King s College Hospital NHS Foundation Trust. Acute on Chronic Liver Failure: Practical management outside the tertiary centre.

Transcription

1 King s College Hospital NHS Foundation Trust NHS Acute on Chronic Liver Failure: Practical management outside the tertiary centre. William Bernal Professor of Liver Critical Care Liver Intensive Therapy Unit Institute of Liver Studies Kings College Hospital United Kingdom

2 ACLF & Practical Management

3 ACLF & Practical Management Admissions: Liver Critical Care Kings College Hospital 2016/17 n=1569 Hepatobiliary Surgery Acute liver failure Chronic liver disease Transplants Previous Transplants Non Liver Patients

4 ACLF & Practical Management Intensive Care National Audit and Research Centre (ICNARC) Extrapolated numbers of cirrhosis ICU admissions and ICU deaths per 100,000 population (England, Wales & NI) Year Admissions Deaths ICNARC 2015 McPhail et al Manuscript Submitted 2017

5 Directly standardised mortality rate per 100,000 ACLF & Practical Management Mortality from chronic liver disease, all ages, England, , Directly standardised mortality rate Number of deaths (persons) 6,000 5,000 4,000 3,000 2,000 1,000 0 Number of deaths (persons) Source: NHS Atlas of Variation in healthcare for people with liver disease 2017 (In press)

6 Acute on Chronic Liver Failure (ACLF): Practical management outside the tertiary centre. Overview: ACLF in the natural history of Chronic Liver Disease. Definitions Controversies ACLF: practical Issues in clinical care. Getting access to ICU: avoiding futility. Ward Interventions: preventing ACLF. ACLF: how can your Liver Unit help? Transfer Transplantation.

7 Natural History Chronic Liver Disease. Compensated Cirrhosis No ascites or overt HE ~ 5-10% patients / year Recompensation of hepatic function Decompensated Cirrhosis Ascites, HE, Variceal bleeding

8 Natural History Chronic Liver Disease. D Amico et al J Hepatology 2006;44:

9 Natural History Chronic Liver Disease Complication 1Year Mortality Variceal Bleeding 20% Ascites 29% Ascites and Variceal Bleeding 49% Hepatic Encephalopathy 64% Jepsen et al Hepatology 2010;51: n=466

10 Natural History Chronic Liver Disease. Compensated Cirrhosis No ascites or overt HE ~ 5-10% patients / year Recompensation of hepatic function Decompensated Cirrhosis Ascites, HE, Variceal bleeding ~ 30% hospitalised patients Resolution of organ failures Acute on Chronic Liver Failure (ACLF) Hepatic and Extra-hepatic organ failure? Up to 50% hospitalised patients Death

11 ACLF & Practical Management Acute on Chronic Liver Failure (ACLF) Acute on chronic liver failure is a syndrome in patients with chronic liver disease with or without cirrhosis which is characterized by acute hepatic decompensation resulting in liver failure (jaundice and prolongation of the INR) and one or more extra-hepatic organ failures that is associated with increased mortality within a period of 28 days from onset.. World Congress of Gastroenterology Gastroenterology 2014 ;147(1);4-10

12 ACLF & Practical Management Who are we discussing? Cirrhotic Precipitating event Bleeding / Sepsis / Drug effect Hepatic failure Jaundiced, coagulopathic Extra-hepatic organ failure Encephalopathy Hypotension Renal dysfunction

13 ACLF & Practical Management CANONIC: Chronic liver failure Acute On-chronic liver failure In Cirrhosis 29 Liver Units, 8 European Countries 1343 Hospitalised patients with cirrhosis Develop a definition and scoring system for ACLF. Moreau et al Gastroenterology :

14 ACLF & Practical Management

15 ACLF & Practical Management CLIF Organ Failures Organ System Hepatic Cerebral Renal Coagulation Circulation Respiratory Criteria Bilirubin 200 mmol / L Encephalopathy Grade 3 Creatinine 180 mmol/l and / or use of renal replacement therapy INR >2.5 and / or platelet count 20 x 109/L Use of vasopressor agents and / or terlipressin Ratio of partial pressure of oxygen/ inspired oxygen 200 or Ratio of Pulse oximetry saturation / inspired oxygen 214 Moreau et al Gastroenterology Jun;144(7): e9.

