Purpose
To investigate the effect of prolonged glucocorticoid treatment for patients with acute respiratory distress syndrome (ARDS).
Methods
We conducted two sets of intention-to-treat analyses: (1) ...a primary analysis of individual patients’ data (IPD) of four randomized controlled trials (RCTs) which investigated methylprednisolone treatment (
n
= 322) and (2) a trial-level meta-analysis incorporating four additional RCTs which investigated hydrocortisone treatment in early ARDS (
n
= 297). We standardized definitions to derive outcomes in all datasets. The primary outcome for the IPD analysis was time to achieving unassisted breathing (UAB) by study day 28. Secondary outcomes included mechanical ventilation (MV) and intensive care unit (ICU)-free days, hospital mortality, and time to hospital mortality by day 28.
Results
By study day 28, compared to the placebo group, the methylprednisolone group had fewer patients who died before achieving UAB (12 vs. 29 %;
p
< 0.001) and more patients who achieved UAB (80 vs. 50 %;
p
< 0.001). In the methylprednisolone group, time to achieving UAB was shorter hazard ratio 2.59, 95 % confidence interval (CI) 1.95–3.43;
p
< 0.001, and hospital mortality was decreased (20 vs. 33 %;
p
= 0.006), leading to increased MV (13.3 ± 11.8 vs. 7.6 ± 5.7;
p
< 0.001) and ICU-free days (10.8 ± 0.71 vs. 6.4 ± 0.85;
p
< 0.001). In those patients randomized before day 14 of ARDS onset, the trial-level meta-analysis indicated decreased hospital mortality (36 vs. 49 %; risk ratio 0.76, 95 % CI 0.59–0.98,
I
2
= 17 %,
p
= 0.035; moderate certainty). Treatment was not associated with increased risk for infections (risk ratio 0.77, 95 % CI 0.56–1.08,
I
2
= 26 %;
p
= 0.13; moderate certainty).
Conclusions
Prolonged methylprednisolone treatment accelerates the resolution of ARDS, improving a broad spectrum of interrelated clinical outcomes and decreasing hospital mortality and healthcare utilization.
Community-acquired pneumonia (CAP) is common and often severe.
To examine the effect of adjunctive corticosteroid therapy on mortality, morbidity, and duration of hospitalization in patients with ...CAP.
MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through 24 May 2015.
Randomized trials of systemic corticosteroids in hospitalized adults with CAP.
Two reviewers independently extracted study data and assessed risk of bias. Quality of evidence was assessed with the Grading of Recommendations Assessment, Development, and Evaluation system by consensus among the authors.
The median age was typically in the 60s, and approximately 60% of patients were male. Adjunctive corticosteroids were associated with possible reductions in all-cause mortality (12 trials; 1974 patients; risk ratio RR, 0.67 95% CI, 0.45 to 1.01; risk difference RD, 2.8%; moderate certainty), need for mechanical ventilation (5 trials; 1060 patients; RR, 0.45 CI, 0.26 to 0.79; RD, 5.0%; moderate certainty), and the acute respiratory distress syndrome (4 trials; 945 patients; RR, 0.24 CI, 0.10 to 0.56; RD, 6.2%; moderate certainty). They also decreased time to clinical stability (5 trials; 1180 patients; mean difference, -1.22 days CI, -2.08 to -0.35 days; high certainty) and duration of hospitalization (6 trials; 1499 patients; mean difference, -1.00 day CI, -1.79 to -0.21 days; high certainty). Adjunctive corticosteroids increased frequency of hyperglycemia requiring treatment (6 trials; 1534 patients; RR, 1.49 CI, 1.01 to 2.19; RD, 3.5%; high certainty) but did not increase frequency of gastrointestinal hemorrhage.
There were few events and trials for many outcomes. Trials often excluded patients at high risk for adverse events.
For hospitalized adults with CAP, systemic corticosteroid therapy may reduce mortality by approximately 3%, need for mechanical ventilation by approximately 5%, and hospital stay by approximately 1 day.
None.
To assess the effectiveness and safety of dual agent antiplatelet therapy combining clopidogrel and aspirin to prevent recurrent thrombotic and bleeding events compared with aspirin alone in patients ...with acute minor ischaemic stroke or transient ischaemic attack (TIA).
Systematic review and meta-analysis of randomised, placebo controlled trials.
Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Library, ClinicalTrials.gov, WHO website, PsycINFO, and grey literature up to 4 July 2018.
Two reviewers independently screened potentially eligible studies according to predefined selection criteria and assessed the risk of bias using a modified version of the Cochrane risk of bias tool. A third team member reviewed all final decisions, and the team resolved disagreements through discussion. When reports omitted data that were considered important, clarification and additional information was sought from the authors. The analysis was conducted in RevMan 5.3 and MAGICapp based on GRADE methodology.
