[Show abstract][Hide abstract] ABSTRACT: Citation:
Niklas Nielsen, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, Pellis T, Stammet P, Wanscher M, Wise MP, Åneman A, Al-Subaie N, Boesgaard S, Bro-Jeppesen J, Brunetti I, Bugge JF, Hingston CD, Juffermans NP, Koopmans M, Køber L, Langørgen J, Lilja G, Møller JE, Rundgren M, Rylander C, Smid O, Werer C, Winkel P, Friberg H. Targeted temperature management at 33 °C versus 36 °C after cardiac arrest. N Engl J Med. 2013;369:2197-206. doi: 10.1056/NEJMoa1310519 . Epub 2013 Nov 17. Pub Med PMID: 20089970.
Brain ischemia and reperfusion injury leading to tissue degeneration and loss of neurological function following return of spontaneous circulation after cardiac arrest (CA) is a well-known entity. Two landmark trials in 2002 showed improved survival and neurological outcome of comatose survivors of out-of-hospital cardiac arrest (OHCA) of presumed cardiac origin when the patients were subjected to therapeutic hypothermia of 32 to 34 °C for 12 to 24 hours. However, the optimal target temperature for these cohorts is yet to be established and also it is not clear whether strict fever management and maintaining near normal body temperature are alone sufficient to improve the outcome.
Objective: The objective is to determine whether a hypothermic goal of a near-normal body temperature of 36 °C reduces all-cause mortality compared with a moderate hypothermia of 33 °C for the unconscious survivors of OHCA of presumed cardiac origin when subjected randomly to these different targeted temperatures.
A multicenter, international, open label, randomized controlled trial.
Thirty-six ICUs in Europe and Australia participated in this study.
Unconscious adults (older than 18 years of age) who survived (Glasgow coma scale less than 8) OHCA due to presumed cardiac origin with subsequent persistent return of spontaneous circulation (more than 20 minutes without chest compressions).
The above participant cohorts were randomized to targeted body temperature of either 33 °C or 36 °C for 36 hours after the CA with gradual rewarming of both groups to 37 °C (hourly increments of 0.5 °C) after the initial 28 hours. Body temperatures in both the groups were then maintained below 37.5 °C for 72 hours after the initial 36 hours.
Primary outcome measure of all-cause mortality in both the groups at the end of the trial with the secondary outcome measure of all-cause mortality, composite neurological function as evaluated by cerebral performance category scale and modified ranking scale at the end of 180 days were studied.
Out of the 939 participants, all-cause mortality at the end of the trial was 50 % in the 33 °C group (225 of 466 patients) compared with 48 % in the 36 °C group (235 of 473 patients); the hazard ratio with a temperature of 33 °C was 1.06 (95 % confidence interval (CI) 0.89 to 1.28, P = 0.51). At the end of 180 days, 54 % of patients in the 33 °C group versus 52 % in the 36 °C group had died or had poor neurological outcome according to cerebral performance category (risk ratio 1.02, 95 % CI 0.88 to 1.16, P = 0.78) but the modified ranking scale at the end of 180 days was unchanged (52 %) in both groups (risk ratio 1.01, 95 % CI 0.89 to 1.14, P = 0.87).
Maintaining targeted lower normothermia of 36 °C had similar outcomes compared with induced moderate hypothermia of 33 °C for unconscious survivors of OHCA of presumed cardiac cause.
[Show abstract][Hide abstract] ABSTRACT: Hypothermia (32-34°C) can mitigate ischemic brain injury, and some evidence suggests that it can reduce infarct size in acute myocardial infarction and acute ischemic stroke. For some indications, speed of cooling may be crucial in determining efficacy. We performed a multicenter prospective intervention study to test an ultrarapid cooling technology, the Velomedix Automated Peritoneal Lavage System using ice-cold fluids continuously circulating through the peritoneal cavity to rapidly induce and maintain hypothermia in comatose patients after cardiac arrest and a small number of awake patients with acute myocardial infarction.
Multicenter prospective intervention study.
Intensive care- and coronary care units of multiple tertiary referral centers.
Access to the peritoneal cavity was gained using a modified blunt dilating instrument, followed by catheter placement. Patients were cooled to a temperature of 32.5°C, maintained for 24 hours (cardiac arrest) or 3 hours (acute myocardial infarction) followed by controlled rewarming. Forty-nine patients were enrolled, and 46 patients completed treatment. One placement was unsuccessful (abdominal wall not breached), two patients were ultimately not cooled, and only safety data are reported. Average catheter insertion time was 2.3 minutes. Mean time to temperature less than 33°C was 10.4 minutes (average cooling rate, 14°C/hr). Median infarct size in patients who had coronary interventions was 16% of LV. No cases of stent thrombosis occurred. Survival in cardiac arrest patients with initial rhythm of ventricular tachycardia/ventricular fibrillation was 56%, of whom 82 had a complete neurologic recovery. This compares favorably to outcomes from previous studies.
Automated peritoneal lavage system is a safe and ultrarapid method to induce and maintain hypothermia, which appears feasible in cardiac arrest patients and awake patients with acute myocardial infarction. The shivering response appeared to be delayed and much reduced with this technology, diminishing metabolic disorders associated with cooling and minimizing sedation requirement. Our data suggest that ultrarapid cooling could prevent subtle neurologic damage compared with slower cooling. This will need to be confirmed in direct comparative studies.
