Continuous Terlipressin Infusion Research Articles

#2564 Terlipressin given by continuous infusion versus boluses in the treatment of hepatorenal syndrome: a systematic review and meta-analysis

Abstract Background and Aims Hepatorenal syndrome (HRS) is one of the complications among patients with cirrhosis. Available guidelines recommended terlipressin with albumin as part of HRS management. To date there is no consensus on whether terlipressin should be given via bolus or continuous intravenous infusion. This study aims to compare the effectiveness and safety of continuous intravenous infusion versus intravenous boluses of terlipressin in the treatment of patients with HRS and cirrhosis. Method A comprehensive search for databases of randomized controlled trials (RCTs) comparing continuous intravenous infusion versus intravenous boluses of terlipressin among adult patients with hepatorenal syndrome was done. PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov were searched using relevant terms including hepatorenal syndrome, acute kidney injury, cirrhosis, terlipressin, bolus, and continuous infusion until December 2023. Response to therapy defined as decrease in serum creatinine or regression of acute kidney injury was the primary outcome of interest, while safety in terms of drug-related events, mortality, and transplant-free survival were the secondary outcomes. Data extraction was performed using a standardized data form. The reviewers independently screened the studies and assessed the methodological quality using the Cochrane Risk of Bias tool and any discrepancies were resolved by consensus among the authors. Random-effects meta-analysis was done using Review Manager 5.4. Results A total of three studies, one high quality and two moderate quality RCTs, were included in the review, involving a total of 240 patients. Pooled analysis showed that continuous infusion was as effective or better than bolus infusion in achieving the primary outcome (RR 1.12, 95% CI 0.95-1.32, I2 = 0%). In one study, 28- and 90-day mortality were not significantly different, while 90-day transplant-free survival was not significantly different between continuous and bolus groups from another trial (53% vs 69% p = 0.26). Higher incidence of adverse events were also reported in the bolus group, RR 0.37, 95% CI 0.13-1.04 (p = 0.06). Conclusion There is limited evidence to suggest that continuous infusion of terlipressin may demonstrate resolution of acute kidney injury more frequently than bolus infusion, and that continuous infusion is associated with decreased adverse events. Larger randomized controlled trials with higher quality are needed to ascertain the effects on mortality, need for renal replacement therapy, and transplant-free survival.

Safety and efficacy of continuous terlipressin infusion in HRS-AKI in a transplant population.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and as such was assessed in a population comprised of liver transplant (LT) candidates. Fifty hospitalized, LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. ACLF grade 3, serum creatinine (SCr)>5.0mg/dL, or MELD≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide (M&O) or norepinephrine (NorEpi) for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as ≥30% decrease in SCr with EOT SCr≤1.5, partial response (PR) as ≥30% decrease in SCr with EOT SCr>1.5, and non-response (NR) as <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p<0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p=0.12; D90: 78% vs. 68%, p=0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p<0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1mg/dL, p<0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical M&O/NorEpi cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders.

Continuous home terlipressin infusion increases handgrip strength and reduces ascites-A prospective randomized crossover study.

Observational studies suggest a beneficial effect of continuous terlipressin infusion (CTI) on ascites and sarcopenia in decompensated cirrhosis with portal hypertension. This single-center, prospective, cross-over study randomized 30 patients with cirrhosis, ascites, and sarcopenia to commence on 12 weeks of home CTI or 12 weeks of observation prior to cross-over. The co-primary outcomes were change in handgrip strength and paracentesis volume. Secondary outcomes included quality of life, sarcopenia measures, renal function, safety, and hospitalization. The median age of participants was 62 years (IQR: 57-64), the median Model for End-Stage Liver Disease-Sodium was 16 (12.3-20.8), and 22 (73%) were male. Handgrip strength increased by a mean adjusted difference (MAD) of 3.09 kg (95% CI: 1.11-5.08 kg) between CTI and observation ( p =0.006); an 11.8% increase from baseline. The total volume of ascites drained decreased by a MAD of 11.39L (2.99-19.85, p =0.01), with 1.75 fewer episodes of paracentesis (0.925-2.59, p <0.001) on CTI. Serum creatinine decreased, urinary sodium excretion increased, and quality of life was significantly higher on CTI (all p <0.001), with an increase in Chronic Liver Disease Questionnaire score of 0.41 points (0.23-0.59). There were 7 minor line-related complications but no cardiac events or pulmonary edema. This novel study demonstrates a significant increase in handgrip strength, reduction in paracentesis volume, and improved quality of life in patients with decompensated cirrhosis treated with continuous terlipressin infusion. These findings provide a strong rationale for the use of ambulatory CTI in appropriately selected patients with cirrhosis.

