The Role of Arginine-Vasopressin in Stroke and the Potential Use of Arginine-Vasopressin Type 1 Receptor Antagonists in Stroke Therapy: A Narrative Review.

Stroke is a life-threatening condition in which accurate diagnoses and timely treatment are critical for successful neurological recovery. The current acute treatment strategies, particularly non-invasive interventions, are limited, thus urging the need for novel therapeutical targets. Arginine vasopressin (AVP) receptor antagonists are emerging as potential targets to treat edema formation and subsequent elevation in intracranial pressure, both significant causes of mortality in acute stroke. Here, we summarize the current knowledge on the mechanisms leading to AVP hyperexcretion in acute stroke and the subsequent secondary neuropathological responses. Furthermore, we discuss the work supporting the predictive value of measuring copeptin, a surrogate marker of AVP in stroke patients, followed by a review of the experimental evidence suggesting AVP receptor antagonists in stroke therapy. As we highlight throughout the narrative, critical gaps in the literature exist and indicate the need for further research to understand better AVP mechanisms in stroke. Likewise, there are advantages and limitations in using copeptin as a prognostic tool, and the translation of findings from experimental animal models to clinical settings has its challenges. Still, monitoring AVP levels and using AVP receptor antagonists as an add-on therapeutic intervention are potential promises in clinical applications to alleviate stroke neurological consequences.

Efficacy and Safety of Vasopressin and Terlipressin in Preterm Neonates: A Systematic Review.

INTRODUCTION: The use of arginine vasopressin (AVP) and terlipressin to treat hypotension in preterm neonates is increasing. Our aim was to review the available evidence on the efficacy and safety of AVP and terlipressin for use in preterm neonates. METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Web of Science, and Google Scholar from inception to September 2021 were searched for studies of AVP and terlipressin in the treatment of hypotension of any cause in preterm neonates. Primary outcomes were improvement in end-organ perfusion and mortality. The risk of bias assessment and certainty of the evidence were performed using appropriate tools. RESULTS: Fifteen studies describing the use of AVP (n = 12) or terlipressin (n = 3) among 148 preterm neonates were included. Certainly, the available evidence for the primary outcome of end-organ perfusion rated as very low. AVP or terlipressin were used to treat 144 and 4 neonates, respectively. Improvement in markers of end-organ perfusion was reported in 143 (99%) neonates treated with AVP and 3 (75%) treated with terlipressin. The mortality rate was 41% (n = 59) and 50% (n = 2) for neonates who received AVP and terlipressin, respectively. Hyponatremia was the most frequently reported adverse event (n = 37, 25%). CONCLUSION: AVP and terlipressin may improve measured blood pressure values and possibly end-organ perfusion among neonates with refractory hypotension. However, the efficacy-safety balance of these drugs should be assessed on an individual basis and as per the underlying cause. Studies on the optimal dosing, efficacy, and safety of AVP and terlipressin in preterm neonates with variable underlying conditions are critically needed.

Ondansetron in dogs with nausea associated with vestibular disease: A double-blinded, randomized placebo-controlled crossover study.

BACKGROUND: Nausea and emesis can be, among other signs, common manifestations of acute vestibular system dysfunction in dogs. Currently, antiemetic drugs, such as maropitant and metoclopramide, are used commonly, but do not appear to control nausea. A non-placebo-controlled preliminary study suggested good efficacy of 5-HT3-receptor antagonists, such as ondansetron, against nausea in dogs with vestibular syndrome. OBJECTIVES: To assess and confirm the effect of ondansetron on behavior suggestive of nausea in dogs with vestibular syndrome. ANIMALS: Fourteen dogs with vestibular syndrome and clinical signs of nausea presented to a neurology service. METHODS: Placebo-controlled, double-blinded, crossover study. Behavioral assessment was performed hourly for 4 hours using an established numerical rating scale. The criteria salivation, lip licking, vocalization, restlessness, lethargy, and general nausea were scored. The occurrence of emesis was recorded. After scoring at T0 (pre-dose) and T2 (2 hours post-dose) either ondansetron (0.5 mg/kg) or placebo was injected IV. Two hours post-dose, treatments were switched. Blood samples were collected to measure serum arginine vasopressin (AVP) concentration, which previously has been shown to correlate with clinical signs of nausea. RESULTS: Clinical resolution of nausea was observed 1 hour after administration of ondansetron, whereas serum AVP concentration decreased 4 hours after ondansetron administration. CONCLUSION AND CLINICAL IMPORTANCE: Administration of ondansetron IV is beneficial for dogs with nausea secondary to acute vestibular syndrome. Ondansetron substantially and rapidly decreased clinical signs of nausea behavior and stopped emesis.

Exploiting Dependence of Castration-Resistant Prostate Cancer on the Arginine Vasopressin Signaling Axis by Repurposing Vaptans.

Men with advanced prostate cancer are treated by androgen deprivation therapy but the disease recurs as incurable castration-resistant prostate cancer (CRPC), requiring new treatment options. We previously demonstrated that the G protein-coupled receptor (GPCR) arginine vasopressin receptor type1A (AVPR1A) is expressed in CRPC and promotes castration-resistant growth in vitro and in vivo. AVPR1A is part of a family of GPCR's including arginine vasopressin receptor type 2 (AVPR2). Interrogation of prostate cancer patient sample data revealed that coexpression of AVPR1A and AVPR2 is highly correlated with disease progression. Stimulation of AVPR2 with a selective agonist desmopressin promoted CRPC cell proliferation through cAMP/protein kinase A signaling, consistent with AVPR2 coupling to the G protein subunit alpha s. In contrast, blocking AVPR2 with a selective FDA-approved antagonist, tolvaptan, reduced cell growth. In CRPC xenografts, antagonizing AVPR2, AVPR1A, or both significantly reduced CRPC tumor growth as well as decreased on-target markers of tumor burden. Combinatorial use of AVPR1A and AVPR2 antagonists promoted apoptosis synergistically in CRPC cells. Furthermore, we found that castration-resistant cells produced AVP, the endogenous ligand for arginine vasopressin receptors, and knockout of AVP in CRPC cells significantly reduced proliferation suggesting possible AVP autocrine signaling. These data indicate that the AVP/arginine vasopressin receptor signaling axis represents a promising and clinically actionable target for CRPC. IMPLICATIONS: The arginine vasopressin signaling axis in CRPC provides a therapeutic window that is targetable through repurposing safe and effective AVPR1A and AVPR2 antagonists.

Influence of Timing and Catecholamine Requirements on Vasopressin Responsiveness in Critically ill Patients with Septic Shock.

Introduction: Despite its widespread use, there is a paucity of data to guide the optimal use of arginine vasopressin (AVP) in critically ill patients with septic shock. Methods: This multicenter retrospective cohort study conducted in critically ill adults sought to evaluate the role of catecholamine requirements and timing on responsiveness to AVP. Responsiveness was defined as both a decrease in ≥ 50% of catecholamine requirements and no decrease in mean arterial pressure (MAP) at 4 hours post-AVP initiation. Primary outcomes of interest included the proportion of patients who started AVP within 4 hours after starting catecholamine therapy, as well as baseline norepinephrine (NE) equivalents (< 15, 15-39, or ≥ 40 mcg/min). Multivariate analyses and logistic regression were performed to identify other factors associated with AVP responsiveness. Results: There were 300 patients included in this study, with 74 patients being responders and 226 being non-responders. There was no significant difference in the number of patients who received AVP within 4 hours from catecholamine initiation between responders and non-responders (35% vs. 42%, P = 0.29). There were more patients in the non-responder group requiring ≥ 40 mcg/min of NE equivalents at AVP initiation (30% vs. 16%, P = 0.023). Stress dose steroid use was less common in responders (35% vs. 52%, P = 0.011), which was consistent with logistic regression analysis (OR 0.56, 95% 0.32-0.98, P = 0.044). Clinical outcomes between responders and non-responders were similar, apart from ICU (5.4% vs. 19.5%) and hospital (5.4% vs. 20.4%) mortality being lower in responders (P = 0.0032 and P = 0.0002, respectively). Conclusion: Shorter times to AVP initiation was not associated with responsiveness at 4 hours post-catecholamine initiation, although non-responders tended to require higher doses of NE equivalents at time of AVP initiation. Concomitant corticosteroids were associated with a lower likelihood of AVP responsiveness.

Comparison of Vasopressin versus Norepinephrine in a Pig Model of Refractory Cardiogenic Shock Complicated by Cardiac Arrest and Resuscitated with Veno-arterial ECMO.

BACKGROUND: The choice of the best vasopressor after ExtraCorporeal Membrane Oxygenation (ECMO) implantation after cardiac arrest is not well defined. Circulatory flow recovery with ECMO is associated with vasoplegia and vasopressor need. The present study aimed to compare the effects of norepinephrine and vasopressin in the first 6 h after ECMO initiation. METHODS: Cardiac arrest was induced in 20 pigs by coronary surgical ligature and veno-arterial-ECMO was started after a 30-min period of cardio-pulmonary resuscitation. Pigs were randomized into two groups, arginine vasopressin (AVP) or norepinephrine (NE), with the drugs titrated to maintain a mean arterial pressure (MAP) at 65 mm Hg. Macrocirculatory and metabolic parameters were assessed by lactate clearance. Microcirculatory parameters were assessed by sublingual microcirculation with Sidestream Dark Field imaging and peripheral Near InfraRed Spectroscopy. Pulmonary edema was evaluated by measuring lung wet/dry weight ratio. RESULTS: No difference was found between groups regarding ECMO flow and MAP. Fluid resuscitation volume was higher in the NE group (14,000 [11,250-15,250] mL vs. 3,500 [1,750-4,000] mL in the AVP group, P < 0.05). Lung wet/dry weight ratio was higher in the Norepinephrine group. Lactate clearance between H0 and H6 was higher in the AVP group (47.84 [13.42-82.73]% vs. the NE group 25.66 [-7.31 to 35.34)% vs. P < 0.05). No significant difference was observed for sublingual microcirculation values. Baseline tissue oxygen saturation was comparable and higher at both H3 and H6 in the Vasopressin group comparatively to the Norepinephrine group (P < 0.05). Renal and liver function evolution also remained similar in the two groups throughout the study. CONCLUSIONS: AVP administration in refractory cardiac arrest resuscitated by veno-arterial-ECMO is associated with a faster lactate clearance, less fluid resuscitation, and less pulmonary edema when compared with NE for similar global and regional hemodynamic effects.

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)

Vasopressin in Patients with Septic Shock and Dynamic Left Ventricular Outflow Tract Obstruction.

PURPOSE: Left ventricular outflow tract obstruction (LVOTO) is a relatively uncommon but severe condition that may lead to hemodynamic impairment. It can be elicited by morphological (left ventricular hypertrophy, sigmoid septum, prominent papillary muscle, prolonged anterior mitral valve leaflet) and functional (hypovolemia, low afterload, hypercontractility, catecholamines) factors. We sought to determine the incidence of the most severe form of LVOTO in septic shock patients and describe the therapeutic effects of vasopressin. METHODS: Over a period of 29 months, 527 patients in septic shock were screened for LVOTO. All were mechanically ventilated and treated according to sepsis bundles, including pre-load optimization and norepinephrine infusion. Vasopressin was added in addition to norepinephrine to reduce the adrenergic burden and decrease LVOTO. RESULTS: Ten patients were diagnosed with the most severe form of LVOTO, including systolic anterior mitral valve motion (SAM) and severe mitral regurgitation (MR) with pulmonary oedema. The median norepinephrine dosage to obtain a mean arterial pressure of ≥70 mmHg was 0.58 mcg/Kg/min (IQR 0.40-0.78). All patients had a hyper-contractile left ventricle, septal hypertrophy, significant LVOTO (peak gradient 78 [56-123] mmHg) associated with SAM and severe MR with pulmonary oedema. Vasopressin (median 4 IU/h) allowed a significant reduction of norepinephrine (0.18 [0.14-0.30] mcg/kg/min; p = 0.01), LVOT gradient (35 [24-60] mmHg; p = 0.01) and MR with a significant paO2/FiO2 increase (174 [125-213] mmHg; p = 0.01). CONCLUSION: Vasopressin allowed a reduction of norepinephrine with subsequent LVOTO reduction and hemodynamic improvement of the most severe form of LVOTO, which represented 1.9% of all septic shock patients.

