Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke

Background We collaboratively designed three large trials of fluoxetine for stroke recovery to facilitate an individual patient data meta-analysis (IPDM). MethodsWe performed fixed effects meta-analyses on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months) and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined. FindingsWe recruited 5907 people (mean age 69∙5 years (SD 12∙3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, UK, Sweden and Vietnam; and randomized them to fluoxetine 20mg daily or matching placebo for 6 months. 5833 (98∙75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0∙96, 95% CI 0∙87 to 1∙05, p=0∙37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2∙64% vs 1∙8%, p=0∙03), falls with injury (6∙26% vs 4∙51%, p=0∙03), fractures (3∙15% vs 1∙39%, p&lt;0∙0001) and hyponatraemia (1∙22% vs 0∙61%, p=0∙01) but reduced new depression (10∙05% vs 13∙42%, p&lt;0∙0001). At 12 months, there was no difference in adjusted mRS (n=5760; COR 0∙98, 95% CI 0∙89 to 1∙07). Sensitivity analyses gave the same results.Interpretation Fluoxetine 20mg daily for six months did not improve functional recovery. It increased seizures, falls with injury, bone fractures but reduced depression frequency at 6 months. Trial Funding Stroke Association, National Institute of Health Research, Australian Government National Health and Medical Research Council, Swedish Research Council, Swedish Heart-Lung Foundation, Swedish Brain Foundation, Swedish Society of Medicine, King Gustav V and Queen Victoria's Foundation of Freemasons and STROKE-Riksförbundet <br/

INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): Study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial

Background: Early intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH.Methods: INTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), cluster-randomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (\u3c 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic \u3c 140 mmHg; glucose control, target 6.1-7.8 mmol/L and 7.8-10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio \u3c 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7-day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions.Discussion: As the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established.Trial registration: ClinicalTrials.gov NCT03209258. Registered on 1 July 2017. Chinese Trial Registry ChiCTR-IOC-17011787. Registered on 28 June 2017

SMARThealth Pregnancy: Feasibility and Acceptability of a Complex Intervention for High-Risk Pregnant Women in Rural India: Protocol for a Pilot Cluster Randomised Controlled Trial.

Introduction: India is in the process of a major epidemiological transition towards non-communicable diseases. Cardiovascular disease (CVD) is the leading cause of death in women in India. Predisposing independent risk factors include pregnancy-related conditions, e.g., hypertensive disorders of pregnancy (HDP) and gestational diabetes (GDM) - also associated with significant perinatal mortality and morbidity. Early identification, referral and management of pregnant women at increased risk of future CVD may offer opportunities for prevention. In rural India, Community Health Workers (CHWs) provide most antenatal and postnatal care. Innovative solutions are required to address integrated care for rural women during transitions between antenatal, postnatal and general health services. The George Institute's SMARThealth Programme has shown that CHWs in rural India screening non-pregnant adults for cardiovascular risk, using a decision support system, is feasible. Building on this, we developed a targeted training programme for CHWs and a complex system-level intervention that uses mobile clinical decision support for CHWs and primary care doctors to screen high-risk pregnant women. In addition to addressing HDP and GDM, the intervention also screens for anaemia in pregnancy. Methods/Design: A pilot study will be undertaken in two diverse rural districts of India: Jhajjar (Haryana) and Guntur (Andhra Pradesh). Two Primary Health Centre clusters will be randomised to intervention or control groups at each study site. The primary objective of this pilot study is to explore the feasibility and acceptability of the SMARThealth Pregnancy intervention. Secondary objectives are to estimate: (a) prevalence rates of moderate to severe anaemia, HDPs and GDM at the study sites; (b) referral and follow-up rates, and (c) mean haemoglobin and blood pressure values at the routine 6 week postnatal visit. A process evaluation will be conducted to explore the acceptability of the SMARThealth Pregnancy intervention for pregnant women and healthcare workers using qualitative methods. Discussion: It is anticipated that the findings of this pilot study will help determine the feasibility and acceptability of the SMARThealth Pregnancy intervention, and highlight how the intervention might be further developed for evaluation in a larger, cluster randomised controlled trial. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03968952

Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units

INTRODUCTION: Recent evidence suggests that choice of fluid used for resuscitation may influence mortality in critically ill patients. METHODS: We conducted a cross-sectional study in 391 intensive care units across 25 countries to describe the types of fluids administered during resuscitation episodes. We used generalized estimating equations to examine the association between patient, prescriber and geographic factors and the type of fluid administered (classified as crystalloid, colloid or blood products). RESULTS: During the 24-hour study period, 1,955 of 5,274 (37.1%) patients received resuscitation fluid during 4,488 resuscitation episodes. The main indications for administering crystalloid or colloid were impaired perfusion (1,526/3,419 (44.6%) of episodes), or to correct abnormal vital signs (1,189/3,419 (34.8%)). Overall, colloid was administered to more patients (1,234 (23.4%) versus 782 (14.8%)) and during more episodes (2,173 (48.4%) versus 1,468 (32.7%)) than crystalloid. After adjusting for patient and prescriber characteristics, practice varied significantly between countries with country being a strong independent determinant of the type of fluid prescribed. Compared to Canada where crystalloid, colloid and blood products were administered in 35.5%, 40.6% and 28.3% of resuscitation episodes respectively, odds ratios for the prescription of crystalloid in China, Great Britain and New Zealand were 0.46 (95% confidence interval (CI) 0.30 to 0.69), 0.18 (0.10 to 0.32) and 3.43 (1.71 to 6.84) respectively; odds ratios for the prescription of colloid in China, Great Britain and New Zealand were 1.72 (1.20 to 2.47), 4.72 (2.99 to 7.44) and 0.39 (0.21 to 0.74) respectively. In contrast, choice of fluid was not influenced by measures of illness severity (for example, Acute Physiology and Chronic Health Evaluation (APACHE) II score). CONCLUSIONS: Administration of resuscitation fluid is a common intervention in intensive care units and choice of fluid varies markedly between countries. Although colloid solutions are more expensive and may possibly be harmful in some patients, they were administered to more patients and during more resuscitation episodes than crystalloids were

A mobile clinical decision support system for high-risk pregnant women in rural India (SMARThealth Pregnancy): pilot cluster randomized controlled trial

Background: Cardiovascular disease (CVD) is the leading cause of death in women in India. Early identification is crucial to reducing deaths. Hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM) carry independent risks for future CVD, and antenatal care is a window to screen and counsel high-risk women. In rural India, community health workers (CHWs) deliver antenatal and postnatal care. We developed a complex intervention (SMARThealth Pregnancy) involving mobile clinical decision support for CHWs and evaluated it in a pilot cluster randomized controlled trial (cRCT). Objective: The aim of the study is to co-design a theory-informed intervention for CHWs to screen, refer, and counsel pregnant women at high risk of future CVD in rural India and evaluate its feasibility and acceptability. Methods: In phase 1, we used qualitative methods to explore community priorities for high-risk pregnant women in rural areas of 2 diverse states in India. In phase 2, informed by behavior change theory and human-centered design, we used these qualitative data to develop the intervention components and implementation strategies for SMARThealth Pregnancy in an iterative process with end users. In phase 3, using mixed methods, we evaluated the intervention in a cRCT with an embedded qualitative substudy across 4 primary health centres: 2 in Jhajjar district, Haryana, and 2 in Guntur district, Andhra Pradesh. Results: SMARThealth Pregnancy embedded a total of 15 behavior change techniques and included (1) community awareness programs; (2) targeted training, including point-of-care blood pressure and hemoglobin measurement; and (3) mobile clinical decision support for CHWs to screen women in their homes. The intervention focused on 3 priority conditions: anemia, HDP, and GDM. The evaluation involved a total of 200 pregnant women, equally randomized to intervention or enhanced standard care (control). Recruitment was completed within 5 months, with minimal loss to follow-up (4/200, 2%) at 6 weeks postpartum. A total of 4 primary care doctors and 54 CHWs in the intervention clusters took part in the study. Fidelity to intervention practices was 100% prepandemic. Over half the study population was affected by moderate to severe anemia at baseline. The prevalence of HDP (2.5%) and GDM (2%) was low in our study population. Results suggest a possible improvement in mean hemoglobin (anemia) in the intervention group, although an adequately powered trial is needed. The model of home-based care was feasible and acceptable for pregnant or postpartum women and CHWs, who perceived improvements in quality of care, self-efficacy, and professional recognition. Conclusions: SMARThealth Pregnancy is an innovative model of home-based care for high-risk pregnant women during the transitions between antenatal and postnatal care and adult health services. The use of theory and co-design during intervention development facilitated acceptability of the intervention and implementation strategies. Our experience has informed the decision to initiate a larger-scale cRCT. Trial Registration: ClinicalTrials.gov NCT03968952; https://clinicaltrials.gov/ct2/show/NCT03968952 International Registered Report Identifier (IRRID): RR2-10.3389/fgwh.2021.62075

Adjunctive Glucocorticoid Therapy in Patients with Septic Shock.

