TTM

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Nielsen N, et al. "Target Temperature Management 33°C vs. 36°C after Out-of Hospital Cardiac Arrest". The New England Journal of Medicine. 2013. 369(23):2197-2206.
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Clinical Question

For patients with out-of-hospital cardiac arrest, does hypothermia to a goal of 33°C reduce all-cause mortality when compared to a goal of 36°C?

Bottom Line

In patients with out-of-hospital cardiac arrest, targeted temperature management to a goal of 33°C was not associated with reduction in all-cause mortality or improvement in neurologic outcomes when compared a goal of 36°C.

Major Points

Two randomized controlled trials in 2002 (Bernard et al.[1] and HACA) demonstrated a survival and neurologic benefit with therapeutic hypothermia (now called targeted temperature management, or TTM) with goal of 32-34°C in patients experiencing out-of-hospital VF or pulseless VT arrest. The AHA guidelines now recommend TTM for comatose patients following out-of-hospital VF arrest (class I, level B) and consideration of the therapy following out-of-hospital asystole or PEA arrest and any in-hospital arrest (class IIb, level B).[2] However, the therapy is not without complications as lower temperatures are associated with decreased cardiac output, infection, electrolyte abnormalities, and need for sedation. Furthermore, the evidence for these interventions was derived from relatively small trials in a population not treated by modern critical care practices. As such, the ideal target temperature for treatment following ROSC after cardiac arrest have not been established.

The 2013 TTM trial randomized 939 patients who suffered shockable or non-shockable cardiac arrest to TTM with goal of 33°C or the more normothermic 36°C in an unblinded fashion. With a mean follow-up of 8.5 months, there was no difference in the primary outcome of all-cause mortality between the two groups. The groups had similar neurologic outcomes.

This trial attempted to build upon existing knowledge of hypothermia in cardiac arrest, and therefore did not include a no-cooling arm. Some argue that the true benefit of the therapy may be in the prevention of hyperthermia rather than in therapeutic cooling.[3]

Guidelines

As of May 2014, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, open-label, controlled trial
  • N=939 adults with out-of-hospital arrest
    • 33°C (n=473)
    • 36°C (n=466)
  • Setting: 36 intensive care units in Europe and Australia
  • Enrollment: 2010-2013
  • Mean follow-up: 256 days
  • Analysis: Modified intention-to-treat
  • Primary outcome: All-cause mortality by the end of the trial

Population

Inclusion Criteria

  • ≥18 years in age
  • Out-of-hospital arrest of presumed cardiac origin with subsequent persistent ROSC (>20 minutes without chest compressions)
  • Unconsciousness, defined by GCS <8 at after attaining sustained ROSC

Exclusion Criteria

  • Unwitnessed arrest with with asystole as the initial rhythm
  • Admission body temperature <30°C
  • Suspected or confirmed acute intracranial hemorrhage or stroke
  • Obvious or suspected pregnancy
  • Known bleeding diathesis
  • Known limitations in therapy (e.g. DNR order)
  • Known disease making 180 days survival unlikely
  • Known pre-arrest Cerebral Performance Category of 3 or 4
  • >4 hours from ROSC to screening
  • Systolic blood pressure <80 mm Hg in spite of fluids, vasopressors, and/or intra-aortic balloon bump

Baseline Characteristics

From the 33°C group.

