References1. Nielsen N, Wetterslev J, Cronberg T et al. the TTM Trial Investigators. Targeted Temperature Management at 33°C versus 36°C after Cardiac Arrest. N Engl J Med. 2013 Nov 17. [Epub ahead of print] 2. Nielsen N, Hovdenes J, Nilsson F et al; Hypothermia Network Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009 Aug;53(7):926-34. 3. Larsson IM, Wallin E, Rubertsson S. Cold saline infusion and ice packs alone are effective in inducing and maintaining therapeutic hypothermia after cardiac arrest. Resuscitation. 2010 Jan;81(1):15-9. 4. Hoedemaekers CW, Ezzahti M, Gerritsen A, van der Hoeven JG. Comparison of cooling methods to induce and maintain normo- and hypothermia in intensive care unit patients: a prospective intervention study. Crit Care. 2007;11(4):R91. 5. Tømte Ø, Drægni T, Mangschau A et al. A comparison of intravascular and surface cooling techniques in comatose cardiac arrest survivors. Crit Care Med. 2011 Mar;39(3):443-9. 6. Kim F, Nichol G, Maynard C et al. Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest: A Randomized Clinical Trial. JAMA. 2013 Nov 17. doi: 10.1001/jama.2013.282173. [Epub ahead of print] 7. Che D, Li L, Kopil CM et al. Impact of therapeutic hypothermia onset and duration on survival, neurologic function, and neurodegeneration after cardiac arrest. Crit Care Med. 2011 Jun;39(6):1423-30. 8. Sendelbach S, Hearst MO, Johnson PJ et al. Effects of variation in temperature management on cerebral performance category scores in patients who received therapeutic hypothermia post cardiac arrest. Resuscitation. 2012 Jul;83(7):829-34. doi: 9. Winters SA, Wolf KH, Kettinger SA et al. Assessment of risk factors for post-rewarming “rebound hyperthermia” in cardiac arrest patients undergoing therapeutic hypothermia. Resuscitation. 2013 Sep;84(9):1245-9. 10. Bro-Jeppesen J, Hassager C, Wanscher M et al. Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest. Resuscitation. 2013 Dec;84(12):1734-40. 11. Oddo M, Frangos S, Maloney-Wilensky E et al. Effect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury. Neurocrit Care. 2010 Feb;12(1):10-6. 12. Hemmen TM, Raman R, Guluma KZ et al. Intravenous thrombolysis plus hypothermia for acute treatment of ischemic stroke (ICTuS-L): final results. Stroke. 2010 Oct;41(10):2265-70. 13. Chesnut RM, Temkin N, Carney N et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med. 2012 Dec 27;367(26):2471-81. 14. Polderman KH. Induced hypothermia and fever control for prevention and treatment of neurological injuries. Lancet. 2008 Jun 7;371(9628):1955-69. 15. Sydenham E, Roberts I, Alderson P. Hypothermia for traumatic head injury. Cochrane Database Syst Rev. 2009 Apr 15;(2):CD001048.

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*This newsletter contains reports on all the topics covered at TTM 2013, but has focused on key presentations within those subject areas.

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2ND INTERNATIONAL TTM TEACHING COURSE NEWSLETTER

TTM Teaching CourseLondon 2013

Early, rapid cooling is the key to successful outcomes following out-of-hospital cardiac arrest (OHCA), but how cold patients need to be – and for how long – remains uncertain. Growing evidence also supports targeted temperature management (TTM) for stroke, traumatic brain injury patients and possibly myocardial infarction patients, and results of important trials are eagerly awaited.

These were the main “take-home” messages for the 270 delegates from 28 countries who filled the Congress hall for the 2nd International TTM Teaching Course, in London, 21-22 November 2013*.

* This newsletter contains reports on all the topics covered at TTM 2013, but has focused on key presentations within those subject areas.

TTM 2013 LondonThe Faculty and Bard Speakers

Top Row: J Rhodes, P Andrews, C Storm, M Oddo, R Kollmar, W Behringer, T Pellis, K Sunde, Bottom Row: S Kraemer (Bard), S Morisset (Bard), M Geurt, C De Deyne, H Friberg

Absent from Photo: M Haugk, P Stratil

Approximately half of patients are likely to survive OHCA, regardless of whether they are cooled to 33ºC or 36ºC, according to results of the recently published TTM trial1 presented at the meeting by Professor Hans Friberg, from Lund University, Sweden.

Data from 939 OHCA patients (median Glasgow Coma Scale [GCS] of 3) analysed at the end of the three year trial showed that 50% of those in the 33ºC group had died compared with 48% of those in the 36ºC group (HR at 33ºC, 1.06; 95% CI 0.89-1.28 [p=0.51]). Mortality at day 180 was 54% and 52% respectively (RR 1.02; 95% CI 0.88-1.16, p=0.78).

