OBJECTIVE: Cardiac dysfunction is a key factor in the pathogenesis of hepatorenal syndrome, for which terlipressin is the recommended first-line treatment. This study investigates whether long-term terlipressin can ameliorate the subclinical cardiac dysfunction observed in decompensated cirrhosis.
METHODS: Twenty-two patients with decompensated cirrhosis and ascites enrolled in a prospective study of home continuous terlipressin infusion were included. Cardiac function was assessed using dobutamine stress echocardiogram before and after 12 weeks of terlipressin. The primary outcome was the impact of terlipressin on cardiac reserve; the change in cardiac output (CO) in response to stress.
RESULTS: Median age was 61 years (IQR 56-64), median MELD score was 15 (IQR 12.3-17.0) and 72.7% were male. The increase in CO in response to low-dose dobutamine was significantly higher following terlipressin (↑4.0L/min [↑57.8%]) as compared to baseline (↑1.8L/min [21.3%], p=0.0001). The proportion of patients with impaired cardiac reserve (defined by ΔCO <25% after low-dose dobutamine) reduced from 81.8% at baseline to 40.9% after terlipressin, (p=0.02), driven primarily by improvement in inotropic function. Resting cardiac output (CO) decreased significantly after terlipressin from 8.9±2.2L/min to 7.2±1.8 L/min (p<0.001, normal range 5-6L/min), due to a decrease in stroke volume from 108 to 86mL/beat (p=0.006).
CONCLUSIONS: Long-term continuous terlipressin infusion resulted in a significant increase in cardiac reserve and attenuation of the hyperdynamic state usually observed in decompensated cirrhosis. These data provide important mechanistic insight into the pathogenesis and reversibility of cardiac dysfunction in cirrhosis. Future studies are required to evaluate whether long-term terlipressin can prevent hepatic decompensating events such as hepatorenal syndrome in high-risk individuals. ANZCTR NUMBER: (http://www.anzctr.org.au/): ACTRN12619000891123.

Terlipressin is an analogue of vasopressin that is indicated as first-line therapy for variceal hemorrhage and hepatorenal syndrome. Hyponatremia is an uncommon complication of terlipressin because it has less effect on vasopressin V2 receptors located in the kidneys. Profound hyponatremia related to terlipressin use is a rare complication that needs to be aware of. We described a 35-year-old previously healthy man, who was admitted for esophageal variceal bleeding that was attributed to hepatitis B-related liver cirrhosis. He had a normal baseline sodium level (Na 139 mmol/L) and developed severe hyponatremia 119 mmol/L (euvolemic, hypo-osmolar) at 72 hours of terlipressin therapy. After holding the medication, the hyponatremia corrected rapidly to 135 mmol/L within 24 hrs. Terlipressin was given again as therapy for overcorrection of hyponatremia and the sodium level decreased before being stabilized without neurological consequences. Severe hyponatremia is an uncommon complication of terlipressin therapy; however, our case emphasizes the importance of sodium monitoring during terlipressin therapy in all patients to prevent this complication, and more importantly, to avoid rapid correction that could happen after holding it.

