Concept: Therapeutic hypothermia
Background Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. Methods In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. Results In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. Conclusions In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916 .).
Background Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. Methods In a trial conducted at 37 children’s hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. Results The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P=0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P=0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P=0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. Conclusions Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087 .).
Carbon monoxide (CO) at low concentrations imparts protective effects in numerous preclinical small animal models of brain injury. Evidence of protection in large animal models of cerebral injury, however, has not been tested. Neurologic deficits following open heart surgery are likely related in part to ischemia reperfusion injury that occurs during cardiopulmonary bypass surgery. Using a model of deep hypothermic circulatory arrest (DHCA) in piglets, we evaluated the effects of CO to reduce cerebral injury. DHCA and cardiopulmonary bypass (CPB) induced significant alterations in metabolic demands, including a decrease in the oxygen/glucose index (OGI), an increase in lactate/glucose index (LGI) and a rise in cerebral blood pressure that ultimately resulted in increased cell death in the neocortex and hippocampus that was completely abrogated in piglets preconditioned with a low, safe dose of CO. Moreover CO-treated animals maintained normal, pre-CPB OGI and LGI and corresponding cerebral sinus pressures with no change in systemic hemodynamics or metabolic intermediates. Collectively, our data demonstrate that inhaled CO may be beneficial in preventing cerebral injury resulting from DHCA and offer important therapeutic options in newborns undergoing DHCA for open heart surgery.
Background Convulsive status epilepticus often results in permanent neurologic impairment. We evaluated the effect of induced hypothermia on neurologic outcomes in patients with convulsive status epilepticus. Methods In a multicenter trial, we randomly assigned 270 critically ill patients with convulsive status epilepticus who were receiving mechanical ventilation to hypothermia (32 to 34°C for 24 hours) in addition to standard care or to standard care alone; 268 patients were included in the analysis. The primary outcome was a good functional outcome at 90 days, defined as a Glasgow Outcome Scale (GOS) score of 5 (range, 1 to 5, with 1 representing death and 5 representing no or minimal neurologic deficit). The main secondary outcomes were mortality at 90 days, progression to electroencephalographically (EEG) confirmed status epilepticus, refractory status epilepticus on day 1, “super-refractory” status epilepticus (resistant to general anesthesia), and functional sequelae on day 90. Results A GOS score of 5 occurred in 67 of 138 patients (49%) in the hypothermia group and in 56 of 130 (43%) in the control group (adjusted common odds ratio, 1.22; 95% confidence interval [CI], 0.75 to 1.99; P=0.43). The rate of progression to EEG-confirmed status epilepticus on the first day was lower in the hypothermia group than in the control group (11% vs. 22%; odds ratio, 0.40; 95% CI, 0.20 to 0.79; P=0.009), but there were no significant differences between groups in the other secondary outcomes. Adverse events were more frequent in the hypothermia group than in the control group. Conclusions In this trial, induced hypothermia added to standard care was not associated with significantly better 90-day outcomes than standard care alone in patients with convulsive status epilepticus. (Funded by the French Ministry of Health; HYBERNATUS ClinicalTrials.gov number, NCT01359332 .).
Background Therapeutic hypothermia is recommended for comatose adults after witnessed out-of-hospital cardiac arrest, but data about this intervention in children are limited. Methods We conducted this trial of two targeted temperature interventions at 38 children’s hospitals involving children who remained unconscious after out-of-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose patients who were older than 2 days and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a Vineland Adaptive Behavior Scales, second edition (VABS-II), score of 70 or higher (on a scale from 20 to 160, with higher scores indicating better function), was evaluated among patients with a VABS-II score of at least 70 before cardiac arrest. Results A total of 295 patients underwent randomization. Among the 260 patients with data that could be could be evaluated and who had a VABS-II score of at least 70 before cardiac arrest, there was no significant difference in the primary outcome between the hypothermia group and the normothermia group (20% vs. 12%; relative likelihood, 1.54; 95% confidence interval [CI], 0.86 to 2.76; P=0.14). Among all the patients with data that could be evaluated, the change in the VABS-II score from baseline to 12 months was not significantly different (P=0.13) and 1-year survival was similar (38% in the hypothermia group vs. 29% in the normothermia group; relative likelihood, 1.29; 95% CI, 0.93 to 1.79; P=0.13). The groups had similar incidences of infection and serious arrhythmias, as well as similar use of blood products and 28-day mortality. Conclusions In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute and others; THAPCA-OH ClinicalTrials.gov number, NCT00878644 .).
PURPOSE: We aimed to evaluate post-resuscitation care, implementation of therapeutic hypothermia (TH) and outcomes of intensive care unit (ICU)-treated out-of-hospital cardiac arrest (OHCA) patients in Finland. METHODS: We included all adult OHCA patients admitted to 21 ICUs in Finland from March 1, 2010 to February 28, 2011 in this prospective observational study. Patients were followed (mortality and neurological outcome evaluated by Cerebral Performance Categories, CPC) within 1 year after cardiac arrest. RESULTS: This study included 548 patients treated after OHCA. Of those, 311 patients (56.8 %) had a shockable initial rhythm (incidence of 7.4/100,000/year) and 237 patients (43.2 %) had a non-shockable rhythm (incidence of 5.6/100,000/year). At ICU admission, 504 (92 %) patients were unconscious. TH was given to 241/281 (85.8 %) unconscious patients resuscitated from shockable rhythms, with unfavourable 1-year neurological outcome (CPC 3-4-5) in 42.0 % with TH versus 77.5 % without TH (p < 0.001). TH was given to 70/223 (31.4 %) unconscious patients resuscitated from non-shockable rhythms, with 1-year CPC of 3-4-5 in 80.6 % (54/70) with TH versus 84.0 % (126/153) without TH (p = 0.56). This lack of difference remained after adjustment for propensity to receive TH in patients with non-shockable rhythms. CONCLUSIONS: One-year unfavourable neurological outcome of patients with shockable rhythms after TH was lower than in previous randomized controlled trials. However, our results do not support use of TH in patients with non-shockable rhythms.