Professor Friberg explained that cause of death was similar in the two groups (mainly cerebrovascular), and there was no significant difference in neurological function outcomes. Adverse events, including serious events and fever, were also comparable, and hypokalaemia was the only event with a significant result 19% in the 33ºC group vs 13% in the 36ºC group (p=0.018).

Sub group analyses also showed no significant difference between the cooling regimens, though there was a slight trend favouring 36ºC in women compared with men, and in patients < 65 years versus > 65.

Professor Friberg reported that participating centres were required to have feedback-controlled cooling devices, and 76% used surface cooling and 24% used intravascular methods. Further analyses will examine neurological recovery and quality of life data, and a sub study is investigating biomarker outcomes.

Asked whether the TTM study results suggested that precise temperature control is immaterial in OHCA cooling, Professor Friberg said that temperature control was precise and successful in both arms of the study, and the results clearly showed no difference between 33ºC and 36ºC.

TTM Study Adds to Debate Over Temperature TargetProfessor Friberg

Clinicians should use the cooling technique best suited to their local setting and temperature management plan, concluded Professor Kjetil Sunde, from Oslo University Hospital, Norway, at the end of an extensive review of hypothermia methodology.

Professor Sunde presented data from the Hypothermia Network (2004-2008) which showed that the most popular methods for induction were cold fluid infusion (80%), circulating water blankets (47%) and ice packs (43%), with circulating water blankets preferred for maintenance treatment (63%)2. He reported studies showing that IV cold saline infusion combined with ice packs was effective in inducing and maintaining therapeutic hypothermia3, and that cooling with water-circulating blankets, gel pads and intravascular cooling was more efficient than conventional cooling and air-circulating blankets4.

Professor Sunde also discussed results from two studies which showed no significant difference in neurological function of survivors following intravascular versus surface cooling. In the first of these, 167 consecutive comatose OHCA patients were allocated to core or surface cooling (Arctic Sun®) according to clinician preference during a five year period in Oslo5. Assessment of survivor neurologic function at 6 to 12 months showed no significant difference in survival with good neurologic function between the two methods, and no difference in shivering. There were significantly more episodes of sustained hyperglycemia with surface cooling (p=0.005) and significantly more hypomagnesaemia among core-cooled patients (p=0.01). In the second study (ICERA), there was no significant difference in survival at ICU discharge or CPC status at day 28 between external and intravascular cooling.

Turning to timing of hypothermia, Professor Sunde explained that there have been conflicting results from studies of early versus delayed hypothermia, and

recently reported data from a study of pre-hospital cooling showed that, although this reduced the time to reach a temperature of 34ºC, it did not impact on survival or neurological status6.

However, as Professor Sunde pointed out, animal data have suggested that the therapeutic window for successful hypothermia is within 4 hours after return of spontaneous circulation (ROSC), with reduced survival and worse neurological outcomes if treatment is delayed until 8 hours7. This animal study also showed higher neuron counts when hypothermia was maintained for 48 hours compared with 24 hours.

Which cooling method?Professor Sunde

Key Points• Important new study questions value of cooling to 33°C in OHCA• No difference in outcomes for 33°C vs 36°C• Further analyses to check neurological recovery, quality of life and biomarkers

Key Points• Core and surface cooling are equally effective• Clinicians should use method most suited to local conditions• Animal data point to importance of early cooling, within 4 hours of ROSC

TTM 2013 LondonEvent Photos

Promising data from the CHILL-MI study of rapid cooling prior to primary percutaneous coronary intervention (PCI) in ST elevation myocardial infarction (STEMi) patients were discussed by Professor Christian Storm.

The results, which were presented at the 25th Annual Transcatheter Cardiovascular Therapeutics (TCT) conference in San Francisco showed that aggressive intravascular cooling below 35°C within 6 hours of symptom onset was associated with a non significant 13% reduction in infarct size (p=0.15) at 4 + 2 days. Amongst patients with anterior STEMi, the reduction was 27%, but this was also non significant as numbers were small.

Professor Storm explained that although the study missed its primary endpoint, there was a significantly lower incidence of clinical heart failure in patients who had received cooling (3% vs 14% [p<0.05]).

He concluded that a further RCT is now needed in patients with infarcts in anterior vessels which will focus on cooling within the first 4 hours after symptoms, so that patients are already at their target temperature by the time they reach hospital.

Therapeutic hypothermia is a promising approach for improving outcomes in ischaemic stroke patients but the optimal temperature remains uncertain, concluded Dr Marjolein Geurts, from the University Medical Centre of Utrecht, Holland, at the end of a presentation focusing on a new study aimed at addressing this important knowledge gap.

