2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia.

RATIONALE: New evidence is available examining the use of corticosteroids in sepsis, acute respiratory distress syndrome (ARDS) and community-acquired pneumonia (CAP), warranting a focused update of the 2017 guideline on critical illness-related corticosteroid insufficiency. OBJECTIVES: To develop evidence-based recommendations for use of corticosteroids in hospitalized adults and children with sepsis, ARDS, and CAP. PANEL DESIGN: The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting. METHODS: After development of five focused Population, Intervention, Control, and Outcomes (PICO) questions, we conducted systematic reviews to identify the best available evidence addressing each question. We evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach and formulated recommendations using the evidence-to-decision framework. RESULTS: In response to the five PICOs, the panel issued four recommendations addressing the use of corticosteroids in patients with sepsis, ARDS, and CAP. These included a conditional recommendation to administer corticosteroids for patients with septic shock and critically ill patients with ARDS and a strong recommendation for use in hospitalized patients with severe CAP. The panel also recommended against high dose/short duration administration of corticosteroids for septic shock. In response to the final PICO regarding type of corticosteroid molecule in ARDS, the panel was unable to provide specific recommendations addressing corticosteroid molecule, dose, and duration of therapy, based on currently available evidence. CONCLUSIONS: The panel provided updated recommendations based on current evidence to inform clinicians, patients, and other stakeholders on the use of corticosteroids for sepsis, ARDS, and CAP.

Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support.

BACKGROUND: An estimated one-quarter to one-half of people diagnosed with haematological malignancies experience anaemia. There are different strategies for red blood cell (RBC) transfusions to treat anaemia. A restrictive transfusion strategy permits a lower haemoglobin (Hb) level whereas a liberal transfusion strategy aims to maintain a higher Hb. The most effective and safest strategy is unknown. OBJECTIVES: To determine the efficacy and safety of restrictive versus liberal RBC transfusion strategies for people diagnosed with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without a haematopoietic stem cell transplant (HSCT). SEARCH METHODS: We searched for randomised controlled trials (RCTs) and non-randomised studies (NRS) in MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1982), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2023, Issue 2), and eight other databases (including three trial registries) to 21 March 2023. We also searched grey literature and contacted experts in transfusion for additional trials. There were no language, date or publication status restrictions. SELECTION CRITERIA: We included RCTs and prospective NRS that evaluated restrictive versus liberal RBC transfusion strategies in children or adults with malignant haematological disorders receiving intensive chemotherapy or radiotherapy, or both, with or without HSCT. DATA COLLECTION AND ANALYSIS: Two authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed the risk of bias. Any disagreement was discussed and resolved with a third review author. Dichotomous outcomes were presented as a risk ratio (RR) with a 95% confidence interval (CI). Narrative syntheses were used for heterogeneous outcome measures. Review Manager Web was used to meta-analyse the data. Main outcomes of interest included: all-cause mortality at 31 to 100 days, quality of life, number of participants with any bleeding, number of participants with clinically significant bleeding, serious infections, length of hospital admission (days) and hospital readmission at 0 to 3 months. The certainty of the evidence was assessed using GRADE. MAIN RESULTS: Nine studies met eligibility; eight RCTs and one NRS. Six hundred and forty-four participants were included from six completed RCTs (n = 560) and one completed NRS (n = 84), with two ongoing RCTs consisting of 294 participants (260 adult and 34 paediatric) pending inclusion. Only one completed RCT included children receiving HSCT (n = 6); the other five RCTs only included adults: 239 with acute leukaemia receiving chemotherapy and 315 receiving HSCT (166 allogeneic and 149 autologous). The transfusion threshold ranged from 70 g/L to 80 g/L for restrictive and from 80 g/L to 120 g/L for liberal strategies. Effects were reported in the summary of findings tables only for the trials that included adults to reduce indirectness due to the limited evidence contributed by the prematurely terminated paediatric trial. Evidence from RCTs Overall, there may be little to no difference in the number of participants who die within 31 to 100 days using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 451 participants; RR 1.00, 95% CI 0.27 to 3.70, P=0.99; very low-certainty evidence). There may be little to no difference in quality of life at 0 to 3 months using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 431 participants; analysis unable to be completed due to heterogeneity; very low-certainty evidence). There may be little to no difference in the number of participants who suffer from any bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies; 448 participants; RR 0.91, 95% CI 0.78 to 1.06, P = 0.22; low-certainty evidence). There may be little to no difference in the number of participants who suffer from clinically significant bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (four studies; 511 participants; RR: 0.94, 95% CI 0.74 to 1.19, P = 0.60; low-certainty evidence). There may be little to no difference in the number of participants who experience serious infections at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies, 451 participants; RR: 1.20, 95% CI 0.93 to 1.55, P = 0.17; low-certainty evidence). A restrictive transfusion strategy likely results in little to no difference in the length of hospital admission at 0 to 3 months compared to a liberal strategy (two studies; 388 participants; analysis unable to be completed due to heterogeneity in reporting; moderate-certainty evidence). There may be little to no difference between hospital readmission using a restrictive transfusion strategy compared to a liberal transfusion strategy (one study, 299 participants; RR: 0.89, 95% CI 0.52 to 1.50; P = 0.65; low-certainty evidence). Evidence from NRS The evidence is very uncertain whether a restrictive RBC transfusion strategy: reduces the risk of death within 100 days (one study, 84 participants, restrictive 1 death; liberal 1 death; very low-certainty evidence); or decreases the risk of clinically significant bleeding (one study, 84 participants, restrictive 3; liberal 8; very low-certainty evidence). No NRS reported on the other eligible outcomes. AUTHORS' CONCLUSIONS: Findings from this review were based on seven studies and 644 participants. Definite conclusions are challenging given the relatively few included studies, low number of included participants, heterogeneity of intervention and outcome reporting, and overall certainty of evidence. To increase the certainty of the true effect of a restrictive RBC transfusion strategy on clinical outcomes, there is a need for rigorously designed and executed studies. The evidence is largely based on two populations: adults with acute leukaemia receiving intensive chemotherapy and adults with haematologic malignancy requiring HSCT. Despite the addition of 405 participants from three RCTs to the previous review's results, there is still insufficient evidence to answer this review's primary outcome. If we assume a mortality rate of 3% within 100 days, we would need a total of 1492 participants to have an 80% chance of detecting, at a 5% level of significance, an increase in all-cause mortality from 3% to 6%. Further RCTs are needed overall, particularly in children.

