Effect of terlipressin infusion therapy on recipient's hepatic and renal functions in living donor liver transplantations: Experience from a tertiary hospital.

BACKGROUND: Patients with end-stage liver disease are prone to hemodynamic disturbances which may be aggravated with liver transplantation. Blood pooling in splanchnic area and portal hypertension cause reduction in central blood volume. Terlipressin reduces mesenteric and hepatic blood flow, causing vasoconstriction in the smooth muscles of the arteries in the splanchnic region. OBJECTIVE: We investigated the efficacy of perioperative terlipressin infusion in patients who received living donor liver transplantation (LDLT) on hepatic and renal functions. DESIGN: Retrospective. SETTING: University hospital. METHOD: The study included 86 adult patients who received LDLT, due to end-stage hepatic disease, between April 2014 and July 2016 in our institute. Data were collected by searching the medical archives of patients. A standard anesthesia protocol was administered to all patients. In a selected group of patients, terlipressin infusion was initiated at 3 µg/kg/h, immediately after anesthesia was induced. The dose was halved following arterial anastomosis and was continued at this dose for the subsequent 3 days. Patients who received terlipressin infusion were compared with patients who did not receive it. MAIN OUTCOME MEASURES: There is no evidence in this trial to show evidence of effectiveness as a result of terlipressin infusion. RESULTS: Patients in the terlipressin group were statistically significantly older. Central venous pressure, cardiac index, global end diastolic volume, and extravascular lung volume did not show significant differences between the groups. Urine output was similar in both groups; however, regarding the use of packed red blood cells and fresh frozen plasma, terlipressin group patients needed more packs. Perioperative liver function tests were similar between the groups except for aspartate aminotransferase and alanine aminotransferase values on the first and third postoperative days. CONCLUSION: Terlipressin infusion was not found to be significantly effective among the liver and kidney function tests. LIMITATIONS: This may be a result of randomization defect of our retrospective study design. Many prospective randomized studies should be planned to reach more accurate results.

Terlipressin: Current and emerging indications in chronic liver disease.

Terlipressin is an analogue of vasopressin that has potent vasoactive properties and has been available for use in most countries for nearly two decades. It has both established roles and emerging indications in the management of complications of decompensated chronic liver disease. We explore historic and emerging literature regarding the use of terlipressin for a range of indications including hepatorenal syndrome, portal hypertensive bleeding, and disruptions in sodium homeostasis. Novel methods of infusion-based terlipressin administration including the beneficial effect in reduction of adverse events are explored, in addition to new indications for the use of terlipressin in decompensated cirrhosis in an outpatient setting.

Terlipressin-induced modifications of Doppler ultrasound signals of systemic arteries in preterm infants with vasoactive-resistant patent ductus arteriosus: A pilot study.

PURPOSE: To study the effects of terlipressin (TP) infusion on systemic perfusion, estimated with pulsed-wave Doppler ultrasonography of systemic arteries, in a population of extremely low birth-weight (ELBW) preterm infants with vasoactive-resistant ductus arteriosus. METHODS: This prospective, observational cohort included, during five years, 12 ELBW infants with hemodynamically significant patent ductus arteriosus and absent or reversed diastolic flow at Doppler ultrasonography of systemic arteries, despite treatment and high-dose vasoactive support. We measured flow velocity of the anterior cerebral, right renal, and superior mesenteric arteries before and after TP infusion. Changes were evaluated by Spearman's rho coefficient analysis, Wilcoxon signed-rank, and Friedman test. RESULTS: Time-averaged mean velocity of the renal artery (P = .028) increased, while renal pulsatility (P = .010) and resistance (P = .004) indexes, and cerebral artery resistance index (P = .021) decreased after TP infusion. Time-averaged mean velocity of the anterior cerebral artery proportionately increased with dopamine dose (rho = 0.678; P = .015), but showed opposite shifts after TP (rho = -0.662; P = .024). CONCLUSIONS: These changes suggest that TP may improve systemic perfusion in the ELBW infants with vasoactive-resistant ductus arteriosus.

