Therapeutic hypothermia: is it effective for non-VF/VT cardiac arrest?

Sudden cardiac death represents a major health problem. In adults, the prevalence of out-of-hospital cardiac arrest (OHCA) attended by the emergency medical services (EMS) ranges from 52 to 112 per 100,000 person-years in developed countries [1], whereas the prevalence of adult in-hospital cardiac arrest (IHCA) ranges from 1 to 5 per 1,000 patient admissions [2].


Introduction
Sudden cardiac death represents a major health problem. In adults, the prevalence of out-of-hospital cardiac arrest (OHCA) attended by the emergency medical services (EMS) ranges from 52 to 112 per 100,000 person-years in developed countries [1], whereas the prevalence of adult in-hospital cardiac arrest (IHCA) ranges from 1 to 5 per 1,000 patient admissions [2].
More than two-thirds of initially resuscitated patients die before hospital discharge [7,8]. Th e m ajor causes of hospital mortality are post-resuscitation brain and myocardial dysfunction [9,10]. Mild therapeutic hypothermia can reduce the sever ity of post-resuscitation brain injury and improve survival in patients who remain comatose after resuscitation from cardiac arrest. In 2002, two randomized clinical trials showed improved neurological outcome [11,12] in a t otal of 350 comatose adults resuscitated from OHCA who were cooled to 32-34°C for 12-24 hours shortly after recovery of spontaneous circulation. Th e largest of these trials [12] also sh owed a signifi cant reduction in mortality within six months in patients treated with mild therapeutic hypothermia. Both these trials included only patients who had VF/VT as the initial rhythm.
Based on these results, subsequently confi rmed by a meta-analysis [13], the International Liaison Committee on Resuscitation (ILCOR) recommended in 2003 the use of mild therapeutic hypothermia for all comatose survivors after OHCA due to VF/VT [14]; this recommendation was confi rmed in the current 2010 Guidelines for Cardiopulmonary Resuscitation [15]. However, only 25-30 % of OHCA patients have VF/VT as the initial recorded cardiac rhythm [1], and this percentage has decreased in recent years [16,17], partly because of the advent of implantable cardioverter-defi brillators for the prevention and treatment of patients at r isk of lethal arrhythmias [18]. Th e prevalence of VF/VT rhythms in IHCA does not exceed 25-30 % either [2]. For the remaining 70-75 % of patients who under go cardiac arrest with non-VF/VT rhythms, indications for receiving therapeutic hypothermia after resuscitation are less clear.

Hypothermia for non-VF/ VT cardiac arrest
Th e evidence on whether use of mild therapeutic hypothermia could improve prognosis in comatose patients resuscitated from non-VF/VT cardiac arrest is sparse. We identifi ed 15 observational studies (Table 1) and 2 randomized trials.

Randomized clinical trials
Use of mild therapeutic hypothermia for the treatment of patients resuscitated from non-VF/VT cardiac arrest has been described in two randomized trials, even thou gh neither was specifi cally designed to assess the benefi t of mild therapeutic hypothermia in this patient population. One trial was a feasibility study on a helmet device for inducing hypothermia after resuscitation [19], the other examined the eff ect of isovolemic high-volume hemofi ltrati on alone or combined with mild therapeutic hypothermia to improve survival after cardiac arrest [20]. Th ese trials included a total of only 44 patients with non-VF/VT rhythms. Within this small subgroup, patients treated with mild therapeutic hypothermia had a higher survival rate at six months than did controls (

