Archive for the HCP Category

Spontaneous Bacterial Peritonitis and Spontaneous Bacterial Pleuritis

Top tips:

  1. Speed is life in cirrhosis when infection is suspected. Early and Appropriate antibiotics reduce mortality.
  2. Paracentesis and Thoracentesis before antibiotics is ideal. But, if you have a high suspicion of infection and these cannot be arranged in a timely manner, do not delay antibiotics.
  3. You must consider risk factors for multi-drug resistance (i.e. recent hospitalizations, colonization with multi-drug resistant organisms, nursing home resident) when choosing your antibiotics.
  4. De-escalate/narrow antibiotics as soon as a pathogen is identified on culture.
  5. All patients should be started on secondary prophylaxis with antibiotics once a diagnosis of SBPeritonitis or SBPleuritis is made. Contrary to earlier evidence, patients with low albumin ascites do not require primary prophylaxis.

Order panel for SB Peritonitis or SB Pleuritis:

For adults with cirrhosis admitted with Spontaneous Bacterial Peritonitis (ascites PMN >250 cells/µL) or Spontaneous Bacterial Pleuritis (pleural fluid PMN >500 cells/µL or >250 cells/µL with positive culture):
 SB-Peritonitis-Pleuritis Order Panel

Thank you to Dr. Saxinger for your efforts creating the content on this page!

Diagnosis

Specific Management

Patient materials:

You can direct patients to the following:
Paracentesis

Lab tests

Downloadable content:

You can download these to print or view offline:
EASL Guidelines

References:

This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.
Authors: Dr. Lynora Saxinger, Dr. Dean Karvellas, Dr. Uma Chandran, Dr. Puneeta Tandon
References:

  1. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018 Aug;69(2):406-460 PMID 29653741
  2. Diagnosis, Evaluation, and Management of Ascites, Spontaneous Bacterial Peritonitis and Hepatorenal Syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology (Baltimore, Md.)74(2), 1014–1048. https://doi.org/10.1002/hep.31884 PMID 33942342

Breathlessness

Top tips:

  1. Breathlessness as a symptom is a subjective sensation.
  2. Breathlessness can be caused by general causes or cirrhosis specific causes (e.g. hepatopulmonary syndrome)
  3. Treat breathlessness if it is affecting quality of life and function. Take into account goals of care.
  4. Opioid therapy may be helpful to manage moderate to severe breathlessness in the last days to weeks of life.
Dr. Sarah Burton McLeod
1doc

Check out the bottom of the page for short videos from Dr. Sarah Burton-Macleod and Dr. Christopher Woodrell.

Expand all Collapse all
Step 1: Assess for breathlessness with validated assessment tools
Investigation and treatment of breathlessness should be in keeping with the patient’s goals of care.
Differential diagnoses
Most Common:

Examples of other potential causes:

Treat the underlying cause

Cirrhosis related causes – A liver specialist may need to be consulted. Some patients may meet criteria for liver transplantation or specialized treatments may be needed (e.g. hepatopulmonary syndrome, portopulmonary hypertension).

Step 2: Consider non-pharmacological therapies
Consider non-pharmacological management in all patients where breathlessness has a significant impact on patient’s quality of life or function.
  1. Sit in an upright position (45 degrees)
  2. Position next to an open window
  3. Have a fan blow air gently across the face (stimulation of the trigeminal nerve V2 branch has central inhibitory effects on dyspnea)
  4. Maintain humidity in room
  5. Supplemental oxygen – the patient must be hypoxic at rest in order to qualify for coverage
  6. Meditation, mindfulness, music and/or relaxation therapy
  7. Provide reassurance

Breathlessness handout in development.

Step 3: If symptoms persist, and patient is at end-of-life, Pharmacological therapy can be considered
If non-pharmacological therapy alone fails, opioids can be considered for the treatment of refractory breathlessness that is having a major impact on quality of life, particularly at the end-of-life.

Always weigh the risks and benefits of opioids with the patients in the context of their goals of care.

  • Always start at a lower dose and titrate to effectiveness.
  • If the patient is already taking an opioid for pain, educate them that it can also be used for the management of breathlessness
  • Monitor closely for signs of opioid toxicity. Prescribe laxatives to avoid constipation

 

If shortness of breath is episodic and primarily associated with a specific activity, consider
Medication: Recommended Dose Additional information
Fentanyl 12.5mcg SC/SL/intranasal q1h PRN
  • For episodic shortness of breath (if associated with activity, take 10 mins prior to activity)
  • Sedation, constipation
  • Start with a lower dose for opioid naïve patients

If shortness of breath is constant or more unpredictable in nature, consider
Medication: Recommended Dose Additional information
Hydromorphone (Dilaudid) 0.5mg PO (or 0.2mg SC) q4h ATC and q1h PRN
Max: 5 mg PO QID
  • For constant shortness of breath
  • Sedation, constipation
  • For older, opioid naive patients, start with 0.25 mg PO q 4h ATC and q1h PRN

Step 4: Special considerations at End of Life (last few days to weeks)
Consider non-pharmacological management in all patients where breathlessness has a significant impact on patient’s quality of life or function.
  • At End of life, as the patient’s condition deteriorates, opioid titration will likely need to be escalated for dyspnea.
  • Consider Palliative Care consultation as required.

See the End of Life Breathlessness Algorithm for the last Days/Weeks of life.

 

 

 Introducing Dr. Sarah Burton-Macleod & Dr. Christopher Woodrell

Video 1 – The breathlessness algorithim in End-of-life

Video 2 - The top tips that may be useful for you to know about this page including assessment and non-pharmacological considerations

This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Adriana Lazarescu, Noush Mirhosseini, Mino Mitri, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

For a comprehensive review on breathlessness, please refer to the links below.

  1. Goals of care
  2. Anxiety
  3. Physical Activity
  4. Hydrothorax
  5. Ascites
  6. Opioid Considerations document: In development

References:

References:

  1. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
  2. European Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol. 2018 Aug;69(2):406-460. doi: 10.1016/j.jhep.2018.03.024. Epub 2018 Apr 10. Erratum in: J Hepatol. 2018 Nov;69(5):1207. PMID: 29653741.
  3. Krowka MJ, Fallon MB, Kawut SM, Fuhrmann V, Heimbach JK, Ramsay MA, Sitbon O, Sokol RJ. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation. 2016 Jul;100(7):1440-52. doi: 10.1097/TP.0000000000001229. PMID: 27326810.
  4. Walling AM, Wenger N. Palliative care for patients with end-stage liver disease. In Uptodate, Mar 06, 2020.

Transjugular Intrahepatic Portosystemic Shunt (TIPS)

Patients with cirrhosis can develop major complications such as ascites and variceal bleeding, related to portal hypertension.

A transjugular intrahepatic portosystemic shunt (TIPS) can be an effective means to decrease portal hypertension, by shunting some of the blood flow from the portal venous system into the hepatic venous system, via a stent.

Placement of a TIPS is a highly specialized interventional procedure, and should only be considered after consultation with a liver specialist.

Step 1:

Evaluate the indication for TIPS

 

Common Indications:

  • Bleeding related to portal hypertension
  • Refractory ascites/hydrothorax

Step 2: 

Consider potential contraindications and risk for complications

 

Potential contraindications:

  • Congestive Heart Failure
  • Pulmonary Hypertension 
  • Tricuspid regurgitation
  • Active infection
  • Hepatocellular Carcinoma (location dependant)
  • Thrombocytopenia (Plt <20,000)
  • Hepatic/Portal vein obstruction
  • Biliary Obstruction
  • Multiple Hepatic Cysts

 

Risk Factors Associated with Post-TIPS Complications:

ComplicationRisk Factor
Liver FailureAdvanced Liver Disease (MELD >18)
Cardiovascular disease
EncephalopathyPrior Encephalopathy
Wider diameter TIPS
Sarcopenia
Hyponatremia
Age>65
Cardiac DecompensationAortic stenosis
Diastolic dysfunction
Prolonged QTc interval
Elevated BNP
MortalityChild Pugh C
Urgent indication (variceal bleed)
Bilirubin >50 umol/L
Pre-insertion consult by an interventional radiologist should be considered in these circumstances

Step 3: 

Perform pre-TIPS investigations

  1. Echocardiogram
  2. Liver Ultrasound Doppler: Evaluate liver vasculature, rule out hepatocellular carcinoma. In most cases CT may be required pre-TIPS insertion.
  3. Labs: TBili, INR, Cr, CBC, BNP

Step 4:

Provide pre-placement patient counselling

  • Patients will require short post-procedure hospital admission
  • Risk of hepatic encephalopathy (30-45%). Treat using standard hepatic encephalopathy therapy. For patients who do not respond to standard therapy – consideration should be given to narrowing or blocking the TIPS. This decision will be based on the severity of symptoms and the potential impact on the patient’s quality of life
  • It can take weeks or months for symptoms like ascites to resolve so patients may require alternate therapy (such paracentesis for ascites) in the initial period post-TIPS
  • Liver failure is rare but can occur, particularly if there is advanced liver dysfunction pre-procedure.
  • Immediate procedural complications (vascular injury, pneumothorax, hepatic injury) are discussed in detail by diagnostic imaging.

Step 5:

Info for liver specialists to arrange the TIPS procedure

Edmonton
  1. Send referral to interventional radiology for “TIPS insertion”
  2. Provide patient instructions regarding admission and pre procedure labs
  3. Ensure admission is coordinated, including notification of admitting physician and completion of admission orders.

Step 6:

Post-procedure follow-up

 

Routine monitoring:

ItemRationaleFrequency
Labs Monitor for worsening liver & renal function, electrolyte abnormalities, hemolytic anemiaDay 1, Week 4, 8 & 12, then based on patient clinical status
Symptom assessment
•Encephalopathy
Common complication post TIPSDay 1, Week 4, 8 & 12, then based on patient clinical status.
•Ascites/hydrothoraxMonitor response to TIPS
Evaluate potential to taper off diuretics as TIPS improves volume management
•Edema, shortness of breathMonitor for cardiac decompensation
•Blood pressure and heart rateEvaluate need to reduce beta blocker used for variceal bleed prophylaxis
•GI bleedingMonitor response to TIPS
Ultrasound DopplerDetect TIPS stenosisMonth 3, 6, and then every 6 months along with routine screening ultrasound performed for hepatocellular carcinoma screening

Downloadable content:

You can download these to print or view offline:

Admission Orders

Alcohol Use Disorder (AUD)

Top tips:

  1. Abstinence from alcohol is the best way to improve outcomes in patients with alcohol-related cirrhosis. In alcohol related liver disease, even 1 or 2 drinks per day can increase mortality.
  2. Some patients won’t be ready or able to quit completely. For those patients who struggle to quit completely, continue to support them with encouragement, motivational interviewing and pharmacotherapy to help them achieve abstinence.
  3. It is important to screen for concurrent mental health concerns alongside addiction. Patients with these issues require further management.

Order panel for Alcohol use disorder:

For adults admitted with Alcohol use disorder:

Alcohol Use Disorder in Cirrhosis Order Panel

General Cirrhosis Admission and Discharge Order Sets

*Add specific panels to general admission orders as appropriate*

For adults with cirrhosis requiring hospital admission
Cirrhosis Adult Admission Orders

For adults with cirrhosis requiring hospital discharge
Cirrhosis Adult Discharge Orders

Dr. Mellinger cartoon
Monty cartoon

Check out the bottom of the page for short videos from Dr. Mellinger and Dr. Ghosh!

