The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.

IntroductionSepsis and septic shock are leading causes of intensive care unit (ICU) mortality. They are characterized by excessive inflammation, upregulation of procoagulant proteins and depletion of natural anticoagulants. Plasma exchange has the potential to improve survival in sepsis by removing inflammatory cytokines and restoring deficient plasma proteins. The objective of this study is to evaluate the efficacy and safety of plasma exchange in patients with sepsis.MethodsWe searched MEDLINE, EMBASE, CENTRAL, Scopus, reference lists of relevant articles, and grey literature for relevant citations. We included randomized controlled trials comparing plasma exchange or plasma filtration with usual care in critically ill patients with sepsis or septic shock. Two reviewers independently identified trials, extracted trial-level data and performed risk of bias assessments using the Cochrane Risk of Bias tool. The primary outcome was all-cause mortality reported at longest follow-up. Meta-analysis was performed using a random-effects model.ResultsOf 1,957 records identified, we included four unique trials enrolling a total of 194 patients (one enrolling adults only, two enrolling children only, one enrolling adults and children). The mean age of adult patients ranged from 38 to 53 years (n = 128) and the mean age of children ranged from 0.9 to 18 years (n = 66). All trials were at unclear to high risk of bias. The use of plasma exchange was not associated with a significant reduction in all-cause mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.45 to 1.52, I2 60%). In adults, plasma exchange was associated with reduced mortality (RR 0.63, 95% CI 0.42 to 0.96; I2 0%), but was not in children (RR 0.96, 95% CI 0.28 to 3.38; I2 60%). None of the trials reported ICU or hospital lengths of stay. Only one trial reported adverse events associated with plasma exchange including six episodes of hypotension and one allergic reaction to fresh frozen plasma.ConclusionsInsufficient evidence exists to recommend plasma exchange as an adjunctive therapy for patients with sepsis or septic shock. Rigorous randomized controlled trials evaluating clinically relevant patient-centered outcomes are required to evaluate the impact of plasma exchange in this condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0699-2) contains supplementary material, which is available to authorized users.

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ObjectiveIron supplementation in iron-deficiency anaemia is standard practice, but the benefits of iron supplementation in iron-deficient non-anaemic (IDNA) individuals remains controversial. Our objective is to identify the effects of iron therapy on fatigue and physical capacity in IDNA adults.DesignSystematic review and meta-analysis of randomised controlled trials (RCTs).SettingPrimary care.ParticipantsAdults (≥18 years) who were iron deficient but non-anaemic.InterventionsOral, intramuscular or intravenous iron supplementation; all therapy doses, frequencies and durations were included.ComparatorsPlacebo or active therapy.ResultsWe identified RCTs in Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health, SportDiscus and CAB Abstracts from inception to 31 October 2016. We searched the WHO’s International Clinical Trials Registry Platform for relevant ongoing trials and performed forward searches of included trials and relevant reviews in Web of Science. We assessed internal validity of included trials using the Cochrane Risk of Bias tool and the external validity using the Grading of Recommendations Assessment, Development and Evaluation methodology. From 11 580 citations, we included 18 unique trials and 2 companion papers enrolling 1170 patients. Using a Mantel-Haenszel random-effects model, iron supplementation was associated with reduced self-reported fatigue (standardised mean difference (SMD) −0.38; 95% CI −0.52 to −0.23; I2 0%; 4 trials; 714 participants) but was not associated with differences in objective measures of physical capacity, including maximal oxygen consumption (SMD 0.11; 95% CI −0.15 to 0.37; I2 0%; 9 trials; 235 participants) and timed methods of exercise testing. Iron supplementation significantly increased serum haemoglobin concentration (MD 4.01 g/L; 95% CI 1.22 to 6.81; I2 48%; 12 trials; 298 participants) and serum ferritin (MD 9.23 µmol/L; 95% CI 6.48 to 11.97; I2 58%; 14 trials; 616 participants).ConclusionIn IDNA adults, iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity. Given the global prevalence of both iron deficiency and fatigue, patients and practitioners could consider consumption of iron-rich foods or iron supplementation to improve symptoms of fatigue in the absence of documented anaemia.PROSPERO registration number CRD42014007085.