INFUSE: Rationale and design of a multi-center, open label, collaborative study to treat HRS-AKI with continuous terlipressin infusion

BackgroundHepatorenal syndrome-acute kidney injury (HRS-AKI) carries significant morbidity and mortality among those with end-stage liver disease. Bolus terlipressin for treatment of HRS-AKI received FDA approval in September 2022. US implementation of terlipressin, however, is hindered by the paucity of local data on the optimal patient population and administration mode, as well as the effect on transplant priority. The INFUSE study is designed to evaluate the use of continuous terlipressin infusion among transplant candidates with advanced liver disease and HRS-AKI. MethodsFifty prospective patients with HRS-AKI will receive a single bolus of terlipressin 0.5 mg followed by continuous infusions of terlipressin from 2 to 8 mg/day for up to 14 days. The cohort will be enriched with those listed, in evaluation, or eligible for liver transplantation, while those with ACLF grade 3, MELD ≥35, and serum creatinine >5.0 mg/dL will be excluded. Fifty patients who received midodrine plus octreotide or norepinephrine for HRS-AKI will serve as a retrospective comparator cohort. ConclusionThe INFUSE study aims to assess the safety and efficacy of continuous terlipressin infusion among largely transplant-eligible patients with HRS-AKI, and to provide US-based data on transplant outcomes. This novel study design simultaneously mitigates terlipressin adverse events while providing renal benefits to patients, thus addressing the unmet medical need of those with HRS-AKI who have limited treatment options and are awaiting liver transplantation in the US.

Continuous vs. intermittent terlipressin infusion for portal hypertension: a systematic review and meta-analysis.

Portal hypertension, a major complication of chronic liver disease, often leads to life-threatening variceal bleeding, managed effectively with vasoactive drugs like terlipressin. However, the most optimal method of terlipressin administration, continuous versus intermittent infusion, remains a subject of debate, necessitating this systematic review and meta-analysis for evidence-based decision-making in managing this critical condition. This systematic review and meta-analysis adhered to the PRISMA standards and explored multiple databases until 6 April 2023, such as MEDLINE through PubMed, Scopus, Web of Science, and CENTRAL. Independent reviewers selected randomized controlled trials (RCTs) that met specific inclusion criteria. After assessing study quality and extracting necessary data, statistical analysis was performed using Review Manager (RevMan), with results presented as risk ratios (RR) or mean differences. Five RCTs (n=395 patients) were included. The continuous terlipressin group had a significantly lower risk of rebleeding (RR=0.43, P=0.0004) and treatment failure (RR=0.22, P=0.02) and fewer total adverse effects (RR=0.52, P<0.00001) compared to the intermittent group. However, there were no significant differences between the two groups in mean arterial pressure (P=0.26), length of hospital stays (P=0.78), and mortality rates (P=0.65). This study provides robust evidence suggesting that continuous terlipressin infusion may be superior to intermittent infusions in reducing the risk of rebleeding, treatment failure, and adverse effects in patients with portal hypertension. However, further large-scale, high-quality RCTs are required to confirm these findings and to investigate the potential benefits of continuous terlipressin infusion on mortality and hospital stays.

THE TREATMENT OF HEPATORENAL SYNDROME WITH TERLIPRESSIN: CONTINUOUS INTRAVENOUS INFUSION VS INTRAVENOUS BOLUSES A RANDOMISED CONTROLLED STUDY ON SYNDROME

