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1.
BMJ Open ; 12(4): e057073, 2022 04 26.
Article in English | MEDLINE | ID: covidwho-1854347

ABSTRACT

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.


Subject(s)
Hypothermia, Induced , Hypoxia-Ischemia, Brain , Body Temperature , Humans , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/therapy , Infant , Infant, Newborn , Protective Devices , Research
2.
Molecules ; 26(16)2021 Aug 22.
Article in English | MEDLINE | ID: covidwho-1376916

ABSTRACT

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.


Subject(s)
Alcohol Drinking/pathology , Cannabinoid Receptor Antagonists/pharmacology , Endotoxemia/pathology , Ethanol/adverse effects , Nitric Oxide Synthase Type II/antagonists & inhibitors , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Alcohol Drinking/blood , Animals , Anxiety/blood , Anxiety/complications , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/complications , Cyclohexanols/administration & dosage , Elevated Plus Maze Test , Endotoxemia/blood , Endotoxemia/complications , Endotoxins/blood , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/metabolism , Hypothermia, Induced , Mice, Inbred C57BL , Nitric Oxide Synthase Type II/metabolism , Pyrazoles/administration & dosage , Receptor, Cannabinoid, CB1/metabolism , Rimonabant/administration & dosage , Rimonabant/pharmacology , Stereoisomerism , Sulfonamides/administration & dosage
3.
N Engl J Med ; 384(24): 2283-2294, 2021 06 17.
Article in English | MEDLINE | ID: covidwho-1275997

ABSTRACT

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.).


Subject(s)
Fever/therapy , Hypothermia, Induced , Out-of-Hospital Cardiac Arrest/therapy , Aged , Body Temperature , Cardiopulmonary Resuscitation/methods , Coma/etiology , Coma/therapy , Female , Fever/etiology , Humans , Hypothermia, Induced/adverse effects , Kaplan-Meier Estimate , Male , Middle Aged , Out-of-Hospital Cardiac Arrest/complications , Out-of-Hospital Cardiac Arrest/mortality , Single-Blind Method , Treatment Outcome
4.
J Crit Care ; 63: 264-268, 2021 06.
Article in English | MEDLINE | ID: covidwho-1060792

ABSTRACT

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.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , Hypothermia, Induced/methods , SARS-CoV-2 , COVID-19/blood , COVID-19/virology , Humans , Interleukin-1/blood , Interleukin-6/blood , Tumor Necrosis Factor-alpha/blood
5.
J Crit Care ; 63: 260-263, 2021 06.
Article in English | MEDLINE | ID: covidwho-1046331

ABSTRACT

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.


Subject(s)
COVID-19/complications , Hypothermia, Induced/methods , Hypoxia/etiology , Hypoxia/therapy , Pandemics , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/therapy , SARS-CoV-2 , Severity of Illness Index , Adult , COVID-19/virology , Humans , Male , Patient Positioning , Prone Position , Respiration, Artificial , Treatment Outcome
7.
Crit Care ; 24(1): 115, 2020 03 23.
Article in English | MEDLINE | ID: covidwho-823719

ABSTRACT

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.


Subject(s)
Acute Kidney Injury/mortality , Acute Kidney Injury/therapy , Hypothermia, Induced , Out-of-Hospital Cardiac Arrest/mortality , Out-of-Hospital Cardiac Arrest/therapy , Renal Replacement Therapy/adverse effects , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Republic of Korea/epidemiology , Retrospective Studies , Risk Factors
9.
Ther Hypothermia Temp Manag ; 10(3): 130, 2020 09.
Article in English | MEDLINE | ID: covidwho-695565
10.
J Neurotrauma ; 37(19): 2057-2068, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-245006

ABSTRACT

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.


Subject(s)
Brain Injuries, Traumatic/therapy , Hypothermia, Induced , Animals , Brain Injuries, Traumatic/diagnosis , Brain Injuries, Traumatic/etiology , Disease Models, Animal , Humans , Outcome Assessment, Health Care , Pragmatic Clinical Trials as Topic
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