Adult Cerebral Malaria: Acute and Subacute Imaging Findings, Long-term Clinical Consequences.

Cerebral malaria is an important cause of mortality and neurodisability in endemic regions. We show magnetic resonance imaging (MRI) features suggestive of cytotoxic and vasogenic cerebral edema followed by microhemorrhages in 2 adult UK cases, comparing them with an Indian cohort. Long-term follow-up images correlate ongoing changes with residual functional impairment.

Upcoming and urgent challenges in critical care research based on COVID-19 pandemic experience.

While the coronavirus disease 2019 (COVID-19) pandemic placed a heavy burden on healthcare systems worldwide, it also induced urgent mobilisation of research teams to develop treatments preventing or curing the disease and its consequences. It has, therefore, challenged critical care research to rapidly focus on specific fields while forcing critical care physicians to make difficult ethical decisions. This narrative review aims to summarise critical care research -from organisation to research fields- in this pandemic setting and to highlight opportunities to improve research efficiency in the future, based on what is learned from COVID-19. This pressure on research revealed, i.e., (i) the need to harmonise regulatory processes between countries, allowing simplified organisation of international research networks to improve their efficiency in answering large-scale questions; (ii) the importance of developing translational research from which therapeutic innovations can emerge; (iii) the need for improved triage and predictive scores to rationalise admission to the intensive care unit. In this context, key areas for future critical care research and better pandemic preparedness are artificial intelligence applied to healthcare, characterisation of long-term symptoms, and ethical considerations. Such collaborative research efforts should involve groups from both high and low-to-middle income countries to propose worldwide solutions. As a conclusion, stress tests on healthcare organisations should be viewed as opportunities to design new research frameworks and strategies. Worldwide availability of research networks ready to operate is essential to be prepared for next pandemics. Importantly, researchers and physicians should prioritise realistic and ethical goals for both clinical care and research.

Transcellular blood-brain barrier disruption in malaria-induced reversible brain edema.

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as brain swelling at the acute stage is difficult to study in humans and animal models with reliable induction of reversible edema are not known. In this study, we show that reversible brain swelling in experimental murine CM can be induced reliably after single vaccination with radiation-attenuated sporozoites as proven by in vivo high-field magnetic resonance imaging. Our results provide evidence that brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In adult CM patients magnetic resonance imaging demonstrate microhemorrhages in more than one third of patients with reversible edema, emphasizing similarities of the experimental model and human disease. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach to reduce edema and may improve neurological outcome.

Evidence of Brain Alterations in Noncerebral Falciparum Malaria.

BACKGROUND: Cerebral malaria in adults is associated with brain hypoxic changes on magnetic resonance (MR) images and has a high fatality rate. Findings of neuroimaging studies suggest that brain involvement also occurs in patients with uncomplicated malaria (UM) or severe noncerebral malaria (SNCM) without coma, but such features were never rigorously characterized. METHODS: Twenty patients with UM and 21 with SNCM underwent MR imaging on admission and 44-72 hours later, as well as plasma analysis. Apparent diffusion coefficient (ADC) maps were generated, with values from 5 healthy individuals serving as controls. RESULTS: Patients with SNCM had a wide spectrum of cerebral ADC values, including both decreased and increased values compared with controls. Patients with low ADC values, indicating cytotoxic edema, showed hypoxic patterns similar to cerebral malaria despite the absence of deep coma. Conversely, high ADC values, indicative of mild vasogenic edema, were observed in both patients with SNCM and patients with UM. Brain involvement was confirmed by elevated circulating levels of S100B. Creatinine was negatively correlated with ADC in SNCM, suggesting an association between acute kidney injury and cytotoxic brain changes. CONCLUSIONS: Brain involvement is common in adults with SNCM and a subgroup of hospitalized patients with UM, which warrants closer neurological follow-up. Increased creatinine in SNCM may render the brain more susceptible to cytotoxic edema.

Impact of COVID-19 on non-COVID intensive care unit service utilization, case mix and outcomes: A registry-based analysis from India.

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 1 st October 2019 and 27 th 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 31 st 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<0.00001), and APACHE II score increased (median [Q1 Q3] 19 [19,20] to 21 [20,22] ; p<0.00001). Unadjusted ICU mortality increased (9.3% to 11.7%, p=0.01519) and the length of ICU stay was similar (median [Q1 Q3] 2.11 [2, 2] vs. 2.24 [2, 3] days; p=0.15096). 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.

