Echocardiography-guided Cirrhosis and Liver Failure-Intensive Care Protocol Sepsis

Официальное название

Point-of-care Echocardiogram (POCUS) Guided Resuscitation Versus Conventional Goal- Directed Therapy in the Management of Cirrhosis With Severe Sepsis or Septic Shock: A Randomised Controlled Trial

Обзор

* Point-of-care echocardiography is used to guide septic shock resuscitation in patients with severe sepsis in the intensive care unit (ICU), but without systematic evidence for efficacy in critically patients with Cirrhosis and Severe Sepsis. * Due to portal hypertension, these patients have a hyperdynamic circulation, increased capillary permeability, splanchnic arteriolar vasodilation, reduced effective circulating blood volume and may have latent cirrhotic cardiomyopathy (CCM). * Hence assessment of volume status and cardiac reserve using conventional central venous pressure (CVP) or mean arterial pressure (MAP) remains difficult. Novelty: * In two recent trials, the role of 5% albumin vs PlasmalyteTM (FRISC study)(1) and 20% albumin vs. PlasmalyteTM (ALPS study) (2) were reported as the primary resuscitation fluid. Neither trial showed a clear long term survival benefit of albumin over balanced salt solution (BSS). In fact, the ALPS trial reported that there was increased risk of pulmonary edema with use of 20% albumin as fluid resuscitation. * A major limitation of such trial data is that the focus is on choice of fluid rather than looking at hemodynamic goals of resuscitation, resulting in protocolized overzealous fluid administration. * This may result in albumin-related pulmonary edema, and precipitation of overt heart failure in patients with silent CCM. * POC-Echo-based fluid resuscitation can prevent pulmonary edema and consequently respiratory failure, while ensuring renal and tissue perfusion. * It is unclear if choice of fluid or appropriate targets of resuscitation drive the survival benefit in the intensive care management of cirrhosis with severe sepsis. Objectives: * The investigators will conduct an ICU based randomised controlled feasibility trial comparing two measures of resuscitation: Echocardiography (ECHO) Guided septic shock resuscitation vs. a modified Goal-Directed Fluid Therapy (GDT) as recommended by sepsis guidelines which use protocol fluids. * The study will validate the role of POC-Echo parameters as volume assessment tools (cardiac index, systemic vascular resistance index) to determine endpoints of fluid resuscitation and need for vasopressors. * Lastly, the study aims to determine the presence of CCM in this population, and its impact on clinical outcomes. Methods POC-ECHO will be done within 1 hours of admission to the liver ICU and at 24h, 48 h and 72 hours in patients with cirrhosis with systolic blood pressure of \<90 mmHg or a mean arterial pressure \<65 mmHg. Resuscitation target is maintenance of MAP ≥65 mmHg with use of fluids and/or vasopressors. Clinical, cardiac biomarkers, and survival data based on resuscitation fluids will be prospectively collected. CCM will be defined as per CCM Consortium (2020) criteria. Expected outcome. The key questions to be answered in the resuscitation of critically ill patients with cirrhosis and sepsis induced hypotension are: 1. What should be best method of ensuring adequate fluid resuscitation i.e. fluid resuscitation protocol? 2. Which measurable clinical parameter can be used to determine adequacy of fluid resuscitation, and as a predictor of mortality outcomes at 7 and 28 days? 3. Whether early fluid resuscitation translates into better clinical outcome in decreasing duration of hospital and intensive care unit (ICU) stay, prevention of AKI and prevention of secondary sepsis?

Подробное описание

* Patients with cirrhosis requiring intensive care for severe sepsis carry a risk of high mortality due to altered hemodynamics with reduced effective arterial volume, portal hypertension, presence of ascites, and risk of complications like acute variceal bleeding (AVB), acute kidney injury (AKI) and circulatory failure(3-5). The main principles for management of severe sepsis include early recognition, control of the source of infection, appropriate and timely administration of antimicrobial agents, and resuscitation with intravenous fluids +/- vasoactive drugs, if needed (6). * Due to portal hypertension, these patients have a hyperdynamic circulation, increased capillary permeability, splanchnic arteriolar vasodilation, and may have latent cirrhotic cardiomyopathy (CCM) (7). Hence assessment of volume status and cardiac reserve using conventional central venous pressure (CVP) or mean arterial pressure (MAP) remains difficult (8). Although inferior vena cava (IVC) dynamics and IVC collapsibility index are reasonable accurate for ventilated patients, their use in spontaneously breathing subjects or those with tense ascites are not defined(9). Even measures like passive leg raising and Valsalva manoeuvre are difficult to perform in cirrhotic patients with tense ascites. * Early goal directed therapy (EGDT) improved outcomes in a randomized trial in patients with severe sepsis(10). Thereafter EGDT was incorporated into the 6-hour resuscitation bundle of the surviving sepsis campaign guidelines, but did not incorporate patients with cirrhosis(11-13). Following the early EGDT trials, studies focussed choice of resuscitation fluid i.e., albumin versus normal saline or balanced salt solution (BSS), concerns about potential risks of volume overload and pulmonary edema and lack of generalisability in subsequent trials showed that there was no associated survival benefit with an aggressive fluid protocol(14, 15). In the ALBIOS study, 1818 patients with severe sepsis or septic shock were randomized either to receive 300 ml of 20% albumin plus crystalloid or to receive crystalloid alone initially to achieve the EGDT goals. However, no mortality benefit was demonstrated at 29 or 90 days(16). * Intravenous albumin improves effective circulatory volume by improving plasma oncotic pressure and expands the total blood volume making it the apparent 'fluid of choice' for resuscitation in cirrhosis. The 5% albumin expands plasma volume by 80% of the administered volume, 20% albumin by 210% and 25% albumin by 260% which is expected to remain in the intravascular compartment longer than balanced salt solutions or normal saline(17). In two recent trials, the role of 5% albumin vs PlasmalyteTM (FRISC study) (1)and 20% albumin vs. PlasmalyteTM (ALPS study)(2) were reported as the primary resuscitation fluid. Neither trial showed a clear long term survival benefit of albumin over BSS. * Point-of-care ultrasonography (POCUS), including cardiac ultrasound, is used to assess volume status, and hemodynamic parameters like cardiac output, systemic vascular resistance, cardiac contractility, and pulmonary artery pressure, which aid in the early and accurate diagnosis of heart failure, cirrhotic cardiomyopathy, porto-pulmonary hypertension, hepatopulmonary syndrome, arrhythmia, pulmonary embolism, and ischemic heart disease. This helps determine the ideal amount of fluids, and vasopressors in resuscitation of patients with cirrhosis.

