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.

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.

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.

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.

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.

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.

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.

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.

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.

Vasopressin in pediatric vasodilatory shock: a multicenter randomized controlled trial.

RATIONALE: Vasopressin has been proposed as a potent vasoactive agent in the treatment of vasodilatory shock in adults and children. The objective of this trial was to evaluate the efficacy and safety of vasopressin as an adjunctive agent in pediatric vasodilatory shock. METHODS: In this multicenter, double-blind trial, children with vasodilatory shock were randomized to receive low-dose vasopressin (0.0005-0.002 U/kg/min) or placebo in addition to open-label vasoactive agents. Vasoactive infusions were titrated to clinical endpoints of adequate perfusion. The primary outcome was time to vasoactive-free hemodynamic stability. Secondary outcomes included mortality, organ-failure-free days, length of critical care unit stay, and adverse events. MEASUREMENTS AND MAIN RESULTS: Sixty-five of 69 children (94%) who were randomized received the study drug (33 vasopressin, 32 placebo) and were included in the analysis. There was no significant difference in the primary outcome between the vasopressin and placebo groups (49.7 vs. 47.1 hours; P = 0.85). There were 10 deaths (30%) in the vasopressin group and five (15.6%) in the placebo group (relative risk, 1.94; 95% confidence interval, 0.75-5.05; P = 0.24). There were no significant differences with respect to organ failure-free days (22 vs. 25.5 days; P = 0.11), ventilator-free days (16.5 23 days; P = 0.15), length of stay (8 vs. 8.5 days; P = 0.93), or adverse event rate ratios (12.0%; 95% confidence interval, -2.6 to 26.7; P = 0.15). CONCLUSIONS: Low-dose vasopressin did not demonstrate any beneficial effects in this pediatric trial. Although not statistically significant, there was a concerning trend toward increased mortality. Clinical trial registered with www.controlled-trials.com (ISRCTN11597444).

Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice.

INTRODUCTION: Arginine vasopressin is a vasoactive drug commonly used in distributive shock states including mixed shock with a cardiac component. However, the direct effect of arginine vasopressin on the function of the ischemia/reperfusion injured heart has not been clearly elucidated. METHODS: We measured left ventricular ejection fraction using trans-thoracic echocardiography in C57B6 mice, both in normal controls and following ischemia/reperfusion injury induced by a one hour ligation of the left anterior descending coronary artery. Mice were treated with one of normal saline, dobutamine (8.33 microg/kg/min), or arginine vasopressin (0.00057 Units/kg/min, equivalent to 0.04 Units/min in a 70 kg human) delivered by an intraperitoneal micro-osmotic pump. Arterial blood pressure was measured using a micromanometer catheter. In addition, mortality was recorded and cardiac tissues processed for RNA and protein. RESULTS: Baseline left ventricular ejection fraction was 65.6% (60 to 72). In normal control mice, there was no difference in left ventricular ejection fraction according to infusion group. Following ischemia/reperfusion injury, AVP treatment significantly reduced day 1 left ventricular ejection fraction 46.2% (34.4 to 52.0), both in comparison with baseline and day 1 saline treated controls 56.9% (42.4 to 60.2). There were no significant differences in preload (left ventricular end diastolic volume), afterload (blood pressure) or heart rate to account for the effect of AVP on left ventricular ejection fraction. The seven-day mortality rate was highest in the arginine vasopressin group. Following ischemia/reperfusion injury, we found no change in cardiac V1 Receptor expression but a 40% decrease in Oxytocin Receptor expression. CONCLUSIONS: Arginine vasopressin infusion significantly depressed the myocardial function in an ischemia/reperfusion model and increased mortality in comparison with both saline and dobutamine treated animals. The use of vasopressin may be contraindicated in non-vasodilatory shock states associated with significant cardiac injury.

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.

Vasopressin in catecholamine-refractory shock in children.

Severe septic and cardiogenic shock is associated with a high mortality in neonates, children and adolescents. Common therapies include the administration of fluids and the use of conventional inotropes. However, in severe forms of shock, cardio-circulatory failure may be secondary to profound vasoparalysis and unresponsive to conventional therapies. We reviewed the literature on the use of arginine-vasopressin (AVP) and terlipressin (TP) as a rescue therapy in neonates, children and adolescents with catecholamine-refractory shock or cardio-circulatory arrest. We identified 17 reports (11 case series, 6 case reports) on a total of 109 patients. Only two studies were prospective. The age of treated patients ranged from extremely low birth weight infants of 23 weeks' gestation to a 19-year-old adolescent. The most common indication for either drug was catecholamine-refractory septic shock (nine reports). Commonly reported responses following AVP/TP administration were a rapid increase in systemic arterial blood pressure, an increase in urine output, and a decrease in serum lactate. In most reports, AVP and TP had a significant impact on the required dose of inotropes which could be reduced. Despite the use of AVP/TP, mortality was high (52/109). In view of the limited number of paediatric patients treated with AVP/TP, no definite recommendations on their use in children with severe forms of cardio-circulatory failure can be issued. There is a need for larger prospective trials assessing the efficacy and safety profiles of these drugs in a defined setting. Until more data are available, and taking into consideration the detrimental impact catecholamine-refractory shock has on children, the use of AVP/TP as a rescue therapy should be considered on an individual basis.

