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Background Excess morbidity and mortality following critical illness is increasingly attributed to potentially avoidable complications occurring as a result of complex ICU management (Berenholtz et al., J Crit Care 17:1-2, 2002; De Vos et al., J Crit Care 22:267-74, 2007; Zimmerman J Crit Care 1:12-5, 2002). Routine measurement of quality indicators (QIs) through an Electronic Health Record (EHR) or registries are increasingly used to benchmark care and evaluate improvement interventions. However, existing indicators of quality for intensive care are derived almost exclusively from relatively narrow subsets of ICU patients from high-income healthcare systems. The aim of this scoping review is to systematically review the literature on QIs for evaluating critical care, identify QIs, map their definitions, evidence base, and describe the variances in measurement, and both the reported advantages and challenges of implementation. Method We searched MEDLINE, EMBASE, CINAHL, and the Cochrane libraries from the earliest available date through to January 2019. To increase the sensitivity of the search, grey literature and reference lists were reviewed. Minimum inclusion criteria were a description of one or more QIs designed to evaluate care for patients in ICU captured through a registry platform or EHR adapted for quality of care surveillance. Results The search identified 4780 citations. Review of abstracts led to retrieval of 276 full-text articles, of which 123 articles were accepted. Fifty-one unique QIs in ICU were classified using the three components of health care quality proposed by the High Quality Health Systems (HQSS) framework. Adverse events including hospital acquired infections (13.7%), hospital processes (54.9%), and outcomes (31.4%) were the most common QIs identified. Patient reported outcome QIs accounted for less than 6%. Barriers to the implementation of QIs were described in 35.7% of articles and divided into operational barriers (51%) and acceptability barriers (49%). Conclusions Despite the complexity and risk associated with ICU care, there are only a small number of operational indicators used. Future selection of QIs would benefit from a stakeholder-driven approach, whereby the values of patients and communities and the priorities for actionable improvement as perceived by healthcare providers are prioritized and include greater focus on measuring discriminable processes of care.

Epidemiology, ventilator management, and outcome in patients receiving invasive ventilation in intensive care units (ICUs) in middle-income countries are largely unknown. PRactice of VENTilation in Middle-income Countries is an international multicenter 4-week observational study of invasively ventilated adult patients in 54 ICUs from 10 Asian countries conducted in 2017/18. Study outcomes included major ventilator settings (including tidal volume [VT] and positive end-expiratory pressure [PEEP]); the proportion of patients at risk for acute respiratory distress syndrome (ARDS), according to the lung injury prediction score (LIPS), or with ARDS; the incidence of pulmonary complications; and ICU mortality. In 1,315 patients included, median VT was similar in patients with LIPS < 4 and patients with LIPS ≥ 4, but lower in patients with ARDS (7.90 [6.8–8.9], 8.0 [6.8–9.2], and 7.0 [5.8–8.4] mL/kg Predicted body weight; P = 0.0001). Median PEEP was similar in patients with LIPS < 4 and LIPS ≥ 4, but higher in patients with ARDS (five [5–7], five [5–8], and 10 [5–12] cmH2O; P < 0.0001). The proportions of patients with LIPS ≥ 4 or with ARDS were 68% (95% CI: 66–71) and 7% (95% CI: 6–8), respectively. Pulmonary complications increased stepwise from patients with LIPS < 4 to patients with LIPS ≥ 4 and patients with ARDS (19%, 21%, and 38% respectively; P = 0.0002), with a similar trend in ICU mortality (17%, 34%, and 45% respectively; P < 0.0001). The capacity of the LIPS to predict development of ARDS was poor (receiver operating characteristic [ROC] area under the curve [AUC] of 0.62, 95% CI: 0.54–0.70). In Asian middle-income countries, where two-thirds of ventilated patients are at risk for ARDS according to the LIPS and pulmonary complications are frequent, setting of VT is globally in line with current recommendations.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Background The burden of critical illness in low-income countries is high and expected to rise. This has implications for wider public health measures including maternal mortality, deaths from communicable diseases, and the global burden of disease related to injury. There is a paucity of data pertaining to the provision of critical care in low-income countries. This study provides a review of critical care services in Ethiopia. Methods Multicenter structured onsite surveys incorporating face-to-face interviews, narrative discussions, and on-site assessment were conducted at intensive care units (ICUs) in September 2020 to ascertain structure, organization, workforce, resources, and service capacity. The 12 recommended variables and classification criteria of the World Federation of Societies of Intensive and Critical Care Medicine (WFSICCM) taskforce criteria were utilized to provide an overview of service and service classification. Results A total of 51 of 53 (96%) ICUs were included, representing 324 beds, for a population of 114 million; this corresponds to approximately 0.3 public ICU beds per 100,000 population. Services were concentrated in the capital Addis Ababa with 25% of bed capacity and 51% of critical care physicians. No ICU had piped oxygen. Only 33% (106) beds had all of the 3 basic recommended noninvasive monitoring devices (sphygmomanometer, pulse oximetry, and electrocardiography). There was limited capacity for ventilation (n = 189; 58%), invasive monitoring (n = 9; 3%), and renal dialysis (n = 4; 8%). Infection prevention and control strategies were lacking. Conclusions This study highlights major deficiencies in quantity, distribution, organization, and provision of intensive care in Ethiopia. Improvement efforts led by the Ministry of Health with input from the acute care workforce are an urgent priority.

Objective To assess the number of adult critical care beds in Asian countries and regions in relation to population size. Design Cross-sectional observational study. Setting Twenty-three Asian countries and regions, covering 92.1% of the continent's population. Participants Ten low-income and lower-middle-income economies, five upper-middle-income economies, and eight high-income economies according to the World Bank classification. Interventions Data closest to 2017 on critical care beds, including ICU and intermediate care unit beds, were obtained through multiple means, including government sources, national critical care societies, colleges, or registries, personal contacts, and extrapolation of data. Measurements and main results Cumulatively, there were 3.6 critical care beds per 100,000 population. The median number of critical care beds per 100,000 population per country and region was significantly lower in low- and lower-middle-income economies (2.3; interquartile range, 1.4-2.7) than in upper-middle-income economies (4.6; interquartile range, 3.5-15.9) and high-income economies (12.3; interquartile range, 8.1-20.8) (p = 0.001), with a large variation even across countries and regions of the same World Bank income classification. This number was independently predicted by the World Bank income classification on multivariable analysis, and significantly correlated with the number of acute hospital beds per 100,000 population (r = 0.19; p = 0.047), the universal health coverage service coverage index (r = 0.35; p = 0.003), and the Human Development Index (r = 0.40; p = 0.001) on univariable analysis. Conclusions Critical care bed capacity varies widely across Asia and is significantly lower in low- and lower-middle-income than in upper-middle-income and high-income countries and regions.