Regulation and Clinical Implication of Arginine Vasopressin in Patients with Severe Aortic Stenosis Referred to Trans-Catheter Aortic Valve Implantation.

Background and objectives: Plasma arginine vasopressin (P-AVP) is regulated by the non-osmotic pathway in patients with heart failure (HF) and reduced ejection fraction. However, the regulation of P-AVP in patients with severe aortic stenosis (AS) remains unknown. Materials and Methods: Consecutive patients with severe AS who received trans-catheter aortic valve implantation (TAVI) between Apr 2016 and Apr 2019 were enrolled in this prospective study. Clinical data including P-AVP were obtained just before TAVI, and the correlation between P-AVP and other variables was investigated. Results: In total, 159 patients with severe AS (85.3 ± 4.6 years, male 26%) were enrolled. P-AVP was 1.45 ± 1.13 ng/mL and cardiac index was relatively preserved (2.76 ± 0.54 L/min/m2). There was no significant correlation between cardiac index and P-AVP (p > 0.05), whereas plasma osmolality had a moderate positive correlation with P-AVP (r = 0.35, p < 0.01), predominantly due to blood urea nitrogen (r = 0.27, p < 0.01). Patients with diuretics had significantly higher P-AVP than those without diuretics (1.65 ± 1.43 vs. 1.22 ± 0.57 pg/mL, p < 0.01). Two-year survivals free from HF readmission were statistically comparable irrespective of the level of pre-procedural P-AVP (p = 0.44). Conclusion: In patients with severe high-gradient AS who received TAVI, the P-AVP level was dominantly regulated by plasma osmolality instead of arterial underfilling. The clinical implication of elevated P-AVP in the TAVI candidates is the next concern.

[Vasopressin in the critically ill patient]. / La vasopressine chez le patient en état critique.

Vasopressin (AVP) is a posterior pituitary hormone initially known for its antidiuretic actions. In this article, we recall the biochemical and pharmacological characteristics of the AVP and its analogues. Currently, its main indication in critical care medicine is vasoplegic shock in view of its vasopressive properties. This strong vasopressive activity is related to the activation of V1 receptors located in the vascular smooth muscle. The scientific evidence of the AVP therapy, and its potential benefits versus norepinephrine in vasoplegic shock, is reviewed in this article. Similarly, we present the other indications of vasopressin in the critical patient, based on recent studies and international guidelines.

La vasopressine (AVP) est une hormone post-hypophysaire connue initialement pour ses effets antidiurétiques. Dans cet article de synthèse, nous rappelons les particularités biochimiques et pharmacologiques de l'AVP et de ses analogues. De nos jours, sa principale indication en médecine intensive est le choc vasoplégique, eu égard à ses propriétés vasopressives qui sont liées à l'activation des récepteurs V1 du muscle lisse des vaisseaux sanguins, résultant en une puissante vasoconstriction. L'évidence scientifique de l'apport de l'AVP, et de ses bénéfices potentiels par rapport à la noradrénaline dans le choc vasoplégique, est revue en détail dans cet article. De même, nous présentons les autres indications de la vasopressine chez le patient en état critique, sur la base des études récentes et les recommandations des sociétés savantes.

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.

Incidence of Hypotension after Discontinuation of Norepinephrine or Arginine Vasopressin in Patients with Septic Shock: a Systematic Review and Meta-Analysis.

