Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Caesarean delivery and subsequent stillbirth or miscarriage: systematic review and meta-analysis

Contains fulltext : 118096.pdf (publisher's version ) (Open Access)OBJECTIVE: To compare the risk of stillbirth and miscarriage in a subsequent pregnancy in women with a previous caesarean or vaginal delivery. DESIGN: Systematic review of the published literature including seven databases: CINAHL; the Cochrane library; Embase; Medline; PubMed; SCOPUS and Web of Knowledge from 1945 until November 11(th) 2011, using a detailed search-strategy and cross-checking of reference lists. STUDY SELECTION: Cohort, case-control and cross-sectional studies examining the association between previous caesarean section and subsequent stillbirth or miscarriage risk. Two assessors screened titles to identify eligible studies, using a standardised data abstraction form and assessed study quality. DATA SYNTHESIS: 11 articles were included for stillbirth, totalling 1,961,829 pregnancies and 7,308 events. Eight eligible articles were included for miscarriage, totalling 147,017 pregnancies and 12,682 events. Pooled estimates across the stillbirth studies were obtained using random-effect models. Among women with a previous caesarean an increase in odds of 1.23 [95% CI 1.08, 1.40] for stillbirth was yielded. Subgroup analyses including unexplained stillbirths yielded an OR of 1.47 [95% CI 1.20, 1.80], an OR of 2.11 [95% CI 1.16, 3.84] for explained stillbirths and an OR of 1.27 [95% CI 0.95, 1.70] for antepartum stillbirths. Only one study reported adjusted estimates in the miscarriage review, therefore results are presented individually. CONCLUSIONS: Given the recent revision of the National Institute for Health and Clinical Excellence guidelines (NICE), providing women the right to request a caesarean, it is essential to establish whether mode of delivery has an association with subsequent risk of stillbirth or miscarriage. Overall, compared to vaginal delivery, the pooled estimates suggest that caesarean delivery may increase the risk of stillbirth by 23%. Results for the miscarriage review were inconsistent and lack of adjustment for confounding was a major limitation. Higher methodological quality research is required to reliably assess the risk of miscarriage in subsequent pregnancies

Neonatal outcomes following elective caesarean delivery at term: a hospital-based cohort study

<div><p></p><p><i>Objective</i>: To assess neonatal outcomes following elective caesarean delivery (CD) at term (≥37 + 0 weeks gestation).</p><p><i>Methods</i>: A retrospective cohort study was conducted in a single Irish maternity hospital. Elective CDs at term between August 2008 and July 2012 were reviewed. Outcome measures were admission to the neonatal intensive care unit (NICU), length of stay, respiratory complications, hypoglycaemia, jaundice, newborn sepsis and medical interventions.</p><p><i>Results</i>: A total of 4242 women had an elective CD at term, accounting for approximately 15% of all term deliveries. Admission rate to the NICU at 37 weeks gestation was 21.8% versus 10% at 39 weeks (<i>p</i> for trend <0.0001). Similar trends of decreasing risk with later gestational age were noted for the other outcomes. An increased odds of admission to the NICU at 37 weeks [adjusted odds ratio (OR) 2.48 (95% CI 1.28, 4.79)] and at 38 weeks [OR 1.34, 95% CI 1.02, 1.77] compared to the reference of 39 weeks gestation was found.</p><p><i>Conclusions</i>: This study supports evidence that, with regard to neonatal outcome, 39 weeks gestational age is the optimal delivery time. Heightened awareness of the increased risk of neonatal morbidity, when delivery is performed electively before 39 weeks, is warranted among healthcare workers.</p></div

Commentary: is a change from the National Early Warning System (NEWS) warranted in patients with chronic respiratory conditions?

