Vasopressin Infusion Research Articles

Abstract P256: Vasopressin Infusion During Pregnancy in Mice Induces Early Histological Placental Phenotypes of Preeclampsia

Human preeclampsia (PE) is associated with elevated secretion of arginine vasopressin (AVP), and chronic infusion of AVP into pregnant mice is sufficient to model PE by causing hypertension, renal glomerular endotheliosis, proteinuria, fetal placental hypoxia, and growth restriction. Early stages of PE are associated with defective trophoblast invasion of maternal spiral arteries, leading to decreased artery diameter and placental oxygenation. AVP infusion (24 ng/hr, sc) into pregnant mice caused placental hypoxia (chromatin-bound HIF1α on gestational day (GD)17.5; saline n=5, 0.31±0.01; AVP n=5, 0.34±0.01 AU, p<0.05) and reduced placental growth factor mRNA (n=18, 1.0 (0.7-1.3) vs n=21, 0.3 (0.2-0.4) fold (1 se), p<0.05). Therefore, we performed histological analyses of placentas collected from mice at GD12.5 infused with saline or AVP, with the hypothesis that AVP leads to early placental PE phenotypes. Similar to effects on GD17.5, this preliminary cohort demonstrated increased urine protein content (n=7, 27±3 vs n=13, 44±3, g/L p<0.05) and mid-gestational systolic blood pressure (-7.6±3.1 vs +3.5±2.2, mmHg p<0.05), similar fetal (75±7 vs 78±4 mg, p=0.75) and placental (83±10 vs 81±4 mg, p=0.80) masses, and similar changes in heart rate (+37±16 vs +39±12 bpm, p=0.93). GD12.5 placentas were then stained with haemotoxylin and eosin or immunostained for cytokeratin-8 to examine morphological changes induced by AVP. AVP infusion had no significant effects on labyrinth (saline n=3, 647±25 vs AVP n=7, 602±35 um, p=0.45), spongiotrophoblast (342±19 vs 363±24 um, p=0.61), or decidua (622±47 vs 520±47 um, p=0.24) layer thicknesses. AVP caused a reduction in average maximum spiral artery diameter (171±28 vs 121±8 um, p<0.05) and a trend toward reduced total spiral artery number (8.4±2.9 vs 4.9±0.7, p=0.13), but no difference in the maximum invasion depth of CK8-positive trophoblasts (310±50 vs 286±37 um, p=0.72). We conclude that AVP infusion is sufficient to induce cardinal mid-gestational features of PE in pregnant mice, including reduced spiral artery diameter. Such morphological changes may be associated with the placental hypoxia and reduced placental growth factor expression in model.

Nor-epinephrine versus vasopressin infusion for prevention of spinal-induced hypotension: a placebo-controlled study

Objectives: To evaluate the prophylactic effect of norepinephrine (NE) and vasopressin (VP) infusion on frequency and severity of spinal anaesthesia-induced hypotension (SAIH).Patients and methods:...

