Studying the effect of vasopressors on therapeutic drug monitoring of two local anesthetics using hybrid micelle liquid chromatography as an analysis tool.

A hybrid micelle based mobile phase was used to develop and validate a liquid chromatographic method for the separation and quantification of two local anesthetics namely; lidocaine hydrochloride (LID), and bupivacaine hydrochloride (BPV) in presence of the frequently co administered vasopressors phenyl ephrine (PHR) and ephedrine (EPH). Optimization of chromatographic separation conditions was performed applying experimental one factor at a time tool, and design of experiment, where the retention behavior of all analytes using both optimization protocols was in accordance. Chromatographic separation was carried on a C8 column operating at 40 °C at a flow rate of 1.5 mL/min. using a mobile phase consisting of 0.18 M sodium dodecyl sulphate, 10% acetonitrile, containing 0.3% triethyl amine and adjusted to pH 7 using 2 M ortho phosphoric acid, adopting UV detection at 230 nm. The proposed method was fully validated and applied to both in vitro and in vivo analysis of rat blood samples. The pharmacokinetics of both LID and BPV was followed when they were solitary injected or when co administered with either PHR or EPH. Moreover, the in vitro spiked experiment was also subjected to documented bio-analytical validation procedures.

The changes of inflammatory mediators and vasoactive substances in dairy cows' plasma with pasture-associated laminitis.

BACKGROUND: Hoof disease is one of the three major diseases that often occur in dairy cows. The impact of this disease on dairy farming is second only to mastitis. Laminitis is a diffuse, aseptic, serous, non-purulent inflammation of the dermal papillae and vascular layers of the cow's hoof wall. In the pasture, laminitis occurs mostly in the laminae, that is, inside the hoof shell. No lesions can be seen on the surface. Therefore, laminitis cannot attract the attention of veterinarians. However, laminitis has become a major factor that seriously affects the health and welfare of dairy cows, making it an important cause of hindering the performance of dairy cows. METHODS: The study was conducted at a dairy farm in Harbin, Heilongjiang province, China. We selected a sample of the laminitis cows based on the veterinary diagnosis, took blood from the jugular vein and then separated the plasma, and measured the index with the Elisa kit. In this study, the markers of inflammatory and vasoactive substances status in dairy cows consisted of subclinical laminitis (SCL, n = 20), chronic laminitis (CL, n = 20) and healthy dairy cows (CON, n = 20) under the local management conditions were investigated. RESULTS: Compared with healthy cattle, HIS, IL-6, LPS, and TNF-α in subclinical laminitis group significantly increased (P < 0.05), especially HIS, LPS, TNF-α (P < 0.01); in chronic laminitis cows, COX-2, HIS, IL-6, LPS, and TNF-α increased significantly (P < 0.05), especially COX-2, HIS, TNF-α (P < 0.01). iNOS (P < 0.05), TXB2 (P < 0.01) in chronic laminitis cows had significantly increased. CONCLUSION: This study reported for the first time that pasture laminitis was divided into subclinical laminitis and clinical chronic laminitis. Through research on the inflammatory factors and vasoactive substances of dairy cows, it is found that there is a close relationship between them, which affects the metabolic cycle of dairy cows. These indicators are abnormally expressed and cause hoof microcirculation disorders.

A Prospective, Randomized, Double-Blinded Study of the Effect of Intravenous Ondansetron on the Effective Dose in 50% of Subjects of Prophylactic Phenylephrine Infusions for Preventing Spinal Anesthesia-Induced Hypotension During Cesarean Delivery.

