Targeted temperature management Critical Care Journal Club, Arrowe Park Hospital, 28th February 2014 Targeted temperature management TTM Trial. Nielsen, et al. NEJM 2013. Dr Craig Denmade

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 Hippocrates – packed wounded patients in snow & ice to reduce haemorrhage Baron Larrey (Napoleon’s Surgeon) – observed injured soldiers who became hypothermic and were put closer to a fire died more rapidly than those who remained hypothermic Osler – systematic rigid protocol, temp 102.5F (39.1 deg) > bath 70F (21.1 deg), every three hours as needed, mortality from 15-25% to 6-7% A small quantity of whiskey before and hot milk with a little whiskey after! Neuroprotection – abandoned infants exposed to cold often remained viable for prolonged periods

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 Australia, Melbourne, 4 participating EDs ROSC not time-limited Cold packs pre-hosp, extensive ice packs in-hospital Core temp – typanic or bladder until PA cath GCS not recorded in ED, no baseline neurological status prior to event T37 passively rewarmed if mild spontaneous hypothermia on arrival Outcome assessment – Specialist in Rehab medicine (blinded) Positive outcome lost if 1 patient with good outcome had a bad outcome

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 Austria, 9 centres in five European countries Stopped early due to lower than expected inclusion rate Normothermia group tendancy towards hyperthermia 1 good recovery, 2 moderate disability, 3 severe disability, 4 vegetative state, 5 death 1 & 2 – sufficient cerebral function to live independently and work at least part-time No mention of withdrawal process Death rate at six months 14% lower in hypothermia group (55% normothermia), RR 0.74, P=0.02

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 American Heart Association

Population Multicentre RCT 36 ICUs in Europe & Australia November 2010 to January 2013 950 patients enrolled Null hypothesis – no difference in all-cause mortality at 180 days between the two groups Type II error – accept the null hypothesis incorrectly

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 Irrespective of the initial rhythm

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 Medically induced coagulopathy e.g. warfarin or clopidogrel does not exclude patient

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 Ice-cold fluids, ice packs, and intravascular or surface temperature management devices at the discretion of the site

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 Secondary 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. No statistical difference in interventions – angio, PCI, CABG, thrombolysis

Results (2) Characteristics. P>0.05 for all comparisons.

Results (3) Characteristics. P>0.05 for all comparisons.

Results (4) 24% intravasc device, 76% surface cooling system

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 Secondary 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