Dexamethasone doses in patients with COVID-19 and hypoxia: A systematic review and meta-analysis.

BACKGROUND: The optimal dose of dexamethasone for severe/critical COVID-19 is uncertain. We compared higher versus standard doses of dexamethasone in adults with COVID-19 and hypoxia. METHODS: We searched PubMed and trial registers until 23 June 2023 for randomised clinical trials comparing higher (>6 mg) versus standard doses (6 mg) of dexamethasone in adults with COVID-19 and hypoxia. The primary outcome was mortality at 1 month. Secondary outcomes were mortality closest to 90 days; days alive without life support; and the occurrence of serious adverse events/reactions (SAEs/SARs) closest to 1 month. We assessed the risk of bias using the Cochrane RoB2 tool, risk of random errors using trial sequential analysis, and certainty of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included eight trials (2478 participants), of which four (1293 participants) had low risk of bias. Higher doses of dexamethasone probably resulted in little to no difference in mortality at 1 month (relative risk [RR] 0.97, 95% CI: 0.79-1.19), mortality closest to Day 90 (RR 1.01, 95% CI: 0.86-1.20), and SAEs/SARs (RR 1.00, 95% CI: 0.97-1.02). Higher doses of dexamethasone probably increased the number of days alive without invasive mechanical ventilation and circulatory support but had no effect on days alive without renal replacement therapy. CONCLUSIONS: Based on low to moderate certainty evidence, higher versus standard doses of dexamethasone probably result in little to no difference in mortality, SAEs/SARs, and days alive without renal replacement therapy, but probably increase the number of days alive without invasive mechanical ventilation and circulatory support.

Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea : A Systematic Review and Network Meta-analysis.

BACKGROUND: Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. PURPOSE: To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. DATA SOURCES: MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. STUDY SELECTION: Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. DATA EXTRACTION: Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. DATA SYNTHESIS: Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. LIMITATIONS: There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. CONCLUSION: Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol. PRIMARY FUNDING SOURCE: None.

Anti-epithelial-derived cytokines for severe asthma: Systematic review and meta-analysis.