Background Whether hydrocortisone reduces mortality among patients with septic shock is unclear. Methods We randomly assigned patients with septic shock who were undergoing mechanical ventilation to receive hydrocortisone (at a dose of 200 mg per day) or placebo for 7 days or until death or discharge from the intensive care unit (ICU), whichever came first. The primary outcome was death from any cause at 90 days. Results From March 2013 through April 2017, a total of 3800 patients underwent randomization. Status with respect to the primary outcome was ascertained in 3658 patients (1832 of whom had been assigned to the hydrocortisone group and 1826 to the placebo group). At 90 days, 511 patients (27.9%) in the hydrocortisone group and 526 (28.8%) in the placebo group had died (odds ratio, 0.95; 95% confidence interval [CI], 0.82 to 1.10; P=0.50). The effect of the trial regimen was similar in six prespecified subgroups. Patients who had been assigned to receive hydrocortisone had faster resolution of shock than those assigned to the placebo group (median duration, 3 days [interquartile range, 2 to 5] vs. 4 days [interquartile range, 2 to 9]; hazard ratio, 1.32; 95% CI, 1.23 to 1.41; P<0.001). Patients in the hydrocortisone group had a shorter duration of the initial episode of mechanical ventilation than those in the placebo group (median, 6 days [interquartile range, 3 to 18] vs. 7 days [interquartile range, 3 to 24]; hazard ratio, 1.13; 95% CI, 1.05 to 1.22; P<0.001), but taking into account episodes of recurrence of ventilation, there were no significant differences in the number of days alive and free from mechanical ventilation. Fewer patients in the hydrocortisone group than in the placebo group received a blood transfusion (37.0% vs. 41.7%; odds ratio, 0.82; 95% CI, 0.72 to 0.94; P=0.004). There were no significant between-group differences with respect to mortality at 28 days, the rate of recurrence of shock, the number of days alive and out of the ICU, the number of days alive and out of the hospital, the recurrence of mechanical ventilation, the rate of renal-replacement therapy, and the incidence of new-onset bacteremia or fungemia. Conclusions Among patients with septic shock undergoing mechanical ventilation, a continuous infusion of hydrocortisone did not result in lower 90-day mortality than placebo. (Funded by the National Health and Medical Research Council of Australia and others; ADRENAL ClinicalTrials.gov number, NCT01448109 .)

Cluster-randomized, crossover trial of head positioning in acute stroke

The role of supine positioning after acute stroke in improving cerebral blood flow and the countervailing risk of aspiration pneumonia have led to variation in head positioning in clinical practice. We wanted to determine whether outcomes in patients with acute ischemic stroke could be improved by positioning the patient to be lying flat (i.e., fully supine with the back horizontal and the face upwards) during treatment to increase cerebral perfusion. METHODS In a pragmatic, cluster-randomized, crossover trial conducted in nine countries, we assigned 11,093 patients with acute stroke (85% of the strokes were ischemic) to receive care in either a lying-flat position or a sitting-up position with the head elevated to at least 30 degrees, according to the randomization assignment of the hospital to which they were admitted; the designated position was initiated soon after hospital admission and was maintained for 24 hours. The primary outcome was degree of disability at 90 days, as assessed with the use of the modified Rankin scale (scores range from 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death). RESULTS The median interval between the onset of stroke symptoms and the initiation of the assigned position was 14 hours (interquartile range, 5 to 35). Patients in the lying-flat group were less likely than patients in the sitting-up group to maintain the position for 24 hours (87% vs. 95%, P\u3c0.001). In a proportional-odds model, there was no significant shift in the distribution of 90-day disability outcomes on the global modified Rankin scale between patients in the lying-flat group and patients in the sitting-up group (unadjusted odds ratio for a difference in the distribution of scores on the modified Rankin scale in the lying-flat group, 1.01; 95% confidence interval, 0.92 to 1.10; P = 0.84). Mortality within 90 days was 7.3% among the patients in the lying-flat group and 7.4% among the patients in the sitting-up group (P = 0.83). There were no significant betweengroup differences in the rates of serious adverse events, including pneumonia. CONCLUSIONS Disability outcomes after acute stroke did not differ significantly between patients assigned to a lying-flat position for 24 hours and patients assigned to a sitting-up position with the head elevated to at least 30 degrees for 24 hours

Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke

Background Three large randomised controlled trials of fluoxetine for stroke recovery have been performed. We perfomed an individual patient data meta-analysis (IPDM) on the combined data. Methods Fixed effects meta-analyses was performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined. Findings The three trials recruited a combined total of 5907 people (mean age 69∙5 years (SD 12∙3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, UK, Sweden and Vietnam; and randomized them to fluoxetine 20mg daily or matching placebo for 6 months. Data on 5833 (98∙75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0∙96, 95% CI 0∙87 to 1∙05, p=0∙37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2∙64% vs 1∙8%, p=0∙03), falls with injury (6∙26% vs 4∙51%, p=0∙03), fractures (3∙15% vs 1∙39%, p<0∙0001) and hyponatraemia (1∙22% vs 0∙61%, p=0∙01) but reduced new depression (10∙05% vs 13∙42%, p<0∙0001). At 12 months, there was no difference in adjusted mRS (n=5760; COR 0∙98, 95% CI 0∙89 to 1∙07). Sensitivity analyses gave the same results. Interpretation Fluoxetine 20mg daily for six months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months

Family-led rehabilitation after stroke in India: a randomised controlled trial

Background: Most people with stroke in India have no access to organised rehabilitation services. The effectiveness of training family members to provide stroke rehabilitation is uncertain. Our primary objective was to determine whether family-led stroke rehabilitation, initiated in hospital and continued at home, would be superior to usual care, in a low resource setting. Methods: The Family-led Rehabilitation after Stroke in India (ATTEND) trial was a prospectively randomised open trial with blinded endpoints (PROBE) conducted across 14 hospitals in India. Patients (and their caregivers) were randomised to intervention or usual care by site Coordinators, using a secure web-based system, with minimisation by site and stroke severity. The intervention group received additional structured rehabilitation training, commenced in hospital and continued at home for up to 2 months. The primary outcome was death or dependency, defined by scores 3 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) as assessed by blinded observers at six months. Secondary outcomes included any serious adverse event, hospital length of stay, activities of daily living, health-related quality of life, anxiety and depression, and caregiver strain. All analyses were intention to treat. Registration: Clinical Trials Registry-India (CTRI/2013/04/003557); Australian New Zealand Clinical Trials Registry (ACTRN12613000078752); and Universal Trial Number (U1111-1138-6707) Findings: A total of 1,250 patients were randomised (623 intervention and 627 control) between 13 January 2014 and 12 February 2016. At six months, 285 of 607 (47·0%) participants in the intervention group were dead or dependent compared to 287 of 605 (47·4%) in the control group (odds ratio 0·98; 95% confidence Interval 0·78 to 1·23, P = 0·87). No significant differences were observed in any of the secondary or safety outcomes. Interpretation: Family-led rehabilitation did not reduce death or dependency after stroke

No benefit of flat head positioning in early moderate-severe acute ischemic stroke: HeadPoST study subgroup analysis

Background Although the Head Positioning in acute Stroke Trial (HeadPoST) showed no effect of the flat head position (FP; vs sitting up head position (SUP)) on functional outcome, we hypothesised that it could still offer benefits if commenced early in those with acute ischaemic stroke (AIS) of at least moderate severity. Methods Subgroup analysis of HeadPoST in participants with National Institutes of Health Stroke Scale (NIHSS) scores ≥7, ≥10 and ≥14, randomised to FP or SUP <4.5 hours of AIS onset on functional outcomes defined by a shift in scores on the modified Rankin scale (mRS) and death/disability (mRS scores 3–6), and any cardiovascular serious adverse event. Logistic regression analyses were undertaken adjusted for study design and baseline risk factors. Results There was no significant differential treatment effect in patient subgroups defined by increasing baseline NIHSS scores: adjusted OR and 95% CI for ordinal shift and binary (3–6) mRS scores: for NIHSS ≥7 (n=867) 0.92 (0.67 to 1.25) and 0.74 (0.52 to 1.04); NIHSS ≥ 10 (n=606) 0.80 (0.58 to 1.10) and 0.77 (0.49 to 1.19); NIHSS ≥14 (n=378) 0.82 (0.54 to 1.24) and 1.22 (0.69 to 2.14). Conclusions Early FP had no significant effect in patients with moderate–severe AI