Status epilepticus (SE) is a common indication for neurocritical care and can be refractory to standard measures. Refractory SE (RSE) is associated with high morbidity and mortality. Unconventional therapies may be utilized in certain cases, including therapeutic hypothermia (TH), bumetanide, and the ketogenic diet. However, the literature describing the use of such therapies in RSE is limited. Details of a case of TH for RSE in an infant with malignant migrating partial seizures of infancy were obtained from the medical record. A 4-month-old child developed SE that was refractory to treatment with concurrent midazolam, phenobarbital, fosphenytoin, topiramate, levetiracetam, folinic acid, and pyridoxal-5-phosphate. This led to progressive implementation of three unconventional therapies: TH, bumetanide, and the ketogentic diet. Electrographic seizures ceased for the entirety of a 43-hour period of TH with a target rectal temperature of 33.0°C-34.0°C. No adverse effects of hypothermia were noted other than a single episode of asymptomatic hypokalemia. Seizures recurred 10 hours after rewarming was begun and did not abate with reinstitution of hypothermia. No effect was seen with administration of bumetanide. Seizures were controlled long-term within 48 hours of institution of the ketogenic diet. TH and the ketogenic diet may be effective for treating RSE in children.

BACKGROUND:

On the basis of mixed results from previous trials, we assessed whether therapeutic hypothermia for 48-72 h with slow rewarming improved mortality in children after brain injury.

METHODS:

In this phase 3, multicenter, multinational, randomised controlled trial, we included patients with severe traumatic brain injury who were younger than 18 years and could be enrolled within 6 h of injury. We used a computer-generated randomisation sequence to randomly allocate patients (1:1; stratified by site and age [<6 years, 6-15 years, 16-17 years]) to either hypothermia (rapidly cooled to 32-33°C for 48-72 h, then rewarmed by 0·5-1·0°C every 12-24 h) or normothermia (maintained at 36·5-37·5°C). The primary outcome was mortality at 3 months, assessed by intention-to-treat analysis; secondary outcomes were global function at 3 months after injury using the Glasgow outcome scale (GOS) and the GOS-extended pediatrics, and the occurrence of serious adverse events. Investigators assessing outcomes were masked to treatment. This trial is registered with ClinicalTrials.gov, number NCT00222742.

FINDINGS:

The study was terminated early for futility after an interim data analysis on data for 77 patients (enrolled between Nov 1, 2007, and Feb 28, 2011): 39 in the hypothermia group and 38 in the normothermia group. We detected no between-group difference in mortality 3 months after injury (6 [15%] of 39 patients in the hypothermia group vs two [5%] of 38 patients in the normothermia group; p=0·15). Poor outcomes did not differ between groups (in the hypothermia group, 16 [42%] patients had a poor outcome by GOS and 18 [47%] had a poor outcome by GOS-extended paediatrics; in the normothermia group, 16 [42%] patients had a poor outcome by GOS and 19 [51%] of 37 patients had a poor outcome by GOS-extended paediatrics). We recorded no between-group differences in the occurrence of adverse events or serious adverse events.

INTERPRETATION:

Hypothermia for 48 h with slow rewarming does not reduce mortality of improve global functional outcome after paediatric severe traumatic brain injury. FUNDING: National Institute of Neurological Disorders and Stroke and National Institutes of Health.

The blood-brain-barrier (BBB) is formed by different cell types, of which brain microvascular endothelial cells are major structural constituents. The goal of this study was to examine the effects of cooling on the permeability of the BBB with reference to tight junction formation of brain microendothelial cells. The sensorimotor cortex above the dura mater in adult male Wistar rats was focally cooled to a temperature of 5 °C for 1 h, then immunostaining for immunoglobulin G (IgG) was performed to evaluate the permeability of the BBB. Permeability produced by cooling was also evaluated in cultured murine brain endothelial cells (bEnd3) based on measurement of trans-epithelial electric resistance (TEER). Immunocytochemistry and Western blotting of proteins associated with tight junctions in bEnd3 were performed to determine protein distribution before and after cooling. After focal cooling of the rat brain cortex, diffuse immunostaining for IgG was observed primarily around the small vasculature and in the extracellular spaces of parenchyma of the cortex. In cultured bEnd3, TEER significantly decreased during cooling (15 °C) and recovered to normal levels after rewarming to 37 °C. Immunocytochemistry and Western blotting showed that claudin-5, a critical regulatory protein for tight junctions, was translocated from the membrane to the cytoplasm after cooling in cultured bEnd3 cells. These results suggest that focal brain cooling may open the BBB transiently through an effect on tight junctions of brain microendothelial cells, and that therapeutically this approach may allow control of BBB function and drug delivery through the BBB.

INTRODUCTION:

Mild induced hypothermia (MIH) is indicated for comatose survivors of sudden cardiac arrest (SCA) to improve clinical outcome. In this study, we compared the efficacy of two different cooling devices for temperature management in SCA survivors.

