Echocardiography-guided Cirrhosis and Liver Failure-Intensive Care Protocol Sepsis
NCT ID: NCT07286643
Last Updated: 2025-12-16
Study Results
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Basic Information
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RECRUITING
NA
140 participants
INTERVENTIONAL
2026-01-01
2028-12-30
Brief Summary
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* 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?
Detailed Description
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* 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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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ECHO arm
Other Names: Point of Care- Echo-cardiogram,POCUS Description: • The patients in septic shock with MAP\< 65mmHg, with IVC diameter \<18mm and IVCCI≥40% in spontaneously breathing patients, would be regarded as fluid depleted state and will be given a fluid challenge with 250-500 ml of balanced salt solution. Those who increment cardiac index by 15% will be continued on fluid boluses with BSS and 5% albumin will be started as ongoing resuscitation within 1 h, which is a standard fluid of choice in patients with cirrhosis soon after the bolus BSS is infused. Fluids will be administered as per periodic POCUS with cardiac US targets, IVC, IJV indices, delta Velocity time integral, and maintenance of MAP\>65 mmHg. In the Intervention arm (ECHO) arm, we propose a dynamic Cardiac ultrasound target-based fluid resuscitation strategy.
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.
* If there is an increment in cardiac index by 15% after giving a fluid bolus (i.e. 250-500 ml of BSS in 15min), we can define 'fluid responsiveness' present.
* The achievement of lactate clearance, MAP target \>65mmHg and ScV02 \>70% remains similar as the fixed target strategy.
The main resuscitation fluid remains 5% albumin in this arm. Albumin infusion will be titrated based on lung ultrasound.
Conventional goal directed therapy. (CGDT)
Fixed Target Strategy Fluid boluses would be administered until a central venous pressure (CVP) of 8-10 mmHg is achieved. Till the central line is placed, the shock index (heart rate/ systolic blood pressure) will be used instead of the CVP and IVC indices. Thus fluids (500 ml balanced salt solution 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 ≥70% and lactate clearance \>10% will be targeted. • If ScVO2 is \<70% and lactate clearance is \<10%, noradrenaline will be started and titrated upwards. take it up to a maximum dose. • Second choice of pressor agent will be vasopressin. • Thus. CGDT group targets CVP, MAP, followed by ScVO2 ≥70% and lactate clearance .
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 ≥70% and lactate clearance \>10% will be targeted.
* If ScVO2 is \<70% and lactate clearance is \<10%, noradrenaline will be started and titrated upwards. take it up to a maximum dose.
* Second choice of pressor agent will be vasopressin.
* Thus. CGDT group targets CVP, MAP\>65 mmHg, followed by ScVO2 ≥70% and lactate clearance in a step wise way.
Interventions
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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.
* If there is an increment in cardiac index by 15% after giving a fluid bolus (i.e. 250-500 ml of BSS in 15min), we can define 'fluid responsiveness' present.
* The achievement of lactate clearance, MAP target \>65mmHg and ScV02 \>70% remains similar as the fixed target strategy.
The main resuscitation fluid remains 5% albumin in this arm. Albumin infusion will be titrated based on lung ultrasound.
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 ≥70% and lactate clearance \>10% will be targeted.
* If ScVO2 is \<70% and lactate clearance is \<10%, noradrenaline will be started and titrated upwards. take it up to a maximum dose.
* Second choice of pressor agent will be vasopressin.
* Thus. CGDT group targets CVP, MAP\>65 mmHg, followed by ScVO2 ≥70% and lactate clearance in a step wise way.
Eligibility Criteria
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Inclusion Criteria
2. Sepsis-related Hypotension (MAP \<65mmHg or SBP \<90mmHg)
3. 18-65 yrs of age -
Exclusion Criteria
2. 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.
3. Poor chest wall window due to left pleural effusion, left pneumothorax, small intercostal spaces that restrict performance of a POCUS.
4. Active bleeding like variceal bleed
5. Cerebrovascular events
6. Chronic renal disease - End Stage Renal Disease (ESRD)/ patient on renal replacement therapy
7. Admission to ICU following liver transplantation, burns, cardiac surgery
8. Previous transjugular intra hepatic portosystemic shunt (TIPS),
9. Hepatocellular carcinoma
10. Pregnant or lactating women
11. Informed consent refused by patient or attendants
12. Active COVID-19 infection
18 Years
65 Years
ALL
No
Sponsors
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Post Graduate Institute of Medical Education and Research, Chandigarh
OTHER
Responsible Party
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Madhumita Premkumar
Additional Professor
Locations
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PGIMER Chandigarh
Chandigarh, , India
Countries
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Central Contacts
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Other Identifiers
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PGI/IEC/02/2024-3008
Identifier Type: -
Identifier Source: org_study_id