Role of vasopressin and terlipressin in refractory shock compared to conventional therapy in the neonatal and pediatric population: a systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Vasopressin (AVP) and terlipressin (TP) have been used as last-line therapy in refractory shock in children. However, the efficacy and safety profiles of AVP and TP have not been determined in pediatric refractory shock of different origins. We aimed to assess the efficacy and safety of the addition of AVP/TP therapy in pediatric refractory shock of all causes compared to conventional therapy with fluid resuscitation and vasopressor and inotropic therapy. METHODS: We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) comparing AVP and TP to conventional therapy. MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched up to February 2016. The systematic review included all reports of AVP/TP use in the pediatric population. Reports of clinical trials were pooled using random-effects models and TSA. Main outcomes were mortality and tissue ischemia. RESULTS: Three randomized controlled trials and five "before-and-after clinical" trials (without comparator) met the inclusion criteria. Among 224 neonates and children (aged 0 to 18 years) with refractory shock, 152 received therapy with AVP or TP. Pooled analyses showed no association between AVP/TP treatment and mortality (relative risk (RR),1.19; 95% confidence interval (CI), 0.71-2.00), length of stay in the pediatric intensive care unit (PICU) (mean difference (MD), -3.58 days; 95% CI, -9.05 to 1.83), and tissue ischemia (RR, 1.48; 95% CI, 0.47-4.62). In TSA, no significant effect on mortality and risk for developing tissue ischemia was observed with AVP/TP therapy. CONCLUSION: Our results emphasize the lack of observed benefit for AVP/TP in terms of mortality and length of stay in the PICU, and suggest an increased risk for ischemic events. Our TSA suggests that further large studies are necessary to demonstrate and establish benefits of AVP/TP in children. PROSPERO registry: CRD42016035872.

Terlipressin, a vasoactive prodrug recommended in hepatorenal syndrome, is an agonist of human V1, V2 and V1B receptors: Implications for its safety profile.

Terlipressin is recommended as a gold standard to treat hepatorenal syndrome complicating liver cirrhosis. It is presented as a specific V1A receptor agonist, beyond its enzymatic conversion into lysine8-Vasopressin (LVP), able to counteract the splanchnic vasodilation. However, the complete pharmacological characterization of this drug with respect to the different vasopressin receptor subtypes is missing. We studied terlipressin intrinsic properties, focusing not only on V1A, but also on other vasopressin receptor subtypes. The experimental studies were conducted on rat and human cellular models. Binding experiments were performed on rat liver membranes and CHO cells transfected with the different human vasopressin receptor subtypes. Agonist status was assessed from inositol phosphate or cyclic AMP assays, and measurement of intracellular calcium variations, performed on cultured vascular smooth muscle cells from rat aorta and human uterine artery and CHO cells. Terlipressin binds to the rat and human V1A receptors with an affinity in the micromolar range, a value 120 fold lower than that of LVP. It induces a rapid and transient intracellular calcium increase, a robust stimulation of phospholipase C but with reduced maximal efficiencies as compared to LVP, indicating a partial V1A agonist property. In addition, terlipressin is also a full agonist of human V2 and V1B receptors, with also a micromomolar affinity. CONCLUSIONS: Terlipressin is a non-selective vasopressin analogue, exhibiting intrinsic agonist properties. Its full V2 receptor agonism may result in renal effects potentially aggravating water retention and hyponatremia of cirrhosis.

Effects of terlipressin on patients with sepsis via improving tissue blood flow.

Terlipressin (TP), an analog of arginine vasopressin, was reported beneficial in sepsis patients when combined use with norepinephrine (NE), but the undetermined action, mechanism, and safety limited it to become the first-line vasopressor for sepsis patients. With 32 septic shock patients, we investigated the effects of a small dose of TP (1.3 µg/kg/h) on hemodynamic, tissue blood flow, vital organ function, acid-base balance, and coagulation function to systemically know the beneficial effect and side effects of TP on septic shock. The results showed that as compared with the single use of NE group (17 patients), a small dose of TP (1.3 µg/kg/h) in combination with NE continuous infusion, except for decreasing the mortality and NE requirement, could better improve and stabilize the hemodynamics, improve the tissue blood flow, increase the blood oxygen saturation and urine volume, and decrease the lactate level and complication rate (47% versus 82.3% in NE group). Meanwhile, TP + NE did not induce blood bilirubin increase and platelet count decrease and hyponatremia that vasopressin has. The results show that low dose of TP continuous infusion can help NE achieve the good resuscitation effect by improving tissue blood flow, stabilizing hemodynamics, and protecting organ function in septic shock patients while did not induce the side effects that high dose or bonus of TP or vasopressin induced. Low dose of TP may be recommended as the first-line vasopressor for refractory hypotension after severe sepsis or septic shock.