METHODS:

Between April 2008 and August 2009, 80 patients after survived in-hospital (IHCA) and out-of-hospital cardiac arrest (OHCA) were included in this prospective, randomized, single center study. Hypothermia was induced after randomization by either invasive Coolgard(®) cooling or non-invasive ArcticSun(®) surface cooling at 33.0 °C core body temperature for 24 h followed by active rewarming. The primary endpoint was defined as the efficacy of both cooling systems, measured by neuron-specific enolase (NSE) levels as a surrogate parameter for brain damage. Secondary efficacy endpoints were the clinical and neurological outcome, time to start of cooling and reaching the target temperature, target temperature-maintenance and hypothermia-associated complications.

RESULTS:

NSE at 72 h did not differ significantly between the 2 groups with 16.5 ng/ml, interquartile range 11.8-46.5 in surface-cooled patients versus 19.0 ng/ml, interquartile range 11.0-42.0 in invasive-cooled patients, p = 0.99. Neurological and clinical outcome was similar in both groups. Target temperature of 33.0 °C was maintained more stable in the invasive group (33.0 versus 32.7 °C, p < 0.001). Bleeding complications were more frequent with invasive cooling (n = 17 [43.6 %] versus n = 7 [17.9 %]; p = 0.03).

CONCLUSION:

Invasive cooling has advantages with respect to temperature management over surface cooling; however, did not result in different outcome as measured by NSE release in SCA survivors. Bleeding complications were more frequently encountered by invasive cooling.

Arch surgery is undoubtedly among the most technically and strategically challenging endeavours in aortic surgery, requiring thorough understanding not only of cardiovascular physiology, but also in particular, of neurophysiology (cerebral and spinal cord), and is still associated with significant mortality and morbidity. In the late 1980s, when deep hypothermic circulatory arrest (HCA) had gained widespread acceptance as the standard approach for arch surgery, antegrade selective cerebral perfusion (SCP), as an adjunct to deep HCA, began its triumphal march, offering excellent neuroprotection and improved overall outcome. This encouraged the use of antegrade SCP in combination with steadily increasing body core temperatures-a trend culminating in the progressive advocation of moderate-to-mild temperatures up to 35°C, and even normothermia. The impetus for progressive temperature elevation was the limitation of adverse effects of profound hypothermia and the most welcome side effect of significantly shorter cooling and rewarming periods on cardiopulmonary bypass (CPB), and thereby, potentially, the alleviation of the systemic inflammatory response and, in particular, the risk of severe postoperative bleeding (and other organ dysfunctions). The safe limits of prolonged distal circulatory arrest, particularly with regard to the ischaemic tolerance of the viscera and the spinal cord, have not yet been clearly defined. Adverse outcomes due to inappropriate temperature management (core temperatures too high for the required duration of distal arrest) are probably highly underreported. Complications historically associated with hypothermia, namely excessive bleeding, are possibly overestimated. Trading effective neuroprotection and excellent outcomes for the risk of prolonged 'warm' distal ischaemia might constitute a significant step back, jeopardizing visceral and, in particular, spinal cord integrity, with unpredictable consequences for long-term outcome and quality of life, particularly affecting those in need of more complex surgery or with previous neurological deficits.

Over recent years, several planktonic and benthic freshwater diatom taxa have been established as laboratory model strains. In common with most freshwater diatoms the pennate diatom Planothidium frequentissimum suffers irreversible cell shrinkage on prolonged maintenance by serial transfers, without induction of the sexual cycle. Therefore, alternative strategies are required for the long-term maintenance of this strain. Conventional colligative cryopreservation approaches have previously proven unsuccessful with no regrowth. However, in this study using 5% dimethyl sulfoxide (Me2SO), controlled cooling at 1°Cmin(-1), automated ice seeding and cooling to -40°C with a final plunge into liquid nitrogen, viability levels were enhanced from 0.3±0.4% to 80±3%, by incorporating a 48h dark-recovery phase after rewarming. Omission, or reduction, of this recovery step resulted in obvious cell damage with photo-bleaching of pigments, indicative of oxidative-stress induced cell damage, with subsequent deterioration of cellular architecture.

There is less information available on cell cultures on the exclusive effects of either duration of cold ischemia (CI) or rewarming-reperfusion in the kidney subjected to initial warm ischemia (WI). Therefore, the goals of our work were: (1) to evaluate the consequences on tubular cellular viability of different durations of CI on a kidney after an initial period of WI, and (2) to analyze the additional effect on tubular cell viability of rewarming of the same kidney.Sixteen mini-pig were used. All the animals were performed a right nephrectomy after 45-minute occlusion of the vascular pedicle. The kidneys were then divided into 2 groups (phase 1): cold storage in university of wisconsin (UW) solution for 3 hours (group A, n = 8) at 4°C, or cold storage in UW for 12 hours (group B, n = 8) at 4°C. Four organs of group A and four organs of group B were autotrasplanted (AT) and reperfused for 1 hour (phase 2). Nephrectomy was finally done. Biopsies were taken from all groups to perform cultures of proximal tubule epithelium cells. The biopsies were subjected to studies of cellular morphological viability (contrast phase microscopy [CPM]) and quantitative (confluence cell [CC]) parameters.Phase of pure CI effects (phase 1): Both CC rate and CPM parameters were significantly lower in group B compared with group A, where cell activity reached almost normal results. Phase of CI + AT (phase 2): At produced additional harmful effects in cell cultures compared with those obtained in phase 1, more evident in group B cells.The presence of cold storage followed by rewarming-reperfusion induces independent and cumulative detrimental effects in viability of renal proximal tubule cells. CI periods ≤3 hours may ameliorate the injuries secondary to reperfusion in comparison with longer CI periods.