Three eligible trials involving 10 447 participants were identified. Compared with aspirin alone, dual antiplatelet therapy with clopidogrel and aspirin that was started within 24 hours of symptom onset reduced the risk of non-fatal recurrent stroke (relative risk 0.70, 95% confidence interval 0.61 to 0.80, I
=0%, absolute risk reduction 1.9%, high quality evidence), without apparent impact on all cause mortality (1.27, 0.73 to 2.23, I
=0%, moderate quality evidence) but with a likely increase in moderate or severe extracranial bleeding (1.71, 0.92 to 3.20, I
=32%, absolute risk increase 0.2%, moderate quality evidence). Most stroke events, and the separation in incidence curves between dual and single therapy arms, occurred within 10 days of randomisation; any benefit after 21 days is extremely unlikely.
Dual antiplatelet therapy with clopidogrel and aspirin given within 24 hours after high risk TIA or minor ischaemic stroke reduces subsequent stroke by about 20 in 1000 population, with a possible increase in moderate to severe bleeding of 2 per 1000 population. Discontinuation of dual antiplatelet therapy within 21 days, and possibly as early as 10 days, of initiation is likely to maximise benefit and minimise harms.
Our aim was to evaluate the benefits and harms of adjunctive corticosteroids in adults hospitalized with community-acquired pneumonia (CAP) using individual patient data from randomized, ...placebo-controlled trials and to explore subgroup differences.
We systematically searched Medline, Embase, Cochrane Central, and trial registers (all through July 2017). Data from 1506 individual patients in 6 trials were analyzed using uniform outcome definitions. We investigated prespecified effect modifiers using multivariable hierarchical regression, adjusting for pneumonia severity, age, and clustering effects.
Within 30 days of randomization, 37 of 748 patients (5.0%) assigned to corticosteroids and 45 of 758 patients (5.9%) assigned to placebo died (adjusted odds ratio aOR, 0.75; 95% confidence interval CI, .46 to 1.21; P = .24). Time to clinical stability and length of hospital stay were reduced by approximately 1 day with corticosteroids (-1.03 days; 95% CI, -1.62 to -.43; P = .001 and -1.15 days; 95% CI, -1.75 to -.55; P < .001, respectively). More patients with corticosteroids had hyperglycemia (160 22.1% vs 88 12.0%; aOR, 2.15; 95% CI, 1.60 to 2.90; P < .001) and CAP-related rehospitalization (33 5.0% vs 18 2.7%; aOR, 1.85; 95% CI, 1.03 to 3.32; P = .04). We did not find significant effect modification by CAP severity or degree of inflammation.
Adjunct corticosteroids for patients hospitalized with CAP reduce time to clinical stability and length of hospital stay by approximately 1 day without a significant effect on overall mortality but with an increased risk for CAP-related rehospitalization and hyperglycemia.
It is a longstanding cultural norm to provide supplemental oxygen to sick patients regardless of their blood oxygen saturation A recent systematic review and meta-analysis has shown that too much ...supplemental oxygen increases mortality for medical patients in hospital For patients receiving oxygen therapy, aim for peripheral capillary oxygen saturation (SpO2) of ≤96% (strong recommendation) For patients with acute myocardial infarction or stroke, do not initiate oxygen therapy in patients with SpO2 ≥90% (for ≥93% strong recommendation, for 90-92% weak recommendation) A target SpO2 range of 90-94% seems reasonable for most patients and 88-92% for patients at risk of hypercapnic respiratory failure; use the minimum amount of oxygen necessary What is the best way to use oxygen therapy for patients with an acute medical illness? A systematic review published in the Lancet in April 2018 found that supplemental oxygen in inpatients with normal oxygen saturation increases mortality.1 Its authors concluded that oxygen should be administered conservatively, but they did not make specific recommendations on how to do it. Proposed limits range from 98% for most patients, to an upper limit of 92% for patients with risk of hypercapnic respiratory failure, such as patients with chronic obstructive pulmonary disease.15 How this recommendation was created Our international panel included methodologists, a respiratory therapist/technician, a nurse, patient partners who have been hospitalised for an acute medical condition, pulmonologists, intensivists, internists, an anaesthesiologist, a cardiologist, emergency physicians, and a surgeon (see appendix 1 on bmj.com for details of panel members). ...in the largest of eight trials of patients with stroke only 240 patients (3.1% of 7677 participants) had an initial SpO2 of 90-93.9%.16 For myocardial infarction, six trials enrolled 7898 patients: in the largest trial, 1062 patients (16.0%) had an initial SpO2 ≤94%.17 For all outcomes, the panel rated down the quality of the evidence for indirectness (uncertain applicability) in patients with a SpO2 of 90-92%. Because trials informing the lower limit of when to start oxygen were restricted to patients with stroke and myocardial infarction, whether the evidence applies to patients without these conditions is uncertain. Chronic obstructive pulmonary disease Obesity hypoventilation Neuromuscular respiratory diseases Obstructive sleep apnoea Decreased central respiratory drive (such as sedative overdose, stroke, encephalitis) Higher target (such as SpO2 approaching 100%) Carbon monoxide poisoning Cluster headaches Sickle cell crisis Pneumothorax Shared decision making The patient panellists said that oxygen therapy is often given to patients with insufficient discussion and explanation.