BACKGROUND: Ondansetron has been shown to reduce the incidence of hypotension and vasopressor requirement during spinal anesthesia for obstetric and nonobstetric surgery. However, the magnitude of this effect has not been fully quantified. In this parallel-group, randomized, double-blinded study, we determined the effective dose in 50% of subjects (ED50) of a prophylactic phenylephrine infusion for preventing hypotension in patients who received a single dose of intravenous ondansetron 4 mg or saline control before combined spinal-epidural anesthesia for elective cesarean delivery. ED50 values obtained were compared to estimate the effect of ondansetron versus placebo on vasopressor requirement. METHODS: Sixty parturients were randomly assigned to receive ondansetron (group O) or saline control (group C) 10 minutes before positioning for induction of spinal anesthesia. A prophylactic phenylephrine infusion was used to prevent hypotension. The first patient in each group received a phenylephrine infusion at the rate of 0.5 µg/kg/min. The infusion rate for each subsequent patient was varied with increments or decrements of 0.05 µg/kg/min based on the response of the previous patient, and the effective dose of the phenylephrine infusion for preventing hypotension in 50% of patients (ED50) was calculated for each group and compared using up-down sequential analysis. Probit regression was applied as a backup and sensitivity analysis was used to compare ED50 values for phenylephrine between groups by comparing calculated relative mean potency. RESULTS: The ED50 (mean [95% confidence interval (CI)]) of the rate of phenylephrine infusion was lower in group O (0.24 µg/kg/min [0.10-0.38 µg/kg/min]) compared with group C (0.32 µg/kg/min [0.14-0.47 µg/kg/min]) (P < .001). The total consumption of phenylephrine (mean ± standard deviation [SD]) until delivery was lower in group O (316.5 ± 25.9 µg) than in group C (387.7 ± 14.7 µg, P = .02). The estimate of relative median potency for phenylephrine for group O versus group C was 0.74 (95% CI, 0.37-0.95). CONCLUSIONS: Under the conditions of this study, intravenous ondansetron 4 mg reduced the ED50 of a prophylactic phenylephrine infusion by approximately 26% in patients undergoing cesarean delivery under combined spinal-epidural anesthesia.

Contrast-Enhanced Ultrasound to Detect Early Microvascular Changes in Skeletal Muscle after High-Dose Radiation Treatment.

The biological response of normal tissue to high-dose radiation treatment remains poorly understood. Alterations to the microenvironment, specifically the microvasculature, have been implicated as a significant contributor to tumoral cytotoxicity. We used contrast-enhanced ultrasound (CEU) perfusion imaging, which is uniquely suited to assess functional status of the microcirculation, to measure microvascular blood flow after high-dose irradiation to normal skeletal muscle tissue in a murine model. Proximal hindlimbs of wild-type C57Bl/6 mice were irradiated with a single fraction using 6 MV photons, 1 cm bolus and a dynamic wedge. Quantitative perfusion CEU imaging of the skeletal muscle was performed at days 1 and 8 postirradiation in three different regions of interest (ROIs): 1. 15 Gy external-beam irradiated leg; 2. 12 Gy irradiated 5 mm proximal area; 3. single ROI in the nonirradiated contralateral (CL) hindlimb. Perfusion imaging was also performed in the hindlimb of nonirradiated mice. CEU time-intensity data were analyzed to measure microvascular blood flow (MBF, also referred to as perfusion), and its parametric components of microvascular flux rate and functional microvascular blood volume (MBV). Plasma measurements of two potent vasoconstrictors, endothelin-1 and angiotensin II, were also performed to assess systemic response. CEU perfusion imaging values for the 12 and 15 Gy irradiated limb regions were pooled. At day 1, MBF in the irradiated limb was significantly lower than in the CL limb (P = 0.016) but quite similar to the nonirradiated mice. At day 8, both limbs of irradiated mice exhibited a trend towards lower MBF than the limbs of nonirradiated mice (28% decrease in mean MBF, P = 0.149 for CL; 39% decrease, P = 0.065 for irradiated limb). Compared to nonirradiated animals, the reduction in perfusion in irradiated limbs at day 8 may have been more influenced by the microvascular flux rate (25% decrease in the mean, P = 0.079) than the MBV (12% decrease in the mean, P = 0.328). Examination of vasoactive compounds revealed that the average plasma concentration for endothelin-1 at day 8 postirradiation was significantly higher in 14 irradiated animals than in 4 nonirradiated animals (3.07 pg/ ml vs. 2.51 pg/ml; P = 0.011). Up to day 8 after high-dose irradiation, flow deficits in irradiated muscle appear to be a consequence of increased vascular resistance more so than loss or functional de-recruitment of microvascular units.