Determinants of brain swelling in pediatric and adult cerebral malaria.

Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A-EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A-EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling.

Epidemiological Characteristics, Ventilator Management, and Clinical Outcome in Patients Receiving Invasive Ventilation in Intensive Care Units from 10 Asian Middle-Income Countries (PRoVENT-iMiC): An International, Multicenter, Prospective Study.

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 [V T ] 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 V T 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 V T is globally in line with current recommendations.

Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BACKGROUND: Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. METHODS: Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. RESULTS: We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. CONCLUSIONS: Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.

Pragmatic Recommendations for Safety while Caring for Hospitalized Patients with COVID-19 in Low- and Middle-Income Countries.

Infection prevention and control measures to control the spread of COVID-19 are challenging to implement in many low- and middle-income countries (LMICs). This is compounded by the fact that most recommendations are based on evidence that mainly originates in high-income countries. There are often availability, affordability, and feasibility barriers to applying such recommendations in LMICs, and therefore, there is a need for developing recommendations that are achievable in LMICs. We used a modified version of the GRADE method to select important questions, searched the literature for relevant evidence, and formulated pragmatic recommendations for safety while caring for patients with COVID-19 in LMICs. We selected five questions related to safety, covering minimal requirements for personal protective equipment (PPE), recommendations for extended use and reuse of PPE, restriction on the number of times healthcare workers enter patients' rooms, hand hygiene, and environmental ventilation. We formulated 21 recommendations that are feasible and affordable in LMICs.

Implementing an intensive care registry in India: preliminary results of the case-mix program and an opportunity for quality improvement and research.

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.

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.

PRactice of VENTilation in Middle-Income Countries (PRoVENT-iMIC): rationale and protocol for a prospective international multicentre observational study in intensive care units in Asia.

INTRODUCTION: Current evidence on epidemiology and outcomes of invasively mechanically ventilated intensive care unit (ICU) patients is predominantly gathered in resource-rich settings. Patient casemix and patterns of critical illnesses, and probably also ventilation practices are likely to be different in resource-limited settings. We aim to investigate the epidemiological characteristics, ventilation practices and clinical outcomes of patients receiving mechanical ventilation in ICUs in Asia. METHODS AND ANALYSIS: PRoVENT-iMIC (study of PRactice of VENTilation in Middle-Income Countries) is an international multicentre observational study to be undertaken in approximately 60 ICUs in 11 Asian countries. Consecutive patients aged 18 years or older who are receiving invasive ventilation in participating ICUs during a predefined 28-day period are to be enrolled, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cm H2O) during the first 3 days of mechanical ventilation-compared between patients at no risk for acute respiratory distress syndrome (ARDS), patients at risk for ARDS and in patients with ARDS (in case the diagnosis of ARDS can be made on admission). Secondary outcomes include occurrence of pulmonary complications and all-cause ICU mortality. ETHICS AND DISSEMINATION: PRoVENT-iMIC will be the first international study that prospectively assesses ventilation practices, outcomes and epidemiology of invasively ventilated patients in ICUs in Asia. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance when designing trials of invasive ventilation in resource-limited ICUs. Access to source data will be made available through national or international anonymised datasets on request and after agreement of the PRoVENT-iMIC steering committee. TRIAL REGISTRATION NUMBER: NCT03188770; Pre-results.

Magnetic Resonance Imaging of Cerebral Malaria Patients Reveals Distinct Pathogenetic Processes in Different Parts of the Brain.