16 ACLF & Practical Management ACLF Grades ACLF-1 Renal or cerebral failure alone or renal dysfunction with other organ failure. ACLF-2 Two Organ Failures. ACLF-3 Three or More Organ Failures. Moreau et al Gastroenterology :

17 Mortality (%) ACLF & Practical Management ACLF Grade and Mortality No ACLF ACLF 1 ACLF 2 ACLF 3 28-Day 90-Day Moreau et al Gastroenterology :

18 % of ACLF Cases ACLF & Practical Management Reported Triggers to ACLF; Europe and China Reactivation HBV Bacterial Infection GI Bleed Active Alcohol Other Not Identifiable More than 1 CANONIC Shi et al CANONIC n=303 Gastro : Shi et al n=405 Hepatology :232-42

19 WBC x 10 9 /l CRP mg/l ACLF & Practical Management ACLF: Systemic Inflammation & Severity of Illness Inflammatory markers at enrolment in CANONIC Study. n=1343 Leucocyte Count C-Reactive Protein No ACLF ACLF 1 ACLF 2 ACLF No ACLF ACLF 1 ACLF 2 ACLF 3 Moreau et al Gastroenterology :

20 pg/ml ACLF & Practical Management Plasma Cytokine Concentrations according to Precipitating Event for ACLF Claria et al Hepatology (4) n=237 Measurements at study enrolment TNF-α Interleukin-6 Interleukin P<0.03 P< P<0.0001

21 ACLF & Practical Management ACLF: Definition Precipitating event, hepatic and extra-hepatic OF. High short term mortality. Key to research and defining practice. ACLF: Controversies Heterogeneous precipitants? Unified pathophysiology? No identifiable precipitants? Scores to instruct care?

22 ACLF & Practical Management. Critical Care: Inevitable Destination?

23 ACLF & Practical Management. Critical Care: Admission Impossible?

24 ACLF & Practical Management Escalation of care? NCEPOD 2013 Alcohol Related Liver Disease: Measuring the Units Both Advisors and clinicians identified patients in whom escalation of care was not received despite it being indicated....escalation of care should be actively pursued for patients with Alcohol-related Liver disease who deteriorate acutely and whose background functional status is good. There should be close liaison between the medical and critical care teams when making escalation decisions..

25 ACLF & Practical Management Escalation of care? Barriers to Critical Care: Aetiology.

26 ACLF & Practical Management Escalation of care? Barriers to Critical Care: Outcome Study Year n ICU Mortality Cholongitas et al % Alim Pharm Ther 2006;23: Fang et al % Neph Dial Trans 2008;23(6): Junea et al % J Crit Care 2009;24(3): Thompson et al % Aliment Pharmacol Ther 2010; 32: Das et al % Crit Care Med : Tu et al % Shock : Olemz et al % Ann Hepatol ; Levesque et al % J Hep : Frolich et al % J Crit Care ;6: 1131 McPhail et al % Clinical Gastro Hep 13(7)

27 ACLF & Practical Management Escalation of care? Barriers to Critical Care: Outcome Prognosis of cirrhotic patients admitted to intensive care unit: a meta-analysis. Weil et al Annals of Intensive Care :33 13 Studies 2532 patients Mortality ICU 43% Hospital 54% 6-Month 75%

28 ACLF & Practical Management Escalation of care? Barriers to Care: Resource Use Liver ITU Kings College Hospital ACLF admissions Patients 226 (42%) ICU mortality 80% 2 or more organ failures Average cost per Patient 28,409 Average cost per Survivor 23,206 Average cost per Non-survivor 37,329 Effective cost per Survivor 51,198 Shawcross et al J Hepatol 2012; 56(5):

29 ACLF & Practical Management Escalation of care? High resistance to ICU admission Constrained resources. Self inflicted aetiologies. High resource use and cost. ICU / Post-ITU Mortality high. Preconception of futility.

