Implicaciones de la arginina-vasopresina y de la copeptina en la gestación normal y en la preeclampsia / Implications of arginine-vasopressin and copeptin in normal gestation and in pre-eclampsia

La preeclampsia representa una complicación específica de hipertensión del embarazo, que aparece de novo después de la 20 semana de gestación, acompañada de proteinuria y/o disfunción orgánica materna o útero-placentaria. A pesar de una etiopatogenia incierta, la alteración en el remodelado vascular de la arteria espiral e isquemia placentaria es la hipótesis más generalizada. El hallazgo de niveles elevados de copeptina, en mujeres con preeclampsia respecto a gestantes normales, ha puesto en valor la implicación de la arginina-vasopresina en la etiopatogenia de esta complicación. En este trabajo se considera su utilidad como marcador de preeclampsia a través de la revisión de los principales estudios efectuados con esta molécula.(AU)

Preeclampsia represents a specific complication of pregnancy hypertension, which appears de novo after the 20th week of gestation, accompanied by proteinuria and/or maternal or utero-placental organ dysfunction. Despite an uncertain etiopathogenesis, impaired vascular remodeling of the spiral artery and placental ischemia is the most widespread hypothesis. The finding of elevated levels of copeptin in women with preeclampsia compared to normal pregnant women has valued the involvement of arginine vasopressin in the etiopathogenesis of this complication. In this paper, its usefulness as a marker of preeclampsia is considered through the review of the main studies carried out with this molecule.(AU)

Melatonin alleviates arginine vasopressin-induced cardiomyocyte apoptosis via increasing Mst1-Nrf2 pathway activity to reduce oxidative stress.

Heart failure patients have elevated arginine vasopressin (AVP) levels, which are involved in inducing peripheral vasoconstriction and cardiac hypertrophy. This hypertrophy, along with cardiomyocyte apoptosis, results from oxidative stress. Therefore, the antioxidant drug, melatonin (Mel), is commonly used to treat cardiac hypertrophy and apoptosis; however, whether it could alleviate AVP-induced myocardialinjury remains to be addressed. In this study, high AVP doses were found to induce H9c2 cardiomyoblast apoptosis, demonstrated by increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) up-regulation, and anti-apoptotic Bcl-2 downregulation. This AVP-induced apoptotic increase, along with lowered cell viability, was also associated with higher reactive oxygen species (ROS) levels and lowered mitochondrial membrane potentials (MMP), which were all reversed upon Mel administration. Further investigations found that apoptosis, ROS, and MMP outcomes under high AVP were associated with Mst1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway suppression, yielding mitochondrial dysfunction, and Mel reversed them via promoting Mst1 phosphorylation, which then activated Nrf2 to increase anti-oxidative enzyme production. These findings were supported by siRNA gene suppression, where knocking down either Nrf2 or Mst1 abrogated the anti-apoptotic effects of Mel in cardiomyoblasts. Therefore, Mel could reduce cardiomyoblast apoptosis under high AVP levels, via Mst1-Nrf2 pathway re-activation, to enhance anti-oxidative responses.

A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia.

Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

Acciones óseas de las hormonas de la neurohipófisis / Bone actions of neuro hypophyseal hormones

La oxitocina (OXT) como la arginina-vasopresina (AVP) son dos hormonas primitivas secretadas por la hipófisis posterior. Sus receptores están mucho más ampliamente distribuidos en el organismo de lo que se pensaba originalmente, incluido el hueso. En los estudios preclínicos, la OXT ha mostrado ser anabólica para el hueso, promoviendo la osteogénesis sobre la adipogénesis y favoreciendo la actividad osteoblástica sobre la osteoclástica. Tanto los osteoblastos como los osteoclastos tienen receptores para la OXT, y los efectos de los estrógenos sobre la masa ósea en ratones está mediada por lo menos en parte por la OXT. El mecanismo preciso por el cual la activación de los receptores de oxitocina (OXTR) se traduce en un incremento de la formación ósea permanece poco claro. La AVP también podría afectar el esqueleto en forma directa. Dos de los receptores de la AVP, V1a y V2 están expresados en osteoblastos y osteoclastos. La inyección de AVP en ratones de tipo salvaje aumenta la formación osteoclastos que producen resorción y reduce los osteoblastos formadores de hueso. En forma opuesta, la exposición de precursores osteoblásticos a antagonistas de los receptores V1a o V2, incrementan la osteoblastogénesis, como también lo hace la deleción genética del receptor V1a. (AU)

