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Currents Journal Watch By: Aimee Aysenne, MD/MPH and Chitra Venkatasubramanian MBBS, MD, MSc. Welcome to Journal Watch! Recent publications advancing the practice of Neurocritical care include 2 international multicenter, randomized control trials: RESCUE ICP and MISTIE. We invite you to check out the NEWS on the NCS website for more information about these and other studies. As always, feel free to email us your comments and feedback! Rescue decompressive craniectomy is lifesaving in severe TBI. P.J. Hutchinson, et al., for the RESCUE-ICP Trial Collaborators* NEJM, 2016, 375, 1119-1130. RESCUE-ICP is an international multicenter randomized trial comparing decompressive craniectomy (DC) versus medical management for refractory intracranial hypertension after traumatic brain injury (TBI). Patients were enrolled if they had ICP > 25 mm Hg for 1-12 hours despite a stepwise approach to medical management. The surgical arm underwent either a large Aimee Aysenne, MD/MPH unilateral frontotemporal DC or bifrontal craniectomy within 4-6 hours after randomization. The medical arm continued medical management with option to add barbiturates. Crossover was allowed at the discretion of the treating clinician if there was further deterioration. The primary outcome was extended Glasgow outcome scale (GOS-E) at 6 months. Poor outcome was defined as death, vegetative state or lower severe disability (i.e. dependent at home and outside). Secondary outcomes were GOS-E at 12 and 24 months, mortality and quality of life at 6, 12 and 24 months using the SF Health Survey, GCS at hospital discharge, assessment of ICP control, SAE’s, time spent in ICU, time to hospital discharge and economic evaluation. 409 patients were recruited from 52 centers in 20 countries; 206 were assigned to surgical and 202 to medical arm. There was no significant difference in the medical management of ICP between groups. Crossover occurred in 37.2% of the medical arm whereas 9% in the surgical group received barbiturates. DC significantly reduced mortality (48.9% to 26.9%) but it resulted in higher rates of disability (30.3% versus 16.5%). There was no difference in good outcomes at 6 months, whereas at 12 months, the surgical group had higher rates of good outcomes (45.4% Vs. 32.4%, p=0.01). The surgical group also had better ICP control, shorter ICU stay, but had more adverse events. In a pre-specified subgroup analysis, benefit of DC for favorable outcome was better for patients < 40 years than for those > 40 years. Commentary: The RESCUE-ICP trial provides Class 1 evidence for using last tier decompressive craniectomy as a life saving intervention for refractory intracranial hypertension in severe TBI. Rescue decompressive craniectomy significantly reduced mortality (absolute reduction 22%) but left more patients dependent at 6 months. Interestingly, at 12 months, DC patients continued improving and 45% were independent at least at home versus 32.4% in the medical group. The 37% cross over rate from the medical arm underscores that maximal medical therapy is often not enough to control ICP, but may have also diluted the impact of DC. The inclusion of patients with refractory ICP, defined as > 25 mm Hg for > 1 hour after exhausting usual medical therapies increases the generalizability and applicability of the study results to real world scenarios unlike in the DECRA (Decompressive Craniectomy) trial where ICP had to be only > 20 mm Hg for 15 min before performing early DC. A life saving procedure is not always to be equated with a return to normal functioning. Quality of life is an individual determination and our discussions with families should take that into account while making life saving (but not always functionality improving) decisions. Minimally invasive surgery + alteplase is safe in ICH and possibly improves 180 day functional outcome. Daniel F Hanley, et al for the MISTIE Investigators. Lancet Neurol 2016; 15: 1228–37 MISTIE was an international, multicenter NIH funded open label phase 2 trial. The aim of the study was to test whether minimally invasive surgery (MIS) followed by alteplase was safe, and improved functional outcome. Patients who were 18-80 years of age with a spontaneous non traumatic supratentorial ICH of ≥ 20 ml that remained stable for ≥ 6 hours, with a GCS of ≤ 14 or NIHSS of ≥ 6 and a baseline mRS of 0 or 1 were included. Patients were allocated within 48 hours of onset to MIS + alteplase or standard medical care with AHA guidelines for ICH management. The first stage of MISTIE (i.e. dose finding stage), 0.3 mg and 1 mg doses of alteplase were tested. In the second stage, the 1 mg dose was used. Surgery involved aspiration of clot followed by placement of a soft catheter into the residual hematoma connected to a closed drainage system After ≥ 3 hours, intraclot alteplase was administered via the catheter every 8 hours for up to 9 doses. The system was closed for 1 hour to allow drug-clot interaction and then reopened. CT’s were done every 24 hours until dosing was complete. Surgical endpoints were a) reduction of clot to 20% of stability CT volume b) 15 ml or less residual clot or c) occurrence of a clinically significant re-bleeding event. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure related mortality, 30 day bacterial brain infection and symptomatic bleeding within 72 hours after the last dose. Pre-specified safety thresholds to ensure there was no difference between treatments were: 70% 30-day mortality, 35% symptomatic re-bleed and 15% infection rate. Secondary outcomes were clot size difference at end of treatment and its effect on functional outcome. Fifty-four patients had MIS and 42 had medical management. Delayed open craniotomy occurred in 4 medical and 1 MIS patient. The MIS and medical groups were well balanced. 15% of MIS group had surgical endpoint without alteplase. Mean reduction in ICH size was 57% in MIS group vs. 5% in medical group for a mean difference of 21 ml. There were more patients with mRS score of ≤ 3 at 180 days in the MIS group than in the medical group (33% vs. 21%). No significant difference was seen at 365 days. Despite meeting all safety thresholds, the MIS group had a non-significant increase in symptomatic bleeds and a significant increase in asymptomatic bleeds (22% vs. 7%, p=0.05). There was no difference in survival or days spent in ICU but the MIS patients returned home faster (51 days vs. 89 days, p=0.03). Commentary: MISTIE is the first randomized trial showing the safety of a minimally invasive approach + alteplase for spontaneous ICH. There are certainly limitations from this small phase 2 clinical trials, and MISTIE-3, a 500 patient randomized trial testing the generalizability of the MIS procedure, stabilization protocol and its impact on functional outcome, is underway. Chitra Venkatasubramanian MBBS, MD, MSc. 26


eMag_264548_NCS Currents_December2016_3
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