Volume Resuscitation in Cirrhosis With Sepsis Induced Hypotension

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.

Objectives:

1. 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 .\[Time Frame at enrolment, 6 hours, 24 hours\]
2. 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

1. Oral temperature \>38.3oC or \<36oC
2. Heart Rate \> 90 beats/min
3. Respiratory Rate \>20 breaths/min or PaCO2 \<32mmHg
4. 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:

1. Increase in SCr by ≥0.3 mg/dl (≥26.5 μmol/l) within 48 hours; or
2. Increase in SCr to ≥1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or
3. 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.

  1. IVC diameter and collapsibility Index
  2. Serum lactate levels
  3. Venous-arterial pCO2 difference
  4. CVP where central line inserted as per treating physician's decision
  5. 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.

Presence of Cirrhotic Cardiomyopathy as per updated 2020 CCMC criteria.

CCM is defined as systolic or diastolic dysfunction in the absence of alternative cardiac pathology in concordance with the Cirrhotic Cardiomyopathy Consortium (CCMC) criteria. 9 Systolic dysfunction was defined as an ejection fraction (EF) ≤50% or an absolute value of GLS \<18%. LVDD will be defined as presence of 3 of the following 4 criteria: septal early diastolic mitral annular flow velocity (e') \<7 cm/s, early diastolic transmitral flow to early diastolic mitral annular velocity (E/e') ≥15, left atrial volume index (LAVI) \>34 mL/m2, tricuspid jet maximum velocity \>2.8 m/s, in the absence of pulmonary hypertension and the presence of measurable early to late diastolic transmitral flow velocity (E/A) ratio (E/A \>2 = grade 3 \& E/A 0.8-2 = grade 2 LVDD). Persons meeting only 2 criteria will be termed as indeterminate for LVDD grade. 19

Eligibility Criteria:
Inclusion Criteria:

1. Clinical/Imaging or Biopsy proven liver cirrhosis of any etiology
2. Hypotension (MAP \<65mmHg or SBP \<90mmHg)
3. 18-65 yrs of age

Exclusion Criteria:

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