Assessment of the hypothalamic-pituitary-adrenocortical axis function using a vasopressin stimulation test in neonatal foals.

BACKGROUND: Bacterial sepsis is the leading cause of death in foals and is associated with hypothalamic-pituitary-adrenocortical axis (HPAA) dysfunction. HPAA function can be evaluated by an arginine-vasopressin (AVP) stimulation test. HYPOTHESES/OBJECTIVES: Administration of AVP will stimulate a dose-dependent rise in systemic adrenocorticotropin-releasing hormone (ACTH) and cortisol in neonatal foals. There will be no response seen in corticotropin-releasing hormone (CRH) and baseline AVP will be within reference interval. ANIMALS: Twelve neonatal foals, <72 hours old. METHODS: HPAA function was assessed in foals utilizing 3 doses of AVP (2.5, 5, and 7.5 IU), administered between 24 and 48 hours of age in this randomized cross-over study. Cortisol, ACTH, CRH and AVP were measured at 0 (baseline), 15, 30, 60 and 90 minutes after AVP administration with immunoassays. The fold increase in cortisol and ACTH was calculated at 15 and 30 minutes compared to baseline. RESULTS: All doses of AVP resulted in a significant increase in cortisol concentration over time, and a dose-dependent increase in ACTH concentration over time. ACTH and cortisol were significantly increased at 15 and 30 minutes, respectively after all 3 doses of AVP compared to baseline (P < .01). There was no change in endogenous CRH after stimulation with AVP. CONCLUSION AND CLINICAL IMPORTANCE: Administration of AVP is safe and results in a significant rise in ACTH and cortisol in neonatal foals. A stimulation test with AVP (5 IU) can be considered for HPAA assessment in septic foals.

Assessment of Tissue Expression of the Oxytocin-Vasopressin Pathway in the Placenta of Women with a First-Episode Psychosis during Pregnancy.

Psychosis refers to a mental health condition characterized by a loss of touch with reality, comprising delusions, hallucinations, disorganized thought, disorganized behavior, catatonia, and negative symptoms. A first-episode psychosis (FEP) is a rare condition that can trigger adverse outcomes both for the mother and newborn. Previously, we demonstrated the existence of histopathological changes in the placenta of pregnant women who suffer an FEP in pregnancy. Altered levels of oxytocin (OXT) and vasopressin (AVP) have been detected in patients who manifested an FEP, whereas abnormal placental expression of these hormones and their receptors (OXTR and AVPR1A) has been proven in different obstetric complications. However, the precise role and expression of these components in the placenta of women after an FEP have not been studied yet. Thus, the purpose of the present study was to analyze the gene and protein expression, using RT-qPCR and immunohistochemistry (IHC), of OXT, OXTR, AVP, and AVPR1a in the placental tissue of pregnant women after an FEP in comparison to pregnant women without any health complication (HC-PW). Our results showed increased gene and protein expression of OXT, AVP, OXTR, and AVPR1A in the placental tissue of pregnant women who suffer an FEP. Therefore, our study suggests that an FEP during pregnancy may be associated with an abnormal paracrine/endocrine activity of the placenta, which can negatively affect the maternofetal wellbeing. Nevertheless, additional research is required to validate our findings and ascertain any potential implications of the observed alterations.

Adjusting vasopressin availability and formulation: A cost-savings initiative.

PURPOSE: The increase in vasopressin price has required many healthcare systems to consider cost-saving strategies. To combat rising medication costs, our institution changed formulations from 50 units/250 mL to 20 units/100 mL and removed vasopressin from automated dispensing cabinets (ADCs). METHODS: This retrospective review occurred at a 545-bed academic medical center with 97 adult intensive care unit beds. Adult patients receiving a continuous vasopressin infusion were included with no exclusion criteria. A 1-month period was assessed before and after changing the formulation (pre and post groups, respectively). Duplicate bags compounded by pharmacy and bedside teams were also assessed in the pre group. The primary outcome was the estimated annual cost savings due to formulation change with a secondary outcome of estimated annual cost savings due to removal of vasopressin from ADCs. Each 20-unit vial of vasopressin cost $183.21 (wholesale acquisition cost) at the time of the study. RESULTS: In the pre group, 39 patients requiring a vasopressin infusion were allocated an average of 2 bags each costing $1,099.26 per patient. In the post group, 41 patients required an average of 4 bags each costing $732.84 per patient. With respect to the primary outcome, a savings of $366.42 per patient and an average of 40 patients per month would lead to an annual cost savings of $175,881.60. Secondary outcome analysis identified 9 duplicate bags prepared in the pre group; therefore, removal of vasopressin from ADCs is estimated to provide additional cost savings of $59,360.04. The estimated annual cost savings from both initiatives is $235,241.64. CONCLUSION: Changing the vasopressin formulation and removing it from ADCs resulted in a significant cost savings to the health system.

