Monitoring of Perfusion in Sepsis and Malaria

NCT ID: NCT03641534

Last Updated: 2021-06-21

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

103 participants

Study Classification

OBSERVATIONAL

Study Start Date

2018-06-04

Study Completion Date

2019-09-26

Brief Summary

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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.

Detailed Description

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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

Conditions

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Severe Sepsis Malaria

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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Sepsis

Lung Ultrasound examination

Intervention Type PROCEDURE

Use of lung ultrasound to detect pulmonary complications

Compression ultrasonography (CUS)

Intervention Type PROCEDURE

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

Echocardiography

Intervention Type 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

Inferior Vena Cava ultrasound

Intervention Type PROCEDURE

Measurement of the inferior vena cava diameter

Passive leg raising test (PLR)

Intervention Type 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.

Orthogonal polarization spectral imaging (OPS)

Intervention Type PROCEDURE

Measurement of capillary flow in the rectal microcirculation

Urine collection (Foley catheter)

Intervention Type PROCEDURE

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

Venous blood samplings

Intervention Type 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)

Electrocardiogram

Intervention Type PROCEDURE

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

GlycoCheck

Intervention Type 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.

Severe malaria

Lung Ultrasound examination

Intervention Type PROCEDURE

Use of lung ultrasound to detect pulmonary complications

Compression ultrasonography (CUS)

Intervention Type PROCEDURE

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

Echocardiography

Intervention Type 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

Inferior Vena Cava ultrasound

Intervention Type PROCEDURE

Measurement of the inferior vena cava diameter

Passive leg raising test (PLR)

Intervention Type 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.

Orthogonal polarization spectral imaging (OPS)

Intervention Type PROCEDURE

Measurement of capillary flow in the rectal microcirculation

Urine collection (Foley catheter)

Intervention Type PROCEDURE

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

Venous blood samplings

Intervention Type 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)

Electrocardiogram

Intervention Type PROCEDURE

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

GlycoCheck

Intervention Type 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.

Uncomplicated malaria

Lung Ultrasound examination

Intervention Type PROCEDURE

Use of lung ultrasound to detect pulmonary complications

Compression ultrasonography (CUS)

Intervention Type PROCEDURE

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

Echocardiography

Intervention Type 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

Inferior Vena Cava ultrasound

Intervention Type PROCEDURE

Measurement of the inferior vena cava diameter

Passive leg raising test (PLR)

Intervention Type 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.

Orthogonal polarization spectral imaging (OPS)

Intervention Type PROCEDURE

Measurement of capillary flow in the rectal microcirculation

Urine collection (Foley catheter)

Intervention Type PROCEDURE

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

Venous blood samplings

Intervention Type 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)

Electrocardiogram

Intervention Type PROCEDURE

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

GlycoCheck

Intervention Type 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.

Interventions

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Lung Ultrasound examination

Use of lung ultrasound to detect pulmonary complications

Intervention Type PROCEDURE

Compression ultrasonography (CUS)

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

Intervention Type PROCEDURE

Echocardiography

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

Intervention Type PROCEDURE

Inferior Vena Cava ultrasound

Measurement of the inferior vena cava diameter

Intervention Type PROCEDURE

Passive leg raising test (PLR)

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.

Intervention Type PROCEDURE

Orthogonal polarization spectral imaging (OPS)

Measurement of capillary flow in the rectal microcirculation

Intervention Type PROCEDURE

Urine collection (Foley catheter)

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

Intervention Type PROCEDURE

Venous blood samplings

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)

Intervention Type PROCEDURE

Electrocardiogram

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

Intervention Type PROCEDURE

GlycoCheck

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.

Intervention Type PROCEDURE

Eligibility Criteria

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Inclusion Criteria

I. Sepsis criteria:

The sepsis criteria include the severe sepsis and septic shock categories according to 2012 Surviving Sepsis Campaign guidelines. Due to a possible delay in obtaining all the enrolment sequential organ failure assessment (SOFA) score variables necessary to fulfil the criteria for the latest 2016 sepsis definition, the 2012 Surviving Sepsis Campaign criteria and the quick SOFA tool will be used for inclusion. However, after study completion, when all admission SOFA scores will be available, all patients will be re-scored according to the Sepsis 3 definition.


1. Documented or suspected infection
2. 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)
3. 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.
4. Age ≥12 years
5. Negative peripheral blood slide for any stages of malaria parasites and a negative rapid diagnostic test (RDT) for falciparum and vivax malaria.
6. 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
* Within 24 hours of antimalarial treatment

III. Uncomplicated malaria criteria (control group)

* P. falciparum slide positive (asexual stages) on peripheral blood slide or positive RDT in combination with none of the above severity criteria.
* Within 24 hours of start of antimalarial treatment
* 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

Exclusion Criteria

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
Minimum Eligible Age

12 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Mahidol Oxford Tropical Medicine Research Unit

OTHER

Sponsor Role collaborator

University of Amsterdam

OTHER

Sponsor Role collaborator

University of British Columbia

OTHER

Sponsor Role collaborator

Chittagong Medical College and Hospital

OTHER

Sponsor Role collaborator

Malaria Research Group & Dev Care Foundation, Dhaka, Bangladesh

UNKNOWN

Sponsor Role collaborator

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role collaborator

University of Oxford

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Locations

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Chittagong Medical College Hospital

Chittagong, , Bangladesh

Site Status

Countries

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Bangladesh

Other Identifiers

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MAL18001

Identifier Type: -

Identifier Source: org_study_id

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