Title:

Prospective multicentre surgical outcome registry for patients with cirrhosis of liver

Introduction:

The prevalence of cirrhosis of the liver is increasing globally and also in India. [1,2]. This translates to a growing number of patients with cirrhosis of liver undergoing surgeries. There is an increased risk of post-operative mortality as well as decompensation for patients with liver cirrhosis undergoing surgery. [3,4].

Risk stratification and prediction of complications and/or mortality is necessary for informed decision making for patient and surgeon, both. Numerous risk prediction models are currently available, and the most used are the Mayo score[3] and the VOCAL- Penn scoring system[4].

While Mayo score only predicted mortality, VOCAL-Penn score also predicted decompensation andpost-operative infection in addition to mortality. The VOCAL-Penn database is based on retrospective data of patients with cirrhosis who underwent diverse surgeries in the Veterans Health Administration, based in US. [4] This includes only 1.1% of Asians and a majority of patients had hepatitis C, along with alcohol as etiology of liver cirrhosis. The Indian population of cirrhosis would differ as compared to this cohort with respects to composition, etiology and possibly a worse nutrition and albumin level.

Thus, it is felt necessary to have a prospective registry of surgical outcomes in patients with cirrhosis of liver in India.

Methods:

1.       Study design: Prospective, multicenter, observational study

2.       Patient selection

All patients with cirrhosis of liver who undergo any surgical intervention will be eligible for the study. Patients will also receive a written explanation of the study and must freely give their informed consent in writing.Patients must fulfil the inclusion and exclusion criteria.

Inclusion criteria

·         Aged 18 years or older 

·         Confirmed cirrhosis of liver as below

o   A combination of clinical, imaging and biochemical findings

o   Liver biopsy confirming bridging fibrosis or F4 on Metavir staging

o   Visualisation of nodular cirrhosis on laparoscopy or laparotomy during surgery

o   Ultrasound or CT demonstrating a shrunken and nodular liver

o   Liver elastography showing >15 kPa, in absence of cardiac failure, liver tumors, biliary obstruction and ascites.

·         Informed consent

Exclusion criteria

·         Co-existing hepatocellular carcinoma

·         Liver transplant surgery

·         Consent refused

3.       Variable collection

Baseline:

·         Demographic data such as age, gender, state of residence

·         Comorbidities: hypertension, diabetes, obesity [BMI ≥ 30], coronary artery disease, congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disease, ischaemic stroke

·         Etiology of liver cirrhosis. This will be classified as alcohol related, NASH, hepatitis B, hepatitis C, Autoimmune liver disease (including autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis and/or any combination), Wilson’s disease and others. For rare liver diseases, the name will be noted down. For those with multiple etiologies, all the etiologies will be recorded.

·         Biochemical tests including complete blood count, S. creatinine, sodium, liver function tests such as total bilirubin(or direct bilirubin wherever available), AST (aspartate aminotransferase), ALT (Alanine aminotransferase), alkaline phosphatase, albumin and prothrombin time with test value, control value and international normalized ratio (INR). The relevant Child-Turcotte-Pugh (CTP)and MELD-Na scores will be calculated based on these values. [Appendix 1]. These values would be within 72 hours of the surgery to be considered valid. Additional values like pH, lactate, CRP, procalcitonin will be recorded whenever available.

·         Compensated or decompensated cirrhosis. If decompensation exists, type of decompensation and grade will be noted. [Appendix 2]

·         Acute on chronic liver failure (ACLF) present or not [Appendix 3] [5]

Surgical  details:

·         Details of surgery [appendix 4 for details]

o   Date of surgery.

o   Emergency or elective #

o   Name of surgery performed *

o   Duration of the surgery

o   Approximate blood loss intra-operatively @

o   Whether surgery is done for an infectious complication

·         Details of anaesthesia

o   ASA (American Society of Anaesthesiologists) classification [appendix 5] [6]

o   Type of anaesthesia given: Local, regional, spinal, general

o   Major events occurring intra-operatively like hemodynamic instability

Outcome

The outcome will be noted at Day 7, 1 month (Day 30), 3 months (Day 60) and 6 months (Day 180).

The timing will be considered from the date of surgery, which will be Day 0.

There will be an allowance of a window period of +/- 7 days for each of the assessments, except for assessment at Day 7, where the window period will be of +/- 3 days.

·         Mortality will be recorded. The number of days for the death from the day of surgery will be calculated and recorded.

·         Occurrence of any new liver related decompensation will be recorded. This will be classified into acute decompensation or ACLF and graded accordingly [Appendix 2 & 3]. Non variceal bleeding will not be considered as a decompensation.

·         Worsening of pre-existing decompensation will be recorded. Grading will be noted as per appendix 2.

·         Occurrence of infections will be noted along with site and severity [Appendix 6]. Only new onset infections will be considered. Pre-existing infections before surgery will not be considered.