Both oxytocin (OXT) and argininevasopressin (AVP) are primitive hormones secreted by the posterior pituitary gland. OXT receptors are much more widely distributed in the body than originally thought, including in bone. In preclinical studies, OXT has been shown to be anabolic for bone, promoting osteogenesis over adipogenesis and favoring osteoblastic over osteoclastic activity. Both osteoblasts and osteoclasts have receptors for OXT, and the effects of estrogen on bone mass in mice is mediated at least in part by OXT. The precise mechanism by which the activation of oxytocin receptors (OXTRs) results in an increase in bone formation remains unclear. AVP could also have direct actions on the skeleton. The two AVP receptors, V1a and V2, are expressed in osteoblasts and osteoclasts. Injection of AVP in wild-type mice increases the formation of osteoclasts increasing bone resorption, and reduces bone-forming osteoblasts. On the contrary, the exposure of osteoblastic precursors to V1a and V2 antagonists increase osteoblastogenesis, the same as the genetic deletion of the V1a receptor. (AU)

Narrative Review of Controversies Involving Vasopressin Use in Septic Shock and Practical Considerations.

Objective: To summarize literature evaluating vasopressin use, focusing on clinical controversies regarding initiation, dosing, and discontinuation and interaction of vasopressin with other therapies in septic shock patients. Data Sources: A PubMed English-language literature search (January 2008 to December 2019) was performed using these terms: arginine vasopressin, septic, shock, and sepsis. Citations, including controlled trials, observational studies, review articles, guidelines, and consensus statements, were reviewed. Study Selection and Data Extraction: Relevant clinical data focusing on specific controversial questions regarding the utility of vasopressin in patients with septic shock were narratively summarized. Data Synthesis: Current literature does not strongly support the use of vasopressin as a first-line initial therapy for septic shock. Additionally, there are conflicting data for weight-based dosing of vasopressin in overweight patients. Evidence for vasopressin renal protection and interaction with corticosteroids is minimal. However, vasopressin has the ability to reduce catecholamine requirements in septic shock patients and may provide a mortality benefit in specific subgroups. Discontinuation of vasopressin last, not second to last, in resolving septic shock may reduce hypotension development. Relevance to Patient Care and Clinical Practice: This review addresses specific clinical controversies that drive vasopressin use in septic shock patients in real-world practice. Conclusion: Vasopressin should remain second-line adjunct to norepinephrine to augment mean arterial pressures. Dosing should be initiated at 0.03 U/min, and higher doses offer minimal benefit. There are conflicting data on the impact of weight on vasopressin response. Studies have failed to show renal benefit with vasopressin use or an interaction with corticosteroid therapy.

Promoter methylation changes and vascular dysfunction in pre-eclamptic umbilical vein.

