HYPO-ECMO

Effect of Moderate Hypothermia vs Normothermia on 30-Day Mortality in Patients With Cardiogenic Shock Receiving Venoarterial Extracorporeal Membrane Oxygenation: The HYPO-ECMO study – A Randomized Clinical Trial

Levy et al | Journal of the American Medical Association | Feb 2022 DOI:10.1001/jama.2021.24776

Clinical Question

In patients with cardiogenic shock receiving venoarterial extracorporeal membrane oxygenation(VA-ECMO), does early use of moderate hypothermia (33-34°C) compared with strict normothermia (36-37 °C) improve 30 day mortality?

Background

  • VA-ECMO is an increasingly common intervention for cardiogenic shock refractory to standard therapies
  • Severe cardiogenic shock, especially in patients with associated cardiac arrest, may be associated with ischemia reperfusion injury
  • Patients with refractory cardiogenic shock requiring VA-ECMO likely have most severe ischaemia reperfusion injury
  • Moderate hypothermia
    • May mitigate effects of ischemia reperfusion injury
    • Well tolerated in patients after cardiac arrest / with cardiogenic shock
    • However, not associated with significant change in haemodynamics or mortality
  • Lack of data addressing hypothermia with ECMO – current recommendation is normothermia
  • Rapid temperature control is easily achieved during ECMO treatment which may improve the effectiveness of moderate hypothermia

Design

  • Multi-centre, unblinded, parallel-group randomised clinical trial
  • Unblinded trial due to nature of intervention
  • Study powered to 80% to detect a 15% relative reduction in the primary outcome (30-day mortality) using an estimated mortality of 50% in patients with cardiogenic shock supported by VA-ECMO

Setting

  • Conducted in ICUs at 20 French cardiac shock care centres between October 2016 and July 2019
  • Final follow-up occurred in November 2019

Population

Inclusion Criteria

  • Endotracheal intubation
  • Receiving VA-ECMO for cardiogenic shock for < 6 hours

Exclusion Criteria

    • Younger than 18 years of age
    • Pregnant
    • VA-ECMO after cardiac surgery for a heart +/- lung transplant
    • LVAD implantation
    • VA-ECMO for acute poisoning with cardiotoxic drugs
    • Uncontrolled bleeding (bleeding despite medical intervention with surgery or drugs)
    • VA-ECMO after CPR > 45 minutes
    • Out-of-hospital refractory cardiac arrest
    • Already participating in interventional research
    • Under guardianship
    • Irreversible neurological injury
    • No longer receiving life-sustaining therapies

786 patients assessed for eligibility after being intubated and treated with VA-ECMO

  • 412 excluded
    • Heart transplant or left ventricular assist device implantation (n=117)
    • CPR >45 minutes (n=72)
    • Uncontrolled bleeding (n=70)
    • Moribund (n=53)
    • Logistical reasons (n=42)
    • Out-of-hospital refractory cardiac arrest (n=36)
    • Poisoning (n=32)
    • Family opposed to patient inclusion (n=26)
  • 374 randomised
    • 186 moderate hypothermia group
    • 188 normothermia group

Baseline characteristics

Moderate hypothermia vs Normothermia – very similar between the two groups

  • Median age: 57 vs 59
  • Male: 76% vs 75%
  • Cardiovascular history
    • Cardiac arrest 48% vs 47%
    • Hypertension 37% vs 37%
    • Heart failure 20% vs 20%
    • Ischaemic cardiomyopathy 19% vs 26%
    • Myocardial infarction 16% vs 14%
    • Valvular cardiomyopathy 13% vs 14%
  • Aetiology of cardiogenic shock
    • Acute coronary syndrome 35% vs 37%
    • Ischaemic cardiomyopathy 23% vs 22%
    • Rhythmic cardiomyopathy 17% vs 9%
    • After cardiac surgery 14% vs 16%
    • Acute myocarditis 10% vs 8%
    • Dilated cardiomyopathy 9% vs 7%
    • Pulmonary embolism 5% vs 5%
    • Takotsubo syndrome 2% vs 4%
  • Echocardiogram and laboratory results
    • LVEF before VA-ECMO 20% vs 20%
    • pH 7.32 vs 7.31
    • Lactate 4.8 vs 4.9
    • Sequential organ failure assessment score 10 vs 10