Vasopressin Antagonists Regulate Immune Responses in Preeclampsia

The early pathogenesis of preeclampsia (PreE) involves altered T helper (TH) cell populations and elevated inflammatory cytokine production. Consistent with current mouse and human literature, we observed an increase in TH1 and TH17 inflammatory cytokine production with a reduction in the TH2‐associated cytokine IL‐4 in our novel, chronic infusion of vasopressin (AVP) mouse model of PreE. The mechanisms of immune modulation by AVP in pregnancy have not been elucidated. As increased CD4+ T cell activity is involved in the development of PreE, the objective of this study was to determine AVP receptor expression in CD4+ T cells and which receptors play a role in the PreE immune phenotype.Splenic CD4+ T cells were negatively purified on gestational day 18 from wild‐type C57BL/6J female mice infused with AVP (24 ng/hr or saline s.c.) throughout pregnancy. AVP receptor (AVPR) 1a, 1b, and 2 expression was determined via qPCR normalized to 18S rRNA endogenous control. Mouse CD4+ T cells express all AVP receptors. AVPR2 is the highest expressed receptor in CD4+ T cells isolated from saline (N=7, p<0.05 and AVP‐infused (N=10, p<0.05) dams. Maternal mid‐gestation mononuclear cells isolated from healthy human control or PreE‐affected pregnancies were obtained from the University of Iowa Maternal‐Fetal Tissue Bank (IRB #200910784) and similarly analyzed. As in mouse CD4+ T cells, human control (N=27, p<0.05) and PreE‐affected (N=26, p<0.05) CD4+ T cells most highly express AVPR2. AVPR1a is also highly expressed while AVPR1b is the least expressed. CD4+ T cells from human PreE‐affected women express significantly lower AVPR1a (N=0.23, p<0.05) versus controls.To evaluate the contribution of specific AVPRs to the PreE immune phenotype, AVP and the AVPR antagonists conivaptan (blocks AVPR1a and AVPR2), relcovaptan (blocks AVPR1a), or nelivaptan (blocks AVPR1b) were infused (22 ng/hour) into dams throughout gestation and cytokines were analyzed via ELISA. Conivaptan (N=5, p<0.05) and nelivaptan (N=5, p<0.05) correct the IL‐4 deficiency in the maternal kidney of PreE dams while relcovaptan (N=5, p=NS) does not. The reduction of IL‐4 production in the placenta of AVP‐infused dams is also corrected by conivaptan (N=5, p<0.05) and nelivaptan (N=5, p<0.05), but not relcovaptan (N=5, p=NS). Interestingly, only relcovaptan (N=5, p<0.05) corrects the increased IL‐17 induced by AVP in the placenta while nelivaptan (N=5, p<0.05) further enhances placental IL‐17.Here, we demonstrate human and mouse CD4+ T cells express AVPRs and inhibition of AVPRs attenuates the TH2 cytokine suppression and elevated TH17 cytokine production observed in PreE. Although the actions of AVP on the vascular and renal systems are well documented, these novel data suggest AVP differentially acts through specific AVP receptors to mediate immune responses in target organs during PreE.Support or Funding InformationDepartment of Obstetrics & Gynecology at the University of Iowa Hospitals &Clinics, The Maternal Fetal Tissue Bank, University of Iowa Hospitals & Clinics, Institute for Clinical and Translational Science (NIH KL2 RR024980‐2 to MKS), The Reproductive Scientist Development Program: NIH K12 HD000849 (MKS), NIHK99/R00 HL098276, and PPG HL084207 (JLG), University of Iowa Carver Collaborative Science Grant (MKS & JLG), University of Iowa Immunology Postdoctoral Training Grant (SMS), AHA Innovation Grant (MKS & JLG), AHA Strategically Focused Research Network Grant (MKS & JLG), AHA Predoctoral Research Fellowship (JAS), AHA Postdoctoral Research Fellowship (SMS), John Warner Maternal Health Grant, Shelly Bridgewater Dreams Foundation Grant (SMS)

Early and sustained vasopressin infusion augments the hemodynamic efficacy of restrictive fluid resuscitation and improves survival in a liver laceration model of hemorrhagic shock

Current management of hemorrhagic shock favors restrictive fluid resuscitation before control of the bleeding source. We investigated the additional effects of early and sustained vasopressin infusion in a swine model of hemorrhagic shock produced by liver laceration. Forty male domestic pigs (32-40 kg) had a liver laceration inflicted with an X-shaped blade clamp, 32 received a second laceration at minute 7.5, and 24 received two additional lacerations at minute 15. Using a two-by-two factorial design, animals were randomized 1:1 to receive vasopressin infusion (0.04 U/kg per minute) or vehicle intraosseously from minute 7 until minute 240 and 1:1 to receive isotonic sodium chloride solution (12 mL/kg) intravenously at minute 30 or no fluids. Kaplan-Meier curves showed greater survival after vasopressin with isotonic sodium chloride solution (8/10) compared to vasopressin without isotonic sodium chloride solution (4/10), vehicle with isotonic sodium chloride solution (3/10), or vehicle without isotonic sodium chloride solution (3/10), but the differences were not statistically significant (p = 0.095 by log-rank test). However, logistic regression showed vasopressin to elicit a statistically significant benefit on survival (p = 0.042). Vasopressin augmented mean aortic pressure between 10 and 20 mm Hg without intensifying the rate of bleeding from liver laceration, which was virtually identical to that of vehicle-treated animals (33.9 ± 5.1 and 33.8 ± 4.8 mL/kg). Vasopressin increased systemic vascular resistance and reduced transcapillary fluid extravasation, augmenting the volume of isotonic sodium chloride solution retained (6.5 ± 2.7 vs 2.4 ± 2.0 mL/kg by minute 60). The cardiac output and blood flow to the myocardium, liver, spleen, kidney, small bowel, and skeletal muscle at minute 120 and minute 180 were comparable or higher in the vasopressin group. Early and sustained vasopressin infusion provided critical hemodynamic stability during hemorrhagic shock induced by liver laceration and increased the hemodynamic efficacy of restrictive fluid resuscitation without intensifying bleeding or compromising organ blood flow resulting in improved 240-minute survival.