Purpose The impact of disruption to the care of non-coronavirus disease (COVID) patients (COVID collateral damage syndrome-CCDS) is largely unknown in resource-limited settings. We investigated CCDS as perceived by healthcare workers (HCWs) providing acute and critical care services in India. Materials and methods A clinician and nurse codesigned and validated an internet-based survey, which was disseminated to HCWs using a multiple frame sampling technique. Results Responses were received from 468 HCWs (completion rate 84%); at the time of the survey, 48% were working in critical care, 41% aged 30–40 years, and 53% represented public institutions. Respondents perceived a decrease in service utilization and disruption to time-sensitive acute interventions (60.1% and 40.8%, respectively), with fear of infection (score, 63.0; standard deviation (SD), 31.8) and restrictions due to lockdown (61.4; SD 32.5) being cited as the causes of service disruption. Being overwhelmed or lack of protective equipment was perceived to contribute less to CCDS. Insistence on COVID test results X2 (p = 0.02) and duty-avoidance (p < 0.01) was perceived as significant causes for CCDS by HCWs from private hospitals and those in leadership roles, respectively. Conclusions Fear of infection and the effect of lockdown were perceived as important contributors to CCDS resulting in disruption to services and decreased service utilization. Perceptions were influenced by HCWs’ role and hospital organizational structure. How to cite this article Tripathy S, Vijayaraghavan BKT, Panigrahi MK, Shetty AP, Haniffa R, Mishra RC, et al. Collateral Impact of the COVID-19 Pandemic on Acute Care of Non-COVID Patients: An Internet-based Survey of Critical Care and Emergency Personnel. Indian J Crit Care Med 2021;25(4):374–381.

Purpose of review Critical care registries are synonymous with measurement of outcomes following critical illness. Their ability to provide longitudinal data to enable benchmarking of outcomes for comparison within units over time, and between units, both regionally and nationally is a key part of the evaluation of quality of care and ICU performance as well as a better understanding of case-mix. This review aims to summarize literature on outcome measures currently being reported in registries internationally, describe the current strengths and challenges with interpreting existing outcomes and highlight areas where registries may help improve implementation and interpretation of both existing and new outcome measures. Recent findings Outcomes being widely reported through ICU registries include measures of survival, events of interest, patient-reported outcomes and measures of resource utilization (including cost). Despite its increasing adoption, challenges with quality of reporting of outcomes measures remain. Measures of short-term survival are feasible but those requiring longer follow-ups are increasingly difficult to interpret given the evolving nature of critical care in the context of acute and chronic disease management. Furthermore, heterogeneity in patient populations and in healthcare organisations in different settings makes use of outcome measures for international benchmarking at best complex, requiring substantial advances in their definitions and implementation to support those seeking to improve patient care. Summary Digital registries could help overcome some of the current challenges with implementing and interpreting ICU outcome data through standardization of reporting and harmonization of data. In addition, ICU registries could be instrumental in enabling data for feedback as part of improvement in both patient-centred outcomes and in service outcomes; notably resource utilization and efficiency.

BACKGROUNDThrombosis and inflammation may contribute to the risk of death and complications among patients with coronavirus disease 2019 (Covid-19). We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.METHODSIn this open-label, adaptive, multiplatform, controlled trial, we randomly assigned patients who were hospitalized with Covid-19 and who were not critically ill (which was defined as an absence of critical care–level organ support at enrollment) to receive pragmatically defined regimens of either therapeutic-dose anticoagulation with heparin or usual-care pharmacologic thromboprophylaxis. The primary outcome was organ support–free days, evaluated on an ordinal scale that combined in-hospital death (assigned a value of −1) and the number of days free of cardiovascular or respiratory organ support up to day 21 among patients who survived to hospital discharge. This outcome was evaluated with the use of a Bayesian statistical model for all patients and according to the baseline d-dimer level.RESULTSThe trial was stopped when prespecified criteria for the superiority of therapeutic-dose anticoagulation were met. Among 2219 patients in the final analysis, the probability that therapeutic-dose anticoagulation increased organ support–free days as compared with usual-care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03 to 1.58). The adjusted absolute between-group difference in survival until hospital discharge without organ support favoring therapeutic-dose anticoagulation was 4.0 percentage points (95% credible interval, 0.5 to 7.2). The final probability of the superiority of therapeutic-dose anticoagulation over usual-care thromboprophylaxis was 97.3% in the high d-dimer cohort, 92.9% in the low d-dimer cohort, and 97.3% in the unknown d-dimer cohort. Major bleeding occurred in 1.9% of the patients receiving therapeutic-dose anticoagulation and in 0.9% of those receiving thromboprophylaxis.CONCLUSIONSIn noncritically ill patients with Covid-19, an initial strategy of therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support as compared with usual-care thromboprophylaxis. (ATTACC, ACTIV-4a, and REMAP-CAP ClinicalTrials.gov numbers, NCT04372589. opens in new tab, NCT04505774. opens in new tab, NCT02735707. opens in new tab, and NCT04359277. opens in new tab.)

AimsAtrial fibrillation is frequently encountered in critical illness and causes adverse effects including haemodynamic decompensation, stroke and longer hospital stay. It is common to supplement serum magnesium for the purpose of preventing new-onset atrial fibrillation. However, no randomised studies support this practice in the non-cardiac surgery critical care population, and its effectiveness is unclear. We sought to investigate the effectiveness of magnesium supplementation in preventing new-onset atrial fibrillation in a mixed critical care population.MethodsWe conducted a single centre retrospective observational study of adult critical care patients. We employed a natural experiment design, using the supplementation preference of the bedside critical care nurse as an instrumental variable.Using the electronic patient record, magnesium supplementation opportunities were defined and linked to the bedside nurse. Nurse preference for administering magnesium was obtained using multilevel modelling. The results were used to define ‘pro’ and ‘anti’ supplementation groups, which were inputted into an instrumental variable regression to obtain an estimate of the effect of magnesium supplementation.Results9,114 magnesium supplementation opportunities were analysed, representing 2,137 critical care admissions for 1,914 patients. There was significant variation in magnesium supplementation practices attributable to the individual nurse, after accounting for covariates. The instrumental variable analysis showed magnesium supplementation was associated with a 3% decreased chance of experiencing new-onset atrial fibrillation (95% CI −0.06 to −0.04, p = 0.03).ConclusionsThis study supports the strategy of routine magnesium supplementation, but further work is required to identify optimal serum magnesium targets for prophylaxis of atrial fibrillation.What’s New?Routine administration of supplemental magnesium sulphate is associated with a reduced chance of developing new-onset Atrial Fibrillation, in a general critical care cohort.This finding agrees with previous Randomised Controlled Trial results which are limited to the cardiac critical care population.This finding disagrees with previously published observational studies, which is likely due to better control of unmeasured confounding.There is significant variation in serum magnesium supplementation attributable to the individual bedside critical care nurse.Electronic health records offer the ability to evaluate the effectiveness of routinely administered treatments which lack evidence in an affordable way.Natural experiments and instrumental variable analysis offer the opportunity to derive causally robust estimations of treatment effectiveness by better accounting for unobserved confounding.

