What is the recommended treatment approach for a patient with Hepatorenal Syndrome (HRS), particularly regarding the use of Terlipressin and Albumin?

Terlipressin Plus Albumin for Hepatorenal Syndrome

Terlipressin combined with albumin is the first-line pharmacological treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI), achieving reversal of HRS in approximately 30-40% of patients and significantly improving survival without renal replacement therapy compared to albumin alone. 1, 2

Treatment Protocol

Initial Assessment and Contraindications

Before initiating therapy, perform the following screening:

• Obtain baseline electrocardiogram to exclude active coronary ischemia 1
• Check oxygen saturation - do not use terlipressin if SpO₂ <90% on room air or supplemental oxygen 3, 4
• Exclude patients with serum creatinine >7.0 mg/dL, active shock, sepsis, or uncontrolled bacterial infection 4
• Assess ACLF grade - patients with ACLF grade 3 require ICU-level monitoring due to increased respiratory failure risk 3

Terlipressin Dosing Regimen

Two administration methods are available, with continuous infusion preferred:

Bolus Dosing (FDA-Approved Protocol)

• Start with 1 mg IV bolus every 6 hours (total 4 mg/day) for days 1-3 4
• Escalate to 2 mg IV bolus every 6 hours (total 8 mg/day) on day 4 if serum creatinine has decreased by <30% from baseline 4
• Maximum duration: 14 days 1

Continuous Infusion (Preferred Method)

• Start at 2 mg/24 hours as continuous IV infusion 1, 5, 3
• Escalate every 24-48 hours up to maximum 12 mg/24 hours if serum creatinine fails to decrease by ≥25% 1, 5, 3
• Continuous infusion provides equal efficacy with lower total daily doses and significantly fewer ischemic adverse events compared to bolus dosing 5, 3

Mandatory Albumin Co-Administration

Terlipressin must always be combined with albumin - terlipressin alone achieves only 25% response rate versus 77% with combination therapy 6:

• Day 1: 1 g/kg IV (maximum 100 g) 1, 3
• Subsequent days: 40-50 g/day IV until treatment completion 1
• Albumin optimizes circulatory function and is essential for treatment efficacy 5, 3

Monitoring and Response Assessment

Daily Monitoring Requirements

• Check serum creatinine daily looking for ≥25-30% reduction by days 3-4 1, 3
• Monitor vital signs including pulse oximetry every 2-4 hours in patients with ACLF grade <3 3
• Assess for ischemic complications (occur in ~12% of patients): abdominal pain, chest pain, digital ischemia, arrhythmias 1, 3
• Monitor for respiratory failure (occurs in 14-30% of patients, particularly with ACLF grade 3) 3, 2

Response Definitions

• Complete response: Serum creatinine ≤1.5 mg/dL or return to within 0.3 mg/dL of baseline 1, 5, 3
• Partial response: Serum creatinine reduction ≥25% but still >1.5 mg/dL 1, 5
• Treatment failure: Creatinine remains at or above baseline after 4 days at maximum tolerated dose - discontinue therapy 1

Predictors of Treatment Success

Favorable prognostic factors include:

• Baseline serum creatinine <3-5 mg/dL 5, 3
• Baseline bilirubin <10 mg/dL 5, 3
• Mean arterial pressure increase ≥5-10 mmHg by day 3 5, 3
• Lower MELD score and Child-Pugh score <13 5

Alternative Vasoconstrictors

Norepinephrine (Second-Line)

If terlipressin is unavailable, contraindicated, or fails:

• Start at 0.5 mg/hour continuous IV infusion 1, 3
• Titrate up to 3 mg/hour to achieve mean arterial pressure increase >10 mmHg 1, 3
• Requires ICU-level monitoring with central venous access 1
• Norepinephrine appears equally effective to terlipressin with response rates of 39-70%, though fewer data exist 1, 3

Midodrine Plus Octreotide (Third-Line)

Use only when terlipressin and norepinephrine are unavailable:

• Midodrine: titrate up to 12.5 mg orally three times daily 7
• Octreotide: 200 μg subcutaneously three times daily 5, 7
• This combination is significantly less effective than terlipressin (much lower efficacy) 1

Critical Safety Considerations

Common Adverse Events

Ischemic complications (12% incidence):

• Abdominal pain or intestinal ischemia
• Digital or skin ischemia
• Cardiac ischemia
• Usually not severe and improve with dose reduction or discontinuation 1

Respiratory complications:

• Pulmonary edema from albumin infusion 1
• Respiratory failure (30% in CONFIRM trial, 11% mortality from respiratory disorders) 2
• Continuous infusion reduces ischemic side effects compared to bolus dosing 1, 5

Treatment Duration and Recurrence

• Continue treatment until complete response or maximum 14 days 1, 5
• Recurrence of HRS-AKI occurs in approximately 17% of responders 6
• In cases of recurrence, repeat course of therapy should be given 1

Renal Replacement Therapy

Initiate RRT based on clinical grounds:

• Worsening kidney function despite vasoconstrictors
• Severe electrolyte disturbances (acidosis, hyperkalemia, hyponatremia) not improving with medical management
• Diuretic intolerance or increasing volume overload 1

Continuous RRT is preferred over intermittent dialysis in hemodynamically unstable patients 1

RRT is typically reserved as bridge to liver transplantation - mortality rates are extremely high in non-transplant candidates regardless of AKI etiology 1

Important Clinical Pitfalls

Do not use terlipressin for HRS-NAKI (formerly type 2 HRS) - recurrence after treatment withdrawal is the norm, and controversial data exists on long-term clinical outcomes 1

TIPS is not recommended in patients with HRS-AKI due to insufficient information and contraindication in severe liver failure 1

Terlipressin can be administered via peripheral vein, unlike norepinephrine which requires central access 5, 3

The CONFIRM trial demonstrated 29.1% verified HRS reversal with terlipressin versus 15.8% with placebo (P=0.012), but also showed increased serious adverse events including respiratory failure 1, 2