Stimulation of V1a receptor increases renal uric acid clearance via urate transporters: insight into pathogenesis of hypouricemia in SIADH.

BACKGROUND: Hypouricemia is pathognomonic in syndrome of inappropriate secretion of antidiuretic hormone (SIADH) but the underlying mechanism remains unclear. Based on the previous studies, we hypothesized that V1a receptor may play a principal role in inducing hypouricemia in SIADH and examined uric acid metabolism using a rat model. METHODS: Terlipressin (25 ng/h), a selective V1a agonist, was subcutaneously infused to 7-week-old male Wistar rats (n = 9). Control rats were infused with normal saline (n = 9). The rats were sacrificed to obtain kidney tissues 3 days after treatment. In addition to electrolyte metabolism, changes in expressions of the urate transporters including URAT1 (SLC22A12), GLUT9 (SLC2A9), ABCG2 and NPT1 (SLC17A1) were examined by western blotting and immunohistochemistry. RESULTS: In the terlipressin-treated rats, serum uric acid (UA) significantly decreased and the excretion of urinary UA significantly increased, resulting in marked increase in fractional excretion of UA. Although no change in the expression of URAT1, GLUT9 expression significantly decreased whereas the expressions of ABCG2 and NPT1 significantly increased in the terlipressin group. The results of immunohistochemistry corroborated with those of the western blotting. Aquaporin 2 expression did not change in the medulla, suggesting the independence of V2 receptor stimulation. CONCLUSION: Stimulation of V1a receptor induces the downregulation of GLUT9, reabsorption urate transporter, together with the upregulation of ABCG2 and NPT1, secretion urate transporters, all changes of which clearly lead to increase in renal UA clearance. Hypouricemia seen in SIADH is attributable to V1a receptor stimulation.

Effects of terlipressin as early treatment for protection of brain in a model of haemorrhagic shock.

INTRODUCTION: We investigated whether treatment with terlipressin during recovery from hypotension due to haemorrhagic shock (HS) is effective in restoring cerebral perfusion pressure (CPP) and brain tissue markers of water balance, oxidative stress and apoptosis. METHODS: In this randomised controlled study, animals undergoing HS (target mean arterial pressure (MAP) 40 mmHg for 30 minutes) were randomised to receive lactated Ringer's solution (LR group; n =14; volume equal to three times the volume bled), terlipressin (TERLI group; n =14; 2-mg bolus), no treatment (HAEMO group; n =12) or sham (n =6). CPP, systemic haemodynamics (thermodilution technique) and blood gas analyses were registered at baseline, shock and 5, 30, 60 (T60), 90 and 120 minutes after treatment (T120). After the animals were killed, brain tissue samples were obtained to measure markers of water balance (aquaporin-4 (AQP4)), Na(+)-K(+)-2Cl(-) co-transporter (NKCC1)), oxidative stress (thiobarbituric acid reactive substances (TBARS) and manganese superoxide dismutase (MnSOD)) and apoptotic damage (Bcl-x and Bax). RESULTS: Despite the HS-induced decrease in cardiac output (CO) and hyperlactataemia, resuscitation with terlipressin recovered MAP and resulted in restoration of CPP and in cerebral protection expressed by normalisation of AQP4, NKCC1, TBARS and MnSOD expression and Bcl-x/Bax ratio at T60 and T120 compared with sham animals. In the LR group, CO and blood lactate levels were recovered, but the CPP and MAP were significantly decreased and TBARS levels and AQP4, NKCC1 and MnSOD expression and Bcl-x/Bax ratio were significantly increased at T60 and T120 compared with the sham group. CONCLUSIONS: During recovery from HS-induced hypotension, terlipressin was effective in normalising CPP and cerebral markers of water balance, oxidative damage and apoptosis. The role of this pressor agent on brain perfusion in HS requires further investigation.

