What is the recommended terlipressin dose, schedule, duration, and albumin co‑administration for an adult patient with cirrhosis‑related acute kidney injury (hepatorenal syndrome)?

Terlipressin Dosing for Hepatorenal Syndrome in Cirrhosis

Start terlipressin at 1 mg IV bolus every 4-6 hours (or 2 mg/day continuous infusion) combined with albumin 1 g/kg on day 1 (maximum 100 g) followed by 20-40 g/day, escalating to 2 mg every 4-6 hours if serum creatinine fails to decrease by ≥25% by day 3-4, with a maximum dose of 12 mg/day for up to 14 days. 1, 2, 3

Initial Dosing Strategy

Bolus dosing approach:

• Administer 1 mg IV bolus every 4-6 hours through a peripheral IV line without requiring central venous access 1, 2, 3
• No dilution is necessary for bolus administration 2
• This translates to 4-6 mg total daily dose initially 2, 4

Continuous infusion alternative:

• Start at 2 mg/day as continuous IV infusion, which provides equal efficacy with lower total daily doses and fewer ischemic side effects compared to bolus dosing 1, 2, 4
• The continuous infusion approach reduces the risk of adverse events such as cardiac or intestinal ischemia, pulmonary edema, or distal necrosis 1

Mandatory Albumin Co-Administration

Albumin is absolutely required—terlipressin monotherapy achieves only 25% response rate versus 77% with combination therapy: 2

• Day 1: 1 g/kg IV (maximum 100 g) 1, 2, 4, 3
• Subsequent days: 20-40 g/day IV until treatment completion 1, 2, 4, 3
• Reassess need for continued albumin after 1-2 days based on volume status to avoid excessive volume expansion 2
• Consider point-of-care ultrasonography for volume assessment 2

Dose Escalation Protocol

On day 4, if serum creatinine has not decreased by ≥25-30% from baseline:

• Increase to 2 mg IV every 4-6 hours (total 8-12 mg/day) 1, 2, 4, 3
• Maximum dose is 12 mg/day regardless of administration method 1, 2, 4
• If serum creatinine is at or above baseline on day 4, discontinue treatment 3

A sustained increase in mean arterial pressure (MAP) by 5-10 mmHg by day 3 predicts treatment response and should guide dose escalation decisions. 1, 2, 4

Treatment Duration and Response Definitions

• Maximum treatment duration is 14 days 1, 3
• Discontinue 24 hours after serum creatinine decreases to <1.5 mg/dL 2
• Median time to response is 14 days, with shorter response times in patients with lower baseline serum creatinine 4

Response definitions:

• Complete response: Serum creatinine returns to within 0.3 mg/dL of baseline 1, 2, 4
• Partial response: Regression of AKI stage with serum creatinine ≥0.3 mg/dL from baseline or ≥25% reduction in creatinine 1, 2, 4
• Verified HRS reversal: Two consecutive serum creatinine values ≤1.5 mg/dL obtained at least 2 hours apart while on treatment 3

Critical Pre-Treatment Assessment

Absolute contraindications:

• SpO₂ <90% on room air or supplemental oxygen 2, 4
• Active coronary, peripheral, or mesenteric ischemia 2, 4
• Serum creatinine >5 mg/dL (unlikely to benefit) 1, 2, 4

Baseline assessment required:

• Obtain baseline electrocardiogram to screen for ischemic heart disease 1, 2, 4
• Check baseline oxygen saturation 1, 2, 4
• Assess ACLF grade and volume status 1, 2, 4

Monitoring Requirements During Treatment

Daily monitoring:

• Check serum creatinine daily looking for ≥25-30% reduction by days 3-4 2, 4
• Monitor vital signs including pulse oximetry every 2-4 hours in patients with ACLF grade <3 2

Watch for complications:

• Ischemic complications occur in ~12% of patients: abdominal pain, chest pain, digital ischemia, arrhythmias 1, 2, 4
• Respiratory failure occurs in 14-30% of patients, especially those with ACLF grade 3 or baseline hypoxemia 1, 2, 4
• Respiratory failure was associated with higher baseline MAP and oxygen saturation in the CONFIRM trial 1

Administration Setting

Ward-based administration is acceptable for most patients:

• Terlipressin can be safely administered via peripheral IV line in ward or ICU settings without requiring central line placement 2, 4
• ICU monitoring is NOT required for patients with ACLF grade <3 1, 2, 4
• ICU admission is mandatory for patients with ACLF grade 3 (≥3 organ failures) due to 30% risk of respiratory failure 1, 2, 4

Predictors of Treatment Response

Favorable prognostic factors:

• Baseline bilirubin <10 mg/dL 1, 2, 4
• Baseline serum creatinine <5 mg/dL 1, 2, 4
• Lower stage of acute-on-chronic liver failure 1
• MAP increase ≥5-10 mmHg by day 3 1, 2, 4
• Presence of systemic inflammatory response syndrome, alcohol-associated hepatitis, or sepsis 1

Clinical significance:

• Each 1 mg/dL reduction in creatinine reduces mortality risk by 27%, even with partial response 5, 4
• Treatment with terlipressin improves renal function in 40-50% of patients with HRS-AKI 4, 6, 7

Management of Non-Response

If no response by day 3-4 despite dose escalation:

• Switch to norepinephrine 0.5 mg/hour (or 5 μg/min) continuous IV infusion 1, 2, 5, 4
• Titrate up to 3 mg/hour (or 10 μg/min) to achieve MAP increase >10 mmHg above baseline 1, 2, 5, 4
• Norepinephrine demonstrates similar response rates of 39-70% compared to terlipressin 1, 2
• In acute-on-chronic liver failure, terlipressin is superior to norepinephrine with day 4 response of 26.1% vs 11.7% (p=0.03) and 28-day survival of 48.3% vs 20% (p=0.001) 2

Common Pitfalls to Avoid

Volume overload from excessive albumin:

• Judicious albumin use is critical as excessive volume expansion increases respiratory failure risk (11% vs 2% placebo) 2
• Reassess volume status after 1-2 days and adjust albumin accordingly 2

Failure to escalate dose appropriately:

• Do not continue same dose beyond day 3-4 if creatinine reduction is <25-30% 2, 4
• Systematic dose escalation to maximum 12 mg/day is required for non-responders 1, 5, 4

Using terlipressin in inappropriate AKI phenotypes:

• Terlipressin is often used outside its primary indication of HRS-AKI in clinical practice 8
• Response to terlipressin is significantly lower in patients with acute tubular necrosis (29% vs 51% in HRS-AKI), where risks may outweigh benefits 8

Continuing treatment despite cardiovascular complications:

• Permanent terlipressin withdrawal is required if ischemic symptoms develop, even if symptoms subside after discontinuation 1
• Exercise extra caution in patients with concomitant organ failure or elevated baseline MAP 1