Role of systemic vasoconstrictors in the treatment of AKI HRS
How are systemic vasoconstrictors used in the treatment of AKI HRS?
Vasoconstrictors are the mainstay of treatment for patients with AKI HRS.
Pharmacological Treatment of Hepatorenal Syndrome
|Midodrine||Alpha agonist ↑ blood pressure ↑ renal perfusion pressure||Start with 5 mg tid and titrate to maintain a mean arterial pressure > 70 mm Hg||Used in combination with octreotide. Combination is inferior to continuous infusion of terlipressin.|
|Octreotide||Long-acting analogue of somatostatin ↓ splanchnic vasodilatation||Continuous intravenous infusion of 25 µ g stat followed by 25 µ g/h; or 100 µ g tid subcutaneously||Octreotide alone has been shown to be ineffective as a treatment for HRS.|
|Vasopressin||V1 receptor agonist. Vasoconstriction of systemic and splanchnic circulations||Not commonly used because of ischemic side effects|
|Terlipressin||Vasopressin analogue||0.5–2 mg q4–6 h IV; or continuous intravenous infusion at 2–12 mg/day||Less ischemic side effects than vasopressin. Continuous infusion is better tolerated and more effective at lower doses than IV boluses.|
|Norepinephrine||Alpha, beta-adrenergic agonist. Systemic vasoconstriction||0.5–3 mg/h||Reversal of HRS. No significant ischemic side effects. Equally efficacious as terlipressin.|
HRS , Hepatorenal syndrome; IV , intravenous.
Terlipressin is a vasopressin analogue, which causes vasoconstriction of the splanchnic vessels, thereby correcting one of the fundamental disease processes of cirrhotic pathophysiology.
This improves the central circulation and reduces renal vasoconstriction. A continuous infusion is better tolerated and more effective at lower doses than intravenous boluses.
There are three randomized, controlled trials with 354 patients comparing the effects of
- • terlipressin plus albumin versus albumin alone, or
- • terlipressin versus placebo with or without albumin in both arms, or
- • terlipressin versus placebo with albumin in both arms.
Reversal of AKI-HRS was observed in 24% to 44% without overall survival benefit. The AKI-HRS reversal rate was low, which was partly related to patients stopping treatment early due to significant ischemic side effects or non-reversal of their AKI-HRS. The lack of overall survival benefit may be related to the fact that many of patients still had end-stage liver disease, which was one of the determinants of their survival. However, the use of terlipressin was able to sufficiently prolong patient survival to allow for liver transplant.
A post hoc analysis of the results of one of these studies found that patients with AKI-HRS and systemic inflammatory response syndrome (SIRS) at enrolment were more likely to respond to terlipressin with reversal of their AKI-HRS. This improved response was noted when compared with patients who received terlipressin without SIRS, and those who received albumin plus placebo with or without SIRS. Patients who received terlipressin and responded by reversing their AKI-HRS also survived better. Terlipressin is used as a first-line agent in AKI-HRS everywhere in the world except North America, where it is used only in the context of clinical trials
Norepinephrine and midodrine
These are systemic vasoconstrictors that raise systemic arterial blood pressure and improve renal perfusion pressure. This leads to decreased renal vasoconstriction and increased GFR. Several randomized, controlled trials and a meta-analysis have shown that norepinephrine is as equally efficacious as terlipressin. Midodrine in combination with octreotide was inferior to terlipressin in reversing AKI-HRS in a randomized, controlled trial. It is popular in North America because terlipressin is not commercially available.
Octreotide is an analogue of somatostatin, a hormone involved in regulation of blood vessel tone in the gastrointestinal tract. Octreotide inhibits splanchnic vasodilatation and is used in combination with midodrine to treat AKI-HRS. Octreotide alone has not been shown to be effective in the treatment of AKI-HRS.
Isolated case reports have suggested the use of N-acetylcysteine (NAC) in combination with systemic vasoconstrictors or endothelin-receptor antagonists. This is based on a small case study of 12 patients with AKI-HRS who showed an improvement in serum creatinine after intravenous infusion of NAC, but it is not standard clinical practice at this time.