Personalized mechanical ventilation guided by ultrasound in patients with acute respiratory distress syndrome (PEGASUS): study protocol for an international randomized clinical trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a frequent cause of hypoxemic respiratory failure with a mortality rate of approximately 30%. Identifying ARDS subphenotypes based on "focal" or "non-focal" lung morphology has the potential to better target mechanical ventilation strategies of individual patients. However, classifying morphology through chest radiography or computed tomography is either inaccurate or impractical. Lung ultrasound (LUS) is a non-invasive bedside tool that can accurately distinguish "focal" from "non-focal" lung morphology. We hypothesize that LUS-guided personalized mechanical ventilation in ARDS patients leads to a reduction in 90-day mortality compared to conventional mechanical ventilation. METHODS: The Personalized Mechanical Ventilation Guided by UltraSound in Patients with Acute Respiratory Distress Syndrome (PEGASUS) study is an investigator-initiated, international, randomized clinical trial (RCT) that plans to enroll 538 invasively ventilated adult intensive care unit (ICU) patients with moderate to severe ARDS. Eligible patients will receive a LUS exam to classify lung morphology as "focal" or "non-focal". Thereafter, patients will be randomized within 12 h after ARDS diagnosis to receive standard care or personalized ventilation where the ventilation strategy is adjusted to the morphology subphenotype, i.e., higher positive end-expiratory pressure (PEEP) and recruitment maneuvers for "non-focal" ARDS and lower PEEP and prone positioning for "focal" ARDS. The primary endpoint is all-cause mortality at day 90. Secondary outcomes are mortality at day 28, ventilator-free days at day 28, ICU length of stay, ICU mortality, hospital length of stay, hospital mortality, and number of complications (ventilator-associated pneumonia, pneumothorax, and need for rescue therapy). After a pilot phase of 80 patients, the correct interpretation of LUS images and correct application of the intervention within the safe limits of mechanical ventilation will be evaluated. DISCUSSION: PEGASUS is the first RCT that compares LUS-guided personalized mechanical ventilation with conventional ventilation in invasively ventilated patients with moderate and severe ARDS. If this study demonstrates that personalized ventilation guided by LUS can improve the outcomes of ARDS patients, it has the potential to shift the existing one-size-fits-all ventilation strategy towards a more individualized approach. TRIAL REGISTRATION: The PEGASUS trial was registered before the inclusion of the first patient, https://clinicaltrials.gov/ (ID: NCT05492344).

Combining species distribution models and big datasets may provide finer assessments of snakebite impacts.

BACKGROUND: Snakebite is a major poverty-related neglected tropical disease. An integrated scientific approach is needed to understand the dynamics of this important health issue. Our objective was to estimate snakebite occurrence in a tropical area by using a blend of ecological modelling and robust statistical analysis. METHODS: The present study used climatic, environmental, and human population density data to determine the area with snakebite occurrence-probability for the first time in Bangladesh. We also analysed a large, 16-year dataset of hospitalized snakebite cases to reveal the epidemiology of snakebite in the south-eastern zone of the country. FINDINGS: Our results show that cobra bite is the most commonly occurring venomous snakebite in humans (around ~12% of the total yearly snakebite records), and men are more frequently bitten than women (2/3 of human victims are men). Most bites occur during the rainy season for cobra and green pit viper, while krait bites are not restricted to any particular season. As snakebite incidents are closely related to climate conditions, we can model snakebite risk using temperature and precipitation variables. Whereas there is a lack of snakebite reports from several parts of the study area in official records, our models predict that the entire study area is favourable for snakebite incidents. Based on the combined evidence we estimate that about 200,000 snakebite events occur every year in the south-eastern part of Bangladesh alone. Considering future global climate change, our model projections show that snakebite incidence in Bangladesh might not significantly decrease in the future (- 2070-); however, the distribution of probabilities might change, with a predicted increase of snakebite incidence in the hilly areas of the country. CONCLUSIONS: Using climatic data to predict snakebite incidence in Bangladesh allowed us to provide estimations of the total annual number of snakebite cases in the study area. As in most countries, the scarcity of accurate epidemiological data in official records might have masked the real magnitude of this problem. Our analysis suggests that the problem of snakebite envenoming in Bangladesh might be worse than currently perceived. A long-term sustainable snakebite program plan should be designed and institutionalized, considering climatic, geographical and human demographic variables, to obtain better data and facilitate the implementation of accurate snakebite management programs for this country.

