Acetazolamide for acute kidney injury in patients undergoing high dose methotrexate therapy: a systematic review and meta-analysis.

BACKGROUND: Urine alkalization is one of the standard treatments to prevent acute kidney injury in patients receiving high-dose methotrexate. Carbonic anhydrase inhibitors are promising adjuvants/substitutes with advantages such as faster urine alkalization time and prevention of fluid overload. However, there is limited and contradictory evidence on its efficacy and safety. We aimed to compare the efficacy and safety of carbonic anhydrase inhibitors to standard treatments in adult patients receiving high-dose methotrexate. METHODS: The protocol was registered at PROSPERO (CRD42022352802) in August 2021. We evaluated the use of carbonic anhydrase inhibitors in combination with standard treatment compared to standard treatment alone. We excluded articles irrelevant to the efficacy and safety of acetazolamide in patients receiving high dose methotrexate and/or did not provide sufficient data regarding doses, recruitment criteria, and follow-up period. Two authors performed the data extraction independently. RESULTS: Among 198 articles retrieved, six observational studies met all eligibility criteria. Four studies with five datasets (totaling 558 patients/cycles) had enough data to be included in the meta-analysis. We independently report the results from the two remaining studies. The results did not show a significant difference between acetazolamide versus standard treatment in acute kidney injury (AKI) rate (OR = 0.79, 95% CI 0.48-1.29, P = 0.34, I2 = 0%). Regarding the time to urine pH goal, there was no significant time difference between the two groups (Mean Difference = 0.07, 95% CI - 1.9 to 2.04, P = 0.95, I2 = 25%). Furthermore, our meta-analysis showed that acetazolamide did not reduce length of stay (Mean Difference = 0.75, 95% CI - 0.8 to 2.31, P = 0.34, I2 = 0%). In one study, the only reported side effect of acetazolamide was hypokalemia (nearly 50% in the acetazolamide group). CONCLUSIONS: This systematic review showed no significant difference between acetazolamide and standard care treatment regarding urine alkalinization time and AKI rate in adult patients receiving high dose methotrexate. We suggest performing a large blinded, randomized, controlled trial to evaluate the potential benefits of this low-cost medication.

Early empiric antibiotic use in COVID-19 patients: results from the international VIRUS registry.

OBJECTIVES: COVID-19 escalated inappropriate antibiotic use. We determined the distribution of pathogens causing community-acquired co-infections, the rate, and factors associated with early empiric antibiotic (EEAB) treatment among hospitalized COVID-19 patients. METHODS: The Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 Registry including 68,428 patients from 28 countries enrolled between January 2020 and October 2021 were screened. After exclusions, 7830 patients were included in the analysis. Azithromycin and/or other antibiotic treatment given within the first 3 days of hospitalization was investigated. Univariate and multivariate analyses were performed to determine factors associated with EEAB use. RESULTS: The majority (6214, 79.4%) of patients received EEAB, with azithromycin combination being the most frequent (3146, 40.2%). As the pandemic advanced, the proportion of patients receiving EEAB regressed from 84.4% (786/931) in January-March 2020 to 65.2% (30/46) in April-June 2021 (P < 0.001). Beta-lactams, especially ceftriaxone was the most commonly used antibiotic. Staphylococcus aureus was the most commonly isolated pathogen. Multivariate analysis showed geographical location and pandemic timeline as the strongest independent predictors of EEAB use. CONCLUSIONS: EEAB administration decreased as pandemic advanced, which may be the result of intensified antimicrobial stewardship efforts. Our study provides worldwide goals for antimicrobial stewardship programs in the post-COVID-19 era.

Discharge Disposition and Loss of Independence Among Survivors of COVID-19 Admitted to Intensive Care: Results From the SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS).

