Monitoring of Perfusion in Sepsis and Malaria

NCT03641534 | Completed

• 1 other identifier: MAL18001
• Study Type: observational
• Target: 103
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Severe Sepsis; Malaria

Keywords

Perfusion; Lung congestion

Outcome Measures

Primary Outcomes (6)

• Fluid balance volume at 24 hours

  Fluid balance volume in milliliters calculated daily as inputs minus outputs.

  On the first 24 hours from enrollment

• Plasma lactate levels

  Plasma venous lactate levels expressed in mmol/L

  72 hours

• Vasopressor therapy

  Expressed as dichotomous variable, use of any vasopressor during the first 72 hours.

  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.

  72 hours

• Fluid balance volume at 48 hours

  Fluid balance volume in milliliters calculated daily as inputs minus outputs.

  On the first 48 hours from enrollment

• Fluid balance volume at 72 hours

  Fluid balance volume in milliliters calculated daily as inputs minus outputs.

  On the first 72 hours from enrollment

Secondary Outcomes (17)

• Plasma creatinine levels

  48 hours

• Positive chest X-ray for pulmonary edema (dichotomous variable)

  72 hours

• The ratio between pulse oxymetry hemoglobin saturation and the fraction of inspired oxygen (SpO2/FiO2 ratio).

  72 hours

• Proportion of fluid responsive patients

  72 hours

• Prolonged capillary refill time (dichotomous variable, defined as ≥3 seconds)

  72 hours

Study Arms (3)

Sepsis

Procedure: Lung Ultrasound examination; Procedure: Compression ultrasonography (CUS); Procedure: Echocardiography; Procedure: Inferior Vena Cava ultrasound; Procedure: Passive leg raising test (PLR); Procedure: Orthogonal polarization spectral imaging (OPS); Procedure: Urine collection (Foley catheter); Procedure: Venous blood samplings; Procedure: Electrocardiogram; Procedure: GlycoCheck

Severe malaria

Procedure: Lung Ultrasound examination; Procedure: Compression ultrasonography (CUS); Procedure: Echocardiography; Procedure: Inferior Vena Cava ultrasound; Procedure: Passive leg raising test (PLR); Procedure: Orthogonal polarization spectral imaging (OPS); Procedure: Urine collection (Foley catheter); Procedure: Venous blood samplings; Procedure: Electrocardiogram; Procedure: GlycoCheck

Uncomplicated malaria

Procedure: Lung Ultrasound examination; Procedure: Compression ultrasonography (CUS); Procedure: Echocardiography; Procedure: Inferior Vena Cava ultrasound; Procedure: Passive leg raising test (PLR); Procedure: Orthogonal polarization spectral imaging (OPS); Procedure: Urine collection (Foley catheter); Procedure: Venous blood samplings; Procedure: Electrocardiogram; Procedure: GlycoCheck

Interventions

Lung Ultrasound examination PROCEDURE

Use of lung ultrasound to detect pulmonary complications

Sepsis; Severe malaria; Uncomplicated malaria

Compression ultrasonography (CUS) PROCEDURE

CUS is a highly sensitive and specific modality used to recognize lower extremity deep venous thrombosis (DVT)

Sepsis; Severe malaria; Uncomplicated malaria

Echocardiography PROCEDURE

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

Sepsis; Severe malaria; Uncomplicated malaria

Inferior Vena Cava ultrasound PROCEDURE

Measurement of the inferior vena cava diameter

Sepsis; Severe malaria; Uncomplicated malaria

Passive leg raising test (PLR) PROCEDURE

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.

Sepsis; Severe malaria; Uncomplicated malaria

Orthogonal polarization spectral imaging (OPS) PROCEDURE

Measurement of capillary flow in the rectal microcirculation

Sepsis; Severe malaria; Uncomplicated malaria

Urine collection (Foley catheter) PROCEDURE

For urinalysis, biochemistry, urine microscopy, pH, and culture.

Sepsis; Severe malaria; Uncomplicated malaria

Venous blood samplings PROCEDURE

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)

Sepsis; Severe malaria; Uncomplicated malaria

Electrocardiogram PROCEDURE

all patients will have an ECG performed on enrolment as a non-invasive investigation

Sepsis; Severe malaria; Uncomplicated malaria

GlycoCheck PROCEDURE

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.