Вмешательства

• Диагностический тест POCUS
  * In the Intervention arm (ECHO) arm, we propose a Cardiac ultrasound target-based fluid resuscitation. This incorporates the fluid assessment based on POCUS and myocardial dysfunction based on cardiac ultrasound (cardiac index, myocardial contractility, stroke volume) and portal hypertension-related systemic vasodilation accentuated by sepsis (systemic vascular resistance index or SVRI). * The POCUS -velocity time integral and stroke volume index will be used to determine fluid responsiveness.
• Диагностический тест Fixed Resuscitation Strategy based on Target MAP
  • Fluid boluses would be administered until a CVP of 8-10 mmHg is achieved and IVC diameter is between 1.8-2 cm with 20-30% collapsibility. Till the central line is placed, the shock index (heart rate/ systolic blood pressure) will be used instead of the CVP. Thus fluids (500 ml crystalloid followed by 5% albumin) will be administered for a shock index ≥1 and till CVP is placed. * When CVP goal is achieved vasopressors will be started to target MAP ≥ 65mmHg. Once MAP target is achieved, ScVO2

Первичные конечные точки

• Reduction in volume of resuscitation fluid to attain reversal of shock in POCUS vs Conventional goal-directed therapy at 24 h [Срок оценки: Time of randomization to 24 hours]

Вторичные конечные точки (12)

• Assessment of all-cause mortality [Срок оценки: From time of randomization up to Day 7]
• Attainment of MAP> 65mmHg [Срок оценки: from time of randomization up to time point of reversal of shock]
• Assessment of all-cause mortality [Срок оценки: From date of randomization until Day 28]
• Total dose of vasopressor usage in either arm. [Срок оценки: From date of randomization until 24 hours]
• Total dose of vasopressor usage in either arm. [Срок оценки: From date of randomization until Day 7]
• Duration of ICU stay. [Срок оценки: From date of randomization until discharge from ICU or death]
• Cardiac related biomarker panel test [Срок оценки: At the Time of Randomization]
• Cardiac biomarker panel test [Срок оценки: The time point of 24 hours from randomization]
• Cardiac related biomarker panel test [Срок оценки: At the Time point of 72h from randomization]
• Sepsis related biomarker panel test [Срок оценки: At the Time of randomization]
• Sepsis related biomarker panel test [Срок оценки: At the time point of 24 hours from randomization]
• Sepsis related biomarker panel test [Срок оценки: At the Time point of 72 h from randomization]

Критерии участия

Критерии включения

• Critically ill patient with cirrhosis of any etiology
• Sepsis-related Hypotension (MAP <65mmHg or SBP <90mmHg)
• 18-65 yrs of age -

Критерии исключения

• Already on vasopressors/inotropes
• Severe pre-existing cardiopulmonary disease like porto-pulmonary hypertension (PPH), known coronary artery disease, congenital or valvular heart disease, prosthetic cardiac valves, dilated or restrictive cardiomyopathy.
• Poor chest wall window due to left pleural effusion, left pneumothorax, small intercostal spaces that restrict performance of a POCUS.
• Active bleeding like variceal bleed
• Cerebrovascular events
• Chronic renal disease - End Stage Renal Disease (ESRD)/ patient on renal replacement therapy
• Admission to ICU following liver transplantation, burns, cardiac surgery
• Previous transjugular intra hepatic portosystemic shunt (TIPS),
• Hepatocellular carcinoma
• Pregnant or lactating women
• Informed consent refused by patient or attendants
• Active COVID-19 infection

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Индия · 1 центр

• PGIMER Chandigarh — Chandigarh

Идентификаторы

NCT: NCT07286643 · PGI/IEC/02/2024-3008

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