She reported that 18 of a target 48 awake ischaemic stroke patients have been randomised to the phase II, Cooling for Ischaemic Stroke Trial (COOLIST) which is investigating the feasibility and safety of surface cooling started within 4.5 hours after stroke onset and maintained for 24 hours. Patients are being randomised to conventional treatment or surface cooling to 34°C, 34.5°C, or 35°C. Cooling starts with IV saline (4°C) over 30 to 60 minutes, followed by surface cooling with Arctic Sun®. An anti-shivering regimen includes IV pethidine and oral buspirone.

Utrecht experience in ischaemic stroke Dr Geurts

Can STEMi patients benefit from cooling? Professor Storm

Key Points• Cooling for Ischaemic Stroke Trial (COOLIST) investigates surface cooling within 4.5 hours after stroke onset • Trial to compare conventional vs Arctic Sun® cooling to 34°C, 34.5°C, or 35°C• Anti-shivering regimen includes IV pethidine and oral buspirone

Key Points• CHILL-MI study shows promise of rapid cooling before PCI in STEMi patients• Cooling within 6 hours of symptom onset reduces infarct size, especially in anterior STEMi• Significant reduction seen in clinical heart failure after cooling post-STEMi

Support for early, rapid cooling came from Dr Moritz Haugk and Dr Peter Stratil from the Medical University of Vienna, Austria, following a review of recent studies.

In the latest published study in 172 cardiac arrest patients, every five minutes of delay in starting cooling was associated with a 6% worsening in neurological outcomes at discharge follow up8. In addition, the likelihood of a poor outcome increased by 17% for every 30 minutes delay in reaching the target temperature.

Given the growing emphasis on early, rapid cooling, Dr Haugk reported results from two recent studies in Vienna which investigated the heat transfer rate with Arctic Sun® surface cooling methods.

In an initial observational case study of 27 cardiac arrest patients treated from 2004-2005, the Arctic Sun® 2000 was shown to cool patients at a rate in line with other cooling devices, with a median reduction of 1.2ºC per hour.

In a second observational study, precise cooling was demonstrated with the Arctic Sun® 5000 in 15 OHCA with a relatively high median BMI of 29. The six month survival rate for the group was 53%, and 47% of patients had a favourable neurological recovery. The median cooling rate was 1.3ºC per hour and, during the maintenance phase, the deviation from the 33ºC target was very small, i.e.: 0.2-0.3ºC.

Dr Stratil concluded that fast early cooling with Arctic Sun® 5000 was achieved, despite the high BMI of the patients, and that surface cooling was very stable.

Impact of Heat Transfer RateDr Haugk | Dr Stratil

Temperature Management – For How Long?Dr Pellis

Temperature management should not finish after a 24-hour period of hypothermia, but should continue for at least 72 hours after a patient is hospitalised following OHCA because of the risks of post-rewarming, rebound hyperthermia (RH) and fever, concluded Dr Tommaso Pellis, from Santa Maria degli Angeli, Pordenone, Italy.

He presented evidence from two recent studies showing adverse outcomes of RH or post hypothermia fever (PHF).

In an observational study of 141 OHCA patients who had received hypothermia treatment, those who experienced RH showed significantly higher hospital mortality compared to those who did not (64.3% vs 40.4%; p=0.011), and increased neurologic morbidity (p=0.011)9.

In a prospective study of 270 OHCA patients who survived TTM of 32-34°C, those with post hypothermia fever (PHF) (median peak temperature ≥38.5°C) within 36h after rewarming had a significantly higher 30 day mortality rate than those without PHF (36% vs 22% corresponding to an adjusted hazard rate (HR) of 1.8 (95% CI: 1.1-2.7), p=0.02)10. Good neurological outcome (CPC1-2) at hospital discharge was found in 61% of the PHF group compared to 75% in those without PHF (p=0.02).

Dr Pellis pointed out that the recent TTM study aimed to maintain body temperature at 37ºC for at least 72 hours after cardiac arrest, by active temperature management in patients that remain unconscious. Data from the study showed that this was achieved in both treatment groups and that temperature management was successfully extended even to day 4 thus underlining the importance of continued temperature management.

Key Points• Early, rapid cooling is essential after OHCA• Arctic Sun® 5000 offers precise cooling during induction and maintenance• High BMI does not impede effectiveness of Arctic Sun® 5000

Key Points• Temperature management should continue for >72 hours after OHCA• Rebound hyperthermia is linked to increased post-hypothermia mortality and morbidity• Anti-fever precautions essential after rewarming

Recruitment is well on track for Eurotherm3235 – the international, multi-centre, randomised controlled trial which is investigating the effects of titrated therapeutic hypothermia (32-35°C) as a treatment for raised intracranial pressure (ICP) after traumatic brain injury.