Lessons from the field: compound-specific management in acute pesticide poisoning.

Pesticide poisoning is a common medical emergency in the rural tropics, with significant associated mortality. Pesticide poisoning is an umbrella term that encompasses a wide variety of substances with differing clinical toxidromes and outcomes. Despite this, confirmation of the specific compound ingested is rarely performed. In this Lessons from the Field, we argue that pesticide-specific management is integral to optimise management. Using data from a quality improvement project in Chittagong, Bangladesh, we demonstrate that identifying the specific compound is possible in most patients through careful history taking and examination of the pesticide bottle. Identification of the specific compound is essential for anticipating and reducing complications, administering appropriate and timely management and reducing the length of hospital stay and cost of unnecessary medical intervention.

Non-COVID-19 intensive care admissions during the pandemic: a multinational registry-based study.

BACKGROUND: The COVID-19 pandemic resulted in a large number of critical care admissions. While national reports have described the outcomes of patients with COVID-19, there is limited international data of the pandemic impact on non-COVID-19 patients requiring intensive care treatment. METHODS: We conducted an international, retrospective cohort study using 2019 and 2020 data from 11 national clinical quality registries covering 15 countries. Non-COVID-19 admissions in 2020 were compared with all admissions in 2019, prepandemic. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included in-hospital mortality and standardised mortality ratio (SMR). Analyses were stratified by the country income level(s) of each registry. FINDINGS: Among 1 642 632 non-COVID-19 admissions, there was an increase in ICU mortality between 2019 (9.3%) and 2020 (10.4%), OR=1.15 (95% CI 1.14 to 1.17, p<0.001). Increased mortality was observed in middle-income countries (OR 1.25 95% CI 1.23 to 1.26), while mortality decreased in high-income countries (OR=0.96 95% CI 0.94 to 0.98). Hospital mortality and SMR trends for each registry were consistent with the observed ICU mortality findings. The burden of COVID-19 was highly variable, with COVID-19 ICU patient-days per bed ranging from 0.4 to 81.6 between registries. This alone did not explain the observed non-COVID-19 mortality changes. INTERPRETATION: Increased ICU mortality occurred among non-COVID-19 patients during the pandemic, driven by increased mortality in middle-income countries, while mortality decreased in high-income countries. The causes for this inequity are likely multi-factorial, but healthcare spending, policy pandemic responses, and ICU strain may play significant roles.

Mixed methods study protocol for combining stakeholder-led rapid evaluation with near real-time continuous registry data to facilitate evaluations of quality of care in intensive care units.

Background: Improved access to healthcare in low- and middle-income countries (LMICs) has not equated to improved health outcomes. Absence or unsustained quality of care is partly to blame. Improving outcomes in intensive care units (ICUs) requires delivery of complex interventions by multiple specialties working in concert, and the simultaneous prevention of avoidable harms associated with the illness and the treatment interventions. Therefore, successful design and implementation of improvement interventions requires understanding of the behavioural, organisational, and external factors that determine care delivery and the likelihood of achieving sustained improvement. We aim to identify care processes that contribute to suboptimal clinical outcomes in ICUs located in LMICs and to establish barriers and enablers for improving the care processes. Methods: Using rapid evaluation methods, we will use four data collection methods: 1) registry embedded indicators to assess quality of care processes and their associated outcomes; 2) process mapping to provide a preliminary framework to understand gaps between current and desired care practices; 3) structured observations of processes of interest identified from the process mapping and; 4) focus group discussions with stakeholders to identify barriers and enablers influencing the gap between current and desired care practices. We will also collect self-assessments of readiness for quality improvement. Data collection and analysis will be led by local stakeholders, performed in parallel and through an iterative process across eight countries: Kenya, India, Malaysia, Nepal, Pakistan, South Africa, Uganda and Vietnam. Conclusions: The results of our study will provide essential information on where and how care processes can be improved to facilitate better quality of care to critically ill patients in LMICs; thus, reduce preventable mortality and morbidity in ICUs. Furthermore, understanding the rapid evaluation methods that will be used for this study will allow other researchers and healthcare professionals to carry out similar research in ICUs and other health services.