Objective: Hepatorenal syndrome (HRS) is a severe complication of cirrhosis, with terlipressin and albumin being the most common treatment. The study aimed to compare the effectiveness and safety of continuous intravenous infusion vs. intravenous boluses of terlipressin in treating type 1 h.&#x0D; Methods: A randomized controlled trial was conducted on cirrhosis patients with type 1 h. Patients were allocated to receive terlipressin via continuous infusion (TERLI-INF group) or intravenous boluses (TERLI-BOL group). Demographic, clinical, and laboratory data were collected, and treatment details were recorded. The primary endpoint was the frequency of drug-related adverse events. Secondary endpoints included therapy responsiveness and 90-day transplant-free survival.&#x0D; Results: Both groups exhibited similar baseline characteristics. While treatment length and cumulative albumin doses were comparable, TERLI-INF patients received lower terlipressin doses. Severe treatment-related adverse events differed between groups. Univariate analysis identified several baseline parameters significantly associated with response to terlipressin. The study supports continuous terlipressin infusion's superiority in treating type 1 h, with lower adverse event rates and improved patient response.&#x0D; Conclusion: The study concludes that continuous intravenous terlipressin infusion is safer and more effective in treating type 1 h in decompensated cirrhosis patients compared to intravenous boluses. Lower terlipressin dosages were effective in continuous infusion, indicating improved safety. The MELD score was an independent predictor of response, and therapy responsiveness was associated with improved 90 d survival.

Comparison of Norepinephrine &amp; Terlipressin vs Norepinephrine Alone for Management for Septic Shock

Introduction: Sepsis is a clinical syndrome that has physiologic, biologic, and biochemical abnormalities caused by a dysregulated inflammatory response to infection. The present study aimed to estimate the dose of injection of norepinephrine in micrograms/ kg/min after 12 hours of starting the vasopressor infusion to keep an MAP of above 65 mm Hg. Materials &amp; Method: The study was done for the period of two years. Patients who were 18 years and above; who were diagnosed with septic shock during their ICU course and whose relatives gave informed written consent were included in the study. Result: Total of 12 patients were lost during the study period and so in total 100 patients were enrolled for the study. Both the groups were comparable with respect to the MAP (p = 0.655). The norepinephrine dose in group I vs group II at 12 hours was found to be 0.163 ± 0.089 vs 0.396 ± 0.18 μg/kg/min (p &lt;0.001). Reduction in blood lactate concentration in 12 hours was significantly higher in group I [1.479 ± 1.46] than group II [0.08 ± 1.50] mmol/L (p = 0.002). Increase in the urine output of the patients in 12 hours in Group I [0.72 ± 0.44] than group II [0.47 ± 0.460] mL/kg/hour (p = 0.001). Conclusion: A low-dose continuous infusion of terlipressin may have a significant role in ensuring better organ perfusion, preventing renal injury, and improving the SOFA score of the patients when used in adjunct to norepinephrine, early in the management of septic shock.

SAT-543 - Continuous terlipressin infusion improves muscle function but not muscle mass in patients with cirrhosis and portal hypertension

SAT-543 - Continuous terlipressin infusion improves muscle function but not muscle mass in patients with cirrhosis and portal hypertension

Comparison of Norepinephrine and Terlipressin vs Norepinephrine Alone for Management of Septic Shock: A Randomized Control Study.

PurposeTo compare norepinephrine and terlipressin vs norepinephrine alone for management of septic shock.Materials and methodsIn this prospective, randomized control trial, 50 adult patients with septic shock were randomized into two groups. Group I received a combination of injection terlipressin 0.02 µg/kg/min (fixed dose) infusion and injection norepinephrine 0.01 µg/kg/min infusion and group II received injection norepinephrine 0.01 µg/kg/min infusion alone. Dose of noradrenaline in both the groups was titrated to achieve the target MAP of 65–70 mm Hg. The data collected were the dose of norepinephrine required to maintain an MAP of above 65 mm Hg, urine output, serum lactate, procalcitonin level, C-reactive protein, sequential organ failure assessment (SOFA) score, total duration of vasopressor support, and incidences of the adverse effects.ResultsThe norepinephrine dose in group I vs group II at 12 hours was found to be 0.141 ± 0.067 vs 0.374 ± 0.096 µg/kg/min (p ≤0.005). The serum lactate was lower, and urine output was higher in group I than group II (p <0.05). Group I had a significantly greater reduction in SOFA score in 12 hours than group II. Group I patient also had a significant decrease in the duration of vasopressor administration than group II patients being discharged from the ICU. However, there was no difference in the mortality between the two groups during their ICU stay.ConclusionA low-dose continuous infusion of terlipressin and norepinephrine could help attain early resuscitation goals for managing patients with septic shock.How to cite this articleSahoo P, Kothari N, Goyal S, Sharma A, Bhatia PK. Comparison of Norepinephrine and Terlipressin vs Norepinephrine Alone for Management of Septic Shock: A Randomized Control Study. Indian J Crit Care Med 2022;26(6):669–675.