BACKGROUND: Hypertension is one of primary clinical presentations of pre-eclampsia. The occurrence and progress of hypertension are closely related to vascular dysfunction. However, information is limited regarding the pathological changes of vascular functions in pre-eclamptic fetuses. Human umbilical cord vein was used to investigate the influence of pre-eclampsia on fetal blood vessels in this study. RESULTS: The present study found that the vasoconstriction responses to arginine vasopressin (AVP) and oxytocin (OXT) were attenuated in the pre-eclamptic umbilical vein as compared to in normal pregnancy, which was related to the downregulated AVP receptor 1a (AVPR1a), OXT receptor (OXTR), and protein kinase C isoform ß (PKCß), owing to the deactivated gene transcription, respectively. The deactivated AVPR1a, OXTR, and PKCB gene transcription were respectively linked with an increased DNA methylation within the gene promoter. CONCLUSIONS: To the best of our knowledge, this study first revealed that a hyper-methylation in gene promoter, leading to relatively reduced patterns of AVPR1a, OXTR, and PKCB expressions, which was responsible for the decreased sensitivity to AVP and OXT in the umbilical vein under conditions of pre-eclampsia. The data offered new and important information for further understanding the pathological features caused by pre-eclampsia in the fetal vascular system, as well as roles of epigenetic-mediated gene expression in umbilical vascular dysfunction.

Selepressin and Arginine Vasopressin Do Not Display Cardiovascular Risk in Atherosclerotic Rabbit.

BACKGROUND: Septic shock remains associated with significant mortality rates. Arginine vasopressin (AVP) and analogs with V1A receptor agonist activity are increasingly used to treat fluid-resistant vasodilatory hypotension, including catecholamine-refractory septic shock. Clinical studies have been restricted to healthy volunteers and catecholamine-refractory septic shock patients excluding subjects with cardiac co-morbidities because of presumed safety issues. The novel selective V1A receptor agonist selepressin, with short half-life, has been designed to avoid V2 receptor-related complications and long-term V1A receptor activation. Cardiovascular safety of selepressin, AVP, and the septic shock standard of care norepinephrine was investigated in a rabbit model of early-stage atherosclerosis. METHODS: Atherosclerosis was established in New Zealand White rabbits using a 1% cholesterol-containing diet. Selepressin, AVP, or norepinephrine was administered as cumulative intravenous infusion rates to atherosclerotic and non-atherosclerotic animals. RESULTS: Selepressin and AVP induced a slight dose-dependent increase in arterial pressure (AP) associated with a moderate decrease in heart rate, no change in stroke volume, and a moderate decrease in aortic blood flow (ABF). In contrast, norepinephrine induced a marked dose-dependent increase in AP associated with a lesser decrease in the heart rate, an increase in stroke volume, and a moderate increase in ABF. For all three vasopressors, there was no difference in responses between atherosclerotic and non-atherosclerotic animals. CONCLUSION: Further studies should be considered using more advanced atherosclerosis models, including with septic shock, before considering septic shock clinical trials of patients with comorbidities. Here, selepressin and AVP treatments did not display relevant cardiovascular risk in early-stage rabbit atherosclerosis.

Intraoperative administration of vasopressin during coronary artery bypass surgery is associated with acute postoperative kidney injury.

BACKGROUND: Severe vasodilatation is commonly seen upon weaning from cardiopulmonary bypass (CPB). We examined the effects of vasopressin (arginine vasopressin [AVP]) on acute kidney injury (AKI) in postoperative period. METHODS: The records of 483 patients undergoing coronary bypass surgery on CPB from 2004 to 2008 were retrospectively reviewed. Demographic, anthropometric, comorbid condition, and perioperative clinical/laboratory data were collected along with postoperative complications. Patients were grouped based on the perioperative use of AVP, and AKI was used as the primary end point. Univariate and multivariate logistic regression analyses were used, followed by propensity score matching for AKI. Null hypothesis was rejected at P < .05. RESULTS: Postoperative AKI occurred in 14.5% of patients. Arginine vasopressin was administered to 280 patients during the perioperative period. The prevalence of AKI in AVP was 20%, whereas it was 6.1% in controls (P < .0001). Arginine vasopressin was an independent factor that predicted the occurrence of AKI (odds ratio, 3.60; 95% confidence interval, 1.22-10.62; P = .02). However, after propensity score matching, the association between AKI and AVP was lost (P = .073). CONCLUSION: Acute kidney injury is a common complication after cardiac surgery, and vasopressin use increases its incidence; however, this effect may rely on several clinical factors, and its true effect should be examined by large randomized trials.