BACKGROUND: Therapies directed against epithelial-derived cytokines, often referred to as alarmins, have been studied in large randomized trials, and reports suggest possible benefit for non-type 2 as well as type 2 severe asthma. METHODS: We performed a systematic review of Medline, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process, and Web of Science databases from inception to March 2022. We performed a random-effects pairwise meta-analysis of randomized controlled trials addressing antialarmin therapy in severe asthma. Results use relative risk (RR) values and 95% confidence intervals (CIs). For continuous outcomes, we report mean difference (MD) values and 95% CIs. We define high eosinophils as ≥300 cells/µL and low eosinophils as <300 cells/µL. We used Cochrane-endorsed RoB 2.0 software to assess the risk of bias of trials, and we used the Grades of Recommendation Assessment, Development, and Evaluation (aka GRADE) framework to assess the certainty of the evidence. RESULTS: We identified 12 randomized trials including 2391 patients. Antialarmins probably reduce annualized exacerbation rates in patients with high eosinophils (RR 0.33 [95% CI 0.28 to 0.38]; moderate certainty). Antialarmins may reduce this rate in patients with low eosinophils (RR 0.59 [95% CI 0.38 to 0.90]; low certainty). Antialarmins improve FEV1 in patients with high eosinophils (MD 218.5 mL [95% CI 160.2 to 276.7]; high certainty). Antialarmin therapy probably does not improve FEV1 in patients with low eosinophils (MD 68.8 mL [95% CI 22.4 to 115.2]; moderate certainty). Antialarmins reduce blood eosinophils, total IgE, and fractional excretion of nitric oxide across studied subjects. CONCLUSION: Antialarmins are effective at improving lung function and probably reduce exacerbations in patients with severe asthma and blood eosinophils ≥300 cells/µL. The effect on patients with lower eosinophils is less certain.

Impact of Allocation Concealment and Blinding in Trials Addressing Treatments for COVID-19: A Methods Study.

We aimed to assess the impact of allocation concealment and blinding on the results of coronavirus disease 2019 (COVID-19) trials, using the World Health Organization COVID-19 database (to February 2022). We identified 488 randomized trials comparing drug therapeutics with placebo or standard care in patients with COVID-19. We performed random-effects meta-regressions comparing the results of trials with and without allocation concealment and blinding of health-care providers and patients. We found that, compared with trials with allocation concealment, trials without allocation concealment may estimate treatments to be more beneficial for mortality, mechanical ventilation, hospital admission, duration of hospitalization, and duration of mechanical ventilation, but results were imprecise. We did not find compelling evidence that, compared with trials with blinding, trials without blinding produce consistently different results for mortality, mechanical ventilation, and duration of hospitalization. We found that trials without blinding may estimate treatments to be more beneficial for hospitalizations and duration of mechanical ventilation. We did not find compelling evidence that COVID-19 trials in which health-care providers and patients are blinded produce different results from trials without blinding, but trials without allocation concealment estimate treatments to be more beneficial compared with trials with allocation concealment. Our study suggests that lack of blinding may not always bias results but that evidence users should remain skeptical of trials without allocation concealment.

Corticosteroids in Community-Acquired Bacterial Pneumonia: a Systematic Review, Pairwise and Dose-Response Meta-Analysis.

INTRODUCTION: International guidelines provide heterogenous guidance on use of corticosteroids for community-acquired pneumonia (CAP). METHODS: We performed a systematic review of randomized controlled trials examining corticosteroids in hospitalized adult patients with suspected or probable CAP. We performed a pairwise and dose-response meta-analysis using the restricted maximum likelihood (REML) heterogeneity estimator. We assessed the certainty of the evidence using GRADE methodology and the credibility of subgroups using the ICEMAN tool. RESULTS: We identified 18 eligible studies that included 4661 patients. Corticosteroids probably reduce mortality in more severe CAP (RR 0.62 [95% CI 0.45 to 0.85]; moderate certainty) with possibly no effect in less severe CAP (RR 1.08 [95% CI 0.83 to 1.42]; low certainty). We found a non-linear dose-response relationship between corticosteroids and mortality, suggesting an optimal dose of approximately 6 mg of dexamethasone (or equivalent) for a duration of therapy of 7 days (RR 0.44 [95% 0.30 to 0.66]). Corticosteroids probably reduce the risk of requiring invasive mechanical ventilation (RR 0.56 [95% CI 0.42 to 74] and probably reduce intensive care unit (ICU) admission (RR 0.65 [95% CI 0.43 to 0.97]) (both moderate certainty). Corticosteroids may reduce the duration of hospitalization and ICU stay (both low certainty). Corticosteroids may increase the risk of hyperglycemia (RR 1.76 [95% CI 1.46 to 2.14]) (low certainty). CONCLUSION: Moderate certainty evidence indicates that corticosteroids reduce mortality in patients with more severe CAP, the need for invasive mechanical ventilation, and ICU admission.