BACKGROUND: There has been no consensus regarding the discontinuation order of vasopressors in patients recovering from septic shock treated with concomitant norepinephrine (NE) and arginine vasopressin (AVP). The aim of this study was to compare the incidence of hypotension within 24 hours based on whether NE or AVP was discontinued first in order to determine the optimal sequence for discontinuation of vasopressors. METHODS: A systematic literature search was conducted in MEDLINE, Embase, and the Cochrane Central Register. The primary end-point was incidence of hypotension within 24 hours after discontinuation of the first vasopressor. RESULTS: We identified five studies comprising 930 patients, of whom 631 (67.8%) discontinued NE first and 299 (32.2%) discontinued AVP first. In pooled estimates, a random-effect model showed that discontinuation of NE first was associated with a significant reduction of the incidence of hypotension compared to discontinuing AVP first (31.8% vs. 54.8%; risk ratios, 0.35; 95% confidence interval, 0.16 to 0.76; P = 0.008; I² = 90.7%). Although a substantial degree of heterogeneity existed among the trials, we could not identify the significant source of bias. In addition, there were no significant differences in intensive care unit (ICU) mortality, in-hospital mortality, 28-day mortality, or ICU length of stay between the groups. CONCLUSION: Discontinuing NE prior to AVP was associated with a lower incidence of hypotension in patients recovering from septic shock. However, our results should be interpreted with caution, due to the considerable between-study heterogeneity.

Hyper-methylation of AVPR1A and PKCΒ gene associated with insensitivity to arginine vasopressin in human pre-eclamptic placental vasculature.

BACKGROUND: Pre-eclampsia is a leading cause of maternal mortality and morbidity. Although the exact mechanisms that cause pre-eclampsia remain unclear, it is undeniable that abnormal placental function and circulation are a center for initiation pre-eclampsia. As a potent vasoconstrictor, arginine vasopressin (AVP) has long been implicated in controlling placental vascular tone and circulation; its secretion is grossly elevated in pre-eclamptic circulation. However, little is known about the reactivity of AVP in pre-eclamptic placental vasculature. METHODS: To reveal the special features of placental vascular regulations with placental pathophysiological changes, as well as the corresponding molecular mechanisms under pre-eclamptic conditions, vascular function and molecular assays were conducted with placental vessel samples from normal and pre-eclamptic pregnancies. FINDINGS: The present study found that vasoconstriction responses of placental vessels to AVP were attenuated in pre-eclampsia as compared to in normal pregnancy. The insensitivity of AVP was correlated with the down-regulated AVP receptor 1a (AVPR1A, AVPR1A gene) and protein kinase C isoform ß (PKCß, PKCΒ gene), particularly the hyper-methylation-mediated AVPR1A and PKCΒ gene down-regulation, respectively. INTERPRETATION: The findings collectively revealed that aberrant DNA methylation-mediated gene expressions are correlated with vascular dysfunction in pre-eclamptic placental circulation. FUND: This work was supported by National Nature & Science Foundation of China. "333 Project", "Six one project", "Shuang Chuang Tuan Dui" and Key Discipline "Fetal medicine" of Jiangsu Province, and the Suzhou city "Wei Sheng Ren Cai" program.

Concurrent Use of Calcium Chloride and Arginine Vasopressin Infusions in Pediatric Patients with Acute Cardiocirculatory Failure.