Approximately half of the planned 600 patients have been randomised at 43 centres, but lead investigator, Professor Peter Andrews, from the University of Edinburgh, UK, is keen to hear from further interested centres who have appropriate facilities, in order to boost patient numbers towards their target.

Explaining the need for Eurotherm3235, Professor Andrews drew attention to the current lack of evidence about the impact of interventions on ICP, despite the strong association between raised ICP and poor outcome following traumatic brain injury. He added that, since hypothermia is a well established effective intervention following OHCA, it is a logical choice for investigation for ICP reduction.

Professor Andrews questioned the findings of a recent study which may have raised doubts about the importance of ICP monitoring following severe traumatic brain injury13. He explained that the failure to show any advantage of ICP monitoring over imaging and clinical examination in improving performance outcomes may have been due to the fact that patients in the ICP group had lower levels of ICP lowering interventions than the imaging group.

Professor Andrews presented results of a meta analysis of animal studies in brain injury which showed a median 43% reduction in infarct size following hypothermia at 32-35ºC. He also shared data from a systematic review of clinical studies which demonstrated that reducing ICP with hypothermia after brain injury led to improved outcomes, though the best results were achieved with the smallest studies14. In addition, a Cochrane review concluded that hypothermia may be effective in reducing death and unfavourable outcomes in patients with traumatic brain injury, but that significant benefit has only been shown in low quality trials15.

Professor Andrews concluded that there are persuasive data to support the value of testing the effects of hypothermia on ICP and Eurotherm3235 will hopefully provide some much needed answers.

How to Manage ShiveringProfessor Storm | Professor Kollmar

Administrators and payers who are concerned that cooling patients after cardiac arrest is too expensive can be reassured that treatment is very cost effective. Results of a new analysis presented by Professor Wilhelm Behringer, from the Medical University of Vienna, Austria, showed a cost per quality adjusted life year (QALY) of €3,827 for hypothermia. This is well below the €24,000-€36,000/QALY used as a cost effectiveness threshold in the UK for NICE approval of novel treatments and the €30,000/QALY threshold used in Austria on whose healthcare costs the analysis was based.

Is Cooling After Cardiac Arrest Cost Effective?Professor Behringer

Eurotherm UpdateProfessor Andrews

“Progress past the shivering threshold of 34ºC to 36ºC as rapidly and aggressively as possible in cardiac arrest patients” was the advice of Professor Christian Storm, from the Charité – Universitätsmedizin, Berlin, Germany.

He recommended using a combination of a cooling device and infusion of 1-2 litres of cold saline, together with deep sedation, counter-warming of hands and feet (from the start) and magnesium 1-2mg IV to reduce the risk of shivering. Paralysis with a muscle relaxant should only be considered if all else has failed to prevent shivering, he added.

Professor Storm pointed out that shivering is least likely to occur if gas sedation is used, and this has the added advantage that patients wake more quickly than other forms of sedation.

A number of speakers pointed out that awake patients find shivering very distressing; in addition shivering can have damaging effects in brain injury patients, due to reduced oxygenation of brain tissue11. However, Professor Rainer Kollmar, from Darmstadt Hospital, Darmstadt, Germany, warned that great care is needed when sedating stroke or brain injury patients during hypothermia, as this has been associated with respiratory depression and increased risk of pneumonia12.

Professor Kollmar reported that, in the ongoing EuroHyp study in stroke patients, an anti-shivering regimen consisting of an IV bolus of ondansetron followed by an IV bolus of pethidine 50mg and oral buspirone 10mg, followed by further boluses of patient administered pethidine 25mg, is proving satisfactory.

Key Points• Rapid cooling below 34ºC to 36 ºC reduces shivering risk• Counter warming of hands and feet and magnesium 1-2mg IV reduces shivering in OHCA patients• Pethidine, buspirone, ondansetron combination useful for awake stroke patients

Key Points• Cooling OHCA patients is cost effective• Cost per QALY of therapeutic hypothermia is €3,827 • Cost per QALY falls well below NICE and other national cost effectiveness thresholds

Key Points• Recruitment underway for Eurotherm3235 • Eurotherm3235 investigates cooling (32-35°C) for raised ICP after traumatic brain injury• Current evidence suggests reducing ICP may improve outcomes after brain injury

Recruitment is also underway for EuroHyp – a pan-European, open, randomised, phase III clinical trial which will assess the benefit of therapeutic cooling (34-35°C) in adult patients with acute ischaemic stroke. Professor Rainer Kollmar explained that the aim is to recruit 1500 patients from some 80 centres in Europe within 4 years, with outcomes including efficacy, safety and the economic impact of therapeutic hypothermia.

EuroHyp UpdateProfessor Kollmar

Key Points• Recruitment underway for EuroHyp• EuroHyp to assess cooling (34-35°C) in adults with acute ischaemic stroke