Survey on sea snakebite and related morbidity and mortality among Bangladeshi fishermen in the Bay of Bengal: A pilot study.

Around two million people are engaged in marine fishing in the Bay of Bengal. Bites by sea snakes were common hazards feared by millions fishing at sea in earlier days. Current morbidity and mortality are also not known. This study was conducted to document and describe sea snake bites among selected communities of sea-going fishermen in Bangladesh. A questionnaire-based cross-sectional survey was conducted from May to October 2019 among three communities of sea-going fishermen living along the coast of the Bay of Bengal in Cox's Bazar district. Fishermen were first asked by trained interviewers to recall any sea snakebites to themselves and among their fellows on board within the last year, then within the last 5 years and at any time before that. For any bite, related information including outcome was noted. Overall, 25.4% of respondents (62 out of 244) had been bitten by sea-snakes. Mean age was 37.6(±14) years; all males. 51.6% received some sort of treatment locally; 71% hot compress and 48% tourniquets. In 80.6% the affected limb was not immobilized. The bitten site was incised in 29%. 22.6% received treatment from traditional healers, 48.4% from local hospitals, 29% from district hospital. Six victims (9.7%) suffered from severe life-threatening consequences of the sea snakebite but none died. 32% of the fishermen had seen the offending snake. Sea snakebites are potentially dangerous; therefore, educating fishermen to avoid contact with sea snakes would dramatically reduce the incidence of sea snakebites. Most bites are treated initially by local measures which are often not scientific. Provision of proper first aid and treatment might reduce mortality and morbidity. A larger survey on sea snake bites among the fishermen in all coastal areas of Bangladesh is needed to determine the nationwide burden of morbidity and mortality related to sea snakebite.

Evaluation of the properties of Bungarus caeruleus venom and checking the efficacy of antivenom used in Bangladesh for its bite treatment.

As a disaster-prone country with unique geographical features, snake biting is a major public health concern in Bangladesh. The primary reasons of mortality from snakebite include late presentation to the hospital, low efficacy of antivenom, and a lack of adequate management facilities. Because snake venom characteristics vary depending on geographical location, antivenom should be manufactured from snakes native to the region in which it would be administered. Bungarus caeruleus is a highly venomous snake contributing to the major snakebite issue in Bangladesh. Therefore, the neutralization efficacy of the antivenom against B. caeruleus venom was evaluated in the current study along with the characterization of venom. For biological characterization of venom, RP-HPLC and SDS-PAGE profiling, hemolytic activity, hemorrhagic activity, phospholipases A2 (PLA2) activity, edema inducing activity and histopathological observations were carried out following standard protocol. LD50 of the venom was calculated along with neutralization potency of Incepta antivenom through probit analysis. Results showed that venom possesses phospholipase A2 activity, hemolytic activity and edema inducing activity while hemorrhagic activity was absent in the skin of envenomed mice. Histopathological alterations including necrosis, congestion and infiltrations were observed in envenomed mice organs after hematoxylin and eosin staining. Neutralization study showed that Incepta polyvalent antivenom could neutralize (potency 0.53 mg/ml) the lethal effect in in vitro study on mice. Further investigation on snakebite epidemiology and clinical observations of the envenomed patients will help in combating the snakebite problem more efficiently.

Field evaluation of the diagnostic performance of EasyScan GO: a digital malaria microscopy device based on machine-learning.

BACKGROUND: Microscopic examination of Giemsa-stained blood films remains the reference standard for malaria parasite detection and quantification, but is undermined by difficulties in ensuring high-quality manual reading and inter-reader reliability. Automated parasite detection and quantification may address this issue. METHODS: A multi-centre, observational study was conducted during 2018 and 2019 at 11 sites to assess the performance of the EasyScan Go, a microscopy device employing machine-learning-based image analysis. Sensitivity, specificity, accuracy of species detection and parasite density estimation were assessed with expert microscopy as the reference. Intra- and inter-device reliability of the device was also evaluated by comparing results from repeat reads on the same and two different devices. This study has been reported in accordance with the Standards for Reporting Diagnostic accuracy studies (STARD) checklist. RESULTS: In total, 2250 Giemsa-stained blood films were prepared and read independently by expert microscopists and the EasyScan Go device. The diagnostic sensitivity of EasyScan Go was 91.1% (95% CI 88.9-92.7), and specificity 75.6% (95% CI 73.1-78.0). With good quality slides sensitivity was similar (89.1%, 95%CI 86.2-91.5), but specificity increased to 85.1% (95%CI 82.6-87.4). Sensitivity increased with parasitaemia rising from 57% at < 200 parasite/µL, to ≥ 90% at > 200-200,000 parasite/µL. Species were identified accurately in 93% of Plasmodium falciparum samples (kappa = 0.76, 95% CI 0.69-0.83), and in 92% of Plasmodium vivax samples (kappa = 0.73, 95% CI 0.66-0.80). Parasite density estimates by the EasyScan Go were within ± 25% of the microscopic reference counts in 23% of slides. CONCLUSIONS: The performance of the EasyScan Go in parasite detection and species identification accuracy fulfil WHO-TDR Research Malaria Microscopy competence level 2 criteria. In terms of parasite quantification and false positive rate, it meets the level 4 WHO-TDR Research Malaria Microscopy criteria. All performance parameters were significantly affected by slide quality. Further software improvement is required to improve sensitivity at low parasitaemia and parasite density estimations. Trial registration ClinicalTrials.gov number NCT03512678.

Performance evaluation of a multinational data platform for critical care in Asia.

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.

Altered Patterns of Compositional and Functional Disruption of the Gut Microbiota in Typhoid Fever and Nontyphoidal Febrile Illness.

BACKGROUND: Experimental murine models and human challenge studies of Salmonella Typhi infection have suggested that the gut microbiome plays an important protective role against the development of typhoid fever. Anaerobic bacterial communities have been hypothesized to mediate colonization resistance against Salmonella species by producing short-chain fatty acids, yet the composition and function of the intestinal microbiota in human patients with typhoid fever remain ill defined. METHODS: We prospectively collected fecal samples from 60 febrile patients admitted to Chittagong Medical College Hospital, Bangladesh, with typhoid fever or nontyphoidal febrile illness and from 36 healthy age-matched controls. The collected fecal samples were subjected to 16s rRNA sequencing followed by targeted metabolomics analysis. RESULTS: Patients with typhoid fever displayed compositional and functional disruption of the gut microbiota compared with patients with nontyphoidal febrile illness and healthy controls. Specifically, typhoid fever patients had lower microbiota richness and alpha diversity and a higher prevalence of potentially pathogenic bacterial taxa. In addition, a lower abundance of short-chain fatty acid-producing taxa was seen in typhoid fever patients. The differences between typhoid fever and nontyphoidal febrile illness could not be explained by a loss of colonization resistance after antibiotic treatment, as antibiotic exposure in both groups was similar. CONCLUSIONS: his first report on the composition and function of the gut microbiota in patients with typhoid fever suggests that the restoration of these intestinal commensal microorganisms could be targeted using adjunctive, preventive, or therapeutic strategies.