UNASSIGNED: Type 1 hepatorenal syndrome (HRS) is a rapid deterioration in kidney function in patients with cirrhosis. Data on efficacy of vasoconstrictors for type 1 HRS have shown mixed results.
UNASSIGNED: Literature searched for randomized controlled trials comparing pharmacological therapy for HRS vs placebo or another drug for HRS. Primary outcome was HRS reversal (serum creatinine <1.5mg/dL on 2 readings), and secondary outcomes were liver transplant (LT) free survival and serious adverse events (SAE).
UNASSIGNED: Sixteen studies on 1244 patients (mean age 50.3 yrs., 67.5% males, serum creatinine of 3.07 mg/dL, serum sodium 127.2 mEq/liter, and Model for End-stage Liver Disease (MELD) score of 30.9, and Child-Pugh score 11) with type 1 HRS treated with vasoconstrictors vs placebo or another drug were analyzed. All the patients received intravenous albumin infusion. (A) terlipressin vs placebo: Odds of HRS reversal were 3.3 folds with terlipressin without difference on LT-free patient survival. Terlipressin was associated with higher odds of SAE. (B) Nor-epinephrine (NE) vs terlipressin: No difference on HRS reversal, LT-free survival, and SAE. (C) Terlipressin or NE vs midodrine and octreotide: 91% lower odds of HRS reversal with midodrine and octreotide. There were no differences on SAE (10 of 64 vs 10 of 58, P = .812). Non-responders vs responders had higher mean MELD score (29 vs 27.8), P = .014 and serum creatinine (3.5 vs 3.1), P = .027.
UNASSIGNED: Terlipressin and NE are similar and superior to midodrine octreotide combination for HRS reversal. No therapy improves LT-free patient survival. Response to treatment is better with lower baseline serum creatinine and MELD score. The risk of adverse effects is similar with terlipressin and NE. Studies are needed as basis to identify candidates with best response to treatment with excellent safety profile.

UNASSIGNED: Although terlipressin is known to cause bradycardia, this adverse effect is usually described in association with hypertension and is considered a benign compensatory response mediated by arterial baroreceptors. Cardiac monitoring for patients receiving terlipressin is not routinely recommended.
UNASSIGNED: A 77-year-old female patient with no history of coronary artery disease and no other coexisting risk factors for cardiac arrhythmias or conduction disturbances was admitted to intensive care unit with severe cholangitis, complicated by variceal bleeding. She developed severe sinus bradycardia following the use of terlipressin, which was associated with significant hypotension that required the infusion of norepinephrine. The bradycardia occurred again when terlipressin therapy was reattempted.
UNASSIGNED: Vasopressin is known to sensitize baroreceptor reflexes by a central mechanism though its actions on V1a receptors in the area postrema, and we speculate that vasopressin analogues such as terlipressin may act in the same manner. That this effect is not widely described in terlipressin safety literature may be due to the overall younger age range of the trial population. This raises the possibility that cardiac monitoring may be warranted for elderly patients receiving terlipressin.

Acute kidney injury (AKI) is a common complication among patients with decompensated cirrhosis and its development is associated with worse prognosis in terms of survival. Patients with decompensated cirrhosis may develop a unique type of AKI, known as hepatorenal syndrome (HRS-AKI), characterized by marked impairment of kidney function due to haemodynamic changes that occur in late stages of liver cirrhosis. Besides, patients with cirrhosis also may develop chronic alterations of kidney function (chronic kidney disease, CKD), the incidence of which is increasing markedly and may be associated with clinical complications. The aim of this review is to provide the reader with an update of the most relevant aspects of alterations of kidney function in patients with cirrhossi that may be useful for theri clinical practice.

UNASSIGNED: Despite having ample literature in hepatorenal syndrome-acute kidney injury (HRS-AKI) in decompensated cirrhosis patients, there is a scarcity of data on acute-on-chronic liver failure-acute kidney injury (ACLF-AKI). We compared terlipressin infusion with bolus in ACLF-AKI patients.
UNASSIGNED: Patients with ACLF (as per the CANONIC study) were screened for AKI as per the 2015 ICA-AKI criteria. If after 48 h of volume expansion with albumin, serum creatinine (sCr) did not improve, patients were randomized into two groups: Terli-infusion (Terli-I) 2 mg/day and Terli-bolus (Terli-B) 1 mg q6h. If sCr did not decrease < 25% of pretreatment value after 48 h, the terlipressin dose was increased to a maximum of 12 mg/day. The primary outcome was taken as regression (full or partial response), stable/no response and progression of AKI to higher stages and secondary outcomes were taken as 28-day and 90-day mortality.
UNASSIGNED: After screening 136 patients with ACLF-AKI, Terli-I (n = 50) and Terli-B (n = 50) with mean sCr 2.4 and 2.1 mg/dl respectively were enrolled. The regression of AKI (full response 37 vs. 27, partial response 3 vs. 9, p = 0.5), stable (2 vs. 5, p = 0.6), progression of AKI (8 vs. 7, p = 0.2) were present in Terli-I and Terli-B respectively. No significant difference was found in 28-and 90-day mortality. In Terli-B, mean terlipressin dose was 8 vs. 4 mg, p < 0.008 with more side effects, 15 vs. 0, p < 0.01 than Terli-I respectively.
UNASSIGNED: Terlipressin infusion is more effective than bolus doses in regression of acute kidney injury and better tolerated in acute-on-chronic liver failure-AKI patients.