OBJECTIVES: To describe incidence and risk factors of loss of previous independent living through nonhome discharge or discharge home with health assistance in survivors of intensive care unit (ICU) admission for coronavirus disease 2019 (COVID-19). DESIGN: Multicenter observational study including patients admitted to the ICU from January 2020 till June 30, 2021. HYPOTHESIS: We hypothesized that there is a high risk of nonhome discharge in patients surviving ICU admission due to COVID-19. SETTING: Data were included from 306 hospitals in 28 countries participating in the SCCM Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 registry. PATIENTS: Previously independently living adult ICU survivors of COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was nonhome discharge. Secondary outcome was the requirement of health assistance among patients who were discharged home. Out of 10 820 patients, 7101 (66%) were discharged alive; 3791 (53%) of these survivors lost their previous independent living status, out of those 2071 (29%) through nonhome discharge, and 1720 (24%) through discharge home requiring health assistance. In adjusted analyses, loss of independence on discharge among survivors was predicted by patient age ≥ 65 years (adjusted odds ratio [aOR] 2.78, 95% confidence interval [CI] 2.47-3.14, P < .0001), former and current smoking status (aOR 1.25, 95% CI 1.08-1.46, P = .003 and 1.60 (95% CI 1.18-2.16), P = .003, respectively), substance use disorder (aOR 1.52, 95% CI 1.12-2.06, P = .007), requirement for mechanical ventilation (aOR 4.17, 95% CI 3.69-4.71, P < .0001), prone positioning (aOR 1.19, 95% CI 1.03-1.38, P = .02), and requirement for extracorporeal membrane oxygenation (aOR 2.28, 95% CI 1.55-3.34, P < .0001). CONCLUSIONS: More than half of ICU survivors hospitalized for COVID-19 are unable to return to independent living status, thereby imposing a significant secondary strain on health care systems worldwide.

A Case of Adult Multisystem Inflammatory Syndrome Following COVID-19 Vaccine.

Multisystem inflammatory syndrome is a life-threatening condition associated with elevated inflammatory markers and multiple organ injury. A diagnosis of exclusion, it has been reported after severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) in children and adults; recently it has been described in some post-COVID-19 vaccinated individuals. The prognosis with supportive care and immunomodulatory therapy is good, although some individuals may require treatment in the intensive care unit (ICU). Here we report a case of a 58-year-old man who developed multi-organ failure after receiving the second dose of the Moderna mRNA-1273 COVID-19 vaccine. He required critical organ support in the ICU. An extensive workup was done to rule out alternative infectious and inflammatory processes. Following a period of gradual in-hospital convalescence, our patient made a full recovery. To our knowledge, this is the first comprehensively described case of multisystem inflammatory syndrome associated with Moderna mRNA-1273 COVID-19 vaccine in an adult over 50 years of age.

How do frontline healthcare workers learn from COVID-19 webinars during a pandemic? An online survey study.

OBJECTIVES: The COVID-19 pandemic severely restricted in-person learning. As a result, many educational institutions switched to online platforms to continue teaching. COVID-19 webinars have been useful for rapidly disseminating information to frontline healthcare workers. While conducting COVID-19 webinars through online platforms is a popular method to train medical professionals, their effectiveness has never been investigated. Our aim was to ascertain the usefulness of COVID-19 webinars during the pandemic. METHODS: We conducted an online survey of about 400 frontline healthcare workers. 112 people responded to the survey (response rate = 28%). In it, we asked several questions to determine whether webinars had been a useful resource to help deal with COVID-19 patients. RESULTS: We found that a majority of healthcare worker respondents had favorable opinions of online education during the pandemic as around 78% of respondents either agreed or highly agreed that webinars are a useful source of knowledge. A significant proportion (34%) did not participate in webinars and gave time constraints as their main reason for not participating. CONCLUSION: Our results indicated that while online education is a great way to disseminate information quickly to a large amount of people, it also comes with its disadvantages. As we transition into a post-pandemic world, we need to make sure that online teaching is designed with the best interests of the healthcare workers in mind to ensure that we get the most out of it.

Admission Code Status and End-of-life Care for Hospitalized Patients With COVID-19.