An investigation of hypothalamic-pituitary-adrenal axis hyperactivity in anorexia nervosa: the role of CRH and AVP.

We hypothesised that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in anorexia nervosa (AN) is associated with (a) elevated arginine vasopressin (AVP) activity and (b) enhanced pituitary sensitivity to AVP, as it is in depressive illness. 16 Healthy women and 18 women with active AN participated in a combined dexamethasone (DXM)/corticotrophin releasing hormone (CRH) challenge test and an AVP challenge test. This combination of tests is designed to assess the functional contribution of AVP to HPA axis activity. 10 of the active AN group repeated participation after weight gain. The cortisol response to AVP was reduced by 138% in the active AN group, suggesting an impairment of pituitary sensitivity to AVP, which began to normalise with weight gain. The cortisol and adreno-corticotrophin (ACTH) responses to the DXM/CRH test were not significantly enhanced in the active AN group, suggesting that there was no elevated endogenous AVP activity augmenting the response to CRH in AN. Weight gain was associated with blunting of the endocrine response to the DXM/CRH test, which may have been related to rising oestrogen levels. Thus, contrary to the hypotheses, we did not find (a) evidence of upregulated AVP activity or (b) enhanced pituitary sensitivity to AVP in AN. These findings suggest that the mechanism of HPA axis hyperactivity differs in depression and AN, with greater involvement of AVP in depressive disorder and perhaps more reliance on CRH to drive the axis in AN. The powerful anorexigenic effect of CRH could contribute to the severity of weight loss associated with AN.

Vasopressin in vasodilatory shock: ensure organ blood flow, but take care of the heart!

Supplementary arginine vasopressin infusion in advanced vasodilatory shock may be accompanied by a decrease in cardiac index and systemic oxygen transport capacity in approximately 40% of patients. While a reduction of cardiac output most frequently occurs in patients with hyperdynamic circulation, it is less often observed in patients with low cardiac index. Infusion of inotropes, such as dobutamine, may be an effective strategy to restore systemic blood flow. However, when administering inotropic drugs, systemic blood flow should be increased to adequately meet systemic demands (assessed by central or mixed venous oxygen saturation) without putting an excessive beta-adrenergic stress on the heart. Overcorrection of cardiac index to hyperdynamic values with inotropes places myocardial oxygen supply at significant risk.

[Arginine-vasopressin in septic and vasodilatorial shock]. / Arginin-Vasopressin im septischen und vasodilatatorischen Schock.

Current therapy of septic/vasodilatory cardiovascular failure includes volume resuscitation and infusion of inotropic and vasopressor agents. Norepinephrine is the first-line vasoconstrictor, and can stabilize hemodynamic variables in most patients. Nonetheless, irreversible cardiovascular failure which is resistant to conventional hemodynamic therapies still is the main cause of death in patients with severe sepsis and septic shock. In such advanced, catecholamine-resistant shock states, arginine-vasopressin (AVP) has repeatedly caused an increase in mean arterial blood pressure, a decrease in toxic norepinephrine-dosages, as well as further beneficial hemodynamic, endocrinologic and renal effects. Although AVP exerted negative inotropic effects in previous clinical trials and in selected animal experiments, a continuous low-dose AVP infusion during advanced septic/vasodilatory shock caused a decrease in cardiac index only in patients with a hyperdynamic circulation. Adverse effects on gastrointestinal circulation and the systemic microcirculation can not be excluded, but have not yet been confirmed in clinical prospective trials. Negative side effects of a supplementary AVP therapy are an increase in total bilirubin concentrations, and a decrease in platelet count. A transient increase in hepatic transaminases during AVP infusion is most likely related to preceding hypotensive episodes. Important points which must be considered when using AVP as a "rescue vasopressor" in septic/vasodilatory shock states are: 1) AVP infusion only in advanced shock states that can not be adequately reversed by conventional hemodynamic therapy (e.g. norepinephrine >0,5-0,6 mug/kg/min), 2) presence of normovolemia, 3) AVP infusion only in combination with norepinephrine, 4) strict avoidance of bolus injections and dosages >4 IU/h. Effects of a supplementary AVP infusion in advanced vasodilatory shock on survival are currently examined in a large, prospective multicenter trial in North America and Australia.

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.