Abstract No.: ABS0369: Comparison of norepinephrine and terlipressin versus norepinephrine alone for management of septic shock: A randomised control study.

Background and Aims:Terlipressin, a V1 receptor-selective analogue of vasopressin, can produce potent vasoconstriction of blood vessels and can reduce the dose of norepinephrine required for maintaining the mean arterial pressure (MAP) and organ perfusion in septic shock, thus avoiding its side effects.Methods:In this prospective, randomised control trial, 50 adult patients with septic shock were divided into two groups. Group 1 received a combination of terlipressin 0.02 µg/kg/min (fixed dose) infusion and noradrenaline 0.01–3.0 µg/kg/min infusion intravenously. Group 2 received intravenous noradrenaline 0.01–3.0 µg/kg/min infusion alone. Noradrenaline in both groups was targeted to achieve an MAP of 65–70 mm of Hg. The data collected were the dose of noradrenaline required to maintain an MAP of above 65 mm of Hg, urine output, serum lactate, procalcitonin level, C-Reactive protein, sequential organ failure assessment score (SOFA) score, total duration of the vasopressor support, and incidence of adverse effects.Results:The noradrenaline dose in group 1 versus group 2 at 12 hours was found to be 0.141 ± 0.067 vs 0.374 ± 0.096 µg/kg/min (p=<0.005). The blood lactate concentration was significantly lower, and the urine output was higher in group 1 than in group 2 (p=<0.005). Group 1 had a significantly greater reduction in SOFA score in 12 hours than group 2. However, there was no difference in the mortality between the two groups during their intensive care unit stay.Conclusion:A low-dose continuous infusion of terlipressin along with norepinephrine could help attain better organ perfusion and early resuscitation goals for management of patients with septic shock without causing the side effects related to catecholamines.

End-stage liver disease: Management of hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a serious complication of cirrhosis with high morbidity and mortality rates. Recently, the definition of HRS type 1 has been updated and is now called HRS-AKI.This new definition reduces the risk of delaying HRS treatment and eliminates the need to establish a minimum creatinine cut-off for the diagnosis of HRS-AKI. From a pathophysiological point of view, newly identified mechanisms involved in the development of HRS are related to the inflammatory response, conditioning the development of extrahepatic organ dysfunction in patients with cirrhosis. One of the main challenges for the diagnosis of HRS is the validation of new biomarkers to obtain an early and differential diagnosis of kidney injury (eg HRS vs. ATN). Treatment of HRS is based on the use of vasoconstrictive agents in combination with albumin and terlipressin is the most widely used vasoconstrictor drug, with a high response rate. The effects of a continuous infusion of terlipressin at a dose of 2-12mg/day was similar to bolus administration, but with lower rates of adverse events. Finally, MELD/MELD-Na which includes creatinine as one of its main determinants gives AKI-HRS patients priority on the waiting list (WL) for liver transplant (LT). However, the MELD and MELD-Na scores are reduced in responding patients, resulting a longer waiting time in these patients than in non-responders. Thus, the initial MELD/MELD-Na score (pre-treatment value) should be used to prioritize patients on the WL for LT in these cases.

Safety and efficacy of outpatient continuous terlipressin infusion for the treatment of portal hypertensive complications in cirrhosis.

Therapeutic options are limited for patients with hepatorenal syndrome (HRS), diuretic refractory ascites and hepatic hydrothorax who are awaiting liver transplant. We assessed the safety and efficacy of continuous terlipressin infusion (CTI) for treating these conditions in an outpatient setting. All patients treated with CTI from May 2013 through March 2018 at our institution were initiated in-hospital on bolus dose terlipressin therapy for 24-72 h prior to commencing CTI for home therapy. Daily home visits for clinical assessment and medication administration were provided. Adverse events, effects of treatment on renal function, model for end-stage liver disease (MELD) score, and paracentesis/thoracentesis requirements were assessed. Twenty-three patients were included (HRS = 17; refractory ascites = 4; refractory hepatic hydrothorax = 2). Median (range) duration of outpatient CTI was 50 (1-437) days with a total of 2482 patient days of treatment. Fourteen patients (60.9%) received a liver transplant; of whom 13 (92.9%) were alive at the end of the study period. There were no cardiac or ischemic complications and no serious adverse events reported. In patients with HRS, median serum creatinine significantly decreased from 202.0 μmol/L at baseline to 125.5 μmol/L at day 14 of CTI (P = 0.0003) and remained stable thereafter. Median MELD score decreased from 22.5 to 19.0 at end of CTI (P = 0.008). Median frequency of paracentesis/thoracentesis was 4 per month prior to CTI versus 1.52 during treatment. Transplant-eligible and otherwise stable patients can be managed with CTI at home for an extended duration under supervision without adverse consequences.