The mechanisms underlying the rapidly reversible brain swelling described in patients with cerebral malaria (CM) are unknown. Using a 1.5-Tesla (T) magnetic resonance imaging (MRI) scanner, we undertook an observational study in Rourkela, India, of 11 Indian patients hospitalized with CM and increased brain volume. Among the 11 cases, there were 5 adults and 6 children. All patients had reduced consciousness and various degrees of cortical swelling at baseline. The latter was predominately posterior in distribution. The findings on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps were consistent with vasogenic edema in all cases. Reversibility after 48 to 72 h was observed in >90% of cases. DWI/ADC mismatch suggested the additional presence of cytotoxic edema in the basal nuclei of 5 patients; all of these had perfusion parameters consistent with vascular engorgement and not with ischemic infarcts. Our results suggest that an impairment of the blood-brain barrier is responsible for the brain swelling in CM. In 5 cases, vasogenic edema occurred in conjunction with changes in the basal nuclei consistent with venous congestion, likely to be caused by the sequestration of Plasmodium falciparum-infected erythrocytes. While both mechanisms have been individually postulated to play an important role in the development of CM, this is the first demonstration of their concurrent involvement in different parts of the brain. The clinical and radiological characteristics observed in the majority of our patients are consistent with posterior reversible encephalopathy syndrome (PRES), and we show for the first time a high frequency of PRES in the context of CM. IMPORTANCE The pathophysiology and molecular mechanisms underlying cerebral malaria (CM) are still poorly understood. Recent neuroimaging studies demonstrated that brain swelling is a common feature in CM and a major contributor to death in pediatric patients. Consequently, determining the precise mechanisms responsible for this swelling could open new adjunct therapeutic avenues in CM patients. Using an MRI scanner with a higher resolution than the ones used in previous reports, we identified two distinct origins of brain swelling in both adult and pediatric patients from India, occurring in distinct parts of the brain. Our results support the hypothesis that both endothelial dysfunction and microvascular obstruction by Plasmodium falciparum-infected erythrocytes make independent contributions to the pathogenesis of CM, providing opportunities for novel therapeutic interventions.

Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future.

BACKGROUND: Sepsis is a major reason for intensive care unit (ICU) admission, also in resource-poor settings. ICUs in low- and middle-income countries (LMICs) face many challenges that could affect patient outcome. AIM: To describe differences between resource-poor and resource-rich settings regarding the epidemiology, pathophysiology, economics and research aspects of sepsis. We restricted this manuscript to the ICU setting even knowing that many sepsis patients in LMICs are treated outside an ICU. FINDINGS: Although many bacterial pathogens causing sepsis in LMICs are similar to those in high-income countries, resistance patterns to antimicrobial drugs can be very different; in addition, causes of sepsis in LMICs often include tropical diseases in which direct damaging effects of pathogens and their products can sometimes be more important than the response of the host. There are substantial and persisting differences in ICU capacities around the world; not surprisingly the lowest capacities are found in LMICs, but with important heterogeneity within individual LMICs. Although many aspects of sepsis management developed in rich countries are applicable in LMICs, implementation requires strong consideration of cost implications and the important differences in resources. CONCLUSIONS: Addressing both disease-specific and setting-specific factors is important to improve performance of ICUs in LMICs. Although critical care for severe sepsis is likely cost-effective in LMIC setting, more detailed evaluation at both at a macro- and micro-economy level is necessary. Sepsis management in resource-limited settings is a largely unexplored frontier with important opportunities for research, training, and other initiatives for improvement.

Haemodynamic assessment and support in sepsis and septic shock in resource-limited settings.

Background: Recommendations for haemodynamic assessment and support in sepsis and septic shock in resource-limited settings are largely lacking. Methods: A task force of six international experts in critical care medicine, all of them members of the Global Intensive Care Working Group of the European Society of Intensive Care Medicine and with extensive bedside experience in resource-limited intensive care units, reviewed the literature and provided recommendations regarding haemodynamic assessment and support, keeping aspects of efficacy and effectiveness, availability and feasibility and affordability and safety in mind. Results: We suggest using capillary refill time, skin mottling scores and skin temperature gradients; suggest a passive leg raise test to guide fluid resuscitation; recommend crystalloid solutions as the initial fluid of choice; recommend initial fluid resuscitation with 30 ml/kg in the first 3 h, but with extreme caution in settings where there is a lack of mechanical ventilation; recommend against an early start of vasopressors; suggest starting a vasopressor in patients with persistent hypotension after initial fluid resuscitation with at least 30 ml/kg, but earlier when there is lack of vasopressors and mechanical ventilation; recommend using norepinephrine (noradrenaline) as a first-line vasopressor; suggest starting an inotrope with persistence of plasma lactate >2 mmol/L or persistence of skin mottling or prolonged capillary refill time when plasma lactate cannot be measured, and only after initial fluid resuscitation; suggest the use of dobutamine as a first-line inotrope; recommend administering vasopressors through a central venous line and suggest administering vasopressors and inotropes via a central venous line using a syringe or infusion pump when available. Conclusion: Recommendations for haemodynamic assessment and support in sepsis and septic shock in resource-limited settings have been developed by a task force of six international experts in critical care medicine with extensive practical experience in resource-limited settings.

International study on microcirculatory shock occurrence in acutely ill patients.

