Search

Introduction: Perinatal asphyxia is one of the three most important causes of neonatal mortality and morbidity. Therapeutic hypothermia represents the standard treatment for infants with moderate-severe perinatal asphyxia, resulting in reduction in the mortality and major neurodevelopmental disability. So far, data in the literature focusing on the endocrine aspects of both asphyxia and hypothermia treatment at birth are scanty, and many aspects are still debated. Aim of this narrative review is to summarize the current knowledge regarding the short- and long-term effects of perinatal asphyxia and of hypothermia treatment on the endocrine system, thus providing suggestions for improving the management of asphyxiated children. Results: Involvement of the endocrine system (especially glucose and electrolyte disturbances, adrenal hemorrhage, non-thyroidal illness syndrome) can occur in a variable percentage of subjects with perinatal asphyxia, potentially affecting mortality as well as neurological outcome. Hypothermia may also affect endocrine homeostasis, leading to a decreased incidence of hypocalcemia and an increased risk of dilutional hyponatremia and hypercalcemia. Conclusions: Metabolic abnormalities in the context of perinatal asphyxia are important modifiable factors that may be associated with a worse outcome. Therefore, clinicians should be aware of the possible occurrence of endocrine complication, in order to establish appropriate screening protocols and allow timely treatment. [ABSTRACT FROM AUTHOR]

Hypoxic-ischemic encephalopathy (HIE) is the leading cause of long-term neurological disability in neonates and adults. Through bibliometric analysis, we analyzed the current research on HIE in various countries, institutions, and authors. At the same time, we extensively summarized the animal HIE models and modeling methods. There are various opinions on the neuroprotective treatment of HIE, and the main therapy in clinical is therapeutic hypothermia, although its efficacy remains to be investigated. Therefore, in this study, we discussed the progress of neural circuits, injured brain tissue, and neural circuits-related technologies, providing new ideas for the treatment and prognosis management of HIE with the combination of neuroendocrine and neuroprotection. [ABSTRACT FROM AUTHOR]

Nowadays, the complexity of disease mechanisms and the inadequacy of single-target therapies in restoring the biological system have inevitably instigated the strategy of multi-target therapeutics with the analysis of each target individually. However, it is not suitable for dealing with the conflicts between targets or between drugs. With the release of high-precision protein structure prediction artificial intelligence, large-scale high-precision protein structure prediction and docking have become possible. In this article, we propose a multi-target drug discovery method by the example of therapeutic hypothermia (TH). First, we performed protein structure prediction for all protein targets of each group by AlphaFold2 and RoseTTAFold. Then, QuickVina 2 is used for molecular docking between the proteins and drugs. After docking, we use PageRank to rank single drugs and drug combinations of each group. The ePharmaLib was used for predicting the side effect targets. Given the differences in the weights of different targets, the method can effectively avoid inhibiting beneficial proteins while inhibiting harmful proteins. So it could minimize the conflicts between different doses and be friendly to chronotherapeutics. Besides, this method also has potential in precision medicine for its high compatibility with bioinformatics and promotes the development of pharmacogenomics and bioinfo-pharmacology. [ABSTRACT FROM AUTHOR]

Background: Women experience worse neurological outcomes following out-of-hospital cardiac arrest (OHCA). It is unknown whether sex disparities exist in the use of targeted temperature management (TTM), a standard of care treatment to improve neurological outcomes.Methods: We performed a retrospective study of prospectively collected patients who survived to hospital admission following OHCA from the Cardiac Arrest Registry to Enhance Survival from 2013 through 2019. We compared receipt of TTM by sex in a mixed-effects model adjusted for patient, arrest, neighborhood, and hospital factors, with the admitting hospital modeled as a random intercept.Results: Among 123,419 patients, women had lower rates of shockable rhythms (24.4 % vs. 39.2%, P < .001) and lower rates of presumed cardiac aetiologies for arrest (74.3% vs. 81.1%, P < .001). Despite receiving a similar rate of TTM in the field (12.1% vs. 12.6%, P = .02), women received less TTM than men upon admission to the hospital (41.6% vs. 46.4%, P < .001). In an adjusted mixed-effects model, women were less likely than men to receive TTM (Odds Ratio 0.91, 95% Confidence Interval 0.89 to 0.94). Among the 27,729 patients with data indicating the reason for not using TTM, a higher percentage of women did not receive TTM due to Do-Not-Resuscitate orders/family requests (15.1% vs. 11.4%, p < .001) and non-shockable rhythms (11.1% vs. 8.4%, p < .001).Conclusions: We found that women received less TTM than men, likely due to early care limitations and a preponderance of non-shockable rhythms. [ABSTRACT FROM AUTHOR]

[West J Emerg Med. 2012;13(1):111–113.]

Background: The effect of renal replacement therapy (RRT) on the outcomes of severe acute kidney injury (AKI) after out-of-hospital cardiac arrest (OHCA) is uncertain. This study aimed to evaluate the association of RRT with 6-month mortality in patients with severe AKI treated with targeted temperature management (TTM) after OHCA.Methods: This was a retrospective analysis of a prospectively collected multicentre observational cohort study that included adult OHCA patients treated with TTM across 22 hospitals in South Korea between October 2015 and December 2018. AKI was diagnosed using the Kidney Disease: Improving Global Outcomes criteria. The primary outcome was 6-month mortality and the secondary outcome was cerebral performance category (CPC) at 6 months. Multivariate Cox regression analysis was performed to define the role of RRT in stage 3 AKI.Results: Among 10,426 patients with OHCA, 1373 were treated with TTM. After excluding those who died within 48 h of return of spontaneous circulation (ROSC) and those with pre-arrest chronic kidney disease, our study cohort comprised 1063 patients. AKI developed in 590 (55.5%) patients and 223 (21.0%) had stage 3 AKI. Among them, 115 (51.6%) were treated with RRT. The most common treatment modality among RRT patients was continuous renal replacement therapy (111 [96.5%]), followed by intermittent haemodialysis (4 [3.5%]). The distributions of CPC (1-5) at 6 months for the non-RRT vs. the RRT group were 3/108 (2.8%) vs. 12/115 (10.4%) for CPC 1, 0/108 (0.0%) vs. 1/115 (0.9%) for CPC 2, 1/108 (0.9%) vs. 3/115 (2.6%) for CPC 3, 6/108 (5.6%) vs. 6/115 (5.2%) for CPC 4, and 98/108 (90.7%) vs. 93/115 (80.9%) for CPC 5, respectively (P = 0.01). The RRT group had significantly lower 6-month mortality than the non-RRT group (93/115 [81%] vs. 98/108 [91%], P = 0.04). Multivariate Cox regression analyses showed that RRT was independently associated with a lower risk of death in patients with stage 3 AKI (hazard ratio, 0.569 [95% confidence interval, 0.377-0.857, P = 0.01]).Conclusion: Dialysis interventions were independently associated with a lower risk of death in patients with stage 3 AKI treated with TTM after OHCA. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate retinal hemorrhages (RHs) in newborns after therapeutic hypothermia performed for hypoxic–ischemic encephalopathy (HIE). From 2014 January to October 2016, full-term newborns who were referred to us from the neonatal intensive care unit at our hospital for ophthalmological examination were evaluated retrospectively. Neonates diagnosed with HIE were examined with a RetCam Digital Retinal Camera (Massie Research Laboratories Inc., Pleasanton, CA) using a 130-degree or binocular indirect ophthalmoscope (Heine, Herrsching, Germany) imaging tool and were classified into three groups. Group 1 included patients without HIE, group 2 included patients with stage I HIE, and group 3 included patients with stage II or III HIE. The RH rates in cases of HIE were retrospectively reviewed. A total of 148 eyes of 74 patients were included in the study. RH was detected in 36 eyes (24.3%); there were two eyes (3.7%), 14 eyes (20.6%), and 20 eyes (76.9%), in groups 1, 2, and 3, respectively. In group 3, RH was mostly seen in a widespread form. RHs involving the macula were resorbed later than haemorrhages in other locations. RHs are frequent in neonates with HIE. RHs were seen significantly more frequently in stage II–III HIE. These haemorrhages may require treatment, especially when the macula is involved. [ABSTRACT FROM AUTHOR]