30 ACLF & Practical Management Escalation of care? Futile Critical Care? Mortality of cirrhotic patients admitted to LITU, Kings College Hospital n=971 p<0.001 Log-rank for comparison of Eras McPhail et al Clin Gastro Hep 2015;13:

31 ACLF & Practical Management Escalation of care? Avoiding Futility: Admission and level of support? Standard ICU considerations Age Co morbidity Functional / nutritional state Severity of acute illness Liver-specific considerations Liver disease severity Indication for admission

32 ACLF & Practical Management Escalation of care? Avoiding Futility: Age and Etiology? Weil et al Annals of Intensive Care :33

33 ACLF & Practical Management Escalation of care? Avoiding Futility: prognostic assessment? Scoring Tools Child-Pugh Classification (CPC) Model for End-stage Liver Disease (MELD) Sequential Organ Failure Assessment (SOFA) Chronic Liver Failure Score (CLIF)

34 ACLF & Practical Management Escalation of care? Avoiding Futility: prognostic assessment? Hospital Survival in ITU Admissions with Cirrhosis KCH n=933 Score AUROC (95% CI) CLIF ( ) SOFA ( ) APA II ( ) SAPS II ( ) MELD ( ) McPhail et al Clin Gastro Hep 2015;13:

35 ACLF & Practical Management Escalation of care? Avoiding Futility: prognostic assessment? Time of Assessment AUROC Score Admission 72 Hrs MELD SOFA CLIF-SOFA McPhail et al Clin Gastro Hep 2015;13:

36 ACLF & Practical Management Withdrawal of Care? Avoiding Futility: prognostic assessment. ACLF Scores to withdraw care? Hernaez et al Gut 2017; 61:

37 ACLF & Practical Management Avoiding Futility: Indications for Admission Variceal Bleeding Encephalopathy Renal failure

38 ACLF & Practical Management. Variceal Bleeding Avoiding Futility: Indication for Admission? P<0.001 McPhail et al Clin Gastro Hep 2015;13:

39 ACLF & Practical Management. Variceal Bleeding. Avoiding Futility: Indication for Admission? Weil et al Annals of Intensive Care :33

40 ACLF & Practical Management Variceal Bleeding Control the Airway Resuscitate Cultures and Antibiotics* Terlipressin* Endoscopic therapy* Band Ligation TIPS? *Evidence Base Level A

41 ACLF & Practical Management. Hepatic Encephalopathy Avoiding Futility: Indication for Admission? Critical Care Environment Nursing levels Compliance with Rx Airway Protection Seek Precipitant Fluids Treat Infection Minimise Medication Treat Constipation Adjunctive agents?

42 ACLF & Practical Management Hepatic Encephalopathy Avoiding Futility: Indication for Admission? Fichet et al J Crit Care 2009;24: Outcomes in 71 patients with CLD and ICU 45 with isolated HE: Median GCS 8/15 Median CPC 11 73% required intubation and ventilation Sole organ support ICU mortality 8.9%

43 ACLF & Practical Management. Hepatic Encephalopathy Complication 1Year Mortality Variceal Bleeding 20% Ascites 29% Ascites and Variceal Bleeding 49% Hepatic Encephalopathy 64% Jepsen et al Hepatology 2010;51: n=466

44 ACLF & Practical Management. Renal Failure. Renal Failure: Futile care? Cholongitis et al Eur J Gastroenterol Hepatol 21: Royal Free Hospital London ICU admissions with Cirrhosis (Mortality 62%) RRT/ Creatinine >300 micmol/l / Urine <500ml/24 hrs (ARF) ARF No ARF p n Mortality 91% 47% < Odds Ratio 13.1 (95% CI )

45 ACLF & Practical Management. Renal Failure. Weil et al Annals of Intensive Care :33

46 ACLF & Practical Management. Renal Failure. Renal Failure and Chronic Liver Disease: Heterogeneity. Martin-Llahi et al Gastro 2011:140: Patients with Cirrhosis and renal failure Serum Creatinine >1.5 mg/dl at 2 points within 48 hours Cause % 3 Month Survival Infection-related 46% 31% Hypovolaemia 32% 46% Hepato-renal 13% 15% Parenchymal 9% 73%

47 ACLF & Practical Management. Renal Failure. Evolving Renal failure: Stop nephrotoxic therapies Volume expand Albumin (?) Antibiotics Vasopressors Terlipressin Decompress Paracentesis Critical Care review

48 ACLF & Practical Management. Renal Failure. Circulating Volume Expansion: Albumin? Thevenot et al Journal of Hepatology 2015(62); Multi-centre RCT. Hospitalised Cirrhotics with non-sbp sepsis (n=193) Daily 20% Albumin + SMT vs. SMT Renal Failure Survival

49 ACLF & Practical Management. Renal Failure. Vasoconstrictors: Terlipressin Systematic Review of Randomised Trials on Vasoconstrictor Drugs for Hepato-renal syndrome Gluud et al Hepatology 2010;51(2)