Mapping the travel patterns of people with malaria in Bangladesh.

BACKGROUND: Spread of malaria and antimalarial resistance through human movement present major threats to current goals to eliminate the disease. Bordering the Greater Mekong Subregion, southeast Bangladesh is a potentially important route of spread to India and beyond, but information on travel patterns in this area are lacking. METHODS: Using a standardised short survey tool, 2090 patients with malaria were interviewed at 57 study sites in 2015-2016 about their demographics and travel patterns in the preceding 2 months. RESULTS: Most travel was in the south of the study region between Cox's Bazar district (coastal region) to forested areas in Bandarban (31% by days and 45% by nights), forming a source-sink route. Less than 1% of travel reported was between the north and south forested areas of the study area. Farmers (21%) and students (19%) were the top two occupations recorded, with 67 and 47% reporting travel to the forest respectively. Males aged 25-49 years accounted for 43% of cases visiting forests but only 24% of the study population. Children did not travel. Women, forest dwellers and farmers did not travel beyond union boundaries. Military personnel travelled the furthest especially to remote forested areas. CONCLUSIONS: The approach demonstrated here provides a framework for identifying key traveller groups and their origins and destinations of travel in combination with knowledge of local epidemiology to inform malaria control and elimination efforts. Working with the NMEP, the findings were used to derive a set of policy recommendations to guide targeting of interventions for elimination.

Associations Between Restrictive Fluid Management and Renal Function and Tissue Perfusion in Adults With Severe Falciparum Malaria: A Prospective Observational Study.

BACKGROUND: Liberal fluid resuscitation has proved harmful in adults with severe malaria, but the level of restriction has not been defined. METHODS: In a prospective observational study in adults with severe falciparum malaria, restrictive fluid management was provided at the discretion of the treating physician. The relationships between the volume of fluid and changes in renal function or tissue perfusion were evaluated. RESULTS: A total of 154 patients were studied, 41 (26.6%) of whom died. Median total fluid intake during the first 6 and 24 hours from enrollment was 3.3 (interquartile range [IQR], 1.8-5.1) mL/kg per hour and 2.2 (IQR, 1.6-3.2) mL/kg per hour, respectively. Total fluid intake at 6 hours was not correlated with changes in plasma creatinine at 24 hours (n = 116; rs = 0.16; P = .089) or lactate at 6 hours (n = 94; rs = -0.05; P = .660). Development of hypotensive shock or pulmonary edema within 24 hours after enrollment were not related to the volume of fluid administration. CONCLUSIONS: Restrictive fluid management did not worsen kidney function and tissue perfusion in adult patients with severe falciparum malaria. We suggest crystalloid administration of 2-3 mL/kg per hour during the first 24 hours without bolus therapy, unless the patient is hypotensive.

Reduced Cardiac Index Reserve and Hypovolemia in Severe Falciparum Malaria.

BACKGROUND: Impaired microvascular perfusion is central to the development of coma and lactic acidosis in severe falciparum malaria. Refractory hypotension is rare on admission but develops frequently in fatal cases. We assessed cardiac function and volume status in severe falciparum malaria and its prognostic significance. METHODS: Patients with severe (N = 101) or acute uncomplicated falciparum malaria (N = 83) were recruited from 2 hospitals in India and Bangladesh, and healthy participants (N = 44) underwent echocardiography. RESULTS: Patients with severe malaria had 38% shorter left ventricular (LV) filling times and 25% shorter LV ejection times than healthy participants because of tachycardia; however, stroke volume, LV internal diameter in diastole (LVIDd), and LV internal diameter in systole (LVIDs) indices were similar. A low endocardial fraction shortening (eFS) was present in 17% (9 of 52) of severe malaria patients. Adjusting for preload and afterload, eFS was similar in health and severe malaria. Fatal cases had smaller baseline LVIDd and LVIDs indices, more collapsible inferior vena cavae (IVC), and higher heart rates than survivors. The LVIDs and IVC collapsibility were independent predictors for mortality, together with base excess and Glasgow Coma Scale. CONCLUSIONS: Patients with severe malaria have rapid ejection of a normal stroke volume. Fatal cases had features of relative hypovolemia and reduced cardiac index reserve.

