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1.
N Engl J Med ; 387(2): 148-159, 2022 07 14.
Article in English | MEDLINE | ID: covidwho-1931553

ABSTRACT

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.).


Subject(s)
Erythropoietin , Hypothermia, Induced , Hypoxia-Ischemia, Brain , Neuroprotective Agents , Administration, Intravenous , Cerebral Palsy/etiology , Double-Blind Method , Erythropoietin/administration & dosage , Erythropoietin/adverse effects , Erythropoietin/therapeutic use , Humans , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/complications , Hypoxia-Ischemia, Brain/drug therapy , Hypoxia-Ischemia, Brain/therapy , Infant , Infant, Newborn , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/adverse effects , Neuroprotective Agents/therapeutic use
2.
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
3.
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
4.
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
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