  • Demographics: Age 64 years, male 83%
  • PMH: HF 7%, MI 23%, ischemic heart disease 31%, arrhythmia 18%, HTN 41%, TIA/stroke 7%, DM 13%, asthma or COPD 10%, PCI 12%, CABG 10%
  • Arrest details:
    • Location: Home/residence 52%, public space 42%, other 7%
    • Bystander witnessed: 89%
    • CPR initiated by bystander: 73%
    • First rhythm identified:
      • Shockable: 79%
        • VF: 74%
        • Non-perfusing VT: 3%
        • Unknown but responsive to shock: 1%
        • Perfusing rhythm after bystander-initiated defibrillation: 2%
      • Asystole: 12%
      • PEA: 8%
      • Unknown, not-responsive to shock: <0.5%
    • Median duration until basic life support started: 1 min
    • Median duration until advanced life support started: 10 min
    • Median duration until ROSC: 25 min
  • Admission data:
    • First temperature measured: 35.2°C
    • GCS score: 3
    • Corneal reflex: 65%
    • Pupillary reflex: 75%
    • Labs:
      • pH: 7.2
      • Lactate: 6.7 mmol/L
    • Circulatory shock: 15%
    • STEMI: 40%

Interventions

  • Randomized to a target body temperature of either 33°C or 36°C through means of ice-cold fluids, ice packs, and intravascular or surface temperature management devices for 36 hours
  • After 28 hours, gradual rewarming to 37°C in hourly increments of 0.5°C
  • Mandatory sedation was discontinued or tapered at 36 hours
  • After the initial 36 hours, body temperatures were maintained below 37.5°C until 72 hours after the cardiac arrest

Outcomes

Comparisons are target temperature 33°C vs 36°C.

Primary Outcomes

All-cause mortality at the end of trial
50% vs. 48% (HR 1.06; 95% CI 0.89-1.28; P=0.51)

Secondary Outcomes

Cerebral Performance Category score 3-5
3 is severe cerebral disability, 4 is coma or vegetative state, 5 is brain death.
54% vs. 52% (HR 1.02; 95% CI 0.88-1.16; P=0.78)
Modified Rankin scale score of 4-6
4 is moderately severe disability, 5 is severe disability, 6 is death.
52% vs. 52% (HR 1.01; 95% CI 0.89-1.14; P=0.87)
All-cause mortality at 180 days
48% vs. 47% (HR 1.01; 95% CI 0.87-1.15; P=0.92)

Subgroup Analysis

There was no difference for the primary outcome when analyzed by age &le:65 years or >65 years, gender, time from cardiac arrest to ROSC, type of initial rhythm, shock on presentation, or enrollment site.

Adverse Events

Hypokalemia
19% vs. 13% (P=0.018)
Any adverse event
93% vs. 90% (P=0.086)

There was no difference among groups for rates of seizures, bleeding, infection, arrhythmias, requirement of renal replacement therapy, or other electrolyte or metabolic disorders.

Criticisms

  • Population less selective than in prior trials as both those with shockable and non-shockable rhythms were included[3]
  • Unable to detect whether improvements in the standard of care in critical care medicine have reduced the ability to detect a small benefit from the target temperature[3]
  • The treatment teams were not blinded
  • Participants with prolonged ROSC are unlikely to regain neurological function and may have introduced bias[4]
  • Initiation of cooling at an earlier point (e.g during the arrest itself) may have improved outcomes[4]
  • The investigators did not use newer measurement scales to assess neurological recovery[4]
  • Unclear if higher rate of bystander CPR may have improved outcomes[4]
  • Unclear use of midazolam and propofol, both of which are thought to be neuroprotective agents[4]
  • Unclear if the investigators had a prescreening protocol[4]

Funding

Both public and private funding. Authors with financial disclosures.

Further Reading

  1. Bernard SA, et al. "Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia." The New England Journal of Medicine. 2002;346(8):557-563.
  2. Peberdy MA, et al. "Part 9: Post-cardiac arrest care: 2010 AHA guidelines for cardiopulmonary resuscitation and emergency cardiovascular care" Circulation 2010;122(18 suppl 3):S768-S786.
  3. 3.0 3.1 3.2 Rittenberger JC and Calaway CW. "Temperature management and modern post-cardiac arrest care." The New England Journal of Medicine. 2013;369(23):2262-2263.
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Multiple authors. "Correspondence: Targeted temperature management after cardiac arrest." The New England Journal of Medicine. 2014;370:1356-1361.