CONTEXT: The COVID-19 pandemic has highlighted variability in intensity of care. We aimed to characterize intensity of care among hospitalized patients with COVID-19. OBJECTIVES: Examine the prevalence and predictors of admission code status, palliative care consultation, comfort-measures-only orders, and cardiopulmonary resuscitation (CPR) among patients hospitalized with COVID-19. METHODS: This cross-sectional study examined data from an international registry of hospitalized patients with COVID-19. A proportional odds model evaluated predictors of more aggressive code status (i.e., Full Code) vs. less (i.e., Do Not Resuscitate, DNR). Among decedents, logistic regression was used to identify predictors of palliative care consultation, comfort measures only, and CPR at time of death. RESULTS: We included 29,923 patients across 179 sites. Among those with admission code status documented, Full Code was selected by 90% (n = 15,273). Adjusting for site, Full Code was more likely for patients who were of Black or Asian race (ORs 1.82, 95% CIs 1.5-2.19; 1.78, 1.15-3.09 respectively, relative to White race), Hispanic ethnicity (OR 1.89, CI 1.35-2.32), and male sex (OR 1.16, CI 1.0-1.33). Of the 4951 decedents, 29% received palliative care consultation, 59% transitioned to comfort measures only, and 29% received CPR, with non-White racial and ethnic groups less likely to receive comfort measures only and more likely to receive CPR. CONCLUSION: In this international cohort of patients with COVID-19, Full Code was the initial code status in the majority, and more likely among patients who were Black or Asian race, Hispanic ethnicity or male. These results provide direction for future studies to improve these disparities in care.

Association of latitude and altitude with adverse outcomes in patients with COVID-19: The VIRUS registry.

BACKGROUND: The coronavirus disease 2019 (COVID-19) course may be affected by environmental factors. Ecological studies previously suggested a link between climatological factors and COVID-19 fatality rates. However, individual-level impact of these factors has not been thoroughly evaluated yet. AIM: To study the association of climatological factors related to patient location with unfavorable outcomes in patients. METHODS: In this observational analysis of the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study: COVID-19 Registry cohort, the latitudes and altitudes of hospitals were examined as a covariate for mortality within 28 d of admission and the length of hospital stay. Adjusting for baseline parameters and admission date, multivariable regression modeling was utilized. Generalized estimating equations were used to fit the models. RESULTS: Twenty-two thousand one hundred eight patients from over 20 countries were evaluated. The median age was 62 (interquartile range: 49-74) years, and 54% of the included patients were males. The median age increased with increasing latitude as well as the frequency of comorbidities. Contrarily, the percentage of comorbidities was lower in elevated altitudes. Mortality within 28 d of hospital admission was found to be 25%. The median hospital-free days among all included patients was 20 d. Despite the significant linear relationship between mortality and hospital-free days (adjusted odds ratio (aOR) = 1.39 (1.04, 1.86), P = 0.025 for mortality within 28 d of admission; aOR = -1.47 (-2.60, -0.33), P = 0.011 for hospital-free days), suggesting that adverse patient outcomes were more common in locations further away from the Equator; the results were no longer significant when adjusted for baseline differences (aOR = 1.32 (1.00, 1.74), P = 0.051 for 28-day mortality; aOR = -1.07 (-2.13, -0.01), P = 0.050 for hospital-free days). When we looked at the altitude's effect, we discovered that it demonstrated a non-linear association with mortality within 28 d of hospital admission (aOR = 0.96 (0.62, 1.47), 1.04 (0.92, 1.19), 0.49 (0.22, 0.90), and 0.51 (0.27, 0.98), for the altitude points of 75 MASL, 125 MASL, 400 MASL, and 600 MASL, in comparison to the reference altitude of 148 m.a.s.l, respectively. P = 0.001). We detected an association between latitude and 28-day mortality as well as hospital-free days in this worldwide study. When the baseline features were taken into account, however, this did not stay significant. CONCLUSION: Our findings suggest that differences observed in previous epidemiological studies may be due to ecological fallacy rather than implying a causal relationship at the patient level.