Intervention

  • Hypothermia
    • Target temperature of 33 °C to 34 °C achieved just after randomization by adjusting VA-ECMO circuit temperature controller for initial 24 hours
    • Followed by progressive rewarming (0.1- 0.2 °C per hour) to 37 °C, and maintained at 37 °C for subsequent 72 hours
    • 18 withdrew consent leaving 168 in primary outcome analysis

Control

  • Normothermia
    • Temperature maintained between 36 °C and 37 °C during first 24 hours and at 37 °C during subsequent 72 hours
    • Among the patients who had a cardiac arrest, core temperature was strictly maintained at 36 °C
    • 22 withdrew consent leaving 166 in primary outcome analysis

Management common to both groups

  • VA-ECMO initiated per local practice with blood flow settings set to ensure adequate tissue perfusion
  • Patients then randomized to moderate hypothermia or normothermia
  • Further ICU therapy provided in accordance with generally accepted intensive care practices

Outcome

Primary Outcome

  • Mortality at 30 days: no significant difference (42% vs 51%) with adjusted OR 0.71 (95% CI 0.45 – 1.13, p=0.15)

Secondary Outcomes

  • Composite outcome of death, heart transplant, escalation to LVAD or stroke
    • At 30 days: 52% vs 64%, OR 0.61 (95% CI 0.39 – 0.96) – statistically significant
    • At 60 days: 58% vs 66%, OR 0.70 (95% CI 0.44 – 1.11)
    • At 180 days: 61% vs 69%, OR 0.69 (95% CI 0.43 – 1.11)
  • Mortality
    • At 48 hours: 6% vs 7%, OR 0.98 (95% CI 0.38 – 2.51)
    • At 7 days: 17% vs 28%, OR 0.53 (95% CI 0.31 – 0.93) – statistically significant
    • At 60 days: 49% vs 55%, OR 0.79 (95% CI 0.50 – 1.25)
    • At 180 days: 52% vs 58%, OR 0.81 (95% CI 0.51 – 1.29)
  • Clinical Outcomes: No difference in any of the below
    • VA-ECMO duration from randomisation
    • Net intake of intravenous fluids at day 7
    • Length of use of vasopressors
    • Time to normalisation of lactate
    • Number of days alive without organ failure at day 7
    • Ventilator free days at day 30, 60 or 180
    • Kidney replacement therapy free days at day 30, 60 or 180
    • Length of stay in ICU or in hospital overall

Adverse Events

  • Number of moderate and severe bleeding events was not different between groups
  • Number of units of packed red blood cells transfused during VA-ECMO was higher in the moderate hypothermia group
  • Number of nosocomial infections was not different between groups

Authors’ Conclusions

  • In a mixed population of adults requiring VA-ECMO for refractory cardiogenic shock, early application of moderate hypothermia for 24 hours did not significantly increase survival compared with normothermia. However, the 95% confidence interval was wide and included a potentially important effect size, warranting further study

Strengths

  • Well-designed, multi-centre study performed in the emergency setting
  • Adequate randomisation with concealment
  • No loss to follow up
  • Standardised protocol for temperature regulation
  • Similar baseline characteristics between groups

Weaknesses

  • Patients with all cardiogenic shock aetiologies were included, leading to a degree of heterogeneity
  • Potential for bias to due lack of blinding
  • Strict inclusion and exclusion criteria – limits applicability of findings
  • Trial was underpowered to statistically detect a survival benefit of <15%
  • No sensitivity analysis excluding patients with cardiac arrest
  • Individual component of the composite secondary outcome not reported
  • Very large number of secondary outcomes without correction increasing risk of a false positive results
  • Medium and long-term outcomes not evaluated, e.g. neurocognitive sequelae, which may have been clinically relevant

The Bottom Line

  • Early moderate hypothermia for patients requiring VA-ECMO was not shown to reduce 30 day mortality
  • The observed effect size could be clinically significant and warrants further investigation
  • I would be interested to know if there was a difference in effect size between those with and without cardiac arrest
  • For now I will continue to utilise normothermia for patients requiring VA-ECMO for refractory cardiogenic shock

External Links

Metadata

Summary author: Dinesh Giritharan
Summary date: 28th May 2022
Peer-review editor: Alastair Brown/Aidan Burrell

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