A single-center cost analysis assessing a change in vasopressin formulation.

PURPOSE: Cost savings achieved at an academic medical center by reformulating the institution's standard vasopressin infusions to reduce waste are described. SUMMARY: After a retrospective review of vasopressin utilization over a 4-month period revealed that only approximately 40% of dispensed vasopressin units were actually administered to patients, pharmacy leaders determined that the institution's standard vasopressin concentration for continuous infusions (100 units in 100 mL of sodium chloride 0.9% injection) was resulting in substantial waste, as many infusion preparations were not needed within the 18- to 24-hour expiration window. A concentration of 20 units/100 mL was adopted as the new standard formulation for vasopressin continuous infusions, with use of alternative concentrations allowed on a restricted basis. A pre-post study to assess the impact of the formulation change indicated a 38.7% decrease in vasopressin utilization (from 21,900 to 8,480 units) relative to utilization in a retrospective sample of patients who received vasopressin infusions prior to the formulation change. This reduced utilization equated to a cost decrease of $55,656.20 (as calculated on the basis of 2017 cost estimates) or $77,214.23 (as calculated on the basis of 2019 cost estimates) for the time period collected. It was estimated that the new formulations could yield annual cost savings ranging from $222,625 to $308,857. CONCLUSION: To our knowledge, this is the first description of cost savings following a change in formulation of vasopressin for continuous infusions. Other institutions could consider employing a similar approach in addition to the previously reported cost-saving interventions, such as lower vasopressin starting doses and vasopressin restriction policies.

Lead (Pb) exposure induces physiological alterations in the serotoninergic and vasopressin systems causing anxiogenic-like behavior in Meriones shawi: Assessment of BDMC as a neuroprotective compound for Pb-neurotoxicity and kidney damages.

BACKGROUND: Studies have shown that lead (Pb) is one of hazardous heavy metals with various adverse effects on human health including mental health; Pb can induce psychiatric disorders like anxiety. In the present work, we examined the potential of bisdemethoxycurcumin (BDMC) as a neuroprotective agent against lead induced anxiety inMeriones shawi (M. shawi). METHODS: We asses, the potential of three consecutive day exposure to Pb (25 mg/kg body weight) in inducing anxiogenic effect, serotoninergic and vasopressinergic disruptions inM. shawi. This was done using neurobehavioral tests (open field, elevated plus maze), immunohistochemestry by anti-serotonin (5-HT), and anti-vasopressin (AVP) antibodies. We also measured the possible restorative potential of BDMC (30 mg/kg body weight), delivered by oral gavage. After that, a biochemical and histopathological studies were done. RESULTS: Our results showed that lead exposure for three consecutive days increases significantly the 5-HT-immunoreactivity in dorsal raphe nucleus (DRN) accompanied with a significant enhancement of AVP-immunoreactivity in the cell bodies and fibers in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. In the collecting tube, AVP binds to the V2 receptor of the epithelial cells and increases the water permeability. Our results showed clearly the epithelial cells degeneration after lead exposure, then we suggest that the increased AVP could be a response to the hydric balance disrupted after degenerative effect of lead exposure on epithelial cells. BDMC produced an anxiolytic effect in meriones. Moreover, it restored 5-HT and AVP immunoreactivity within studying nuclei. The biochemical and histopathological studies showed that Pb induced renal damages. In addition, BDMC restored the renal alterations. CONCLUSION: According to the obtained results, we suggest new pharmacological effects of BDMC; while it has an anxiolytic effect against Pb-induced anxiety by working on serotoninergic and vasopressinergic systems with an obvious restoration of the renal injuries induced by lead exposure.