Cell-Free Hemoglobin Is Associated With Increased Vascular Resistance and Reduced Peripheral Perfusion in Severe Malaria.

BACKGROUND: In severe falciparum malaria, unlike sepsis, hypotension on admission is uncommon. We hypothesized that low nitric oxide bioavailability due to the presence of cell-free hemoglobin (CFH) increases vascular tone in severe malaria. METHODS: Patients with severe malaria (n = 119), uncomplicated malaria (n = 91), or suspected bacterial sepsis (n = 56), as well as healthy participants (n = 50), were recruited. The systemic vascular resistance index (SVRI) was estimated from the echocardiographic cardiac index and the mean arterial pressure. RESULTS: SVRI and hematocrit levels were lower and plasma CFH and asymmetric dimethylarginine levels were higher in patients with malaria, compared with healthy participants. In multivariate linear regression models for mean arterial pressure or SVRI in patients with severe malaria, hematocrit and CFH but not asymmetric dimethylarginine were significant predictors. The SVRI was lower in patients with suspected bacterial sepsis than in those with severe malaria, after adjustment for hematocrit and age. Plasma CFH levels correlated positively with the core-peripheral temperature gradient and plasma lactate levels and inversely with the perfusion index. Impaired peripheral perfusion, as reflected by a low perfusion index or a high core-peripheral temperature gradient, predicted mortality in patients with severe malaria. CONCLUSIONS: CFH is associated with mean arterial pressure, SVRI, and peripheral perfusion in patients with severe malaria. This may be mediated through the nitric oxide scavenging potency of CFH, increasing basal vascular tone and impairing tissue perfusion.

Amino acid derangements in adults with severe falciparum malaria.

Amino acid derangements are common in severe falciparum malaria and have been associated with endothelial dysfunction (L-arginine), metabolic acidosis (alanine and lactate), and disease severity (phenylalanine and tryptophan metabolites). Whether these amino acid perturbations reflect isolated pathogenic mechanisms or if they are part of overall changes in amino acid metabolism is unclear. To investigate this, we prospectively simultaneously quantified a broad range of plasma free amino acids (PFAA) using HPLC-MRM-Mass spectrometry in relation to presenting symptoms in adults with severe malaria (n = 88), septicaemia (n = 88), uncomplicated malaria (n = 71), and healthy controls (n = 48) from Bangladesh. The total plasma concentration of measured amino acids was significantly reduced in each of the patient groups when compared to normal levels observed in healthy local controls: uncomplicated malaria -54%, severe malaria -23%, and sepsis -32%, (p = <0.001). Inspection of amino acid profiles revealed that in each group the majority of amino acids were below normal levels, except for phenylalanine. Among patients with severe malaria, L-lactate was strongly associated with an increase of the total amino acid concentration, likely because this reflects tissue hypoxia. Our data confirm previously described amino acid abnormalities, likely resulting from overall changes in the concentration of PFAA.

Mapping imported malaria in Bangladesh using parasite genetic and human mobility data.

For countries aiming for malaria elimination, travel of infected individuals between endemic areas undermines local interventions. Quantifying parasite importation has therefore become a priority for national control programs. We analyzed epidemiological surveillance data, travel surveys, parasite genetic data, and anonymized mobile phone data to measure the spatial spread of malaria parasites in southeast Bangladesh. We developed a genetic mixing index to estimate the likelihood of samples being local or imported from parasite genetic data and inferred the direction and intensity of parasite flow between locations using an epidemiological model integrating the travel survey and mobile phone calling data. Our approach indicates that, contrary to dogma, frequent mixing occurs in low transmission regions in the southwest, and elimination will require interventions in addition to reducing imported infections from forested regions. Unlike risk maps generated from clinical case counts alone, therefore, our approach distinguishes areas of frequent importation as well as high transmission.

