades, there still exists significant uncertainty about the optimal temperature for TH.18, 19 While clinical guidelines have advised a target temperature ranging from 32 °C to 34 °C, a recent update from the International Liaison Committee on Resuscitation (ILCOR) suggests that the temperature range should be liberalized to 32–36 °C.19 Beyond the issue of temperature, there is also growing skepticism about the benefits of cooling and some researchers have suggested that the improved outcomes in these patients are really due to a practice of fever avoidance.20
We conducted an updated meta-analysis to assess the performance of TH after OHCA on hospital mortality and good neurological outcome at hospital discharge when treating patients within and beyond the initial criteria of the landmark trials. We also performed a systematic review and pooled analysis to determine the impact of different temperature goals on outcomes at discharge.
Section snippets
Methods
The results of this meta-analysis were written using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) reporting guidelines for randomized trials and MOOSE (Meta-analysis Of Observational Studies in Epidemiology) reporting guidelines for observational studies. We used the PICOS (Participants, Intervention, Comparison, Outcomes and Study Design) model to generate the research questions, create a search strategy and guide study selection.21, 22
Study characteristics
Our search strategy yielded 32,275 citations after de-duplication. We retrieved 149 articles for a detailed evaluation and based on our inclusion criteria included 24 articles for our final review and analysis (Fig. 1).
Eleven studies (three randomized controlled trials and eight cohort studies) compared TH versus normothermia and were included in our meta-analysis (Table 1).8, 9, 26, 27, 28, 29, 30, 31, 32, 33, 34 These 11 studies contained 1381 patients with a mean age of 61.3 years. Shockable
Discussion
This meta-analysis examined the benefit of TH post-cardiac arrest, beyond just the unconscious patient who had a witnessed OHCA stemming from a shockable rhythm, with less than 30 min of downtime and no persistent shock upon ROSC. We expanded our cohort to comatose survivors of OHCA with any initial rhythm, more flexible downtimes, without restriction in regards of witnessed arrest or shock after ROSC. This approach is radically different from previous meta-analyses that have reported outcomes
Conclusion
The use of therapeutic hypothermia is associated with a survival and neuroprotective benefit after OHCA, even when including patients with non-shockable rhythms, more lenient downtimes, unwitnessed arrest and/or persistent shock after ROSC. An expanded use of this intervention in daily practice might be appropriate in patients with good baseline functional status, regardless of the initial rhythm, unwitnessed arrest status or persistent shock. However, we found no evidence to support one
Conflict of interest statement
None to declare.
Declaration
None of the authors involved with this manuscript have any financial and personal relationships with other people or organizations that could inappropriately influence or bias their work.
Funding
No funding to disclose.
Authors’ contributions
Aldo Schenone, Aaron Cohen, Gabriel Patarroyo and Abhijit Duggal had substantial contributions to the conception and design of the work. Aldo Schenone, Aaron Cohen, Gabriel Patarroyo and Logan Harper were responsible for the acquisition of data. Aldo Schenone, Aaron Cohen, Mehdi Shishehbor, Venu Menon and Abhijit Duggal were responsible for the analysis and interpretation of data for this manuscript. Aldo Schenone, Aaron Cohen, Mehdi Shishehbor, Venu Menon and Abhijit Duggal were responsible
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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.2016.07.238.