What is the recommended norepinephrine (Norad) dosing regimen for an adult with advanced cirrhosis and type 1 hepatorenal syndrome who has no severe cardiac disease, peripheral vascular disease, or uncontrolled hypertension?

Norepinephrine Dosing for Hepatorenal Syndrome Type 1

Start norepinephrine as a continuous intravenous infusion at 0.5 mg/h and titrate upward by 0.5 mg/h every 4 hours to a maximum of 3 mg/h, targeting a mean arterial pressure increase of ≥10 mmHg and/or urine output >50 mL/h for at least 4 hours, always combined with albumin. 1

Initial Dosing Protocol

• Starting dose: Begin norepinephrine at 0.5 mg/h (approximately 5 μg/min) as a continuous IV infusion through a central or peripheral line. 1, 2
• Titration schedule: Increase the dose by 0.5 mg/h increments every 4 hours based on hemodynamic response. 1
• Maximum dose: Do not exceed 3 mg/h (approximately 10 μg/min). 1, 2
• Target endpoints: Aim for a mean arterial pressure increase of ≥10 mmHg above baseline and/or urine output exceeding 50 mL/h sustained for at least 4 hours. 1

Mandatory Albumin Co-Administration

Norepinephrine monotherapy is inadequate; albumin must be given concurrently to optimize circulatory function and treatment efficacy. 1

• Day 1: Administer 1 g/kg IV albumin (maximum 100 g). 1
• Subsequent days: Continue 20–40 g/day IV albumin until treatment completion or HRS reversal. 1, 3
• Rationale: Albumin expansion addresses the underlying splanchnic vasodilation and improves response rates from 25% to 77% when combined with vasoconstrictors. 4

Treatment Duration and Response Monitoring

• Duration: Continue therapy until serum creatinine returns to within 0.3 mg/dL of baseline for 2 consecutive days, or for a maximum of 14 days. 1
• Daily monitoring: Check serum creatinine daily; a ≥25% reduction by day 3–4 predicts favorable response. 1, 5
• Complete response: Serum creatinine returns to within 0.3 mg/dL of pre-AKI baseline. 1
• Partial response: Regression of AKI stage with ≥25% creatinine reduction or ≥0.3 mg/dL decrease from baseline. 1

Clinical Efficacy Compared to Terlipressin

Norepinephrine achieves HRS reversal in 47–83% of patients, comparable to terlipressin's 45–83% response rate. 6, 5, 3, 2 Multiple randomized trials demonstrate equivalent efficacy:

• A 2016 trial showed HRS reversal in 47.6% with norepinephrine versus 45% with terlipressin (p=1.00). 6
• A 2008 study reported 50% response rates in both norepinephrine and terlipressin groups. 5
• A 2002 pilot study achieved 83% HRS reversal with norepinephrine plus albumin. 3
• Both agents significantly reduce serum creatinine, increase creatinine clearance, and suppress plasma renin activity. 5, 3

When to Use Norepinephrine Instead of Terlipressin

Use norepinephrine as first-line therapy when terlipressin is unavailable, unaffordable, or contraindicated, or as second-line therapy after terlipressin failure. 1, 4

• Cost advantage: Norepinephrine is significantly less expensive than terlipressin. 6, 2
• Availability: Norepinephrine is widely available in all ICUs, whereas terlipressin may not be stocked or approved in all regions. 2
• Terlipressin failure: Switch to norepinephrine if no response by days 3–4 despite terlipressin dose escalation. 4
• Contraindications to terlipressin: Use norepinephrine when baseline SpO₂ <90%, serum creatinine >5 mg/dL, or active ischemic disease precludes terlipressin. 1, 4

Critical Safety Monitoring

• ICU requirement: Norepinephrine mandates ICU-level monitoring due to the need for continuous infusion and hemodynamic surveillance. 1, 3
• Ischemic complications: Monitor for cardiac ischemia, digital ischemia, and mesenteric ischemia, which occur in approximately 12% of patients on vasoconstrictors. 1, 3
• Reversible cardiac events: One study reported reversible myocardial hypokinesia that resolved with dose reduction. 3
• Pulmonary edema risk: Judicious albumin use is critical; excessive volume expansion increases respiratory failure risk. 1, 4

Predictors of Favorable Response

Baseline characteristics that predict HRS reversal with norepinephrine include: 5

• Lower MELD score (independent predictor on multivariate analysis). 6, 5
• Higher baseline creatinine clearance. 5
• Higher baseline mean arterial pressure. 5
• Lower plasma renin activity. 5
• Lower grade of hepatic encephalopathy. 5

A delta creatinine decrease of ≥0.15 mg/dL/day by day 4 predicts response with 90% sensitivity and 75% specificity. 5

Common Pitfalls and How to Avoid Them

• Inadequate dose escalation: Do not maintain the starting dose if creatinine fails to decrease by 25% at day 3–4; titrate upward to the maximum 3 mg/h. 1
• Omitting albumin: Never use norepinephrine without concurrent albumin; monotherapy is ineffective. 1, 3
• Excessive albumin: Reassess volume status after 1–2 days using clinical examination or point-of-care ultrasound to avoid pulmonary edema. 1, 4
• Premature discontinuation: Continue therapy until creatinine normalizes or 14 days elapse, even if partial response occurs; each 1 mg/dL creatinine reduction decreases mortality by 27%. 4
• Ignoring ischemic symptoms: Permanently discontinue norepinephrine if any ischemic manifestations develop (chest pain, abdominal pain, digital ischemia). 1, 4

Alternative Vasoconstrictor Regimen

If norepinephrine is unavailable or contraindicated, use the combination of midodrine and octreotide: 1

• Midodrine: Start at 7.5 mg orally three times daily, titrate to 12.5 mg three times daily. 1
• Octreotide: Start at 100 μg subcutaneously three times daily, titrate to 200 μg three times daily. 1
• Efficacy: This combination achieves 75% HRS reversal, comparable to norepinephrine. 7
• Advantage: Can be administered outside the ICU. 1