Observational studies
A series of observational studies evaluated the eff ects of mild therapeutic hypothermia in non-VF/VT patients (Table 1). In a retrospective analysis from Oddo et al. [21] of a database on the implementation of mild therapeutic hypothermia in an intensive care unit (ICU), th e rates of good neurological outcome (Cerebral Performance Category [CPC] 1-2 [22]) in a small subgroup of patients resuscitated from non-VF/VT arrest and treated with mild therapeut ic hypotherm ia was not signifi cantly better than that of historical controls (2/12 vs. 1/11; p = 0.99).
In 2007, the resul ts of the European Resuscitation Council Hypothermia After Cardiac A rrest Registry (HACA-R) were published [23]. Th is multicenter observational study included data from 19 participating centers on 587 patients resuscitated from cardiac arrest, around 18 % of which had occurred in hospital. Th e non-FV/VT subgroup included 197 subjects, 124 (63 %) of whom were treated using mild therapeutic hypothermia. Th e rate of survival to hospital discharge was signifi cantly higher in mild therapeutic hypothermia-treated patients (45/124 (35 %) vs. 14/73 (19 %); p = 0.023). Th e rate of the combined en dpoint of death (CPC = 5) and poor neurological outcome (CPC 3-4) was also lower -although not signifi cantly -in the mild therapeutic hypothermia group (89/124 [71 %] vs. 59/73 [81 %] p = 0.21). In this study, only univariate anal ysis was performed, so no correction was made for pre-and intra-arrest potential confounders. Another limitation was the risk of selection bias, because the choice of using hypothermia in a given patient was left to the discretion of the treating physician.
I n 2009, a large, retrospective study by Don et al. [24] on implementation of mil d therapeutic hy pothermia in a community hospi tal during a fi ve year-period was published. Th e study included a total of 491 patients with OHCA with all rhythms, of whom 313 (74 %) had non-VF/VT cardiac arrest. Patients enrolled after implementa tion of the therapeutic hypothermia protocol were co mpared with historical controls. Results showed that whereas in patients with VF/VT the hypothermia period was associated with signifi cantly higher rates of survival to hospital discharge and favorable neurological outcome as compared to the pre-hypothermia period ( [25][26][27][28][29][30]. None of these studies was designed to speci fically investigate the association between mild thera peutic hypothermia and prognosis of non-VF/VT rhythms. Th e majority o f thes e studies documented a non-signifi cant trend towards better outcome when mild therapeutic hypothermia was used in patients with non-VF/VT cardiac arrest. A recent systematic review and meta-analysis by Kim et al. [31] evaluated the two randomized studies reported above and 12 non-r andomized studies for a total of 1,336 non-VF/VT patients, 412 (30.8 %) of whom were treated using mild therapeutic hypothermia. Th e q uality of evidence was assessed using the GRADE methodology [32]. Th e results showed that the quality of evidence in all studies was very low. Most of the studies had substantial risks of bias and 9/12 had a high degree of imprecision, because of their small sample size. Pooled data from the two small randomized studies showed a non-signifi cant trend toward a lower 6-month mortality with mild therapeutic hypothermia (RR 0.85 [0.65-1.11]). Metaanalysis of the 12 observational studies showed a sig nificant r eduction in hospital mortality (RR 0.84 [0.78-0.92]) and a non-signifi cant trend towards better neurological ou t co me (RR for poor neurological outcome 0.95 [0.90-1.01]) after mild therapeutic hypothermia. Th e authors conclud ed tha t mild the rapeutic hypothermia was associated with reduced in-hospital mortality for adult patients resuscitated from non-shockable cardiac arrest, but also suggested caution in interpreting the results, given a substantial risks of bias and the low quality of the evidence.