Effects of terlipressin on microcirculation of small bowel mesentery in rats with endotoxic shock.

BACKGROUND: Septic shock is still related to unacceptably high morbidity and mortality. Microcirculatory alteration has been demonstrated to be one important reason associated with this evolution. Vasoactive drugs are often used to restore adequate arterial pressure and tissue perfusion in septic shock. To define the roles of different drugs, the effects of terlipressin (TP) on the microcirculation of small bowel mesentery in rats with endotoxic shock were evaluated and compared with those of norepinephrine (NE). METHODS: Twenty-five adult male Wistar rats were randomized to the control (n = 5), TP (n = 10), and NE (n = 10) groups. After endotoxic shock was induced by intravenous lipopolysaccharide administration for 30 min, rats in the NE and TP groups were infused with saline 5 mL/kg/h and simultaneously given NE 4 µg/kg/min or TP 8 µg/kg/h. The mean arterial pressure, heart rate, blood gas analysis, and microvascular blood flow images of small bowel mesentery were recorded. RESULTS: After fluid resuscitation and vasopressor infusion, the mean arterial pressure was restored to the baseline values in the NE and TP groups. In the TP group, the heart rate was significantly lower compared with the NE group (P = 0.013). The proportion of perfused vessels and the microvascular flow index (MFI) were significantly increased; furthermore, the heterogeneity index of small vessels was markedly decreased in both the interventional groups with respect to the control group. Compared with the NE group, the MFI was significantly higher (P < 0.05) and the heterogeneity index was significantly lower (P < 0.05) in the TP group. CONCLUSIONS: Both TP and NE improved hemodynamic and microcirculatory alterations in rats with endotoxic shock. Compared with NE, TP was more effective in promoting MFI and improving the heterogeneity of small bowel mesentery in rats.

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

BACKGROUND AND AIM: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Continuous infusion of terlipressin reduces PVP stably and may become an alternative to traditional bolus injection.

The effect of terlipressin on hepatic hemodynamics in small-for-size livers.

BACKGROUND/AIMS: The aim of this study was to investigate the effect of terlipressin on hepatic hemodynamics in small-for-size livers at early phase after major hepatectomy. METHODOLOGY: Thirty-six rats were divided into treatment group (Group Th) and control group (Group Ch) for hemodynamic study. Hepatic hemodynamic parameters were detected before hepatectomy (baseline values), 30min, 1h, and 2h after reperfusion. Twenty rats were divided into the treatment group (Group Ts) and control group (Group Cs) for survival study. The survival rate and hemodynamic parameters were studied. RESULTS: The 10-day survival rate of the Ts group was significantly higher than that of the Cs group (p<0.05). The portal pressure of Group Th1/2 was significantly lower than that of Group Ch1/2 (p<0.05). Portal pressure of Group Th1 was significantly lower than that of Group Ch1 (p<0.05). The portal blood flow of Group Th1/2 was significantly lower than that of Group Ch1/2, and so was that between Group Th1 and Ch1, (both p<0.05). The portal blood flow of Group Ch1/2 was significantly higher compared to its baseline value (p<0.05). CONCLUSIONS: The survival rate of rats with small-for-size liver can be significantly improved by terlipressin. Terlipressin ameliorates portal hyperperfusion in small-for-size liver by effectively reducing portal pressure and portal blood flow at early phase after hepatectomy.

Vasopressin analogues and V1a receptor agonists in septic shock.

This article reviews the role of arginine-vasopressin and the vasopressin analogue terlipressin as potent alternative vasoconstrictors in the treatment of fluid and catecholamine-refractory septic shock. Terlipressin is the most selective, clinically available V1 receptor agonist, and may be more potent than arginine-vasopressin in restoring catecholamine refractory septic shock. Recent experimental and clinical studies on terlipressin, as well as the possible benefit of selective V1a receptor agonists, are discussed.

Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock.

