In chronic liver disease patients who develop type‑1 hepatorenal syndrome (HRS‑AKI), what is the recommended first‑line use of terlipressin, including dosing regimen, contraindications, monitoring parameters, and alternative vasoconstrictor options?

Use of Terlipressin in Chronic Liver Disease

Terlipressin plus albumin is the first-line treatment for hepatorenal syndrome-acute kidney injury (HRS-AKI) stage ≥2 in patients with chronic liver disease, initiated at 1 mg IV every 4–6 hours via peripheral line, escalated to 2 mg every 4–6 hours if serum creatinine fails to decrease by ≥25% after 2–4 days, with mandatory albumin co-administration and careful screening for cardiovascular contraindications. 1

Indications and Patient Selection

When to initiate terlipressin:

• All patients meeting diagnostic criteria for HRS-AKI stage ≥2 (formerly type-1 HRS) should receive vasoconstrictors plus albumin expeditiously 1
• Stage 1 AKI currently has no recommendation for vasoconstrictor use 1
• Terlipressin is indicated specifically in hospitalized patients without ACLF-3 (EASL-CLIF criteria) or major cardiopulmonary/vascular disease 1

Absolute contraindications:

• Baseline oxygen saturation <90% on room air or supplemental oxygen 1, 2
• Active coronary, peripheral, or mesenteric ischemia 1
• Serum creatinine >5 mg/dL (unlikely to benefit) 1

Dosing Regimen

Initial dosing options:

Bolus regimen (standard):

• Start 1 mg IV every 4–6 hours through peripheral line (total 4–6 mg/day) 1
• No central venous access required; can be administered on regular ward for ACLF grade <3 1

Continuous infusion (alternative):

• Start 2 mg/day as continuous IV infusion 1
• Provides equal efficacy with lower total daily dose and reduced rate of ischemic adverse effects 1
• Not currently FDA-approved in the United States but widely used in Europe 1

Dose escalation protocol:

• If serum creatinine has not decreased by ≥25% from peak value after 2–4 days, increase dose in stepwise manner 1
• Escalate to 2 mg IV every 4–6 hours (total 8–12 mg/day) 1
• Maximum dose: 12 mg/day regardless of administration method 1

Treatment duration:

• Continue until serum creatinine returns to baseline values, up to 14 days maximum 1, 2
• Discontinue 24 hours after creatinine decreases to <1.5 mg/dL 1
• In patients with very high pretreatment creatinine, treatment may need to exceed 14 days to reach baseline 1
• If creatinine remains at or above pretreatment level after 4 days with maximum tolerated doses, therapy may be discontinued 1

Mandatory Albumin Co-Administration

Albumin is essential and must always be given with terlipressin:

• Day 1: 1 g/kg IV (maximum 100 g/day) 1
• Subsequent days: 20–40 g/day IV until treatment completion 1
• Terlipressin alone achieves only 25% response rate versus 77% with combination therapy 1

Albumin monitoring to prevent volume overload:

• Serial measurement of central venous pressure or other measures of central blood volume helps prevent circulatory overload and optimize albumin dosing 1
• Judicious albumin use is critical as excessive volume expansion increases respiratory failure risk (11% vs 2% placebo) 1
• Reassess need for continued albumin after 1–2 days based on volume status 1

Pre-Treatment Assessment

Mandatory baseline screening:

• Electrocardiogram to screen for ischemic heart disease 1
• Baseline oxygen saturation measurement 1, 2
• ACLF grade assessment 1
• Volume status evaluation 1

Monitoring Parameters During Treatment

Daily monitoring requirements:

• Serum creatinine daily, looking for ≥25–30% reduction by days 3–4 1
• Vital signs including pulse oximetry every 2–4 hours in patients with ACLF grade <3 1
• Mean arterial pressure: sustained increase of ≥5–10 mmHg by day 3 predicts treatment response 1

Surveillance for adverse events:

• Ischemic complications occur in approximately 12% of patients: abdominal pain, chest pain, digital ischemia, arrhythmias 1
• Respiratory failure develops in 14–30% of patients, particularly those with ACLF grade 3 or baseline hypoxemia 1, 3
• According to type and severity of side effects, treatment should be modified or discontinued 1