Does reduced oxygen delivery cause lactic acidosis in falciparum malaria? An observational study.

BACKGROUND: Lactic acidosis with an elevated lactate-pyruvate ratio suggesting anoxia is a common feature of severe falciparum malaria. High lactate levels are associated with parasitized erythrocyte sequestration in the microcirculation. To assess if there is an additional contribution to hyperlactataemia from relatively inadequate total oxygen delivery, oxygen consumption and delivery were investigated in patients with malaria. METHODS: Adult Bangladeshi and Indian patients with uncomplicated (N = 50) or severe (N = 46) falciparum malaria or suspected bacterial sepsis (N = 27) and healthy participants as controls (N = 26) were recruited at Chittagong Medical College Hospital, Chittagong, Bangladesh and Ispat General Hospital, Rourkela, India. Oxygen delivery (DO2I) was estimated from pulse oximetry, echocardiographic estimates of cardiac index and haematocrit. Oxygen consumption (VO2I) was estimated by expired gas collection. RESULTS: VO2I was elevated in uncomplicated median (IQR) 185.1 ml/min/m2 (135-215.9) and severe malaria 192 ml/min/m2 (140.7-227.9) relative to healthy persons 107.9 ml/min/m2 (69.9-138.1) (both p < 0.001). Median DO2I was similar in uncomplicated 515 ml/min/m2 (432-612) and severe 487 ml/min/m2 (382-601) malaria and healthy persons 503 ml/min/m2 (447-517) (p = 0.27 and 0.89, respectively). The VO2/DO2 ratio was, therefore, increased by similar amounts in both uncomplicated 0.35 (0.28-0.44) and severe malaria 0.38 (0.29-0.48) relative to healthy participants 0.23 (0.17-0.28) (both p < 0.001). VO2I, DO2I and VO2/DO2 did not correlate with plasma lactate concentrations in severe malaria. CONCLUSIONS: Reduced total oxygen delivery is not a major contributor to lactic acidosis in severe falciparum malaria.

Short-term glucose dysregulation following acute poisoning with organophosphorus insecticides but not herbicides, carbamate or pyrethroid insecticides in South Asia.

BACKGROUND: Ingestion of organophosphorus (OP) insecticides is associated with acute hyperglycaemia. We conducted a prospective study to determine whether glucose dysregulation on admission associated with ingestion of OP insecticides or other pesticides is sustained to hospital discharge or to 3-12 months later. METHODS: We recruited participants to two similar studies performed in parallel in Anuradhapura, Sri Lanka, and Chittagong, Bangladesh, following hospitalisation for OP insecticide, herbicide or other pesticide self-poisoning. Two-hour 75 g oral glucose tolerance testing (OGTT) was performed after recovery from the acute poisoning, at around the time of discharge. In Sri Lanka, a four time-point OGTT for area-under-the-curve (AUC), C-peptide and homeostatic modelling of insulin resistance (HOMA-IR) was undertaken, repeated after 1 year. In Bangladesh, a 2-h OGTT for glucose was undertaken and repeated after 3 months in participants with initial elevated 2-h glucose. We compared glucose homeostasis by poison group and adjusted findings for age, BMI and sex. FINDINGS: Seventy-three Sri Lankan and 151 Bangladeshi participants were recruited. We observed higher mean [SD] fasting (4.91 [0.74] vs. 4.66 [0.46] mmol/L, p = .003) and 2-h glucose (7.94 [2.54] vs. 6.71 [1.90] mmol/L, p < .0001) in OP-poisoned groups than pyrethroid, carbamate, herbicide or 'other poison' groups at discharge from hospital. In Sri Lanka, HOMA-IR, glucose and C-peptide AUC were higher in OP than carbamate or herbicide groups. Adjusted analyses remained significant except for fasting glucose. Follow-up analysis included 92 participants. There was no significant difference in OGTT results between OP-poisoned and other participants at follow-up (mean [SD] 2-h fasting glucose 4.67 [0.92] vs. 4.82 [0.62], p = .352; 2-h glucose 6.96 [2.31] mmol/L vs. 6.27 [1.86] mmol/L, p = .225). CONCLUSION: We found in this small prospective study that acute OP insecticide poisoning caused acute glucose dysregulation that was sustained to hospital discharge but had recovered by 3-12 months. Acute glucose dysregulation was related to defects in insulin action and secretion. This study did not address long-term risk of diabetes following acute OP insecticide poisoning, but could provide the data for a power calculation for such a study.