Association of hypothyroidism with outcomes in hospitalized adults with COVID-19: Results from the International SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS): COVID-19 Registry.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is associated with high rates of morbidity and mortality. Primary hypothyroidism is a common comorbid condition, but little is known about its association with COVID-19 severity and outcomes. This study aims to identify the frequency of hypothyroidism in hospitalized patients with COVID-19 as well as describe the differences in outcomes between patients with and without pre-existing hypothyroidism using an observational, multinational registry. METHODS: In an observational cohort study we enrolled patients 18 years or older, with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between March 2020 and February 2021. The primary outcomes were (1) the disease severity defined as per the World Health Organization Scale for Clinical Improvement, which is an ordinal outcome corresponding with the highest severity level recorded during a patient's index COVID-19 hospitalization, (2) in-hospital mortality and (3) hospital-free days. Secondary outcomes were the rate of intensive care unit (ICU) admission and ICU mortality. RESULTS: Among the 20,366 adult patients included in the study, pre-existing hypothyroidism was identified in 1616 (7.9%). The median age for the Hypothyroidism group was 70 (interquartile range: 59-80) years, and 65% were female and 67% were White. The most common comorbidities were hypertension (68%), diabetes (42%), dyslipidemia (37%) and obesity (28%). After adjusting for age, body mass index, sex, admission date in the quarter year since March 2020, race, smoking history and other comorbid conditions (coronary artery disease, hypertension, diabetes and dyslipidemia), pre-existing hypothyroidism was not associated with higher odds of severe disease using the World Health Organization disease severity index (odds ratio [OR]: 1.02; 95% confidence interval [CI]: 0.92, 1.13; p = .69), in-hospital mortality (OR: 1.03; 95% CI: 0.92, 1.15; p = .58) or differences in hospital-free days (estimated difference 0.01 days; 95% CI: -0.45, 0.47; p = .97). Pre-existing hypothyroidism was not associated with ICU admission or ICU mortality in unadjusted as well as in adjusted analysis. CONCLUSIONS: In an international registry, hypothyroidism was identified in around 1 of every 12 adult hospitalized patients with COVID-19. Pre-existing hypothyroidism in hospitalized patients with COVID-19 was not associated with higher disease severity or increased risk of mortality or ICU admissions. However, more research on the possible effects of COVID-19 on the thyroid gland and its function is needed in the future.

The Association of Latitude and Altitude with COVID-19 Symptoms: A VIRUS: COVID-19 Registry Analysis.

Background: Better delineation of COVID-19 presentations in different climatological conditions might assist with prompt diagnosis and isolation of patients. Objectives: To study the association of latitude and altitude with COVID-19 symptomatology. Methods: This observational cohort study included 12267 adult COVID-19 patients hospitalized between 03/2020 and 01/2021 at 181 hospitals in 24 countries within the SCCM Discovery VIRUS: COVID-19 Registry. The outcome was symptoms at admission, categorized as respiratory, gastrointestinal, neurological, mucocutaneous, cardiovascular, and constitutional. Other symptoms were grouped as atypical. Multivariable regression modeling was performed, adjusting for baseline characteristics. Models were fitted using generalized estimating equations to account for the clustering. Results: The median age was 62 years, with 57% males. The median age and percentage of patients with comorbidities increased with higher latitude. Conversely, patients with comorbidities decreased with elevated altitudes. The most common symptoms were respiratory (80%), followed by constitutional (75%). Presentation with respiratory symptoms was not associated with the location. After adjustment, at lower latitudes (<30º), patients presented less commonly with gastrointestinal symptoms (p<.001, odds ratios for 15º, 25º, and 30º: 0.32, 0.81, and 0.98, respectively). Atypical symptoms were present in 21% of the patients and showed an association with altitude (p=.026, odds ratios for 75, 125, 400, and 600 meters above sea level: 0.44, 0.60, 0.84, and 0.77, respectively). Conclusions: We observed geographic variability in symptoms of COVID-19 patients. Respiratory symptoms were most common but were not associated with the location. Gastrointestinal symptoms were less frequent in lower latitudes. Atypical symptoms were associated with higher altitude.