Diagnosis

Video about screening, brief intervention, and assessing readiness to change

DSM 5 AUD


Information about AUD relapse prevention medications
Medication: Acamprosate
Dose: 666 mg po TID; 333 mg po TID if renal impairment (CrCl 30 to 50 mL/min) or weight <60 kg; Generally abstinence for >3 days before initiation, although studies show reduction in heavy drinking days even when initiated prior to abstinence.
Contraindications: Creatinine clearance <30 ml/min
Considerations: Pregnancy risk category ‘C’; As above, consider in pregnant women if potential benefit outweighs risk; Although TID dosing is cumbersome, it may be useful for patients who cannot take naltrexone due to liver disease or taking opioids or with polypharmacy because no significant interactions with other drugs; Caution if depression or suicidal ideation;
Side Effects: GI upset ; somnolence, rarely suicidality
Monitoring: Initial close weekly follow-up may be helpful; Monitor renal function and adjust dose if CrCl 30-50 ml/min
Health Canada for AUD: Approved
Coverage: Funded via Special Authorization Request Form for Income Support, AISH or AB Adult Health Benefit. View Alberta Blue Cross Drug Special Authorization Request. Limited use benefit under NIHB (abstinent >3 days and enrolled in treatment program where available, prior approval required).
Est. cost with no coverage ~ $200/mo.

Medication: Gabapentin
Dose: With history of Hepatic Encephalopathy: Start low dose – 100 mg po TID and titrate up as tolerated. Without Hepatic encephalopathy: 300 mg po day one, 300 mg po BID day 2 ; 300 mg po TID day 3; increasing by 300 mg po each day up to 600 mg TID on day 6 as tolerated; abstinence at 12 weeks 4.1% placebo group; 11.1% gabapentin 900 mg/day; 17% for 1,800 mg/day.
Contraindications: Decrease dose with renal impairment. Start at lower doses with Hepatic encephalopathy.
Considerations: Risk of dependence in post-marketing database; increased risk of CNS depression esp. with opioids and other CNS depressants; Pregnancy risk category ‘C’; Consider in pregnant women if potential benefit outweighs risk
Side Effects: Somnolence, dizziness, ataxia, fatigue, nystagmus, tremor
Monitoring: Routine monitoring not required; consider if renal impairment
Health Canada for AUD: Not approved
Coverage: Drug benefit under Income Support, AISH, AAHB, NIHB and CFS
Est. cost with no coverage ~$30/mo. partial coverage by many drug plans
Clinical pearls: Gabapentin has some off-label utility in treating mild to moderate alcohol withdrawal which means it can be useful in early sobriety particularly in AUD patients who have comorbid anxiety and/or insomnia alongside their other symptoms. It is also another good medication for patients with comorbid neuropathic pain.
Requires attention to kidney function due to renal clearance and could worsen hepatic encephalopathy due to potential sedating effects.

Medication: Baclofen
Dose: Initiated at 5mg TID with increases 3-5 days based on patient tolerance and absence of side effects. The maximum recommended dose for alcohol related liver disease is 15mg TID. Higher doses can be tried but with extreme caution due to limited evidence and increased risk of side effects
Contraindications: Care must be taken in patients with both renal and liver disease. This drug should be avoided in individuals with hepatic encephalopathy. Due to a lack of studies, baclofen should be avoided in pregnant patients. Baclofen toxicity can lead to overdose. Caution must be taken for individuals with severe suicide risk.
Considerations: The maximum recommended dose for alcoholic liver disease is 15mg TID. Care must be taken for patients with renal failure or hepatorenal failure, as baclofen is predominantly excreted renally, and impairments in excretion can lead to delirium, and drug toxicity and doses of 5mg TID max should be prescribed in this setting. Operation of heavy machinery is discouraged when first using the medication until they learn how the sedation affects them or they reach a stable dose.
Side Effects: Severe sedation, dizziness, and/or confusion. Potentially dangerous side effects are seizures, respiratory depression with sleep apnea and potentially coma (in case of intoxication), severe mood disorders (mania or depression, with the risk of suicide), and mental confusion/delirium
Monitoring: No specific monitoring required.
Health Canada for AUD: Not approved
Coverage: Drug benefit under Income Support. Covered by many private drug plans.
Est. cost with no coverage If 80% covered by a private drug plan, cost to patient: $6/month, based on 60 mg daily. Cost to patient if no coverage: $28/month.

Medication: Notes:
Naltrexone In the US, naltrexone is a first-line and FDA-approved medication whose utility in AUD is often in patients trying to gain early sobriety or who commonly relapse due to its ability to reduce heavy drinking and dampen cravings.
It has been shown to have a larger effect size than Acamprosate in some studies but its use is limited in liver disease patients due to drug-related LFT elevation and metabolite accumulation in hepatic insufficiency.
We are not using naltrexone in patients with disease more severe than Childs Pugh A.
It is contraindicated in patients using opioids.
Disulfiram Should not be used in patients with liver disease.
Topiramate Has some off-label utility in promoting AUD sobriety and may be adjunctively useful in patients who have co-occurring weight-related challenges.
Requires attention to kidney function due to renal clearance and could worsen hepatic encephalopathy due to potential sedating effects
Varenicline May also have some off-label effect in reducing alcohol craving and consumption alongside its treatment of nicotine dependence.
It requires attention to renal function for dosing.
Ondansetron Has been shown to reduce alcohol use as an off-label treatment though we have little experience using it for this purpose.

Pearls from the UMichigan integrated care team
Medication: Notes:
Naltrexone In the US, naltrexone is a first-line and FDA-approved medication whose utility in AUD is often in patients trying to gain early sobriety or who commonly relapse due to its ability to reduce heavy drinking and dampen cravings.
It has been shown to have a larger effect size than Acamprosate in some studies but its use is limited in liver disease patients due to drug-related LFT elevation and metabolite accumulation in hepatic insufficiency.
We are not using naltrexone in patients with disease more severe than Childs Pugh A.
It is contraindicated in patients using opioids.
Disulfiram Should not be used in patients with liver disease.
Topiramate Has some off-label utility in promoting AUD sobriety and may be adjunctively useful in patients who have co-occurring weight-related challenges.
Requires attention to kidney function due to renal clearance and could worsen hepatic encephalopathy due to potential sedating effects
Varenicline May also have some off-label effect in reducing alcohol craving and consumption alongside its treatment of nicotine dependence.
It requires attention to renal function for dosing.
Ondansetron Has been shown to reduce alcohol use as an off-label treatment though we have little experience using it for this purpose.