Microcirculation improvement after short-term infusion of vasopressin in septic shock is dependent on noradrenaline

OBJECTIVES:To assess the impact of vasopressin on the microcirculation and to develop a predictive model to estimate the probability of microcirculatory recruitment in patients with septic shock.METHODS:This prospective interventional study included patients with septic shock receiving noradrenaline for less than 48 hours. We infused vasopressin at 0.04 U/min for one hour. Hemodynamic measurements, including sidestream dark-field imaging, were obtained immediately before vasopressin infusion, 1 hour after vasopressin infusion and 1 hour after vasopressin withdrawal. We defined patients with more than a 10% increase in total vascular density and perfused vascular density as responders. ClinicalTrials.gov: NCT02053675.RESULTS:Eighteen patients were included, and nine (50%) showed improved microcirculation after infusion of vasopressin. The noradrenaline dose was significantly reduced after vasopressin (p=0.001) and was higher both at baseline and during vasopressin infusion in the responders than in the non-responders. The strongest predictor for a favorable microcirculatory response was the dose of noradrenaline at baseline (OR=4.5; 95% CI: 1.2-17.0; p=0.027). For patients using a noradrenaline dose higher than 0.38 mcg/kg/min, the probability that microcirculatory perfusion would be improved with vasopressin was 53% (sensitivity 78%, specificity 77%).CONCLUSIONS:In patients with septic shock for no longer than 48 h, administration of vasopressin is likely to result in an improvement in microcirculation when the baseline noradrenaline dose is higher than 0.38 mcg/kg/min.

Vasopressin in perioperative management of congenital diaphragmatic hernia

Perioperative care of infants with diaphragmatic hernias can be a challenge because of pulmonary hypertension and systemic hypotension. The objective of this study was to report the usefulness of vasopressin infusion in improving pulmonary and systemic haemodynamics in an infant with congenital diaphragmatic hernia. Oxygenation failure, pulmonary hypertension and refractory systemic hypotension in infants with diaphragmatic hernia are managed by ventilation and conventional inotropes (dobutamine and dopamine). Vasopressin is a recent addition that exerts vasodilatory effects on the pulmonary circulation and vasotonic effects on the systemic circulation. The net effect is a reduction in pulmonary vascular resistance and improvement in cardiac output and reduced need for inotropes. This paradoxical response (vasodilation in some vascular beds) distinguishes it from other vasoconstrictor agents. The infant was administered intravenous vasopressin infusion for severe pulmonary hypertension that needed inhaled nitric oxide and for systemic hypotension that needed multiple inotropes under close echocardiographic monitoring. Informed parental consent and appropriate institutional ethics approval were obtained. Addition of vasopressin led to improved oxygenation and weaning off from nitric therapy. Improvement in cardiac output and blood pressure facilitated the weaning off from inotropes. Close echocardiographic monitoring was performed to ascertain the haemodynamic effects of vasopressin. Under echocardiographic monitoring, vasopressin is a useful adjunct for managing pulmonary and systemic perioperative haemodynamic instability in infants with diaphragmatic hernia.Keywords: congenital diaphragmatic hernia, echocardiography, vasopressin

Vasopressin in Septic Shock; Assessment of Sepsis Biomarkers: A Randomized, Controlled Trial.

Background and Aims:Vasopressin (VP) in sepsis apart from vasoconstrictive effect may have some immunomodulatory effects. The aim of this study was to evaluate the effect of VP on different aspect of sepsis by measuring of sepsis biomarkers.Materials and Methods:In this trial, a total number of 42 septic shock patients were included. The first group received norepinephrine (NE) infusion to reach the target mean arterial pressure (MAP) of ≥ 65 mm Hg and the second group received arginine vasopressin (AVP) infusion in addition to NE. Serum lactate, C-reactive protein (CRP), interleukin-6 (IL-6), IL-10, pentraxin 3 (PTX3), angiopoietin 1 and 2 (Ang 1 and 2) levels were assessed.Results:Level of IL-6 and IL-10 decreased, but there was no significant difference between the two groups after 48 h. CRP and PTX3 levels were not also significantly different between groups. Although Angs were not statistically different, there was a trend toward higher Ang-1 in and lower Ang 2 in AVP group after 24 and 48 h. In addition, lactate level did not differ between NE and AVP groups. There was no interaction between VP and hydrocortisone use on IL-6, IL-10, and PTX3, but a significant statistical interaction on Ang 1 and Ang 2 were observed.Conclusions:Although analysis of sepsis biomarkers showed no significant difference between two groups, no immunomodulatory effect for VP alone, subgroup analysis of hydrocortisone used in this study showed that the combination of glucocorticoids and AVP had a significant effect on Angs level which eventually causes less endothelial permeability and higher MAP in this group of patients.

A brief review of the use of vasopressin in critically ill children

Robust clinical evidence for the use of vasopressin in children is scant. Low dose vasopressin infusions may be tried in catecholamine resistant shock or refractory cardiac arrest. It significantly improves hemodynamic indices without necessarily translating into clinical benefit. There appears to be a trend to greater tissue ischemia with its use. Evidence to date has not demonstrated clear efficacy for vasopressin’s routine use in management of pediatric shock. Further high-quality research is essential before it can be recommended as a routine standard of care.

Hypothalamic Vasopressinergic Projections Innervate Central Amygdala GABAergic Neurons: Implications for Anxiety and Stress Coping.