Simultaneous Use of Hypertonic Saline and IV Furosemide for Fluid Overload: A Systematic Review and Meta-Analysis.

OBJECTIVES: To evaluate the efficacy of the simultaneous hypertonic saline solution and IV furosemide (HSS+Fx) for patients with fluid overload compared with IV furosemide alone (Fx). DATA SOURCES: Electronic databases (MEDLINE, EMBASE, CENTRAL, Cochrane Database of Systematic Reviews, PsycINFO, Scopus, and WOS) were searched from inception to March 2020. STUDY SELECTION: Randomized controlled trials on the use of HSS+Fx in adult patients with fluid overload versus Fx were included. DATA EXTRACTION: Data were collected on all-cause mortality, hospital length of stay, heart failure-related readmission, along with inpatient weight loss, change of daily diuresis, serum creatinine, and 24-hour urine sodium excretion from prior to post intervention. Pooled analysis with random effects models yielded relative risk or mean difference with 95% CIs. DATA SYNTHESIS: Eleven randomized controlled trials comprising 2,987 acute decompensated heart failure patients were included. Meta-analysis demonstrated that HSS+Fx was associated with lower all-cause mortality (relative risk, 0.55; 95% CI, 0.46-0.67; p < 0.05; I2 = 12%) and heart failure-related readmissions (relative risk, 0.50; 95% CI, 0.33-0.76; p < 0.05; I2 = 61%), shorter hospital length of stay (mean difference, -3.28 d; 95% CI, -4.14 to -2.43; p < 0.05; I2 = 93%), increased daily diuresis (mean difference, 583.87 mL; 95% CI, 504.92-662.81; p < 0.05; I2 = 76%), weight loss (mean difference, -1.76 kg; 95% CI, -2.52 to -1.00; p < 0.05; I2 = 57%), serum sodium change (mean difference, 6.89 mEq/L; 95% CI, 4.98-8.79; p < 0.05; I2 = 95%), and higher 24-hour urine sodium excretion (mean difference, 61.10 mEq; 95% CI, 51.47-70.73; p < 0.05; I2 = 95%), along with decreased serum creatinine (mean difference, -0.46 mg/dL; 95% CI, -0.51 to -0.41; p < 0.05; I2 = 89%) when compared with Fx. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from low to moderate. CONCLUSIONS: Benefits of the HSS+Fx over Fx were observed across all examined outcomes in acute decompensated heart failure patients with fluid overload. There is at least moderate certainty that HSS+Fx is associated with a reduction in mortality in patients with acute decompensated heart failure. Factors associated with a successful HSS+Fx utilization are still unknown. Current evidence cannot be extrapolated to other than fluid overload states in acute decompensated heart failure.

Outcomes of Patients With Coronavirus Disease 2019 Receiving Organ Support Therapies: The International Viral Infection and Respiratory Illness Universal Study Registry.

OBJECTIVES: To describe the outcomes of hospitalized patients in a multicenter, international coronavirus disease 2019 registry. DESIGN: Cross-sectional observational study including coronavirus disease 2019 patients hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between February 15, 2020, and November 30, 2020, according to age and type of organ support therapies. SETTING: About 168 hospitals in 16 countries within the Society of Critical Care Medicine's Discovery Viral Infection and Respiratory Illness University Study coronavirus disease 2019 registry. PATIENTS: Adult hospitalized coronavirus disease 2019 patients who did and did not require various types and combinations of organ support (mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was hospital mortality. Secondary outcomes were discharge home with or without assistance and hospital length of stay. Risk-adjusted variation in hospital mortality for patients receiving invasive mechanical ventilation was assessed by using multilevel models with hospitals as a random effect, adjusted for age, race/ethnicity, sex, and comorbidities. Among 20,608 patients with coronavirus disease 2019, the mean (± sd) age was 60.5 (±17), 11,1887 (54.3%) were men, 8,745 (42.4%) were admitted to the ICU, and 3,906 (19%) died in the hospital. Hospital mortality was 8.2% for patients receiving no organ support (n = 15,001). The most common organ support therapy was invasive mechanical ventilation (n = 5,005; 24.3%), with a hospital mortality of 49.8%. Mortality ranged from 40.8% among patients receiving only invasive mechanical ventilation (n =1,749) to 71.6% for patients receiving invasive mechanical ventilation, vasoactive drugs, and new renal replacement therapy (n = 655). Mortality was 39% for patients receiving extracorporeal membrane oxygenation (n = 389). Rates of discharge home ranged from 73.5% for patients who did not require organ support therapies to 29.8% for patients who only received invasive mechanical ventilation, and 8.8% for invasive mechanical ventilation, vasoactive drugs, and renal replacement; 10.8% of patients older than 74 years who received invasive mechanical ventilation were discharged home. Median hospital length of stay for patients on mechanical ventilation was 17.1 days (9.7-28 d). Adjusted interhospital variation in mortality among patients receiving invasive mechanical ventilation was large (median odds ratio 1.69). CONCLUSIONS: Coronavirus disease 2019 prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation.

World Health Organization (WHO) antibiotic regimen against other regimens for the treatment of leprosy: a systematic review and meta-analysis.

BACKGROUND: To evaluate the effectiveness and safety of the World Health Organization antibiotic regimen for the treatment of paucibacillary (PB) and multibacillary (MB) leprosy compared to other available regimens. METHODS: We performed a search from 1982 to July 2018 without language restriction. We included randomized controlled trials, quasi-randomized trials, and comparative observational studies (cohorts and case-control studies) that enrolled patients of any age with PB or MB leprosy that were treated with any of the leprosy antibiotic regimens established by the WHO in 1982 and used any other antimicrobial regimen as a controller. Primary efficacy outcomes included: complete clinical cure, clinical improvement of the lesions, relapse rate, treatment failure. Data were pooled using a random effects model to estimate the treatment effects reported as relative risk (RR) with 95% confidence intervals (CI). RESULTS: We found 25 eligible studies, 11 evaluated patients with paucibacillary leprosy, while 13 evaluated patients with MB leprosy and 1 evaluated patients of both groups. Diverse regimen treatments and outcomes were studied. Complete cure at 6 months of multidrug therapy (MDT) in comparison to rifampin-ofloxacin-minocycline (ROM) found RR of 1.06 (95% CI 0.88-1.27) in five studies. Whereas six studies compare the same outcome at different follow up periods between 6 months and 5 years, according to the analysis ROM was not better than MDT (RR of 1.01 (95% CI 0.78-1.31)) in PB leprosy. CONCLUSION: Not better treatment than the implemented by the WHO was found. Diverse outcome and treatment regimens were studied, more statements to standardized the measurements of outcomes are needed.

Medications Affecting the Biochemical Conversion to Type 2 Diabetes: A Systematic Review and Meta-Analysis.

CONTEXT: The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to type 2 diabetes mellitus (T2DM) in at-risk individuals is unclear. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus through 24 August 2017 for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM. RESULTS: We included 43 trials with 192,156 subjects (mean age, 60 years; 56% men; mean body mass index, 30.4 kg/m2). α-Glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine/topiramate, and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period. CONCLUSIONS: Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality, and patient-important outcomes instead of biochemical conversion to T2DM.

Randomized trials addressing a similar question are commonly published after a trial stopped early for benefit.

