Daily Respiratory Research Analysis

IMPORTANCE: Sildenafil citrate may increase uteroplacental blood flow. Its ability to reduce perinatal complications related to fetal hypoxia during labor is uncertain. OBJECTIVE: To compare the effectiveness of intrapartum maternal oral sildenafil citrate vs placebo in improving perinatal outcomes potentially related to intrapartum hypoxia in term pregnancies. DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, multicenter, investigator-initiated, placebo-controlled randomized clinical trial including 3257 women was conducted in 13 Australian hospitals from September 6, 2021, to June 28, 2024. The last date of follow-up (28-day neonatal mortality) was July 26, 2024. Women aged 18 years or older with singleton or dichorionic twin pregnancies, planning vaginal birth at term by either spontaneous labor or induction of labor, were recruited. INTERVENTIONS: Women were assigned to 50 mg oral sildenafil citrate every 8 hours up to 150 mg or equivalent placebo. MAIN OUTCOME AND MEASURES: The primary composite outcome was intrapartum stillbirth, neonatal death, Apgar score less than 4 at 5 minutes (a score of <4 at 5 minutes is indicative of severe neonatal depression at birth, with scores ranging from 0 to 10), acidosis at birth (umbilical cord artery pH <7.0), hypoxic ischemic encephalopathy, neonatal seizures, neonatal respiratory support for greater than 4 hours, neonatal unit admission for greater than 48 hours, persistent pulmonary hypertension of the newborn, or meconium aspiration syndrome. Secondary outcomes were the individual components of the primary composite and emergency cesarean delivery or instrumental birth for intrapartum fetal distress. RESULTS: A total of 3257 women were randomized to sildenafil citrate (n = 1626 women and 1634 infants) or placebo (n = 1631 women and 1641 infants). Mean (SD) maternal age and gestation at randomization were similar in both groups (31.7 [5.1] vs 31.5 [5.0] years and 39.5 [1.2] vs 39.5 [1.1] weeks, respectively). A total of 868 participants (53.4%) vs 874 participants (53.6%) were of Australia/New Zealand ethnicity and 315 participants (19.4%) vs 311 participants (19.1%) were of European ethnicity. Most participants were nulliparous (944 of 1624 [58.1%; 2 missing values] vs 966 of 1630 [59.3%; 1 missing value]). Induction of labor occurred in 1353 of 1621 women (83.5%) in the sildenafil citrate group and 1348 of 1627 women (82.9%) in the placebo group. The primary outcome occurred in 83 of 1625 women (5.1%) in the sildenafil citrate group and 84 of 1625 (5.2%) in the placebo group (relative risk, 1.02; 95% CI, 0.75-1.37). Sildenafil citrate had no significant effect on emergency cesarean delivery or instrumental vaginal birth for fetal distress (relative risk, 1.12; 95% CI, 0.98-1.29) or on any of the individual components of the primary outcome. Subgroup analyses showed no evidence of heterogeneity of treatment effect. CONCLUSIONS AND RELEVANCE: Sildenafil citrate did not result in a lower incidence of adverse perinatal outcomes potentially related to intrapartum hypoxia. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12621000231842.

