terlipressin

The HRS Gold Standard

Gold standard for HRS-AKI globally, but unavailable in Canada (requires Special Access Programme). Higher risk of respiratory failure compared to Norepinephrine.

• Mechanism: Synthetic Vasopressin analog (V1 receptor agonist). Causes profound systemic vasoconstriction (increased Afterload/SVR). Splanchnic-to-central blood shifting (increased Preload). Crucially: Lacks inotropic properties; the heart must pump against sudden high resistance without contractility support. May cause direct pulmonary venoconstriction.

• Dosing: Continuous IV Infusion (Preferred): Start $2\text{ mg/day}$, max $12\text{ mg/day}$. Intermittent IV: $0.5–1\text{ mg}$ q4–6h (less preferred). Titration: Target MAP increase of $10–15\text{ mmHg}$ or MAP $>65\text{ mmHg}$.

• PK: Onset: 30–60 minutes (IV). Half-life: ~6 hours (long-acting; longer than vasopressin due to slow conversion to active metabolite). Metabolism: Cleaved by tissue peptidases to lysine-vasopressin (active metabolite); conversion is rate-limiting, providing sustained effect. Elimination: Renal (active metabolite).

indications

• Hepatorenal Syndrome (HRS-AKI) – Gold Standard globally. Raises MAP by $10–15\text{ mmHg}$ (or target $>65\text{ mmHg}$) to restore renal autoregulation.

evidence & efficacy

• CONFIRM Trial: Terlipressin plus albumin superior to placebo for HRS reversal (32% vs 17%, p=0.006).
• Meta-analyses: Non-inferiority to Norepinephrine for HRS reversal, but with higher risk of respiratory failure.
• Response Rate: ~40–50% achieve HRS reversal (Cr returns to within $26.5\mu \text{mol/L}$ of baseline).

cautions/contraindications

• Respiratory: Hypoxia ($Sp{O}_2<90\%$) or ACLF Grade 3 ($\ge 3$ organ failures)
• Renal: Serum Cr $>440\mu \text{mol/L}$ ($5\text{ mg/dL}$)
• Vascular: Severe ischaemic disease

• Respiratory Failure Risk: High rate of respiratory failure (14% vs 5% in CONFIRM trial) due to:
  • Increased preload/afterload without inotropic support
  • Potential direct pulmonary venoconstriction
  • “Two-Hit” Injury: Drug effect PLUS excessive albumin (protocol-driven volume overload)
• Ischaemia: Risk of digital, mesenteric, or cardiac ischaemia.

stopping rules:

• Success: Serum Cr returns to within $26.5\mu \text{mol/L}$ of baseline
• Futility: No improvement after 48 hours on maximum dose (or 3 days depending on guideline)
• Safety: Severe adverse reaction (ischaemia, pulmonary oedema)
• Maximum Duration: 14 days

special considerations (canada/royal college)

• Availability: Unavailable in Canada (requires Special Access Programme application).
• Canadian Standard: Norepinephrine is the practical first-line in Canadian ICUs due to Terlipressin unavailability.

albumin protocol warning

The CONFIRM trial’s high respiratory failure rate was partly due to rigid albumin dosing. Albumin should be administered only to achieve euvolemia, then STOPPED immediately if volume overloaded.

exam pearl

Terlipressin lacks inotropy, unlike Norepinephrine (${\alpha }_1+{\beta }_1$), making it more prone to pulmonary oedema when combined with volume overload.

clinical pearl

“No BP, No PP” – Once MAP is raised by vasoconstrictors, diuretics can be reintroduced to manage volume overload.

related pages: Hepatorenal syndrome (HRS-AKI)