OBJECTIVE: We explored how investigators of ongoing or planned trials respond to the publication of a trial stopped early for benefit addressing a similar question. STUDY DESIGN AND SETTING: We searched multiple databases from the date of publication of the truncated trial through August, 2015. Independent reviewers selected trials and extracted data. RESULTS: We identified 207 trials truncated for early benefit; of which 102 (49%) were followed by subsequent trials (262 subsequent trials, median 2 per truncated trial, range 1-13). Only 99 (38%) provided a rationale justifying conducting a trial despite prior stopping. The top reasons were to address different population or setting (33%), skepticism of truncated trials findings because of small sample size (12%), inconsistency with other evidence (11%), or increased risk of bias (7%). We did not identify significant associations between subsequent trials and characteristics of truncated ones (risk of bias, precision, funding, or rigor of stopping decision). CONCLUSION: About half of the trials stopped early for benefit were followed by subsequent trials addressing a similar question. This suggests that future trialists may have been skeptic about the decision to stop prior trials. A more rigorous threshold for stopping early for benefit is needed.

Antifibrinolytic therapy to reduce haemoptysis from any cause.

BACKGROUND: Haemoptysis is a common pathology around the world, occurring with more frequency in low-income countries. It has different etiologies, many of which have infectious characteristics. Antifibrinolytic agents are commonly used to manage bleeding from different sources, but their usefulness in pulmonology is unclear. OBJECTIVES: To evaluate the effectiveness and safety of antifibrinolytic agents in reducing the volume and duration of haemoptysis in adult and paediatric patients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library, EMBASE and LILACS for publications that describe randomized controlled trials (RCTs) of antifibrinolytic therapy in patients presenting with haemoptysis. We also performed an independent search in MEDLINE for relevant trials not yet included in CENTRAL or DARE. Searches are up to date to the 19th September 2016. We conducted electronic and manual searches of relevant national and international journals. We reviewed the reference lists of included studies to locate relevant randomized controlled trials (RCTs). An additional search was carried out to find unpublished RCTs. SELECTION CRITERIA: We included RCTs designed to evaluate the effectiveness and safety of antifibrinolytic agents in reducing haemoptysis in adult and paediatric patients of both genders presenting with haemoptysis of any etiology and severity. The intervention of interest was the administration of antifibrinolytic agents compared with placebo or no treatment. DATA COLLECTION AND ANALYSIS: All reviewers independently assessed methodological quality and extracted data tables pre-designed for this review. MAIN RESULTS: The electronic literature search identified 1 original study that met the eligibility criteria. One unpublished study was also identified through manual searches. Therefore two randomized controlled trials met the inclusion criteria: Tscheikuna 2002 (via electronic searches) and Ruiz 1994 (via manual searches). Tscheikuna 2002, a double-blind RCT performed in Thailand, evaluated the effectiveness of tranexamic acid (TXA, an antifibrinolytic agent) administered orally in 46 hospital in- and outpatients with haemoptysis of various etiologies. Ruiz 1994, a double-blind RCT performed in Peru, evaluated the effectiveness of intravenous TXA in 24 hospitalised patients presenting with haemoptysis secondary to tuberculosis.Pooled together, results demonstrated a significant reduction in bleeding time between patients receiving TXA and patients receiving placebo with a weighted mean difference (WMD) of -19.47 (95% CI -26.90 to -12.03 hours), but with high heterogeneity (I² = 52%). TXA did not affect remission of haemoptysis evaluated at seven days after the start of treatment. Adverse effects caused by the drug's mechanism of action were not reported. There was no significant difference in the incidence of mild side effects between active and placebo groups (OR 3.13, 95% CI 0.80 to 12.24). AUTHORS' CONCLUSIONS: There is insufficient evidence to judge whether antifibrinolytics should be used to treat haemoptysis from any cause, though limited evidence suggests they may reduce the duration of bleeding.

Early goal-directed therapy in severe sepsis and septic shock: insights and comparisons to ProCESS, ProMISe, and ARISE.