Effects of aged stored autologous red blood cells on human plasma metabolome.

Cold storage of blood for 5 to 6 weeks has been shown to impair endothelial function after transfusion and has been associated with measures of end-organ dysfunction. Although the products of hemolysis, such as cell-free plasma hemoglobin, arginase, heme, and iron, in part mediate these effects, a complete analysis of transfused metabolites that may affect organ function has not been evaluated to date. Blood stored for either 5 or 42 days was collected from 18 healthy autologous volunteers, prior to and after autologous transfusion into the forearm circulation, followed by metabolomics analyses. Significant metabolic changes were observed in the plasma levels of hemolytic markers, oxidized purines, plasticizers, and oxidized lipids in recipients of blood stored for 42 days, compared with 5 days. Notably, transfusion of day 42 red blood cells (RBCs) increased circulating levels of plasticizers (diethylhexyl phthalate and derivatives) by up to 18-fold. Similarly, transfusion of day 42 blood significantly increased circulating levels of proinflammatory oxylipins, including prostaglandins, hydroxyeicosatrienoic acids (HETEs), and dihydroxyoctadecenoic acids. Oxylipins were the most significantly increasing metabolites (for 9-HETE: up to ∼41-fold, P = 3.7e-06) in day 42 supernatants. Measurements of arginine metabolism confirmed an increase in arginase activity at the expense of nitric oxide synthesis capacity in the bloodstream of recipients of day 42 blood, which correlated with measurements of hemodynamics. Metabolic changes in stored RBC supernatants impact the plasma metabolome of healthy transfusion recipients, with observed increases in plasticizers, as well as vasoactive, pro-oxidative, proinflammatory, and immunomodulatory metabolites after 42 days of storage.

Humerus intraosseous administration of epinephrine in normovolemic and hypovolemic porcine model.

OBJECTIVE: Compare the maximum concentration (Cmax), time to maximum concentration (Tmax), mean concentration, rate of return of spontaneous circulation (ROSC), time to ROSC, and odds of ROSC when epinephrine is administered by humerus intraosseous (HIO) compared to intravenous (IV) routes in both a hypovolemic and normovolemic cardiac arrest model. DESIGN: Prospective, between subjects, randomized experimental study. SETTING: TriService Facility. SUBJECTS: Twenty-eight adult Yorkshire Swine were randomly assigned to four groups: HIO normovolemia; HIO hypovolemia; IV normovolemia; and IV hypovolemia. INTERVENTION: Swine were anesthetized. The hypovolemic group was exsanguinated 31 percent of their blood volume. Subjects were placed into arrest. After 2 minutes, cardiopulmonary resuscitation (CPR) was initiated. After another 2 minutes, 1 mg epinephrine was given by IV or HIO routes; blood samples were collected over 4 minutes. Hypovolemic groups received 500 mL of 5 percent albumin following blood sampling. CPR continued until ROSC or for 30 minutes. MAIN OUTCOME MEASURES: ROSC, time to ROSC, Cmax, Tmax, mean concentrations over time, odds of ROSC. RESULTS: Cmax was significantly higher, the Tmax, and the time to ROSC were significantly faster in the HIO normovolemic compared to the HIO hypovolemic group (p < 0.05). All seven in the HIO normovolemic group achieved ROSC compared to three of the HIO hypovolemic group. Odds of ROSC were 19.2 times greater in the HIO normovolemic compared the HIO hypovolemic group. CONCLUSION: The HIO is an effective route in a normovolemic model. However, the findings indicate that sufficient blood volume is essential for ROSC in a hypovolemic scenario.

Dynamics of Renin, Angiotensin II, and Angiotensin (1-7) during Pregnancy and Predisposition to Hypertension-Associated Complications.

Changes in the levels of rennin, angiotensin II, and angiotensin (1-7) were studied during normal pregnancy. The blood was taken on gestation days 140-237 and 238-280. No significant changes in renin concentration were observed during normal pregnancy (p=0.423). The level of angiotensin II increased during normal pregnancy from 9.7±1.2 to 14.7±1.9 pg/ml (p=0.019). On the contrary, angiotensin (1-7) concentration decreased from 771.1±44.2 to 390.7±13.9 pg/ml (p<0.001). The shift in the proportion between vasoconstrictor angiotensin II and vasodilaltor angiotensin (1-7) attests to high predisposition of pregnant women to hypertension-related complications.

