Design and rationale of the CHILL phase II trial of hypothermia and neuromuscular blockade for acute respiratory distress syndrome.

The Cooling to Help Injured Lungs (CHILL) trial is an open label, two group, parallel design multicenter, randomized phase IIB clinical trial assessing the efficacy and safety of targeted temperature management with combined external cooling and neuromuscular blockade to block shivering in patients with early moderate-severe acute respiratory distress syndrome (ARDS). This report provides the background and rationale for the clinical trial and outlines the methods using the Consolidated Standards of Reporting Trials guidelines. Key design challenges include: [1] protocolizing important co-interventions; [2] incorporation of patients with COVID-19 as the cause of ARDS; [3] inability to blind the investigators; and [4] ability to obtain timely informed consent from patients or legally authorized representatives early in the disease process. Results of the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial informed the decision to mandate sedation and neuromuscular blockade only in the group assigned to therapeutic hypothermia and proceed without this mandate in the control group assigned to a usual temperature management protocol. Previous trials conducted in National Heart, Lung, and Blood Institute ARDS Clinical Trials (ARDSNet) and Prevention and Early Treatment of Acute Lung Injury (PETAL) Networks informed ventilator management, ventilation liberation and fluid management protocols. Since ARDS due to COVID-19 is a common cause of ARDS during pandemic surges and shares many features with ARDS from other causes, patients with ARDS due to COVID-19 are included. Finally, a stepwise approach to obtaining informed consent prior to documenting critical hypoxemia was adopted to facilitate enrollment and reduce the number of candidates excluded because eligibility time window expiration.

Foetal Intrapartum Compromise at Term: Could COVID-19 Infection Be Involved? A Case Report.

The impact of the SARS-CoV-2 infection on pregnancy has been studied and many reports have been published, mainly focussing on complications and in utero transmission with neonatal consequences. Although the effects of other viruses on foetuses are well known, the impact of maternal COVID-19 during pregnancy is not completely understood. We report a case of acute foetal intrapartum hypoxia without other risk factors than maternal COVID-19 disease 2 weeks previous to birth at term. Placental histological changes suggested that the viral infection could have been the culprit for the unfavourable outcome during labour. The neonate was promptly delivered by Caesarean section. Neonatal intensive care was started, including therapeutic hypothermia. The procedure was successful, the evolution of the neonate was favourable, and she was discharged after 10 days. Follow-up at 2 months of life indicated a normal neurological development but a drop in head growth. The case raises the idea that pregnancies with even mild COVID-19 symptoms may represent the cause of neonate compromise in a low-risk pregnancy. An important follow-up in the neonatal period and infancy is required to identify and treat any subsequent conditions. Further long-term studies are necessary to identify a cause-effect relationship between COVID-19 pregnancies and the whole spectrum of neonatal and infant consequences.

'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.

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.

STEMI care 2021: Addressing the knowledge gaps.

Tremendous progress has been made in the treatment of ST-segment elevation myocardial infarction (STEMI), the most severe and time-sensitive acute coronary syndrome. Primary percutaneous coronary intervention (PCI) is the preferred method of reperfusion, which has stimulated the development of regional STEMI systems of care with standardized protocols designed to optimize care. However, challenges remain for patients with cardiogenic shock, out-of-hospital cardiac arrest, an expected delay to reperfusion (>120 min), in-hospital STEMI, and more recently, those with Covid-19 infection. Ultimately, the goal is to provide timely reperfusion with primary PCI coupled with the optimal antiplatelet and anticoagulant therapies. We review the challenges and provide insights into the remaining knowledge gaps for contemporary STEMI care.

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.

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.