Continuous infusion of terlipressin for hepatorenal syndrome therapy: evaluation of efficacy and safety in real-life setting

Continuous infusion of terlipressin for hepatorenal syndrome therapy: evaluation of efficacy and safety in real-life setting

A prospective study of the effect of terlipressin on portal vein pressure and clinical outcomes after hepatectomy: A pilot study

BackgroundPortal hypertension after hepatectomy is associated with impaired postoperative recovery. Terlipressin decreased portal vein pressure in patients with variceal bleeding and improved patient survival, but the role of postoperative terlipressin treatment for patients who underwent liver resection is not clear. MethodsWe determined the effect of terlipressin on portal vein pressure in patients with portal vein pressure >12 mmHg after hepatectomy. If portal vein pressure was decreased (ie, Responders), a continuous infusion of terlipressin at 2 mg/day for 4 days was given. The incidence of posthepatectomy liver failure, abdominal drainage, acute kidney injury, operative complications, and side-effects of terlipressin in the Responders were compared with those whose portal vein pressure did not decrease (ie, non-Responders) and patients whose portal vein pressure was ≤12 mmHg after hepatectomy (low portal vein pressure group). ResultsWe recruited 110 patients, 65 of whom were eligible for terlipressin administration. Portal vein pressure decreased in 46 patients (71%) with the mean portal vein pressure decreasing from 15.8 ± 2.6 mmHg to 14.3 ± 2.9 mmHg (P < .001). The median [interquartile range] postoperative abdominal drainage for the first 3 postoperative days was less in the Responders than in the non-Responders (350 mL [228–573] vs 730 mL [330–980]; P = .004). Incidence of posthepatectomy liver failure in the Responders was less than the non-Responders (26% vs 53%, P = .04). Acute kidney injury, operative complications, and side-effects of terlipressin were not different between groups. ConclusionTerlipressin decreased posthepatectomy portal vein pressure and may decrease the incidence of posthepatectomy liver failure and postoperative abdominal drainage (NCT03352349).

Continuous terlipressin infusion is associated with improved diet intake and muscle strength in patients awaiting liver transplant.

Background & AimsPortal hypertension contributes to the pathogenesis of malnutrition and sarcopenia in cirrhosis via multiple mechanisms. Terlipressin is a vasopressin analogue that we administer via continuous outpatient infusion, as a bridge to transplantation in patients with hepatorenal syndrome or refractory ascites. We describe, for the first time, the impact of outpatient terlipressin on nutritional and muscle parameters.MethodsNutrition (subjective global assessment), handgrip strength, dietary intake (energy, protein), frequency of paracentesis and severity of liver disease (model for end-stage liver disease score) were prospectively recorded at terlipressin commencement and follow-up (transplantation, cessation or census date).ResultsNineteen patients were included (89% male, median age 59.6 years, median model for end-stage liver disease score 24), of whom 12 had hepatorenal syndrome and 7 had refractory ascites. All patients were malnourished at baseline, 63% (n = 12) had sarcopenic-range grip strength, and mean paracentesis frequency was 2.86 ± 1.62/month. Median duration of terlipressin was 51 days (interquartile range 29–222). Fourteen patients (74%) were transplanted, 2 delisted (10%) and 3 (16%) continued terlipressin. Energy and protein intake improved significantly following terlipressin, from 17.94 ± 5.43 kcal/kg to 27.70 ± 7.48 kcal/kg, and 0.74 ± 0.28 g/kg to 1.16 ± 0.31 g/kg, respectively (both p < 0.001). Handgrip strength increased from 25.36 ± 8.13 kg to 28.49 ± 7.63 kg (p = 0.001). Linear regression analysis demonstrated hand grip strength increased 0.075% for every 1-day of terlipressin (p = 0.005). The frequency of large-volume paracentesis reduced by 46%, to 1.57 ± 1.51/month (p = 0.001).ConclusionContinuous terlipressin infusion reduces the complications of portal hypertension and is associated with an improvement in nutritional and muscle parameters in patients on the liver transplant waiting list, in whom such characteristics usually demonstrate progressive decline. This validates both the aetiological role of portal hypertension in malnutrition and represents a promising new anabolic therapy.Lay summaryMalnutrition and poor muscle strength are common in liver disease and often get worse while patients await liver transplant. Terlipressin is a medication used to treat portal hypertension in patients with hepatorenal syndrome. It is usually given for a few days or weeks in patients confined to hospital. Our centre provides outpatient terlipressin for weeks to months as a bridge to liver transplant. In patients treated with terlipressin at our hospital, we observed a substantial increase in their dietary intake and muscle strength, which may improve their quality of life and outcomes after liver transplant.