Aim To examine the effects of therapeutic hypothermia on the outcome of patients with the diagnosis of out-of-hospital cardiac arrest (OHCA). Methods The study included 76 patients who were hospitalised at the Medical Intensive Care Unit (MICU) of the Clinical Centre University of Sarajevo, with the diagnosis of out-of-hospital cardiac arrest, following the return of spontaneous circulation. Therapeutic hypothermia was performed with an average temperature of 33oC (32.3 - 34.1oC) on the patients who had coma, according to the Glasgow Coma Scale (GCS). Results Multiple organ dysfunction syndrome (MODS) signifi- cantly affected survival (p=0.0001), as its presence reduced patients' survival by 96%. In addition, ventricular fibrillation (VF) as the presenting rhythm, also significantly affected survival (p=0.019). A degree of patient's coma, as measured by the GCS, significantly affected survival (p=0.011). For each increasing point on the GCS, the chance for survival increased twice. Moreover, other physiological factors such as the pH and the lactate serum levels significantly affected patients' survival (p=0.012 and p=0.01, respectively). Conclusion In patients with the diagnosis of OHCA who underwent to the treatment with therapeutic hypothermia, verified VF as a presenting rhythm was a positive predictive factor for their outcome. Therefore, therapeutic hypothermia represents an option of therapeutic modality for this type of patients. [ABSTRACT FROM AUTHOR]

Dexmedetomidine (Dex) is a sedative and analgesic agent that is widely administered to patients admitted to the intensive care unit, and has been demonstrated to result in hypothermia. Many patients have been revealed to benefit from therapeutic hypothermia, which can mitigate cerebral ischemia/reperfusion (I/R) injury following successful cardiopulmonary resuscitation. However, studies investigating the efficacy of Dex in I/R treatment is lacking. The present study aimed to investigate the efficacy of Dex in mitigating neuronal damage, and to determine the possible mechanism of its effects in a rat model of cardiac arrest (CA). CA was induced in Sprague-Dawley rats by asphyxiation for 5 min. Following successful resuscitation, the surviving rats were randomly divided into two treatment groups; one group was intraperitoneally administered with Dex (D group), whereas the control group was treated with normal saline (N group). Critical parameters, including core temperature and blood pressure were monitored following return of spontaneous circulation (ROSC). Arterial blood samples were collected at 10 min after surgery (baseline) 30 and 120 min post-ROSC; and neurological deficit scores (NDS) of the rats were taken 12 or 24 h after ROSC prior to euthanasia. The hippocampal tissue was then removed for analysis by histology, electron microscopy and western blotting. Rats in the D group exhibited a lower core temperature and higher NDS scores compared with the N group (P<0.05). In addition, Dex injection resulted in reduced expression of apoptotic and autophagy-associated factors in the hippocampus (P<0.05). Dex treatment induced hypothermia and improved neurological function in rats after ROSC following resuscitation from CA by inhibiting neuronal apoptosis and reducing autophagy, which suggested that Dex may be a potential therapy option for patients with CA. [ABSTRACT FROM AUTHOR]

Objectives: Dorsal-stream functions are vulnerable to early brain injury associated with neonatal encephalopathy (NE) following perinatal asphyxia, even in children not developing cerebral palsy (CP). Since therapeutic hypothermia (TH) became the standard treatment for NE, the incidence of CP is reduced but the impact on dorsal-stream functions is unknown. We aimed to compare dorsal-stream functions in TH-treated survivors of NE, without CP, with those of matched controls. Methods: We administered tests of dorsal-stream function to 29 case children aged 6-to-8 years treated with TH for NE and without CP, and 20 age, sex and social class matched controls. We used the Conner's Continuous Performance Test (CPT) 2nd Edition to assess attentiveness, based upon Hit Reaction Time (HRT) percentile score and HRT standard error percentile, the CPT HRT block change measure to assess sustained attention and the NEPSY-II block construction and arrows tests to assess visuo-spatial performance and mental rotation. Results: Case children performed significantly worse than controls on measures of attention and visuo-spatial function. Conclusions: Children given TH treatment for NE can have subtle attention difficulties with slower reaction times and reduced visuo-spatial processing. These findings illustrate the continued vulnerability of dorsal-stream functions following NE despite the use of TH. [ABSTRACT FROM AUTHOR]

The mammalian fetus and newborn can survive far more prolonged periods of hypoxia-ischaemia without neural injury than adults. In part, this remarkable physiological resilience reflects the effectiveness of its endogenous protective processes that help to suppress injurious events that evolve over time after hypoxia-ischaemia (HI). Many cells are able to recover from even relatively severe periods of HI, in a latent phase marked by adaptive hypometabolism, with reduced brain activity, leading to a high rate of mild body and brain hypothermia, unless it is prevented by external warming. From approximately 4 to 8 h after HI secondary energy failure progressively develops, leading to delayed cell swelling and secondary seizures and ultimately cell death. The latent phase offers the key window for interventions to prevent bulk cell loss, as strongly supported by the successful clinical translation of therapeutic hypothermia. Therapeutic hypothermia is partially protective. Thus, promoting endogenous protective processes may help further improve treatment of acute neonatal encephalopathy. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic ischemic (HI) brain injury causes lifelong neurologic disability. Therapeutic hypothermia (TH) is the only approved therapy that partially mitigates mortality and morbidity. Therapies specifically targeting HI-induced brain cell death are currently lacking. Intracellular calcium dysregulation, oxidative stress, and mitochondrial dysfunction through the formation of the mitochondrial permeability transition pore (mPTP) are drivers of HI cellular injury. GNX-4728, a small molecule direct inhibitor of the mPTP that increases mitochondrial calcium retention capacity, is highly effective in adult neurodegenerative disease models and could have potential as a therapy in neonatal HI. A dose of GNX-4728, equivalent to that used in animal models, 300 mg/kg, IP was highly toxic in p10 mice. We then tested the hypothesis that acute administration of 30 mg/kg, IP of GNX-4728 immediately after HI in a neonatal mouse model would provide neuroprotection. This non-lethal lower dose of GNX-4728 (30 mg/kg, IP) improved the respiratory control ratio of neonatal female HI brain tissue but not in males. Brain injury, assessed histologically with a novel metric approach at 1 and 30 days after HI, was not mitigated by GNX-4728. Our work demonstrates that a small molecule inhibitor of the mPTP has i) an age related toxicity, ii) a sex-related brain mitoprotective profile after HI but iii) this is not sufficient to attenuate forebrain HI neuropathology. • Usage of a mPTP inhibitor at therapeutic adult doses is toxic in neonatal mice. • Low dose mPTP inhibition protected brain mitochondria in females after neonatal HI. • mPTP inhibition did not prevent brain damage acutely or long term after neonatal HI. [ABSTRACT FROM AUTHOR]