Introducing Dr. Mellinger and Dr. Ghosh

Video 1 – Practical tips on how to decide if a patient with cirrhosis needs alcohol use disorder therapy, if they are ready for it and what agent to choose.

Video 2 – Practical tips to accessing support for alcohol use disorder therapy in Alberta – how to refer your patient for counselling and how to get help with prescribing relapse prevention medications.

  Calculators:

Use these calculators to help with the diagnosis:

AUDIT-C calculator

References:

This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

Authors: Dr. Monty Ghosh, Dr. Jessica Mellinger, Dr. Kathryn Dong, Dr. Laura Evans, Dr. Nicholas Mitchell, Dr. Meredith Borman, Dr. Scott G Winder, Emily Johnson, Dr. Puneeta Tandon

References:

  1. Crabb DW et al. Diagnosis and Treatment of Alcohol-Related Liver Diseases: 2019 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology 2019 July 17 epub ahead of print, PMID 31314133

Assess Disease Severity and Peri-op Risk Assessment

Top tips:

  1. MELD-Na, Child Pugh are key prognostic scores in cirrhosis
  2. Decompensating events (variceal bleed, ascites, etc.) place patients at higher risk of further complications and death. Decompensation should trigger consideration for liver transplantation.
  3. Patients with cholestatic liver disease (PBC, PSC) have additional models that can be used for prognostication.
Dr. Kamath cartoon

Check out the bottom of the page for a short video from Dr. Kamath!

Assessing Liver Disease Severity

D’Amico’s prognostic sub-stages
  Compensated Cirrhosis Decompensated Cirrhosis
Stage Stage 1 Stage 2
Stage 3
Stage 4
Stage 5
Definition No Varices

no other decomp. complications

Varices

no other decomp. complications

Bleeding

no other decomp. complications

Single non-bleeding decomp. complications

Two decomp. complications

1 year mortality rate 1% 3%
15%
26%
57%

More info on the Child Pugh score and the MELD Na score including prognostic limitations

Child-Pugh score

The Child-Pugh (CP) score is used as a prognostic tool in cirrhosis and is based on 2 clinical (ascites & encephalopathy) and 3 laboratory (albumin, bilirubin & INR) parameters.

  • CP A (5-6 points): mostly compensated
  • CP B patients (7-9 points) more likely to have early decompensation
  • CP C patients (10-15 points) decompensated, typically late stage
Factor 1 point 2 points 3 points
Total Bilirubin (μmol/L) <34 34-50 >50
Serum Albumin (g/L) >35 28-35 <28
PT INR <1.7 1.71-2.30 >2.30
Ascites None Controlled, on diuretics Refractory
Hepatic Encephalopathy None Controlled, on medical therapy Refractory

  Class A Class B Class C
Total Points 5-6 7-9 10-15
1 year survial 100% 80% 45%

MELD-Na Score

The MELD-Na score is a predictor of death in patients with decompensated cirrhosis and is based on one clinical (need for dialysis) and four laboratory (creatinine, bilirubin, INR, and sodium) parameters. For transplant evaluation, this has replaced the original MELD score which does not include the serum sodium. Patients with MELD-Na >15 and evidence of decompensation should be considered for liver transplantation.

MELD-Na Score 90-day Mortality
<17 <2%
17-20 3-4%
21-22 7-10%
23-26 14-15%
27-31 27-32%
≥32 65-66%

Other prognostic considerations

It is important to consider the prognostic limitations of both the Child-Pugh and MELD-Na scores. Other factors that can independently impact prognosis include (but are not limited to):

  1. Hepatocellular Carcinoma
  2. Presence of varices in compensated patients indicates higher likelihood of decompensation
  3.  Serum sodium (only captured in MELD-Na)
  4. Hepatic encephalopathy (only captured in Child-Pugh)
  5. Sarcopenia
  6. Frailty
  7. Cardiovascular disease
  8. Obesity
  9. Ongoing exposure to the etiological precipitant (i.e. obesity, alcohol use)
  10. Serum albumin level

Assessing Surgical Risk

Surgical risk assessment is “as much art as science” (see editorial by Dr. Kamath at PMID 33220099).

**Before using the algorithm below, consider standard factors associated with pre-operative risk assessment  – bleeding risk, cardiopulmonary risk, frailty as well as surgeon and patient preferences. If the patient is still deemed a possible candidate despite these considerations, then apply the algorithms. 

Introducing Dr. Kamath

Video 1 – A brief tour through prognostication in cirrhosis & practical tips that I use for surgical risk assessment in cirrhosis

Patient materials:

You can direct patients to the following:
Patient education for cirrhosis 

Stages of cirrhosis

Calculators:

Use these calculators to help with the diagnosis:

Child Pugh

MELD-Na

MELD

References:

This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

Authors: Michelle Carbonneau NP, Dr. Patrick Kamath, Dr. Juan G. Abraldes, Dr. Puneeta Tandon

References:

  1. D’Amico G et al. Competing risks and prognostic stages of cirrhosis: a 25-year inception cohort study of 494 patients. Aliment Pharmacol Ther 2014; 39:1180-1193. PMID 24654740
  2. D’Amico G et al. Clinical states of cirrhosis and competing risks. J Hepatol 2018 Mar; 68(3):563-576 PMID 29111320
  3. Northup P.G. et al. AGA Clinical Practice Update on Surgical Risk Assessment and Perioperative Management in Cirrhosis: Expert Review. Clin Gastroenterol Hepatol 2019 Mar; 17(4):595-606 PMID 30273751
  4. Reverter E et al. The prognostic role of hepatic venous pressure gradient in cirrhotic patients undergoing elective extrahepatic surgery. J Hepatol 2019 Nov; 71(5):942-950 PMID 31330170
  5. Arroyo V et al. Acute-on-Chronic Liver Failure: Definition, Diagnosis and Clinical Characteristics. Semin Liver Dis 2016 May;36(2):109-16 PMID 27172351
  6. Bajaj JS et al. Acute-on-Chronic Liver Failure: Getting Ready for Prime Time? Hepatology 2018 Oct;68(4):1621-1632 PMID 29689120
  7. Gustot T et al. Acute-on-chronic liver failure vs traditional acute decompensation of cirrhosis. J Hepatol 2018 Dec;69(6):1384-1393 PMID 30195459
  8. D’Amico G et al. Ordinal outcomes are superior to binary outcomes for designing and evaluating clinical trials in compensated cirrhosis. Hepatology 2019 Dec PMID 31837238

