Urine Output and Mortality in Patients Resuscitated from out of Hospital Cardiac Arrest.

BACKGROUND: Limited data exist regarding urine output (UO) as a prognostic marker in out-of-hospital-cardiac-arrest (OHCA) survivors undergoing targeted temperature management (TTM). METHODS: We included 247 comatose adult patients who underwent TTM after OHCA between 2007 and 2017, excluding patients with end-stage renal disease. Three groups were defined based on mean hourly UO during the first 24 h: Group 1 (<0.5 mL/kg/h, n = 73), Group 2 (0.5-1 mL/kg/h, n = 81) and Group 3 (>1 mL/kg/h, n = 93). Serum creatinine was used to classify acute kidney injury (AKI). The primary and secondary outcomes respectively were in-hospital mortality and favorable neurological outcome at hospital discharge (modified Rankin Scale [mRS]<3). RESULTS: In-hospital mortality decreased incrementally as UO increased (adjusted OR 0.9 per 0.1 mL/kg/h higher; p = 0.002). UO < 0.5 mL/kg/h was strongly associated with higher in-hospital mortality (adjusted OR 4.2 [1.6-10.8], p = 0.003) and less favorable neurological outcomes (adjusted OR 0.4 [0.2-0.8], p = 0.007). Even among patients without AKI, lower UO portended higher mortality (40% vs 15% vs 9% for UO groups 1, 2, and 3 respectively, p < 0.001). CONCLUSION: Higher UO is incrementally associated with lower in-hospital mortality and better neurological outcomes. Oliguria may be a more sensitive early prognostic marker than creatinine-based AKI after OHCA.

'Opportunity to bond and a sense of normality': Parent and staff views of cuddling babies undergoing therapeutic hypothermia in neonatal intensive care: 'CoolCuddle'.

BACKGROUND: Currently, parents whose sick babies are undergoing three days of cooling therapy for hypoxic-ischaemic encephalopathy in neonatal intensive care units (NICUs) are not permitted to cuddle their cooled babies, due to concerns of warming the baby or dislodging breathing tubes or vascular catheters. Parents want to stay and care for their cooled babies and have reported that bonding is adversely affected when they are not permitted to hold them. DESIGN AND PARTICIPANTS: Qualitative interviews with 21 parents of cooled babies in NICU (11 mothers and 10 fathers) and 10 neonatal staff (4 consultants and 6 nurses) explored their views and experiences of an intervention to enable parents to cuddle their cooled babies (CoolCuddle). Thematic analysis methods were used to develop the themes and compare them between parents and staff. RESULTS: Five themes were produced. Three themes were comparable between parents and staff: Closeness, a sense of normality and reassurance and support. An additional parent theme reflected their mixed feelings about initial participation as they were apprehensive, but felt that it was an amazing opportunity. Parents and staff described the closeness between parents and babies as important for bonding and breastfeeding. Fathers particularly appreciated the opportunity to hold and bond with their infants. Parents valued the reassurance and support received from staff, and the cuddles helped them feel more normal and more like a family at a very stressful time. In a final staff theme, they discussed the skills, number of staff and training needed to undertake CoolCuddle in NICU. CONCLUSIONS: Parents cuddling their babies during cooling therapy enhanced parent-infant bonding and family-centred care in NICU and was positively received. Adverse perinatal mental health, impaired mother-infant bonding and their effects on the establishment of breastfeeding may be ameliorated by introducing CoolCuddle. PATIENT CONTRIBUTION: Our parent advisors contributed to the interview topic guides and endorsed the themes from the analysis.

Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Outcomes of infants with hypoxic-ischemic encephalopathy during COVID-19 pandemic lockdown in Canada: a cohort study.