Importance The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.Objective To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.Design, Setting, and Participants The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021.Interventions The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916).Main Outcomes and Measures The primary ordinal end point was organ support–free days (days alive and free of intensive care unit–based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned –1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support–free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support–free days; cardiovascular support–free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.Results Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support–free days was 0 (IQR, –1 to 16) in the convalescent plasma group and 3 (IQR, –1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR Conclusions and Relevance Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support–free days.Trial Registration ClinicalTrials.gov Identifier: NCT02735707

Background Reports on the occurrence and outcome of Visceral Leishmaniasis (VL) in pregnant women is rare in published literature. The occurrence of VL in pregnancy is not systematically captured and cases are rarely followed-up to detect consequences of infection and treatment on the mother and foetus. Methods A review of all published literature was undertaken to identify cases of VL infections during pregnancy by searching the following database: Ovid MEDLINE®; Ovid Embase; Cochrane Database of Systematic Reviews; Cochrane Central Register of Controlled Trials; World Health Organization Global Index Medicus: LILACS (Americas); IMSEAR (South- East Asia); IMEMR (Eastern Mediterranean); WPRIM (Western Pacific); ClinicalTrials.gov; and the WHO International Clinical Trials Registry Platform. Selection criteria included any clinical reports describing the disease in pregnancy or vertical transmission of the disease in humans. Articles meeting pre-specified inclusion criteria and non-primary research articles such as textbook, chapters, letters, retrospective case description, or reports of accidental inclusion in trials were also considered. Results We screened 272 publications and identified a total of 70 records (1926–2020) describing 447 VL cases in pregnant women. The disease was detected during pregnancy in 394 (88.1%), retrospectively confirmed after giving birth in 52 (11.6%), and the time of identification was not clear in 1 (0.2%). Of the 394 mothers whose infection was identified during pregnancy, 344 (89.1%) received a treatment, 3 (0.8%) were untreated, and the treatment status was not clear in the remaining 47 (12.2%). Of 344 mothers, Liposomal Amphotericin B (L-AmB) was administered in 202 (58.7%) and pentavalent antimony (PA) in 92 (26.7%). Outcomes were reported in 176 mothers treated L-AmB with 4 (2.3%) reports of maternal deaths, 5 (2.8%) miscarriages, and 2 (1.1%) foetal death/stillbirth. For PA, outcomes were reported in 87 mothers of whom 4 (4.6%) died, 24 (27.6%) had spontaneous abortion, 2 (2.3%) had miscarriages. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified and the median time to detection was 6 months (range: 0–18 months). Conclusions Outcomes of VL treatment during pregnancy is rarely reported and under- researched. When it is reported, information is often incomplete and it is difficult to derive generalisable information on outcomes for mothers and babies, although reported data favours the usage of liposomal amphotericin B for the treatment of VL in pregnant women. Author summary Visceral Leishmaniasis (VL) is a neglected tropical disease with an estimated incidence of 50,000 to 90,000 cases in 2019. Women who are susceptible to becoming pregnant or those who are pregnant and lactating are regularly excluded from clinical studies of VL. A specific concern of public health relevance is the little knowledge of the consequences of VL and its treatment on the mother and the foetus. We did a systematic review of all published literature with an overarching aim of identifying cases of VL in pregnancy and assess the risk-benefit balance of antileishmanial therapies to the mother and the child. We identified a total of 70 records (1926–2020) describing 447 VL cases in pregnant women. In 394 mothers, infection was identified during pregnancy of whom 202 received Liposomal Amphotericin B (L-AmB) and 92 received pentavalent antimony (PA). Reports of maternal deaths, abortion, and miscarriages were proportionally lower among those who received L- AmB compared to PA regimens. A total of 26 cases of confirmed, probable or suspected cases of vertical transmission were identified and the median time to detection was 6 months (range: 0–18 months). Our review brings together scattered observations of VL in pregnant women in the clinical literature and clearly highlights that the disease in pregnancy is under-reported and under-studied. Our findings indicate that L-AmB should be the preferred treatment for VL during pregnancy.

Background: The value of medical registries strongly depends on the quality of the data collected. This must be objectively measured before large clinical databases can be promoted for observational research, quality improvement, and clinical trials. We aimed to evaluate the quality of a multinational intensive care unit (ICU) network of registries of critically ill patients established in seven Asian low- and middle-income countries (LMICs). Methods: The Critical Care Asia federated registry platform enables ICUs to collect clinical, outcome and process data for aggregate and unit-level analysis. The evaluation used the standardised criteria of the Directory of Clinical Databases (DoCDat) and a framework for data quality assurance in medical registries. Six reviewers assessed structure, coverage, reliability and validity of the ICU registry data. Case mix and process measures on patient episodes from June to December 2020 were analysed. Results: Data on 20,507 consecutive patient episodes from 97 ICUs in Afghanistan, Bangladesh, India, Malaysia, Nepal, Pakistan and Vietnam were included. The quality level achieved according to the ten prespecified DoCDat criteria was high (average score 3.4 out of 4) as was the structural and organizational performance -- comparable to ICU registries in high-income countries. Identified strengths were types of variables included, reliability of coding, data completeness and validation. Potential improvements included extension of national coverage, optimization of recruitment completeness validation in all centers and the use of interobserver reliability checks. Conclusions: The Critical Care Asia platform evaluates well using standardised frameworks for data quality and equally to registries in resource-rich settings.

Background: The epidemiology of critical illness in India is distinct from high-income countries. However, limited data exist on resource availability, staffing patterns, case-mix and outcomes from critical illness. Critical care registries, by enabling a continual evaluation of service provision, epidemiology, resource availability and quality, can bridge these gaps in information. In January 2019, we established the Indian Registry of IntenSive care to map capacity and describe case-mix and outcomes. In this report, we describe the implementation process, preliminary results, opportunities for improvement, challenges and future directions. Methods: All adult and paediatric ICUs in India were eligible to join if they committed to entering data for ICU admissions. Data are collected by a designated representative through the electronic data collection platform of the registry. IRIS hosts data on a secure cloud-based server and access to the data is restricted to designated personnel and is protected with standard firewall and a valid secure socket layer (SSL) certificate. Each participating ICU owns and has access to its own data. All participating units have access to de-identified network-wide aggregate data which enables benchmarking and comparison. Results: The registry currently includes 14 adult and 1 paediatric ICU in the network (232 adult ICU beds and 9 paediatric ICU beds). There have been 8721 patient encounters with a mean age of 56.9 (SD 18.9); 61.4% of patients were male and admissions to participating ICUs were predominantly unplanned (87.5%). At admission, most patients (61.5%) received antibiotics, 17.3% needed vasopressors, and 23.7% were mechanically ventilated. Mortality for the entire cohort was 9%. Data availability for demographics, clinical parameters, and indicators of admission severity was greater than 95%. Conclusions: IRIS represents a successful model for the continual evaluation of critical illness epidemiology in India and provides a framework for the deployment of multi-centre quality improvement and context-relevant clinical research.