Background: Hypophosphatasia (HPP) is a rare inherited disorder affecting bone and teeth development. Perinatal HPP is the most severe form and associated with a high mortality. Features include respiratory distress, skeletal abnormalities and low alkaline phosphatase (ALP) activity.Case: A baby boy developed respiratory distress, hypotonia and seizures within an hour of birth. Blood gas showed mixed acidosis and abnormal base deficit. Hypoxic-ischaemic encephalopathy (HIE) was suspected and managed with therapeutic hypothermia. Subsequent investigations identified low ALP activity and abnormal bone mineralisation, leading to a diagnosis of HPP. On day 5 of life, enzyme replacement therapy (ERT) was commenced, its first use via direct NHS England funding since UK licensing in 2017.Conclusions: Early hypotonia is an atypical presentation for perinatal HPP. Combined with acidosis and encephalopathy, it can clinically mimic HIE. Early recognition of biochemical and radiological features of HPP is essential for rapid diagnosis and timely initiation of life-saving ERT. [ABSTRACT FROM AUTHOR]

Aim: Neonatal hypoxic ischemic encephalopathy (HIE) patients are at times accompanied by persistent pulmonary hypertension (PPHN), which is by itself another risk factor of adverse outcomes. We aimed to assess the outcome of therapeutic hypothermia (TH) in these patients whom we managed to reverse the shunt flow, as they are expected to be at much higher risk of adverse neurodevelopmental outcome.Methods: We reviewed the medical records of 116 HIE infants (13 with PPHN and 103 without PPHN) who underwent TH between 2012 and 2016. We analyzed the short-term hospital outcomes and brain study results (electroencephalogram and magnetic resonance imaging) of TH in these patients.Results: While infants with PPHN were significantly more likely to be outborn or have meconium aspiration syndrome, and required a longer duration of inotrope and intensive care support, electroencephalographic and brain magnetic resonance findings did not significantly differ according to PPHN status.Conclusion: Based on our study, the hospital outcomes of infants with HIE accompanied by reversible PPHN who underwent TH were in general not significantly graver than those not accompanied by PPHN. Our results suggest that undergoing TH may be more beneficial in HIE infants with PPHN and the risks for possible adverse effects may not be as so high. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of therapeutic hypothermia on myocardial dysfunction in term neonates with perinatal asphyxia.Material and Methods: This randomized controlled trial (RCT) conducted in a tertiary care teaching hospital, south India included 120 newborns with perinatal asphyxia that were randomized to two groups (therapeutic hypothermia and normothermia). Cardiac enzyme profile changes between groups were assessed at 0, 24, 72 h CPK-MB and troponin I levels were estimated by immune inhibition and quantitative immunochromatography methods, respectively. Electrocardiography (ECG) and Echocardiography (ECHO) were done at 0 and 72 h to evaluate the cardiac function and pulmonary hypertension. Neurodevelopment was assessed at 6 months of age in both groups using Developmental Assessment Scales for Indian Infants.Results: The median values of CPK-MB in the normothermia and hypothermia groups at 0, 24, and 72 h were 198, 127, and 92 IU/L and 202, 111 and 64 IU/L, respectively. The median values of troponin I in normothermia and hypothermia groups at 0, 24, and 72 hrs were 2.45, 1.53, and 0.9 ng/mL and 1.97, 0.93, and 0.01 ng/mL, respectively. ECG and ECHO findings also suggest lesser myocardial dysfunction in therapeutic hypothermia group compared with the normothermia group.Conclusions: Therapeutic hypothermia significantly decreases the myocardial damage in term asphyxiated neonates. [ABSTRACT FROM AUTHOR]

Abstract Hypoxic ischaemic encephalopathy (HIE) occurs in 1.5–2/1000 births in developed countries and 26/1000 births in developing countries. Therapeutic cooling to a core temperature of 33.5°C for 72 h has become the mainstay of treatment for term infants with moderate and severe HIE with clinically proven improvements in both mortality and morbidity. This review article first explores current knowledge and limits of the use for therapeutic hypothermia, and then goes on to explore the potential new therapies that can provide additional neuroprotection. Currently researched neuroprotective treatments include pharmacological therapies (allopurinol, cannabinoids, erythropoietin, magnesium sulphate, melatonin, topiramate, and the noble gases xenon and argon), remote ischaemic post-conditioning, and the use of stem cells. The evidence available for these therapies and the current stage of their research are discussed. [ABSTRACT FROM AUTHOR]

Copyright of Turkish Journal of Trauma & Emergency Surgery / Ulusal Travma ve Acil Cerrahi Dergisi is the property of KARE Publishing and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: The effects of therapeutic hypothermia (TH) on hemodynamics in newborns with hypoxic-ischemic encephalopathy (HIE) were evaluated.Materials and Methods: Thirty-two neonates (gestational age, 39.4 ± 1.3 weeks) who had TH for HIE and echocardiographic hemodynamic assessments during TH and post-TH period were studied. Gestational-age-matched 34 healthy neonates were enrolled for comparison.Results: During TH, patients had significantly decreased left ventricular cardiac output (LVCO), descending aorta blood flow (DABF), and DABF/LVCO ratio, and increased resistive index of DA compared to controls. Upper body blood flow (UBBF) remained unchanged but UBBF/LVCO ratio significantly increased during TH. Urine output decreased significantly during TH and increased after rewarming, and showed significant positive correlation with DABF/LVCO ratio. Sixteen patients (50%) showed hypoxic-ischemic (HI) lesions on brain magnetic resonance imaging (MRI) and had significantly increased UBBF/LVCO ratio during TH compared to patients without HI lesions. Patients with UBBF/LVCO ratio >55% had significantly higher risk of having HI lesions on brain MRI (odds ratio 13.0; 95% CI, 2.4-70.2).Conclusions: Decrease in cardiac output and descending aorta blood flow, and preferential cerebral redistribution of cardiac output along with an increase in systemic peripheral vascular resistance may affect systemic organ perfusion and cerebral metabolism. [ABSTRACT FROM AUTHOR]

Aims Of the Study: Most interventional and observational studies include cardiac arrest from cardiac origin. However, an increasing proportion of cardiac arrest results from an extra-cardiac origin, mainly respiratory. The aim of our study was to compare the characteristics and outcome of cardiac arrest patients according to the presumed cardiac or respiratory causes.Methods: This retrospective multicenter observational study included out-of-hospital cardiac arrest patients from presumed cardiac and respiratory origin treated with therapeutic hypothermia. Demographic data (age, sex, initial rhythm as shockable or non-shockable, durations of no-flow and low-flow), clinical evolution in ICU, lactate and outcome (CPC scale at ICU discharge) were compared between patients according to the presumed cardiac or respiratory origin of the cardiac arrest.Results: Two hundred and fifty-one cardiac arrest patients were included, 156 from presumed cardiac origin (62%) and 95 from presumed respiratory origin (38%). Patients with presumed cardiac cause presented more frequently a shockable rhythm (68% vs. 5%, p < 0.001), received more defibrillations attempts (2 [1-5] vs. 0 [0-0], <0.001) and needed less adrenaline (3 mg [0-5] vs. 4 mg [2-7], p = 0.01). The arterial lactate concentration on admission was higher in patients with presumed respiratory causes (6.3 mmol/L [4.2-9.8] vs. 3.2 mmol/L [1.6-5.0], p < 0.001). The proportion of patients presenting a favorable outcome was higher in the population with presumed cardiac causes, compared to its respiratory counterpart (42% vs. 19%, p < 0.001).Conclusions: Compared to presumed cardiac origin, a worse outcome and a different mode of death are associated with the presumed respiratory origin, resulting from a greater insult preceding cardiac arrest. The presumed cause of cardiac arrest could be integrated in the multimodal prognostication process. [ABSTRACT FROM AUTHOR]