The selective vasopressin type 1a receptor agonist selepressin (FE 202158) blocks vascular leak in ovine severe sepsis*.

OBJECTIVE: To determine if the selective vasopressin type 1a receptor agonist selepressin (FE 202158) is as effective as the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist vasopressor hormone arginine vasopressin when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis. DESIGN: Prospective, randomized, controlled laboratory experiment. SETTING: University animal research facility. SUBJECTS: Forty-five chronically instrumented sheep. INTERVENTIONS: Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure fell by more than 10 mm Hg from baseline level, an additional continuous IV infusion of arginine vasopressin or selepressin was titrated to raise and maintain mean arterial pressure within no less than 10 mm Hg from baseline level. Effects of combination treatment of selepressin with the selective vasopressin V2 receptor agonist desmopressin were similarly investigated. MEASUREMENTS AND MAIN RESULTS: In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index decreased by ~50%, and ~7 L of fluid were retained over 24 hours; this fluid accumulation was partially reduced by arginine vasopressin and almost completely blocked by selepressin; and combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to arginine vasopressin treatment. CONCLUSIONS: Resuscitation with the selective vasopressin type 1a receptor agonist selepressin blocked vascular leak more effectively than the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist arginine vasopressin because of its lack of agonist activity at the vasopressin V2 receptor.

In-stent thrombosis following DDAVP administration: case report and review of the literature.

A 67-year-old man with a drug-eluting stent in his proximal left anterior descending artery was admitted to the hospital after sustaining a traumatic injury to the skull. Due to persistent bleeding from a subgaleal hematoma, intravenous 1-desamino-8-D-arginine vasopressin (DDAVP) was administered. Five hours later, the patient complained of crushing chest pain. A 12-lead electrocardiogram demonstrated 2 mm ST-segment elevations in the precordial leads with reciprocal depressions in the inferior leads. Emergency cardiac catheterization demonstrated total occlusion of the proximal left anterior descending stent with TIMI 0 flow. Another drug-eluting stent was placed inside the original stent with restoration of TIMI 3 flow. During the catheterization, the patient became progressively hypoxic and hypotensive requiring intubation, dopamine drip, and placement of an intra-aortic balloon pump. The patient's hospitalization was complicated by prolonged shock requiring inotropes and vasopressors. This is the first reported case of an ST-elevation myocardial infarction due to in-stent thrombosis occurring after DDAVP administration. Though DDAVP is well tolerated and efficacious in treating several types of coagulopathies, this case illustrates its potential pro-thrombotic effects. Therefore, DDAVP should be used with caution in patients with known coronary artery disease and coronary stents.

Under general anesthesia arginine vasopressin prevents hypotension but impairs cerebral oxygenation during arthroscopic shoulder surgery in the beach chair position.

BACKGROUND: Patients undergoing surgery in the beach chair position (BCP) are at a risk of cerebral ischemia. We evaluated the effect of arginine vasopressin (AVP) on hemodynamics and cerebral oxygenation during surgery in the BCP. METHODS: Thirty patients undergoing shoulder surgery in BCP under propofol-remifentanil anesthesia were randomly allocated either to receive IV AVP 0.07 U/kg (AVP group, N = 15) or an equal volume of saline (control group, N = 15) 2 minutes before taking BCP. Mean arterial blood pressure (MAP), heart rate (HR), jugular venous bulb oxygen saturation (SjvO2), and regional cerebral tissue oxygen saturation (SctO2) were measured after induction of anesthesia and before (presitting in supine position) and after patients took BCP. RESULTS: AVP itself given before the positioning increased MAP and decreased SjvO2 and SctO2 (P < 0.0001), with HR unaffected. Although MAP was decreased by BCP in both groups, it was higher in the AVP group (P < 0.0001). While in BCP, HR remained unaltered in the control and decreased in the AVP group. SjvO2 in BCP did not differ between the groups. SctO2 was decreased by BCP in both groups, which was more pronounced in the AVP group until the end of study. The incidence of hypotension (13% vs 67%; P = 0.003) was less frequent, and that of cerebral desaturation (>20% SctO2 decrease from presitting value) (80% vs 13%; P = 0.0003) was higher in the AVP group. The incidence of jugular desaturation (SjvO2 <50%) was comparable between the groups. CONCLUSIONS: A prophylactic bolus administration of AVP prevents hypotension associated with BCP in patients undergoing shoulder surgery under general anesthesia. However, it was associated with regional cerebral but not jugular venous oxygen desaturation on upright positioning.