Hepatorenal syndrome (HRS) is a feared complication in patients with advanced cirrhosis and is associated with significant morbidity and mortality. While recognized as a distinct physiologic condition for well over one hundred years, a lack of objective diagnostic tests has made the diagnosis one of exclusion. Since 1979, multiple sets of diagnostic criteria have been proposed. Though varying in detail, the principal intent of these criteria is to identify patients with severe, functional acute kidney injury that is unresponsive to volume resuscitation and exclude those with structural injury. However, accurate differential diagnosis remains challenging. Recently, multiple urinary biomarkers of kidney injury, including neutrophil gelatinase-associated lipocalin, have been studied as a means of objectively phenotyping etiologies of acute kidney injury in patients with cirrhosis. Along with markers reflecting tubular functional integrity, including the fractional excretion of sodium, injury markers will likely be incorporated into future diagnostic criteria. Making an accurate diagnosis is critical, as therapeutic options exist for HRS but must be given in a timely manner and only to those patients likely to benefit. Terlipressin, an analog of vasopressin, is the first line of therapy for HRS in much of the world and has recently been approved for use in the United States. Significant questions remain regarding the optimal dosing strategy, metrics for titration, and the potential role of point-of-care ultrasound to help guide concurrent albumin administration.

OBJECTIVE: Terlipressin infusion is effective in hepatorenal syndrome (HRS-AKI). However, its efficacy for HRS-AKI resolution in acute-on-chronic liver failure (ACLF) patients has been suboptimal. Progression of AKI is rapid in ACLF. We investigated whether early initiation of terlipressin(eTerli) can improve response rates.
METHODS: Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation (40 g) were randomized to receive terlipressin at 2 mg/24 h plus albumin at 12 h (ET, n = 35) or at 48 h as standard therapy (ST, n = 35). (June 22, 2020 to June 10, 2022). The primary end-point was AKI reversal by day7.
RESULTS: Baseline parameters including AKI stage and ACLF-AARC scores in two arms were comparable. Full AKI response at day 7 was higher in ET [24/35 (68.6%)] than ST arm [11/35 (31.4%; P 0.03]. Day3 AKI response was also higher in ET arm [11/35 (31.4%) vs. 4/35 (11.4%), P 0.04]. Using ST compared to ET [HR 4.3; P 0.026] and day 3 serum creatinine > 1.6 mg/dl [HR 9.1; AUROC-0.866; P < 0.001] predicted HRS-AKI non-response at day 7. ET patients showed greater improvement in ACLF grade, mean arterial pressure, and urine output at day 3, and required lower albumin within 7 days than ET arm (149.1 ± 41.8 g vs. 177.5 ± 40.3 g, P 0.006) and had lower 28-day mortality: 40% vs. 65.7%, P 0.031]. Early use of terlipressin than ST [HR 2.079; P 0.038], baseline HE [HR 2.929; P 0.018], and AKI persistence at day 3 [HR 1.369; P 0.011] predicted 28-day mortality. Fifteen (21.4%) patients had treatment related adverse effects, none was life threatening.
CONCLUSIONS: In ACLF patients, early initiation of terlipressin for AKI persisting after 12 h of volume expansion with albumin helps in reduced short-term mortality and early AKI reversal with regression of ACLF stage. These results indicate need for change in current practice for terlipressin usage in HRS-AKI.