Calculators

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    Advance Care Planning

    Top tips:

    1. Advanced care planning is an iterative and longitudinal process of patient-centered medical decision-making that is guided by patients’ personal goals, values, and current health circumstances to elicit their goals and preferences for medical care
    2. Identifying, documenting, and preparing surrogate decision-makers early in the disease course is a key component of advance care planning in cirrhosis care prior to patients losing capacity
    3. Goals of care should be reassessed regularly during routine care but especially after sentinel events such as new clinical deteriorations or acute changes in health status or home/social circumstances
    4. Anticipatory guidance for medical decision-making should include an assessment of preferences for future treatment options (e.g. endoscopic procedures, renal replacement therapy, mechanical ventilation, cardiopulmonary resuscitation) and place of care in the event of progressive or terminal illness

    Thank you to Dr. Woodrell, Dr. Patel, and Dr. Ufere for your efforts creating the content on this page!

    The ACP process in cirrhosis care

    Figure 1. The ACP Process and Key Elements
    Fig-1

    Figure 1. The ACP process in cirrhosis care. Adapted [reprinted] from “Advance care planning (ACP) for specialists managing cirrhosis: A focus on patient-centered care,” by Amanda Brisebois, Kathleen P. Ismond, Michelle Carbonneau, Jan Kowalczewski, and Puneeta Tandon, 2017, Hepatology, 67(5). Copyright year 2018 by All Authors.

    Talking points:

    • Assessing goals/values/perspectives
    • Assessing readiness
    • Early identification and documentation of surrogate decision-maker
    • Preparation of surrogate decision-maker
        Caregiver focused website
      • Cirrhosis education
    • Discussing prognosis
    • Reviewing cirrhosis complications
    • Document GOC including preferences for future medical care and place of care

    When to initiate ACP discussions for patients with cirrhosis

    Table 1. Suggested Clinical Milestones and Life Events That Should Trigger ACP Discussions for Patients with Advanced Liver Disease
    Liver-Specific FactorsPatient FactorsMajor Life Events
    New liver-related complications (ascites, hepatic encephalopathy, variceal bleeding, hepatocellular carcinoma)Advanced multimorbidityRecent ICU admission
    New diagnosis of refractory ascitesPoor performance status and/or progressive frailtyRecent unplanned hospitalization for a liver-related complication
    New diagnosis of acute kidney injury or hepatorenal syndromeOngoing substance use disorderLoss of a spouse or primary caregiver
    Recently delisted or declined for liver transplantationNew comorbid diagnosis of cancer, cardiovascular disease, neurological disease, or other life-limiting conditionAdvanced age

    Note. Reprinted [adapted] from “Advance Care Planning and Goals of Care Discussions in Advanced Liver Disease,” by Nneka N. Ufere, 2021, Current Hepatology Reports, 20, 77. 2021 by Author(s).

    How to initiate ACP discussions for patients with cirrhosis

    Conversation starters for ACP discussions
    Topics Conversation Starters
    Patient perspectives Level of detail
    —Are you a detail-oriented learner or do you prefer a general overview and plan?Learning style
    —Some people are visual leaners while others process conversations best. Which learning approach suits you the best?
    Values and fears
    —What is most important to you in life?
    —What aspect of health would need to be taken from you, for you to feel that living was worse than dying?
    Education —Meeting for the first time about a new illness that you have been diagnosed with can be overwhelming
    —We have created educational pamphlets we can provide for you, which can help guide our future discussions.
    —Our clinic communicates with your other health providers, so that we all know your wishes and details regarding your health
    Readiness Readiness to discuss ACP and GCD
    —Very ill patients with cirrhosis cannot always make their own health care decisions. We like to talk about these things early on to understand what you value in case such a situation arises. How would you feel discussing how cirrhosis may affect you in the future?
    Readiness to choose a surrogate
    —If you were to get very sick, is there anyone you trust to make medical decisions for you? Does this person know what is important to you?
    Focus of care —Recently, you had a complication of cirrhosis and were quite unwell. I would like to explain how cirrhosis may affect you in the future.
    —It is important to understand how disease-modifying treatments and symptom control therapies are used together an illness.
    Prognosis Discuss in general terms
    —To make sure that both you and your family are prepared, I like to address both the best-and worst-case scenarios regarding how your cirrhosis may progress. Can we talk about these now?
    —Some patients ask me how their cirrhosis will affect how long they live. Are you interested in this type of information?
    Review cirrhosis Disease complications
    —The investigations that we have done show that your disease has worsened. I would like to discuss how that affects what treatments and therapies are going to help you live the best-quality of life possible
    End-of-life wishes
    —What would be important to you in your last months of life?
    —Where would you prefer to die?
    Resources —Many communities have additional supports for patients with medical, social, psychological, and spiritual needs. Would you be interested in learning about some of these resources?
    Documentation —This depends on where patient is located. Various websites describe local and regional Goals of Care Medical Orders.
    — In Alberta, Canada, Conversations Matter describes local requirements
    Review and compare —Please tell me what you understand of your decisions with respect to your GCD. What impact do they have on your life? I want ot ensure that the designation properly reflects your values and wishes
    —Since we last met, have you had any experiences that may change your view about living with cirrhosis?
    — Are your wishes outlined anywhere else, such as in a Will or legal document? If so, we should look at it to ensure your wishes are consistent with your medical documents
    SPIKES Framework
    Setting Setting up the interview
    •Arrange for some privacy
    •Involve significant others if the patient chooses
    •Invite other relevant parties: Interpreter, social worker, surgeon, palliative care physician
    •Sit down with the patient
    •Make a connection and establish rapport with the patient
    •Manage time constraints and interruptions
    Perception Assessing the patient's perception
    •Use open-ended questions to determine the patient's level of comprehension about his or her medical condition (i.e. "What have you been told about your medical situation so far?")
    Invitation Obtaining the patient's invitation
    •Assess the patient's readiness to receive information
    •Discuss information disclosure at the time of ordering studies (i.e. "I have some updates on your condition to discuss. Would it be all right if I share these with you now?")
    •If the patient does not want to know details, offer to answer any questions they may have in the future or to talk to a caregiver
    Knowledge Giving knowledge and information to the patient
    •Consider a warning prior to disclosing bad news to the patient (i.e. "Unfortunately, I do not have good news" or "I'm sorry to tell you that...")
    •Start at the level of comprehension and vocabulary of the patient
    •Try to use nontechnical words and avoid medical jargon
    •Avoid excessive bluntness
    •Give information in small chunks, and periodically reassess the patient's understanding
    •When the prognosis is poor, avoid using phrases such as "There is nothing we can do for you" as patients may have other important therapeutic goals outside of curative therapy such as good symptom relief
    Emotion Addressing the patient's emotions with empathic responses
    •Observe for any emotion on the part of the patient
    •Identify the emotion experienced by the patient by naming it to oneself-use open ended questions to query the patient as to what they are feeling
    •Identify the reason for the emotion - if you are not sure, ask the patient
    •After you have given the patient time to express his or her feelings, show the patient that you recognize and empathize with his or her emotional response
    Strategy and Summarize Presenting a clear plan for the future with the patient
    •Assess whether the patient needs clarification on what has been discussed
    •Ask the patient if he or she is ready for a discussion regarding next steps in management
    •Set out a medical plan of action