Vasopressin for the treatment of neonatal hypotension.

Vasopressin (pitressin), also known as arginine vasopressin (AVP), is an antidiuretic hormone formed in the hypothalamus and secreted from the posterior pituitary gland. Various forms of exogenous vasopressin exist and have been used in neonates to treat conditions such as diabetes insipidus. Vasopressin has also been studied on a limited basis for use in the treatment of catecholamine-resistant hypotension in vasodilatory shock. Hypotension is a significant problem resulting in increased morbidity in preterm, septic, and postsurgical neonates. This article will discuss the role of vasopressin and its use as a therapeutic agent in the treatment of hypotension in the neonate.

Hyponatremia during arginine vasopressin therapy in children following cardiac surgery.

OBJECTIVE: To describe the incidence and severity of hyponatremia after initiation of arginine vasopressin therapy in children recovering from cardiothoracic surgery, and to compare these patients with a control group with similar disease complexity and severity who did not receive arginine vasopressin. DESIGN: Retrospective chart review. SETTING: PICU at a tertiary care university hospital. PATIENTS: Twenty-nine patients who received arginine vasopressin for at least 6 hours during the first 48 postoperative hours following cardiothoracic surgery were compared with 47 patients who did not receive arginine vasopressin. After surgery, all patients received intravenous fluids consisting of dextrose and 0.22% saline for daily fluid requirements as well as isotonic colloid and blood products as needed for additional resuscitation. RESULTS: Mean initial postoperative serum sodium did not differ between groups, 144.6 ± 3.4 in those patients who received arginine vasopressin and 144.5 ± 3.7 in those who did not, p = 0.969. Mean lowest sodium in the first 72 hours, however, was 134.7 ± 3.8 in those who received arginine vasopressin as compared with 137.1 ± 4.3 in the control group, p = 0.019. Hyponatremia occurred in 14 of the patients (48%) who received arginine vasopressin but only in 8 of the patients (17%) in the control group, p = 0.004. Mean age, weight, sex, Aristotle score, and duration of cardiopulmonary bypass were not statistically different between groups. Mean volumes of hypotonic fluids administered and cumulative diuretic dosing during the first 72 hours post-surgery were also not statistically different between groups. CONCLUSIONS: Hyponatremia occurred in nearly half of the infants and children receiving arginine vasopressin therapy in this study. Clinicians should be aware of this association, monitor serum sodium values closely, and consider providing less free water to these patients before hyponatremia occurs.

Genetic deletion of the P2Y2 receptor offers significant resistance to development of lithium-induced polyuria accompanied by alterations in PGE2 signaling.