The arginine-vasopressin (AVP)-containing hypothalamic magnocellular neurosecretory neurons (VPMNNs) are known for their role in hydro-electrolytic balance control via their projections to the neurohypophysis. Recently, projections from these same neurons to hippocampus, habenula and other brain regions in which vasopressin infusion modulates contingent social and emotionally-affected behaviors, have been reported. Here, we present evidence that VPMNN collaterals also project to the amygdaloid complex, and establish synaptic connections with neurons in central amygdala (CeA). The density of AVP innervation in amygdala was substantially increased in adult rats that had experienced neonatal maternal separation (MS), consistent with our previous observations that MS enhances VPMNN number in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus. In the CeA, V1a AVP receptor mRNA was only observed in GABAergic neurons, demonstrated by complete co-localization of V1a transcripts in neurons expressing Gad1 and Gad2 transcripts in CeA using the RNAscope method. V1b and V2 receptor mRNAs were not detected, using the same method. Water-deprivation (WD) for 24 h, which increased the metabolic activity of VPMNNs, also increased anxiety-like behavior measured using the elevated plus maze (EPM) test, and this effect was mimicked by bilateral microinfusion of AVP into the CeA. Anxious behavior induced by either WD or AVP infusion was reversed by CeA infusion of V1a antagonist. VPMNNs are thus a newly discovered source of CeA inhibitory circuit modulation, through which both early-life and adult stress coping signals are conveyed from the hypothalamus to the amygdala.

Risk of Hyponatremia in Patients with Aneurysmal Subarachnoid Hemorrhage Treated with Exogenous Vasopressin Infusion.

Vasopressin is one of the vasopressors used to augment blood pressure in subarachnoid hemorrhage (SAH) patients with clinically significant vasospasm. The purpose of the present study was to determine whether the administration of vasopressin to a population of SAH patients was an independent predictor of developing hyponatremia. A retrospective review on the health records of 106 patients admitted to the University of Alberta Hospital Neurosciences ICU, Edmonton AB, Canada, with SAH from June 2013 to December 2015 was conducted. Serum sodium changes in patients receiving vasoactive drugs were compared. In addition, independent predictors for hyponatremia (Na<135mmol/L) were determined using a multivariate logistic regression model. Patients treated with vasopressin in addition to other vasoactive drugs had significantly higher sodium changes compared to those treated with other vasoactive drugs (-4.7±6 vs -0.1±2.4mmol/L, respectively, p value 0.001). Hyponatremia occurred in 14 patients (70%) treated with vasopressin, 10 patients (44%) treated with vasoactive drugs other than vasopressin (p value 0.081), and 24 patients (38%) who did not receive any vasoactive drug (p value 0.013). In multivariate logistic regression analysis, when adjusting for disease severity, age, sex, aneurysm location, and treatment, vasopressin was associated with hyponatremia (OR 3.58, 95% CI, 1.02-12.5, p value 0.046). The results of the present study suggest that hyponatremia may be more common in SAH patients treated with exogenous vasopressin compared to those who did not receive it. Serum sodium should be monitored closely when vasopressin is being used in the SAH population. Further studies are needed to confirm the effect of exogenous vasopressin on serum sodium levels in SAH populations.

Abstract 033: Differential Vasopressin Receptor Expression on CD4+ T Cells from Mouse and Human Preeclamptic Pregnancies

The pathogenesis of preeclampsia (PreE) involves the failure of the maternal immune system to normally tolerate the pregnancy. Inflammatory cytokines are elevated in PreE-affected women with a concurrent decrease in anti-inflammatory cytokine production. Consistent with what other groups have observed in mouse models of hypertension during pregnancy and in human PreE-affected pregnancies, we observed increased inflammatory cytokine production and CD4+ T helper populations in our chronic infusion of vasopressin (AVP) mouse model of PreE. The mechanisms of immune modulation by AVP have not been elucidated. As increased T cell activity is involved in the development of PreE, the objective of this study was to investigate if CD4+ T cells express AVP receptors. Splenic CD4+ T cells were negatively purified from C57BL/6J saline and AVP-infused (24 ng/hour) dams. Expression of AVP receptors (AVPR) 1a, 1b, 2, and the aminopeptidase LNPEP (catalyzes AVP degradation) was determined via qPCR. Raw cycle threshold (Ct) values were normalized (ΔCt) against the 18S rRNA endogenous control. Mouse CD4+ T cells express all AVP receptors and LNPEP. By ANOVA, AVPR2 is the highest expressed receptor in CD4+ T cells from saline (N=7, p=0.002) and AVP-infused (N=10, p&lt;0.0001) dams. Human maternal mononuclear cells, obtained from the University of Iowa Maternal-Fetal Tissue Bank (IRB #200910784) from control and PreE-affected women, were similarly analyzed. As in mouse CD4+ T cells, human control (N=27, p&lt;0.0001) and PreE-affected (N=26, p&lt;0.0001) CD4+ T cells most highly expressed AVPR2. AVPR1a was also highly expressed while AVPR1b was the least expressed. CD4+ T cells isolated from human PreE-affected women expressed significantly lower AVPR1a (10.0±0.3 N=27 vs. 11.1±0.2 N=0.23, p=0.009) and increased LNPEP (17.2±0.5 N=27 vs. 15.1±0.3 N=26, p=0.001) than controls. Here, we demonstrate CD4+ T cells, both mouse and human, express AVP receptors and that 1a and 2 are highest expressed. Although the actions of AVP on the vasculature are primarily mediated through AVPR1a, these data suggest AVP may differentially act through AVPR1a to mediate immune responses during PreE.