A comparison of the effectiveness of biologic therapies for asthma: A systematic review and network meta-analysis.

BACKGROUND: Trials have not directly compared biologics for the treatment of asthma. OBJECTIVE: To compare the relative efficacy of biologics in asthma. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov from inception to May 31, 2022 for randomized trials addressing biologic therapies for asthma. Reviewers worked independently and in duplicate to screen references, extract data, and assess risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations approach. We present dichotomous outcomes as absolute risk differences per 1000 patients and relative risk with 95% confidence intervals (95% CI) and continuous outcomes as mean difference (MD) and 95% CI. RESULTS: We identified 64 trials, including 26,630 patients. For patients with eosinophilic asthma, tezepelumab (329 fewer exacerbations per 1000 [95% CI, 272.6-366.6 fewer]) and dupilumab (319.6 fewer exacerbations per 1000 [95% CI, 272.6-357.2 fewer]) reduce exacerbations compared with placebo (high certainty). Tezepelumab (MD, 0.24 L [95% CI, 0.16-0.32]) and dupilumab (0.25 L [95% CI, 0.21-0.29]) improve lung function compared with placebo (high certainty). Both tezepelumab (110.97 fewer hospital admissions per 1000 [95% CI, 94.53-120.56 fewer]) and dupilumab (97.27 fewer hospitalizations [4.11-124.67 fewer]) probably reduce hospital admissions compared with placebo (moderate certainty). For patients with low eosinophils, biologics probably do not improve asthma outcomes. For these patients, tezepelumab (MD, 0.1 L [95% CI, 0-0.19]) and dupilumab (MD, 0.1 L [95% CI, 0-0.20]) may improve lung function (low certainty). CONCLUSION: Tezepelumab and dupilumab are effective at reducing exacerbations. For patients with low eosinophils, however, clinicians should probably be more judicious in using biologics, including tezepelumab, because they probably do not confer substantial benefit.

Intraoperative use of balanced crystalloids versus 0.9% saline: a systematic review and meta-analysis of randomised controlled studies.

BACKGROUND: The evidence regarding optimal crystalloid use in the perioperative period remains unclear. As the primary aim of this study, we sought to summarise the data from RCTs examining whether use of balanced crystalloids compared with 0.9% saline (saline) leads to differences in patient-important outcomes. METHODS: We searched Ovid MEDLINE, Embase, the Cochrane library, and Clinicaltrials.gov, from inception until December 15, 2022, and included RCTs that intraoperatively randomised adult participants to receive either balanced fluids or saline. We pooled data using a random-effects model and present risk ratios (RRs) or mean differences (MDs), along with 95% confidence intervals (CIs). We assessed individual study risk of bias using the modified Cochrane tool, and certainty of evidence using GRADE. RESULTS: Of 5959 citations, we included 38 RCTs (n=3776 patients). Pooled analysis showed that intraoperative use of balanced fluids compared with saline had an uncertain effect on postoperative mortality analysed at the longest point of follow-up (RR 1.51, 95% CI: 0.42-5.36) and postoperative need for renal replacement therapy (RR 0.95, 95% CI: 0.56-1.59), both very low certainty. Furthermore, use of balanced crystalloids probably leads to a higher postoperative serum pH (MD 0.05, 95% CI: 0.04-0.06), moderate certainty. CONCLUSIONS: Use of balanced crystalloids, compared with saline, in the perioperative setting has an uncertain effect on mortality and need for renal replacement therapy but probably improves postoperative acid-base status. Further research is needed to determine whether balanced crystalloid use affects patient-important outcomes. CLINICAL TRIAL REGISTRATION: CRD42022367593.