    Adapted from Baile et al, Oncologist 2000

    Physician communication skills training
    Patient facing educational tools
    Best Case/Worst Case Tool

    Best Case/Worst Case

    Optimizing outpatient processes for ACP


    U.S.A Tools
    Billing guidance
    Tips for ACP Billing in Hepatology Practice

    • Health care professionals who may furnish and bill ACP: Physicians, clinical nurse specialist, nurse practitioners, physician assistants
    • Since ACP services are voluntary, Medicare beneficiaries (or their legal proxies when applicable) should be given a clear opportunity to decline to receive ACP services. Beneficiaries, family members and/or surrogates may receive assistance for completing legal documents from others outside the scope of the Medicare program in addition to, or separately from, the physician or NPP.
    • Examples of appropriate documentation would include an account of the discussion with the beneficiary (or family members and/or surrogate) regarding the voluntary nature of the encounter; documentation indicating the explanation of advance directives (along with completion of those forms, when performed); who was present; and the time spent in the face-to-face encounter
    • To bill for advance care planning services provided during an Evaluation and Management (E/M) office visit or inpatient consult/follow-up visit, providers can use the modifier code 25 and the following ACP codes as follows:
      • CPT Code 99497: Can be used to bill for advance care planning performed by a qualified health care professional for the first 30 minutes (minimum of 16 minutes) spent face-to-face with the patient, family member(s), and/or surrogate. This includes the explanation and discussion of advance directives such as health care proxy or MOLST forms. This include, but does not require, the completion of such forms.
      • CPT Code 99498: Can be used for each additional 30 minutes (minimum of 16 minutes past the first 30 minutes documented) of advance care planning performed by a qualified health professional. List separately in addition to code for primary procedure
      • Visits that are dedicated to ACP alone may also be billed separately using CPT codes 99497 and 99498

    Quick reference billing for ACP
    FAQ: Billing ACP services

    Patient materials:

    You can direct patients to the following:
    Personal Directive
    Power of Attorney
    Living Wills
    Patient Educational Brochures

    References:

    This section was adapted from content using the following evidence-based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors: Dr. Nneka Ufere, Dr. Arpan Patel, Dr. Christopher Woodrell, Dr. Amanda Brisebois, Dr. Rebecca Sudore, Dr. Puneeta Tandon

    References:

      1. Tandon P, Walling A, Patton H, Taddei T. AGA Clinical Practice Update on Palliative Care Management in Cirrhosis: Expert Review. Clinical Gastroenterology and Hepatology. 2021;19(4):646-656.e3. doi:10.1016/j.cgh.2020.11.027. PMID 33221550
      2. Brisebois A, Ismond KP, Carbonneau M, Kowalczewski J, Tandon P. Advance care planning (ACP) for specialists managing cirrhosis: A focus on patient-centered care. Hepatology. 2018;67(5):2025-2040. doi:10.1002/hep.29731.PMID 29251778
      3. Ufere NN. Advance Care Planning and Goals of Care Discussions in Advanced Liver Disease. Current Hepatology Reports. 2021;20(3):77-84. doi:10.1007/s11901-021-00565-x.
      4. Baile, W. F., Buckman, R., Lenzi, R., Glober, G., Beale, E. A., & Kudelka, A. P. (2000). SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. The oncologist5(4), 302–311. https://doi.org/10.1634/theoncologist.5-4-302PMID 10964998

    Fatigue

     Top tips:

    1. Fatigue is very common in cirrhosis, and is often multifactorial
    2. Potential contributing factors include pain, pruritus, anxiety, depression
    3. Treat the patient’s fatigue if it is affecting their quality of life or daily functioning
    4. At the end of life (last few weeks or days), as the patient’s condition deteriorates, certain non-pharmacological interventions will become unrealistic (e.g. exercise), and pharmacologic interventions may become less effective. Reassess patient’s GOC as appropriate

    Expand all Collapse all
    Step 1: Assess for possible modifiable factors contributing to fatigue
    Differential diagnosis for fatigue encompasses various conditions
    • Medications or medication withdrawal (assess recent medication changes)
    • Anemia (Anemia Document in development)
    • Metabolic – Metabolic acidosis, hypothyroidism/hyperthyroidism, hyponatremia
    • Malnutrition (Malnutrition Document in Development), Vitamin D deficiency
    • Mood disorders such as anxiety, depression
    • Sleep disturbances
    Step 2: Consider Non-pharmacological management

    Consider non-pharmacological management in all patients where fatigue has a significant impact on patient’s quality of life