Background Chagas disease (CD), caused by the parasite Trypanosoma cruzi, affects ~6–7 million people worldwide. Significant limitations still exist in our understanding of CD. Harnessing individual participant data (IPD) from studies could support more in-depth analyses to address the many outstanding research questions. This systematic review aims to describe the characteristics and treatment practices of clinical studies in CD and assess the breadth and availability of research data for the potential establishment of a data-sharing platform. Methodology/Principal findings This review includes prospective CD clinical studies published after 1997 with patients receiving a trypanocidal treatment. The following electronic databases and clinical trial registry platforms were searched: Cochrane Library, PubMed, Embase, LILACS, Scielo, Clintrials.gov, and WHO ICTRP. Of the 11,966 unique citations screened, 109 (0.9%) studies (31 observational and 78 interventional) representing 23,116 patients were included. Diagnosis for patient enrolment required 1 positive test result in 5 (4.6%) studies (2 used molecular method, 1 used molecular and serology, 2 used serology and parasitological methods), 2 in 60 (55.0%), 3 in 14 (12.8%) and 4 or more in 4 (3.7%) studies. A description of treatment regimen was available for 19,199 (83.1%) patients, of whom 14,605 (76.1%) received an active treatment and 4,594 (23.9%) were assigned to a placebo/no-treatment. Of the 14,605 patients who received an active treatment, benznidazole was administered in 12,467 (85.4%), nifurtimox in 825 (5.6%), itraconazole in 284 (1.9%), allopurinol in 251 (1.7%) and other drugs in 286 (1.9%). Assessment of efficacy varied largely and was based primarily on biological outcome; parasitological efficacy relied on serology in 67/85 (78.8%) studies, molecular methods in 52/85 (61.2%), parasitological in 34/85 (40.0%), microscopy in 3/85 (3.5%) and immunohistochemistry in 1/85 (1.2%). The median time at which parasitological assessment was carried out was 79 days [interquartile range (IQR): 30–180] for the first assessment, 180 days [IQR: 60–500] for second, and 270 days [IQR: 18–545] for the third assessment. Conclusions/Significance This review demonstrates the heterogeneity of clinical practice in CD treatment and in the conduct of clinical studies. The sheer volume of potential IPD identified demonstrates the potential for development of an IPD platform for CD and that such efforts would enable in-depth analyses to optimise the limited pharmacopoeia of CD and inform prospective data collection., Author summary Chagas disease, also known as American trypanosomiasis, is a neglected tropical disease transmitted by triatomine insects, first identified in 1909. Chagas disease affects approximately 6–7 million people globally and is highly prevalent in Latin America where most cases are reported. However, there is increasing evidence that Chagas disease is now an important public health issue outside the “classical” endemic countries due to population migration. Our understanding of Chagas disease, including its pathologies and factors relating to progression, remains to date limited, and is also challenged by lack of diagnosis and highly effective treatment. This systematic review aims to describe studies with Chagas patients receiving antiparasitic treatment. Databases were searched for relevant studies published after 1997, and the results of these searches were screened. Although a large volume of studies was identified in the review, heterogeneity was observed in study design, diagnostic methods, outcome assessment, and treatment regimens. While this aspect will be a limitation in pooling individual patient data, the volume of data available should allow sufficient comparison to form the basis of guidelines for future studies. The results of this review demonstrate that development of a Chagas disease data platform for clinical research would enable optimisation of existing data to strengthen evidence for the treatment and diagnosis of Chagas disease.

ObjectiveWe aimed to evaluate the quality of a multinational intensive care unit (ICU) network of registries of critically ill patients established in seven Asian low and middle income countries (LMICs).MethodsThe Critical Care Asia federated registry platform enables ICUs to collect clinical, outcome and process data for aggregate and unit-level analysis. The evaluation used the standardised criteria of the Directory of Clinical Databases (DoCDat) and a framework for data quality assurance in medical registries. Six reviewers assessed structure, coverage, reliability and validity of the ICU registry data. Case mix and process measures on patient episodes from June to December 2020 were analysed.ResultsData on 20,507 consecutive patient episodes from 97 ICUs in Afghanistan, Bangladesh, India, Malaysia, Nepal, Pakistan and Vietnam were included. The quality level achieved according to the ten prespecified DoCDat criteria was high (average score 3.4 out of 4) as was the structural and organizational performance -- comparable to ICU registries in high-income countries. Identified strengths were types of variables included, reliability of coding, data completeness and validation. Potential improvements include extension of national coverage.ConclusionThe Critical Care Asia platform evaluates well using standardised frameworks for data quality and equally to registries in resource-rich settings.FundingThis work was undertaken as part of the existing Wellcome Innovations Flagship award, Collaboration for Research, Improvement and Training in Critical CARE in ASIA (ref. 215522/Z/19/Z). The funder had no role in the decision to publish or in the preparation of this manuscript.

BACKGROUNDThe evidence for benefit of convalescent plasma for critically ill patients with Covid-19 is inconsistent. We hypothesized that convalescent plasma would improve outcomes for critically ill adult patients with Covid-19.METHODSIn an ongoing adaptive platform trial, critically ill patients with confirmed Covid-19, defined as receiving intensive care-level organ support, were randomized to open-label convalescent plasma or not (i.e., control group). The primary end point was organ support-free days (i.e., days alive and free of ICU-based organ support) up to day 21. The primary analysis was a Bayesian cumulative logistic model with predefined criteria for superiority or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both.RESULTSThe convalescent plasma intervention was stopped after pre-specified criteria for futility were met. At that time, 1084 participants had been randomized to convalescent plasma and 916 to no convalescent plasma (control). The median organ support-free days were 0 (interquartile range, -1 to 16) for the convalescent plasma group and 3 (interquartile range, -1 to 16) days for the control group. The median adjusted odds ratio (OR) was 0.97 (95% credible interval 0.83 to 1.15) and posterior probability of futility (OR < 1.2) was 99.4% for convalescent plasma compared to control. In-hospital mortality was 37.3% (401/1075) in convalescent plasma group, and 38.4% (347/904) in controls. The observed treatment effects were consistent across primary and secondary outcomes.CONCLUSIONSIn critically ill adults with confirmed Covid-19, treatment with convalescent plasma, did not improve clinical outcomes.Clinicaltrials.gov:NCT02735707

Therapeutic efficacy in COVID-19 is dependent upon disease stage and severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation ‘living’ guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of “lack of therapeutic benefit” shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19.

Background Despite a historical association with poor tolerability, a comprehensive review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs). Methods For this updated systematic review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression. Results We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041–0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001–2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368–1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021–0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244–1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020–0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections. Conclusion Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research., Author summary Visceral leishmaniasis, also known as Kala-Azar, is a neglected infectious disease of poverty affecting countries in the Indian Subcontinent and Eastern Africa. Existing treatments have concerning safety profiles and are far from ideal, with documented reports of serious adverse events (SAEs) following therapy. We did a systematic review of all published clinical trials in VL (1980–2019) to document SAEs following treatment administration reported in clinical literature and carried out a meta-analysis to quantify the incidence rate of mortality within 30 days of treatment initiation. We found that safety outcomes are poorly reported in published literature with substantial missing information regarding timing and frequency of the events. We also observed that mortality following treatment with antileishmanial drugs, as reported in the literature, is a rare event. There was substantial variability in mortality rates across geographical regions and patient sub-groups. Results from this review can provide benchmark estimates for comparing data from prospective trials and pharmacovigilance studies and support the need to assemble individual patient data (IPD) to conduct a robust IPD meta-analyses to overcome some of the underlying limitations.

Background: Coronavirus disease 2019 (COVID-19) has been responsible for over 3.4 million deaths globally and over 25 million cases in India. As part of the response, India imposed a nation-wide lockdown and prioritized COVID-19 care in hospitals and intensive care units (ICUs). Leveraging data from the Indian Registry of IntenSive care, we sought to understand the impact of the COVID-19 pandemic on critical care service utilization, case-mix, and clinical outcomes in non-COVID ICUs. Methods: We included all consecutive patients admitted between 1st October 2019 and 27th September 2020. Data were extracted from the registry database and included patients admitted to the non-COVID or general ICUs at each of the sites. Outcomes included measures of resource-availability, utilisation, case-mix, acuity, and demand for ICU beds. We used a Mann-Whitney test to compare the pre-pandemic period (October 2019 - February 2020) to the pandemic period (March-September 2020). In addition, we also compared the period of intense lockdown (March-May 31st 2020) with the pre-pandemic period. Results: There were 3424 patient encounters in the pre-pandemic period and 3524 encounters in the pandemic period. Comparing these periods, weekly admissions declined (median [Q1 Q3] 160 [145,168] to 113 [98.5,134]; p=0.00002); unit turnover declined (median [Q1 Q3] 12.1 [11.32,13] to 8.58 [7.24,10], p Conclusion: Our registry-based analysis of the impact of COVID-19 on non-COVID critical care demonstrates significant disruptions to healthcare utilization during the pandemic and an increase in the severity of illness.