STUDY DESIGN.: An experimental comparative study on moderate epidural hypothermia (MEH) versus moderate systemic hypothermia (MSH) after spinal cord injury (SCI). OBJECTIVE.: To compare neuroprotective effects of hypothermia between MEH and MSH after SCI in rats. SUMMARY OF BACKGROUND DATA.: Experimental MEH or MSH has been attempted for neuroprotection after ischemic or traumatic SCI. However, there is no comparative study on neuroprotective effect of MEH and MSH after SCI. If hypothermia is to be considered as 1 modality for treating SCI, further studies on the advantages and disadvantages of hypothermia will be mandatory. METHODS.: A spinal cord contusion was produced in all 32 rats, and these rats were randomly divided into 4 groups-8 rats in each group: (1) the control group (spinal cord contusion only), (2) the methylprednisolone group, (3) the MEH group (28°C for 48 hr), and (4) the MSH group (32°C for 48 hr). The functional recovery was assessed using Basso, Beattie, Bresnahan scale and antiapoptotic and anti-inflammatory effects were assessed. RESULTS.: The Basso, Beattie, Bresnahan scale scores in both the hypothermia groups were significantly higher than that in the control group at 6 weeks. The numbers of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and OX-42 positive cells were significantly lower in both the MEH and MSH groups than that in the control group. The p38 mitogen-activated protein kinases expression of the treated groups was significantly lower than that of the control group. The expression of caspase-8 and caspase-9 significantly decreased in the treated groups compared with that of the control group. However, in terms of caspase-3, only the MSH group has shown to be significantly lower than that of the control group. CONCLUSION.: This study presented that both systemic and epidural hypothermia demonstrated neuroprotective effects after SCI. Systemic hypothermia showed more neuroprotective effect by antiapoptotic and anti-inflammatory effects.
Despite treatment with therapeutic hypothermia, almost 50% of infants with neonatal encephalopathy still have adverse outcomes. Additional treatments are required to maximize neuroprotection. Melatonin is a naturally occurring hormone involved in physiological processes that also has neuroprotective actions against hypoxic-ischaemic brain injury in animal models. The objective of this study was to assess neuroprotective effects of combining melatonin with therapeutic hypothermia after transient hypoxia-ischaemia in a piglet model of perinatal asphyxia using clinically relevant magnetic resonance spectroscopy biomarkers supported by immunohistochemistry. After a quantified global hypoxic-ischaemic insult, 17 newborn piglets were randomized to the following: (i) therapeutic hypothermia (33.5°C from 2 to 26 h after resuscitation, n = 8) and (ii) therapeutic hypothermia plus intravenous melatonin (5 mg/kg/h over 6 h started at 10 min after resuscitation and repeated at 24 h, n = 9). Cortical white matter and deep grey matter voxel proton and whole brain (31)P magnetic resonance spectroscopy were acquired before and during hypoxia-ischaemia, at 24 and 48 h after resuscitation. There was no difference in baseline variables, insult severity or any physiological or biochemical measure, including mean arterial blood pressure and inotrope use during the 48 h after hypoxia-ischaemia. Plasma levels of melatonin were 10 000 times higher in the hypothermia plus melatonin than hypothermia alone group. Melatonin-augmented hypothermia significantly reduced the hypoxic-ischaemic-induced increase in the area under the curve for proton magnetic resonance spectroscopy lactate/N-acetyl aspartate and lactate/total creatine ratios in the deep grey matter. Melatonin-augmented hypothermia increased levels of whole brain (31)P magnetic resonance spectroscopy nucleotide triphosphate/exchangeable phosphate pool. Correlating with improved cerebral energy metabolism, TUNEL-positive nuclei were reduced in the hypothermia plus melatonin group compared with hypothermia alone in the thalamus, internal capsule, putamen and caudate, and there was reduced cleaved caspase 3 in the thalamus. Although total numbers of microglia were not decreased in grey or white matter, expression of the prototypical cytotoxic microglial activation marker CD86 was decreased in the cortex at 48 h after hypoxia-ischaemia. The safety and improved neuroprotection with a combination of melatonin with cooling support phase II clinical trials in infants with moderate and severe neonatal encephalopathy.
Therapeutic hypothermia has become a widely accepted intervention that is improving neurological outcomes following return of spontaneous circulation after cardiac arrest. This intervention is highly complex but infrequently used, and prompt implementation of the many steps involved, especially achieving the target body temperature, can be difficult. A checklist was introduced to guide nurses in implementing the therapeutic hypothermia protocol during the different phases of the intervention (initiation, maintenance, rewarming, and normothermia) in an intensive care unit. An interprofessional committee began by developing the protocol, a template for an order set, and a shivering algorithm. At first, implementation of the protocol was inconsistent, and a lack of clarity and urgency in managing patients during the different phases of the protocol was apparent. The nursing checklist has provided all of the intensive care nurses with an easy-to-follow reference to facilitate compliance with the required steps in the protocol for therapeutic hypothermia. Observations of practice and feedback from nursing staff in all units confirm the utility of the checklist. Use of the checklist has helped reduce the time from admission to the unit to reaching the target temperature and the time from admission to continuous electroencephalographic monitoring in the cardiac intensive care unit. Evaluation of patients' outcomes as related to compliance with the protocol interventions is ongoing.
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.