Simultaneous anterior and posterior serosal mapping of gastric slow-wave dysrhythmias induced by vasopressin.

What is the central question of this study? This study aimed to provide the first comparison of simultaneous high-resolution mapping of anterior and posterior gastric serosa over sustained periods. What is the main finding and its importance? Episodes of spontaneous gastric slow-wave dysrhythmias increased significantly following intravenous infusion of vasopressin compared with the baseline state. A number of persistent dysrhythmias were defined, including ectopic activation, conduction block, rotor, retrograde and collision/merger of wavefronts. Slow-wave dysrhythmias could occur either simultaneously or independently on the anterior and posterior gastric serosa, and interacted depending on activation-repolarization and frequency dynamics. High-resolution mapping enables mechanistic insights into gastric slow-wave dysrhythmias and is now achieving clinical translation. However, previous studies have focused mainly on dysrhythmias occurring on the anterior gastric wall. The present study simultaneously mapped the anterior and posterior gastric serosa during episodes of dysrhythmias induced by vasopressin to aid understanding of dysrhythmia initiation, maintenance and termination. High-resolution mapping (8×16 electrodes on each serosa; 20-74cm2 ) was performed in anaesthetized dogs. Baseline recordings (21±8min) were followed by intravenous infusion of vasopressin (0.1-0.5IUml-1 at 60-190mlh-1 ) and further recordings (22±13min). Slow-wave activation maps, amplitudes, velocity, interval and frequency were calculated, and differences compared between baseline and postinfusion. All dogs demonstrated an increased prevalence of dysrhythmic events following infusion of vasopressin (17 versus 51%). Both amplitude and velocity demonstrated significant differences (baseline versus postinfusion: 3.6versus 2.2mV; 7.7versus 6.5mm s-1 ; P<0.05 for both). Dysrhythmias occurred simultaneously or independently on the anterior and posterior serosa, and then interacted according to frequency dynamics. A number of persistent dysrhythmias were compared, including the following: ectopic activation (n=2 animals), conduction block (n=1), rotor (n=2), retrograde (n=3) and collision/merger of wavefronts (n=2). We conclude that infusion of vasopressin induces gastric dysrhythmias, which occur across a heterogeneous range of frequencies and patterns. The results demonstrate that different classes of gastric dysrhythmias may arise simultaneously or independently in one or both surfaces of the serosa, then interact according to their relative frequencies. These results will help to inform interpretation of clinical dysrhythmia.

The use of angiotensin II in distributive shock.