    Recommend exercise to build strength (if appropriate)
    More information on recommended exercise can be found here: Exercise
    Nutrition and hydration management
    More information on nutrition can be found here: Nutrition

    Energy Conservation Strategies (See: Tiredness Patient Handout)
    More information on energy conservation strategies can be found here (Tiredness Patient Handout- in Development)
    Promote good sleep hygiene
    More information on sleep hygiene recommendations can be found here (Sleep Hygiene document in Development).
    Cognitive and psychological approaches (e.g. mindfulness-based stress reduction therapy)
    A study in cirrhosis (Bajaj 2017) associated 4-weeks of mindfulness and supportive group therapy with improved sleep quality, health related quality of life and depression scores in patients and improved caregiver burden in caregivers.
    Step 3: If symptoms persist, consider Pharmacological therapy
    (there is limited evidence to support this)

    If non-pharmacological therapy alone fails, and fatigue is having a severe impact on the patient’s quality of life and ability to function, a trial of pharmacological therapy can be considered.

    There is limited data in this area. This suggestion is based on expert opinion rather than strong evidence.

    Medication: Recommended Dose Additional information
    Methylphenidate (Ritalin) 2.5mg to 5mg PO qAM and noon
    • Limited data in cirrhosis
    • Adverse effects include dry mouth, dizziness, anxiety etc.

    Special considerations at End-of-life (last few days to weeks)
    Special considerations at End-of-life (last few days to weeks)
    At End of life, as the patient’s condition deteriorates, certain non-pharmacological interventions will become unrealistic (e.g. exercise).

    • Ongoing discussions with patients and caregivers are needed to address patient’s goals of care as condition and prognosis changes.
    • Energy conservation will become more important
    • Ensure appropriate supports are in place to assist with activities of daily living and nursing care is available as needed

    We gratefully acknowledge the Physician Learning Program for their design assistance.


    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages. 

    Helpful Links:

    1. Hepatic Encephalopathy
    2. Hyponatremia treatment
    3. Sleep Disturbance 
    References:
    1. Davison SN on behalf of the Kidney Supportive Care Research Group. Conservative Kidney Management Pathway; Available from: https//:www.CKMcare.com.
    2. Bajaj JS, Ellwood M, Ainger T, Burroughs T, Fagan A, Gavis EA, Heuman DM, Fuchs M, John B, Wade JB. Mindfulness-Based Stress Reduction Therapy Improves Patient and Caregiver-Reported Outcomes in Cirrhosis. Clin Transl Gastroenterol. 2017 Jul 27;8(7):e108. doi: 10.1038/ctg.2017.38. PMID: 28749453; PMCID: PMC5539344.
    3. Blockmans D, Persoons P, Van Houdenhove B, Bobbaers H. Does methylphenidate reduce the symptoms of chronic fatigue syndrome? Am J Med. 2006 Feb;119(2):167.e23-30. doi: 10.1016/j.amjmed.2005.07.047. PMID: 16443425. PMID: 16443425
    4. Dyson JK, Elsharkawy AM, Lamb CA, Al-Rifai A, Newton JL, Jones DE, Hudson M. Fatigue in primary sclerosing cholangitis is associated with sympathetic over-activity and increased cardiac output. Liver Int. 2015 May;35(5):1633-41. doi: 10.1111/liv.12709. Epub 2014 Dec 4. PMID: 25363895; PMCID: PMC4737110.
    5. Ian Gan S, de Jongh M, Kaplan MM. Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience. Dig Dis Sci. 2009 Oct;54(10):2242-6. doi: 10.1007/s10620-008-0613-3. Epub 2008 Dec 12. PMID: 19082890.
    6. Jones DE, Newton JL. An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Aliment Pharmacol Ther. 2007 Feb 15;25(4):471-6. doi: 10.1111/j.1365-2036.2006.03223.x. PMID: 17270003.
    7. Jopson L, Dyson JK, Jones DE. Understanding and Treating Fatigue in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis. Clin Liver Dis. 2016 Feb;20(1):131-42. doi: 10.1016/j.cld.2015.08.007. PMID: 26593295.

    Sleep Disturbance

    Top tips:

    1. Sleep disturbances occur in 27-70% of patients with cirrhosis
    2. Hepatic encephalopathy must be considered in any patient with cirrhosis and excessive daytime sleepiness
    3. Treat if sleep disturbances are impacting the patient’s quality of life and daily functioning
    4. Consider non-pharmacological interventions before pharmacological therapy
    5. At the end of life (last few days or weeks), sleepiness may increase due to disease progression (and/or medications)

    Step 1: Assess for sleep disturbance with validated assessment tools

    Hepatic encephalopathy (HE) is the diagnosis of exclusion in any patient with cirrhosis and excessive daytime sleepiness. In patients with cirrhosis and HE, studies of lactulose or rifaximin have demonstrated improved sleep. See HE page for treatment of suspected HE.

     

    If the presentation does not fit with HE, assess sleep health using validated tools

    These tools assess difficulty falling and/or staying asleep, or daytime sleepiness

    Step 2: Consider potential contributing causes

     

    Contributing factors
      • Cirrhosis complications – e.g., ascites, muscle cramps, pruritus, pain, breathlessness
      • Medications/toxins – e.g., diuretics, alcohol use
      • Other acute or chronic comorbidities – e.g., obstructive sleep apnea, mood disorders – anxiety/depression, cognitive impairment
    Step 3: : Consider Non-pharmacological management

    Consider non-pharmacological management in all patients where sleep disturbance is having a significant impact on the patient’s quality of life and ability to function.