Mortality, Morbidity, and Costs After Implementation of a Vasopressin Guideline in Medical Intensive Care Patients With Septic Shock: An Interrupted Time Series Analysis.

Background: Vasopressin decreases vasopressor requirements in patients with septic shock. However, the optimal norepinephrine dose for initiation or cessation of vasopressin is unclear. Objective: Analyze monthly intensive care unit (ICU) mortality rates 1 year preimplementation and postimplementation of a guideline suggesting a norepinephrine dose of 50 µg/min or more for initiation of vasopressin and early cessation of vasopressin. Methods: This retrospective quasi-experimental study included adult patients with septic shock admitted to the medical ICU of a tertiary care medical center over 2 years. Time periods were evaluated with interrupted time series analysis. Results: A total of 1148 patients were included: 573 patients preguideline and 575 patients postguideline. Group characteristics were well balanced at baseline, except patients postguideline had higher sequential organ failure assessment scores. Postguideline, fewer patients were initiated on vasopressin (305 [53.2%] vs 217 [37.7%], absolute difference -15.5% [95% CI -21.2% to -9.8%]), and the norepinephrine dose at vasopressin initiation was higher (median 25 [interquartile range 18, 40] µg/min vs 40 [22, 52] µg/min; median difference 15 [95% CI 11 to 19] µg/min; P < 0.01). After guideline implementation, there was no evidence for a difference in ICU mortality rate slope (slope change 0.07% [95% CI -0.8% to 1.0%] per month; P 0.87), but the vasoactive cost level decreased by US$183 (95% CI -US$327 to -US$39) per patient immediately after implementation. Conclusion and Relevance: Implementation of a guideline suggesting a high norepinephrine dose threshold for vasopressin initiation and early vasopressin cessation in patients with septic shock appears to be safe and may decrease vasoactive costs.

Delayed vasopressor initiation is associated with increased mortality in patients with septic shock.

PURPOSE: Mortality rate for septic shock, despite advancements in knowledge and treatment, remains high. Treatment includes administration of broad-spectrum antibiotics and stabilization of the mean arterial pressure (MAP) with intravenous fluid resuscitation. Fluid-refractory shock warrants vasopressor initiation. There is a paucity of evidence regarding the timing of vasopressor initiation and its effect on patient outcomes. MATERIALS AND METHODS: This retrospective, single-centered, cohort study included patients with septic shock from January 2017 to July 2017. Time from initial hypotension to vasopressor initiation was measured for each patient. The primary outcome was 30-day mortality. RESULTS: Of 530 patients screened,119 patients were included. There were no differences in baseline patient characteristics. Thirty-day mortality was higher in patients who received vasopressors after 6 h (51.1% vs 25%, p < .01). Patients who received vasopressors within the first 6 h had more vasopressor-free hours at 72 h (34.5 h vs 13.1, p = .03) and shorter time to MAP of 65 mmHg (1.5 h vs 3.0, p < .01). CONCLUSION: Vasopressor initiation after 6 h from shock recognition is associated with a significant increase in 30-day mortality. Vasopressor administration within 6 h was associated with shorter time to achievement of MAP goals and higher vasopressor-free hours within the first 72 h.

Cost-effectiveness of second-line vasopressors for the treatment of septic shock.