Sepsis; Severe malaria; Uncomplicated malaria

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Male or female subjects, aged ≥12 years hospitalized with malaria or sepsis.

You may qualify if:

• I. Sepsis criteria:
• Documented or suspected infection
• Systolic blood pressure ≤ 100 mmHg, or receiving vasopressor (epinephrine, norepinephrine, dopamine)
• PLUS one or more of the following:
• A. Respiratory rate ≥22 breaths per minute or under oxygen therapy or mechanical ventilation B. Altered mental status (Glasgow Coma Scale ≤ 14)
• Fully informed written consent obtained, including written informed consent from a relative or parent/guardian in case of reduced consciousness and/or age \< 16 years.
• Age ≥12 years
• Negative peripheral blood slide for any stages of malaria parasites and a negative rapid diagnostic test (RDT) for falciparum and vivax malaria.
• Within 24 hours of hospital or ICU admission
• Note: Positive blood or urine cultures not required as eligibility criteria due to limited microbiology laboratory availability.
• II. Severe malaria criteria Using modified World Health Organization criteria for severe falciparum malaria, as defined previously.
• Any P. falciparum or P. vivax parasitaemia in adults, detected by asexual stages on a peripheral blood- slide or a positive RDT in combination with one or more:
• i. GCS \<11 ii. Hematocrit \< 20% with parasite count \>100,000/mm3 iii. Jaundice with parasite count \>100,000/mm3 iv. Serum creatinine \>3 mg/dL (or anuria) v. Hypoglycemia with venous glucose \<40 mg/dL vi. Systolic blood pressure \<80 mmHg with cool extremities vii. Peripheral asexual stage parasitemia \>10 % viii. Peripheral venous lactate \>4 mmol/L ix. Peripheral venous bicarbonate \<15 mmol/L x. Respiratory distress/pulmonary edema: radiologically confirmed, or oxygen saturation \<92% on room air with a respiratory rate \>30/min, often with chest indrawing and crepitations on auscultation xi. Spontaneous bleeding xii. Generalized convulsions (≥2 in 24 hours)
• Fully informed written consent obtained, including written informed consent from relative or parent/guardian in case of reduced consciousness and/or age \< 16 years.
• Age ≥12 years

You may not qualify if:

• The participant may not enter the study if ANY of the following apply:
• Patients admitted with known malignancy or liver disease
• Recent surgery (as part of current admission)
• Trauma (resulting in current admission)
• Antimalarial treatment ≥24 hours prior to screening

Sponsors & Collaborators

• University of Oxford: lead
• Mahidol Oxford Tropical Medicine Research Unit: collaborator
• University of Amsterdam: collaborator
• University of British Columbia: collaborator
• Chittagong Medical College and Hospital: collaborator
• Malaria Research Group & Dev Care Foundation, Dhaka, Bangladesh: collaborator
• Beth Israel Deaconess Medical Center: collaborator

Study Sites (1)

Chittagong Medical College Hospital

Chittagong, Bangladesh

Location

Biospecimen

Retention: SAMPLES WITH DNA

Hematocrit and peripheral blood parasitemia in thin and thick films will be assessed at T=0 (enrolment) then 6-hourly until parasite clearance (two consecutive negative thick smears per 500 white blood cells). Plasma creatinine will be measured 24-hourly for 72 hours, at discharge and day 14. Venous blood gas and lactate will be assessed 6-hourly until lactate \<2 mmol/L. Arterial blood gas will be collected at T0 and after 24 hours if the subject is in respiratory distress, defined as respiratory rate \> 30 breaths per minute and SpO2 \<92% on room air. More frequent hematological and biochemical measurements may be done if clinically indicated at the discretion of the treating clinician. Plasma cell-free hemoglobin (CFH) will be analyzed at hour 0, 6, 24, 48, 72 and day 7 in the severe malaria group and only hour 0 in sepsis and uncomplicated malaria groups. Blood cultures and additional microbiology assays will be drawn at enrolment and performed locally.

MeSH Terms

Conditions

Sepsis; Malaria

Interventions

Urine Specimen Collection

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Protozoan Infections; Parasitic Diseases; Mosquito-Borne Diseases; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 29, 2018
• First Posted: August 22, 2018
• Study Start: June 4, 2018
• Primary Completion: August 29, 2019
• Study Completion: September 26, 2019
• Last Updated: June 21, 2021

Record last verified: 2020-09

Locations

BA (1)