Terlipressin has Stood the Test of Time

Clinical Overview in 2020 and Future Perspectives

Anand V. Kulkarni; Juan Pablo Arab; Madhumita Premkumar; Carlos Benítez; Sowmya Tirumalige Ravikumar; Pramod Kumar; Mithun Sharma; Duvvuru Nageshwar Reddy; Douglas A. Simonetto; Padaki Nagaraja Rao

Disclosures

Liver International. 2020;40(12):2888-2905. 

In This Article

Evidence for the Role of Terlipressin in Liver Disease

Hepatorenal Syndrome

HRS-1, recently renamed as HRS-AKI (acute kidney injury), is defined as an increase in serum creatinine (sCr) by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 hours; or, a percentage increase by ≥50% from an sCr obtained within the prior 3 months and/or urine output ≤0.5 mL/kg bodyweight for ≥6 hours.[18] This should be in the context of cirrhosis or acute-on-chronic liver failure (ACLF) or acute liver failure (ALF) with no partial or full response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin (1 g per kg of body weight), in the absence of shock and no current or recent use of nephrotoxic drugs. There should also be no evidence of parenchymal kidney disease as indicated by the absence of proteinuria (>500 mg/day), microhematuria (>50 RBCs per high power field), urinary injury biomarkers (if available) and a normal renal ultrasound.[18]

HRS-1 patients are frequently oliguric with avid sodium retention and yet may maintain a relatively normal GFR or may have an increased urine output because of diuretic treatment. Hence, the initial definition included only the dynamic changes in sCr for diagnosing AKI in cirrhosis.[19] The International club of ascites (ICA) also did not include ACLF or ALF patients, urine output criteria and urinary biomarkers, which is now part of the proposed new diagnostic criteria.[18]

HRS-1 is a consequence of splanchnic and systemic arterial vasodilation along with a reduced mean arterial pressure (MAP) and cardiac output, which leads to a marked decrease in effective circulating volume.[20,21] This component of HRS is potentially reversible with vasoconstrictors. Vasoconstrictors counteract the effects of intense splanchnic vasodilatation and increase the effective arterial blood volume, thereby suppressing endogenous renal vasoconstrictors and improving the renal function (Figure 1).[22] Terlipressin is probably the most commonly used drug for HRS outside the USA.

HRS-2 was recently renamed as HRS-NAKI (HRS-non-acute kidney injury).[18] HRS-NAKI comprises two forms of chronicity. Patients with cirrhosis having an eGFR <60mL/min/1.73 m3 for >3 months in the absence of parenchymal/structural damage are labelled as HRS-CKD (chronic kidney disease). If the eGFR <60mL/min/1.73 m3 for <3 months, then they are labelled as HRS-AKD (acute kidney disease).[18] The pathophysiology of HRS-AKI and HRS-NAKI is the same, but why certain patients progress to HRS-CKD is unknown. In a prospective study of 501 cirrhosis patients with AKI, 53% and 16% were diagnosed as prerenal AKI and HRS-AKI respectively. The remaining were diagnosed as acute tubular necrosis (ATN). Thirty-three per cent developed CKD and the median time to development of CKD was 173 days. Baseline MELD, serum cystatin C and the number of episodes of AKI predicted the development of CKD. Interestingly neither diabetes mellitus nor hypertension were significant predictors on multivariate analysis.[23]

Role of Terlipressin in Hepatorenal Syndrome. Several studies on cirrhotic patients with HRS-1 have shown a variable response to terlipressin (Table 1). HRS reversal, defined as a decrease in serum creatinine to ≤1.5 mg/dL (≤133 μmol/L), is reported among 35%-80% with terlipressin therapy.[2,3,24,25] The response to terlipressin in HRS-2 seems to be similar to HRS-1, but the risk of recurrence is high (~50% vs 8% in HRS-1).[26] HRS-1 reversal with terlipressin is as high as 80%, and there seems to be a definite survival benefit with terlipressin and albumin when compared to placebo (or no treatment), albumin alone or terlipressin alone.[2,5,27–30] There is no survival benefit reported when compared to other vasoconstrictors.[3,27,31–34] Terlipressin plus albumin is more effective than midodrine/octreotide plus albumin in improving renal function in patients with HRS-1.[3] In patients awaiting liver transplantation (LT), response to terlipressin may reduce the model for end-stage liver disease (MELD/MELD-Na) score.[35] Consequently, terlipressin responders may have a prolonged waiting list time and are disadvantaged in a MELD score-based allocation system. This represents an important issue against the use of terlipressin. In contrast, a recent study by Piano et al have shown that terlipressin non-responders developed severe AKI frequently requiring renal replacement therapy (RRT), and a greater number of non-responders progressed to CKD post-LT.[36] Terlipressin responders had longer waiting list time and lower MELD at LT. But terlipressin response was associated with better transplant-free survival at day 30 and lesser incidence of CKD/requirement of RRT post-LT. Hence, terlipressin response is crucial for both pre- and post-LT outcomes. It may be worth considering HRS as a MELD exception or weighted pretreatment sCr value (similar to RRT) for MELD calculation and prevent HRS patients from being disadvantaged.[37]