PURPOSE: To determine the cost-effectiveness of escalating doses of norepinephrine or norepinephrine plus the adjunctive use of vasopressin or angiotensin II as a second-line vasopressor for septic shock. MATERIALS AND METHODS: Decision tree analysis was performed to compare costs and outcomes associated with norepinephrine monotherapy or the two adjunctive second-line vasopressors. Short- and long-term outcomes modeled included ICU survival and lifetime quality-adjusted-life-years (QALY) gained. Costs were modeled from a payer's perspective, with a willingness-to-pay threshold set at $100,000/unit gained. One-way (tornado diagrams) and probabilistic sensitivity analyses were performed. RESULTS: Adjunctive vasopressin was the most cost-effective therapy, and dominated both norepinephrine monotherapy and adjunctive angiotensin II by producing higher ICU survival at less cost. For the lifetime horizon, while norepinephrine monotherapy was least expensive, adjunctive vasopressin was the most cost-effective with an incremental cost-effectiveness ratio of $19,762 / QALY gained. Although adjunctive angiotensin II produced more QALYs compared to norepinephrine monotherapy, it was dominated in the long-term evaluation by second-line vasopressin. Sensitivity analyses demonstrated model robustness and medication costs were not significant drivers of model results. CONCLUSIONS: Vasopressin is the most cost-effective second-line vasopressor in both the short- and long-term evaluations. Vasopressor price is a minor contributor to overall cost.

Hyperinflation of Vasopressors (Vasopressin, Norepinephrine, Ephedrine, etc).

PURPOSE: Hyperinflation refers to the increasing cost of drugs which occurs due to continued drug shortages and rebranding. Hyperinflation has significant implications in increasing overall healthcare costs with reduced reimbursement, increased patient acuity, and an aging population, but published strategies to reduce costs and minimize waste are limited. OBJECTIVE: To describe the hyperinflation and cost mitigation strategies of three vasopressor medications, vasopressin, epinephrine, and ephedrine. CONCLUSION: The steep increase in medications is expected to continue, and mitigation strategies to reduce waste and select the most cost effective therapy to offset the price increase is crucial for healthcare systems.

US Food and Drug Administration Disruption of Generic Drug Market Increases Hospital Costs.

BACKGROUND: The purpose of the US Food and Drug Administration's Marketed Unapproved Drugs Initiative is to decrease marketing of older unapproved medications. The administration has recently extended its rulings by including sterile injectable drugs administered in the inpatient environment. The impact of this initiative on the inpatient environment has been minimally studied. METHODS: Consecutive retrospective purchase data of vasopressin for injection (vasopressin) and neostigmine methylsulfate for injection (neostigmine) from 720 hospitals and 746 hospitals, respectively, were included. Purchases occurred from January 1, 2010 to December 31, 2016. The average noncontract drug price was calculated and compared to the purchase data during the impact of the initiative. Comparison was made of hospital purchases made before and after the initiative. The year 2014 was considered a washout transition year due to the large amounts of discontinued unapproved formulations that were still available and purchased by hospitals. The analysis was completed using a matched paired t test. RESULTS: The noncontract price for vasopressin increased from $12.83 per vial to $158.83 per vial (1138% increase) and for neostigmine from $27.74 per vial to $175.14 per vial (531% increase) across the pre- and postinitiative intervals; however, purchase volumes after the price increases were not found to have a statistically significant difference compared to purchases before the price increases (P = .98 and P = .4, respectively). CONCLUSIONS: Health systems have experienced a significant cost increase of vasopressin and neostigmine and are absorbing price increases for these older, generic sterile injectable drugs.

Assessment of obestatin and arginine vasopressin (AVP) levels in acute renal failure and acute heart failure.

OBJECTIVE: We conducted this study to assess the clinical application of obestatin and arginine vasopressin (AVP) levels in cases of acute renal failure (ARF) and acute heart failure (AHF). PATIENTS AND METHODS: 30 cases of ARF, 30 cases of AHF, 30 cases of ARF complicated with AHF, and 30 cases of healthy subjects (control group) were successively selected. An ELISA test was conducted to detect levels of obestatin and AVP. Routine biochemistry testing was applied to detect the levels of serum creatinine and calculate the glomerular filtration rate (GFR). Electrochemiluminescence double antibody sandwich fluorescence immune testing was applied to detect NT-proBNP and color Doppler ultrasound diagnostic apparatus was applied to detect renal arterial resistive index (RI) and left ventricular ejection fraction (LVEF). The 30-day mortality was documented. RESULTS: Compared to other groups, the group of patients suffering from ARF complicated with AHF had significantly higher levels of obestatin and AVP, and significantly higher levels of serum creatinine, NT-proBNP and RI; however, their GFR and LVEF levels were the lowest. Differences were statistically significant (p < 0.05). Levels of obestatin and AVP are positively correlated with serum creatinine, NT-proBNP and RI levels, but negatively correlated with GFR and LVEF levels. The mortality rate of the group suffering from ARF complicated with AHF was markedly increased (p = 0.035). The obestatin and AVP levels of the death group were significantly higher than that of the survival group. However, the comparison among levels of serum creatinine, GFR, NT-proBNP, RI and LVEF revealed no statistical significance (p > 0.05). CONCLUSIONS: Obestatin and AVP levels were closely related to the severity of ARF and AHF and survival prognosis, which could be a sensitive indicator for diagnoses and prognoses.