Aims: Mechanical ventilation practices in patients with cardiac arrest are not well described. Also, the effect of temperature on mechanical ventilation settings is not known. The aims of this study were 1) to describe practice of mechanical ventilation and its relation with outcome 2) to determine effects of different target temperatures strategies (33 °C versus 36 °C) on mechanical ventilation settings.Methods: This is a substudy of the TTM-trial in which unconscious survivors of a cardiac arrest due to a cardiac cause were randomized to two TTM strategies, 33 °C (TTM33) and 36 °C (TTM36). Mechanical ventilation data were obtained at three time points: 1) before TTM; 2) at the end of TTM (before rewarming) and 3) after rewarming. Logistic regression was used to determine an association between mechanical ventilation variables and outcome. Repeated-measures mixed modelling was performed to determine the effect of TTM on ventilation settings.Results: Mechanical ventilation data was available for 567 of the 950 TTM patients. Of these, 81% was male with a mean (SD) age of 64 (12) years. At the end of TTM median tidal volume was 7.7 ml/kg predicted body weight (PBW)(6.4-8.7) and 60% of patients were ventilated with a tidal volume ≤ 8 ml/kg PBW. Median PEEP was 7.7cmH2O (6.4-8.7) and mean driving pressure was 14.6 cmH2O (±4.3). The median FiO2 fraction was 0.35 (0.30-0.45). Multivariate analysis showed an independent relationship between increased respiratory rate and 28-day mortality. TTM33 resulted in lower end-tidal CO2 (Pgroup = 0.0003) and higher alveolar dead space fraction (Pgroup = 0.003) compared to TTM36, while PCO2 levels and respiratory minute volume were similar between groups.Conclusions: In the majority of the cardiac arrest patients, protective ventilation settings are applied, including low tidal volumes and driving pressures. High respiratory rate was associated with mortality. TTM33 results in lower end-tidal CO2 levels and a higher alveolar dead space fraction compared to TTTM36. [ABSTRACT FROM AUTHOR]

Glibenclamide (GBC) is an antidiabetic drug that is in a class of medications known as sulfonylureas, which play critical roles in attenuating brain edema and reducing mortality in ischemic stroke patients. Therapeutic hypothermia (TH) is another robust neuroprotectant that prevents brain swelling and improves the neurological outcomes of stroke patients. However, whether the combination of GBC and TH can be used as a reliable neuroprotectant in ischemic stroke remains largely unknown. We used the middle cerebral artery occlusion (MCAO) rat model as well as oxygen and glucose deprivation-reoxygenation (OGD/R) endothelial cells as ischemic stroke models to investigate the efficacy and mechanisms of treating ischemic stroke with the combination of GBC and TH. The serum glucose, mortality rate, neurobehavioral functions, tight junctions, endothelial cells and inflammatory cytokines were evaluated in the stroke models after treatment with GBC, TH or the combination of them. After 5-hour occlusion and subsequent reperfusion, rats exhibited a large volume of hemispheric swelling and a high mortality rate. Stroke rats treated with the combined therapy did not exhibit hypoglycemia. The combination of GBC and TH exhibited synergistic neuroprotective effects in stroke rats that were associated with greater reductions in edema volume, better improvement in neurobehavioral functions, prevention of tight junction loss, and reduction of expression of the inflammatory cytokines COX-2 and iNOS. In OGD/R endothelia cells, the combination reduced endothelial cell death. This study demonstrated that both GBC and TH are neuroprotective after the severe stroke; however, combined therapy with GBC and TH enhanced the efficiency and efficacy of the effects of TH and GBC in the treatment of ischemia. This combined therapy may facilitate the clinical translation of TH management for severe stroke. The combination of GBC and TH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following severe stroke. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia is considered as a standard of care in the treatment of moderate to severe hypoxic ischaemic encephalopathy in neonates ≥36 weeks of gestation and is considered safe and effective. The time period to initiate it is critical as it should start before the onset of secondary brain injury. This article reviews the criterion to initiate therapeutic hypothermia in hypoxic ischaemic encephalopathy, management and neuroimaging related to it and adjuvant treatment options for HIE. [ABSTRACT FROM AUTHOR]

Background: Currently, there are limited data of prognostic clues for neurological recovery in comatose survivors undergoing therapeutic hypothermia (TH). We aimed to evaluate clinical signs and findings that could predict neurological outcomes, and determine the optimal time for the prognostication. Materials and Methods: We retrospectively reviewed database of postarrest survivors treated with TH in our hospital from 2006 to 2014. Cerebral performance category (CPC), neurological signs and findings in electroencephalography (EEG) and brain computed tomography (CT) were evaluated. In addition, the optimal time to evaluate neurological status was analyzed. Results: TH was performed in 51 postarrest patients. Approximately 53% of TH patients survived at discharge and 33% of the hospital survivors had favorable outcome (CPC1-2). The prognostic clues for unfavorable outcome (CPC3-5) at discharge were lack of pupillary light response (PLR) and/or gag reflex after rewarming, and the absence of at least one of the brainstem reflexes, no eye-opening, or abnormal motor response on the 7th day. Myoclonus and seizure could not be used to indicate poor prognosis. In addition, prognostic values of EEG and CT findings were inconclusive. Conclusions: Our study showed the simple neurological signs helped predict short-term neurological prognosis. The most reliable sign determining unfavorable outcome was the lack of PLR. The optimal time to assess prognosis was either at 48-72 h or 7 days after return of spontaneous circulation. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia is a standard of care for infants ≥36 weeks gestational age (GA) with moderate-to-severe hypoxic-ischemic encephalopathy. Because some studies included infants born at 35 weeks GA, hypothermia should be considered if they meet other criteria. Cooling for infants <35 weeks GA is not recommended. Passive cooling should be started promptly in community centres, in consultation with a tertiary care centre neonatologist, while closely monitoring the infant's temperature. Best evidence suggests that maintaining core body temperature between 33°C and 34°C for 72 hours, followed by a period of rewarming of 6 to 12 hours, is optimal. Antiepileptic medications should be used when clinical or electrographic seizures are present. Maintaining serum electrolytes and glucose within normal ranges, and avoiding hypo- or hypercarbia and hyperoxia, are important adjunct treatments. A brain magnetic resonance image (MRI) is advised shortly after rewarming and, in cases where earlier findings do not match the clinical picture, a repeat MRI after 10 days of life is suggested. Multidisciplinary neurodevelopmental follow-up is recommended. [ABSTRACT FROM AUTHOR]