The interest in the use of non-catecholamine vasopressors for the treatment of hypotension and shock has increased in recent years. The use of vasopressin as an adjunctive vasopressor in shock was reinvigorated by Landry and colleagues [1] and then carefully assessed in the Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock (VASST) trial [2]. In a large, international, multi-center trial, vasopressin demonstrated a satisfactory safety profile, but did not show an improvement in survival compared to norepinephrine [2]. In addition to vasopressin, angiotensin II (ATII) has been proposed as a useful vasopressor for the management of shock [3, 4]. The original studies that assessed ATII for the management of shock were conducted decades ago [3, 5]. In those trials, ATII was assessed primarily in head-to-head studies compared to catecholamine vasopressors, and was shown to have comparable vasopressor effect to norepinephrine [5]. Multiple case reports demonstrated the ability of ATII to work effectively as a vasopressor and also showed that ATII could be used in combination with catecholamines. However, ATII has not been subjected to a randomized controlled trial (RCT) and ATII has not been available at the bedside for at least 15 years. ATII has been used extensively in physiology, hypertension, cancer, and pregnancy studies in humans and has a good safety profile. Recently, we published in Critical Care the first RCT of ATII in patients with distributive shock, and showed that a dose of ATII of 5–40 ng/kg/min was associated with improved blood pressure that resulted in significant catecholamine sparing [6]. In that modest-sized study, we noted that 2 of the 10 patients treated with ATII were exquisitely sensitive to ATII. In these two cases, the subjects receiving physiologic doses of ATII were hypertensive despite the discontinuation of their norepinephrine. When ATII was stopped in these two patients, re-initiation of a high dose of norepinephrine (i.e., 0.3 μg/kg/min) was immediately required in order to maintain mean arterial pressure goals. We speculated that the reason for this sensitivity was likely due to premorbid exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the development of shock. Our theory was that if the subjects were previously treated with ACE inhibitors, their ATII Type I receptors would be upregulated, thus making the patient more sensitive to exogenous ATII infusion. However, after a thorough chart review and re-review, we could not document an ACE inhibitor exposure. While it is possible that the ACE inhibitor exposure was present and not documented, there is an alternative explanation which is related to the nature and distribution of ACE. Angiotensin I (ATI) is converted efficiently to ATII almost exclusively in the lung [7]. ACE is an ectoenzyme which is distributed primarily on the pulmonary capillary endothelium [8, 9]. As a consequence, diseases that affect the pulmonary capillary endothelium can disrupt ACE functionality. Acute respiratory distress syndrome (ARDS) is often associated with significant pulmonary endothelial injury [10]. Patients with more severe ARDS have less capacity to convert angiotensin ATI to ATII, and this disturbance is inversely correlated to the severity of ARDS [11]. Upon re-review, we found that the two patients in our study who were exquisitely ATII sensitive had severe ARDS. Our revised hypothesis is that patients with severe ARDS may have significant pulmonary endothelial injury, which results in either an absolute or relative insufficiency of ATII due to loss of pulmonary ACE. Pre-clinical and human case reports demonstrate that when ATII production is inhibited by ACE inhibition, patients become catecholamine resistant [12]. Thus, patients with ARDS may be at particular risk for ATII insufficiency, which would likely exacerbate existing hypotension. In addition, ATII insufficiency can lead to acute kidney injury due to decreased intra-glomerular pressure. We hypothesize that some patients with shock and ARDS may be at particular risk for a deleterious cascade of events related to ATII insufficiency (Fig. 1). Fig. 1 Proposed cascade of events leading to angiotensin II insufficiency. The figure outlines a cascade of events that could occur amongst patients with inflammation and/or lung injury. When acute lung injury is significantly complicated by pulmonary endothelial ... We would anticipate that, for those patients with ATII insufficiency, increased levels of ATI and reduced ATII may be indicative of this pathophysiology, and that ATI and ATII levels, as well as the ratio of ATI/ATII, may be useful as biomarkers of early ARDS or ARDS severity prior to the development of severe hypoxemia. Moreover, we would anticipate these patients to be ATII-sensitive. We believe that further research to test this hypothesis is warranted. Currently, ATII is being studied in a multi-center international RCT (NCT02338843) wherein some of these parameters will be assessed and may shed further light on this proposed hypothesis.

Vasopressin‐induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection

To minimize blood loss during hepatic surgery, various methods are used to reduce pressure and flow within the hepato-splanchnic circulation. In this study, the effect of low- to moderate doses of vasopressin, a potent splanchnic vasoconstrictor, on changes in portal and hepatic venous pressures and splanchnic and hepato-splanchnic blood flows were assessed in elective liver resection surgery. Twelve patients were studied. Cardiac output (CO), stroke volume (SV), mean arterial (MAP), central venous (CVP), portal venous (PVP) and hepatic venous pressures (HVP) were measured, intraoperatively, at baseline and during vasopressin infusion at two infusion rates (2.4 and 4.8 U/h). From arterial and venous blood gases, the portal (splanchnic) and hepato-splanchnic blood flow changes were calculated, using Fick's equation. CO, SV, MAP and CVP increased slightly, but significantly, while systemic vascular resistance and heart rate remained unchanged at the highest infusion rate of vasopressin. PVP was not affected by vasopressin, while HVP increased slightly. Vasopressin infusion at 2.4 and 4.8 U/h reduced portal blood flow (-26% and -37%, respectively) and to a lesser extent hepato-splanchnic blood flow (-9% and -14%, respectively). The arterial-portal vein lactate gradient was not significantly affected by vasopressin. Postoperative serum creatinine was not affected by vasopressin. Short-term low to moderate infusion rates of vasopressin induced a splanchnic vasoconstriction without metabolic signs of splanchnic hypoperfusion or subsequent renal impairment. Vasopressin caused a centralization of blood volume and increased cardiac output. Vasopressin does not lower portal or hepatic venous pressures in this clinical setting.

Prevention of hypotension induced by combined spinal epidural anesthesia using continuous infusion of vasopressin: A randomized trial.

