Clinical trial NCT03641534: Monitoring of Perfusion in Sepsis and Malaria
Official title: Perfusion and Lung Congestion Evaluation Related to Fluids and Vasopressors in Sepsis and Malaria. (PERFuSE): an Observational Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Severe Sepsis
Malaria
Keywords: Perfusion
Lung congestion
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Mahidol Oxford Tropical Medicine Research Unit
name: University of Amsterdam
name: University of British Columbia
name: Chittagong Medical College and Hospital
name: Malaria Research Group & Dev Care Foundation, Dhaka, Bangladesh
name: Beth Israel Deaconess Medical Center
First posted: 2018-08-22
Enrollment: 103
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Male or female subjects, aged ≥12 years hospitalized with malaria or sepsis.

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.

Detailed description: 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

Eligibility criteria: 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.

Inclusion criteria for sepsis:

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

Primary outcomes:
measure: Fluid balance volume at 24 hours
timeFrame: On the first 24 hours from enrollment
measure: Plasma lactate levels
timeFrame: 72 hours
measure: Vasopressor therapy
timeFrame: 72 hours
measure: Global ultrasound aeration score
timeFrame: 72 hours
measure: Fluid balance volume at 48 hours
timeFrame: On the first 48 hours from enrollment
measure: Fluid balance volume at 72 hours
timeFrame: On the first 72 hours from enrollment
Secondary outcomes:
measure: Plasma creatinine levels
timeFrame: 48 hours
measure: Positive chest X-ray for pulmonary edema (dichotomous variable)
timeFrame: 72 hours
measure: The ratio between pulse oxymetry hemoglobin saturation and the fraction of inspired oxygen (SpO2/FiO2 ratio).
timeFrame: 72 hours
measure: Proportion of fluid responsive patients
timeFrame: 72 hours
measure: Prolonged capillary refill time (dichotomous variable, defined as ≥3 seconds)
timeFrame: 72 hours
measure: Skin mottling score (0-5)
timeFrame: 72 hours
measure: Cardiac index (in liters per minute per square meter of body surface area)
timeFrame: 72 hours
measure: Core-periphery temperature gradient(°C)
timeFrame: 72 hours
measure: Proportion of patients at enrolment and during admission with a low cardiac index and hypoperfusion state.
timeFrame: 72 hours
measure: Proportion of patients with microvasculature obstruction or abnormalities
timeFrame: 24 hours
measure: Proportion of patients that develop pulmonary edema and acute respiratory distress syndrome (ARDS).
timeFrame: 72 hours
measure: Case fatality in first 30 days.
timeFrame: 30 days
measure: Acute kidney injury (AKI)
timeFrame: At admission, up to day 14, and renal recovery by 30 days
measure: Proportion of patients that develop lower extremity deep venous thrombosis.
timeFrame: 72 hours
measure: Microbiological etiology of sepsis.
timeFrame: 72 hours
measure: Number of patients with ARDS according to the Kigali Modification of the Berlin Definition of ARDS
timeFrame: 72 hours
measure: Diagnostic performance measures (sensitivity, specificity, positive predictive value, negative predictive value) of the digital microscope with expert microscopy as the gold standard
timeFrame: 7 days
Other outcomes:
Locations:
city: Chittagong
country: Bangladesh
facility: Chittagong Medical College Hospital
Study officials:
References: