Nicardipine or Nitroprusside for Postoperative Blood Pressure Control in Infants After Surgery for Congenital Heart Disease: Single-Center Retrospective Noninferiority and Cost Analysis, 2016-2020.

OBJECTIVES: Postoperative hypertension frequently occurs after surgery for congenital heart disease. Given safety concerns when using calcium channel blockers in infants along with the cost and side-effect profile of nitroprusside, we retrospectively assessed our experience of using nicardipine and nitroprusside for postoperative blood pressure control in infants who underwent surgery for congenital heart disease. We also investigated the cost difference between the medications. DESIGN: This study was a single-center retrospective, pre-post chart review of patients who had surgery for congenital heart disease between 2016 and 2020. The primary aim was a noninferiority comparison of achievement of blood pressure goal at 1-hour post-initiation of an antihypertensive agent. Secondary comparisons included achievement of blood pressure goal at 2 hours after medication initiation, Vasoactive-Inotropic Score (VIS), and blood transfusion, crystalloid volume, and calcium needs. SETTING: Academic quaternary-care center. PATIENTS: Infants under 1 year old who required treatment for hypertension with nitroprusside ( n = 71) or nicardipine ( n = 52) within 24 hours of surgery for congenital heart disease. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We failed to identify any difference in proportion of patients that achieved blood pressure control at 1-hour after medication initiation (nitroprusside 52% vs. nicardipine 54%; p = 0.86), with nicardipine noninferior to nitroprusside within a 15% margin. Of patients who did not achieve control at 1-hour post-medication initiation, receiving nicardipine was associated with blood pressure control at 2 hours post-medication initiation (79% vs. 38%; p = 0.003). We also failed to identify an association between antihypertensive types and mean VIS scores, blood transfusion volumes, crystalloid volumes, and quantities of calcium administered. Index cost of using nitroprusside was 16 times higher than using nicardipine, primarily due to difference in wholesale cost. CONCLUSIONS: In our experience of achieving blood pressure control in infants after surgery for congenital heart disease (2016-2020), antihypertensive treatment with nicardipine was noninferior to nitroprusside. Furthermore, nicardipine use was significantly less expensive than nitroprusside. Our contemporary practice is therefore to use nicardipine in preference to nitroprusside.

Randomized controlled dose-escalation design to evaluate the safety of a novel pharmacological cardiopulmonary resuscitation strategy.

BACKGROUND/AIMS: The motivating randomized controlled phase I trial evaluates three sodium nitroprusside doses in a novel sodium nitroprusside-enhanced cardiopulmonary resuscitation strategy for improved end-organ perfusion relative to local standard of care. Sodium nitroprusside is a vasodilator with an established safety profile in other indications, whereas the local standard of care uses vasoconstrictors, typically epinephrine. The purpose of the proposed trial is to identify the highest safe dose of sodium nitroprusside in this new context as excessive doses may cause severe hypotension with compromised end-organ perfusion. METHODS: The proposed phase I trial design expands upon traditional dose-finding designs to include a randomized control arm, which is needed to assess safety through the relative increase in serum lactate on hospital admission. For guiding dose escalation, we propose and compare six Bayesian models which characterize expected serum lactate as a function of sodium nitroprusside dose and randomization group. Each model makes a different assumption about the expected change in serum lactate across control cohorts concurrently randomized with each dose. Model selection aims to minimize the expected number of times that a dose is incorrectly classified as safe or unsafe while sample size selection targets an expected number of incorrectly classified doses. Randomization is 1:1 for the initial cohort, and for subsequent cohorts is chosen to maximize the lower confidence bound. RESULTS: The spike-and-slab model minimizes the expected number of times that a dose is incorrectly classified as safe or unsafe under the most scenarios in the motivating three-dose trial, but all six models exhibit relatively similar performance. A 2:1 randomization ratio for the second and third cohorts maximizes the lower confidence bound when using the spike-and-slab model. With the optimal design, on average, 70 individuals will ensure 1 incorrectly classified dose in 6 opportunities. CONCLUSION: We recommend that the motivating trial use the spike-and-slab model with a 1:1 randomization ratio for the initial cohort and 2:1 randomization ratio for subsequent cohorts; however, the simpler fixed effects approaches performed similarly well.

Renal Hemodynamics and Renin-Angiotensin-Aldosterone System Profiles in Patients With Heart Failure.

OBJECTIVE: Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF. METHODS: In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5). RESULTS: The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only. CONCLUSIONS: A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile.

Comparison of Intravenous Antihypertensives on Blood Pressure Control in Acute Neurovascular Emergencies: A Systematic Review.

BACKGROUND: Acute blood pressure (BP) management in neurologic patients is paramount. Different neurologic emergencies dictate various BP goals. There remains a lack of literature determining the optimal BP regimen regarding safety and efficacy. The objective of this study was to identify which intravenous antihypertensive is the most effective and safest for acute BP management in neurologic emergencies. METHODS: Ovid EBM (Evidence Based Medicine) Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science Core Collection were searched from inception to August 2020. Randomized controlled trials or comparative observational studies that evaluated clevidipine, nicardipine, labetalol, esmolol, or nitroprusside for acute neurologic emergencies were included. Outcomes of interest included mortality, functional outcome, BP variability, time to goal BP, time within goal BP, incidence of hypotension, and need for rescue antihypertensives. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to evaluate the degree of certainty in the evidence available. RESULTS: A total of 3878 titles and abstracts were screened, and 183 articles were selected for full-text review. Ten studies met the inclusion criteria; however, the significant heterogeneity and very low quality of studies precluded a meta-analysis. All studies included nicardipine. Five studies compared nicardipine with labetalol, three studies compared nicardipine with clevidipine, and two studies compared nicardipine with nitroprusside. Compared with labetalol, nicardipine appears to reach goal BP faster, have less BP variability, and need less rescue antihypertensives. Compared with clevidipine, nicardipine appears to reach goal BP goal slower. Lastly, nicardipine appears to be similar for BP-related outcomes when compared with nitroprusside; however, nitroprusside may be associated with increased mortality. The confidence in the evidence available for all the outcomes was deemed very low. CONCLUSIONS: Because of the very low quality of evidence, an optimal BP agent for the treatment of patients with neurologic emergencies was unable to be determined. Future randomized controlled trials are needed to compare the most promising agents.

Combined effects of hydralazine and nitrate on serum biochemistry and left ventricular remodeling in chronic heart failure patients.

To investigate the effects of hydralazine combined with nitrate on serum levels of Adropin and brain natriuretic peptide (BNP), left ventricular remodeling and prognosis in patients with chronic heart failure (CHF). 126 CHF patients were divided into control group (n=13, sodium nitroprusside) and combined treatment group (n=63, sodium nitroprusside ± hydralazine). Serum Adropin and BNP levels and left ventricular mass index (LVMI) of patients before treatment and 10 days after treatment were recorded, so did patient's end-point events. It was found that compared with those before treatment, the serum levels of Adropin, BNP, and LVMI in combined group and control group after 10 days of treatment were lower (P<0.05). The end-point event rate in the combined group was 19.05% (12/63). The serum levels of Adropin, BNP, and LVMI in the combined group with end-point events were higher than those of patients without end-point events (P<0.05). Spearman correlation analysis showed that serum levels of Adropin and BNP were positively correlated with LVMI and the end-point events rate (P<0.05). To sum up, hydralazine combined with sodium nitroprusside treatment can effectively reduce serum Adropin and BNP levels, and the risk of left ventricular remodeling and poor prognosis in patients with CHF.

Repeated but not acute exposure with a low dose range of the nitric oxide (NO) donor sodium nitroprusside (SNP) induces anxiolytic-like behaviour in a dose-independent manner in two different rat models of anxiety.

Sodium nitroprusside (SNP) is a nitric oxide (NO) donor which actually is under assessment as a potential candidate for the treatment of schizophrenia. It is well documented that anxiety symptoms are a prominent future in various psychiatric diseases comprising schizophrenia. Prior research has shown that acute challenge with SNP (1-3 mg/kg) induced anti-anxiety effects in rats but these effects at high doses were confounded by sedation and were disappeared after repeated application of it. It is still unknown if administration of a lower SNP dose range, either acutely or sub-chronically, could induce anxiolytic-like behaviour. The present study was designed to investigate this issue in rats. For this aim, the light/dark and the open field tests were used. Acute challenge with SNP (0.1 and 0.3 mg/kg, 30 min before testing) did not affect rodents' performance in the above mentioned behavioural paradigms. Conversely, rats treated sub-chronically with SNP (0.1 and 0.3 mg/kg, once per day, for 5 consecutive days), displayed longer time spent in the light chamber of the light/dark box and in the central area of the open field with respect to their vehicle-treated counterparts. Interestingly, SNP did not influence the first latency to enter the dark chamber and the number of transitions between the light and dark compartments of the apparatus in the light/dark test and did not modify the number of squares crossed, grooming episodes and rearings in the open field test. Finally, acute administration of SNP (0.1, 0.3 and 1 mg/kg, 10 min before testing) also did not influence rats' performance in the light/dark test. The present results indicate that short-term repeated but not acute application of a range of low doses of the NO donor SNP in a dose-independent manner induced an anti-anxiety behaviour in the rat which was not accompanied by undesired effects.

Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis.

BACKGROUND: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers. METHODS: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach. RESULTS: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics. CONCLUSIONS: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites. CLINICAL TRIAL REGISTRATION: Dutch Cochrane Center 5359.

Nitric Oxide-Based Treatment of Poor-Grade Patients After Severe Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Patients with aneurysmal subarachnoid hemorrhage (aSAH) require close treatment in neuro intensive care units (NICUs). The treatments available to counteract secondary deterioration and delayed ischemic events remain restricted; moreover, available neuro-monitoring of comatose patients is undependable. In comatose patients, clinical signs are hidden, and timing interventions to prevent the evolution of a perfusion disorder in response to fixed ischemic brain damage remain a challenge for NICU teams. Consequently, comatose patients often suffer secondary brain infarctions. The outcomes for long-term intubated patients w/wo pupil dilatation are the worst, with only 10% surviving. We previously added two nitroxide (NO) donors to the standard treatment: continuous intravenous administration of Molsidomine in patients with mild-to-moderate aSAH and, if required as a supplement, intraventricular boluses of sodium nitroprusside (SNP) in high-risk patients to overcome the so-called NO-sink effect, which leads to vasospasm and perfusion disorders. NO boluses were guided by clinical status and promptly reversed recurrent episodes of delayed ischemic neurological deficit. In this study, we tried to translate this concept, the initiation of intraventricular NO application on top of continuous Molsidomine infusion, from awake to comatose patients who lack neurological-clinical monitoring but are primarily monitored using frequently applied transcranial Doppler (TCD). METHODS: In this observational, retrospective, nonrandomized feasibility study, 18 consecutive aSAH comatose/intubated patients (Hunt and Hess IV/V with/without pupil dilatation) whose poor clinical status precluded clinical monitoring received standard neuro-intensive care, frequent TCD monitoring, continuous intravenous Molsidomine plus intraventricular SNP boluses after TCD-confirmed macrospasm during the daytime and on a fixed nighttime schedule. RESULTS: Very likely associated with the application of SNP, which is a matter of further investigation, vasospasm-related TCD findings promptly and reliably reversed or substantially weakened (p < 0.0001) afterward. Delayed cerebral ischemia (DCI) occurred only during loose, low-dose or interrupted treatment (17% vs. an estimated 65% with secondary infarctions) in 17 responders. However, despite their worse initial condition, 29.4% of the responders survived (expected 10%) and four achieved Glasgow Outcome Scale Extended (GOSE) 8-6, modified Rankin Scale (mRS) 0-1 or National Institutes of Health Stroke Scale (NIHSS) 0-2. CONCLUSIONS: Even in comatose/intubated patients, TCD-guided dual-compartment administration of NO donors probably could reverse macrospasm and seems to be feasible. The number of DCI was much lower than expected in this specific subgroup, indicating that this treatment possibly provides a positive impact on outcomes. A randomized trial should verify or falsify our results.

Sodium nitroprusside versus nicardipine for hypertension management after surgery: A systematic review and meta-analysis.

BACKGROUND: Vasoactive medications are commonly administered for afterload reduction and arterial hypertension treatment in patients after cardiac surgery. A systematic review and meta-analysis were conducted to determine the effects of sodium nitroprusside and nicardipine on hemodynamics and cardiac performance in this population. METHODS: A systematic review of published manuscripts was performed to identify studies of patients who received sodium nitroprusside and nicardipine as part of the treatment for arterial hypertension or afterload reduction after cardiac surgery. A meta-analysis was then conducted to determine the effects of sodium nitroprusside and nicardipine on hemodynamics and cardiac performance. The following parameters were captured: blood pressure, heart rate, right atrial pressure, systemic vascular resistance, and stroke volume. RESULTS: In total, five studies with 571 patients were pooled for these analyses. Systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were similar in both groups. The cardiac index was greater with nicardipine while mean pulmonary artery pressure was lower with sodium nitroprusside. CONCLUSION: Nicardipine and sodium nitroprusside have similar abilities in reducing afterload in the postoperative cardiac population. Statistically significant differences were found in pulmonary artery pressure and cardiac index. It may be beneficial to consider nicardipine for afterload reduction in patients with a low cardiac index.

Pharmacologic Control of Blood Pressure in Infants and Children.

Alterations in blood pressure are common during the perioperative period in infants and children. Perioperative hypertension may be the result of renal failure, volume overload, or activation of the sympathetic nervous system. Concerns regarding end-organ effects or postoperative bleeding may mandate regulation of blood pressure. During the perioperative period, various pharmacologic agents have been used for blood pressure control including sodium nitroprusside, nitroglycerin, ß-adrenergic antagonists, fenoldopam, and calcium channel antagonists. The following manuscript outlines the commonly used pharmacologic agents for perioperative BP including dosing regimens and adverse effect profiles. Previously published clinical trials are discussed and efficacy in the perioperative period reviewed.

Blood Glucose Regulation for Post-Operative Patients with Diabetics and Hypertension Continuum: A Cascade Control-Based Approach.

Management of glycemic level in post-operative condition is critical for hypertensive patients and the post-operative stress may results in hyperglycemia, hyper insulin and osmotic diuresis. Recent medical research shows that diabetic and hypertension hands together in a significant overlap in its etiology and its disease mechanism. It is clear that there is a call for monitoring in the parameter and controlling the glucose level particularly in the presence of hypertension. This paper proposes the novel complex (cascade) control system to control the insulin infusion level particularly in the presence of hypertension. Based on the requirements the structure has been designed and the simulation results indicates that the proposed control strategy shows better results and may achieve potentially better glycemic control to the hypersensitive diabetic patients.

Performance comparison of ventricular and arterial dP/dtmax for assessing left ventricular systolic function during different experimental loading and contractile conditions.

BACKGROUND: Maximal left ventricular (LV) pressure rise (LV dP/dtmax), a classical marker of LV systolic function, requires LV catheterization, thus surrogate arterial pressure waveform measures have been proposed. We compared LV and arterial (femoral and radial) dP/dtmax to the slope of the LV end-systolic pressure-volume relationship (Ees), a load-independent measure of LV contractility, to determine the interactions between dP/dtmax and Ees as loading and LV contractility varied. METHODS: We measured LV pressure-volume data using a conductance catheter and femoral and radial arterial pressures using a fluid-filled catheter in 10 anesthetized pigs. Ees was calculated as the slope of the end-systolic pressure-volume relationship during a transient inferior vena cava occlusion. Afterload was assessed by the effective arterial elastance. The experimental protocol consisted of sequentially changing afterload (phenylephrine/nitroprusside), preload (bleeding/fluid bolus), and contractility (esmolol/dobutamine). A linear-mixed analysis was used to assess the contribution of cardiac (Ees, end-diastolic volume, effective arterial elastance, heart rate, preload-dependency) and arterial factors (total vascular resistance and arterial compliance) to LV and arterial dP/dtmax. RESULTS: Both LV and arterial dP/dtmax allowed the tracking of Ees changes, especially during afterload and contractility changes, although arterial dP/dtmax was lower compared to LV dP/dtmax (bias 732 ± 539 mmHg⋅s- 1 for femoral dP/dtmax, and 625 ± 501 mmHg⋅s- 1 for radial dP/dtmax). Changes in cardiac contractility (Ees) were the main determinant of LV and arterial dP/dtmax changes. CONCLUSION: Although arterial dP/dtmax is a complex function of central and peripheral arterial factors, radial and particularly femoral dP/dtmax allowed reasonably good tracking of LV contractility changes as loading and inotropic conditions varied.

3-Methylcholanthrene/Aryl-Hydrocarbon Receptor-Mediated Hypertension Through eNOS Inactivation.