A simple method to ensure homogeneous drug distribution during intrarenal infusion.

Intrarenal drug infusion plays an important role in renal experimental research. Laminar flow of the blood can cause streaming and inhomogeneous intrarenal distribution of infused drugs. We suggest a simple method to achieve a homogeneous intravascular distribution of drugs infused into the renal artery of anesthetized rats. The method employs a multiple sidehole catheter inserted into the renal artery, which enables an efficient drug mixing with the arterial blood. To verify the efficiency of this method, we use laser speckle imaging and renal artery flowmetry. The results show that, compared with the conventional single-hole catheter, the multiple sidehole catheter provides a more uniform drug distribution and a homogenous vascular response on the surface of the kidney.

Lidocaine Concentration in Oral Tissue by the Addition of Epinephrine.

The vasoconstrictive effect due to the addition of epinephrine to local anesthetic has been clearly shown by measuring blood-flow volume or blood anesthetic concentration in oral mucosal tissue. However, there are no reports on the measurement of anesthetic concentration using samples directly taken from the jawbone and oral mucosal tissue. Consequently, in this study, the effect of lidocaine concentration in the jawbone and oral mucosal tissue by the addition of epinephrine to the local anesthetic lidocaine was considered by quantitatively measuring lidocaine concentration within the tissue. Japanese white male rabbits (n = 96) were used as test animals. General anesthesia was induced by sevoflurane and oxygen, and then cannulation to the femoral artery was performed while arterial pressure was constantly recorded. Infiltration anesthesia was achieved by 0.5 mL of 2% lidocaine containing 1 : 80,000 epinephrine in the upper jawbone (E(+)) and 0.5 mL of 2% of epinephrine additive-free lidocaine (E(0)) under the periosteum. At specified time increments (10, 20, 30, 40, 50, and 60 minutes), samples from the jawbone, oral mucosa, and blood were collected, and lidocaine concentration was directly measured by high-performance liquid chromatography. No significant differences in the change in blood pressure were observed either in E(+) or E(0). In both E(+) and E(0) groups, the serum lidocaine concentration peaked 10 minutes after local anesthesia and decreased thereafter. At all time increments, serum lidocaine concentration in E(+) was significantly lower than that in E(0). There were no significant differences in measured lidocaine concentration between jawbone and mucosa within either the E(+) or the E(0) groups at all time points, although the E(0) group had significantly lower jawbone and mucosa concentrations than the E(+) group at all time points when comparing the 2 groups to each other. Addition of epinephrine to the local anesthetic inhibited systemic absorption of local anesthetic into the blood such that a high concentration could be maintained in the tissue. Epinephrine-induced vasoconstrictive effect was observed not only in the oral mucosa but also in the jawbone.

