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Background An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. Methods Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. Results Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p  = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). Conclusion In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. Impact In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Background Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. Methods We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18–22 months of corrected age. Results A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P  = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). Conclusion We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. Impact Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research Network Induced Hypothermia trial.

Study designProspective multi-center trial.ObjectivesTo characterize the complication profile associated with modest systemic hypothermia after acute cervical SCI in a prospective multi-center study.SettingFive trauma centers in the United States.MethodsWe analyzed data from a prospective, multi-center trial on the use of modest systemic hypothermia for acute cervical SCI. Patients with acute cervical SCI were assigned to receive modest systemic hypothermia (33 C) or standard of care medical treatment. Patients in the hypothermia group were cooled to 33 C and maintained at the target temperature for 48 h. Complication profile and the rate of complications within the first 6 weeks after injury were compared between the two groups. Multiple regression analysis was performed to determine risk factors for complications after injury.ResultsFifty patients (hypothermia: 27, control: 23) were analyzed for this study. Median age was significantly lower in the hypothermia arm (39 vs 59 years, p = 0.02). Respiratory complications were the most common (hypothermia: 55.6% vs control: 52.2%, p = 0.81). The rate of deep vein thrombosis was not significantly different between the two groups (hypothermia: 14.8% vs control 17.4%, p = 0.71). The rate of complications was not statistically different between the two groups.ConclusionIn this prospective multi-center controlled trial, preliminary data show that modest systemic hypothermia was not associated with increased risk of complications within the first 6 weeks after acute cervical SCI.Trial informationThe study is registered on clinicaltrials.gov NCT02991690. University of Miami IRB (Central IRB) approval No.: 20160758. Emory University IRB #IRB00093786.

Aim The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. Methods Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. Results Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95 % confidence interval 0.0392–0.0537) and 1.58 L (95 % confidence interval 1.29–1.87), respectively. Conclusions A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.

Background Accidental hypothermia is associated with high morbidity and mortality. Research on treatment strategies for accidental hypothermia is complicated by the low incidence and heterogeneous patient population. We have developed a new method for clinical trials of experimental hypothermia, to enable further studies of active rewarming. If cold ambient air is effective as a cooling method, this would mimic the most frequent clinical setting of hypothermic patients and provide a feasible cooling method for field studies. We aimed to induce mild hypothermia in healthy volunteers by exposure to cold ambient air, and tested the hypothesis that drug-induced suppression of endogenous thermoregulation would be required. Methods In a randomized, double-blind, crossover design, 15 healthy volunteers wearing wet clothes were put in a windy climate chamber set to 5 °C. Each participant completed the experimental procedure twice, once receiving active drugs (meperidine and buspirone) and once receiving placebo. The experiments were separated by a one-week wash-out period. Primary outcome was core temperature at termination, defined as 3 h of exposure or 35 °C. The between-groups difference was assessed using analysis of covariance (ANCOVA) with left censoring (Tobit model) and individual random intercept. Secondary outcomes were trajectory of core temperature and reduction of shivering. Results At termination, the active drug vs placebo group differed in temperature by 1.4 °C. With adjustment for the removal of participants reaching 35 °C, the estimated mean difference was 1.7 °C (1.4–2.0, p  < 0.001). Shivering was effectively reduced, but not completely inhibited by the drug regimen, and core temperature declined at a rate of − 0.82 °C per hour. Conclusion The novel protocol utilizing cold air as a cooling method and drug-induced suppression of endogenous thermoregulation, is effective and enables future research projects. We have provided suggestions for minor alterations. Trial registration: EudraCT ID 2023–506020-81–00.

IntroductionAccidental hypothermia (AH) can occur in mild-to-severe cases; however, its management is crucial in severe cases as it can cause ventricular fibrillation and lead to death. Among various rewarming therapies for AH, endovascular catheter rewarming has been the focus of recent studies as a minimally invasive alternative to invasive internal rewarming, such as extracorporeal membrane oxygenation (ECMO). However, no study has demonstrated the efficacy and safety of endovascular catheter rewarming therapy. This study aimed to validate the efficacy and safety of endovascular catheter rewarming for patients with AH.Methods and analysesThe intensive care with endovascular catheter rewarming in accidental severe hypothermia (ICE-CRASH II) study is a multicentre, randomised study of patients with AH. This study will include patients with AH (age ≥65 years, core temperature <30°C) with preserved circulation and a target sample size of 88. Patients with cardiac arrest (CA), those who have undergone hospital transfers, and those in whom a central venous catheter could not be accessed through the femoral vein will be excluded from the study. Patients will be assigned to either the endovascular catheter plus conventional rewarming group or the conventional rewarming group based on stratified-substitution block randomisation. Patients will be followed up for 30 days after the initiation of the intervention or until discharge. The primary outcome will be to compare the percentage of patients achieving a rewarming rate ≥1.5°C/hour between the endovascular catheter plus conventional rewarming group and the conventional rewarming group.Ethics and disseminationThis study was approved by the Hokkaido University Certified Review Board (approval number: 024-00013). Written informed consent will be obtained from all the participants or their legally acceptable representatives. The results will be disseminated through publications and presentations.Trial registration numberJapan Registry of Clinical Trials (jRCT1012240051).