The recent CONFIRM trial recruited 300 cirrhotic patients with HRS-1.[6] The study was a multicentre, double-blind, randomised controlled trial conducted in North America. HRS-1 was defined as rapidly deteriorating renal function to sCr ≥2.25 mg/dL, with an actual or projected doubling of SCr within 2 weeks, without improvement in renal function (<20% decrease in SCr 48 hours after both diuretic withdrawal and albumin-fluid challenge) in adult patients with cirrhosis and ascites. Subjects were randomised in 2:1 ratio. Terlipressin was given as 1 mg every 6th hourly for 14 days. The mean baseline MELD score was 33 in both the groups.[6] The baseline sCr was similar in both the groups (3.5 mg/dL). The primary endpoint was verified HRS reversal (VHRSR) defined as two consecutive sCr ≤1.5 mg/dL at least 2 hours apart, with subjects being alive without the need for renal replacement therapy for the next 10 days. The trial reported VHRSR in 29.1% in the terlipressin group compared to 15.8% in the placebo arm (P = .01). The trial also reported 36.2% HRS reversal in the terlipressin group (of 199 patients) compared to only 16.8% in the placebo group (of 101 patients) (P < .001). However, a similar number of patients (~28% in each group) were alive without a liver transplant at day 90. Terlipressin was also effective in reversing HRS in patients with systemic inflammatory response syndrome (SIRS). VHRSR-SIRS was documented in 33.43% in the terlipressin group compared to 6.3% in the placebo group. Also, the requirement of RRT was significantly lower in the terlipressin group.

In another multicentre study of 203 patients with HRS-AKI, terlipressin responders had better survival at 3 months. The median time to terlipressin response was 8 days, and 50% of patients achieved a complete response.[38] While only 23% of the 22 patients who were treated with other vasoactive agents achieved a complete response. Twenty-five per cent in the terlipressin arm and 40% in other vasoconstrictor group developed adverse events. The main drawback of the study was the small size in other vasoconstrictors group. And of those 22 patients treated with other vasoconstrictors, 60% had received vasopressin therapy, which precludes the conclusion about efficacy and safety.

A network meta-analysis of 16 trials concluded that terlipressin combined with albumin has strong evidence of improving short-term survival in patients with type 1 but not type 2 HRS.[39] Rates of complete HRS reversal were significantly higher with terlipressin and noradrenaline combined with albumin than octreotide/midodrine and placebo.[39–41] There is a significant benefit in short-term mortality with terlipressin and albumin compared to placebo.[40] However, in a recent network meta-analysis of 25 RCTs and 1263 participants of cirrhosis with HRS comparing 12 different interventions concluded that noradrenaline plus albumin should be compared with terlipressin plus albumin in future trials. The analysis suggested a lower number of adverse events with noradrenaline.[42] However, noradrenaline has a half-life of 1–2 minutes, and noradrenaline infusion requires central line insertion and regular intensive care monitoring, which is a significant disadvantage.[43] Noradrenaline, an economical choice, has efficacy similar to terlipressin and is associated with lower adverse events without any added mortality benefit.[27] However, RCTs with a sufficient sample size are needed comparing noradrenaline vs terlipressin to assess the mortality benefit.

