Volume Resuscitation in Cirrhosis With Sepsis Induced Hypotension

Sponsor

Postgraduate Institute of Medical Education and Research (Other)

Overall Status

Recruiting

CT.gov ID

NCT05059795

Collaborator

(none)

Enrollment

Locations

Anticipated Duration (Months)

37.5

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

In critically ill patients with liver disease like cirrhosis or ACLF, fluid therapy needs to be instituted after identification of patients who will be fluid responsive and initiate appropriate inotropes early to prevent the mortality associated with fluid overload.

The parameters and methodology used for assessing fluid responsiveness have been studied earlier, but the optimum method is not established. Existing recommendations based on data regarding fluid responsiveness and choice of fluid for resuscitation from intensive care units in general cannot be applied to those with liver disease as the hemodynamic alterations that occur with liver disease, presence of hypoalbuminemia at baseline and presence of cardiac dysfunction interfere with the conventional methods of fluid status assessment, fluid responsiveness as well as the response to different types of resuscitation fluids.

Therefore the investigators attempt to compare various methods to estimate current intravascular volume status of patient which could be helpful in guiding fluid therapy.

Condition or Disease	Intervention/Treatment	Phase
Cirrhosis, Liver Sepsis Acute on Chronic Liver Failure	Drug: Albumin

Detailed Description

Objectives:

To compare the accuracy of central venous pressure and inferior vena cava dynamic assessment and lactate clearance for estimating adequacy of fluid resuscitation in patients with cirrhosis with sepsis induced hypotension .[Time Frame at enrolment, 6 hours, 24 hours]
Predictors of all-cause mortality at Day 7 and day 28. [Time Frame Day 7 and Day 28]

PATIENTS AND METHODS Study Design: A Prospective observational study

Case Definition:

Cirrhosis will be defined by - "clinical features consistent with chronic liver disease (CLD) including a consistent history as well as a documented complication of CLD (i.e., ascites, varices, hepatic encephalopathy) and/or imaging results consistent with cirrhosis and/or liver histologic findings consistent with cirrhosis" ACLF will be defined as per EASL criteria with documentation of organ failures.

Systemic Inflammatory Response Syndrome (SIRS) - 2 more of following 4

Oral temperature >38.3oC or <36oC
Heart Rate > 90 beats/min
Respiratory Rate >20 breaths/min or PaCO2 <32mmHg
WBC count >12000/cumm, <4000/cumm or >10% immature band forms Sepsis is a SIRS in response to proven or suspected microbial event 'Sepsis induced hypotension' implies mean arterial pressure < 65 mmHg or a reduction of >40 mm Hg from baseline in the absence of other causes of hypotension Severe sepsis - sepsis-induced tissue hypoperfusion or organ dysfunction (any of the following thought to be due to the infection)

Sepsis-induced hypotension
Lactate above upper limits laboratory normal
Urine output < 0.5 mL/kg/hr for more than 2 hrs despite adequate fluid resuscitation
Acute lung injury with PaO2/FIO2 < 250 in the absence of pneumonia as infection source
Acute lung injury with PaO2/FIO2 < 200 in the presence of pneumonia as infection source
Creatinine > 2.0 mg/dL (176.8 μmol/L)
Bilirubin > 2 mg/dL (34.2 μmol/L)
Platelet count < 100,000 μL
Coagulopathy (international normalized ratio > 1.5) Septic shock is "sepsis induced hypotension despite adequate fluid resuscitation along with organ dysfunction or perfusion abnormality".

Acute kidney injury (AKI) is defined as any of the following:

Increase in SCr by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or
Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or
Urine volume <0.5 ml/kg/h for 6 hours

Definition of Adequate Intravascular volume - IVC diameter ≥ 18mm and IVCCI <40% Definition of Adequate fluid resuscitation - Achieving MAP ≥ 65mmHg with Fluid bolus

All patients eligible for the study will undergo screening as per the above criteria. The ones who satisfy the criteria will be counselled for participation in the study and written informed consent will be taken from the patient / the legal guardian in patients who are unable to do so. Patient information sheets will also be signed, briefing the patients about why the research work is necessary and also about the methodology.

Detail history and clinical examination will be done in all cases and the findings along with all investigation results will be recorded in a standard case record form. Information would be collected regarding the onset and duration of symptoms, etiology, and severity of disease, other baseline clinical features, demographic characteristics, routine biochemical and hematological investigations.

After enrolment, baseline samples would be taken for routine investigations and samples for evaluation of sepsis - blood culture, urine culture, fluid cultures, procalcitonin will be taken.
The patient would be assessed for 5 parameters and will be reassessed 30min and 4hours after starting fluid resuscitation.