Heparin in patients with sepsis, septic shock, and disseminated intravascular coagulation associated with infection may be associated with decreased mortality; however, the overall impact remains uncertain. Safety outcomes have been underreported and require further study. Increased major bleeding with heparin administration cannot be excluded. Large rigorous randomized trials are needed to evaluate more carefully the efficacy and safety of heparin in patients with sepsis, severe sepsis, and septic shock.

Objectives: To characterize the prevalence, incidence, and temporal evolution of thrombocytopenia (platelets < 100 × 109/L) in septic shock and to investigate the independent association of thrombocytopenia on clinical outcomes. Design: Retrospective, propensity-matched, cohort study. Setting: Two academic ICUs in Winnipeg, Canada. Patients: Nine-hundred eighty adult patients diagnosed with septic shock between 2007 and 2012. Interventions: Propensity-matched cohort analysis and Cox proportional hazard model evaluating thrombocytopenia over time. Measurements and Main Results: Of 980 adults, 165 patients (16.8%) had thrombocytopenia at ICU admission (prevalent), whereas 271 (27.7%) developed thrombocytopenia during ICU admission (incident). Among patients with incident thrombocytopenia, the median time from ICU admission to thrombocytopenia was 2 days (interquartile range, 1–3 d). Among survivors, the median time from incident thrombocytopenia to platelet recovery was 6 days (interquartile range, 4–8 d). The median time from liberation of vasopressors to recovery of platelets concentration (≥ 100 × 109/L) was 2 days (interquartile range, 0–4 d). In a propensity-matched analysis, thrombocytopenia was associated with increased durations of ICU length of stay (9 vs 6 d; p < 0.01), mechanical ventilation (7 vs 4 d; p < 0.01), and vasopressor use (4 vs 3 d; p < 0.01), as well as increased major bleeding events (41% vs 18%; p < 0.01). In an adjusted Cox proportional hazards model, thrombocytopenia was significantly associated with both increased ICU mortality (hazard ratio, 1.99; 95% CI, 1.51–2.63) and hospital mortality (hazard ratio, 1.93; 95% CI, 1.48–2.51). Conclusions: Both the prevalence and incidence of thrombocytopenia are high in septic shock. Incident thrombocytopenia occurs early in septic shock, and platelet recovery lags behind clinical recovery. In septic shock, thrombocytopenia is associated with increased length of stay, longer duration of organ support, major bleeding events, and mortality.

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The levonorgestrel-releasing intrauterine system (LNG-IUS) is indicated for the management of menorrhagia and for contraception. The LNG-IUS is effective at reducing menstrual bleeding and improving haemoglobin among women with bleeding disorders. Expulsion rates for the LNG-IUS among normal women are reported to be approximately 5-10%. The aim of this study was to examine the malposition and expulsion rates of the LNG-IUS among women with inherited bleeding disorders. We conducted a retrospective study of women with an inherited bleeding disorder in Kingston, Canada treated with an LNG-IUS between May 2005 and June 2012. The primary outcome was a combined endpoint of expulsion and/or malposition. Predetermined secondary outcomes were patient satisfaction and changes in haemoglobin and ferritin levels. The median age of the women at the time of LNG-IUS insertion was 31 years (range 18-43, mean 32.1 years). The most common diagnosis was type 1 VWD (12/20, 60%). There were three LNG-IUS expulsions and two episodes of device malposition resulting in removal [5/20 (25.0%), 95% CI 11.2-46.9%]. An additional five women had their device removed prematurely. The overall proportion of devices resulting in discontinuation in this population was 10/20 (50.0%, 95% CI 29.9-70.1%). In this retrospective study, a significant proportion of women with an inherited bleeding disorder had an LGN-IUS removed due to poor patient satisfaction, malposition, or expulsion. Further studies into the causes of higher complication rates and interventions such as premedication or prolonged treatment with antifibrinolytic agents targeted at improving outcomes in this population are required.