Acute heart failure (AHF) can cause low cardiac output and poor end-organ perfusion. Inotropic agents along with vasodilators can improve organ perfusion. Arginine vasopressin (AVP) and calcium chloride (CaCl) infusions are increasingly being used in low cardiac output states in pediatric AHF. We retrospectively reviewed 77 patients (0-18 years) with AHF admitted between January 2014 and May 2017 who received concurrent AVP and CaCl infusions. Surrogates of cardiac output and organ perfusion included hemodynamic vital signs, laboratory parameters, and urine output (UO). Organ dysfunction and vasopressor inotropic scores were also calculated. Median (IQR) age was 0.88 years (0, 3.75), and median weight was 6.62 kg (3.5, 13.7). Congenital heart disease was present in 70% (46/77) patients. Univentricular physiology was present in 25% (25/77) patients. None of the patients were in the immediate postoperative period. Median durations of AVP and CaCl were 2 days (1, 3) and 3 days (2, 6), respectively. Using Wilcoxon-signed rank test and Bonferroni correction, post hoc comparison showed that at 8 h post infusion, all systolic blood pressure (SBP) and diastolic blood pressure (DBP) results, and UO were greater than those 1 h prior to infusion. Median SBP increased from 79 mm Hg (71, 92) 1 h prior to 97 mm Hg (84, 107) 8 h post. Median DBP increased from 44 mm Hg (35, 52) 1 h prior to 54 mm Hg (44, 62) 8 h post. Heart rate showed a decrease between measurements 1 h prior to infusion and 8 h post, with median scores 146 (127, 162) and 136 (114, 150) beats per minute, respectively. Within first 8 h, median UO continuously increased from 6 mL/h. (0, 25) at 1 h post infusion to 20 mL/h. (2, 62) at 8 h post infusion. Median pediatric logarithmic organ dysfunction scores on days 4 through 7 post infusion were lower compared to day 1; median vasopressor inotropic scores on day 2 through 7 post infusion were lower compared to day 1. Serum lactate level, arterial pH, and base excess all showed favorable trend. Concurrent use of AVP and CaCl infusions may improve surrogates of cardiac output, and intensive care outcomes, and prevent organ dysfunction in children with AHF.

Manipulating the Microcirculation in Sepsis - the Impact of Vasoactive Medications on Microcirculatory Blood Flow: A Systematic Review.

BACKGROUND: Sepsis is life-threatening organ dysfunction because of a dysregulated host response to infection. Disturbed microvascular blood flow is associated with excess mortality and is a potential future target for interventions. This review addresses the evidence for pharmacological manipulation of the microcirculation in sepsis assessed by techniques that evaluate the sublingual microvasculature. METHODS: Systematic review using a published protocol. Eligibility criteria were studies of septic patients published from January 2000 to February 2018. Interventions were drugs aimed at improving perfusion. Outcome was improvement in microvascular flow using orthogonal polarization spectral, sidestream dark field, or incident dark field imaging (Grades of Recommendation, Assessment, Development, and Evaluation criteria used). RESULTS: Two thousand six hundred and six articles were screened and 22 included. (6 randomized controlled trials, 12 interventional, 3 observational, and 1 pilot, n = 572 participants). Multiple measurement techniques were described, including: automated analyses, subjective, and composite scoring systems. Norepinephrine was not found to improve microvascular flow (low-grade evidence, n = 6 studies); except in chronic hypertension (low, n = 1 study). Addition of arginine vasopressin or terlipressin to norepinephrine maintained flow while decreasing norepinephrine requirements (high, n = 2 studies). Neither dobutamine nor glyceryl trinitrate consistently improved flow (low, n = 6 studies). A single study (n = 40 participants) demonstrated improved flow with levosimendan (high). In a risk of bias assessment 16/16 interventional, pilot and observational studies were found to be high risk. CONCLUSIONS: There is no robust evidence to date that any one agent can reproducibly lead to improved microvascular flow. Furthermore, no study demonstrated outcome benefit of one therapeutic agent over another. Updated consensus guidelines could improve comparable reporting of measurements and reduce bias, to enable meaningful comparisons around the effects of individual pharmacological agents.

Supplemental arginine vasopressin during the resuscitation of severe hemorrhagic shock preserves renal mitochondrial function.