Method of Terlipressin Dosing in HRS. The dosing of terlipressin also plays an important role. Gerbes et al first reported the advantages of continuous infusion of terlipressin.[44] Of the 32 consecutive patients with HRS treated with continuous terlipressin (starting dose, 3 mg/day, and increased by 1 mg/day in case of non-response), 42% achieved reversal of HRS. Adverse events were noted in only 9%.

In an RCT by Cavallin et al, 78 patients with HRS were randomised to receive either terlipressin boluses (0.5 mg every 4th hourly) or continuous infusion of terlipressin (2 mg/day).[45] The rate of response to terlipressin therapy was similar in both groups. But the incidence of adverse effects was significantly higher in the bolus group. Only 35% in the infusion group developed side effects, while 62% in the bolus group developed adverse effects. Furthermore, the effective daily dose of terlipressin was lower in the infusion group (2.23 mg/day) than the bolus group (3.51 mg/day). A single dose of terlipressin bolus (1 to 2 mg) suppresses the portal pressure for a maximum duration of 3–4 hours and maintains the elevated MAP for 1 hour.[46] Continuous infusion maintains a sustained suppression of portal pressure and high MAP throughout the infusion. A lower dose of terlipressin (per day) is required with continuous infusion for HRS reversal, and this low dose leads to a lesser incidence of adverse events.[44,45] Hence, it is certain that the employment of a continuous infusion is advantageous.

Predictors of HRS Reversal. Specific clinical and biochemical variables can aid in predicting response to terlipressin. As most of these variables are non-modifiable (except albumin infusion), these predictors can only assist clinicians in prognosticating and planning the management of patients with HRS.

Lower MELD and sCr at baseline predict HRS reversal and survival in patients with HRS.[24,47] Younger patients and Child score of <13 have higher chances of HRS reversal.[2,28] Furthermore, terlipressin responders have better survival till 1 year.[2,28,30,48,49] Concomitant albumin infusion improves the systemic haemodynamics, suppresses the neurohormonal activity and improves the GFR.[28,48] Hence, concomitant albumin administration increases the chance of HRS reversal and survival.[28,30,48] Each dose of terlipressin rises the MAP by at least 3 mm Hg.[24] However, a rise in MAP by >5 mm Hg at day 3 is required to achieve terlipressin response.[49] A higher sCr, total leucocyte count (TLC) and lower urine output at baseline predict non-response to terlipressin therapy.[30] A higher TLC and lower urine output indicate sepsis/variceal bleed-induced ATN, which poorly responds to vasoconstrictor therapy.[50] Pooled individual data analysis from two major trials supported the lack of prior rifaximin use as a predictor of HRS reversal.[5] The plausible explanation is patients who are not using rifaximin are usually less sick and, hence, have a higher chance of HRS reversal.[5] However, this unique finding has not been reported in any other study and needs further validation. (The predictors from each study have been shown in the last column of Table 1.)

Terlipressin in ACLF With HRS. The published literature on the use of terlipressin for HRS-1 in ACLF is limited. The response to terlipressin is poorer in ACLF patients (32%-53% HRS reversal) compared to decompensated cirrhotics.[51] The reason for this inadequate response is the different mechanisms of renal failure in ACLF patients. ACLF patients have profound inflammation and invariably high bilirubin and cholestasis. The microvascular dysfunction and inflammation amplify the effects of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) on the proximal tubule.[18] This leads to mitochondria-mediated metabolic downregulation and the reprioritisation of cell functions favouring survival processes above all others. The absorption of sodium and chloride on the luminal side is, therefore, sacrificed. The increased delivery of sodium chloride to the macula densa triggers further intrarenal activation of the renin-angiotensin system and lowers the GFR.[18] Lastly, cholestasis in ACLF may further impair renal function by worsening inflammation, macrovascular dysfunction or by promoting bile salt-related direct tubular damage.[52] These features are dominant in ACLF patients, even in the absence of circulatory dysfunction, and may lead to reduced response to vasoconstrictors. Furthermore, HRS-AKI may evolve to non–HRS-AKI and the duration of HRS increases unresponsiveness to these agents with time.[53] Hence, it is necessary to diagnose HRS early, and initiation of vasoactive agents early may improve the response. A randomised controlled trial (ClinicalTrials.gov Identifier: NCT04416282) on early initiation of terlipressin in ACLF patients with AKI is underway.

