Sepsis and severe malaria together contribute to an estimated 13 million deaths annually, a great burden of which is in low-income countries. Optimal fluid management is critical yet remains one of the most challenging clinical care elements as volume overload precipitates pulmonary edema and volume restriction may exacerbate acute kidney injury. These complications of sepsis and severe malaria significantly increase mortality, particularly in resource-limited settings lacking mechanical ventilation and renal replacement therapy. Point-of-care ultrasound and passive leg raise testing are two easily implementable, safe and non-invasive clinical bedside fluid assessment tools that could be applied towards developing a fluid management algorithm in low resource settings. Similarly, simple tissue perfusion measures can facilitate understanding of precise indications or contraindication to fluid and vasopressor therapy. However, the performance of these tools has yet to be confirmed in these settings. Accurate assessment of pulmonary tolerance and fluid responsive patients could aid to tailor vasopressor and fluid therapy to the patient condition and disease phase, thus preventing or detecting iatrogenic pulmonary edema and other pulmonary complications. As there is currently limited evidence supporting fluid management recommendations for severe malaria and sepsis in low-resource settings, the potential application of these management tools could optimize supportive therapy and improve outcomes in these populations. The main activity proposed is a prospective, observational study of patients with sepsis and severe malaria to describe the relationship between fluid therapy and vasopressor therapy against measures of tissue perfusion and pulmonary congestion in adult patients with severe malaria or severe sepsis. In addition, the study will assess the performance of simple bedside clinical tools assessing fluid responsiveness, pulmonary congestion and peripheral tissue perfusion. The data from this observational study will facilitate the preparation of a follow-up study to test a clinical algorithm to guide individualized fluid and vasopressor administration.
This will be a single center, prospective, longitudinal, observational study of patients with sepsis or severe malaria. It is planned that this initial observational study will inform a follow-up intervention study, based on the observational study findings (Lung Ultrasound and Passive Leg Raising- guided Vasopressors and Fluid Management in Patients with Sepsis and Severe Malaria). The follow-up study will propose testing of a clinical algorithm to individualize titration of vasopressors, diuretics and fluids based on the simple tools evaluated during the observational study. The expected duration of study patient participation is 30 days. Patients will be assessed every 6 hours until fever clearance, parasite clearance (in malaria patients) and GCS normalization (score of 15) on two consecutive assessments. Thereafter, patients will be assessed daily until discharge or death with one follow-up visit at 14 days and a follow-up call at day 30. The prospective, observational recruitment phase of the study is expected to last 15 months. Funder: Wellcome Trust of Great Britain, Grant reference number: 220211/A/20/Z
Study Type
OBSERVATIONAL
Enrollment
103
Use of lung ultrasound to detect pulmonary complications
CUS is a highly sensitive and specific modality used to recognize lower extremity deep venous thrombosis (DVT)
Echocardiogram can be (i) identify imminent life-threatening causes of hemodynamic failure, (ii) recognize coexisting diagnoses that complicate management, (iii) follow the evolution of the disease process, and (iv) monitor response to treatment
Measurement of the inferior vena cava diameter
Baseline assessment (including pulse rate, systolic and diastolic blood pressure, velocity time integral (VTI) and stroke volume (SV) echocardiographic measurements) will be performed in the resting semi-recumbent position, defined as a position with the trunk elevated 30° to 45° relative to the lower limbs.
Measurement of capillary flow in the rectal microcirculation
For urinalysis, biochemistry, urine microscopy, pH, and culture.
for: parasitological and microbiological diagnostics, complete blood count, biochemistry, red cell deformability analyzed by laser assisted rotational cell analyser (LORCA), markers of oxidative stress (peripheral intravenous catheter)
all patients will have an ECG performed on enrolment as a non-invasive investigation
GlycoCheck is a clinical sublingual handheld, bedside microscope that detects erythrocytes within the small sublingual blood vessels measuring 5 to 25 micrometers in diameter. The sublingual vasculature is a validated site for measuring thickness of the endothelial glycocalyx.
Chittagong Medical College Hospital
Chittagong, Bangladesh
Fluid balance volume at 24 hours
Fluid balance volume in milliliters calculated daily as inputs minus outputs.
Time frame: On the first 24 hours from enrollment
Plasma lactate levels
Plasma venous lactate levels expressed in mmol/L
Time frame: 72 hours
Vasopressor therapy
Expressed as dichotomous variable, use of any vasopressor during the first 72 hours.
Time frame: 72 hours
Global ultrasound aeration score
The score ( range 0-36) is calculated over 12 lung zones where each zone is scored 0 to 3.
Time frame: 72 hours
Fluid balance volume at 48 hours
Fluid balance volume in milliliters calculated daily as inputs minus outputs.
Time frame: On the first 48 hours from enrollment
Fluid balance volume at 72 hours
Fluid balance volume in milliliters calculated daily as inputs minus outputs.
Time frame: On the first 72 hours from enrollment
Plasma creatinine levels
Measured in millimoles per liter.
Time frame: 48 hours
Positive chest X-ray for pulmonary edema (dichotomous variable)
Other measures evaluating pulmonary congestion
Time frame: 72 hours
The ratio between pulse oxymetry hemoglobin saturation and the fraction of inspired oxygen (SpO2/FiO2 ratio).
Other measures evaluating pulmonary congestion
Time frame: 72 hours
Proportion of fluid responsive patients
Fluid responsiveness is defined as a positive pulse pressure passive leg raise test (change in pulse pressure \>10% after leg raise manouver) or cardiac output-guided passive leg raise test (change in cardiac output \>10% after leg raise manouver). The passive leg raise test is performed both a standard maneuver (bed tilting) and a modified maneuver (manual leg raise).
Time frame: 72 hours
Prolonged capillary refill time (dichotomous variable, defined as ≥3 seconds)
Other measures evaluating tissue perfusion
Time frame: 72 hours
Skin mottling score (0-5)
Other measures evaluating tissue perfusion
Time frame: 72 hours
Cardiac index (in liters per minute per square meter of body surface area)
Other measures evaluating tissue perfusion
Time frame: 72 hours
Core-periphery temperature gradient(°C)
Other measures evaluating tissue perfusion
Time frame: 72 hours
Proportion of patients at enrolment and during admission with a low cardiac index and hypoperfusion state.
Time frame: 72 hours
Proportion of patients with microvasculature obstruction or abnormalities
Microvasculature obstruction and abnormalities are detected with orthogonal polarization spectral imaging (OPS); red cell deformability is studied by laser assisted rotational cell analyser (LORCA).
Time frame: 24 hours
Proportion of patients that develop pulmonary edema and acute respiratory distress syndrome (ARDS).
Pulmonary edema is defined as the presence of 2 or more positive lung zones per hemithorax on the lung ultrasound. Acute respiratory distress syndrome is defined according to the Berlin Definition criteria.
Time frame: 72 hours
Case fatality in first 30 days.
Time frame: 30 days
Acute kidney injury (AKI)
Proportion of AKI as per Kidney Diseases Improving Global Outcomes definition: serum creatinine increase by ≥ 3 mg/dl within 48 hours, or serum creatinine increase by ≥ 1.5 times baseline, or urine volume \<0.5 mg/kg/h for 6 hours. Outcome of AKI defined as renal recovery (time in days until creatinine returns to baseline).
Time frame: At admission, up to day 14, and renal recovery by 30 days
Proportion of patients that develop lower extremity deep venous thrombosis.
Deep venous thrombosis is defined as a positive compressive ultrasonography on femoral or popliteal veins of lower limbs.
Time frame: 72 hours
Microbiological etiology of sepsis.
Results of blood culture and organism identified in case of positive result
Time frame: 72 hours
Number of patients with ARDS according to the Kigali Modification of the Berlin Definition of ARDS
Time frame: 72 hours
Diagnostic performance measures (sensitivity, specificity, positive predictive value, negative predictive value) of the digital microscope with expert microscopy as the gold standard
Time frame: 7 days
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