Arginine vasopressin (AVP), a hormone secreted by the posterior pituitary, plays a vital role in maintaining vasomotor tone during acute blood loss. We hypothesized that decompensated hemorrhagic shock is associated with decreased AVP stores and supplementation during resuscitation would improve both blood pressure and renal function. Using a decompensated hemorrhagic shock model, male Long-Evans rats were bled to mean arterial blood pressure (MAP) of 40mmHg and maintained until the MAP could not be sustained without fluid. Once 40% of the shed volume was returned in lactated Ringer's (Severe Shock), animals were resuscitated over 60 minutes with 4x the shed volume in lactated Ringer's (LR) or the same fluids with AVP (0.5 units/kg+ 0.03 units/kg/min). Animals (n = 6-9/group) were sacrificed before hemorrhage (Sham), at Severe Shock, following resuscitation (60R, 60R with AVP) or 18 hours post-resuscitation (18hr, 18hr with AVP). Blood samples were taken to measure AVP levels and renal function. Pituitaries were harvested and assayed for AVP. Kidney samples were taken to assess mitochondrial function, histology, and oxidative damage. Baseline pituitary AVP stores (30,364 ± 5311 pg/mg) decreased with severe shock and were significantly depressed post-resuscitation (13,910 ± 3016 pg/ml. p<0.05) and at 18hr (15,592 ±1169 pg/ml, p<0.05). Resuscitation with LR+AVP led to higher serum AVP levels at 60R (31±8 vs 79±12; p<0.01) with an improved MAP both at 60R (125±3 vs 77±7mmHg; p<0.01) and 18hr (82±6 vs 69±5mmHg;p<0.05). AVP supplementation preserved complex I respiratory capacity at 60R and both complex I and II function at 18hr (p<0.05). AVP was also associated with decreased reactive oxygen species at 60R (856±67 vs 622±48F RFU) and significantly decreased oxidative damage as measured by mitochondrial lipid peroxidation (0.9±0.1 vs 1.7±0.1 fold change, p<0.01) and nitrosylation (0.9±0.1 vs 1.4±0.2 fold change, p<0.05). With AVP, renal damage was mitigated at 60R and histologic architecture was conserved at 18 hours. In conclusion, pituitary and serum AVP levels decrease during severe hemorrhage and may contribute to the development of decompensated hemorrhagic shock. Supplementing exogenous AVP during resuscitation improves blood pressure, preserves renal mitochondrial function, and mitigates acute kidney injury.

Arginine vasopressin improves the memory deficits in Han Chinese patients with first-episode schizophrenia.

The memory impairment is a core deficit in the first-episode schizophrenia patients. Arginine vasopressin (AVP) in the brain can improve learning and memory. We performed multicentre, randomized, double-blind, placebo-controlled, parallel-group clinical trial to study the cognitive functioning in Han Chinese first-episode schizophrenic patients in a 12-week treatment regime with the intranasal administration of AVP (128 cases) or placebo (131 cases) in addition to the conventional treatment. The methods of positive and negative syndrome scale (PANSS), Wechsler memory scale-4th edition (WMS-IV) and event-related potential (ERP) were used to study the effects of AVP on the cognitive function. The results showed that (1) AVP concentration decreased in cerebrospinal fluid (CSF) of the right-handed Han Chinese first-episode schizophrenic patients comparing with that of the health volunteers (7.1±1.5pg/ml vs 13.3±1.9pg/ml, p<0.01), and did not change in plasma; (2) AVP significantly improved PANSS scores including total scores, positive symptoms, negative symptoms and general psychopathology comparing with those of the placebo group; (3) AVP elevated WMS-IV scores including the long-term memory (accumulation), short-term memory (recognition, comprehension), immediate memory (number recitation) and memory quotient 4, 8 and 12 weeks after treatment; and (4) AVP did not influence the latency and wave amplitude of target stimulus of P300 of right-handed Han Chinese first-episode schizophrenic patients. The data suggested that AVP might improve cognitive process, such as memorizing and extraction of the information although there were many changes of cognitive functions in the right-handed Han Chinese first-episode schizophrenic patients.

Arginine-vasopressin therapy in hypotensive neonates and infants after cardiac surgery: response is unrelated to baseline ventricular function.