BackgroundThe efficacy of interleukin-6 receptor antagonists in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.MethodsWe evaluated tocilizumab and sarilumab in an ongoing international, multifactorial, adaptive platform trial. Adult patients with Covid-19, within 24 hours of commencing organ support in an intensive care unit, were randomized to receive either tocilizumab (8mg/kg) or sarilumab (400mg) or standard care (control). The primary outcome was an ordinal scale combining in-hospital mortality (assigned −1) and days free of organ support to day 21. The trial uses a Bayesian statistical model with pre-defined triggers to declare superiority, efficacy, equivalence or futility.ResultsTocilizumab and sarilumab both met the pre-defined triggers for efficacy. At the time of full analysis 353 patients had been assigned to tocilizumab, 48 to sarilumab and 402 to control. Median organ support-free days were 10 (interquartile range [IQR] −1, 16), 11 (IQR 0, 16) and 0 (IQR −1, 15) for tocilizumab, sarilumab and control, respectively. Relative to control, median adjusted odds ratios were 1.64 (95% credible intervals [CrI] 1.25, 2.14) for tocilizumab and 1.76 (95%CrI 1.17, 2.91) for sarilumab, yielding >99.9% and 99.5% posterior probabilities of superiority compared with control. Hospital mortality was 28.0% (98/350) for tocilizumab, 22.2% (10/45) for sarilumab and 35.8% (142/397) for control. All secondary outcomes and analyses supported efficacy of these IL-6 receptor antagonists.ConclusionsIn critically ill patients with Covid-19 receiving organ support in intensive care, treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, improved outcome, including survival. (ClinicalTrials.govnumber:NCT02735707)

[Importance] Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm., [Objective] To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes., [Data Sources] Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts., [Study Selection] Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria., [Data Extraction and Synthesis] In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality., [Main Outcomes and Measures] The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days., [Results] A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P, [Conclusions and Relevance] In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality., [Trial Registration] PROSPERO Identifier: CRD42021230155., Funding for administrative and communications support was provided by the World Health Organization.

Purpose To describe the extent and variation of critical care services in Pakistan. Materials and methods A cross-sectional survey was conducted in all intensive care units (ICUs) recognised for postgraduate training to determine administration, infrastructure, equipment, staffing, and training. Results There were 151 hospitals recognised for training, providing 2166 ICU beds and 1473 ventilators. Regional distribution of ICU beds per 100,000 population ranged from 1.0 in Sindh to none in Gilgit Baltistan (median 0.7). A senior clinician trained in critical care was available in 19 (12.1%) of units. One to one nurse to bed ratio during the day was available in 84 (53.5%) of units, dropping to 75 (47.8%) at night. Availability of 1:1 nursing also varied between provinces, ranging from 56.5% in Punjab compared to 0% in Azad Jamu Kashmir. Similarly there was disparity in availability of ventilators between provinces. All ICUs had basic infrastructure (electricity, running water, piped oxygen) and basic equipment (electronic monitoring and infusion pumps). Conclusion Pakistan, a lower middle-income country, has an established network of critical care facilities with access to basic equipment, but inequalities in its distribution. Investment in critical care training for doctors and nurses is needed., Highlights • Critical care services are well established in Pakistan. • All intensive care units have access to basic equipment for essential critical care. • Inequity exists in access to critical care within and between regions. • Investment in specialist training for doctors and nurses is an urgent priority.

International audience; Benchmarking is a common and effective method for measuring and analyzing ICU performance. With the existence of national registries, objective information can now be obtained to allow benchmarking of ICU care within and between countries. The present manuscript briefly describes the current status of benchmarking in healthcare and critical care and presents the LOGIC project, an initiative to promote international benchmarking for intensive care units. Currently 13 registries have joined LOGIC. We showed large differences in the utilization of ICU as well as resources and in outcomes. Despite the need for careful interpretation of differences due to variation in definitions and limited risk adjustment, LOGIC is a growing worldwide initiative that allows access to insightful epidemiologic data from ICUs in multiple databases and registries.

Introduction: Confrontation with COVID-19 has threatened all people of the world, including pregnant women, as a high-risk group. Case Presentation: The present study presents a 29-year-old female G1P0 at 33 weeks’ gestation. The patient’s initial complaint was the premature rupture of membranes. The patient’s vital signs showed an abnormal pulse rate and temperature. Initial assessments were carried out, including regular monitoring and recording of vital signs, mother’s blood ABG, uterine contractions, laboratory tests, and fetal heart rate. Treatment for chorioamnionitis began with intravenous ampicillin, gentamicin, and oral erythromycin. Because of the epidemic of COVID-19 in Iran and Ilam, a throat swab specimen was obtained from the upper respiratory tract of the patient. The RT-PCR assay confirmed that the throat swab sample of the patient was positive for COVID-19. A throat swab specimen was taken from the newborn for RT-PCR. Also, the mother’s chest CT scan was done that showed abnormality; however, the RT-PCR throat swab specimen was negative for the newborn. The patient was transferred to the COVID-19 care unit. She was healthily discharged from the hospital with two negative RT-PCR tests. Her newborn was followed for two weeks, and no symptoms of COVID-19 were reported. Conclusions: Some major prenatal complications, including fetal distress, preterm labor, premature rupture of membranes, and amniotic fluid abnormalities, have been reported among some pregnant women infected with COVID-19 (7); however, the clinical manifestations of COVID-19 are deceptive. Therefore, low attention to all aspects of COVID-19 and late examination would increase the risk of spreading the disease among therapists providing services and other hospitalized mothers. These concerns make pregnant mothers afraid of even the most necessary referrals for appropriate and necessary midwifery interventions. Therefore, it is necessary to pay attention to two important issues: first, the concerns and anxieties of pregnant mothers and second, making the diagnosis in suspected cases as soon as possible.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

