1. 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

2. 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

3. 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

4. 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

5. TTM trial

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. Results (1) Characteristics. P>0.05 for all comparisons.
No statistical difference in interventions – angio, PCI, CABG, thrombolysis

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

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

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

20. Results (5)
During the first 7 days of hospitalisation, life-sustaining therapy was withdrawn in 247 patients, 132 in T33 and 115 in T36.

22. 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

23. Summary of results (1) Primary outcome Secondary 50% T33 vs 48% T36
Hazard ratio 1.06
95% CI ( ), P=0.51
Secondary
CPC 3-5
T33 risk ratio 1.02
95% CI ( ), P=0.78
mRS 4-6
T33 risk ratio 1.01
95% CI ( ), P=0.87
Deaths at 180 days
48% T33 vs 47% T36
Risk ratio 1.01
95% CI ( ), P=0.92

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

25. 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

26. 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

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