INTRODUCTION: The present study was designed to determine the effects of continuously infused norepinephrine (NE) plus (1) terlipressin (TP) or (2) arginine vasopressin (AVP) or (3) placebo on sublingual microcirculation in septic shock patients. The primary study end point was a difference of ≥ 20% in the microvascular flow index of small vessels among groups. METHODS: The design of the study was a prospective, randomized, double-blind clinical trial. NE was titrated to maintain mean arterial pressure (MAP) between 65 and 75 mmHg after establishment of normovolemia in 60 septic shock patients. Thereafter patients (n = 20 per group) were randomized to receive continuous infusions of either TP (1 µg/kg/hour), AVP (0.04 U/minute) or placebo (isotonic saline). In all groups, open-label NE was adjusted to maintain MAP within threshold values if needed. The sublingual microcirculatory blood flow of small vessels was assessed by sidestream dark-field imaging. All measurements, including data from right heart catheterization and norepinephrine requirements, were obtained at baseline and 6 hours after randomization. RESULTS: TP and AVP decreased NE requirements at the end of the 6-hour study period. The data are medians (25th and 75th interquartile ranges (IQRs)): 0.57 µg/kg/minute (0.29 to 1.04) vs. 0.16 µg/kg/minute (0.03 to 0.37) for TP and 0.40 µg/kg/minute (0.20 to 1.05) vs. 0.23 µg/kg/minute (0.03 to 0.77) for AVP, with statistical significance of P < 0.05 vs. baseline and vs. placebo. There were no differences in sublingual microcirculatory variables, systemic hemodynamics, oxygen transport and acid-base homeostasis among the three study groups during the entire observation period. The proportions of perfused vessels increased in relation to baseline within all study groups, and there were no significant differences between groups. The specific data were as follows (median (IQR)): 9.7% (2.6 to 19.8) for TP, 8.9% (0.0 to 17.8) for AVP, and 6.9% (3.5 to 10.1) for placebo (P < 0.05 vs. baseline for each comparison), as well as perfused vessel density 18.6% (8.6 to 36.9) for TP, 20.2% (-3.0 to 37.2) for AVP, and 11.4% (-3.0 to 19.4) for placebo (P < 0.05 vs. baseline for each comparison). CONCLUSIONS: The present study suggests that to achieve a MAP of 65 to 75 mmHg in septic patients treated with NE, the addition of continuously infused low-dose TP or AVP does not affect sublingual microcirculatory blood flow. In addition, our results suggest that microcirculatory flow abnormalities are mainly related to other factors (for example, volume status, timing, hemodynamics and progression of the disease) rather than to the vasopressor per se. TRIAL REGISTRATION: ClinicalTrial.gov NCT00995839.

Effects of the vasopressin agonist terlipressin on plasma cAMP and ENaC excretion in the urine in patients with cirrhosis and water retention.

BACKGROUND: Terlipressin is a vasopressin analogue used for its potent V1a effects in cirrhotic patients. Recent data suggest that terlipressin has affinity to renal V2 receptors and modulates Aquaporin 2 (AQP2) expression and free water clearance. Stimulation of renal V2 receptors may also affect sodium transport via the Epithelial Sodium Channel (ENaC). Furthermore, endothelial V2 receptors may indirectly affect proximal sodium handling by increasing plasma cAMP. METHODS: We investigated 18 patients with cirrhosis and ascites before and after infusion of 2 mg of terlipressin. Plasma cAMP and urine AQP2 were measured and a newly developed radioimmunoassay was used to quantify ENaC in the urine. RESULTS: Mean arterial blood pressure increased from 87 ± 15 to 105 ± 19 mmHg, p < 0.001 after terlipressin infusion and GFR increased from 52 ± 6 to 69 ± 9 mL/min, p < 0.01. Urine-ENaC in ng/mmol creatinine increased from 42 ± 6 to 50 ± 7 ng/mmol creatinine, p = 0.05. Urine sodium increased from 43 ± 8 to 62 ± 9 mmol/L, p < 0.01. Plasma cAMP was not affected by terlipressin, 106 (63-673) vs. 103.5 (69-774) pmol/mL, NS. The rise in ENaC excretion correlated with the rise in AQP2 excretion, r = 0.63, p < 0.01. There was a weak correlation between the change in MAP and the rise in AQP2 excretion (p < 0.05). CONCLUSIONS: Increased ENaC excretion suggests increased abundance of ENaC and resultant increased distal sodium reabsorption. The V2 effects of terlipressin are insufficient to stimulate the endothelial V2 receptors since plasma cAMP is unaltered. Despite pronounced V1a and some V2 effects of terlipressin, additional effects on proximal sodium handling are therefore not likely.