50 ACLF & Practical Management. Renal Failure: Early Intervention. Response to Terlipressin: Predictors Responders Non-responders p (n=12) (n=34) Creatinine (μmol/l) 256 (±71) 369 (± 194) <0.001 Urine Vol. (ml/24hrs) 880 (± 440) 496 (± 420) WBC 6.6 (± 3.5) 10.9 (± 8.1) EARLY Intervention Martin-Llahi M et al Gastroenterology 2008:134

51 ACLF & Practical Management. Prevention: Early Ward Intervention Cirrhosis and Outcome of Septic Shock Arabi et al Hepatology 2012 ;56: n=638 Cirrhosis and Septic Shock ICU Mortality 62% Adjusted OR p Inappropriate Antimicrobials 9.5 (4.3-21) <0.001 Single vs. Combination Rx 1.8 ( ) <0.05 Delay to Administration 1.1 ( ) <0.001

52 ACLF & Practical Management. Prevention: Early Ward Intervention Cirrhosis and Outcome of Septic Shock: Antibiotic Delay Arabi et al Hepatology 2012 ;56: Adjusted OR ; APACHE II, MELD, Immune compromise, Culture +ve

53 ACLF & Practical Management. Prevention: Early Ward Interventions. Timely and effective bedside review: Recognition of illness severity. Recognition of risk of deterioration. Escalation & Critical Care review. Antibiotic Therapy Prompt, appropriate. Intravenous Fluids Prescription Chart Review

54 ACLF & Practical Management. Critical Care Admission & Level of therapy? Standard ICU criteria Age Nutritional state & Physiologic reserve Co-morbidity Severity of acute illness Severity of underlying liver disease How severity is measured may not be important Response to therapy key Indication for admission Variceal bleeding Isolated HE

55 ACLF & Practical Management. Critical Care Admission & Level of therapy? Difficult decisions Is there a right answer? Resource considerations Give the patient the benefit of the doubt? Consider short and medium term prognosis. If in doubt, admit and treat Aggressive short term therapy Review after hours Set ceilings for therapy Consider withdrawal if no response.

56 Bed Occupancy ACLF & Practical Management. How can your Liver Unit Help? Bed Occupancy: Liver Intensive Therapy Unit, Kings College Hospital October 2016-May % 100% 80% 60% 40% 20% 0% Oct-16 Nov-16 Dec-16 Jan-17 Feb-17 Mar-17 Apr-17 May-17

57 ACLF & Practical Management. How can your Liver Unit help? Always happy to discuss (!) Getting early interventions right. ICU Admission / Escalation / withdrawal decisions. Consideration for Transfer Age Complexity Specialist Radiology / Endoscopy Transplant wait-listed patients Expedited Transplantation?

58 ACLF & Practical Management Futile Hospital Care? Cirrhosis: Hospital Mortality in USA Schmidt et al Gastroenterology 2015;148:

59 ACLF & Practical Management. How can your Liver Unit help? Expedited Transplantation?

60 90-Day Mortality ACLF & Practical Management. Expedited Transplantation? Inferior Outcomes 90-Day Patient Survival for First Elective Liver Transplant for Cirrhosis By Pre-LT status. United Kingdom n=7479 p< % 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% Outpatient Inpatient; No Organ Failure Inpatient: Organ Failure Bernal et al Clinical Liver Disease 2017 In Press.

61 ACLF & Practical Management. Expedited Transplantation? Resource use and cost? Markley Earl et al Transplantation 2008;86: Cost analysis: Single Centre: 163 first transplants for CLD Pre-transplant ICU stay Median Cost / LT (IQR) No n=149 (91%) $81,134 (73,800-97,113) Yes n=14 (9%) $149,890 (132, ,964) p<0.0001

62 ACLF & Practical Management. Expedited Transplantation? Practicalities? Finklestedt et al Liver Transplantation : n= % Fulfilling ACLF Criteria (n=144) Not Evaluated (n=50) 67% Evaluated for LT (n=94) Not Listed (n=23) 49% Listed for LT (n=71) Waitlist Mortality 54% Died on Waitlist (n=36) 23% Underwent LT (n=33) Died (n=5) 19% Survived (n=28)

63 ACLF & Practical Management. Expedited Transplantation? An option only in a small minority Contraindications Waitlist deterioration Outcomes probably worse Highly selective use Previously assessed Young Seldom from ICU Minimal organ support