Renal dysfunction and cirrhosis.

Hepatorenal syndrome (HRS) does not represent the predominant phenotype of acute kidney injury (AKI) in cirrhosis. Early recognition of HRS helps initiate appropriate therapy. The aims of this review are to present redefinition of AKI, to list new biomarkers, to report recent data on vasopressors in HRS and to propose criteria for simultaneous liver and kidney transplantation (SLKT). Urine output, which was not part of the definition of AKI might be reconsidered as it has an independent prognostic value. Biomarkers (NGAL and IL-18) could help identify ATN. However, cut-off values have to be clarified. Vasopressors with albumin represent first option in HRS. Continuous infusion of terlipressin has a better safety profile than intravenous boluses. SLKT should be considered whenever native kidney recovery is unlikely [i.e. prolonged renal replacement therapy (RRT) and/or GFR less than 25 ml/min for 6 weeks prior to transplantation]. New definitions and recent biomarkers may help differentiate HRS from ATN at an earlier stage. Urine output should be reconsidered in the definitions. Even in patients who are not candidates for transplantation, a short trial of RRT is justified whenever needed. SLKT should be considered whenever posttransplant renal recovery is unlikely.

Hemodynamic effects of continuous versus bolus infusion of terlipressin for portal hypertension: A randomized comparison

The hemodynamics of patients with portal hypertension within 4 h after a single injection of terlipressin has been studied. However, the hemodynamics in a longer phase under different infusion styles is unknown. This study aims to compare the effects of bolus and continuous infusion of terlipressin on systemic and hepatic hemodynamics in patients with portal hypertension. Twenty patients who underwent transjugular intrahepatic portosystemic shunt procedure were randomly assigned to be treated with either intravenous bolus infusion of terlipressin (1 mg) followed by a continuous infusion (4 mg/24 h, n = 10), or intravenous bolus injection of terlipressin (2 mg) followed by intermittent injections (1 mg/6 h, n = 10). The mean arterial pressure, heart rate, and portal venous pressure (PVP) were monitored and recorded at baseline, 1 min, 5 min, 10 min, 30 min, and then once an hour. Serum renin activity, serum angiotensin II, and aldosterone levels were measured prior to and 24 h after the administration of terlipressin. PVP dropped rapidly in both groups, and reduced 16.46% and 28.22%, respectively, at the 1-h time point. Thereafter, PVP remained stable in continuous group while rebounded obviously in intermittent group. One hour after the start of drug administration, heart rate decreased significantly in both groups (84.1 ± 12.8 vs 73.8 ± 12.6 in intermittent group and 86.7 ± 11.5 vs 77.1 ± 13.6 in continuous group, P < 0.005), and mean arterial pressure increased in both groups, although no statistical differences were found. Continuous infusion of terlipressin reduces PVP stably and may become an alternative to traditional bolus injection.

Terlipressin in the treatment of late phase catecholamine-resistant septic shock.

