Tadalafil in patients with chronic obstructive pulmonary disease:a randomised, double-blind, parallel-group, placebo-controlled trial

SummaryBackgroundPhosphodiesterase-5 (PDE5) inhibitors improve exercise capacity and quality of life in patients with idiopathic pulmonary arterial hypertension. However, whether such beneficial effects take place in selected populations with chronic obstructive pulmonary disease (COPD) remains uncertain. We aimed to assess the effects of tadalafil—a PDE5 inhibitor—on exercise capacity and quality of life in patients with COPD and mild pulmonary hypertension.MethodsWe did a randomised, double-blind, parallel-group, placebo-controlled trial at three centres in Scotland, UK, between Sept 1, 2010, and Sept 1, 2012. Patients with moderate to severe COPD were randomly assigned (1:1), via centralised randomisation with a computer-generated sequence and block sizes of four, to receive daily tadalafil 10 mg or placebo for 12 weeks. Patients, study investigators, outcome assessors, and those administering drugs were masked to group allocation. The primary endpoint was the mean placebo-corrected difference between the baseline and final 6 min walk distance after 12 weeks. We measured change in quality of life at baseline, 8 weeks, and 12 weeks, with standardised questionnaires. Analysis was per protocol and by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01197469.Findings120 patients were randomly assigned to receive tadalafil (n=60) or placebo (n=60), of whom 56 (93%) versus 57 (95%) completed the study. At 12 weeks the difference in 6 min walking distance between the tadalafil and placebo groups was 0·5 m (95% CI −11·6 to 12·5; p=0·937). We recorded no statistically significant changes in quality of life (between-group difference on the St George's Respiratory Questionnaire −2·64 [95% CI −6·43 to 1·15]; Research and Development version 1 short-form-36 4·08 [–1·35 to 9·52]; Minnesota Living with Heart Failure questionnaire −2·31 [–7·06 to 2·45]). 19 (32%) of 60 patients in the treatment group had dyspepsia; the severity of dyspepsia ranged from mild to severe, with four (21%) of 19 patients needing a proton-pump inhibitor. Five (8%) of 60 participants had dyspepsia in the placebo group. Headache was noted in 17 (28%) patients in the treatment group versus 5 (8%) in the placebo group, but was mild in all patients. Two (3%) patients in the treatment group had facial flushing, which resulted in one withdrawal. Other withdrawals within the tadalafil group happened after a transient ischaemic attack and two deaths (ruptured abdominal aortic aneurysm and pneumonia).InterpretationTadalafil does not improve exercise capacity or quality of life despite exerting pulmonary vasodilation.FundingChief Scientist Office for Scotland

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Role of wetlands and developed land use on dissolved organic nitrogen concentrations and DON/TDN in northeastern U.S. rivers and streams

Previous studies have shown that watersheds with significant human development (i.e., urban and agricultural land use) generally have higher concentrations and fluxes of dissolved inorganic nitrogen (DIN) in comparison to less‐developed or forested watersheds. However, the impact of watershed development on dissolved organic nitrogen (DON) concentrations in drainage waters has received little attention. We present data from 39 watersheds in Massachusetts (Ipswich River watershed) encompassing a gradient of developed land use (0%–92% urban plus agriculture) and wetland abundance (0%–32%) to assess controls on mean annual DON concentrations and DON/total dissolved nitrogen (TDN) in drainage waters. In addition, we compiled published data from 119 northeastern U.S. watersheds to evaluate broader‐scale relationships between DON, developed land use, and wetlands. The percentage of developed land is a poor predictor of DON concentrations in the Ipswich watersheds (r2 = 0.09) and the compiled dataset (r2 = 0.27). In contrast, wetland percentage explains 56% of the variability in DON concentrations in the Ipswich watersheds, and 60% when all literature data are included. Excluding watersheds with direct wastewater inputs to surface waters improves the regional relationship significantly (r2 = 0.79). The DON:TDN ratio is best explained by a multiple regression of wetland percentage and developed land use percentage for both the Ipswich watersheds (r2 = 0.73) and the compiled dataset (r2 = 0.50). Watersheds with abundant wetlands may therefore have high DON concentrations and DON:TDN ratios despite elevated anthropogenic nitrogen inputs associated with human development