OBJECTIVES: Microcirculatory alterations are associated with adverse outcome in subsets of critically ill patients. The prevalence and significance of microcirculatory alterations in the general ICU population are unknown. We studied the prevalence of microcirculatory alterations in a heterogeneous ICU population and its predictive value in an integrative model of macro- and microcirculatory variables. DESIGN: Multicenter observational point prevalence study. SETTING: The Microcirculatory Shock Occurrence in Acutely ill Patients study was conducted in 36 ICUs worldwide. PATIENTS: A heterogeneous ICU population consisting of 501 patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic, hemodynamic, and laboratory data were collected in all ICU patients who were 18 years old or older. Sublingual Sidestream Dark Field imaging was performed to determine the prevalence of an abnormal capillary microvascular flow index (< 2.6) and its additional value in predicting hospital mortality. In 501 patients with a median Acute Physiology and Chronic Health Evaluation II score of 15 (10-21), a Sequential Organ Failure Assessment score of 5 (2-8), and a hospital mortality of 28.4%, 17% exhibited an abnormal capillary microvascular flow index. Tachycardia (heart rate > 90 beats/min) (odds ratio, 2.71; 95% CI, 1.67-4.39; p < 0.001), mean arterial pressure (odds ratio, 0.979; 95% CI, 0.963-0.996; p = 0.013), vasopressor use (odds ratio, 1.84; 95% CI, 1.11-3.07; p = 0.019), and lactate level more than 1.5 mEq/L (odds ratio, 2.15; 95% CI, 1.28-3.62; p = 0.004) were independent risk factors for hospital mortality, but not abnormal microvascular flow index. In reference to microvascular flow index, a significant interaction was observed with tachycardia. In patients with tachycardia, the presence of an abnormal microvascular flow index was an independent, additive predictor for in-hospital mortality (odds ratio, 3.24; 95% CI, 1.30-8.06; p = 0.011). This was not true for nontachycardic patients nor for the total group of patients. CONCLUSIONS: In a heterogeneous ICU population, an abnormal microvascular flow index was present in 17% of patients. This was not associated with mortality. However, in patients with tachycardia, an abnormal microvascular flow index was independently associated with an increased risk of hospital death.

The reliability of the physical examination to guide fluid therapy in adults with severe falciparum malaria: an observational study.

BACKGROUND: Adults with severe malaria frequently require intravenous fluid therapy to restore their circulating volume. However, fluid must be delivered judiciously as both under- and over-hydration increase the risk of complications and, potentially, death. As most patients will be cared for in a resource-poor setting, management guidelines necessarily recommend that physical examination should guide fluid resuscitation. However, the reliability of this strategy is uncertain. METHODS: To determine the ability of physical examination to identify hypovolaemia, volume responsiveness, and pulmonary oedema, clinical signs and invasive measures of volume status were collected independently during an observational study of 28 adults with severe malaria. RESULTS: The physical examination defined volume status poorly. Jugular venous pressure (JVP) did not correlate with intravascular volume as determined by global end diastolic volume index (GEDVI; r(s) = 0.07, p = 0.19), neither did dry mucous membranes (p = 0.85), or dry axillae (p = 0.09). GEDVI was actually higher in patients with decreased tissue turgor (p < 0.001). Poor capillary return correlated with GEDVI, but was present infrequently (7% of observations) and, therefore, insensitive. Mean arterial pressure (MAP) correlated with GEDVI (rs = 0.16, p = 0.002), but even before resuscitation patients with a low GEDVI had a preserved MAP. Anuria on admission was unrelated to GEDVI and although liberal fluid resuscitation led to a median hourly urine output of 100 ml in 19 patients who were not anuric on admission, four (21%) developed clinical pulmonary oedema subsequently. MAP was unrelated to volume responsiveness (p = 0.71), while a low JVP, dry mucous membranes, dry axillae, increased tissue turgor, prolonged capillary refill, and tachycardia all had a positive predictive value for volume responsiveness of ≤50%. Extravascular lung water ≥11 ml/kg indicating pulmonary oedema was present on 99 of the 353 times that it was assessed during the study, but was identified on less than half these occasions by tachypnoea, chest auscultation, or an elevated JVP. A clear chest on auscultation and a respiratory rate <30 breaths/minute could exclude pulmonary oedema on 82% and 72% of occasions respectively. CONCLUSIONS: Findings on physical examination correlate poorly with true volume status in adults with severe malaria and must be used with caution to guide fluid therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00692627.