Purpose: Although guidelines on post-resuscitation care recommend the use of short-acting agents for sedation during targeted temperature management (TTM) after cardiac arrest (CA), the potential advantages of this strategy have not been clinically demonstrated.Methods: We compared two sedation regimens (propofol-remifentanil, period P2, vs midazolam-fentanyl, period P1) among comatose TTM-treated CA survivors. Management protocol, apart from sedation and neuromuscular blockers use, did not change between the two periods. Baseline severity was assessed with Cardiac-Arrest-Hospital-Prognosis (CAHP) score. Time to awakening was measured starting from discontinuation of sedation at the end of rewarming. Awakening was defined as delayed when it occurred after more than 48 h.Results: 460 patients (134 in P2, 326 in P1) were included. CAHP score did not significantly differ between P2 and P1 (P = 0.93). Sixty percent of patients awoke in both periods (81/134 vs. 194/326, P = 0.85). Median time to awakening was 2.5 (IQR 1-9) hours in P2 vs. 17 (IQR 7-60) hours in P1. Awakening was delayed in 6% of patients in P2 vs. 29% in P1 (p < 0.001). After adjustment, P2 was associated with significantly lower odds of delayed awakening (OR 0.08, 95% CI 0.03-0.2; P < 0.001). Patients in P2 had significantly more ventilator-free days (25 vs. 24 days; P = 0.007), and lower catecholamine-free days within day 28. Survival and favorable neurologic outcome at discharge did not differ across periods.Conclusions: During TTM following resuscitation from CA, sedation with propofol-remifentanil was associated with significantly earlier awakening and more ventilator-free days as compared with midazolam-fentanyl. [ABSTRACT FROM AUTHOR]

We examined the brain injury and neurodevelopmental outcomes in a prospective cohort of 10 babies with mild encephalopathy who had early cessation of cooling therapy. All babies had MRI and spectroscopy within 2 weeks after birth and neurodevelopmental assessment at 2 years. Cooling was prematurely discontinued at a median age of 9 hours (IQR 5-13) due to rapid clinical improvement. Five (50%) had injury on MRI or spectroscopy, and two (20%) had an abnormal neurodevelopmental outcome at 2 years. Premature cessation of cooling therapy in babies with mild neonatal encephalopathy does not exclude residual brain injury and adverse long-term neurodevelopmental outcomes. This study refers to babies recruited into the MARBLE study (NCT01309711, pre-results stage). [ABSTRACT FROM AUTHOR]

Although major cooling trials (and subsequent guidelines) excluded babies with mild encephalopathy, anecdotal evidence suggests that cooling is often offered to these infants. We report a national survey on current cooling practices for babies with mild encephalopathy in the UK. From 74 neonatal units contacted, 68 were cooling centres. We received 54 responses (79%) and included 48 (five excluded due to incomplete data and one found later not to offer cooling). Of these, 36 centres (75%) offered cooling to infants with mild encephalopathy. Although most of the participating units reported targeting 33-34°C core temperature, seven (19%) considered initiating cooling beyond 6 hours of age and 13 (36%) discontinued cooling prior to 72 hours. Babies were ventilated for cooling in two (6%) units and 13 (36%) sedated all cooled babies. Enteral feeding was withheld in 15 (42%) units and reduced below 25% of requirements in eight (22%) units. MRI and neurodevelopmental outcome evaluation were offered to all cooled babies in 29 (80%) and 27 (75%) units, respectively. Further research is necessary to ensure optimal neuroprotection in mild encephalopathy. [ABSTRACT FROM AUTHOR]

Aims: Hypoxic ischaemic encephalopathy (HIE) remains a significant cause of long term neurodisability despite therapeutic hypothermia (TH). Infants with mild HIE, representing 50% of those with HIE, are perceived as low risk and are currently not eligible for TH [1]. This review examines the available evidence of outcome in term infants with mild HIE.Methods: Medline, Embase and Cochrane Clinical Trials databases were searched in March 2017. Studies with well-defined HIE grading at birth and standardised neurodevelopmental assessment at ≥18 months were included. Abnormal outcome was defined as death, cerebral palsy or standardised neurodevelopmental test score more than 1 standard deviation below the mean.Result: Twenty studies were included. Abnormal outcome was reported in 86/341 (25%) of infants. There was insufficient evidence to examine the effect of TH on outcome.Conclusion: A significant proportion of infants with mild HIE have abnormal outcome at follow up. [ABSTRACT FROM AUTHOR]

Abstract: Background: Thyroid function in asphyxiated newborns who received hypothermia therapy and its relation to neurological outcome are not well described. Methods: We performed a prospective study to measure thyroid function in 12 asphyxiated newborns who received hypothermia therapy. We measured serum thyroid‐stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4) on admission, at 24, 72, and 96 h after birth, and at discharge (range, 17–54 days). The 12 newborns were divided into two groups based on the presence of brain injury on head magnetic resonance imaging (six in the abnormal imaging group and six in the normal imaging group), and thyroid function was compared between the two groups. Results: Serum TSH was within the normal range in the 12 newborns. Serum FT3 and FT4 remained low at 24, 72, and 96 h after birth, and returned to normal range at discharge in the 12 newborns. There was no significant difference in serum TSH between the two groups, but serum FT3 at 96 h after birth, and serum FT4 at 72 and 96 h after birth, were significantly lower in the abnormal imaging group than in the normal imaging group (P = 0.02; P = 0.03; and P = 0.01, respectively). Conclusions: Asphyxiated newborns have transient low thyroid hormone levels at 24–96 h after birth. Serum FT3 and FT4 between 72 and 96 h after birth may predict brain injury in asphyxiated newborns. [ABSTRACT FROM AUTHOR]

Perinatal hypoxia is a devastating event before, during, or immediately after birth that deprives an infant’s vital organs of oxygen. This injury at birth often requires a complex resuscitation and increases the newborn’s risk of hypoxic-ischemic encephalopathy (HIE). The resuscitation team in a community hospital nursery may have less experience with complex resuscitation and post-resuscitation care of this infant than a NICU. This article provides the neonatal nurse in a Level I or Level II nursery with information about resuscitation and post-resuscitation care of an infant at risk of HIE while awaiting transport to a NICU for therapeutic cooling. The article describes the infant at risk for HIE, discusses pathophysiology and treatment of HIE, and lists essential components of post-resuscitation care while awaiting transport to an NICU, the importance of communication with the receiving NICU, and strategies for supporting the family. [ABSTRACT FROM AUTHOR]

Background: Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection. Objectives: The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia. Methods: This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria. Results and Conclusions: Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia, also referred to as targeted temperature management, has been a component of the postcardiac arrest treatment guidelines since 2010. Although almost a decade has passed since its inclusion in the postarrest guidelines, many unanswered questions remain regarding selection of the appropriate patient population, optimal target temperature, ideal window of time in which to initiate therapy after arrest, most efficient, safe, and accurate equipment choice for inducing and maintaining hypothermia, most effective duration of treatment, and rate of cooling or rewarming. On a national and international level, critical care nurses are in a unique position to participate in research that will define targeted temperature management protocols and practices. Nurses are also ideal for standardizing the targeted temperature management policy and protocol locally and nationally based on current available evidence. This review aims to serve 2 purposes: first, to provide a broad update on the current clarifications and limitations per research findings on target temperature management therapy; second, to explain how critical care nurses can use this updated information to improve outcomes for their patients with cardiac arrest. [ABSTRACT FROM AUTHOR]

Background: Mild therapeutic hypothermia (32-36 °C) is associated with improved outcomes in patients with brain injury after cardiac arrest (CA). Various devices are available to induce and maintain hypothermia, but few studies have compared the performance of these devices. We performed a prospective study to compare four frequently used cooling systems in inducing and maintaining hypothermia followed by controlled rewarming.Methods: We performed a prospective multi-centered study in ten ICU's in three hospitals within the UPMC health system. Four different cooling technologies (seven cooling methods in total) were studied: two external water-circulating cooling blankets (Meditherm® and Blanketrol®), gel-coated adhesive cooling pads (Arctic Sun®), and endovascular cooling catheters with balloons circulating ice-cold saline (Thermogard®). For the latter system we studied three different types of catheter with two, three or four water-circulating balloons, respectively. In contrast to previous studies, we not only studied the cooling rate (i.e., time to target temperature) in the induction phase, but also the percentage of the time during the maintenance phase that temperature was on target ±0.5 °C, and the efficacy of devices to control rewarming. We believe that these are more important indicators of device performance than induction speed alone.Results: 129 consecutive patients admitted after CA and treated with hypothermia were screened, and 120 were enrolled in the study. Two researchers dedicated fulltime to this study monitored TH treatment in all patients, including antishivering measures, additional cooling measures used (e.g. icepacks and cold fluid infusion), and all other issues related to temperature management. Baseline characteristics were similar for all groups. Cooling rates were 2.06 ± 1.12 °C/h for endovascular cooling, 1.49 ± 0.82 for Arctic sun, 0.61 ± 0.36 for Meditherm and 1.22 ± 1.12 for Blanketrol. Time within target range ±0.5 °C was 97.3 ± 6.0% for Thermogard, 81.8 ± 25.2% for Arctic Sun, 57.4 ± 29.3% for Meditherm, and 64.5 ± 20.1% for Blanketrol. The following differences were significant: Thermogard vs. Meditherm (p < 0.01), Thermogard vs. Blanketrol (p < 0.01), and Arctic Sun vs. Meditherm (p < 0.02). No major complications occurred with any device.Conclusions: Endovascular cooling and gel-adhesive pads provide more rapid hypothermia induction and more effective temperature maintenance compared to water-circulating cooling blankets. This applied to induction speed, but (more importantly) also to time within target range during maintenance. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to determine the prognosis of 26 consecutive adults with alpha coma (AC), theta coma (TC) or alpha-theta coma (ATC) following CRA and to describe the clinical setting and EEG features of these patients.Methods: We retrospective analyzed a prospectively collected cohort of adult patients diagnosed as having AC, TC or ATC after CRA between January 2008 and June 2016. None of patients included in this analysis underwent therapeutic hypothermia (TH). Neurological outcome was expressed as the best score 6 months after CRA using the five-point Glasgow-Pisttsburgh Cerebral Performance Categories (CPC) RESULTS: Twenty-six patients were identified with a diagnosis of postanoxic AC, TC or ATC coma. There were 20 (77%) men and 6 (23%) women. The mean age was 63 ± 16 years. The most frequent EEG pattern was TC (21 patients, 80%), followed by AC (3 patients, 12%) and ATC (2 patients, 8%). The cardiac rhythm as primary origin of the CRA was ventricular fibrillation (VF) in 16 patients (61.5%), asystole in 8 patients (34.6%) and ventricular tachycardia (VT) in one patient (3.8%). The presence of EEG reactivity was present in 8 patients (30%). The mortality rate was 85%. Of the 4 surviving patients, two (3.8%) had moderate disability (CPC 2), one (3.8%) had severe disability (CPC 3) and one (3.8%) reached a good recovery. The age was significantly lower in survivors 46.2 ± 10.8 versus nonsurvivors 63.3 ± 15.5 (p = 0.04). There was increased association of EEG reactivity with survival (p = 0.07).Conclusion: Hypoxic-ischemic AC, TC and ATC are associated with a poor prognosis and a high rate of mortality. In younger patients with AC, TC and ATC and incomplete forms showing reactivity on the EEG, there is a greater probability of clinical recovery. [ABSTRACT FROM AUTHOR]

Background: Therapeutic hypothermia is neuroprotective in asphyxiated neonates by counteracting mechanisms contributing to brain injury. Although an initial increased permeability is part of an inflammatory reaction and thereby a natural healing process, an excessive endothelial permeability with edema formation may result in impaired hemodynamics. Reduced permeability may, however, benefit healing. Although plasma and interstitial colloid osmotic pressure are accessible and essential parameters for understanding fluid imbalance, the mechanisms of fluid exchange remain poorly understood. The potential influence of therapeutic hypothermia on plasma and interstitial colloid osmotic pressure, and the relationship between inflammatory markers and colloid osmotic pressure in asphyxiated neonates, was investigated.Methods: Seventeen neonates with moderate to severe hypoxic ischemic encephalopathy, born after 35 weeks gestation, received servo-controlled whole body cooling before 6 h of age, followed by gradual rewarming after 72 h. All infants were treated according to a national hypothermia protocol. Interstitial fluid in the skin was collected at 7, 13, 25, 49, and 73 h after birth by subcutaneous implantation of multifilamentous nylon wicks with 60 min of implantation time. Biomarkers of inflammation and colloid osmotic pressure were measured in serum and interstitial fluid.Results: A modest decrease in serum and interstitial colloid osmotic pressure was measured, leaving an unaltered difference in colloid osmotic pressure gradient. A decline in mean arterial pressure was observed between 7 and 13 h of life, with a concomitant decrease in positive fluid balance within the same time frame. White blood cell count and leukocyte subclasses dropped significantly throughout treatment, with elevated interstitial interleukin (IL)-1α and decreased serum IL-1RA, IL-6, and IL-10 during treatment time points.Conclusions: Colloid osmotic pressures measured in serum and interstitial fluid during asphyxia is lower than previously reported, with small alteration of pressure differences across capillaries, reducing vascular filtration. An inherent local and systemic regulation of inflammation together with changes in colloid osmotic pressure may indicate a possible preventive mechanism of edema generation during neonatal asphyxia and therapeutic hypothermia.Trial Registration: ClinicalTrials.gov Identifier: NCT01044940 . Date of registration: January 8, 2010. [ABSTRACT FROM AUTHOR]

Objectives: The Eurotherm3235 trial showed that therapeutic hypothermia was deleterious in patients with raised intracranial pressure following traumatic brain injury. We sought to ascertain if increased temperature variability within the first 48 hours, or for 7 days post randomization, were modifiable risk factors associated with poorer outcome.Design: Eurotherm3235 was a multicenter randomized controlled trial. Patients were randomized to receive either therapeutic hypothermia in addition to standard care or the later only. Mean moving range (mr) was used to stratify subjects into tertiles by the variability present in their core temperature within the first 48 hours post randomization and within 7 days post randomization. The primary outcome measure was a collapsed Glasgow Outcome Scale-Extended at 6 months post randomization. The temperature variability effect was estimated with ordinal logistic regression adjusted for baseline covariates and treatment effect.Setting: Forty-seven critical care units in 18 countries.Patients: Patients enrolled in the Eurotherm3235 trial to either therapeutic hypothermia or control treatments only.Measurements and Main Results: Three hundred eighty-six patients were included in our study. High level of temperature variability during the first 48 hours was associated with poorer collapsed Glasgow Outcome Scale-Extended. This effect remained statistically significant when only the control arm of the study was analyzed. No statistically significant effect was seen within the first 48 hours in the hypothermia group or within 7 days in either group.Conclusions: When targeting normothermia, temperature variability may be a statistically significant variable in an ordinal analysis adjusted for baseline covariates. [ABSTRACT FROM AUTHOR]