Prior to 2001 there was no standard for early management of severe sepsis and septic shock in the emergency department. In the presence of standard or usual care, the prevailing mortality was over 40-50 %. In response, a systems-based approach, similar to that in acute myocardial infarction, stroke and trauma, called early goal-directed therapy was compared to standard care and this clinical trial resulted in a significant mortality reduction. Since the publication of that trial, similar outcome benefits have been reported in over 70 observational and randomized controlled studies comprising over 70,000 patients. As a result, early goal-directed therapy was largely incorporated into the first 6 hours of sepsis management (resuscitation bundle) adopted by the Surviving Sepsis Campaign and disseminated internationally as the standard of care for early sepsis management. Recently a trio of trials (ProCESS, ARISE, and ProMISe), while reporting an all-time low sepsis mortality, question the continued need for all of the elements of early goal-directed therapy or the need for protocolized care for patients with severe and septic shock. A review of the early hemodynamic pathogenesis, historical development, and definition of early goal-directed therapy, comparing trial conduction methodology and the changing landscape of sepsis mortality, are essential for an appropriate interpretation of these trials and their conclusions.

A systematic review and meta-analysis of glycemic control for the prevention of diabetic foot syndrome.

OBJECTIVE: The objective of this review was to synthesize the available randomized controlled trials (RCTs) estimating the relative efficacy and safety of intensive vs less intensive glycemic control in preventing diabetic foot syndrome. METHODS: We used the umbrella design (systematic review of systematic reviews) to identify eligible RCTs. Two reviewers determined RCT eligibility and extracted descriptive, methodologic, and diabetic foot outcome data. Random-effects meta-analysis was used to pool outcome data across studies, and the I(2) statistic was used to quantify heterogeneity. RESULTS: Nine RCTs enrolling 10,897 patients with type 2 diabetes were included and deemed to be at moderate risk of bias. Compared with less intensive glycemic control, intensive control (hemoglobin A1c, 6%-7.5%) was associated with a significant decrease in risk of amputation (relative risk [RR], 0.65; 95% confidence interval [CI], 0.45-0.94; I(2) = 0%). Intensive control was significantly associated with slower decline in sensory vibration threshold (mean difference, -8.27; 95% CI, -9.75 to -6.79). There was no effect on other neuropathic changes (RR, 0.89; 95% CI, 0.75-1.05; I(2) = 32%) or ischemic changes (RR, 0.92; 95% CI, 0.67-1.26; I(2) = 0%). The quality of evidence is likely moderate. CONCLUSIONS: Compared with less intensive glycemic control therapy, intensive control may decrease the risk of amputation in patients with diabetic foot syndrome. The reported risk reduction is likely overestimated because the trials were open and the decision to proceed with amputation could be influenced by glycemic control.

A systematic review and meta-analysis of débridement methods for chronic diabetic foot ulcers.

BACKGROUND: Several methods of débridement of diabetic foot ulcers are currently used. The relative efficacy of these methods is not well established. METHODS: This systematic review and meta-analysis was conducted to find the best available evidence for the effect of débridement on diabetic foot wound outcomes. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011 for randomized controlled studies (RCTs) and observational comparative studies. RESULTS: We identified 11 RCTs and three nonrandomized studies reporting on 800 patients. The risk of bias was moderate overall. Meta-analysis of three RCTs showed that autolytic débridement significantly increased the healing rate (relative risk [RR], 1.89; 95% confidence interval [CI] 1.35-2.64). Meta-analysis of four studies (one RCT) showed that larval débridement reduced amputation (RR, 0.43; 95% CI, 0.21-0.88) but did not increase complete healing (RR, 1.27; 95% CI, 0.84-1.91). Surgical débridement was associated with shorter healing time compared with conventional wound care (one RCT). Insufficient evidence was found for comparisons between autolytic and larval débridement (one RCT), between ultrasound-guided and surgical débridement, and between hydrosurgical and surgical débridement. CONCLUSIONS: The available literature supports the efficacy of several débridement methods, including surgical, autolytic, and larval débridement. Comparative effectiveness evidence between these methods and supportive evidence for other methods is of low quality due to methodologic limitations and imprecision. Hence, the choice of débridement method at the present time should be based on the available expertise, patient preferences, the clinical context and cost.