Targeted temperature management

TTM Trial. Nielsen, et al. NEJM 2013.Dr Craig Denmade

Critical Care Journal Club, Arrowe Park Hospital, 28th February 2014

Introduction

• Egyptians, Greeks and Romans…• Surgeon General Baron Larrey…• Ernst Brand & Sir William Osler…– The Cold-Bath Treatment of Typhoid Fever (1892)

• Fay, Bigelow, Rosomoff, Safar…• Animal models…– Mild rather than moderate or deep hypothermia

Seminal papers (1)

• 77 patients, VF only, randomised by day of month (hypothermia odd days)• Cooled to T33 for 12h vs standard care (normothermia, T37)• No allocation concealment, T33 = 43, T37 = 34• Actively rewarmed at 18h, standard ICU care after 24h• Withdrawal – deeply comatose at 72h• Bad outcome – death or long-term nursing facility• Good outcome – discharged home or rehab facility• 21 (49%) hypothermia group vs 9 (26%) normothermia, P=0.046• ARR for death or severe disability of 23%, NNT 4.5

Seminal papers (2)

• Multicentre RCT, n=273, VF/VT, ROSC <60 mins• 32-34 deg for 24h (n=136) vs standard care (n=137)• Ext cooling device, if not achieved > ice packs, passive rewarming• Primary outcome – favourable neurological outcome 6/12 post-event• Secondary outcomes – mortality within 6/12, rate complications within 7d• Pittsburgh cerebral performance category, assessment blinded• 75 (55%) hypothermia group vs 54 (39%) normothermia group, favourable

neurological outcome• ARR for unfavourable neurological outcome of 24%, NNT 4

TTM trial

Why TTM?• Therapeutic hypothermia is recommended in international

resuscitation guidelines• Use extended to other presenting rhythms as well as in-

hospital cardiac arrest• Cochrane review 2009 (updated 2012) supports hypothermia

for neuroprotection following cardiopulmonary resuscitation• Fever developed in HACA standard care group• Unclear whether the reported treatment effect was due to

hypothermia or to the prevention of fever, which is associated with a poor outcome

• Clinical equipoise

Population• Multicentre RCT• 36 ICUs in Europe & Australia• November 2010 to January 2013• 950 patients enrolled

Inclusion criteria• 18 years of age• OOHCA of presumed cardiac cause• Sustained ROSC for 20 consecutive minutes• Unconsciousness (GCS <8, not able to obey verbal commands)

after sustained ROSC

Exclusion criteria• Obvious or suspected pregnancy• Known bleeding diathesis• Suspected or confirmed acute intracranial bleeding• Suspected or confirmed acute stroke• Unwitnessed cardiac arrest with initial rhythm asystole• Known limitations in therapy or DNACPR• Known disease making 180 days survival unlikely• Known pre-arrest CPC of 3 or 4• >4h (240 mins) from ROSC to screening• SBP <80mmHg in spite of fluid loading/vasopressor and/or

inotropic medication/IABP• Temp on admission <30 degrees

Intervention• 36h intervention period commenced at time of randomisation• Sedation mandated in both groups• Choice of sedation, analgesics & NMBA at discretion of

treating physician• Goal to achieve assigned temperature as rapidly as possible• After 28h, rewarming commenced at 0.5 deg/hr• At 36h, sedation discontinued or tapered• After intervention period, body temperature for unconscious

patients maintained below 37.5 deg for 72h• Fever control measures at discretion of the sites

Comparison• T36, otherwise similar treatment to intervention group• Patients with an initial body temperature between 30 and 33

degrees were actively rewarmed at a maximum rate of 0.5 deg/hr to 33 degrees in both groups

• For patients allocated to T36, passive rewarming was mandated between 33 and 36 degrees, after which controlled temperature management was commenced

Outcomes• Primary

– All-cause mortality through the end of the trial• Secondary

– Composite of poor neurological function or death• Cerebral Performance Category (CPC) 3 to 5

– CPC 3 – severe cerebral disability, conscious, dependent on others– CPC 4 – coma or vegetative state– CPC 5 – death

• Modified Rankin Scale, score 4 to 6– mRS 4 – moderately severe disability, unable attend bodily needs

without assistance, unable to walk unassisted– mRS 5 – severe disability, constant nursing care and attention,

bedridden, incontinent– mRS 6 – death

Neurological prognostication• Physician evaluation (blinded to intervention assignments) at

72h for patients who remained unconscious• Neurological examination, SSEP and EEG• Discontinuation of active intensive care

– Brain dead due to cerebral herniation– Severe myoclonus status in the first 24h and bilateral negative SSEP– After 72h, persisting coma with a Glasgow Motor Score 1-2 and

bilateral negative SSEP– After 72h, persisting coma with a Glasgow Motor Score 1-2 and

refractory status epilepticus• Discontinuation before 72h, 1st & 2nd point plus ethical reasons

e.g. previously unknown information about disseminated malignancy or refractory shock with MSOF

Follow-up• Face-to-face interview with the patient• Structured telephone interview with the patient• Telephone call to the patient or a relative• Telephone call to a proxy provider of information i.e. staff

member of nursing home or GP

Randomisation• Randomised centrally• Computer generated assignment sequence• 1:1 ratio either T33 or T36• 939 patients modified intention-to-treat population• T33 = 473• T36 = 466

Results (1)

• Characteristics. P>0.05 for all comparisons.

Results (2)

• Characteristics. P>0.05 for all comparisons.

Results (3)

• Characteristics. P>0.05 for all comparisons.

Results (4)

Results (5)

During the first 7 days of hospitalisation, life-sustaining therapy was withdrawn in 247 patients, 132 in T33 and 115 in T36.

Serious adverse events• One or more SAE

– T33 93% vs T36 90%, P=0.09• Hypokalaemia more frequent in T33

– 19% vs 13%, P=0.02• Pneumonia more common in T33

– 52% vs 46%, P=0.09– Shorter duration of mechanical ventilation T36, P=0.006

Summary of results (1)• Primary outcome

– 50% T33 vs 48% T36– Hazard ratio 1.06– 95% CI (0.89-1.28), P=0.51

• Secondary– CPC 3-5

• T33 risk ratio 1.02• 95% CI (0.88-1.16), P=0.78

– mRS 4-6• T33 risk ratio 1.01• 95% CI (0.89-1.14), P=0.87

– Deaths at 180 days• 48% T33 vs 47% T36• Risk ratio 1.01• 95% CI (0.87-1.15), P=0.92

Summary of results (2)• Null hypothesis is correct• P>0.05• Confidence intervals straddle zero• No statistical difference between T33 and T36

Strengths• Multicentre RCT• Groups comparable (no significant difference in characteristics)• Robust methodology• Standardised protocol for neurological prognostication and

withdrawal of life-sustaining therapy• Generalisable results

Limitations• Allocation concealment – ICU staff members were aware of the

assigned target temperature• One country required written consent from a legal surrogate

before randomisation, resulting in exclusion of a substantial proportion of eligible patients

• No data on dose and type of sedation or use of NMBA

Thoughts• VT/VF vs non-shockable• In-hospital vs out-of-hospital• When to start cooling?• Optimum target temperature• Duration of therapy