Lithium (Li)-induced polyuria is due to resistance of the medullary collecting duct (mCD) to the action of arginine vasopressin (AVP), apparently mediated by increased production of PGE(2). We previously reported that the P2Y(2) receptor (P2Y(2)-R) antagonizes the action of AVP on the mCD and may play a role in Li-induced polyuria by enhancing the production of PGE(2) in mCD. Hence, we hypothesized that genetic deletion of P2Y(2)-R should ameliorate Li-induced polyuria. Wild-type (WT) or P2Y(2)-R knockout (KO) mice were fed normal or Li-added diets for 14 days and euthanized. Li-induced polyuria, and decreases in urine osmolality and AQP2 protein abundance in the renal medulla, were significantly less compared with WT mice despite the lack of differences in Li intake or terminal serum or inner medullary tissue Li levels. Li-induced increased urinary excretion of PGE(2) was not affected in KO mice. However, prostanoid EP(3) receptor (EP3-R) protein abundance in the renal medulla of KO mice was markedly lower vs. WT mice, irrespective of the dietary regimen. The protein abundances of other EP-Rs were not altered across the groups irrespective of the dietary regimen. Ex vivo stimulation of mCD with PGE(2) generated significantly more cAMP in Li-fed KO mice (130%) vs. Li-fed WT mice (100%). Taken together, these data suggest 1) genetic deletion of P2Y(2)-R offers significant resistance to the development of Li-induced polyuria; and 2) this resistance is apparently due to altered PGE(2) signaling mediated by a marked decrease in EP3-R protein abundance in the medulla, thus attenuating the EP3-mediated decrease in cAMP levels in mCD.

Intravenous arginine vasopressin infusion in refractory vasodilatory shock: a clinical study.

OBJECTIVE: To assess the efficacy of arginine vasopressin (AVP) as a rescue therapy in children with catecholamine refractory vasodilatory shock and its effect on various hemodynamic, clinical, and laboratory variables. METHODS: This prospective hospital based study was conducted from January 2008 through July 2008 at a tertiary pediatric cardiac critical care unit. Twelve post cardiac surgery patients with advanced vasodilatory shock requiring intravenous vasopressin infusion longer than 60 min were included and continuous vasopressin infusion was given. The primary outcome measures were restoration of Mean arterial blood pressure (MAP) after starting AVP infusion and decrease in other concurrent catecholamines requirement. The secondary outcome measures were survival to hospital discharge, adverse effects, and laboratory variables. RESULTS: Vasopressin was infused in the dose range of 0.0005 to 0.003 units/kg/min for a mean duration of 55.6 h. MAP improved from 41.08 ± 6.15 mmHg at baseline to 48.92 ± 10.05 mmHg after 1 h (P < 0.05), to 57.01 ± 8.30 mmHg after 4 h of AVP infusion (P < 0.001), and to 62.33 ± 8.55 mmHg after 12 h (P < 0.001), which further increased to 71.75 ± 9.55 mmHg after 24 h (P < 0.001). Inotrope score and requirement of other concurrent inotropes declined significantly in all patients after starting AVP infusion (P < 0.001). Lactate levels also declined significantly (P < 0.0001). No significant adverse effect due to end organ ischemia was observed. Only one patient expired while on vasopressin infusion due to refractory hypotension. CONCLUSIONS: Concurrent addition of vasopressin at an appropriate stage help improving MAP significantly with decreased dependence on high dose catecholamines without any significant adverse effects.

Terlipressin in hepatorenal syndrome.

OBJECTIVE: To compare the pharmacology, dosing, and adverse reactions of vasopressin and terlipressin for the treatment of hepatorenal syndrome (HRS) and assess the efficacy of the investigational drug terlipressin for HRS. DATA SOURCES: Articles evaluating prospective studies for vasopressin and terlipressin were discussed after being identified through PubMed (1966-November 2010), International Pharmaceutical Abstracts (1970-November 2010), and EMBASE (1985-November 2010) with combinations of the following terms: vasopressin, terlipressin, and hepatorenal syndrome. In addition, reference citations from publications identified were reviewed. Thirteen studies were identified for terlipressin, along with 4 meta-analyses and 1 case report. For vasopressin, 2 studies were identified. STUDY SELECTION AND DATA EXTRACTION: Prospective clinical studies directly comparing terlipressin and vasopressin were evaluated, as well as prospective clinical studies and meta-analyses for terlipressin in HRS. DATA SYNTHESIS: No randomized, placebo-controlled trials using vasopressin for the treatment of type I HRS have been published, and 4 randomized studies involving 197 patients provide the most current outcome data for use of terlipressin in HRS. Terlipressin differs significantly from vasopressin with regard to its pharmacology, dosing, and adverse drug reaction profile. There is a paucity of data on vasopressin for HRS. CONCLUSIONS: No definitive recommendations can be made for the use of terlipressin for this indication until further, well-conducted studies are performed.

