Therapeutic hypothermia in adult patients receiving extracorporeal life support: early results of a randomized controlled study

Cardiac arrest with cerebral ischaemia frequently leads to severe neurological impairment. Extracorporeal life support (ECLS) has emerged as a valuable adjunct in resuscitation of cardiac arrest. Despite ECLS, the incidence of permanent neurological injury remains high. We hypothesize that patients receiving ECLS for cardiac arrest treated with therapeutic hypothermia at 34 °C have lower neurological complication rates compared to standard ECLS therapy at normothermia. Early results of this randomized study suggest that therapeutic hypothermia is safe in adult patients receiving ECLS, with similar complication rates as ECLS without hypothermia. Further studies are warranted to measure the efficacy of this therapy.


Introduction
Cardiac arrest with widespread cerebral ischaemia frequently leads to severe neurological impairment. Extracorporeal life support (ECLS) is a valuable adjunct in resuscitation of cardiac arrest and is instituted whenever indicated [1]. Despite ECLS, the rate of survival to hospital discharge with good neurological function remains low, ranging from 26 to 47 % [2][3][4].
Ischaemia has a key role in all forms of brain injury and preventing ischaemic (or secondary) injury is at the core of all neuroprotective strategies. Therapeutic induced hypothermia via surface cooling has been shown to lower the rate of neurological complications in patients resuscitated from cardiac arrest by up to 23 % [5,6].
ECLS is an ideal tool for the institution of cooling as the extracorporeal pump can achieve flow rates of up to 5 L/min. This allows for rapid and homogenous cooling and subsequent rewarming via large bore cannulas placed in the common femoral artery and vein. Cooling via the ECLS circuit can be augmented with surface cooling using cooling blankets and ice packs. To date, there are few reports from studies evaluating the use of therapeutic hypothermia in adult patients receiving ECLS [2][3][4]7]. The objective of this study is to evaluate the safety and clinical efficacy of therapeutic induced hypothermia in patients receiving ECLS following cardiopulmonary resuscitation (CPR) for cardiac arrest.

Methods
Following approval from the SingHealth institutional review board (reference: 2013/153/C), a randomized controlled study was commenced at our tertiary referral center, to investigate the outcome of patients who remain unconscious after initiation of ECLS for cardiac arrest. All patients received good quality CPR and were adequately resuscitated by qualified medical staff prior to commencement of ECLS. Patients in the control group received ECLS at normothermia (37°C) whereas the treatment group received ECLS at induced hypothermia (34°C) for 24 h. The target recruitment is 50 patients over a period of 36 months.

Inclusion criteria
Cardiac arrest patients with ECLS instituted and any of the following: Eligible patients were randomly assigned to hypothermia or normothermia according to the day of the month, with patients assigned to hypothermia on odd-numbered days.
The primary outcome measure was survival to hospital discharge with sufficiently good neurological function to be discharged home or to a rehabilitation facility, defined as a cerebral performance category (CPC) of 1-2. The CPC, shown in Table 1, is a commonly used 5-category scale which has been the historical gold standard for measuring neurological status after cardiac arrest [8,9]. The 5 categories are: CPC 1, conscious and alert with good cerebral performance; CPC 2, conscious and alert with moderate cerebral performance; CPC 3, conscious with severe cerebral disability; CPC 4, comatose or in persistent vegetative state; and CPC 5, brain dead, circulation preserved. Good and poor neurological outcomes were

Statistical analysis
Statistical analyses were performed with the Statistical Package for Social Science, version 17 (SPSS, Chicago, IL, USA). Continuous variables were expressed as either means with standard deviation or median with interquartile range, as appropriate. These were compared using two-tailed t-test or Mann-Whitney U-test, respectively. Categorical variables, expressed as percentages, were analyzed with χ2 or Fisher's exact test. All two-tailed P-values <0.05 were taken as significant.

Findings
From Aug 2013 to Jan 2015, 21 patients (9 hypothermia, 12 normothermia) received ECLS as salvage therapy for cardiac arrest. Patient demographics and baseline clinical data are shown in Table 2. The mean age was 52.5 ± 11.0 years. Seventeen patients (81.0 %) were male. Nineteen patients (90.5 %) suffered a witnessed in-hospital cardiac arrest. Seventeen events (81.0 %) were attributable to acute coronary syndrome. Pre-ECLS data are shown in Table 3. The initial rhythm was pulseless ventricular tachycardia or ventricular fibrillation in 7 patients (33.3 %), pulseless electrical activity in 10 (47.6 %) and asystole in 4 (19.0 %).  The mean duration of CPR and ECLS were respectively, 25.7 min and 4.4 days. Target cooling to 34°C was achieved in all 9 patients assigned to the hypothermia arm. ECLS-related complications are shown in Table 4. There were no intergroup differences in the frequency of ECLS-related adverse events. Follow-up data are shown in Table 5. Twelve patients (57.1 %) were successfully weaned off ECLS, of which 5 (23.8 %) survived to hospital discharge and were alive at 6 months follow-up. The causes of death in the 15 patients who died were multi-system organ failure in 12 patients (80.0 %) and severe anoxic brain injury in 3 patients (20.0 %). The median follow-up period for inhospital survivors was 191 (85, 399) days. Two patients (22.2 %) in the hypothermia group, compared to 1 (8.3 %) in the normothermia group, survived with a good neurological outcome.

Discussion
A recent large randomized trial has shown a lack of benefit of hypothermia at a targeted temperature of 33°C compared with a targeted temperature of 36°C in terms of survival and preservation of cognitive function in unconscious survivors of out-of-hospital cardiac arrest [10,11]. Despite these findings, therapeutic hypothermia may still benefit patients suffering from refractory cardiac arrest with prolonged resuscitation unresponsive to conventional CPR, who require ECLS as salvage therapy. ECLS-assisted CPR has been reported to improve survival and neurological outcomes compared to conventional CPR. Overall survival and survival with good neurological function rates range from 31 to 50 and 26 to 47 % respectively [2][3][4]12].
Survival to hospital discharge and survival with good neurological function in patients receiving therapeutic hypothermia in our randomized cohort were 33.3 and 22.2 % respectively. Superior results have been reported from the recent CHEER trial, during which therapeutic hypothermia (33°C maintained for 24 h) in conjunction with ECLS was instituted for 24 patients, of which 13 patients (54 %) were successfully weaned from ECMO support. Survival to hospital discharge with full neurological recovery (CPC score 1) occurred in 12 patients (50 %) [7].
The main limitation of this study is the small number of surviving patients and total number of patients recruited to date, thus limiting statistical power. Further study recruitment may shed more light on the benefit of therapeutic hypothermia in adult patients receiving ECLS. In addition, patients receiving hypothermia were significantly younger, with possibly greater potential for neurological recovery compared to older patients.

Conclusion
The preliminary results of this randomized study suggest that therapeutic hypothermia is safe to use in adult patients receiving ECLS, with similar complication rates compared with ECLS without hypothermia. Further studies are warranted to measure the efficacy of this therapy.