Identifying the Components of Acidosis in Patients With Severe Plasmodium falciparum Malaria Using Metabolomics.

BACKGROUND: Acidosis in severe Plasmodium falciparum malaria is associated with high mortality, yet the pathogenesis remains incompletely understood. The aim of this study was to determine the nature and source of metabolic acids contributing to acidosis in patients with severe falciparum malaria. METHODS: A prospective observational study was conducted to characterize circulating acids in adults with P. falciparum malaria (n = 107) and healthy controls (n = 45) from Bangladesh using high-resolution liquid chromatography-mass spectrometry metabolomics. Additional in vitro P. falciparum culture studies were performed to determine if parasites release the acids detected in plasma from patients with severe malaria acidosis. RESULTS: We identified previously unmeasured plasma acids strongly associated with acidosis in severe malaria. Metabolomic analysis of P. falciparum parasites in vitro showed no evidence that these acids are released by the parasite during its life cycle. Instead, 10 of the plasma acids could be mapped to a gut microbial origin. Patients with malaria had low L-citrulline levels, a plasma marker indicating reduced gut barrier integrity. Longitudinal data showed the clearance of these newly identified acids was delayed in fatal cases. CONCLUSIONS: These data suggest that a compromise in intestinal barrier function may contribute significantly to the pathogenesis of life-threatening acidosis in severe falciparum malaria. CLINICAL TRIALS REGISTRATION: NCT02451904.

Point-of-care lung ultrasound for the detection of pulmonary manifestations of malaria and sepsis: An observational study.

INTRODUCTION: Patients with severe malaria or sepsis are at risk of developing life-threatening acute respiratory distress syndrome (ARDS). The objective of this study was to evaluate point-of-care lung ultrasound as a novel tool to determine the prevalence and early signs of ARDS in a resource-limited setting among patients with severe malaria or sepsis. MATERIALS AND METHODS: Serial point-of-care lung ultrasound studies were performed on four consecutive days in a planned sub study of an observational cohort of patients with malaria or sepsis in Bangladesh. We quantified aeration patterns across 12 lung regions. ARDS was defined according to the Kigali Modification of the Berlin Definition. RESULTS: Of 102 patients enrolled, 71 had sepsis and 31 had malaria. Normal lung ultrasound findings were observed in 44 patients on enrolment and associated with 7% case fatality. ARDS was detected in 10 patients on enrolment and associated with 90% case fatality. All patients with ARDS had sepsis, 4 had underlying pneumonia. Two patients developing ARDS during hospitalisation already had reduced aeration patterns on enrolment. The SpO2/FiO2 ratio combined with the number of regions with reduced aeration was a strong prognosticator for mortality in patients with sepsis (AUROC 91.5% (95% Confidence Interval: 84.6%-98.4%)). CONCLUSIONS: This study demonstrates the potential usefulness of point-of-care lung ultrasound to detect lung abnormalities in patients with malaria or sepsis in a resource-constrained hospital setting. LUS was highly feasible and allowed to accurately identify patients at risk of death in a resource limited setting.