Background:Central neuraxial blockade (CNB) is an established technique of providing anesthesia for surgeries of the lower limb and abdomen. Hypotension is the most common side effect of CNB. It was hypothesized that by supplementing the initial burst of vasopressin following hypovolemia, hypotension following combined spinal epidural anesthesia (CSEA) could be avoided.Materials and Methods:A total of 122 patients undergoing lower limb and abdomen surgeries were included in the study, with 61 patients randomized into two groups - I and II. Patients in Group I received infusion of normal saline as soon as CSEA was applied. When systolic blood pressure (SBP) decreased to <90 mmHg, they received a 6 mg bolus of mephentermine to counteract hypotension. Patients in Group II received a continuous infusion of vasopressin as soon as CSEA was applied. If despite maximum dose of vasopressin, SBP dropped to < 90 mmHg, then intravenous mephentermine was administered to counteract hypotension. Hemodynamic parameters and side effects were noted.Results:Level of block attained in both groups was comparable in terms of dermatomal height. The mean SBP and mean arterial pressure values of Group I were significantly lower than in Group II in the initial 14 min. Diastolic BP was also significantly lower in Group I. Heart rate was found to be lower in Group II, especially after 30 min (P < 0.05).Conclusion:Maintaining plasma levels of the physiological burst of vasopressin helps to avoid hypotension following neuraxial blockade. Continuous infusion of vasopressin at 1–3 U/h can prevent hypotension following neuraxial blockade.

Abstract P094: Vasopressin Infusion in Mice During Pregnancy Results in Immune Alterations Consistent with Human Preeclampsia

The immediate and long-term maternal and fetal health complications of preeclampsia (PreE) have been linked to an aberrant T helper immune response and pro-inflammatory cytokine profile. AVP secretion is both stimulated by and stimulates pro-inflammatory cytokine secretion and activation of lymphocytes. Our AVP infusion mouse model of PreE closely replicates human PreE. The objective of this study was to investigate if AVP infusion induces the maternal-fetal immune alterations in PreE. Immune responses were evaluated in wild-type C57BL/6 female mice chronically infused with AVP (24 ng/hr or saline s.c.) throughout pregnancy. By flow cytometry, we observed an increase in the frequency of IL-17 (1.2% vs. 2.6%, p&lt;0.05), TNFα (0.9% vs. 1.6%, p&lt;0.0001), and IFNγ (1.8% vs. 3.4%, p&lt;0.05) expressing T cells in AVP dams. An increase in the frequency of IL-12 producing cells (1.0% vs. 2.4%, p&lt;0.05) and elevated expression of co-stimulatory molecules on dendritic cells (DCs) from AVP dams suggested enhanced DC function. The maternal plasma revealed a significant reduction in IL-17 (7.1e+6 vs. 3.4e+5 ng/g, p&lt;0.05) and IL-6 (3.4e+5 vs. 0.0 ng/g, p&lt;0.01) production in AVP dams by ELISA as seen in human PreE. Pro-inflammatory TNFα was also significantly decreased in the maternal kidney of AVP dams (2.3e+9 vs. 1.3e+9 ng/g, p&lt;0.05). IL-4 production was significantly reduced in the maternal kidney of AVP dams (5.7e+7 vs. 3.4+7 ng/g, p&lt;0.05) suggesting a blunted Th2 response as seen in human PreE. AVP infusion did not result in alterations of cytokine production in the maternal liver, or fetal liver and kidney. Interestingly, IL-17 production was increased in the amniotic fluid (3.0e+6 vs. 1.3e+7 ng/g, p&lt;0.05) and lower in the placenta (2.5e+7 vs. 1.3e+7 ng/g, p&lt;0.0001) of AVP dams. IL-4 production was decreased in both the amniotic fluid (4.5e+5 vs. 2.0e+5 ng/g, p&lt;0.05) and placenta (3.1e+6 vs. 2.0e+6 ng/g, p&lt;0.05) of AVP dams again suggesting a lower Th2 response. These data support our hypothesis that AVP induces maternal-fetal immune alterations consistent with human PreE. Ongoing experiments are aimed at identifying the lymphocytes and cytokines involved as well as local vs. systemic immune dysfunction induced by AVP in pregnancy.

Vasopressin Infusion with Small-Volume Fluid Resuscitation during Hemorrhagic Shock Promotes Hemodynamic Stability and Survival in Swine.