Rodriguez et al were the first to demonstrate the safety and efficacy of terlipressin in ACLF patients with sepsis.[54] Eighteen consecutive ACLF patients with sepsis and HRS-AKI were treated with 1 mg terlipressin every 4th hour. The dose was increased to 2 mg every 4th hourly if the sCr did not decrease by 25% by day 3. HRS reversal was achieved in 67% and was associated with improved 3-month survival compared to non-responders. Transient bradycardia and abdominal pain were commonly reported adverse events.[54] ACLF patients have a poorer response to terlipressin therapy and a higher rate of progression to stage III AKI.[51] Piano et al analysed 298 ACLF patients with AKI treated with terlipressin and albumin.[55] The study included both bolus and infusion dosing. Fifty-three per cent of patients responded to treatment.

More recently, an open-labelled randomised trial compared terlipressin infusion (n = 60) with noradrenaline infusion (n = 60) for ACLF patients with HRS.[56] Terlipressin led to 40% reversal in HRS compared to only 16.7% in the noradrenaline group. Further terlipressin also reduced the need for RRT. Fifty-six per cent in the terlipressin group and 80% in the noradrenaline group required RRT. Terlipressin therapy was also associated with improved 28-day survival when compared to noradrenaline (48.3% vs 20%; P = .001).[56] Patients with sepsis-related HRS-AKI had a lower response rate to therapy (22.41%) than non-sepsis–related AKI (33.87%). Data on terlipressin in ACLF with HRS have been detailed in Table 2.[51,54–56]

Predictors of HRS Reversal in ACLF. Chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score, baseline sCr and ACLF grade predict the response to terlipressin therapy in ACLF.[54,55] The response to terlipressin inversely correlates with the grade of ACLF.[51,55] Furthermore, ACLF grade and terlipressin non-response predict 90-day mortality.[55] It is important to note that terlipressin non-response can predict mortality and, hence, non-responders need to be prioritised for LT. In the study comparing noradrenaline against terlipressin for ACLF patients with HRS, MELD score and noradrenaline therapy predicted non-response.[56] The use of noradrenaline also predicted higher mortality. However, this the only trial to support the superiority of terlipressin with a mortality benefit in ACLF.[56]

Acute Variceal Bleed

Terlipressin increases the tone in both vasal and extra-vasal smooth muscles.[57] The contraction of the oesophageal muscles compresses the oesophageal varices.[57] Terlipressin acts on V1 receptors located on the arterial smooth muscle in the splanchnic circulation.[57] This leads to vasoconstriction in the superior mesenteric artery and celiac trunk vascular bed, reducing the splanchnic perfusion and portal vein pressure (Figure 1).[12,57]

Freeman et al published the first landmark trial.[58] Terlipressin controlled bleeding in 70% of patients compared to only 9% in the vasopressin group.[58] Terlipressin was given 2 mg every 6th hourly till the bleeding ceased, ie stabilisation of haemodynamic measures with no visible loss of fresh blood. This was followed by another three doses of terlipressin 1 mg given 6th hourly for 18 hours. The median time to rebleed after initial control was 72 hours in the terlipressin group compared to 26 hours in the vasopressin group.[58] Some of the landmark trials[58–64] are described in Table 3.

Terlipressin is superior to vasopressin and placebo in controlling variceal bleed.[58–60] Terlipressin is also associated with mortality benefit when compared to placebo.[60] However, the efficacy of terlipressin in controlling variceal bleed is similar to somatostatin and octreotide.[61–64]

A Cochrane review reported a 34% decrease in all-cause mortality with terlipressin therapy in AVB compared to placebo.[65] Terlipressin may be the vasoactive agent of choice in AVB, as no other vasoactive agents have shown to reduce the mortality either in single studies or meta-analysis. A network meta-analysis of 37 studies reported terlipressin as the best vasoactive agent to control the variceal bleed.[66] Terlipressin is the only vasoactive intervention associated with a significant reduction in the rebleeding rate and the need for blood transfusions.[66] Although the adverse events are more frequent with terlipressin therapy.[66] Terlipressin is one of the first-line treatment in controlling variceal bleed.[7,8,67] Octreotide is preferred in some countries for variceal bleed primarily as a result of its safety profile and unavailability of terlipressin.[8,64]