ISARIC (International Severe Acute Respiratory and emerging Infections Consortium) partnerships and outbreak preparedness initiatives enabled the rapid launch of standardised clinical data collection on COVID-19 in Jan 2020. Extensive global participation has resulted in a large, standardised collection of comprehensive clinical data from hundreds of sites across dozens of countries. Data are analysed regularly and reported publicly to inform patient care and public health response. This report, our 17th report, is a part of a series published over the past 2 years. Data have been entered for 800,459 individuals from 1701 partner institutions and networks across 60 countries.The comprehensive analyses detailed in this report includes hospitalised individuals of all ages for whom data collection occurred between 30 January 2020 and up to and including 5 January 2022, AND who have laboratory-confirmed SARS-COV-2 infection or clinically diagnosed COVID-19.For the 699,014 cases who meet eligibility criteria for this report, selected findings include: median age of 58 years, with an approximately equal (50/50) male:female sex distribution29% of the cohort are at least 70 years of age, whereas 4% are 0-19 years of agethe most common symptom combination in this hospitalised cohort is shortness of breath, cough, and history of fever, which has remained constant over timethe five most common symptoms at admission were shortness of breath, cough, history of fever, fatigue/malaise, and altered consciousness/confusion, which is unchanged from the previous reportsage-associated differences in symptoms are evident, including the frequency of altered consciousness increasing with age, and fever, respiratory and constitutional symptoms being present mostly in those 40 years and above16% of patients with relevant data available were admitted at some point during their illness into an intensive care unit (ICU), which is slightly lower than previously reported (19%)antibiotic agents were used in 35% of patients for whom relevant data are available (669,630), a significant reduction from our previous reports (80%) which reflects a shifting proportion of data contributed by different institutions; in ICU/HDU admitted patients with data available (50,560), 91% received antibioticsuse of corticosteroids was reported in 24% of all patients for whom data were available (677,012); in ICU/HDU admitted patients with data available (50,646), 69% received corticosteroidsoutcomes are known for 632,518 patients and the overall estimated case fatality ratio (CFR) is 23.9% (95%CI 23.8-24.1), rising to 37.1% (95%CI 36.8-37.4) for patients who were admitted to ICU/HDU, demonstrating worse outcomes in those with the most severe disease To access previous versions of ISARIC COVID-19 Clinical Data Report please use the link below: https://isaric.org/research/covid-19-clinical-research-resources/evidence-reports/

PurposeTo describe the extent and variation of critical care services in PakistanMaterials and methodsA cross-sectional survey was conducted in all CCUs recognised for postgraduate training to determine administration, infrastructure, equipment, staffing, and training.ResultsThere were 220 CCUs registered for training, providing 2166 CCU beds and 1473 ventilators. Regional distribution of CCU beds per 100,000 population ranged from 1.0 in Sindh to none in Gilgit Baltistan (median 0.7). A senior clinician trained in critical care was available in 19 (12.1%) of units, giving a ratio of one trained intensivist for every 82 CCU beds and 0.009 trained intensivists per 100,000 population. One to one nurse to bed ratio during the day was available in 84 (53.5%) of units, dropping to 75 (47.8%) at night. Availability of 1:1 nursing also varied between provinces, ranging from 56.5% in Punjab compared to 0% in Azad Jamu Kashmir. All CCUs had basic infrastructure (electricity, running water, piped oxygen) and basic equipment (electronic monitoring and infusion pumps).ConclusionPakistan, a lower middle-income country has an established network of critical care facilities with access to basic equipment, but inequalities in its distribution. Investment in critical care training for doctors and nurses is needed.

The present study attempts to evaluate the effects of different doses of morphine on experimental epileptiform activity caused by pentylenetetrazol (PTZ) in rats.Thirty adult male rats were assigned to saline (The results revealed that morphine at a dose of 2 mg/kg decreased, and at doses of 5 and 10 mg/kg had an increasing effect on seizure-like events (SLEs). Nevertheless, morphine at a dose of 10 mg/kg enhanced SLEs significantly (Morphine has biphasic effects on PTZ-induced epileptiform activities that way at a low dose has an inhibitory effect, but if the dose is increased, it will intensify the desired event and that the stimulatory effects of morphine appear not to be

ObjectivesExisting UK prognostic models for patients admitted to hospital with COVID-19 are limited by reliance on comorbidities, which are under-recorded in secondary care, and lack of imaging data among the candidate predictors. Our aims were to develop and externally validate novel prognostic models for adverse outcomes (death, intensive therapy unit (ITU) admission) in UK secondary care; and externally validate the existing 4C score. DesignCandidate predictors included demographic variables, symptoms, physiological measures, imaging, laboratory tests. Final models used logistic regression with stepwise selection. SettingModel development was performed in data from University Hospitals Birmingham (UHB). External validation was performed in the CovidCollab dataset. ParticipantsPatients with COVID-19 admitted to UHB January-August 2020 were included. Main outcome measuresDeath and ITU admission within 28 days of admission. Results1040 patients with COVID-19 were included in the derivation cohort; 288 (28%) died and 183 (18%) were admitted to ITU within 28 days of admission. Area under the receiver operating curve (AUROC) for mortality was 0.791 (95%CI 0.761-0.822) in UHB and 0.767 (95%CI 0.754-0.780) in CovidCollab; AUROC for ITU admission was 0.906 (95%CI 0.883-0.929) in UHB and 0.811 (95%CI 0.795-0.828) in CovidCollab. Models showed good calibration. Addition of comorbidities to candidate predictors did not improve model performance. AUROC for the 4C score in the UHB dataset was 0.754 (95%CI 0.721-0.786). ConclusionsThe novel prognostic models showed good discrimination and calibration in derivation and external validation datasets, and outperformed the existing 4C score. The models can be integrated into electronic medical records systems to calculate each individual patients probability of death or ITU admission at the time of hospital admission. Implementation of the models and clinical utility should be evaluated. Article SummaryO_ST_ABSStrengths and limitations of this studyC_ST_ABSO_LIWe developed novel prognostic models predicting mortality and ITU admission within 28 days of admission for patients hospitalised with COVID-19, using a large routinely collected dataset gathered at admission with a wide range of possible predictors (demographic variables, symptoms, physiological measures, imaging, laboratory test results). C_LIO_LIThese novel models showed good discrimination and calibration in both derivation and external validation cohorts, and outperformed the existing ISARIC model and 4C score in the derivation dataset. We found that addition of comorbidities to the set of candidate predictors included in model derivation did not improve model performance. C_LIO_LIIf integrated into hospital electronic medical records systems, the model algorithms will provide a predicted probability of mortality or ITU admission for each patient based on their individual data at, or close to, the time of admission, which will support clinicians decision making with regard to appropriate patient care pathways and triage. This information might also assist clinicians in explaining complex prognostic assessments and decisions to patients and their relatives. C_LIO_LIA limitation of the study was that in the external validation cohort we were unable to examine all of the predictors included in the original full UHB model due to only a reduced set of candidate predictors being available in CovidCollab. Nevertheless, the reduced model performed well and the results suggest it may be applicable in a wide range of datasets where only a reduced set of predictor variables is available. C_LIO_LIFurthermore, it was not possible to carry out stratified analysis by ethnicity as the UHB dataset contained too few patients in most of the strata, and no ethnicity data was available in the CovidCollab dataset. C_LI

A better understanding of the context-specific epidemiology, outcomes, and risk factors for death of critically ill parturients in resource-poor hospitals is needed to tackle the still alarming in-hospital maternal mortality in African countries. From October 2017 to October 2018, we performed a 1-year retrospective cohort study in a referral maternity hospital in Freetown, Sierra Leone. The primary endpoint was the association between risk factors and high-dependency unit (HDU) mortality. Five hundred twenty-three patients (median age 25 years, interquartile range [IQR]: 21-30 years) were admitted to the HDU for a median of 2 (IQR: 1-3) days. Among them, 65% were referred with a red obstetric early warning score (OEWS) code, representing 1.17 cases per HDU bed per week; 11% of patients died in HDU, mostly in the first 24 hours from admission. The factors independently associated with HDU mortality were ward rather than postoperative referrals (odds ratio [OR]: 3.21; 95% CI: 1.48-7.01; P = 0.003); admissions with red (high impairment of patients' vital signs) versus yellow (impairment of vital signs) or green (little or no impairment of patients' vital signs) OEWS (OR: 3.66; 95% CI: 1.15-16.96; P = 0.04); responsiveness to pain or unresponsiveness on the alert, voice, pain unresponsive scale (OR: 5.25; 95% CI: 2.64-10.94; P ≤ 0.0001); and use of vasopressors (OR: 3.24; 95% CI: 1.32-7.66; P = 0.008). Critically ill parturients were predominantly referred with a red OEWS code and usually required intermediate care for 48 hours. Despite the provided interventions, death in the HDU was frequent, affecting one of 10 critically ill parturients. Medical admission, a red OEWS code, and a poor neurological and hemodynamic status were independently associated with mortality, whereas adequate oxygenation was associated with survival.