     

    Changing habits by promoting good sleep hygiene
    • Wake up at the same time every morning
    • Do not go to bed until you feel sleepy
    • Develop a relaxing bedtime ritual such as taking a warm shower or reading something relaxing before going to bed
    • Do not “try” to fall asleep
    • Avoid napping during the day
    • Avoid caffeine and nicotine in the evening
    • Avoid treating sleep problems with alcohol
    • Exercise early in the day. Avoid exercising before bed as this may keep you up at night
    • Save your bedroom for sleep (and sex) only
    • Don’t watch television or use mobile phones, tablets or computers in bed as these activate your brain
    Changing environmental factors
    • Keep bedroom dark and cool at night
    • If you have gone to bed and are unable to sleep, get out of bed and do something relaxing before returning to bed
    Complementary treatments
    • Cognitive and psychological therapies such as mindfulness: evidence supports 4-weeks of mindfulness and supportive group therapy to improve sleep quality and reduce depression scores
    • Bright-light therapy: to date there are inadequate studies in cirrhosis, but this treatment is promising. Promote bright light exposure in the early hours of the morning and bright light avoidance, including light that comes from mobile phones, tablets or computers in the evening
    Step 4: If symptoms persist, weigh the risks and benefits of Pharmacological therapy
    • Be VERY cautious of using pharmacological interventions, as they increase risks of cognitive dysfunction and falls especially if daytime sleepiness is already present
    • Use the sleep assessment tools to reassess the effectiveness of medications 2-4 weeks after prescription
    • Avoid over the counter sleep aids, and benzodiazepines if possible

    There is limited evidence for the pharmacological management of sleep disturbances in cirrhosis. Small randomized controlled trials are available for the use of Zolpidem and for Melatonin.

    Medication: Recommended Dose Additional information

    Zolpidem

    5mg PO qhs for SHORT term use (<2weeks)

    Limited Evidence - 4-week RCT (Sharma 2019) in Child Pugh A/B patients showed increased sleep time and sleep efficiency

    Melatonin

    3mg PO/SL qhs
    For SHORT term use (<2 weeks)

    Limited Evidence 2 week RCT (De Silva 2020) in Child Pugh A/B patients showed increased sleep quality and decreased daytime sleepiness

    Additional Expert opinion based consideration

    Formal studies are required to establish the risks and benefits of these medications in cirrhosis.

    If this Expert opinion based medications is used, it should only be used short term unless the patient is in their last few months of life when symptom control is the priority.

    Medication: Recommended Dose Additional information

    Zopiclone

    3.75-5mg PO qhs
    For SHORT term use (<2 weeks)

    Limited Evidence Based on expert opinion only - In non-cirrhosis patients, this can be helpful with early insomnia (insomnia at the earlier hours of sleep)

    Titrate to effect, as per pharmaceutical guidelines (CPS in Canada)

    Special considerations at End of Life
    • As a patient’s condition deteriorates, certain non-pharmacological interventions will become less realistic (e.g. exercise). Energy conservation and restoration will become of utmost importance.
    • Ensure that If the appropriate supports are in place to assist with activities of daily living and that nursing care is available as needed.
    • Drowsiness may increase as the end of life approaches due to disease progression (and/or medications). Some families and patients may even prefer increased sleepiness if it makes the patient more comfortable.
    • Hepatic encephalopathy therapy can be continued during this time if the patient is able to swallow.
    • The following medications can be considered if the first line pharmacological therapies are ineffective.
    Medication: Recommended Dose Additional information

    Mirtazapine (Remeron)

    7.5 mg PO qhs

    For use at End of Life For use at End of Life
    -AVOID if taking tramadol or antidepressants
    -Added benefit of appetite stimulation and elevated mood

    Trazadone

    25mg PO qhs Max dose 100mg PO qhs

    For use at End of Life-Can be helpful in mid-late insomnia

    Quetiapine

    12.5-25mg PO qhs
    Maximum: 50 mg po daily

    For use at End of Life QT prolongation, hepatic metabolism

    This section was adapted from content using the following evidence based resources in combination with expert consensus. The presented information is not intended to replace the independent medical or professional judgment of physicians or other health care providers in the context of individual clinical circumstances to determine a patient’s care.

    Authors (Alphabetical): Amanda Brisebois, Sarah Burton-Macleod, Ingrid DeKock , Martin Labrie, Noush Mirhosseini, Mino Mitri, Sara Montagnese, Kinjal Patel, Aynharan Sinnarajah, Puneeta Tandon

    Thank you to pharmacists Omer Ghutmy and Meghan Mior for their help with reviewing these pages.

    Helpful links:
    1. Hepatic Encephalopathy:http://cirrhosiscare.ca/treatment-provider/hepatic-encephalopathy-hcp/
    2. Sleep-wake patterns in patients with cirrhosis: All you need to know on a single sheet. A simple sleep questionnaire for clinical use: https://europepmc.org/article/med/19664835
    3. Epworth Sleepiness Scale (ESS): https://epworthsleepinessscale.com/about-the-ess/
    References:
    1. Bajaj JS, Elwood M, Ainger T et al. Mindfulness-based stress reduction therapy improves patient and caregiver-reported outcomes in cirrhosis. Clin Transl Gastronenterol 2017;8(7):e108. PMID: 28749453.
    2. Formentin C, Garrido M, Montagnese S et al. Assessment and Management of Sleep Disturbance in Cirrhsois. Current Hepatology Reports 2018 17:52-69. PMID: 29876197.
    3. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991; 14(6):540-5. PMID: 1798888.
    4. Montagnese S et al. Sleep-wake patterns in patients with cirrhosis: All you need to know on a single sheet. A simple sleep questionnaire for clinical use. J Hepatol 2009 51:690-695. PMID: 19664835.
    5. Moore C. Evaluation and management of insomnia, muscle cramps, fatigue, and itching in cirrhotic patients. Clin Liver Dis (Hoboken). 2016 Jan 29;7(1):5-7. doi: 10.1002/cld.516. PMID: 31041016; PMCID: PMC6490243.
    6. Newton JL, Jones DE. Managing systemic symptoms in chronic liver disease. J Hepatol. 2012;56 Suppl 1:S46-55. doi: 10.1016/S0168-8278(12)60006-3. PMID: 22300465.
    7. Sharma MK, Kainth S et al. Effects of zolpidem on sleep parameters in patients with cirrhosis and sleep disturbances: A randomized, placebo-controled trial. Clin Mol Hepatol 2019 Jun; 25(2):199-209. PMID: 30856689.
    We gratefully acknowledge the Physician Learning Program for their design assistance.