The role of vasopressin and terlipressin in catecholamine-resistant shock and cardio-circulatory arrest in children: review of the literature.

INTRODUCTION: Arginine-vasopressin (AVP) and terlipressin (TP) are used as rescue drugs for states of shock and cardio-circulatory failure. METHODS: Review to assess AVP/TP as a rescue therapy in children with catecholamine-resistant shock or cardio-circulatory arrest. RESULTS: A total of 31 reports were included (428 patients); sixteen articles were case series, 10 case reports, 3 clinical evaluation studies, one study was a non-blind RCT while one study was a multicentre double-blind RCT. The most common indication for either drug was catecholamine-refractory septic shock (12 reports). Commonly reported responses following AVP/TP administration were a rapid increase in blood pressure, an increase in urine output, and a decrease in serum lactate. In most reports, AVP and TP led to the reduction of catecholamines. The cumulative mortality rate remained high (188/428; 43.9%) despite the use of AVP/TP. CONCLUSIONS: No firm recommendations on the use of AVP/TP in children with severe forms of cardio-circulatory failure can be issued.

Vasopressin in sepsis and septic shock.

Arginine vasopressin (AVP) and its synthetic, long-acting analog terlipressin (TP) are potent alternative vasoconstrictors in the treatment of septic patients with catecholamine-refractive vasodilatatory shock. The results from one large randomized clinical trial suggest that AVP plus norepinephrine (NE) infusion is as safe and effective as treatment with NE alone in patients with septic shock. Because the desired effects of vasopressin analogs are basically related to their vasopressinergic effects via the V1a receptor, more selective V1 agonists, such as TP, may be more potent in reversing sepsis-related arterial hypotension. In this regard, recent evidence from small-scale studies suggests that continuous low-dose infusion rather than intermittent bolus injection of TP is associated with fewer side effects, such as depression of cardiac output and rebound arterial hypotension. However, because clinical data on the administration of TP in patients with sepsis are limited, it should not currently be used beyond the scope of controlled trials. The optimal time point for the initiation of therapy with vasopressin analogs has yet to be determined. While AVP and TP are commonly used as last-resort therapies in severe septic shock, some evidence supports the initiation of treatment in a less severe state of the disease.

Arginine vasopressin for the treatment of septic shock in adults.

Sepsis remains one of the leading causes of mortality in the United States. Cardiovascular compromise is one of the major contributors to the high mortality associated with sepsis. Current cardiovascular support in patients with septic shock involves fluid administration, use of catecholamines, and potentially the use of inotropes, corticosteroids, or arginine vasopressin. Vasopressin is an endogenous hormone essential for both osmotic and cardiovascular homeostasis. Various studies have suggested that exogenous administration of arginine vasopressin may be an effective adjunctive therapy to traditional catecholamines for the management of hypotension during septic shock. Of particular interest is the Vasopressin and Septic Shock Trial (VASST), which found no mortality benefit when comparing the addition of arginine vasopressin to norepinephrine versus continuous dose increases in norepinephrine alone. However, results of the a priori subgroup and post hoc analyses of this trial suggest that patients may benefit if arginine vasopressin is used in patients with less severe shock, defined as those receiving a relatively low norepinephrine-equivalent dose of 5-14 µg/minute, or in those at risk for renal failure. Current guidelines from the Surviving Sepsis Campaign recommend arginine vasopressin 0.03 unit/minute may be added to norepinephrine with the anticipation of an effect equal to higher doses of norepinephrine alone. Many practitioners continue to utilize arginine vasopressin for patients with septic shock due to its mechanisms of benefit on pathophysiologic derangements in this disease. Clinicians must be knowledgeable about the use of arginine vasopressin in septic shock, including controversial areas where guidelines do not always provide concrete recommendations.