Terlipressin facilitates gastric and autonomic system dysfunctions in liver cirrhosis.

BACKGROUND/AIMS: The aim of this study was to evaluate gastric myoelectric activity and autonomic activity in patients with esophageal varices treated by an analogue of vasopressin. METHODOLOGY: Included in this study are 20 patients divided into two groups: Group A: 10 patients treated with terlipressin (the bleeding from oesophageal varices) and Group B: 10 healthy persons matched with age and gender. The studies were performed before and after intravenous administration of vasopressin (VP) analogue. In both groups the fasting plasma levels of vasopressin, adrenaline and noradrenaline were measured by immunochemistry. RESULTS: In group A disturbances of gastric myoelectric activity with high timing of dysrhythmic pattern were observed before VP. VP administration further increased the timing of gastric dysrhythmia from 35 ± 16 to 41 ± 13%, and decreased PDF from 1.4 ± 0.6cpm to 1.19 ± 0.6cpm, PDP from 1891 ± 851µV2 to 718 ± 678µV2. VP induced an increase in SDANN, lnLF, nLF (p<0.05) as well as a decrease in SDNN, pNN50, lnHF (p<0.05). Although there was no retching or vomiting, 80% of patients presented with nausea and exhibited a significant increase in plasma levels of VP, adrenaline and noradrenaline after administration of VP analogue. CONCLUSIONS: VPinduced gastroparesis is characterized by suppressed slow wave amplitude and with increase of their frequency. The existing parasympathetic impairment and increased sympathetic drive of the autonomic system is responsible for vasopressin-induced gastric dysrrhythmia and its clinical consequences.

The effects of vasopressin and its analogues on the liver and its disorders in the critically ill.

PURPOSE OF REVIEW: Vasopressin and terlipressin, a long-acting V1a analogue, are increasingly used in intensive care. The main clinical indications are the treatment of patients with septic shock and of patients with cirrhosis, who develop variceal bleeding, the hepatorenal syndrome or both. In this review, we summarize the effects of these drugs on splanchnic hemodynamics and organ function. RECENT FINDINGS: A recent systematic meta-analysis of randomized trials suggests that terlipressin may improve renal function in hepatorenal syndrome and thereby reduce mortality by 34%. Moreover, a recent study reported that association of terlipressin and albumin was more effective than terlipressin alone. In patients with variceal bleeding, the bleeding control is significantly improved by early administration of terlipressin. The place of vasopressin in the treatment of patients with septic shock is still discussed, but compared with norepinephrine, vasopressin showed at least an equal efficacy. SUMMARY: The use of vasopressin and its synthetic analogues has shown beneficial effects in the management of patients with cirrhosis, especially in the context of variceal bleeding, the hepatorenal syndrome or both. In both cases, the use of terlipressin improved survival. Therefore, in these clinical indications, terlipressin is a part of recommendations. The role of vasopressin in patients with septic shock remains to be precisely evaluated.

Effects of a single dose of terlipressin on transcutaneous oxygen pressures.

OBJECTIVE: Terlipressin (TP) is a potent vasoconstrictor, which is widely used in the treatment of bleeding esophageal varices and the hepatorenal syndrome. Side effects to TP are often related to skin hypoxaemia. The aim of the study was to investigate the transcutaneous oxygen pressures (TcPO(2) mmHg) after administration of 2 mg of TP. PATIENTS AND METHODS: Nineteen patients with cirrhosis and ascites were included. TcPO(2) mmHg were measured continuously measured at the chest, abdominal wall and at the lower extremity at baseline and after 2 mg TP in 15 patients and placebo in 4 patients. RESULTS: The mean whole body TcPO(2) decreased after TP by 34% (p < 0.005). The decrease was even more pronounced in the lower extremity: above knee -33% (50 vs. 33 mmHg, p = 0.01) and below knee -52% (52 vs. 26 mmHg, p = 0.001). Levels below 30 mmHg, were found in 60% of the patients after TP compared to 0% in the placebo group, p = 0.005. There were no significant changes in TcPO(2) after placebo. The baseline leg TcPO(2) correlated inversely with the MELD score (r = -0.64 and p < 0.003) and the increase in MAP after TP correlated inversely with TcPO(2) at the thorax (r = -0.60, p = 0.009). CONCLUSIONS: Sixty percent of patients with decompensated cirrhosis develop hypoxaemia in the lower limb after one dose of TP.