Early warning systems (EWS) were introduced in hospital systems in a number of countries including the UK (NEWS-1 and NEWS-2 UK) and Ireland (NEWS now INEWS V2) with the aim of identifying patients with acute physiological deterioration in a timely manner in order to prevent or reduce cardiopulmonary arrest, admission to the intensive care unit and premature death . Both NEWS-1 and NEWS-2 UK and INEWS are based on the ViEWS VitalPac EWS. However, INEWS uses precisely the same parameter ranges and scoring system as ViEWS while some minor modifications were made in NEWS-1 and NEWS-2 UK. These modifications included NEWS-2 UK introduced a second SpO2 scoring system for use in patients with hypercapnic respiratory failure who had a prescribed oxygen saturation requirement of 88 − 92%. The existing SpO2 scoring system (SpO2 scale 1) used in both NEWS-1 and NEWS-2 UK applies to the majority of patients. The new dedicated SpO2 scoring system (SpO2 scale 2) in NEWS-2 UK is used for patients with confirmed hypercapnic respiratory failure with the NEWS-2 UK scoring system adjusted accordingly. Previous reports have voiced concern that the SpO2 scoring system within the NEWS-1 UK and the Irish NEWS is not suitable for specific patient sub-populations, in particular those with chronic respiratory conditions including chronic obstructive pulmonary disorder (COPD). Some of these patients have a lived baseline of lower oxygen saturation levels, usually between 88 to 92% SpO2. An SpO2 below 95% triggers an alert within NEWS. This can result in excessive triggering and false alarms in this high risk sub-population of chronic respiratory patients as well as the potential for the inappropriate use of high levels of supplemental oxygen in hypercapnic patients. As part of the update to the Irish National Early Warning System (INEWS) National Clinical Guideline No.1 [see INEWS Guideline Version 2], the authors undertook a systematic review of the evidence comparing the NEWS-1 UK to modified EWSs (EWSs in which parameters are adjusted) in sub-populations of patients with chronic respiratory conditions including chronic hypoxia, chronic hypoxaemia, chronic physiological abnormalities, pulmonary fibrosis or COPD. The effectiveness of the modified EWSs in predicting mortality in this sub-population was compared to the NEWS-1 UK only.</p

The confounding effect of smoking on the association between maternal age and adverse pregnancy outcome.

<p>^aAdjusted for , parity, maternal BMI, social deprivation score and ethnicity; Highlighted estimates indicate a significant interaction test with p<0.05. <b>VSGA</b> (Very small-for-gestational age, <5^th percentile); <b>VLGA</b> (Very-large-for-gestational age, >95^th percentile).</p

Relative risks of pregnancy outcome and maternal age according to social deprivation group.

<p>^aAdjusted for , parity, maternal BMI, parity and ethnicity; Highlighted estimates indicate a significant interaction test with p<0.05. <b>VSGA</b> (Very small-for-gestational age, <5^th percentile); <b>VLGA</b> (Very-large-for-gestational age, >95^th percentile).</p

Crude and adjusted relative risks of the association between maternal age and adverse pregnancy outcome.

<p>^aAdjusted for , parity, maternal BMI, social deprivation score and ethnic origin;</p>b<p>model based on 2007–2008 data only. <b>ESGA</b> (Extremely small-for-gestational age, <3^rd percentile); <b>VSGA</b> (Very small-for-gestational age, <5^th percentile); <b>SGA</b> (Small-for-gestational age, <10^th percentile); <b>LGA</b> (Large-for-gestational age, >90^th percentile); <b>VLGA</b> (Very-large-for-gestational age, >95^th percentile); <b>ELGA</b> (Extremely-large-for-gestational-age, >97^th percentile).</p

Relative risks of pregnancy outcome and maternal age according to parity.

<p>^aAdjusted for , parity, maternal BMI, social deprivation score and ethnicity; Highlighted estimates indicate a significant interaction test with p<0.05. <b>VSGA</b> (Very small-for-gestational age, <5^th percentile); <b>VLGA</b> (Very-large-for-gestational age, >95^th percentile).</p

Maternal characteristics and pregnancy outcome in relation to maternal age.

<p>Data refers to <b>N (%).</b><b>*Birth weight</b><b>ESGA</b> (Extremely small-for-gestational age, <3^rd percentile); <b>VSGA</b> (Very small-for-gestational age, <5^th percentile); <b>SGA</b> (Small-for-gestational age, <10^th percentile); <b>LGA</b> (Large-for-gestational age, >90^th percentile); <b>VLGA</b> (Very-large-for-gestational age, >95^th percentile); <b>ELGA</b> (Extremely-large-for-gestational-age, >97^th percentile).</p

Number of births, inclusions and exclusions during the study period.

<p>Number of births, inclusions and exclusions during the study period.</p