The quality of cold-stored livers declines with the extension of ischemic time, increasing the risk of primary dys or nonfunction. A new concept to rescue preserved marginal liver grafts by gentle oxygenated warming-up prior to blood reperfusion was investigated. Porcine livers were preserved by cold storage (CS) in modified HTK-solution for 18 h. Some grafts were subsequently subjected to 90 min of controlled oxygenated rewarming (COR) by machine perfusion with gradual increase of perfusate temperature up to 20°C or simple oxygenated machine perfusion in hypothermia (HMP) or subnormothermia (SNP). Graft viability was assessed thereafter by 4 h of normothermic blood reperfusion ex vivo. Endischemic tissue energetics were significantly improved by COR or SNP and to a notably lesser extent by HMP. COR significantly reduced cellular enzyme loss, gene expression and perfusate activities of TNF-alpha, radical mediated lipid peroxidation (LPO) and increase of portal vascular perfusion resistance upon reperfusion, while HMP or SNP were less protective. Only COR resulted in significantly more bile production than after CS. Histological injury score and caspase 3-activation were significantly lower after COR than after CS. Oxygenated rewarming prior to reperfusion seems to be a promising technique to improve subsequent organ recovery upon reperfusion of long preserved liver grafts.

Conventional reoperative mitral valve surgery by median sternotomy has several difficulties. We performed mitral valve replacement (MVR) under ventricular fibrillation (VF) through right mini-thoracotomy with three-dimensional videoscope for avoiding the problems.Between 2006 and 2011, we performed 257 cases of MVR, in which 125 cases underwent isolated MVR. Ten cases of patients underwent reoperative MVR under VF through thoracotomy with three-dimensional videoscope (Group I), and 27 cases of patients underwent reoperative conventional MVR through median sternotomy (Group II). We retrospectively reviewed the outcomes and compared Group I with Group II. Preoperative left ventricular ejection fraction (LVEF) was significantly lower (50.5 ± 19.8% vs 64.4 ± 12.0%; p = 0.046), and significantly higher Euro SCORE was found in Group I (4.8 ± 2.0 vs 3.8 ± 2.4; p = 0.037).Although Group I required cooling and rewarming time, average operative times was significantly shorter in Group I (262 ± 46 min vs 300 ± 57 min; p = 0.044), and cardiopulmonary bypass times and average VF times in Group I and aortic cross-clamp times in Group II were equivalent. There was no significant difference in the average of postoperative maximum creatine kinase (CK)-MB. In-hospital mortality was 0/10 (0%) and 1/27 (3.7%), and postoperative paravalvular leakage occurred in 0/10 (0%) and 1/27 (3.7%), and stroke occurred in 1/10 (10%) and 1/27 (3.7%) for Groups I and II. Two patients underwent reoperation for bleeding in Group II. Intensive care unit stay in Group I was significantly shorter than in Group II (1.8 ± 0.6 days vs 3.0 ± 1.7 days; p = 0.025).The higher risk of preoperative background in Group I had no effect on the operation. Mitral valve surgery under VF through right mini-thoracotomy can be an alternative procedure for reoperation after conventional various cardiothoracic surgeries.

Accidental hypothermia complicated by cardiac arrest carries a high mortality rate in urban areas. For moderate hypothermia cases conventional rewarming methods are usually adequate, however in severe cases extracorporeal membrane oxygenation (ECMO) is known to provide the most efficient rewarming with complete cardiopulmonary support. We report a case of severe hypothermia complicated by prolonged cardiac arrest successfully resuscitated using ECMO.A 45 year old female was brought to our emergency department with a core body temperature <25°C. Shortly after arrival she had witnessed cardiac arrest in the department. Resuscitative efforts were started immediately including conventional rewarming techniques, followed by ECMO support. ECMO was used successfully in this case to resuscitate this patient from prolonged arrest (3.5 hours) when conventional techniques likely would have failed. After a prolonged hospital course this patient was discharged with her baseline mental and physical capacities intact.This case demonstrates the advantages of advanced internal rewarming techniques, such as ECMO, for quick and efficient rewarming of severely hypothermic patients. This case supports the use of ECMO in severely hypothermic patients as the standard of care.