[Effects of Electroacupuncture Stimulation of "Neiguan" (PC 6) at Different Frequencies on Plasma Vasoactive Substance Levels in Myocardial Ischemic Reperfusion Rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Neiguan" (PC 6) at different frequencies on plasma vasoactive substance levels in myocardial ischemia-reperfusion (MIR) injury rats, so as to explore its mechanisms underlying improvement of acute myocardial ischemia. METHODS: A total of 40 Wistar rats were randomized into control, model, high frequency (HF, 120 Hz) and low frequency (LF, 20 Hz) groups (n = 10 in each group). The MIR model was established by occlusion of the anterior descending branch (ADB) of the left coronary artery for 30 min, followed by reperfusion for 40 min. EA (3 V, 120 Hz or 20 Hz) was applied to bilateral "Neiguan" (PC 6) for 50 min immediately after occlusion of ADB. Subsequently, the contents of plasma endothelin (ET), atrial natriuretic peptide (ANP), thromboxane B 2 (TXB2) and 6-Keto-PGF1, were assayed by radioimmunoassay, and the content of serum nitric oxide (NO) was detected by nitrate reductase method. RESULTS: Compared with the control group, the contents of plasma ET, ANP and TXB2 in the model group were significantly increased (P < 0.05), and that of plasma 6-Keto-PGF1α in the model group was notably decreased (P < 0.05), but no significant change was found in serum NO level (P > 0.05). Compared with the model group, the contents of plasma ET, ANP and TXB2 were considerably decreased, and plasma 6-Keto-PGF1α and serum NO contents were obviously increased in both HF and LF groups (P < 0.05). No significant differences were found between the HF and LF groups in plasma ET , ANP, TXB2 and 6-Keto-PGF1α contents (P > 0.05), but the HF EA was markedly superior to the LF EA in up-regulating the content of serum NO (P < 0.05). CONCLUSION: EA stimulation of "Neiguan" (PC 6) can down-regulate the contents of plasma ET, ANP and TXB2 and up-regulate contents of plasma 6-Keto-PGF1α and serum NO in MIR rats, which may contribute to its effect in relieving acute ischemic myocardial injury. The effect of HF EA is better than LF EA in raising blood NO level.

Hormonal Neuroendocrine and Vasoconstrictor Peptide Responses of Ball Game and Cyclic Sport Elite Athletes by Treadmill Test.

OBJECTIVE: Our objective was to evaluate complex hormonal response in ball game and cyclic sport elite athletes through an incremental treadmill test, since, so far, variables in experimental procedures have often hampered comparisons of data. METHODS: We determined anthropometric data, heart rate, maximal oxygen uptake, workload, plasma levels of lactate, adrenaline, noradrenaline, dopamine, cortisol, angiontensinogen and endothelin in control (n = 6), soccer (n = 8), handball (n = 12), kayaking (n = 9) and triathlon (n = 9) groups based on a Bruce protocol through a maximal exercise type of spiroergometric test. RESULTS: We obtained significant increases for adrenaline, 2.9- and 3.9-fold by comparing the normalized means for soccer players and kayakers and soccer players and triathletes after/before test, respectively. For noradrenaline, we observed an even stronger, three-time significant difference between each type of ball game and cyclic sport activity. CONCLUSIONS: Exercise related adrenaline and noradrenaline changes were more pronounced than dopamine plasma level changes and revealed an opportunity to differentiate cyclic and ball game activities and control group upon these parameters. Normalization of concentration ratios of the monitored compounds by the corresponding maximal oxygen uptake reflected better the differences in the response level of adrenaline, noradrenaline, dopamine and cortisol.

Prolonged blood pressure elevation following continuous infusion of angiotensin II-a baroreflex study in healthy humans.

ANG II interacts with the sympathetic nervous system at central nervous blood pressure-regulating structures, including the baroreflex. It is unknown whether prolonged BP elevation mediated by high ANG II plasma levels could induce a persistent shift of the central nervous baroreflex setpoint, lasting beyond the short ANG II plasmatic half time of a few seconds, thereby consolidating elevated BP and/or increased SNA in healthy humans. In a blinded crossover design, ANG II or placebo (saline) was infused for a 6-h period in 12 resting normotensive students (6 males, 6 females) raising BP to borderline hypertensive levels. Between 60 and 120 min after the infusion period, muscle sympathetic nerve activity (MSNA) was assessed microneurographically and correlated with oscillometric BP measurements and heart rate at supine rest (baseline) and during pharmacologic baroreceptor challenge. Infusion of ANG II increased BP to borderline-hypertensive levels, as intended, whereas heart rate remained unaltered. At baroreflex assessment (i.e., 60-120 min after end of infusion period), systolic BP was significantly higher compared with placebo (Δ8.4 ± 3.1 mmHg; P < 0.05), whereas diastolic values were nearly equal between conditions. Baseline MSNA was neither decreased nor increased, and baroreflex sensitivity to vasoactive drug challenge was not altered. Our results show that elevation of ANG II plasma levels over 6 h was able to increase systolic, but not diastolic, BP far beyond blood-mediated ANG II effects. MSNA or heart rate did not counter-regulate this BP elevation, indicating that ANG II had sustainably reset the central nervous BP threshold of sympathetic baroreflex function to accept elevated BP input signals without counter-regulatory response.