Medical treatments for idiopathic pulmonary fibrosis: a systematic review and network meta-analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a respiratory disorder with a poor prognosis. Our objective is to assess the comparative effectiveness of 22 approved or studied IPF drug treatments. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov from inception to 2 April 2021. We included randomised controlled trials (RCTs) for adult patients with IPF receiving one or more of 22 drug treatments. Pairs of reviewers independently identified randomised trials that compared one or more of the target medical treatments in patients with IPF. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach for network meta-analysis. We calculated pooled relative risk (RR) ratios and presented direct or network estimates with 95% credibility intervals (95% CI), within the GRADE framework. RESULTS: We identified 48 (10 326 patients) eligible studies for analysis. Nintedanib [RR 0.69 (0.44 to 1.1), pirfenidone [RR 0.63 (0.37 to 1.09); direct estimate), and sildenafil [RR (0.44 (0.16 to 1.09)] probably reduce mortality (all moderate certainty). Nintedanib (2.92% (1.51 to 4.14)), nintedanib+sildenafil (157 mL (-88.35 to 411.12)), pirfenidone (2.47% (-0.1 to 5)), pamrevlumab (4.3% (0.5 to 8.1)) and pentraxin (2.74% (1 to 4.83)) probably reduce decline of overall forced vital capacity (all moderate certainty). Only sildenafil probably reduces acute exacerbation and hospitalisations (moderate certainty). Corticosteroids+azathioprine+N-acetylcysteine increased risk of serious adverse events versus placebo (high certainty). CONCLUSION AND RELEVANCE: Future guidelines should consider sildenafil for IPF and further research needs to be done on promising IPF treatments such as pamrevlumab and pentraxin as phase 3 trials are completed.

The Comparative Effectiveness of Vasoactive Treatments for Hepatorenal Syndrome: A Systematic Review and Network Meta-Analysis.

OBJECTIVE: Hepatorenal syndrome (HRS) is associated with high rates of morbidity and mortality. Evidence examining commonly used drug treatments remains uncertain. We assessed the comparative effectiveness of inpatient treatments for HRS by performing a network meta-analysis of randomized clinical trials (RCTs). DATA SOURCES: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Medline In-Process & Other Non-Indexed Citations, Scopus, and Web of Science from inception. STUDY SELECTION AND DATA EXTRACTION: Pairs of reviewers independently identified eligible RCTs that enrolled patients with type 1 or 2 HRS. Pairs of reviewers independently extracted data. DATA SYNTHESIS: We assessed risk of bias using the Cochrane tool for RCTs and certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations approach. Our main outcomes are all-cause mortality, HRS reversal, and serious adverse events. Of 3,079 citations, we included 26 RCTs examining 1,736 patients. Based on pooled analysis, terlipressin increases HRS reversal compared with placebo (142 reversals per 1,000 [95% CI, >87.7 to >210.9]; high certainty). Norepinephrine (112.7 reversals per 1,000 [95% CI, 52.6 to >192.3]) may increase HRS reversal compared with placebo (low certainty). The effect of midodrine+octreotide (67.8 reversals per 1,000 [95% CI, <2.8 to >177.4]; very low) on HRS reversal is uncertain. Terlipressin may reduce mortality compared with placebo (93.7 fewer deaths [95% CI, 168.7 to <12.5]; low certainty). Terlipressin probably increases the risk of serious adverse events compared with placebo (20.4 more events per 1,000 [95% CI, <5.1 to >51]; moderate certainty). CONCLUSIONS: Terlipressin increases HRS reversal compared with placebo. Terlipressin may reduce mortality. Until access to terlipressin improves, initial norepinephrine administration may be more appropriate than initial trial with midodrine+octreotide. Our review has the potential to inform future guideline and practice in the treatment of HRS.

Sildenafil for idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

BACKGROUND: Patients with idiopathic pulmonary fibrosis have a poor overall prognosis and there are few evidence-based drug therapies that reduce mortality. OBJECTIVE: We aimed to perform a systematic review and meta-analysis to assess whether sildenafil reduces mortality, disease progression and adverse side effects. METHODS: We reviewed randomized controlled studies (RCTs) from MEDLINE, Cochrane registry of clinical trials, and EMBASE. Our outcomes of interest included mortality, change in FVC, acute exacerbations and hospitalizations and adverse drug effects leading to discontinuation. We used an inverse variance fixed effects meta-analysis method to calculate pooled relative risk (RR) and mean difference (MD). RESULTS: A total of 4 studies were included in the systematic review. Sildenafil probably reduces mortality when compared to placebo or to standard care, [RR 0.73 (95% CI 0.51 to 1.04); moderate certainty]. Pooled estimates showed sildenafil may not alter the rate of change of FVC [MD 0.61% (95% CI -0.29 to 1.52)], or DLCO [MD 0.97% (95% CI 0.04 to 1.90)] (both low certainty). Pooled estimated showed sildenafil may not reduce the number of hospitalizations or acute exacerbations, [RR 1.10 (95% CI 0.61 to 1.98); low certainty]. There is probably no difference in drug discontinuation due to adverse effects when comparing sildenafil to the control group, [RR 0.79 (95% CI 0.56, 1.10); moderate certainty]. CONCLUSION: Sildenafil probably reduces all-cause mortality in IPF patients. More studies need to be done to confirm the magnitude and reliability of the point estimate.

Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis.

BACKGROUND: Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear. METHODS: We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir-ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir-ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty). INTERPRETATION: Molnupiravir and nirmatrelvir-ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir-ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.

Inhaled corticosteroids, COPD, and the incidence of lung cancer: a systematic review and dose response meta-analysis.

BACKGROUND: There has been debate on whether inhaled corticosteroids (ICS) reduce the incidence of lung cancer amongst patients with Chronic Obstructive Lung Disease (COPD). We aimed to perform a systematic review and dose-response meta-analysis on available observational data. METHODS: We performed both a dose response and high versus low random effects meta-analysis on observational studies measuring whether lung cancer incidence was lower in patients using ICS with COPD. We report relative risk (RR) with 95% confidence intervals (CI), as well as risk difference. We use the GRADE framework to report our results. RESULTS: Our dose-response suggested a reduction in the incidence of lung cancer for every 500 ug/day of fluticasone equivalent ICS (RR 0.82 [95% 0.68-0.95]). Using a baseline risk of 7.2%, we calculated risk difference of 14 fewer cases per 1000 ([95% CI 24.7-3.8 fewer]). Similarly, our results suggested that for every 1000 ug/day of fluticasone equivalent ICS, there was a larger reduction in incidence of lung cancer (RR 0.68 [0.44-0.93]), with a risk difference of 24.7 fewer cases per 1000 ([95% CI 43.2-5.4 fewer]). The certainty of the evidence was low to very low, due to risk of bias and inconsistency. CONCLUSION: There may be a reduction in the incidence for lung cancer in COPD patients who use ICS. However, the quality of the evidence is low to very low, therefore, we are limited in making strong claims about the true effect of ICS on lung cancer incidence.

The influence of income on medical school admissions in Canada: a retrospective cohort study.

BACKGROUND: The socioeconomic status of applicants to Canadian medical schools has been understudied in the past two decades. Institutional efforts have been made to address the lack of socioeconomic diversity across Canada during this time. We investigated the income characteristics of medical school applicants, as well as the relationship between applicant income and offer of admission, to characterize the current state of socioeconomic diversity in medical admissions. METHODS: We conducted a retrospective cohort study on 26,120 applicants at one Ontario medical school from 2013 to 2018. Characteristics of applicants who were offered admission were compared to the general population and applicants not offered admission. Regression analyses were used to investigate the association between median total neighborhood income and successful admission. RESULTS: The median total neighborhood income for medical school applicants was $98,816, which was approximately $28,480 higher than the Canadian general population. Those not admitted to the medical school had a median total neighborhood income of $98,304 compared to $105,984 for those offered admission (p < 0.001). This trend was seen in every province and territory in Canada. Median total neighborhood income was a predictor of an offer of admission; applicants in the >75th percentile income group had 54% increased odds of being offered admission when compared to applicants in the <25th percentile in our unadjusted model. Income was not significant in our adjusted models but showed that the income medians drastically shifted between pre-interview and post-interview periods, from $98,816 to $104,960 (p < 0.001). CONCLUSION: Medical school applicants are from higher economic strata compared to the general population. Despite already representing a high economic stratum, a higher median total neighborhood income relative to other applicants was associated with an offer of admission.

Drug induced hepatitis mimicking Wilson's disease secondary to the use of complex naturopathic regimens: a case report.

