Determinants of Vascular Leakage During Systemic Inflammatory Response Syndrome

Обзор

BACKGROUND Controlling vascular leakage, which is independently associated with mortality during Sepsis and cardiogenic shock, may be a promising approach during systemic inflammatory response syndrome (SIRS). During a collaborative work between La Pitié-Salpêtrière intensive care unit (ICU) and the unit INSERM U1050 (National Institute oh Health and medical Research), we identified 38 genes associated with capillary leakage during systemic inflammation response syndrome (SIRS) in humans. The aim of this study is to evaluate their possible implication in vascular hyperpermeability associated with METHODS SIRS-PERM is a prospective multicenter cohort study, testing the correlation between the plasma and broncho-alveolar levels of proteins isolated from our first screening, and the level of vascular leakage during SIRS. All patients admitted in the European Georges-Pompidou or La Pitié-Salpêtrière ICU and presenting a SIRS will be eligible for inclusion. Plasma samples will be collected at day 0, D1, D3 and D7, as well as broncho-alveolar lavage samples if clinically indicated. Concentration of each protein will be determined by ELISA in those samples. A statistical association will be then tested between each protein concentration and, for each time-point, the level of capillary leakage (daily weight and fluid balance, extra-vascular lung water index and pulmonary permeability index measured by transpulmonary thermodilution), and ARDS (acute respiratory distress syndrome) severity (PaO2/FiO2 ratio, Murray score and pulmonary compliance). Its link with hemodynamic status, the level of multiple organ failure, and vital status at day 30, will be also assessed. Basing the calculation of the sample size on the variations of VEGF (Vascular endothelial growth factor) expression in our first screening cohort, we calculated a sample size of 180 patients for this study, for a total duration of the study of 5 years. IMPLICATIONS: SIRS-PERM will assess the determinants of capillary leakage during SIRS. It may thus provide a better understanding of the pathophysiology of this disease, with the goal to isolate new markers of severity, as well as new therapeutic targets to treat it. Modulating specifically capillary leakage is indeed a totally new approach during this pathology.

Подробное описание

1. Intervention Six ml of blood will be sampled at Day 0 (beginning of the SIRS), D1, D3, D7. Concentrations of candidate proteins will be determined in the plasma by ELISA, and the link between each concentration and each outcome analyzed.

Additionally, broncho-alveolar lavage will be analyzed in the same way, if performed for the routine care of the patient. 2. Statistical analysis

The link between plasma and alveolar levels of each protein and each outcome will be evaluated, using Mann-Whitney U-test and one-way ANOVA for categorical variables (for example comparison of protein X plasma level between survivors or nonsurvivors at 30 days), and Pearson's correlation for continuous variables (for example link between protein X plasma level and daily fluid balance at each time point).

Sample size calculation. Plasma and pulmonary concentrations of each protein that we will study have never been described during SIRS. Based on our first screening cohort patients with severe capillary leakage had a difference in VEGF plasma concentration of 15.5 pg/ml, with a standard deviation of 32 pg/ml. Basing the calculation on this parameter, with an alpha risk of 5% and a power of 90%, a sample size of 180 patients would provide 90% chances to find a statistical link between one protein concentration and the outcomes of the patients.

Вмешательства

• Другое Blood sampling
  6 ml blood sampling at Day 0, 1, 3, 7. Broncho-alveolar sampling, if performed in routine care.

Первичные конечные точки

• Fluid balance from Day 0 to day 3 (ml/kg of initial body weight). [Срок оценки: Between Day 0 and Day 3]

Вторичные конечные точки (8)

• Fluid balance (ml/kg of initial body weight). [Срок оценки: Day 1, Day 3, Day 7]
• Extra-vascular lung water index [Срок оценки: Day 0, Day 1, Day 3, Day 7]
• SOFA score [Срок оценки: Day 0, Day 1, Day 3, Day 7,]
• Serum albuminemia [Срок оценки: Day 0, Day 1, Day 3, Day 7,]
• Catecholamine-free days [Срок оценки: Day 0, Day 1, Day 3, Day 7, Day 30]
• Ventilatory-free days [Срок оценки: Day 0, Day 1, Day 3, Day 7, Day 30]
• Renal replacement therapy-free Number of days alive without receiving any renal replacement therapy [Срок оценки: Day 0, Day 1, Day 3, Day 7, Day 30]
• Mortality [Срок оценки: Day 30]

Критерии участия

Критерии включения

• All patients admitted in the European Georges Pompidou Hospital or La Pitié-Salpêtrière ICU, and exhibiting a systemic inflammatory response syndrome (SIRS), characterized by the following items:

• Temperature > 38°C ou <36°C
• Heart rate >90/min
• Respiratory rate >20/min or PaCO2<32mmHg
• White cell count > 12 000/mm3 ou < 4 000/mm3

Критерии исключения

• Age <18 years
• Decline to participate
• Pregnancy
• Cirrhosis Child-Pugh > B
• Denutrition with BMI<15kg/m2
• Nephrotic syndrome
• Persons deprived of their liberty by a judicial or administrative decision (guardianship or tutelage measure)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Франция · 2 центра

• Adult Medical-Surgical Intensive Care Unit, Necker Hospital of the Sick Children — Paris
• Medical Intensive Care Unit, Georges Pompidou European Hospital — Paris

Идентификаторы

NCT: NCT05663216 · APHP220418

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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