Background: We aimed to investigate the impact of prolonged targeted temperature management (TTM) in cardiac arrest patients on release of serum levels of NSE and S-100b and their prognostic performances.Methods: This is a substudy of the Targeted Temperature Management for 24 vs 48h trial. NSE and S-100b levels were analysed retrospectively in serum samples collected upon admission, at 24, 48, and 72h after reaching the target temperature of 33±1°C. The primary outcome was biomarker serum concentrations and secondary outcome was the cerebral performance category score after 6 months.Results: 115 patients from two centres were analysed. NSE and S-100b levels did not differ between TTM groups at any single time-point. Poor outcome patients had higher biomarker levels at 24, 48, and 72h: NSE: 9.73 (7.2; 10.9) versus 20.40 (12.7; 27.2), 8.86 (6.6; 9.6) versus 17.47 (11.1; 37.3) and 6.23 (5.3; 8.5) versus 31.05 (12.8; 52.5) respectively and S-100b: 0.09 (0.07; 0.11) versus 0.23 (0.19; 0.39), 0.08 (0.07; 0.09) versus 0.18 (0.15; 0.33) and 0.07 (0.06; 0.08) versus 0.13 (0.09; 0.23). The daily changes in NSE from admission to Day 2 after the cardiac arrest (CA) were also related to the outcome (p=0.003 and p=0.02). The best prediction of outcome was found at 72h for NSE and at 24h as well as 48h for S100b.Conclusions: No clinically relevant differences were found in the levels of NSE or S-100b between standard and prolonged TTM. Prognostic reliability of NSE and S-100b was unaltered by prolonged TTM. [ABSTRACT FROM AUTHOR]

Advances in medical care of the acute liver failure patient have led to a significant reduction in mortality related to the condition. Nevertheless, cerebral edema and ensuing brain herniation remains one of the top causes of demise in acute liver failure. Controversy remains regarding the utility of invasive intracranial pressure monitoring as well as usage of novel treatment modalities including therapeutic hypothermia. This review provides a brief summary into the pathophysiology and risk factors for developing cerebral edema in the context of acute liver failure; this review particularly provides a practical focus on general management of the patient with established cerebral edema as well as specific intracranial pressure-lowering strategies. [ABSTRACT FROM AUTHOR]

Seizure is a serious complication of stroke, indicating poor prognosis. Notch signaling is associated with neuronal activity. Inhibition of Notch signaling suppresses seizure activity induced by kainic acid. The present study investigated the effect of the Notch inhibitor, DAPT, alone or in combination with mild hypothermia, on post-stroke seizures. A global cerebral ischemia (GCI) model was performed in Sprague Dawley (SD) male rats. Seizure activity was evaluated by the frequency of seizure attacks, seizure severity scores, and seizure discharges. Without any intervention, seizures occurred intensively between 24 h and 48 h following GCI. Seizure activity was confirmed using EEG monitoring. The expression of Notch intracellular domains (NICD) 1 and 2 were up-regulated in the cerebral cortex and hippocampus following GCI. DAPT was injected into the hippocampus of the rats to inhibit local Notch signaling. Active whole-body cooling was performed to maintain the core temperatures of rats at 33.5 °C (mild hypothermia). Mild hypothermia and DAPT synergistically inhibited NICD 1 and 2 up-regulation, and post-stroke seizures. GCI augmented excitatory synaptic neurotransmission by up-regulating glutamate receptor subunits (GluN2A, GluA1) and the cotransporter, NKCC1, but attenuated inhibitory synaptic neurotransmission by down-regulating gamma amino acid, butyric acid (GABA), and the cotransporter, KCC2. DAPT treatment normalized the homeostasis of excitatory and inhibitory synaptic neurotransmission, suggesting that aberrant activation of Notch signaling is involved in post-stroke seizures. The present study adds to the further understanding of the pathogenesis of post-stroke seizures and the improvement of the treatment provided with hypothermia. [ABSTRACT FROM AUTHOR]

Rationale: Targeted temperature management (TTM) improves survival with good neurological outcome after out-of-hospital cardiac arrest (OHCA), but is delivered inconsistently and often with delay.Objective: To determine if prehospital cooling by paramedics leads to higher rates of 'successful TTM', defined as achieving a target temperature of 32-34°C within 6h of hospital arrival.Methods: Pragmatic RCT comparing prehospital cooling (surface ice packs, cold saline infusion, wristband reminders) initiated 5min after return of spontaneous circulation (ROSC) versus usual resuscitation and transport. The primary outcome was rate of 'successful TTM'; secondary outcomes were rates of applying TTM in hospital, survival with good neurological outcome, pulmonary edema in emergency department, and re-arrest during transport.Results: 585 patients were randomized to receive prehospital cooling (n=279) or control (n=306). Prehospital cooling did not increase rates of 'successful TTM' (30% vs 25%; RR, 1.17; 95% confidence interval [CI] 0.91-1.52; p=0.22), but increased rates of applying TTM in hospital (68% vs 56%; RR, 1.21; 95%CI 1.07-1.37; p=0.003). Survival with good neurological outcome (29% vs 26%; RR, 1.13, 95%CI 0.87-1.47; p=0.37) was similar. Prehospital cooling was not associated with re-arrest during transport (7.5% vs 8.2%; RR, 0.94; 95%CI 0.54-1.63; p=0.83) but was associated with decreased incidence of pulmonary edema in emergency department (12% vs 18%; RR, 0.66; 95%CI 0.44-0.99; p=0.04).Conclusions: Prehospital cooling initiated 5min after ROSC did not increase rates of achieving a target temperature of 32-34°C within 6h of hospital arrival but was safe and increased application of TTM in hospital. [ABSTRACT FROM AUTHOR]

Background: Targeted temperature management (TTM) between 32 and 36°C is recommended after out-of-hospital cardiac arrest (OHCA). We aimed to assess the feasibility and safety of the "Esophageal Cooling Device" (ECD) in performing TTM.Patients and Methods: This single-centre, prospective, interventional study included 17 comatose OHCA patients. Main exclusion criteria were: delay between OHCA and return of spontaneous circulation (ROSC)>60min, delay between sustained ROSC and inclusion >360min, known oesophageal disease. A TTM between 32 and 34°C was performed using the ECD (Advanced Cooling Therapy, USA) connected to a heat exchanger console (Meditherm III®, Gaymar, France), without cold fluids' use. Primary endpoint was feasibility of inducing, maintaining TTM, and rewarming using the ECD alone. Secondary endpoints were adverse events, focusing on potential digestive damages. Results were expressed as median (interquartiles 25-75).Results: Cooling rate to reach the Target Temperature (33°C-TT) was 0.26°C/h [0.19-0.36]. All patients reached the 32-34°C range with a time spent within the range of 26h [21-28] (3 patients did not reach 33°C). Temperature deviation outside the TT during TTM-maintenance was 0.10°C [0.03-0.20]. Time with deviation >1°C was 0h. Rewarming rate was 0.20°C/h [0.18-0.22]. Among the 16 gastrointestinal endoscopy procedures performed, 10 (62.5%) were normal. Minor oeso-gastric injuries (37.5% and 19%, respectively) were similar to usual orogastric tube injuries. One patient experienced severe oesophagitis mimicking peptic lesions, not cooling-related. No patient among the 9 alive at 3-month follow-up had gastrointestinal complains.Conclusion: ECD seems an interesting, safe, accurate, semi-invasive cooling method in OHCA patients treated with 33°C-TTM, particularly during the maintenance phase. [ABSTRACT FROM AUTHOR]