BACKGROUND: Hepatorenal syndrome (HRS), a multiorgan condition of acute kidney injury, is seen in advanced liver disease. This study aims to evaluate the current treatment for HRS.
METHODS: The authors searched PubMed, Scopus and Google Scholar literature. After quality assessment, 31 studies were included in this review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology and the population, intervention, comparison and outcome scheme were used. We included human-controlled trials that evaluate the current treatment for HRS. Two authors independently screened articles for inclusion, extracted data and assessed the quality of included studies.
RESULTS: This study investigated the studies conducted on the effects of different treatments on follow-up of HRS patients. We gathered 440 articles, so 31 articles remained in our study. Of which 24 articles were conducted on terlipressin versus placebo or other treatments (midodrine/octreotide, norepinephrine, etc) that showed the higher rate of HRS reversal was detected for terlipressin in 17 studies (10 of them were significant), 2 studies achieved an insignificant lower rate of the model for end-stage liver disease score for terlipressin, 15 studies showed a decreased mortality rate in the terlipressin group (4 of them were significant).
CONCLUSIONS: This review showed that terlipressin has a significantly higher reversal rate of HRS than the other treatments. Even the results showed that terlipressin is more efficient than midodrine/octreotide and norepinephrine as a previous medication, in reverse HRS, increasing patient survival.

BACKGROUND: Liver disease causes 2 million deaths annually, accounting for 4% of all deaths worldwide. Liver surgery is one of the effective therapeutic options. Bleeding is a major complication during liver surgery. Perioperative bleeding and allogeneic blood transfusion may deteriorate the prognosis. Terlipressin (TP), a synthetic analogue of the antidiuretic hormone, may reduceblood loss during abdominal surgery. Several clinical centres have attempted to use TP during liver surgery, but the evidence for its effectiveness in reducing blood loss and the need for allogeneic blood transfusion, as well as its safety during the perioperative period, remains unclear. The aim of this systematic review and meta-analysis is to evaluate the efficacy and safety of TP in reducing blood loss and allogeneic blood transfusion needs during liver surgery.
METHODS: We will search PubMed, EMBASE, the Cochrane Library and Web of Science for studies on perioperative use of TP during liver surgery from inception to July 2023. We will limit the language to English, and two reviewers will independently screen and select articles. The primary study outcomes are estimated blood loss and the need for allogeneic blood transfusion. Secondary outcomes include operating time, intensive care unit stay, length of stay, intraoperative urine output, acute kidney injury rate, postoperative complications, hepatic and renal function during follow-up, and TP-related adverse effects. We will include studies that met the following criteria: (1) randomised controlled trials (RCTs), cohort studies or case-control studies; (2) the publication time was till July 2023; (3) adult patients (≥18 years old) undergoing elective liver surgery; (4) comparison of TP with other treatments and (5) the study includes at least one outcome. We will exclude animal studies, case reports, case series, non-original articles, reviews, paediatric articles, non-controlled trials, unpublished articles, non-English articles and other studies that are duplicates. We will use Review Manager V.5.3 software for meta-analysis and perform stratification analysis for the study quality of RCTs based on the Jadad score. For cohort or case-control studies, the study quality will be analysed based on Newcastle-Ottawa Scale scores. Grading of Recommendations, Assessment, Development and Evaluation will be used to assess confidence in the cumulative evidence. For primary outcomes, we will conduct subgroup analyses based on meta-regression. We will also perform leave-one-out sensitivity analyses to evaluate the effect of each individual study on the combined results by removing the individual studies one by one for outcomes with significant heterogeneity. The protocol follows the Cochrane Handbook for Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guidelines.
BACKGROUND: This study is a secondary analysis of existing data; therefore, it does not require ethical approval. We will disseminate the results through peer-reviewed publications.
UNASSIGNED: CRD42023450333.