PURPOSE: To evaluate change in the severity of hypoxic-ischemic encephalopathy (HIE) and associated morbidities between pre- and during COVID-19 pandemic periods in Canada. METHODS: We conducted a retrospective cohort study extracting the data from level-3 NICUs participating in Canadian Neonatal Network (CNN). The primary outcome was a composite of death in the first week after birth and/or stage 3 HIE (Sarnat and Sarnat). Secondary outcomes included rate and severity of HIE among admitted neonates, overall mortality, brain injury on magnetic resonance imaging (MRI), neonates requiring resuscitation, organ dysfunction, and therapeutic hypothermia (TH) usage. We included 1591 neonates with gestational age ≥ 36 weeks with HIE during the specified periods: pandemic cohort from April 1st to December 31st of 2020; pre-pandemic cohort between April 1st and December 31st of 2017, 2018, and 2019. We calculated the odds ratio (OR) and confidence intervals (CI). RESULTS: We observed no significant difference in the primary outcome (15% vs. 16%; OR 1.08; 95%CI 0.78-1.48), mortality in the first week after birth (6% vs. 6%; OR 1.10, 95%CI 0.69-1.75), neonates requiring resuscitation, organ dysfunction, TH usage, or rate of brain injury. In the ad hoc analysis, per 1000 live births, there was an increase in the rate of infants with HIE and TH use. CONCLUSIONS: Severity of HIE, associated morbidities, and mortality were not significantly different during the pandemic lockdown compared to a pre-pandemic period in Canada. Anticipated risks and difficulties in accessing healthcare have not increased the mortality and morbidities in neonates with HIE in Canada.

Safety and tolerability of a multilineage-differentiating stress-enduring cell-based product in neonatal hypoxic-ischaemic encephalopathy with therapeutic hypothermia (SHIELD trial): a clinical trial protocol open-label, non-randomised, dose-escalation trial.

INTRODUCTION: Neonatal hypoxic-ischaemic encephalopathy (HIE) is an important illness associated with death or cerebral palsy. This study aims to assess the safety and tolerability of the allogenic human multilineage-differentiating stress-enduring cell (Muse cell)-based product (CL2020) cells in newborns with HIE. This is the first clinical trial of CL2020 cells in neonates. METHODS AND ANALYSIS: This is a single-centre, open-label, dose-escalation study enrolling up to 12 patients. Neonates with HIE who receive a course of therapeutic hypothermia therapy, which cools to a body temperature of 33°C-34°C for 72 hours, will be included in this study. A single intravenous injection of CL2020 cells will be administered between 5 and 14 days of age. Subjects in the low-dose and high-dose cohorts will receive 1.5 and 15 million cells per dose, respectively. The primary outcome is the occurrence of any adverse events within 12 weeks after administration. The main secondary outcome is the Bayley Scales of Infant and Toddler Development Third Edition score and the developmental quotient per the Kyoto Scale of Psychological Development 2001 at 78 weeks. ETHICS AND DISSEMINATION: This study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The Nagoya University Hospital Institutional Review Board (No. 312005) approved this study on 13 November 2019. The results of this study will be published in peer-reviewed journal and reported in international conferences. TRIAL REGISTRATION NUMBERS: NCT04261335, jRCT2043190112.

Effects of a Peripherally Restricted Hybrid Inhibitor of CB1 Receptors and iNOS on Alcohol Drinking Behavior and Alcohol-Induced Endotoxemia.

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.

Hypothermia versus Normothermia after Out-of-Hospital Cardiac Arrest.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

Cheap and simple, could it get even cooler? Mild hypothermia and COVID-19.