Effect of different phenylephrine bolus doses for treatment of hypotension during spinal anaesthesia in patients undergoing elective caesarean section.

The efficacy of phenylephrine might be improved by giving doses higher than that traditionally used (100 µg). This study compared the effects of three initial bolus doses of intravenous phenylephrine; 100 µg (group P100), 125 µg (group P125) and 150 µg (group P150), for the treatment of post-spinal hypotension in patients undergoing elective caesarean delivery. If hypotension was not corrected by this dose, additional boluses of 25 µg were given every minute. Further hypotensive episodes were treated with half the initial bolus dose, followed by 25 µg boluses, as required. Umbilical arterial and venous blood samples were obtained for blood gas analysis and Apgar scores recorded. One hundred and twenty subjects (40 per group) who developed post-spinal hypotension (75%) were included in this randomised, double blind trial. Although systolic blood pressure was higher at certain time-points after 150 µg phenylephrine, there were no statistically significant differences in the effectiveness of the first bolus of phenylephrine to treat hypotension (85%, 95% and 95% in groups P100, P125 and P150, respectively, P=0.215); the additional dose of phenylephrine after the first bolus (P=0.810); the number of additional boluses (P=0.318) or of hypotensive episodes (P=0.118). There were no significant differences in the number of patients developing reactive hypertension or bradycardia, in maternal side-effects or in neonatal outcomes. Although the study may have been underpowered, initial phenylephrine bolus doses of 100 µg, 125 µg and 150 µg did not significantly differ in efficacy to treat post-spinal hypotension in these patients.

Maternal plasma levels of interleukin-6, C-reactive protein, vitamins C, E and A, 8-isoprostane and oxidative status in women with preterm premature rupture of membranes.

OBJECTIVE: Preterm premature rupture of membranes (PPROM) is associated with significant maternal and perinatal morbidity. This study examined maternal oxidative stress in PPROM. METHODS: This was a prospective cross-sectional study conducted in a university hospital. A total of 72 pregnant women were recruited into two groups, those with PPROM (38 cases) and those without PPROM (34 controls) matched for gestational age. Plasma interleukin-6, C-reactive protein, vitamins C, E and A, 8-isoprostane, total oxidant status (TOS) and antioxidant status (TAS) were determined for all study participants and the data were compared between the PPROM and control groups. RESULTS: Both case and control groups were comparably matched in age, parity, gestational age and smoking status. There was a significant association between low 8-isoprostane, low vitamin C and high total oxidant status and the occurrence of PPROM (p < 0.001). CONCLUSIONS: Plasma vitamin C and 8-isoprostane levels were lower and TOS higher in women with PPROM. Further research is needed to identify robust biological markers for the prevention and also prognosis of PPROM.

Serious adverse events associated with vasopressin and norepinephrine infusion in septic shock.

OBJECTIVE: The frequency, risk factors, and mortality rates of serious adverse events associated with the use of vasopressin and norepinephrine are not clear. The objectives of this study were to determine frequency, risk factors (including candidate gene polymorphisms), and outcomes of serious adverse events in septic shock patients. DESIGN: Retrospective cohort study using multicenter discovery and single-center validation cohorts. SETTING: ICUs at academic teaching centers. PATIENTS: Five hundred ninety-seven patients with septic shock in discovery (Vasopressin and Septic Shock trial) and 533 patients in validation (St. Paul's Hospital) cohorts. INTERVENTION: Vasopressin and norepinephrine for septic shock. MEASUREMENTS AND MAIN RESULTS: The primary outcome variable was 90-day mortality rates of patients with and without serious adverse events. Secondary outcome variables were the association between vasopressor genotype pathway polymorphisms, plasma vasopressin levels, and serious adverse events. Plasma vasopressin concentrations were measured at baseline, 6 hours, 24 hours, 72 hours, and 7 days after vasopressor infusion. Patients with septic shock were genotyped for 268 vasopressor pathway tag single-nucleotide polymorphisms. Serious adverse events occurred in 10.5% and 9.7% of patients in Vasopressin and Septic Shock trial and St. Paul's Hospital cohorts, respectively. Patients who had serious adverse events had higher mortality (p < 0.01) than patients without serious adverse events (adjusted for age, serum lactate, Acute Physiology and Chronic Health Evaluation II, and maximum dose of norepinephrine day 1) (hazard ratio, 2.97; 95% CI, 2.20-4.00; p < 0.001 and hazard ratio, 1.89; 95% CI, 1.26-2.85; p = 0.002 in Vasopressin and Septic Shock trial and St. Paul's Hospital, respectively). There was no difference in the area under the plasma vasopressin concentration curve between patients with and without serious adverse events (p = 0.1). The AA genotype of rs28418396 single-nucleotide polymorphism (near the arginine vasopressin receptor 1b gene) was significantly associated with serious adverse events in discovery and validation cohorts (p = 0.001 and p = 0.04, respectively). CONCLUSION: Serious adverse events associated with vasopressin and norepinephrine in patients who have septic shock are associated with increased mortality and morbidity. AA genotype of rs28418396 single-nucleotide polymorphism near the arginine vasopressin receptor 1b gene is associated with serious adverse events. The mechanism of this association requires investigation.

Impact of catecholamines in cardiac arrest due to acute asphyxia--a study in piglets.

BACKGROUND: Early intravenous epinephrine administration may help to achieve return of spontaneous circulation in cardiac arrest (CA). However, venous access can be challenging in small children. This study investigates the effect of intravenous and intramuscular epinephrine in treatment of asphyxial CA. METHODS: Twenty-eight, 2-5-weeks-old, anesthetized piglets were asphyxiated by ventilation withdrawal. CA was untreated for 8 min, followed by 2 min of basic life support. Following this, epinephrine iv (10 µg·kg(-1) , group IV), epinephrine im (100 µg·kg(-1) , group IM), or normal saline (group NS) were administered. Further doses of epinephrine were given in group IV every 4 min, in group IM after 10 min if required. After twenty-two minutes of CA, iv epinephrine was given to all animals still in CA. Outcome measures were survival and epinephrine plasma concentrations. RESULTS: Ten animals regained spontaneous circulation after 2 min of basic life support. Therefore, no drug treatment was administered (drop out). Resuscitation was effective in 2 pigs of group IM (n = 6), in 6 of group NS (n = 8) and in all of group IV (n = 4). Nonsurvivors had higher epinephrine (P < 0.01) and norepinephrine (P < 0.01) plasma concentrations prior to start of resuscitation. Median increase in epinephrine plasma concentration from T0 to T5 was 138, 134, and 29 nm in group IV, IM, and NS, respectively. CONCLUSIONS: Intravenous and intramuscular administered epinephrine led to similar increase in plasma concentrations during resuscitation of asphyxial CA without hemodynamic or survival benefit. High endogenous epinephrine and norepinephrine plasma concentrations were negative predictors for survival.

Ventilatory responses to chemoreflex stimulation are not enhanced by angiotensin II in healthy humans.

The chemoreflexes exert significant control over respiration and sympathetic outflow. Abnormalities in chemoreflex function may contribute to various disease processes. Based on prior animal studies, we developed the hypothesis that acutely elevating circulating angiotensin II levels into the pathophysiological range increases chemoreflex responsiveness in healthy humans. Eighteen adults were studied before (Pre) and during (Post) low (protocol 1; 2ng/kg/min; n=9) or high (protocol 2; 5ng/kg/min; n=9) dose angiotensin II infusion (study day 1). Chemoreflex responses were quantified by the pure nitrogen breathing method [slope of the minute ventilation vs. arterial oxygen saturation plot generated during a series (n=10) of 100% inspired nitrogen exposures (1-8 breaths)] and by measuring responses to hypercapnia (7% inspired carbon dioxide). Responses to a non-chemoreflex stimulus were also determined (cold pressor test). Measurements were repeated on a subsequent day (study day 2) before and during infusion of a control vasoconstrictor (phenylephrine) infused at a dose (0.6-1.2µg/kg/min) sufficient to increase blood pressure to the same degree as that achieved during angiotensin II infusion. We found that despite increasing plasma angiotensin II levels to pathophysiological levels responses to pure nitrogen breathing, hypercapnia, and the cold pressor test were unchanged by low (2ng/kg/min) and high dose (5ng/kg/min) angiotensin II infusion (protocols 1 and 2). Similarly, responses measured during phenylephrine infusion (Post) were unchanged (from Pre). These findings indicate that acutely increasing plasma angiotensin II levels to levels observed in disease states, such as human heart failure, do not increase chemoreflex responsiveness in healthy humans.

