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Journal Watch By Aimee Aysenne, MD and Chitra Venkatasubramanian, MD Winter temperatures have been higher than expected throughout the country, but this season has brought us a series of trials of targeted temperature management (TTM) for a variety of conditions including acute ischemic strokes, status epilepticus and pediatric in hospital cardiac arrest. While we may be warmer than normal outside, in our ICU’s cooler temperatures abound! TTM in post-tPA stroke patients, the results of ICTuS-2 Lyden P, Hemmen T, Grotta J, Rapp K et al. Stroke 2016; 47 (12): 2888-2895 The ICTuS trial demonstrated safety of intravascular cooling in stroke patients but the subsequent ICTuS-L found increased pneumonia rates in the therapeutic hypothermia (TH) group. Phase 2 of the ICTuS-2/-3 compared tPA treatment versus tPA + hypothermia at 33° C with emphasis on safety. Patients received tPA within three hours, had moderate stroke severity and were between 22-82 years. Intra-arterial recanalization was an initial exclusion criterion, but due to a change in standard of care, the study was halted after 120 patients (original target = 400) to redesign the protocol. Hypothermia was achieved using a cold saline bolus and intravascular cooling for 24 hours and controlled rewarming for 12 hours. Shivering was controlled using meperidine, buspirone and surface-warming measures. One hundred twenty patients were enrolled with 63 assigned to hypothermia. Groups were well matched in demographics and pre treatment clinical measures. In the intent to treat (ITT) analysis, 33 percent of the TH group and 38 percent of the normothermia group had a good outcome, defined as 90-day mRS 0-1. In the per protocol (PP) analysis, 24 percent of TH group and 38 percent of the normothermia group had a good outcome. Mortality and pneumonia was higher in the TH group but was not statistically significant. Commentary: Enrollment for this study was halted early and given the small sample size, it is difficult to draw robust conclusions. However, this study found no evidence for the benefit for therapeutic hypothermia in stroke patients treated with tPA. TTM does not improve neurologic outcomes after convulsive status epilepticus. Legriel S, Lemiale V, Schenck M, et al. NEJM. 2016; 375:2457-67. This is a multicenter, open label, prospective randomized trial evaluating neurologic outcomes after TTM (32 to 34o C) for the treatment of convulsive status epilepticus (CSE). Patients who required mechanical ventilation for CSE were randomized to standard therapy versus standard therapy plus TTM with cold IV fluids, ice packs and cold air for 24 hours. Exclusion criteria were return to neurological baseline, need for emergent surgery, post anoxic brain injury, imminent death, DNR orders and bacterial meningitis. Primary outcome was 90 day return to previous functional status with no or minimal neurologic deficits (Glasgow Outcome Scale (GOS) score of 5). Two hundred sixty-eight patients (138 patients for TH0) were enrolled. Cooling was initiated at a median of 5.8 hours after seizure onset. The control group was kept normothermic at 37.0o C. In the intention to treat analysis, a GOS of 5 was reached in 49 percent of patients in the TH group and in 43 percent of the control group. There was no difference in mortality. Of the four main secondary outcome measures, only progression to EEG confirmed status was statistically significant, 10.9 percent in the hypothermia group and 22.3 percent of the control group. This trial was not powered for subgroup analysis by age, but those ≤ 65 years when treated with hypothermia were more likely to return to GOS 5. Pneumonia was the most common adverse event in both groups. One person experienced propofol infusion syndrome in the hypothermia group. Commentary: This study did not demonstrate any additional benefit of therapeutic hypothermia at 32-34o C for convulsive status epilepticus in achieving good functional outcome at 90 days. A trend toward benefit for younger patient (≤ 65 years) may have potential for further investigation. The most common adverse event was pneumonia. TTM for pediatric in hospital cardiac arrest- No benefit of therapeutic hypothermia. Moler FW, Silverstein FS, Holubkov R et al. NEJM 2017; 376: 318-29. Therapeutic hypothermia after pediatric cardiac arrest (THAPCA-IH) is a randomized trial of TTM to 33° C versus normothermia at 36.8° C for 48 hours followed by gradual rewarming and maintenance of 36.8° C for an additional 72 hours in pediatric in- hospital cardiac arrest (IHCA). Children were sedated and paralyzed with TH. If they were on ECMO, the target temperature was adjusted on the circuit. Primary outcome was favorable neurobehavioral outcome at 12 months on the Vineland Adaptive Behavior Scale (VABS-II) (age corrected standard score of ≥ 70 (on a scale of 20 to 160)). Secondary outcomes were survival at 12 months and change in VABS-II from baseline. The trial was halted early for futility. Three hundred twenty-nine children were randomized (TH=166) and (normothermia=163). Median age was one year, 60 percent were male and 91 had a pre-existing medical condition. Initial rhythm was bradycardia in 57 percent and Vfib/VT in 10 percent. Slightly more than 50 percent of children had ECMO. There was no difference between TH and normothermia in primary or secondary outcome measures. Primary cause of mortality was brain death or withdrawal of life support due to poor neurologic prognosis (TH 39 percent, normothermia 33 percent). Commentary: The THAPCA-IH trial did not demonstrate any neurocognitive or survival benefit between TH at 33° C or normothermia at 36.8 ° C for pediatric in hospital cardiac arrest. Main limitations include early halt for futility and ineligibility for primary analysis (18 percent) due to baseline poor neurocognitive functioning resulting in smaller that expected numbers, less precise estimates of treatment and inability to determine any subgroup benefit. JOURNAL WATCH Aimee Aysenne, MD Chitra Venkatasubramanian, MD 30


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