Effects of terlipressin on water excretion after oral water load test in nonazotemic cirrhotic patients with ascites without hyponatremia.

OBJECTIVE: Impaired water excretion is a major prognostic factor in decompensated cirrhotic patients. We investigated if terlipressin improves water excretion after a water load test in nonazotemic cirrhotic patients with ascites without hyponatremia. METHODS: Fifteen patients (Child-Pugh B/C: 6/9) were studied after an oral water intake of 20 ml/kg within 40 min and water excretion over 5 h was measured at baseline: day 1, and after a bolus infusion (2 mg) of terlipressin: day 3. Mean arterial pressure (MAP) before and after water loading on day 1, and MAP, cardiac output (CO), and systemic vascular resistance (SVR) before and 1 h after terlipressin infusion on day 3, were evaluated. The 5-h creatinine clearance (ClCre), diuresis, and sodium excretion were also evaluated in each study day. RESULTS: The water load excreted on day 1 was significantly correlated with Child-Pugh score, ClCre, sodium excretion, and SVR. The water load excreted and diuresis increased significantly after terlipressin infusion in the 12 patients that completed the study (48.3±3.3% vs. 39.5±4.9%; p=0.001 and 2.51±0.21 vs. 2.06±0.29 ml/min; p=0.001, respectively); significant increases in ClCre and sodium excretion, a significant decrease in CO and significant increases in MAP and SVR were also noted. The changes in the percentage of water load excreted were significantly correlated with the changes in SVR and ClCre. CONCLUSIONS: Terlipressin increases water excretion during a water load test in nonazotemic cirrhotic patients without hyponatremia, suggesting that the administration of arterial vasoconstrictors could influence the prognosis of these patients.

Continuous terlipressin infusion as rescue treatment in a case series of children with refractory septic shock.

BACKGROUND: 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. OBJECTIVE: To report the clinical effects of continuous terlipressin infusion as rescue treatment for children with septic shock refractory to high catecholamine doses. METHODS: 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. RESULTS: 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. CONCLUSIONS: Continuous terlipressin infusion may improve hemodynamics and survival in some children with refractory septic shock. Terlipressin could contribute to tissue ischemia.

Pediatric cardiac arrest refractory to advanced life support: is there a role for terlipressin?

OBJECTIVE: Pediatric cardiac arrest unresponsive to advanced life support and several adrenaline doses has a very poor prognosis. Alternative vasopressors could improve the results of resuscitation in such cases. We report our experience with the compassionate administration of terlipressin in children who suffered in-pediatric intensive care unit cardiac arrest and did not respond to immediate advanced life support and at least three epinephrine doses. DESIGN: Prospective multicenter registry. SETTING: Three pediatric intensive care units at university-affiliated tertiary care children's hospitals. PATIENTS: Five pediatric patients, aged 5 mos to 12 yrs, with in-pediatric intensive care unit cardiac arrest unresponsive to advanced life support that included at least three epinephrine doses. INTERVENTIONS: Addition of terlipressin (10-20 microg/kg intravenous, up to two doses) to standard cardiopulmonary resuscitation. MEASUREMENTS AND MAIN RESULTS: Sustained return of spontaneous circulation was achieved in four cases, two of them were declared dead 6 and 12 hrs later, and the remaining two survived without cardiopulmonary procedures-related sequelae and with good neurologic condition. CONCLUSIONS: Terlipressin might contribute to obtain sustained return of spontaneous circulation in children with refractory in-hospital cardiac arrest. A randomized controlled clinical trial should be conducted to investigate the optimal drug treatment in pediatric cardiac arrest.