Cocaine-induced vasoconstriction in the human coronary microcirculation: new evidence from myocardial contrast echocardiography.

BACKGROUND: Cocaine is a major cause of acute coronary syndrome, especially in young adults; however, the mechanistic underpinning of cocaine-induced acute coronary syndrome remains limited. Previous studies in animals and in patients undergoing cardiac catheterization suggest that cocaine constricts coronary microvessels, yet direct evidence is lacking. METHODS AND RESULTS: We used myocardial contrast echocardiography to test the hypothesis that cocaine causes vasoconstriction in the human coronary microcirculation. Measurements were performed at baseline and after a low, nonintoxicating dose of intranasal cocaine (2 mg/kg) in 10 healthy cocaine-naïve young men (median age, 32 years). Postdestruction time-intensity myocardial contrast echocardiography kinetic data were fit to the equation y=A(1-e(-ßt)) to quantify functional capillary blood volume (A), microvascular flow velocity (ß), and myocardial perfusion (A×ß). Heart rate, mean arterial pressure, and left ventricular work (2-dimensional echocardiography) were measured before and 45 minutes after cocaine. Cocaine increased mean arterial pressure (by 14±2 mm Hg [mean±SE]), heart rate (by 8±3 bpm), and left ventricular work (by 50±18 mm Hg·mL(-1)·bpm(-1)). Despite the increases in these determinants of myocardial oxygen demand, myocardial perfusion decreased by 30% (103.7±9.8 to 75.9±10.8 arbitrary units [AU]/s; P<0.01) mainly as a result of decreased capillary blood volume (133.9±5.1 to 111.7±7.7 AU; P<0.05) with no significant change in microvascular flow velocity (0.8±0.1 to 0.7±0.1 AU). CONCLUSIONS: In healthy cocaine-naïve young adults, a low-dose cocaine challenge evokes a sizeable decrease in myocardial perfusion. Moreover, the predominant effect is to decrease myocardial capillary blood volume rather than microvascular flow velocity, suggesting a specific action of cocaine to constrict terminal feed arteries.

Selepressin, a new V1A receptor agonist: hemodynamic comparison to vasopressin in dogs.

Selepressin is a new selective vasopressin V1a agonist for treatment of vasodilatory hypotension in shock. Its effect on coronary and aortic blood flow, hemodynamics, and electrocardiogram as an indication of drug safety in healthy dogs was compared with arginine vasopressin (AVP). Eight dogs were fasted, anesthetized, intubated, and ventilated. Following thoracotomy, coronary and aortic blood flows were monitored, left ventricular and peripheral arterial blood pressures were measured, and electrocardiogram was recorded. Selepressin or AVP was administered by dose-escalating infusions (1-300, 0.3-100 ng · kg(-1) · min(-1), respectively). Drug formulation analysis and plasma bioanalysis confirmed exposure. For each dose level, hemodynamic parameters, drug potency, and efficacy were determined. Selepressin and AVP induced a similar increase in mean blood pressure (+13% to 18%), a moderate decrease in aortic blood flow (-40% to 45%), and a slight decrease in coronary blood flow (-16% to 22%). These vasopressors displayed similar hemodynamic characteristics, with peripheral vasoconstriction and decreased aortic blood flow being more pronounced than the increase in coronary resistance and decrease in coronary blood flow. Importantly, selepressin bore no relevant coronary ischemic liability, suggesting that V1a receptor agonists are a potential pharmacological target for treatment of vasodilatory hypotension in shock.