Method of Terlipressin Dosing in AVB. A recent randomised trial of 86 patients compared continuous infusion of terlipressin against bolus dosing of terlipressin for control of AVB.[68] Terlipressin was administered at 1 mg bolus followed by 4 mg/day infusion, and the other group received 2 mg bolus followed by 1 mg QID. Both groups received treatment for 5 days. Treatment failure at 5 days was significantly lower in infusion group (4.7%) than bolus group (21%). Rebleeding at 6 weeks was also lower in the infusion group (11.6%) than the bolus group (28%). However, mortality at 6 weeks and adverse effects were similar in both groups. Sustained reduction in portal pressure with continuous infusion is beneficial in AVB. However, in the absence of sufficient evidence to support the continuous infusion, intermittent bolus dosing is the recommended method of dosing. The recommended dose of terlipressin in variceal bleed is 2 mg QID during the first 48 hours, followed by 1 mg QID for the next 72 hours.[7,8,67]

Septic Shock

Catecholamine responsiveness may decrease over time during severe sepsis, possibly as a result of an increase in nitric oxide (NO)–induced vasodilation, hypoxia and receptor internalisation. As a result, patients may develop septic shock that is resistant to catecholamine treatment.[12] Furthermore, there is relative vasopressin deficiency in septic shock, leading to worsening of haemodynamics.[12] Terlipressin acting through V1 receptors leads vasoconstriction, rises the MAP, prevents NO release and prevents rebound hypotension.[12,69]

In an open-labelled RCT of 84 patients, 50% of patients were randomised to terlipressin (2–8 mg over 24 hours) and the other 50% to noradrenaline.[70] Ninety-three per cent of patients in the terlipressin group were able to maintain the MAP >65 mm Hg for 48 hours compared to only 69% in noradrenaline group. Furthermore, terlipressin led to improved survival at 48 hours but not at 28 days. The adverse events were significantly high (40%) and occurred early, ie within a median time of 6 hours in the terlipressin group.[70] While in noradrenaline group, 21.4% developed adverse effects at a median time of 21 hours. Terlipressin may be safe and effective in cirrhotic patients with septic shock. However, a combination of terlipressin and noradrenaline may be further evaluated to reduce the adverse effects associated with terlipressin and validate the utility of terlipressin in cirrhotics with septic shock.

Refractory Ascites and Hepatic Hydrothorax

Terlipressin has been shown to increase the GFR, urinary sodium excretion and contain the vasodilatory and antinatriuretic systems in cirrhotics with ascites.[10] A pilot study of 26 cirrhosis patients with refractory ascites without HRS reported increased urinary sodium excretion and ascites control with terlipressin therapy.[71] Terlipressin was administered at a dose of 0.5–1 mg QID for 3 weeks. Sixty-one per cent of patients achieved ascites control, which was defined comprehensively as a 4-fold increase in urinary sodium excretion along with improvement in ascites grade, reduction in body weight and a 10% reduction in abdominal circumference.[71] Fifteen per cent developed adverse effects (abdominal pain and diarrhoea). Another small study of 5 patients with refractory ascites reported a significant reduction in the volume and number of paracentesis with ambulatory terlipressin infusion for 4 weeks.[72] Terlipressin improves the MAP, 24-hours urine output and ascites control.[73] Terlipressin also leads to a reduction in sCr in patients with refractory ascites and AKI.[73]

One of the mechanisms of hydrothorax formation is the pressure-gradient–directed flow through diaphragmatic defects, which is reduced by targeting the portal pressure and controlling ascites.[74] Terlipressin is useful in hepatic hydrothorax caused by its vasoconstrictor effect on mesenteric vessels.[74] Although transjugular intrahepatic portosystemic shunt (TIPS), alfa pump and midodrine are effective non-transplant alternatives available for refractory ascites, terlipressin may be one of the choices for treating refractory ascites who have concomitant AKI and high MELD.[7,75]