Objective Hypothermia is considered the treatment of choice for newborns with hypoxic-ischemic encephalopathy. Even though currently no consensus exists regarding the opportunity to extend this treatment also to newborns with sudden unexpected postnatal collapse (SUPC), this treatment is frequently adopted. The aim of the study was to evaluate whether the availability of hypothermia also for collapsed newborns in a tertiary level center may impact the estimated incidence of SUPC. Study Design A retrospective study was performed comparing the number of newborns admitted with the diagnosis of SUPC in the tertiary referral Neonatal intensive care unit of Florence in the period before (2008-2010) and after (20112014) the introduction of hypothermia treatment for newborns with SUPC. Result After introducing active cooling also to newborns with SUPC, the number of newborns with SUPC admitted to our center augmented and, consequently, SUPC incidence apparently increased from 5.3 to 15.5/100,000 live births, even though this difference did not reach statistical significance (odds ratio = 0.340; 95% confidence interval = 0.071-1.639; p = 0.179). Conclusion The apparent increase of SUPC incidence is probably related to a more effective centralization of newborns in our referral center but suggests that the real incidence of SUPC is probably significantly higher than currently estimated. [ABSTRACT FROM AUTHOR]

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours.Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy.Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size.Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C).Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization.Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively.Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness.Trial Registration: clinicaltrials.gov Identifier: NCT00614744. [ABSTRACT FROM AUTHOR]

Therapeutic hypothermia (TH) is now provided as standard care to infants with moderate-severe hypoxic ischemic encephalopathy (HIE). The role of TH in limiting neuronal injury is well recognized, but its effect on hepatic injury which occurs frequently in neonatal HIE is not known. Our objective was to characterize biomarkers of liver injury and function in the setting of neonatal HIE and to describe whether HIE severity and provision of TH influence these hepatic biomarkers. We performed a multicenter retrospective study and compared hepatic biomarkers obtained during the first postnatal week, according to the severity of HIE and whether treated with TH. Of a total of 361 infants with HIE, 223 (62%) received TH and 138 (38%) were managed at normal temperature. Most hepatic biomarkers and C-reactive protein (CRP) were significantly associated with the severity of HIE (p < 0.001). Infants treated with TH had lower peak alanine aminotransferase (ALT) concentrations (p = 0.025) and a delay in reaching peak CRP concentration (p < 0.001).Conclusion: We observed a significant association between the clinical grade of HIE and biomarkers of liver metabolism and function. Therapeutic hypothermia was associated with delayed CRP responses and with lower ALT concentrations and so may have the potential to modulate hepatic injury. What is Known: • Ischemic hepatic injury occurs frequently as a part of multiorgan dysfunction in infants with hypoxic ischemic encephalopathy (HIE). • The neuroprotective role of therapeutic hypothermia in management of infants with HIE is well recognized, but the potential hepato-protective effects of hypothermia are unclear. What is New/What this study adds: • Therapeutic hypothermia was associated with lower alanine aminotransferase and albumin concentrations and a delayed C-reactive protein (CRP) response and so may have the potential to modulate hepatic injury. • An elevated CRP concentration during the first postnatal week may be regarded as an expected finding in moderate and severe HIE and, in the overwhelming majority of cases, occurs secondary to hepatic hypoxia-ischemia in the absence of blood culture-positive sepsis. [ABSTRACT FROM AUTHOR]

After the return of spontaneous circulation (ROSC), as a result of global ischaemia due to cardiac arrest followed by reperfusion, a condition develops called post-cardiac arrest syndrome. It manifests, alongside the pathology that caused the cardiac arrest, as a systemic inflammatory response, including severe cardio-circulatory and neurological dysfunction, leading to a fatal outcome. The aim of post-resuscitation care is to reduce the consequences of circulatory arrest, reperfusion, and the inflammatory response of the body on vital organ functions. Th e basis of post-resuscitation care comprises application of therapeutic hypothermia and early coronary angiography with PCI. However, after the initial enthusiasm, the validity of applying these aggressive methods in all comatose post-cardiac arrest patients was questioned. Currently, instead of therapeutic hypothermia, a strategy of maintaining a targeted body temperature, usually 36°C, is being applied because there is no clear evidence of benefit for maintaining a lower body temperature in relation to the outcome. Additionally, patients with an obvious cardiac aetiology of cardiac arrest do not undergo early coronarography unless there is a clear indication of coronary artery occlusion. In the post-resuscitation period, the maintenance of adequate ventilation, maintaining levels of oxygen and carbon dioxide in the normal range, haemodynamic stability, control of blood glucose and electrolytes, and epileptic attack prevention are all strongly recommended measures. There is no evidence to suggest that the application of the so-called neuroprotective agents affects the outcome of cardiac arrest. [ABSTRACT FROM AUTHOR]

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of neonatal brain injury. Therapeutic hypothermia (TH) is the standard treatment for term newborns after perinatal hypoxic ischemic injury (HI). Despite this, TH does not provide complete neuroprotection. Allopurinol seems to be a good neuroprotector in several animal studies, but it has never been tested in combination with hypothermia. Clinical findings show that male infants with (HI) fare more poorly than matched females in cognitive outcomes. However, there are few studies about neuroprotection taking gender into account in the results. The aim of the present study was to evaluate the potential additive neuroprotective effect of allopurinol when administrated in association with TH in a rodent model of moderate HI. Gender differences in neuroprotection were also evaluated. Methods: P10 male and female rat pups were subjected to HI (Vannucci model) and randomized into five groups: sham intervention (Control), no treatment (HI), hypothermia (HIH), allopurinol (HIA), and dual therapy (hypothermia and allopurinol) (HIHA). To evaluate a treatment’s neuroprotective efficiency, 24 hours after the HI event caspase3 activation was measured. Damaged area and hippocampal volume were also measured 72 hours after the HI event. Negative geotaxis test was performed to evaluate early neurobehavioral reflexes. Learning and spatial memory were assessed via Morris Water Maze (MWM) test at 25 days of life. Results: Damaged area and hippocampal volume were different among treatment groups (p = 0.001). The largest tissue lesion was observed in the HI group, followed by HIA. There were no differences between control, HIH, and HIHA. When learning process was analyzed, no differences were found. Females from the HIA group had similar results to the HIH and HIHA groups. Cleaved caspase 3 expression was increased in both HI and HIA. Despite this, in females cleaved caspase-3 was only differently increased in the HI group. All treated animals present an improvement in short-term (Negative geotaxis) and long-term (WMT) functional tests. Despite this, treated females present better long-term outcome. In short-term outcome no sex differences were observed. Conclusions: Our results suggest that dual therapy confers great neuroprotection after an HI event. There were functional, histological, and molecular improvements in all treated groups. These differences were more important in females than in males. No statistically significant differences were found between HIHA and HIH; both of them present a great improvement. Our results support the idea of different regulation mechanisms and pathways of cell death, depending on gender. [ABSTRACT FROM AUTHOR]