PURPOSE: The pathophysiology theories of COVID-19 attach the injury of target organs to faulty immune responses and occasionally hyper-inflammation. The damage frequently extends beyond the respiratory system, accompanying cardiovascular, renal, central nervous system, and/or coagulation derangements. Tumor necrosis factor-α (TNF-α) and interleukins (IL)-1 and - 6 suppression may improve outcomes, as experimentally shown. Targeted therapies have been proposed, but mild therapeutic hypothermia-a more multifaceted approach-could be suitable. FINDINGS: According to evidence derived from previous applications, therapeutic hypothermia diminishes the release of IL-1, IL-6, and TNF-α in serum and at the tissue level. PaCO2 is reduced and the PaO2/FiO2 ratio is increased, possibly lasting after rewarming. Cooling might mitigate both ventilator and infectious-induced lung injury, and suppress microthrombi development, enhancing V/Q mismatch. Improvements in microhemodynamics and tissue O2 diffusion, along with the ischemia-tolerance heightening of tissues, could be reached. Arrhythmia incidence diminishes. Moreover, hypothermia may address the coagulopathy, promoting normalization of both hypo- and hyper-coagulability patterns, which are apparently sustained after a return to normothermia. CONCLUSIONS: As per prior therapeutic hypothermia literature, the benefits regarding inflammatory response and organic damage might be seen. Following the safety-cornerstones of the technique, the overall infection rate and infection-related mortality are not expected to rise, and increased viral replication does not seem to be a concern. Therefore, the possibility of a low cost and widely available therapy being capable of improving COVID-19 outcomes deserves further study.

Successful use of mild therapeutic hypothermia as compassionate treatment for severe refractory hypoxemia in COVID-19.

BACKGROUND: COVID-19 is a disease associated with an intense systemic inflammation that could induce severe acute respiratory distress syndrome (ARDS), with life-threatening hypoxia and hypercapnia. We present a case where mild therapeutic hypothermia was associated with improved gas exchange, facing other therapies' unavailability due to the pandemic. CASE REPORT: A healthy 38-year-old male admitted for COVID-19 pneumonia developed extreme hypoxia (PaO2/FiO2 ratio 42 mmHg), respiratory acidosis, and hyperthermia, refractory to usual treatment (mechanical ventilation, neuromuscular blockade, and prone position), and advanced therapies were not available. Mild therapeutic hypothermia management (target 33-34 °C) was maintained for five days, with progressive gas exchange improvement, which allowed his recovery over the following weeks. He was discharged home after 68 days without significant ICU associated morbidity. CONCLUSIONS: Mild hypothermia is a widely available therapy, that given some specific characteristics of COVID-19, may be explored as adjunctive therapy for life-threatening ARDS, especially during a shortage of other rescue therapies.

Renal replacement therapy is independently associated with a lower risk of death in patients with severe acute kidney injury treated with targeted temperature management after out-of-hospital cardiac arrest.

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.

A Systematic Review and Meta-Analysis of Hypothermia in Experimental Traumatic Brain Injury: Why Have Promising Animal Studies Not Been Replicated in Pragmatic Clinical Trials?

Therapeutic hypothermia was a mainstay of severe traumatic brain injury (TBI) management for half a century. Recent trials have suggested that its effect on long-term functional outcome is neutral or negative, despite apparently promising pre-clinical data. Systematic review and meta-analysis is a useful tool to collate experimental data and investigate the basis of its conclusions. We searched three online databases to identify studies testing systemic hypothermia as monotherapy for treatment of animals subjected to a TBI. Data pertaining to TBI paradigm, animal subjects, and hypothermia management were extracted as well as those relating to risk of bias. We pooled outcome data where sufficient numbers allowed and investigated heterogeneity in neurobehavioral outcomes using multi-variate meta-regression. We identified 90 publications reporting 272 experiments testing hypothermia in animals subject to TBI. The subjects were mostly small animals, with well-established models predominating. Target temperature was comparable to clinical trial data but treatment was initiated very early. Study quality was low and there was some evidence of publication bias. Delay to treatment, comorbidity, and blinded outcome assessment appeared to predict neurobehavioral outcome on multi-variate meta-regression. Therapeutic hypothermia appears to be an efficacious treatment in experimental TBI, which differs from the clinical evidence. The pre-clinical literature showed limitations in quality and design and these both appeared to affect neurobehavioral experiment outcome. These should be acknowledged when designing and interpreting pre-clinical TBI studies in the future.