Paracentesis-induced Circulatory Dysfunction

Paracentesis causes mechanical decompression of the splanchnic vascular bed leading to vasodilation, a further decrease in the arterial filling and activation of neurohormonal systems.[43] These haemodynamic alterations lead to paracentesis-induced circulatory dysfunction (PICD). Two pilot studies on PICD comparing terlipressin vs albumin infusion concluded that terlipressin is as efficacious as albumin in preventing PICD.[76,77] Moreau et al included 20 cirrhosis patients (10 in each arm), and Singh et al recruited 40 cirrhosis patients (20 in each arm) undergoing large-volume paracentesis.[76,77] In both the studies, terlipressin was administered as an intravenous bolus of 1 mg each at the onset of paracentesis, at 8 and 16 hours after the first bolus. In comparison, the other group of patients received albumin infusion at a dose of 8 g/L of ascitic fluid tapped. A similar number of patients developed PICD in both groups. Terlipressin administration immediately before ascites removal prevents paracentesis-induced arteriolar vasodilation and subsequent decrease in effective arterial blood volume and rise in plasma renin activity.[76] In a network meta-analysis of nine RCTs, low-quality evidence supported midodrine as superior and economical to albumin to prevent PICD.[78] However, albumin remains the drug of choice and is recommended for the prevention of PICD.[7]

Perioperative use in Liver Transplantation

Haemodynamic alterations are common during liver transplantation. Terlipressin leads to a reduction in portal blood flow and pressure during recipient hepatectomy, thereby decreases blood loss and the need for blood transfusion.[79] It also improves the MAP, systemic vascular resistance and reduces the need for vasopressors post-surgery.[80–82] Its use in the post-transplant period has been hypothesised to decrease graft injury owing to portal hyperperfusion, decrease residual portal hypertension and improve renal blood flow.[79–81,83,84]

In a study of 30 living donor liver transplant (LDLT), recipients with portal pressure >20 mm Hg, 15 recipients were randomly allocated to receive terlipressin and the other 15 patients to saline.[79] An initial bolus dose of terlipressin 1 mg followed immediately by a continuous infusion of 2 μg/kg/h for 48 hours was administered. Portal pressure decreased significantly from 26.3 to 21.3 mm Hg with terlipressin but remained unchanged in the control group. The Control group required higher amounts of colloids and norepinephrine than the terlipressin group. Serum creatinine and cystatin C were significantly elevated in the control group, with a concomitant decline in creatinine clearance (CrCl). However, the CrCl was similar at discharge in both groups. Perioperative use of terlipressin during LDLT abrogates the early post-operative decline in renal function without any detrimental effect on hepatosplanchnic gas exchange and lactate metabolism.[79]

In another open-labelled RCT of 50 LDLT recipients, terlipressin was compared with placebo.[80] Terlipressin was infused at the beginning of surgery at a dose of 1 μg/kg/h and later titrated (1–4 μg/kg/h) to maintain a MAP of >65 mm Hg and systemic vascular resistance index (SVRI) <2600.dyne.s/cm5/m2 which was calculated by transoesophageal echocardiography till 4th post-operative day. Norepinephrine was added if the MAP dropped to <65 mm Hg. Eighty per cent in the control group required norepinephrine, while only 20% in the terlipressin group required norepinephrine. Urea, creatinine and urine output (UOP) were significantly better with terlipressin. Terlipressin reduced the peak portal vein blood flow velocity (PPV) without hepatic artery vasoconstriction and improved post-operative UOP. Another study involving 80 patients undergoing LDLT in which terlipressin was administered until the third post-operative day reported similar outcomes.[81] Terlipressin reduced the incidence of AKI post-operatively in a study of 303 patients undergoing LDLT.[83]

However, a double-blind RCT involving 41 patients reported higher adverse events with terlipressin.[84] Terlipressin reduced the post-operative ascitic drain output resulting in less frequent percutaneous interventions and reduced hospital stay. But terlipressin therapy resulted in significant intraoperative hyperlactatemia and symptomatic bradycardia.[84] On the contrary, a higher number of patients in the placebo group developed AKI. The use of terlipressin in LDLT should be restricted to patients with high-volume ascites with strict close monitoring during drug infusion.