Introduction In resource-limited settings – with inequalities in access to and outcomes for trauma, surgical and critical care – intensive care registries are uncommon. Aim The Pakistan Society of Critical Care Medicine, Intensive Care Society (UK) and the Network for Improving Critical Care Systems and Training (NICST) aim to implement a clinician-led real-time national intensive care registry in Pakistan: the Pakistan Registry of Intensive CarE (PRICE). Method This was adapted from a successful clinician co-designed national registry in Sri Lanka; ICU information has been linked to real-time dashboards, providing clinicians and administrators individual patient and service delivery activity respectively. Output Commenced in August 2017, five ICU’s (three administrative regions – 104 beds) were recruited and have reported over 1100 critical care admissions to PRICE. Impact and future PRICE is being rolled out nationally in Pakistan and will provide continuous granular healthcare information necessary to empower clinicians to drive setting-specific priorities for service improvement and research.

Purpose: To determine the utility of APACHE II in a low-and middle-income (LMIC) setting and the implications of missing data. Materials and methods: Patients meeting APACHE II inclusion criteria admitted to 18 ICUs in Sri Lanka over three consecutive months had data necessary for the calculation of APACHE II, probabilities prospectively extracted from case notes. APACHE II physiology score (APS), probabilities, Standardised (ICU) Mortality Ratio (SMR), discrimination (AUROC), and calibration (C-statistic) were calculated, both by imputing missing measurements with normal values and by Multiple Imputation using Chained Equations (MICE). Results: From a total of 995 patients admitted during the study period, 736 had APACHE II probabilities calculated. Data availability for APS calculation ranged from 70.6% to 88.4% for bedside observations and 18.7% to 63.4% for invasive measurements. SMR (95% CI) was 1.27 (1.17, 1.40) and 0.46 (0.44, 0.49), AUROC (95% CI) was 0.70 (0.65, 0.76) and 0.74 (0.68, 0.80), and C-statistic was 68.8 and 156.6 for normal value imputation and MICE, respectively. Conclusions: An incomplete dataset confounds interpretation of prognostic model performance in LMICs, wherein imputation using normal values is not a suitable strategy. Improving data availability, researching imputation methods and developing setting-adapted and simpler prognostic models are warranted. (c) 2017 Elsevier Inc. All rights reserved

Background The use of severity of illness scoring systems such as the Acute Physiology and Chronic Health Evaluation in lower-middle income settings comes with important limitations, primarily due to data burden, missingness of key variables and lack of resources. To overcome these challenges, in Asia, a simplified model, designated as e-TropICS was previously developed. We sought to externally validate this model using data from a multi-centre critical care registry in India. Methods Seven ICUs from the Indian Registry of IntenSive care(IRIS) contributed data to this study. Patients > 18 years of age with an ICU length of stay > 6 hours were included. Data including age, gender, co-morbidity, diagnostic category, type of admission, vital signs, laboratory measurements and outcomes were collected for all admissions. e-TropICS was calculated as per original methods. The area under the receiver operator characteristic curve was used to express the model’s power to discriminate between survivors and non-survivors. For all tests of significance, a 2-sided P less than or equal to 0.05 was considered to be significant. AUROC values were considered poor when ≤ to 0.70, adequate between 0.71 to 0.80, good between 0.81 to 0.90, and excellent at 0.91 or higher. Calibration was assessed using Hosmer-Lemeshow C -statistic. Results We included data from 2062 consecutive patient episodes. The median age of the cohort was 60 and predominantly male (n = 1350, 65.47%). Mechanical Ventilation and vasopressors were administered at admission in 504 (24.44%) and 423 (20.51%) patients respectively. Overall, mortality at ICU discharge was 10.28% (n = 212). Discrimination (AUC) for the e-TropICS model was 0.83 (95% CI 0.812–0.839) with an HL C statistic p value of < 0.05. The best sensitivity and specificity (84% and 72% respectively) were achieved with the model at an optimal cut-off for probability of 0.29. Conclusion e-TropICS has utility in the care of critically unwell patients in the South Asia region with good discriminative capacity. Further refinement of calibration in larger datasets from India and across the South-East Asia region will help in improving model performance.

Background This study evaluates post-ICU outcoes of patients admitted with moderate and severe Traumatic Brain Injury (TBI) in a tertiary neurocritical care unit in an low middle income country and the performance of trauma scores: A Severity Characterization of Trauma, Trauma and Injury Severity Score, Injury Severity Score and Revised Trauma Score in this setting. Methods Adult patients directly admitted to the neurosurgical intensive care units of the National Hospital of Sri Lanka between 21st July 2014 and 1st October 2014 with moderate or severe TBI were recruited. A telephone administered questionnaire based on the Glasgow Outcome Scale Extended (GOSE) was used to assess functional outcome of patients at 3 and 6 months after injury. The economic impact of the injury was assessed before injury, and at 3 and 6 months after injury. Results One hundred and one patients were included in the study. Survival at ICU discharge, 3 and 6 months after injury was 68.3%, 49.5% and 45.5% respectively. Of the survivors at 3 months after injury, 43 (86%) were living at home. Only 19 (38%) patients had a good recovery (as defined by GOSE 7 and 8). Three months and six months after injury, respectively 25 (50%) and 14 (30.4%) patients had become “economically dependent”. Selected trauma scores had poor discriminatory ability in predicting mortality. Conclusions This observational study of patients sustaining moderate or severe TBI in Sri Lanka (a LMIC) reveals only 46% of patients were alive at 6 months after ICU discharge and only 20% overall attained a good (GOSE 7 or 8) recovery. The social and economic consequences of TBI were long lasting in this setting. Injury Severity Score, Revised Trauma Score, A Severity Characterization of Trauma and Trauma and Injury Severity Score, all performed poorly in predicting mortality in this setting and illustrate the need for setting adapted tools.

Objectives: Ethmoid punch sinusotomy (EPS) is a feasible treatment for ethmoid sinusitis in a subset of chronic rhinosinusitis (CRS) patients per a recent report. This adjunctive work investigates the technical characteristics of EPS and determines if EPS measurably alters the topical delivery of irrigant into the ethmoid sinuses in a cadaveric model. Methods: The sinonasal cavities of 10 human cadaver heads were irrigated with a solution containing methylene blue and radio-opaque contrast prior to and following EPS. Procedural characteristics and irrigant distribution were assessed by endoscopy and computed tomography. Results: Forty EPS procedures were performed through the ethmoid bulla and basal lamella. Compared to controls, EPS enhanced dye distribution into the anterior (90% vs 35%, P < .004) and posterior (90% vs 35%, P < .002) ethmoid sinuses, representing a 157% increase for each of these sites. Contrast was detected in a higher proportion of anterior (65% vs 5%, P < .001) and posterior (60% vs 0%, P < .001) ethmoid sinuses. Endoscopically guided catheter instillation of contrast through the EPS sites achieved radiotracer distribution throughout the ethmoid complex. Conclusions: Ethmoid punch sinusotomy sites can be reliably created via micro-minimally invasive procedures. Ethmoid punch sinusotomy improves irrigant delivery to the ethmoid sinuses, providing mechanistic understanding for the clinical outcomes observed in CRS patients.