No preview · Article · Jul 2015 · Critical care medicine
[Show abstract][Hide abstract] ABSTRACT: Dozens of observational studies published over the past two decades have shown that fever in patients with acute neurologic injury, regardless of its cause, is independently linked to higher mortality, poor neurologic outcome, and increased length of stay in the intensive care unit (ICU) and hospital. This has been demonstrated for traumatic brain injury, acute ischemic stroke (AIS), subarachnoid haemorrhage, intracranial haemorrhage, and cardiac arrest (CA).(1,2) Therefore, therapeutic temperature management (TTM) is a key goal of care in all patients with acute brain injury. In most cases the goal is strict fever control, i.e. controlled normothermia; in patients with post-hypoxic injuries the goals is often to achieve below-normal core temperature, i.e. to induce therapeutic hypothermia (TH).
[Show abstract][Hide abstract] ABSTRACT: Neuroprotective strategies that limit secondary tissue loss and/or improve functional outcomes have been identified in multiple animal models of ischemic, hemorrhagic, traumatic and nontraumatic cerebral lesions. However, use of these potential interventions in human randomized controlled studies has generally given disappointing results. In this paper, we summarize the current status in terms of neuroprotective strategies, both in the immediate and later stages of acute brain injury in adults. We also review potential new strategies and highlight areas for future research.
[Show abstract][Hide abstract] ABSTRACT: Dear Editor,We read with interest the paper by Zhang et al.  comparing hemodynamic management guided by transpulmonary thermodilution (PiCCO device) to central venous pressure (CVP) guidance. We congratulate the authors on tackling this issue in a randomized trial. However, in general, monitoring tools can improve outcomes only indirectly, through the therapeutic interventions based on the measurements obtained, while poor therapeutic decisions based on (mis-)interpreted data can cause harm.We have several concerns regarding this study.Patients with septic shock, septic shock with ARDS, and ARDS alone were enrolled. This is illogical; ARDS in non-septic patients requires completely different fluid management strategies.28-day mortality was 49.4 versus 49.5 % . Although this meets APACHE-II score predictions, APACHE-II is 30 years old; actual mortality should be lower, as was the case in all major sepsis/ARDS trials performed since 2000. We have listed a number of trials enrolling ...
No preview · Article · Mar 2015 · Intensive Care Medicine
[Show abstract][Hide abstract] ABSTRACT: The targeted temperature management (TTM) trial, which found that cooling to 33°C after witnessed cardiac arrest (CA) conferred no benefits compared with 36°C, has led to much debate in the hypothermia community. This article discusses what lessons can be drawn. The TTM trial achieved far better outcomes in controls than any previous randomized controlled trial (RCT) or any nonrandomized study where no fever control was applied. On the other hand, rates of good outcomes in the hypothermia group were somewhat lower than in previous RCTs and most nonrandomized studies. The TTM authors conclude that benefits of temperature management are derived exclusively from fever control and that further lowering of temperature confers no benefit. Indeed, without doubt, the TTM trial demonstrates the crucial importance of strict fever control after CA and that this provides sufficient neuroprotection for some patients. However, we argue that the hypothermia intervention was executed suboptimally (possibly inadvertent selection bias; late start of cooling, up to 4 hours after ROSC; slow cooling rates, 10 hours to target temperature; more rapid rewarming than previous studies; and some other issues). This could explain high rates of good outcomes in controls and lower-than-expected rates in patients cooled to 33°C compared with previous randomized and nonrandomized studies. Outside of two previous RCTs, the use of hypothermia after CA is supported by hundreds of animal experiments, evidence from 46 before-after studies and large registries, and indirect supporting evidence from 7 RCTs in newborns with neonatal asphyxia. In addition, one RCT found improved outcomes with 32°C compared with 34°C. It remains to be explained why the TTM results so completely contradict previous studies in this field. These issues should be thoroughly discussed before changes in guidelines and protocols are made. Ending or modifying hypothermia treatment after CA should require the strongest possible evidence.
[Show abstract][Hide abstract] ABSTRACT: Therapeutic hypothermia (TH) is recommended to reduce ischemic brain injury after cardiac arrest. The variables that predict heat generation by patients receiving TH are uncertain, as is how this heat generation relates to neurologic outcome. We hypothesized that patient characteristics, medication use, inflammation, and organ injury would be associated with heat generation. We further hypothesized that neurologic outcome would be most strongly associated with heat generation.
Surface and intravascular cooling devices were used to provide TH in 57 consecutive cardiac arrest patients. Device water temperatures during the maintenance (33°C) phase were collected. Patient heat generation was quantified as the "heat index" (HI), which was the inverse average water temperature over a minimum of 2 hours of maintenance hypothermia. Variables measuring reduced ischemic injury and improved baseline health were significantly associated with HI. After controlling for presenting rhythm, a higher HI was independently associated with favorable disposition (OR=2.2; 95% CI 1.2 to 4.1; P=0.014) and favorable Cerebral Performance Category (OR=1.8; 95% CI 1.0 to 3.1; P=0.035). Higher HI predicted favorable disposition (receiver-operator area under the curve 0.71, P=0.029). HI was linearly correlated with arteriovenous CO2 (r=0.69; P=0.041) but not O2 (r=0.13; P=0.741) gradients.
In cardiac arrest patients receiving TH, greater heat generation is associated with better baseline health, reduced ischemic injury, and improved neurologic function, which results in higher metabolism. HI can control for confounding effects of patient heat generation in future clinical trials of rapid TH and offers early prognostic information.
Full-text · Article · Apr 2014 · Journal of the American Heart Association