This article presents official guidance from the Grading of Recommendations Assessments, Development, and Evaluation (GRADE) working group on how to address incoherence when assessing the certainty ...in the evidence from network meta-analysis. Incoherence represents important differences between direct and indirect estimates that contribute to a network estimate. Bias due to limitations in study design or publication bias, indirectness, and intransitivity may be responsible for incoherence. Addressing incoherence requires a judgment regarding the importance of the impact on the network estimate. Reviewers need to be alert to the possibility of misguidedly arriving at excessively low ratings of certainty by rating down for both incoherence and other closely related GRADE domains. This article describes and illustrates each of these issues and provides explicit guidance on how to deal with them.
To provide practical principles and examples to help GRADE users make optimal choices regarding their ratings of certainty of evidence using a minimally or partially contextualized approach.
Based on ...the GRADE clarification of certainty of evidence in 2017, a project group within the GRADE Working Group conducted iterative discussions and presentations at GRADE Working Group meetings to refine this construct and produce practical guidance.
Systematic review and health technology assessment authors need to clarify what it is in which they are rating their certainty of evidence (i.e., the target of their certainty rating). The decision depends on the degree of contextualization (partially or minimally contextualized), thresholds (null, small, moderate or large effect threshold), and where the point estimate lies in relation to the chosen threshold(s). When the 95% confidence interval crosses multiple possible thresholds (i.e., including both large benefit and large harm), it is not worthwhile for authors to determine the target of certainty rating.
GRADE provides practical principles to help systematic review and health technology assessment authors specify the target of their certainty of evidence rating.
Abstract Context Pharmacological thromboprophylaxis involves balancing a lower risk of venous thromboembolism (VTE) against a higher risk of bleeding, a trade-off that critically depends on the risks ...of VTE and bleeding in the absence of prophylaxis (baseline risk). Objective To provide estimates of the baseline risk of symptomatic VTE and bleeding requiring reoperation in urological cancer surgery. Evidence acquisition We identified contemporary observational studies reporting symptomatic VTE or bleeding after urological procedures. We used studies with the lowest risk of bias and accounted for use of thromboprophylaxis and length of follow-up to derive best estimates of the baseline risks within 4 wk of surgery. We used the GRADE approach to assess the quality of the evidence. Evidence synthesis We included 71 studies reporting on 14 urological cancer procedures. The quality of the evidence was generally moderate for prostatectomy and cystectomy, and low or very low for other procedures. The duration of thromboprophylaxis was highly variable. The risk of VTE in cystectomies was high (2.6–11.6% across risk groups) whereas the risk of bleeding was low (0.3%). The risk of VTE in prostatectomies varied by procedure, from 0.2–0.9% in robotic prostatectomy without pelvic lymph node dissection (PLND) to 3.9–15.7% in open prostatectomy with extended PLND. The risk of bleeding was 0.1–1.0%. The risk of VTE following renal procedures was 0.7–2.9% for low-risk patients and 2.6–11.6% for high-risk patients; the risk of bleeding was 0.1–2.0%. Conclusions Extended thromboprophylaxis is warranted in some procedures (eg, open and robotic cystectomy) but not others (eg, robotic prostatectomy without PLND in low-risk patients). For “close call” procedures, decisions will depend on values and preferences with regard to VTE and bleeding. Patient summary Clinicians often give blood thinners to patients to prevent blood clots after surgery for urological cancer. Unfortunately, blood thinners also increase bleeding. This study provides information on the risk of clots and bleeding that is crucial in deciding for or against giving blood thinners.
This article describes conceptual advances of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group guidance to evaluate the certainty of evidence (confidence ...in evidence, quality of evidence) from network meta-analysis (NMA). Application of the original GRADE guidance, published in 2014, in a number of NMAs has resulted in advances that strengthen its conceptual basis and make the process more efficient. This guidance will be useful for systematic review authors who aim to assess the certainty of all pairwise comparisons from an NMA and who are familiar with the basic concepts of NMA and the traditional GRADE approach for pairwise meta-analysis. Two principles of the original GRADE NMA guidance are that we need to rate the certainty of the evidence for each pairwise comparison within a network separately and that in doing so we need to consider both the direct and indirect evidence. We present, discuss, and illustrate four conceptual advances: (1) consideration of imprecision is not necessary when rating the direct and indirect estimates to inform the rating of NMA estimates, (2) there is no need to rate the indirect evidence when the certainty of the direct evidence is high and the contribution of the direct evidence to the network estimate is at least as great as that of the indirect evidence, (3) we should not trust a statistical test of global incoherence of the network to assess incoherence at the pairwise comparison level, and (4) in the presence of incoherence between direct and indirect evidence, the certainty of the evidence of each estimate can help decide which estimate to believe.
•The application of the Grading of Recommendations Assessments, Development, and Evaluation approach to a number of network meta-analyses in the 3 years since the original guidance publication has led to advances that have strengthened the conceptual basis.•We present, discuss, and illustrate four conceptual advances. These are based on two principles: we need to rate the certainty of the evidence of each pairwise comparison within a network separately and that we need to consider both the direct and indirect evidence contributing to each network estimate.•Although maximizing the efficiency of the process is desirable, as illustrated in the conceptual advances, use of these strategies requires careful judgment.
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