Background Physical and psychological symptoms are among main manifestations of Chronic Kidney Disease (CKD). This study aimed to assess the symptom burden and self-perceived severity of symptoms among CKD patients living in a district in Sri Lanka. Method A community based cross-sectional study included a sample of randomly selected 1174 CKD patients from all 19 Medical Officer of Health areas in the district of Anuradhapura. Trained para-medical staff visited the households and administered the locally validated questionnaire to assess the presence and severity of symptoms. The inquiry was on 25 symptoms in a 5 point Likert scale indicating the severity during the previous week. Symptom burden score was constructed by summing each symptom severity score which ranged from 0 to 125. Results A total of 1118 CKD patients participated with a response rate of 95.2%. The mean age was 58.3 (SD 10.8) years and 62.7% were males. A majority were in CKD stage 4 (58.3%). Bone/joint pain was the most experienced symptom (87.6%; 95%CI 85.6–89.5). Loss of libido was the most severe symptom. The median symptom burden score was 35.0 (IQR 20.0–50.0). Multiple linear regression revealed education up to Advanced Level (β −9.176), CKD stage V (β 3.373), being dialyzed (β 20.944), comorbidities (β 4.241) and being employed (β −9.176) to be significant predictors of symptom burden. Conclusions Patients in all stages of CKD experience high symptom burden warranting rigorous measures to relieve symptoms and to improve the well-being of CKD patients. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0638-y) contains supplementary material, which is available to authorized users.

Purpose The Good Intern Programme (GIP) in Sri Lanka has been implemented to bridge the ’theory to practice gap’ of doctors preparing for their internship. This paper evaluates the impact of a 2-day peer-delivered Acute Care Skills Training (ACST) course as part of the GIP. Study design The ACST course was developed by an interprofessional faculty, including newly graduated doctors awaiting internship (pre-intern), focusing on the recognition and management of common medical and surgical emergencies. Course delivery was entirely by pre-intern doctors to their peers. Knowledge was evaluated by a pre- and post-course multiple choice test. Participants’ confidence (post-course) and 12 acute care skills (pre- and post-course) were assessed using Likert scale-based questions. A subset of participants provided feedback on the peer learning experience. Results Seventeen courses were delivered by a faculty consisting of eight peer trainers over 4 months, training 320 participants. The mean (SD) multiple choice questionnaire score was 71.03 (13.19) pre-course compared with 77.98 (7.7) post-course (p Conclusions A peer-delivered ACST course was extremely well received and can improve newly qualified medical graduates’ knowledge, skills and confidence in managing medical and surgical emergencies. This peer-based model may have utility beyond pre-interns and beyond Sri Lanka.

Background and Aims Retention of junior doctors in specialties such as critical care is difficult, especially in resource‑limited settings. This study describes the profile of junior doctors in adult state intensive care units in Sri Lanka, a lower middle‑income country. Materials and Methods This was a national cross‑sectional survey using an anonymous self‑administered electronic questionnaire. Results Five hundred and thirty‑nine doctors in 93 Intensive Care Units (ICUs) were contacted, generating 207 responses. Just under half of the respondents (93, 47%) work exclusively in ICUs. Most junior doctors (150, 75.8%) had no previous exposure to anesthesia and 134 (67.7%) had no previous ICU experience while 116 (60.7%) ICU doctors wished to specialize in critical care. However, only a few (12, 6.3%) doctors had completed a critical care diploma course. There was a statistically significant difference (P < 0.05) between the self‑assessed confidence of anesthetic background junior doctors and non-anesthetists. The overall median competency for doctors improves with the length of ICU experience and is statistically significant (P < 0.05). ICU postings were less happy and more stressful compared to the last non‑ICU posting (P < 0.05 for both). The vast majority, i.e., 173 (88.2%) of doctors felt the care provided for patients in their ICUs was good, very good, or excellent while 71 doctors (36.2%) would be happy to recommend the ICU where they work to a relative with the highest possible score of 10. Conclusion Measures to improve training opportunities for these doctors and strategies to improve their retention in ICUs need to be addressed.

Purpose To evaluate perceptions of intensive care unit (ICU) workers from low-and-middle income countries (LMICs) and high income countries (HICs). Materials and methods A cross sectional design. Data collected from doctors using an anonymous online, questionnaire. Results Hundred seventy-five from LMICs and 43 from HICs participated. Barriers in LMICs were lack of formal training (Likert score median 3 [inter quartile range 3]), lack of nurses (3[3]) and low wages (3[4]). Strategies for LMICs improvement were formal training of ICU staff (4[3]), an increase in number of ICU nurses (4[2]), collection of outcome data (3[4]), as well as maintenance of available equipment [3(3)]. The most useful role of HIC ICU staff was training of LMIC staff (4[2]). Donation of equipment [2(4)], drugs [2(4)], and supplies (2[4]) perceived to be of limited usefulness. The most striking difference between HIC and LMIC staff was the perception on the lack of physician leadership as an obstacle to ICU functioning (4[3] vs. 0[2], p Conclusion LMICs ICU workers perceived lack of training, lack of nurses, and low wages as major barriers to functioning. Training, increase of nurse workforce, and collection of outcome data were proposed as useful strategies to improve LMIC ICU services.

MRationale: There is conflicting evidence on harm related to exposure to supra-physiologic arterial oxygen tensions (hyperoxemia) in critically ill patients. Objectives: To examine the association between longitudinal exposure to hyperoxemia and mortality in patients admitted to intensive care units (ICUs) in 5 UK University Hospitals. Methods: Retrospective cohort of ICU admissions between 31st January 2014 - 31st December 2018, from the National Institute of Health Research Critical Care Health Informatics Collaborative (CC-HIC). Multivariable logistic regression modelled death in ICU by exposure to hyperoxemia. Measurements: Subsets with oxygen exposure windows of 0-1, 0-3, 0-5 and 0-7 days were evaluated, capturing 19,515, 10,525, 6,360 and 4,296 patients, respectively. Hyperoxemia dose was defined as the area between the PaO2 time curve and a boundary of 13.3 kPa (100 mmHg) divided by the hours of potential exposure (24, 72, 120, or 168 hours). Main Results: An association was found between exposure to hyperoxemia and ICU mortality [odds ratios (95% compatibility intervals); 1.15 (0.95-1.38), p = 0.15; 1.35 (1.04-1.74), p = 0.02; 1.5 (1.07-2.13), p = 0.02; and 1.74 (1.11-2.72), p = 0.02 for exposure windows of 0-1, 0-3, 0-5 and 0-7 days’ duration, respectively. However, a dose-response relationship was not observed. There was no evidence to support a differential effect between hyperoxemia and either a respiratory diagnosis or mechanical ventilation. Conclusions: An association between hyperoxemia and mortality was observed in our large, unselected multicenter cohort. The absence of a dose-response relationship weakens causal interpretation. Further experimental research is warranted to elucidate this important question.