BACKGROUND: Physician diagnosed COPD with normal spirometry (dnsCOPD) (sometimes labeled pre-COPD) and Preserved Ratio Impaired Spirometry (PRISm) has been studied in population-based cohorts, but not in physician diagnosed COPD (dCOPD) patients from routine clinical practice. The Swedish National Airway Register (SNAR) is a large nationwide register including data from dCOPD patients from over 1000 clinics across all regions of Sweden and is representative of the COPD care in Sweden. We aimed to identify and characterize patients with dnsCOPD, PRISm and spirometrically confirmed COPD (sCOPD) from dCOPD patients in SNAR, stratify them further according to symptoms and exacerbations risk using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) A/B/E classification, and assess differences in risk for exacerbations, cause-specific hospitalisations and mortality. METHODS: We enrolled patients aged ≥30 years with dCOPD in the SNAR from 1 January 2014 to 30 June 2022 with complete spirometry i.e., postbronchodilator values for both forced expiratory volume in 1 s (FEV FINDINGS: Of 45,653 patients with dCOPD, 5.4% had dnsCOPD, 11.4% had PRISm and 83.3% had sCOPD. Smoking history was similar between groups (ever smoker: dnsCOPD: 79% PRISm: 82% sCOPD: 86%) and inhalation therapy was common in all groups (any inhaler: 75%, 80% and 80%, triple combination: 22%, 28% and 35%). Patients with PRISm had a high prevalence of obesity (dnsCOPD: 30%, PRISm: 43%, COPD: 22%), cardiovascular disease (dnsCOPD: 39%, PRISm: 48%, COPD: 41%) and diabetes (dnsCOPD: 10%, PRISm: 17%, COPD: 9%). Baseline GOLD group B or E were highly prevalent in dnsCOPD (B: 54%, E: 11%), PRISm (B: 59%, E: 14%), as well as in COPD (B: 54%, E: 17%). DnsCOPD and PRISm patients had lower risk of exacerbations (SHR 0.69, 95%CI 0.64-0.74 and 0.85, 95%CI 0.81-0.89), respiratory hospitalisation (0.40, 95%CI 0.34-0.46 and 0.68, 95%CI 0.62-0.73), and respiratory mortality (0.22, 95%CI 0.13-0.37 and 0.60, 95%CI 0.48-0.75) compared to sCOPD. Cardiovascular mortality was lower in dnsCOPD (0.41, 95%CI 0.19-0.86), but similar in PRISm (0.73, 95%CI 0.49-1.08) compared to sCOPD. The A/B/E classification was predictive for all outcomes in dnsCOPD and PRISm. DnsCOPD and PRISm group E patients had higher risks for all outcomes than sCOPD group A or B. INTERPRETATION: DnsCOPD and PRISm are prevalent in a real-life cohort of patients with a physician diagnosis of COPD. These patients are symptomatic, might suffer from exacerbations and are commonly treated with inhaled therapy, equally to sCOPD. Patients with PRISm had a high prevalence of obesity, diabetes and cardiovascular disease. DnsCOPD and PRISm had generally lower overall risks of exacerbation or respiratory events, although PRISm patients showed similar cardiovascular risk to sCOPD. The A/B/E classification predicted future events, even in dnsCOPD and PRISm patients. FUNDING: This study is performed with support from The Swedish Heart-Lung Foundation (20200150) and the Swedish government and country council ALF grant (ALFGBG-824371).

Wildfire smoke and extreme heat events are worsening in California, but their combined health effects are not well understood. This study estimates joint effects of extreme heat and wildfire smoke on hospitalizations in California, 2011-2020. We used a case crossover design with time-stratified controls and conditional logistic regression to estimate these effects at multiplicative and additive scales. Exposures were assessed for 16 combinations of exposure lags (0-3 days) for extreme heat and wildfire influenced fine particulate matter. Among over 28 million cases of all-natural cause morbidity, the majority were adults aged 65 and older (41.4%), English speakers (85.1%), and White, non-Hispanic (49.7%), mostly residing in urban areas (97.2%). The study found roughly 8% of respiratory morbidities (95% CI, 2.4%-13.8%) were attributable to the interaction of wildfire smoke and extreme heat. Significant joint effects were also observed for cardiovascular (5.5%) and renal morbidities (6.2%). Subgroup analyses revealed stronger effects: Respiratory (19.2%, 95% CI 6.5%-32.1%) and cerebrovascular morbidities (15.7%, 95% CI 4%-27.4%) were most pronounced in Black individuals; older adults (50-64 years) showed strong effects for renal morbidities (15.4%, 95% CI -1.6%-32.6%); and cardiovascular effects were highest among females (9.8%, 95% CI 2.9%-16.7%). Effects on all-natural cause morbidity were generally null. The interaction of wildfire smoke and extreme heat within a short exposure window (4 days) increases hospitalizations; highlighting the need for joint heat and wildfire smoke interventions that target populations at greater risk.