Perioperative use in Hepatobiliary Surgery

Post-hepatectomy liver failure is a common occurrence, especially if the liver function is compromised prior to surgery. Minor elevations of portal venous pressure after partial hepatectomy is pivotal for the initiation of liver regeneration.[85] Conversely, extended liver resections or small-for-size liver transplantations that are associated with a marked increase in portal pressure may impair the regenerative capacity of the liver and lead to liver failure. Terlipressin in the immediate post-operative period prevents an early rise in portal pressure. The reduction in elevated portal pressure after major hepatectomy by terlipressin is associated with increased hepatocellular proliferation and increased survival.[86] Mechanistically, terlipressin alleviates IL-6 mRNA expression following hepatectomy and downregulates p21 and GADD45 mRNA suggesting a reduction in cell cycle inhibition and cellular stress.[86] Reduction in elevated portal pressure post-hepatectomy by the use of terlipressin improves liver regeneration both in lean and steatotic mouse livers.[86]

Beneficial effects have been demonstrated with the perioperative use of terlipressin in patients undergoing hepatobiliary surgery in a double-blind RCT.[87] The terlipressin group received an initial bolus dose of 1 mg over 30 minutes, followed by a continuous infusion of 2 μg/kg/h throughout the surgery. The drug was gradually weaned over the first 4 post-operative hours. The control group received an equivalent dose of normal saline. An equal number of patients underwent liver resection, right hepatectomy, left hepatectomy and Whipple's surgery in both the groups. Terlipressin reduced the portal pressure, maintained the MAP, reduced the blood loss and maintained the UOP better during the surgery and on the first post-operative day. However, there was no difference in the incidence of AKI in either group. Neither any patients developed adverse events such as intestinal hypoperfusion or hyperlactatemia. Intraoperative infusion of terlipressin during hepatobiliary surgery may improve the portal haemodynamics with a subsequent reduction in blood loss.[87]

Another similar double-blind placebo-controlled randomised study on terlipressin infusion during major liver resection reported less blood loss and blood transfusions in the terlipressin group.[88] Terlipressin infusion during major hepatobiliary surgery and liver transplantation has several benefits, but owing to its associated adverse effects, terlipressin is generally not recommended in routine practice.

Acute Liver Failure

Acute liver failure (ALF) is a state of unbalanced vasodilatation that leads to systemic and splanchnic hyperperfusion.[89] Encephalopathy in patients with ALF is associated with cerebral oedema and high intracranial pressure (ICP).[90] Terlipressin has been used in ALF patients with hypotension as an add-on therapy to noradrenaline.[89] Terlipressin increases cerebral perfusion pressure with little influence on intracranial pressure (ICP) and cerebral lactate in ALF patients.[89] Contrary to this, terlipressin at a dose that did not alter systemic haemodynamics resulted in the worsening of cerebral hyperaemia by increasing cerebral blood flow and intracranial hypertension in patients with ALF and severe hepatic encephalopathy.[91] Thus, terlipressin should be used with caution in ALF patients with norepinephrine refractory shock.[92]

Other uses of Terlipressin in Cirrhosis

Porto-pulmonary Hypertension. Terlipressin has been used in Porto-pulmonary hypertension (PoPH). The proposed mechanism is the differential action of terlipressin in patients with pulmonary hypertension as a result of receptor remodelling. Vasopressin mediates vasoconstriction in the systemic circulation via the G protein-coupled V1 receptor on vascular smooth muscle cells. In the pulmonary circulation, vasopressin causes vasodilatation, but only in preconstricted pulmonary arteries.[93] This effect can be significantly attenuated by blocking the V1 receptor, suggesting that vasopressin acts via the V1 receptor to increase NO production and cause pulmonary vasodilation.[93] The other proposed mechanism is arginine–vasopressin induced dose-dependent pulmonary arterial vasoconstriction in animal models without pulmonary hypertension, possibly via activation of V2 receptors, overriding an initial V1-stimulated vasodilatory response which is reversed in the presence of pulmonary hypertension.[94] Further terlipressin reduces the portal pressure and flow, thereby decreasing the azygos blood flow and pulmonary blood flow and pressure.[95]

Twelve cirrhotic patients with a mean pulmonary systolic pressure of 25.5 ± 3.6 mm Hg were treated with 1 mg terlipressin.[95] Forty-one per cent of patients had dyspnoea. Fifty-eight per cent of the patients had a reduction in pulmonary systolic pressure after terlipressin.[95] Two weeks of terlipressin therapy can reduce the mean pulmonary arterial systolic pressure (PASP) along with a significant reduction in pulmonary vascular resistance.[94] More extensive studies are required to validate the use of terlipressin in PoPH.

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