BACKGROUND: Drug induced liver injury (DILI) is an important cause of acute liver injury and accounts for approximately 10% of all cases of acute hepatitis. Both prescription and natural health products (NHPs) have been implicated in DILI. There is a dearth of studies on NHPs induced liver injury. CASE PRESENTATION: A previously healthy 37-year-old female presented with subacute hepatitis, in the context of a previous admission to a separate institution, months prior for undiagnosed acute hepatitis. Importantly, she had disclosed taking complex regiments of natural health products (NHPs) for months. Her only other medication was rivaroxaban for her homozygous Factor V Leiden deficiency. She had an extensive work up for causes of acute and unresolving hepatitis. She discontinued several but not all of her NHPs after her initial presentation for acute hepatitis at the first institution and continued taking NHPs until shortly after admission to our institution. The predominant pathological features were that of drug induced liver injury, although an abnormal amount of copper was noted in the core liver biopsies. However, Wilson's disease was ruled out with normal serum ceruloplasmin and 24-urine copper. After 2 months of stopping all the NHPs, our patient improved significantly since discharge, although there is evidence of fibrosis on ultrasound at last available follow up. CONCLUSION: NHPs are a well-established but poorly understood etiology of DILI. The situation is exacerbated by the unregulated and unpredictable nature of many of the potential hepatotoxic effects of these agents, especially in cases of multiple potential toxic agents. This highlights the importance of acquiring a clear history of all medications regardless of prescription status.

Comparative Effectiveness of Sotatercept and Approved Add-On Pulmonary Arterial Hypertension Therapies: A Systematic Review and Network Meta-Analysis.

RATIONALE: There are no direct comparisons of sotatercept to add-on therapies approved for PAH. OBJECTIVE: This study aimed to compare the efficacy and safety of add-on sotatercept versus other add-on therapies using a network meta-analysis. METHODS: We searched MEDLINE, Embase, the Cochrane CENTRAL, and Clinicaltrials.gov until April 15, 2023, for randomized trials involving PAH patients treated with add-on sotatercept or add-on other PAH therapies. Data extraction and risk of bias assessments were performed independently and in duplicate using the Cochrane RoB 2.0 tool. We performed frequentist random-effects network meta-analysis using the restricted maximum likelihood (REML) estimator and assessed the certainty of evidence using the GRADE approach. RESULTS: Our search found 18 trials (5777 patients) eligible for analysis. Sotatercept reduces clinical worsening as compared to placebo (RR 0.21 [95% CI 0.11 to 0.41]; high certainty). Sotatercept probably reduces clinical worsening more compared to add-on ERA (RR 0.28 [95% CI 0.14 to 0.55]), prostanoid (Inh) (RR 0.21 [95% CI 0.07 to 0.67]), and prostanoid (PO) (RR 0.32 [95% CI 0.16 to 0.67]) (all moderate certainty). Sotatercept probably improves 6MWD as compared to placebo (MD 36.89m [95% CI 25.26 to 48.51]). Although sotatercept probably improves 6MWD more than add-on ERA (MD 18.38m [95% CI 5.92 to 30.84]) and prostanoid (PO) (MD 25.66m [95% CI 13.71 to 37.61]), it did not exceed the MCID of 33m (both moderate certainty). CONCLUSION: Sotatercept is an effective add-on therapy for PAH, likely superior to many approved add-on PAH therapies in reducing clinical worsening.

Home respiratory strategies in COPD patients with chronic hypercapnic respiratory failure: a systematic review and network meta-analysis.

Background: Home non-invasive positive pressure ventilation (NPPV) may improve chronic hypercarbia in COPD and patient important outcomes. The efficacy of home high flow nasal cannula (HFNC) as an alternative is unclear.Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL, SCOPUS, and Clinicaltrials.gov for randomized trials of patients from inception to March 31st and updated the search on July 14, 2023. We performed a frequentist network meta-analysis and assessed the certainty of the evidence using the GRADE approach. We analyzed randomized trials (RCTs) comparing NPPV, HFNC, or standard care in adult COPD patients with chronic hypercapnic respiratory failure. Outcomes included mortality, COPD exacerbations, hospitalizations, and quality of life (SGRQ).Results: We analyzed twenty-four RCTs (1850 patients). We found that NPPV may reduce death risk compared to standard care (relative risk [RR] 0.82 [95% CI 0.66 to 1.00]) and probably reduces acute exacerbations (RR 0.71 [95% CI 0.58 to 0.87]). HFNC probably reduces acute exacerbations compared to standard care (RR 0.77 [0.68 to 0.88]) but its effect on mortality is uncertain (RR 1.20 [95% CI 0.63 to 2.28]). HFNC probably improves SGRQ scores (mean difference [MD] -7.01 [95% CI -12.27 to -1.77]) and may reduce hospitalizations (RR 0.87 [0.69 to 1.09]) compared to standard care. No significant difference was observed between HFNC and NPPV in reducing exacerbations.Conclusion: Both NPPV and HFNC reduce exacerbation risks in COPD patients compared to standard care. HFNC may offer advantages in improving quality of life.