Norepinephrine, but also dopamine and epinephrine are recommended as first line vasopressors in the treatment of septic shock. In some patients, septic shock deteriorates and becomes to be resistant to catecholamines. In this situation, addition of vasopressin or terlipressin can be advantageous. The aim of our pilot study was to evaluate the impact of terlipressin on open label norepinephrine requirements and mortality. In a randomized, controlled, single centre study we assigned patients with late advanced septic shock refractory to catecholamines (norepinephrine >0.6µg/kg/min for more than 24h) to receive either continuously terlipressin 4mg/24h for 72 hours in addition to open label norepinephrine (TERLI group) or to continue therapy only with catecholamines (CON group). All vasopressor infusions were titrated to maintain a target blood pressure. We enrolled 30 patients, of whom 13 were assigned to terlipressin and in 17 we continued in catecholamine therapy. There was no significant difference in norepinephrine consumption between the groups. Open label norepinephrine infusion rates decreased significantly in the TERLI group as compared with initial consumption, but the decrease we observed only in 7 (54%) patients. There was no significant difference between groups in the rate of death at day 28 (77% in TERLI group and 94% in CON group; p=0.18) or at day 90 (91% vs. 94%; p=0.85). Continuous terlipressin infusion was not effective in reducing norepinephrine consumption or in the mortality of patients, if administered in late phase of catecholamine refractory septic shock.

Effects of two different dosing regimens of terlipressin on organ functions in ovine endotoxemia

To test the hypothesis that a continuous infusion of the vasopressin analog terlipressin is associated with less organ dysfunction as compared to intermittent bolus infusion in an ovine sepsis model. Twenty-seven adult female sheep. All sheep were subjected to a Salmonella typhosa endotoxin infusion (10 ng/kg/min). After 16 h of endotoxemia, the surviving animals (n = 24) were randomized to (1) an untreated control group, (2) a continuous terlipressin group (2 mg/24 h), or (3) a terlipressin bolus group (1 mg/6 h). Hemodynamic variables were measured and blood was withdrawn at specific time points for the assessment of organ functions. Continuous terlipressin infusion was associated with improved surrogate parameters of myocardial, renal, and hepatic function as compared with terlipressin bolus infusion. Reduced vascular hyperpermeability was evidenced by an attenuated decrease in plasma protein concentrations in sheep treated with continuous terlipressin infusion as compared to bolus injection or no treatment. Continuous infusion of low-dose terlipressin preserved several surrogate parameters of organ function better than intermittent bolus injections in sheep with systemic inflammation.

Continuous Terlipressin Infusion as Rescue Treatment in a Case Series of Children with Refractory Septic Shock

Despite intensive therapy, refractory pediatric septic shock has a high rate of morbidity and mortality. Additional treatments are needed to improve outcomes in such cases. To report the clinical effects of continuous terlipressin infusion as rescue treatment for children with septic shock refractory to high catecholamine doses. Sixteen episodes of catecholamine-resistant septic shock were recorded in 15 children (aged from newborn to 15 years) who received compassionate rescue treatment with terlipressin at 6 pediatric intensive care units. Terlipressin treatment consisted of a loading dose (20 μg/kg) followed by continuous infusion at a rate of 4-20 μg/kg/h. Terlipressin was titrated at increases of 1 μg/kg/h to maintain mean arterial pressure (MAP) in normal range for age and to reduce catecholamine dosage. The main outcome was survival of the episode. Secondary outcomes included hemodynamic effects, ischemia, and terlipressin-related adverse events. Terlipressin increased median MAP from 48 (range 42-63) to 68 (45-115) mm Hg 30 minutes after terlipressin administration (p < 0.01). MAP was subsequently sustained, which allowed for the reduction of norepinephrine infusion from 2 μg/kg/min (1-4) at baseline to 1.5 μg/kg/min (0.4-4) at 1 hour, 1.3 μg/kg/min (0-8) at 4 hours, 1 μg/kg/min (0-2) at 12 hours, 0.45 μg/kg/min (0-1.4) at 24 hours, and 0 μg/kg/min (0-0.6) at 48 hours (p < 0.05 vs baseline in all cases). In 8 (50%) of the 16 septic shock episodes the patients survived, 7 (44%) without sequelae. One patient survived with sequelae (minor amputation and mild cutaneous ischemia). Eight patients had signs of ischemia at admission; terlipressin induced reversible ischemia in another 4 patients. Meningococcal infection, prior ischemia, and MAP were risk factors for mortality. Continuous terlipressin infusion may improve hemodynamics and survival in some children with refractory septic shock. Terlipressin could contribute to tissue ischemia.