ObjectiveEvaluate trends in targeted temperature management with regards to temperature selection, its effect on neurologic outcomes at discharge, and compare this with recent large randomized controlled trial outcomes.DesignRetrospective cohort study between January 2010 and December 2019.SettingSingle large tertiary academic community hospital.Patients634 adult non-traumatic patients presenting with out of hospital cardiac arrest with persistent comatose state treated with active targeted temperature management.Interventions, measurements, and Main results473 patients received hypothermia of 33 °C and were compared to 161 patients who received targeted normothermia of 36.5 °C. The primary outcome was Cerebral Performance Category (CPC) at hospital discharge, with levels 1 or 2 considered good outcomes. Mortality, ICU days, ventilator days, and overall hospital stay length were secondary outcomes.Patients receiving T33 had more favorable CPC outcomes when compared to patients receiving T36.5 (OR = 2.4 [1.3, 4.6], p = 0.006). Subgroup analysis of initial non-shockable rhythms demonstrated improved CPC scores (OR = 2.5, p = 0.04), however this was not maintained in the shockable rhythm group. T33 patients had a shorter length of stay. Mortality, ICU days, and ventilator days did not differ between the groups.ConclusionsOut of hospital cardiac arrest patients with persistent comatose state treated with hypothermia of 33 °C had improved odds of discharge with good neurologic outcomes when compared to those treated with targeted normothermia. This improvement of outcomes appears to have been driven by the improved outcomes in the patients who had presented with non-shockable rhythm.

Objective: To compare the admission temperatures, incidence of hypothermia and discharge outcomes of preterm neonates managed with Trans-warmer mattress (TWM) initiated in the delivery room (DR) and controls. Study Design: A prospective quasi-randomized controlled trial was performed between January and November 2009 on preterm neonates <32 weeks gestation. Infants in the intervention group were resuscitated and transported to neonatal intensive care unit (NICU) on a TWM, in addition to other measures recommended by the Neonatal Resuscitation Program. Result: The mean (s.d.) gestational age 28.7 (3) vs 28.7 (2.4) weeks and birth weight 1151 (407) vs 1175 (413) g) were comparable in the intervention ( n =53) and control ( n =49) groups. Temperature of the DR, maternal temperature, 5 min Apgar score, mode of delivery, cord pH and need for resuscitation were similar in both groups. Temperature of neonates in the DR (36.3 vs 36.0 °C) was also similar. Admission temperature in the NICU was significantly higher 36.2 °C (0.8) vs 35.7 °C (0.8) and incidence of hypothermia (temperatures <36 °C) lower in the intervention group (34 vs 57%, P <0.05). TWM use was not associated with any adverse effects. On logistic regression, low birth weight, lack of use of TWM and low DR temperature were independently associated with admission hypothermia. Conclusion: In this quasi-randomized controlled trial, the admission temperatures of preterm neonates on whom TWM was used were significantly higher compared to controls with a reduction in the incidence of hypothermia. A TWM initiated in the DR may be a simple efficacious method of reducing hypothermia in preterm neonates.

Advances in rewarming have improved the prognosis for patients with hypothermia, especially those with cardiac arrest treated with extracorporeal rewarming. This review covers prehospital care, transport, resuscitation fluids, and extracorporeal membrane oxygenation. Accidental hypothermia (i.e., an involuntary drop in core body temperature to <35°C [95°F]) is a condition associated with significant morbidity and mortality. 1 – 4 Each year, approximately 1500 patients in the United States have hypothermia noted on their death certificate; however, the incidence of primary and secondary hypothermia and the associated morbidity and mortality remain unknown. 5 In a single tertiary care center, 14 different rewarming methods were used to treat 84 cases of accidental hypothermia, 3 which reflects the uncertainties about treatment and the potential for complications. 3 Certain treatment approaches are available only in specialized centers, and clarification is needed regarding the . . .

Objective: Two-thirds of women globally give birth at home, yet little data are available on use of skin-to-skin care (STSC) in the community. We describe the acceptability of STSC in rural Uttar Pradesh, India, and measured maternal, newborn, and ambient temperature in the home in order to inform strategies for introduction of STSC in the community. Study design: Community-based workers in intervention clusters implemented a community mobilization and behavior change communication program that promoted birth preparedness and essential newborn care, including adoption of STSC, with pregnant mothers, their families, and key influential community members. Acceptance of STSC was assessed through in-depth interviews and focus groups, and temperature was measured during home visits on day of life 0 or 1. Results: Incidence of hypothermia (<36.5°C) was high in both low birth weight (LBW) and normal birth weight (NBW) infants (49.2%, (361/733) and 43% (418/971), respectively). Mean body temperature of newborns was lower ( P <0.01) in ambient temperatures <20°C (35.9±1.4°C, n =225) compared to ⩾20°C (36.5±0.9°C, n =1450). Among hypothermic newborns, 42% (331/787) of their mothers had a lower temperature (range −6.7 to 0.1°C, mean difference 0.4±1.2°C). Acceptance of STSC was nearly universal. No adverse events from STSC were reported. STSC was perceived to prevent newborn hypothermia, enhance mother's capability to protect her baby from evil spirits, and make the baby more content. Conclusion: STSC was highly acceptable in rural India when introduced through appropriate cultural paradigms. STSC may be of benefit for all newborns and for many mothers as well. New approaches are needed for introduction of STSC in the community compared to the hospital.