IVC diameter and collapsibility Index
Serum lactate levels
Venous-arterial pCO2 difference
CVP where central line inserted as per treating physician's decision
ScVO2 where central line available

The patients in septic shock where IVC diameter <18mm or IVCCI≥40% in spontaneously breathing patients, would be regarded in fluid depleted state and will be given aggressive fluid resuscitation with 20% albumin 100 ml started within 30 min which is a standard fluid of choice in patients with cirrhosis and other fluids - Normal Saline/ balanced salt solution 30ml/kg over 3hrs.

(The patients who not fulfil above criteria would be assumed in a fluid replete state and be started on maintenance fluid management along with inotrope support as per standard dosage guidelines) Norepinephrine would be 1st choice vasopressor - started at a dose of 4μg/min and titrated every 20 min to a maximum of 21.3μg/min. If MAP still <65mmHg, Vasopressor would be added starting from a 0.01U/min to 0.04U/min. Adrenaline would be added in shock refractory to both vasopressors in dose of 4-24μg/min.

Along with fluid and inotrope support, the patient will also receive standard of care including empiric broad spectrum antibiotics, oxygen support/ventilator support if needed.
MAP would be rechecked 30 min after starting fluid therapy. IVC diameter and IVCCI would also be checked at same time to see if change in MAP (if any) is reflected in the IVC status. Adequate fluid resuscitation would be defined by achieving a MAP ≥ 65mmHg. In patients achieving MAP≥65mmHg, fluid therapy will be continued. The patients still having MAP<65 mmHg will be started on inotrope support according to standard guidelines.
IVC, IVCCI, Lactate, venous-arterial pCO2 difference, CVP and ScVO2 would be remeasured at 4 hrs.
The patient would be the followed with serial examinations, calculations of SOFA score, CTP and MELD.
Samples to test for sepsis such as procalcitonin, galactomannan, beta D Glucan and high sensitivity CRP will be done every 48-72 hours as determined by the treating clinician.
Cultures for bacterial and fungal sepsis will be taken as per the Liver ICU protocol.
If discharged earlier, for the purpose of 28-day mortality the patients' kin would be contacted telephonically.
Data regarding total amount of fluids, type of fluids, urine output, dose and duration of inotropes, initiation of RRT, total days in ICU/Hospital, immediate cause of death (In case of mortality) would be noted.

Study Design

Study Type:

Observational

Anticipated Enrollment :

75 participants

Observational Model:

Case-Only

Time Perspective:

Prospective

Official Title:

To Compare the Effectiveness of Various Methods of Estimating Volume Resuscitation in Patients With Cirrhosis With Sepsis Induced Hypotension

Actual Study Start Date :

Feb 1, 2020

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Jun 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Cirrhosis/ACLF of any etiology	Drug: Albumin Type of resuscitation fluid, dose and use of inotrope Other Names: Crystalloid

Arm

Intervention/Treatment

Cirrhosis/ACLF of any etiology

Drug: Albumin

Type of resuscitation fluid, dose and use of inotrope

Other Names:

Crystalloid

Outcome Measures

Primary Outcome Measures

Achievement of IVC diameter ≥ 18mm and IVCCI <40% [4 hours]
Achievement of Mean Arterial pressure >65 mmHg [4 hours]

Secondary Outcome Measures

Requirement of inotrope and fluid support (median dose) [4 hours and 24 hours]
Incidence of Acute Kidney Injury [day 0 and day 7]
Incidence of new organ dysfunction (encephalopathy, coagulation failure, respiratory failure) [Day 0 and Day 7]
Duration of ICU stay [Total duration of ICU stay in days]
The total duration of stay in intensive care, which will be assessed till 28 days
Duration of hospital stay [Total duration of admission as a hospital inpatient, assessed till 28 days]
The total duration of stay in hospital, which will be assessed till 28 days
Mortality [Day 7 and Day 28]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Clinical/Imaging or Biopsy proven liver cirrhosis of any etiology
Hypotension (MAP <65mmHg or SBP <90mmHg)
18-65 yrs of age

Exclusion Criteria:

Already received colloid or 2 litres of fluid within the first 2 hours of presentation, without echocardiographic assessment.
Already on vasopressors/inotropes
Severe pre-existing cardiopulmonary disease
Acute Respiratory Distress Syndrome (ARDS)
Active bleeding like variceal bleed 28
Cerebrovascular events
Chronic renal disease - End Stage Renal Disease (ESRD)/ patient on renal replacement therapy
Admission to ICU following liver transplantation, burns, cardiac surgery
Brain death or likely brain death within 24 hours
Previous adverse reaction to human albumin solution
Pregnant or lactating women
Informed consent refused by patient or attendants