Vasopressin: physiology, assessment and osmosensation.

Vasopressin (AVP) plays a major role in the regulation of water and sodium homeostasis by its antidiuretic action on the kidney, mediated by V2 receptors. AVP secretion is stimulated by a rise in plasma osmolality, a decline in blood volume or stress. V1a receptors are expressed in vascular smooth muscle cells, but the role of vasopressin in blood pressure regulation is still a matter of debate. AVP may also play a role in some metabolic pathways, including gluconeogenesis, through its action on V1a receptors expressed in the liver. It is now understood that thirst and arginine vasopressin (AVP) release are regulated not only by the classical homeostatic, intero-sensory plasma osmolality negative feedback, but also by novel, extero-sensory, anticipatory signals. AVP measurement is time-consuming, and AVP level in the blood in the physiological range is often below the detection limit of the assays. Recently, an immunoassay has been developed for the measurement of copeptin, a fragment of the pre-provasopressin molecule that is easier to measure. It has been shown to be a good surrogate marker of AVP.

Assessment of the Anti-anginal Effect of Tetramethylpyrazine Using Vasopressin-Induced Angina Model Rats.

Intravenous tetramethylpyrazine has been widely used in China as a complementary and/or alternative medicine to treat patients with ischemic heart disease. We assessed the anti-anginal effect of tetramethylpyrazine (10 mg/kg, intravenously (i.v.), n=6) in comparison with that of its vehicle, saline (1 mL/kg, i.v., n=6), using vasopressin-induced angina model rats. First, Donryu rats were anesthetized with pentobarbital sodium (60 mg/kg, intraperitoneally (i.p.)), and the surface lead I electrocardiogram was continuously monitored. Administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram, indicating the onset of subendocardial ischemia. However, pretreatment with tetramethylpyrazine suppressed the vasopressin-induced depression of the S-wave level, which was not observed following pretreatment with its vehicle alone (saline), suggesting that tetramethylpyrazine ameliorated the vasopressin-induced subendocardial ischemia in vivo. These results may provide experimental evidence for the empirically known clinical efficacy of tetramethylpyrazine against ischemic heart disease, and could provide clues to better understanding its in vivo mechanism of action.

Relevance of Assessment Methods for Fluid Intake.

Reliable data at population level are essential to firmly establish links between fluid intake, hydration and health, investigate dose-response relationships and develop meaningful public health strategies or reference intake values. However, limited research exists regarding the most appropriate methodology for assessing beverage or total fluid intake (TFI). To date, methodologies have been developed to assess food and nutrient intake without due consideration of water or fluid intake behavior. A recent crossover study showed that a 24-hour food recall significantly underestimated mean TFI by 382 ml (95% CI 299-465) compared with a fluid specific 7-day record. The authors postulated that this average difference was mainly the result of missed drinking acts between meals a 24-hour recall was used. Using a 7-day record administered in paper form or on-line has also been shown to lead to a significantly different mean TFI of 129 ml. Therefore, the choice of methodology might result in measurement errors that limit between-survey or between-country comparisons. Such errors may contribute to variations in estimates of TFI that cannot be explained by differences in climate, physical activity or cultural habits. A recent survey confirmed the variation in methodologies used in European national dietary surveys. Since these surveys form the basis for setting adequate intakes for total water intake, measurement error between surveys should be limited, highlighting the need for the development of a consistent methodology that is validated for water and TFI estimation.