Which Vasoconstrictor Is Preferred For Hepatorenal Syndrome?

Acute kidney injury (AKI) occurs in about 19% of hospitalized patients with cirrhosis, and AKI has a great impact on the prognosis of patients with cirrhosis. Although hepatorenal syndrome (HRS) is not the most common cause of AKI in patients with cirrhosis (approximately 23%), it is the one with the worst prognosis.

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In a prospective cohort study of 562 cirrhotic patients with impaired renal function, the 3-month survival rates for patients with the renal parenchymal disease, hypovolemic renal insufficiency, infection-related renal injury, or HRS were 73% and 46%, respectively. , 31%, and 15%.

Despite its poor prognosis, the essence of HRS is functional renal failure, usually without significant histological damage, which can be reversed with treatment.

The pathophysiology of HRS is mainly that liver cirrhosis with portal hypertension causes bacterial translocation, which induces a large amount of pro-inflammatory molecules reactive nitrogen, and reactive oxygen species, and then visceral vasodilation leads to effective arterial blood volume insufficiency and activation of the vasoconstrictor system, which eventually causes renal artery vasodilation. Contraction, renal hypoperfusion, and decreased glomerular filtration rate. The main goal of treating HRS with vasoconstrictors is to reverse splanchnic vasodilation.

Diagnosis and treatment of cirrhotic AKI

In 2015, the International Ascites Club published its recommendations and management opinions on the diagnosis and classification of cirrhotic AKI. In 2018, the European Association for the Study of the Liver (EASL) made fine adjustments on this basis.

Currently, the diagnostic criteria for AKI in patients with liver cirrhosis are: serum creatinine increased by ≥0.3 mg/dL within 48 hours or increased by ≥50% from baseline in the past 7 days.

For patients with AKI stage 1a, the risk factors for renal damage should be identified and removed first. For patients with stage >1a, diuretics should be stopped, and albumin 1g/kg/d should be given for 2 consecutive days. If renal function recovers after treatment, consider prerenal azotemia.

If the renal function does not improve, there is no shock, recent use of nephrotoxic substances is excluded, and the possibility of substantial renal disease is low (24h urine protein <500 mg, urine sediment RBC count <50/HP, renal ultrasonography is normal), consider HRS diagnosis. In the absence of contraindications, albumin, and vasoconstrictor therapy should be initiated.

For patients with AKI stage 1a who do not recover after initial treatment, further treatment should be considered on a case-by-case basis.

The role of vasoconstrictors in HRS

Although the definitive treatment for HRS is liver transplantation, the pharmacological role of albumin and vasoconstrictors is crucial and can be used as a bridge before liver transplantation, especially given the high short-term mortality of HRS, while liver transplantation donors The waiting time is longer. Studies have shown that vasoconstrictor treatment of HRS can improve patient survival, and there is an association between the increase in mean arterial pressure caused by vasoconstrictors and the decrease in serum creatinine.

Terlipressin, norepinephrine, or midodrine (in combination with octreotide) are recommended vasoconstrictors for HRS and should be administered with albumin to enhance efficacy. The recommended dose of albumin is 1 g/kg (not to exceed 100 g) on the first day, followed by 20-40 g/d. A recent meta-analysis showed that the survival of HRS patients was prolonged with increasing cumulative albumin dose. Based on this, the recommended albumin dosage is 40 g/d.

Terlipressin

Terlipressin, an analog of the pituitary hormone, is the most extensively studied drug in the treatment of HRS. Terlipressin acts as a potent vasoconstrictor by binding to the vasopressin receptor V1. Since its effect on vascular receptor, V1 is much greater than that on renal receptor V2, it can promote selective vasoconstriction of the splanchnic circulation.

A systematic review and Meta-analysis confirmed the efficacy of terlipressin and reduced mortality in HRS patients. Terlipressin may be more effective in critically ill patients, especially those with systemic inflammatory response syndrome and hemodynamic derangements.

The dosage of terlipressin for the treatment of HRS is 0.5-1.0 mg, administered intravenously every 4-6 hours. If the creatinine drops <25%, the dose can be doubled every 2 days, with a maximum of 12 mg/d. Therapy can be continued for 2 weeks, but may be discontinued earlier if HRS is fully reversed. Recurrent HRS can be treated again in the same manner.

In order to reduce adverse reactions, terlipressin can also be continuously infused intravenously, but the curative effect and patient survival rate are not as good as the traditional administration.

Given the potential risks associated with terlipressin, it should not be used in patients with ischemic heart disease, cerebrovascular disease, or peripheral vascular disease.

Norepinephrine

Because terlipressin is not available in many regions and is expensive, studies have evaluated the effect of norepinephrine in the treatment of HRS. Norepinephrine is a catecholamine with predominantly α-adrenergic effects, causing vasoconstriction with less stimulant effect on the myocardium, correcting the low systemic vascular resistance associated with HRS.

For the treatment of HRS, the recommended dose of norepinephrine is 0.5–3.0 mg/h in combination with albumin, with the aim of raising mean arterial pressure by 10 mmHg.

Prior to 2015, no randomized controlled trial (RCT) comparing norepinephrine with terlipressin found a difference in HRS reversal or survival.

However, another RCT published in 2018 that included only HRS-AKI patients meeting the criteria for acute exacerbation of chronic liver failure (ACLF) showed a higher rate of HRS reversal with continuous infusion of terlipressin compared with norepinephrine ( 40.0% vs. 16.7%, p=0.004) and 28-day survival (48.3% vs. 20.0%, p=0.001) were better. These findings may reinforce the notion that terlipressin is more effective in patients with severe inflammatory responses and circulatory disturbances.

In patients with ACLF-induced HRS, ACLF grade was directly associated with mortality and was inversely associated with terlipressin response: in one study, 60% of patients with ACLF grade 1 responded to terlipressin, 3-month mortality was 30%; ACLF grade 2 patients responded to the drug in 48% and mortality was 50%; ACLF grade 3 patients responded to treatment in 29% and mortality was 79%.

Midodrine + Octreotide

Midodrine is an alpha-adrenergic agonist and octreotide is a somatostatin analog. In areas where terlipressin is not available, the two agents are often used in combination to treat HRS. However, in an RCT published in 2015, the study was terminated early because terlipressin was significantly superior to midodrine + octreotide in reversing HRS (55.5% vs. 4.8%, p<0.001). There was also a trend toward improved 3-month survival in the terlipressin group, although this was not statistically significant (59.0% vs. 43.0%, p>0.05).

Therefore, midodrine (oral, initial dose 7.5 mg, tid, maximum dose 12.5 mg, tid) + octreotide (subcutaneous injection, initial dose 100 μg, tid, maximum dose 200 μg, tid) combined with albumin for the treatment of HRS, Only if terlipressin and norepinephrine are contraindicated.

Based on the evidence for the use of different vasoconstrictors in HRS, the figure below provides a selection of vasoconstrictors for HRS.

Summary

In conclusion, the combination of vasoconstrictors and albumin plays an important role in the treatment of HRS. Based on existing studies, terlipressin is the drug of choice in the absence of contraindications and should be used as the first-line drug treatment for HRS. Albumin combined with vasoconstrictors should be started immediately after the diagnosis of HRS to improve the chances of HRS reversal and liver transplantation.

Despite important advances in the treatment of HRS over the past few decades, nearly half of the patients are still ineffective, and further research is still needed in this area.

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