We hypothesised that infants with ventricular dysfunction after cardiac surgery have impaired haemodynamic response to arginine-vasopressin therapy. We retrospectively reviewed the medical records of neonates and infants treated with arginine-vasopressin within 48 hours of corrective or palliative cardiac surgery who underwent echocardiographic assessment of ventricular function before initiation of therapy. Patients were classified as "responders" if their systolic blood pressure increased by ⩾10% without increase in catecholamine score or if it was maintained with decreased catecholamine score. Response was assessed 1 hour after maximum upward titration of arginine-vasopressin. A total of 36 children (15 neonates) were reviewed (17 male). The median (interquartile) age was 10.4 weeks (1.1-26.9), and the median weight was 4.3 kg (3.2-5.8). Diagnoses included single ventricle (eight), arch abnormalities (five), atrioventricular septal defect (four), double-outlet right ventricle (three), tetralogy of Fallot (three), and others (13). In all, 12 patients (33%) had ventricular dysfunction. Only 15 (42%) responded favourably according to our definition 1 hour after the "target" arginine-vasopressin dose was achieved. Ventricular dysfunction was not associated with poor response. The overall mortality was 25%, but mortality in patients with ventricular dysfunction was 42%. Favourable response was associated with shorter ICU stay (9.5 days versus 19.5 days, p=0.01). We conclude that arginine-vasopressin fails to increase blood pressure in ~50% of hypotensive children after cardiac surgery. The response rate does not increase with duration of therapy. Ventricular function does not predict haemodynamic response. The mortality in this group is very high. Prospective comparison of vasopressin with other vasoactive agents and/or inotropes is warranted.

The effect of vasoactive drugs on mortality in patients with severe sepsis and septic shock. A network meta-analysis of randomized trials.

PURPOSE: Inotropes and vasopressors are cornerstone of therapy in septic shock, but search for the best agent is ongoing. We aimed to determine which vasoactive drug is associated with the best survival. MATERIALS AND METHODS: PubMed, BioMedCentral, Embase, and the Cochrane Central Register were searched. Randomized trials performed in septic patients with at least 1 group allocated to an inotrope/vasopressor were included. Network meta-analysis with a frequentist approach was performed. RESULTS: The 33 included studies randomized 3470 patients to 16 different comparators. As compared with placebo, levosimendan (odds ratio [OR], 0.17, 95%; confidence interval [CI], 0.05-0.60), dobutamine (OR, 0.30; 95% CI, 0.09-0.99), epinephrine (OR, 0.35; 95% CI, 0.13-0.96), vasopressin (OR, 0.37; 95% CI, 0.16-0.89), and norepinephrine plus dobutamine (OR, 0.4; 95% CI, 0.11-0.96) were significantly associated with survival. Norepinephrine improved survival compared with dopamine (OR, 0.81; 95% CI, 0.66-1.00). Rank analysis showed that levosimendan had the highest probability of being the best treatment. CONCLUSIONS: Among several regimens for pharmacological cardiovascular support in septic patients, regimens based on inodilators have the highest probability of improve survival.

[Influence of preventive use of vasopressin tannate on diabetes insipidus and serum sodium at the early postoperation of craniopharyngioma].

OBJECTIVE: To explore the influence of preventive use of vasopressin tannate on diabetes insipidus and serum sodium at the early postoperation of craniopharyngioma.
 Methods: The data of 83 patients, who underwent unilateral sub-frontal approach resection of craniopharyngioma between 2010 and 2014 by the same senior neurosurgeon, were retrospectively analyzed. The patients were divided into a vasopressin tannate group (used group) and a control group. The diabetes insipidus and serum sodium changes were compared between the two groups.
 Results: Compared with the control group, the incidence of diabetes insipidus decreased at the early postoperation in the vasopressin tannate group (P<0.05). There was high incidence of diabetes insipidus in patients with pituitary stalk excision and tumor close adhesion to the third ventricle floor at the early postoperation (P<0.05). Under such conditions, the incidence of diabetes insipidus in the vasopressin tannate group was decreased compared with the control group (P<0.05). Postoperative hypernatremia occurred in 37 patients (44.6%), and hyponatremia occurred in 60 patients (72.3%), the average time of the occurrence of hpernatremia and hyponatremia was 1.4 and 3.7 days after surgery. Postoperative high serum sodium and low serum sodium appeared alternately in 19 patients (22.9%). There was significant difference in the serum sodium distribution in the first day after surgery in both groups (P<0.05), and the percent of hpernatremia in the vasopressin tannate group was significantly less than that in the control group (P<0.05).
 Conclusion: Preventive use of vasopressin tannate can effectively reduce diabetes insipidus and hypernatremia incidence at the early postoperative stage after microsurgery for craniopharyngioma.