ICU transfer criteria:

• Patients with ACLF grade 3 (≥3 organ failures) require ICU monitoring due to ~30% risk of respiratory failure 1
• Decision to transfer to higher dependency care should be case-based 1

Response Definitions

Complete response:

• Final serum creatinine within 0.3 mg/dL (26.5 μmol/L) from baseline value 1

Partial response:

• Regression of AKI stage to final serum creatinine ≥0.3 mg/dL from baseline value 1
• OR ≥25% reduction in serum creatinine 1

Clinical significance:

• Each 1 mg/dL reduction in creatinine reduces mortality risk by 27%, even with partial response 1
• Response rate averages approximately 40–50% across studies 1, 4

Predictors of Treatment Response

Favorable prognostic factors:

• Baseline serum bilirubin <10 mg/dL 1
• Baseline serum creatinine <5 mg/dL 1
• Lower stage of acute-on-chronic liver failure 1
• Mean arterial pressure increase ≥5–10 mmHg by day 3 1
• Presence of systemic inflammatory response syndrome, alcohol-associated hepatitis, or sepsis 1

Factors associated with poor response:

• Higher number of extra-renal organ failures correlates with lower response rate for same baseline creatinine 1
• ACLF-3 grade 1

Alternative Vasoconstrictor Options

Norepinephrine:

• Can be used as alternative to terlipressin with comparable efficacy 1
• May be preferred in patients with shock 1
• Start 0.5 mg/hour (≈5 μg/min) continuous IV infusion, titrate up to 3 mg/hour (≈10 μg/min) to achieve mean arterial pressure increase >10 mmHg above baseline 1
• Response rates: 39–70% 1
• Key limitation: Always requires central venous line and, in several countries, transfer to ICU 1

Midodrine plus octreotide:

• Option only when terlipressin or norepinephrine are unavailable 1
• Efficacy is much lower than terlipressin 1
• Midodrine 7.5 mg orally three times daily plus octreotide 100–200 μg subcutaneously three times daily or continuous IV infusion 1

Management of Recurrence and Non-Response

Recurrence after treatment cessation:

• Repeat course of therapy should be given 1

Non-responders to pharmacotherapy:

• Renal replacement therapy should be considered, particularly in patients who are liver transplant candidates or being considered for transplant 1
• Continuous renal replacement therapy is preferable to intermittent hemodialysis in hemodynamically unstable patients 1
• Patients who are non-responders and not liver transplant candidates should be referred for palliative care 1

Special Considerations

HRS-NAKI (formerly type-2 HRS):

• Terlipressin plus albumin is effective in treatment of HRS outside criteria of AKI 1
• However, recurrence after withdrawal is the norm, and controversial data exists on impact on long-term clinical outcome 1
• Vasoconstrictors and albumin are NOT recommended in this clinical scenario 1

Liver transplantation context:

• Liver transplant is the definitive treatment for HRS-AKI; all patients with HRS-AKI who are potential transplant candidates should be referred for evaluation without delay 1
• Response to vasoconstrictor therapy improves post-transplant outcomes, with fewer patients needing renal replacement therapy and developing chronic kidney disease at 1 year post-transplant 1
• Patients with prolonged pre-transplant renal replacement therapy >6 weeks should be considered for simultaneous liver-kidney transplant 1

Common Pitfalls to Avoid

• Failing to escalate dose: Do not continue same dose beyond day 3–4 if creatinine reduction is <25–30%; systematic escalation to maximum 12 mg/day is required 1
• Excessive albumin administration: Judicious use is critical to avoid volume overload and respiratory complications; reassess after 1–2 days 1
• Inadequate pre-treatment screening: Always obtain baseline ECG and oxygen saturation; do not initiate if SpO₂ <90% 1, 2
• Continuing treatment despite ischemic symptoms: Permanent discontinuation is required if any ischemic manifestations develop, even if they resolve after drug cessation 1
• Using terlipressin in ACLF-3 without ICU monitoring: These patients have ~30% risk of respiratory failure and require intensive care 1