Results of the most recent studies
Th ree very recent studies that were not included in the systematic review by Kim et al. [31] reported confl icting results on the potential benefi t of mild therapeutic hypothermia in patients with non-VF/VT cardiac arrest. A fi rst study by Dumas et al. [33] reported data from a prospective French database including 1,145 OHCA pa tients, 437 of whom were non-VF/VT patients. Th e association between mild therapeutic hypothermia and good neurological outcome at discharge (CPC 1 or 2) was quantifi ed by logistic regression analysis. Mild therapeutic hypothermia was induced in 457/708 (65 %) patients with VF/VT and in 261/437 (60 %) with non-VF/VT. After adjust ment for confounders, the results showed that whereas mild therapeutic hypothermia was associated with a signifi cantly better neurological outcome at discharge in VF/VT patients, there was a trend towards a worse outcome in non-VF/VT patients ( Another prospective single-center observational study was conducted by Storm et al . [34] in a university hospita l setting wi th histori cal controls. Th e paper enrolled 387 consecutive patients with all rhythms who had been admitted to the ICU after cardiac arrest. Mild therapeutic hypothermia was induced in 201 patients (87 with non-VF/VT), who were compared with 186 historical controls (88 with non-VF/VT). Univariate analysis showed a nonsignifi cant trend towards better neurological outcome in non-VF/VT patients treated with mild therapeutic hypothermia ( Finally, a recent small single-center observational study by Lundbye et al. [35] co mpared neurological outcome and survival at hospital discharge in 52 non-VF/VT cardiac arrest patients treated using mild therapeutic hypothermia compared with 4 8 historical controls who did not receive mild therapeutic hypothermia. In contrast with the previous two studies, the rates of good neurological outcome ( Th e Forest plots in Fig. 1a, b summarize the re sults of 12 observationa l studies repo rting su rvival to discharge (1,581 patients, Fi g. 1a) and of 13 observational studies reporting neurological outcome (1, 998 p atients, Fig . 1b). Dat a pooled according to a fi xed eff ect model show a signifi cant reduction in the RR for hospital mortality (0.88 [0.82-0.95]) and a smaller but signifi cant reduction in RR for poor neurological outcome (0.95 [0.90-0.99]) i n pati ents treat ed using mild therapeutic hypothermia. How ever, in spite of pooled results favo ring t reatment, the eff ect is not consistent, with large studies showing increased RR for poor neurological outcome associated with use of mild therapeutic hypothermia [33] (Fig. 1b).
In comparison with the results of randomized trials in VF/VT patients [36], analysis of the availab le evidence shows that use of mild therapeutic hypothermia in comatose patients resuscitated from non-VF/VT cardiac arrest is associated with a small eff ect size, particularly as regards neurological outcome, with several studies [24,30,33,37,38] suggesting no eff ect or even a possible harm from mild therapeutic hypothermia. Th ere are many possible exp lanati ons fo r this observation. One explanation could be that patients who undergo a cardiac arrest with non-VF/VT rhythms represent a more heterogeneous population as compared to those with a VF/VT arrest. Sudden death due to VF/VT is usually the result of cardiac causes, such as arrhythmia or acute myocardial ischemia, whereas non-VF/VT rhythms (asystole or PEA) have a wider variety of causes, such as hypoxia, hypovolemia, sepsis, pulmonary thromboembolism, or cardiac tamponade. Th ese causes are often associated with major comorbidities, which could reduce the chances of patient survival after resuscitation, regardless of the protective eff ect of mild therapeutic hypothermia. Moreover, cardiac arrest from these causes is often preceded by generalized hypoxia or hypoperfusion, which may further worsen cerebral anoxic damage. Finally, since asystole represents the fi nal evolution of all cardiac arrest rhythms, its presence may indicate a long collapse-to-resuscitation interval and/or poor or absent bystander resuscitation, both of which are associated with a high risk of irreversible neurological damage. In some studies, therefore, non-VF/VT patients could have been simply too ill to benefi t from mild therapeutic hypothermia.
Heterogeneity observed in study results may also be explained by diff erences in case mix and in cooling protocols. For example, some studies included only OHCA patients, whereas others included both IHCA and OHCA (see Table 1). Two of the studies that documented lack of benefi t from mild therapeutic hypothermia used the external surface cooling method, which may require longer times to achieve the target temperature than with intravascular cooling.
Finally, apart from two trials with minimal sample sizes, all the published studies on mild therapeutic hypot hermia for non-VF/VT arrest are observational. Th is makes controlling of confounders extremely diffi cult to achieve and introduces further sources of bias. Studies in which the control group was represented by concurrent patients not treated using mild therapeutic hypothermia are prone to selection bias, and in those with historical  controls, the results may refl ect secular trends in patient or disease characteristics or changes in resuscitation practice rather than the eff ect of the study intervention.
To be correctly addressed, the question as to whether mild therapeutic hypothermia may be benefi cial in patients with asystole or PEA as the initial cardiac rhythm will require a purposely designed, high-quality randomized controlled trial. However, in order to demonstrate an increase in survival from 25 % to 30 % with a 0.05 risk of a type-1 error (alpha) and a 0.20 risk of type-II error (beta) using univariate analysis, a minimum of 1 ,100 patients resuscitated from non-VF/VT w ould be required. Such a large sample size would be diffi cult to collect, considering that only about 10 % of patients resuscitated from cardiac arrest of all rhythms survive to hospital admission [8]. Moreover, this trial may even raise ethical issues, since pooled results from observational studies suggest a modest b ut signifi cant benefi t from mild therapeutic hypothermia in non-FV/VT cardiac arrests.

Conclusions
Non-VF/VT are the most common initial cardiac rhythms recorded in both in-hospital and out-of-hospital cardiac arrests. Unfortunately, patients with non-VF/ VT rhythms also represent the majority of those who die despite resuscitation, and interventions able to improve the prognosis of this patient category are eager ly awaited. Whereas mild therapeutic hypothermia has been consistently demonstrated to improve outcomes after VF/VT cardiac arrest, its use in patients with non-VF/VT arrest has produced confl icting results. Pooled data from available studies show that the use of mild therapeutic hypothermia for 24 hours in comatose patients resuscitated from non-VF/VT arrest was associated with a 15 % reduction in hospital mortality and with a minimal, albeit signifi cant improvement in neurological outcome at discharge. Th e quality of evidence supporting these results, however, is very poor, since it is based almost exclusively on observational studies, most of which were not specifi cally designed to evaluate the benefi t of mild therapeutic hypothermia in non-VF/VT patients. Randomized controlled trials of adequate sample size are necessary to address this question.