·         Biochemical tests including complete blood count, S. creatinine, sodium, liver function tests such as total bilirubin(or direct bilirubin wherever available), AST (aspartate aminotransferase), ALT (Alanine aminotransferase), alkaline phosphatase, albumin and prothrombin time with test value, control value and international normalized ratio (INR) will be recorded whenever available. The relevant Child-Turcotte-Pugh (CTP)and MELD-Na scores will be calculated based on these values. [Appendix 1].  Additional values like pH, lactate, CRP, procalcitonin will be recorded whenever available.

Collection of data

The data will be collected via a website. The investigators will be given a username and password for identification and authentication.

The Clinical record form (CRF) will be electronic and will be saved on server online. They will be editable till the 6 month follow up is completed.

References:

1.       10.1016/S2468-1253(19)30349-8 (global trend)

2.       10.1002/cld.1177 (India)

3.       10.1053/j.gastro.2007.01.040 (Mayo score)

4.       10.1016/j.cgh.2021.06.050 (Vocal Penn)

5.       10.1007/s12072-019-09946-3 (APASL ACLF)

6.       https://www.asahq.org/standards-and-guidelines/asa-physical-status-classification-system [ASA classification]

7.       10.1007/s40265-018-1018-z (West Haven)

8.       10.1016/j.jhep.2010.05.004 (EASL ascites, HRS)

9.       10.1002/hep.22605 (AASLD AKI)

Appendix

1.      CHILD-TURCOTTE-PUGH (CTP) AND MELD-NA SCORES

Child-Turcotte-Pugh (CTP)

CTP class A: score 5-6 points

CTP class B: Score 7-9 points

CTP class C: Score 10-15 points

MELD score:

MELD Score = (0.957 * ln(Serum Cr) + 0.378 * ln(Serum Bilirubin) + 1.120 * ln(INR) + 0.643 ) * 10 (if hemodialysis, value for Creatinine is automatically set to 4.0)

MELD-Na = MELD Score - Na - 0.025 x MELD x (140-Na) + 140

2.      DECOMPENSATION NOTATION AND GRADING

List of decompensations:

·         Hepatic encephalopathy

·         Acute Kidney Injury

·         Hepato-renal syndrome (HRS)

·         Ascites

·         Variceal bleeding

·         Jaundice

·         Coagulopathy

·         New onset portal vein thrombosis

Grading of Hepatic Encephalopathy [7]

Grading of ascites [8]

Acute Kidney Injury grading [9]

Diagnostic criteria of Hepato-renal syndrome (HRS) [9]

·         Cirrhosis with ascites

·         Serum creatinine >1.5 mg/dL

·         HRS-1 doubling of the initial serum creatinine concentrations to a level greater than 2.5 mg/dL (>226 μmol/L) in less than 2 weeks

·         No improvement in serum creatinine (decrease to 1.5 mg/dL or less) after at least 2 days of diuretic withdrawal and expansion of plasma volume with albumin (1 g/kg body weight/day up to a maximum of 100 g/day)

·         Absence of shock

·         No current or recent treatment with nephrotoxic drugs or vasodilators

·         Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (>50 red blood cells per high-power field), or abnormal renal ultrasonography

Grading of Jaundice:

Any increase or decrease in serum Bilirubin will be noted as a percentage (%) of the previous value.

Grading of coagulopathy:

Any increase or decrease in prothrombin time will be noted as a percentage (%) of the previous value.

3.      ACUTE ON CHRONIC LIVER FAILURE (ACLF)

ACLF is defined as following as per APASL consensus:

ACLF is an acute hepatic insult manifesting as jaundice (serum bilirubin≥5 mg/dL) and coagulopathy (INR≥1.5 or prothrombin activity < 40%) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/cirrhosis, and is associated with a high 28-day mortality.

4.      SURGICAL DETAILS

·         Emergency surgeries will be defined as those requiring surgical intervention within 24 hours of admission to the hospital. The decision will be taken by attending clinician based on indication on indication of surgery and patient factors.

·         Name of surgery performed:  A list of standardised nomenclature will be generated after first hundred registrations. The surgeries with minor technical variations will be considered into a single category. If more than one surgery is performed in a single session, the surgery with higher complexity will be considered. The complexity in such cases will be subjectively based on expected mortality rate, amount of trauma, extent of dissection, potential functional or cosmetic loss, usual duration of operation, space requirements, equipment required, anaesthesia use, number of assistants required, and special training required. The decision will be taken by the attending clinician. If more than one complex surgery is performed, both the surgical procedures will be noted

·         The estimation of blood loss will be provided by the attending clinician. Method used to estimate the  blood loss will be recorded. E.g. visual, formula based, gravimetric etc

5.      ASA PHYSICAL STATUS CLASSIFICATION SYSTEM