IntroductionCurrent management of hemorrhagic shock (HS) in the battlefield and civilian settings favors small-volume fluid resuscitation before controlling the source of bleeding. We investigated in a swine model of HS the effects of vasopressin infusion along with small-volume fluid resuscitation; with erythropoietin (EPO) and HS severity as additional factors.MethodsHS was induced in 24 male domestic pigs (36 to 41 kg) by blood withdrawal (BW) through a right atrial cannula modeling spontaneous bleeding by a mono-exponential decay function. The initial 12 pigs received no fluids; the last 12 pigs received normal saline (NS) half the BW volume. Pigs were randomized 2:1 to receive intraosseously vasopressin (0.04 U/kg·min-1) or vehicle control from minute 7 to minute 210. Pigs assigned to vasopressin were further randomized 1:1 to receive EPO (1,200 U/kg) or vehicle control and 1:1 to have 65% or 75% BW of their blood volume. Shed blood was reinfused at 210 minutes and the pigs recovered from anesthesia.ResultsSurvival at 72 hours was influenced by vasopressin and NS but not by EPO or % BW. Vasopressin with NS promoted the highest survival (8/8) followed by vasopressin without NS (3/8), NS without vasopressin (1/4), and neither treatment (0/4) with overall statistical significance (log-rank test, p = 0.009) and each subset different from vasopressin with NS by Holm-Sidak test. Vasopressin increased systemic vascular resistance whereas NS increased cardiac output.ConclusionVasopressin infusion with small-volume fluid resuscitation during severe HS was highly effective enabling critical hemodynamic stabilization and improved 72 hour survival.

Vasopressin decreases pulmonary-to-systemic vascular resistance ratio in a porcine model of severe hemorrhagic shock.

Vasopressors are gaining renewed interest as treatment adjuncts in hemorrhagic shock. The ideal vasoconstrictor will increase systemic blood pressure without increasing pulmonary vascular resistance (PVR), which hinders pulmonary perfusion and exacerbates hypoxemia. However, the selectivity of pressors for pulmonary versus systemic vasoconstriction during hemorrhage has not been characterized. The purpose of this study was to test the hypothesis that vasopressin (VP) has distinct effects on pulmonary versus systemic hemodynamics, unlike the catecholamine vasopressors norepinephrine (NE) and phenylephrine (PE). Anesthetized and ventilated pigs were assigned to resuscitation with saline only (n = 7) or saline with VP (n = 6), NE (n = 6), or PE (n = 6). Animals were hemorrhaged to a target volume of 30 mL/kg and a mean arterial pressure of 35 mmHg. One hour after the start of hemorrhage, animals were resuscitated with saline up to one shed blood volume, followed by either additional saline or a vasopressor. Hemodynamics and oxygenation were measured hourly for 4 h after the start of hemorrhage. Vasopressin increased systemic vascular resistance (SVR) while sparing the pulmonary vasculature, leading to a 45% decrease in the PVR/SVR ratio compared with treatment with PE. Conversely, NE induced pulmonary hypertension and led to an increased PVR/SVR ratio associated with decreased oxygen saturation. Phenylephrine and crystalloid had no significant effect on the PVR/SVR ratio. Sparing of pulmonary vasoconstriction occurs only with VP, not with administration of crystalloid or catecholamine pressors. The ability of VP to maintain blood oxygenation indicates that VP may prevent hypoxemia in the management of hemorrhagic shock.

Vasopressin attenuates ischemia–reperfusion injury via reduction of oxidative stress and inhibition of mitochondrial permeability transition pore opening in rat hearts

Aim of this study was to investigate the involvement of the mitochondrial permeability transition pore (MPTP) and oxidative stress in the cardioprotective effect of vasopressin (AVP) on ischemia/reperfusion (I/R) injury. Anesthetized male wistar rats were subjected to regional 30min ischemia and 120min reperfusion and randomly divided into nine groups: (1) Control; saline was administered intravenously before ischemia, (2) vasopressin was administrated 10min prior to ischemia, (3, 4) Atractyloside as MPTP opener, was injected 5min prior to reperfusion without and with vasopressin, (5, 6) Cyclosporine A as a MPTP closer, was injected 5min prior to reperfusion without and with vasopressin, (7) mitochondria were isolated from control group and CaCl2 was added as MPTP opener and swelling inducer, (8) isolated mitochondria from Control hearts was incubated with Cyclosporine A before adding the CaCl2 (9) CaCl2 was added to isolated mitochondria from vasopressin group. Infusion of vasopressin decreased infarct size (18.6±1.7% vs. control group 37.6±2.4%), biochemical parameters [LDH (Lactate Dehydrogenase), CK-MB (Creatine Kinase-MB) and MDA (Malondialdehyde) plasma levels, PAB (Prooxidant–antioxidant balance)] compared to control group. Atactyloside suppressed the cardioprotective effect of vasopressin (32.5±1.9% vs. 18.6±1.7%) but administration of the Cyclosporine A without and with vasopressin significantly reduced infarct size to 17.7±4% (P<0.001) and 22.7±3% (P<0.01) respectively, vs. 37.6±2.4% in control group. Also, vasopressin, similar to Cyclosporine A, led to decrease in CaCl2-induced swelling. It seems that vasopressin through antioxidant effect and MPTP inhibition has created a cardioprotection against ischemia/reperfusion injuries.

Vasopressin Infusion During Pregnancy is Associated with Cardiovascular and Metabolic Dysfunction in Offspring

Vasopressin Infusion During Pregnancy is Associated with Cardiovascular and Metabolic Dysfunction in Offspring