Endothelial nitric oxide synthase (eNOS) modulates vascular blood pressure and is predominantly expressed in endothelial cells and activated through the protein kinase B (Akt/PKB)-dependent pathway. We previously reported that 3-methylcholanthrene (3MC) activates the aryl hydrocarbon receptor (AhR) and reduces PI3K/Akt phosphorylation. This study investigated the mechanism underlying the downregulatory effects of 3-MC on nitric oxide (NO) production occurring through the AhR/RhoA/Akt-mediated mechanism. The mechanism underlying the effects of 3-MC on eNOS activity and blood pressure was examined in vitro and in vivo through genetic and pharmacological approaches. Results indicated that 3-MC modified heat shock protein 90 (HSP90), caveolin-1, dynein, and eNOS mRNA and protein expression through the AhR/RhoA-dependent mechanism in mouse cerebral vascular endothelial cells (MCVECs) and that 3-MC reduced eNOS phosphorylation through the AhR/RhoA-mediated inactivation of Akt1. The upregulation of dynein expression was associated with decreased eNOS dimer formation (eNOS dimer; an activated form of the enzyme). Coimmunoprecipitation assay results indicated that 3-MC significantly reduced the interaction between eNOS and its regulatory proteins, including Akt1 and HSP90, but increased the interaction between eNOS and caveolin-1. Immunofluorescence and Western blot analysis revealed that 3-MC reduced the amount of membrane-bound activated eNOS, and a modified Griess assay revealed that 3-MC concomitantly reduced NO production. However, simvastatin reduced 3-MC-mediated murine hypertension. Our study results indicate that AhR, RhoA, and eNOS have major roles in blood pressure regulation. Statin intervention might provide a potential therapeutic approach for reducing hypertension caused by 3-MC. J. Cell. Physiol. 232: 1020-1029, 2017. © 2016 Wiley Periodicals, Inc.

Acute and repeated exposure with the nitric oxide (NO) donor sodium nitroprusside (SNP) differentially modulate responses in a rat model of anxiety.

The nitric oxide (NO) donor sodium nitroprusside (SNP) actually is under investigation for the treatment of schizophrenia. That anxiety disorders are noted to occur commonly in schizophrenia patients is known. Contradictory results were reported however, concerning the effects of SNP in animal models of anxiety disorders. The present study investigated the effects of acute and repeated administration of SNP on anxiety-like behaviour in rats assessed in the light/dark test. The effects of SNP on motility in a locomotor activity chamber were also investigated in rats. Acute administration of 1 mg/kg SNP 30 but not 60 min before testing induced anxiolytic-like behaviour which cannot be attributed to changes in locomotor activity. Conversely, a single injection of 3 mg/kg SNP at 30 min before testing depressed rats' general activity, while at 60 min this dose did not influence performance of animals either in the light/dark or in the motor activity test. Repeated application of SNP (1 and 3 mg/kg, for 5 consecutive days) did not alter rodents' performance in the above described behavioural paradigms. The present results suggest that the effects exerted by SNP in the light/dark test in rats are dose, time and treatment schedule-dependent. The current findings propose also a narrow therapeutic window for SNP in this animal model of anxiety.

The beneficial hemodynamic effects of afterload reduction by sodium nitroprusside during rewarming from experimental hypothermia.

BACKGROUND: Rewarming from hypothermia is associated with depressed cardiac function, known as hypothermia-induced cardiac dysfunction (HCD), and increased systemic vascular resistance (SVR). Previous studies on pharmacological treatment of HCD have demonstrated beneficial effects when using drugs with the combined effects; cardiac inotropic support and peripheral vasodilation. The presented study aims to investigate the isolated effects of arterial dilatation on cardiac functional variables during rewarming from hypothermia using sodium nitroprusside (SNP). METHODS: We utilized a rat model designed to induce HCD following 4 h at 15 °C and rewarming. To study effects on left ventricular (LV) functional variables in response to afterload reduction by SNP during rewarming a conductance catheter was used. Index of LV contractility, preload recruitable stroke work (PRSW), was obtained with inferior vena cava occlusions at 37 °C before and after hypothermia. Pressure signals from a catheter in the left femoral artery was used to pharmacologically adjust SVR. RESULTS: After rewarming both animal groups showed significant reduction in both SV and CO as a manifestation of HCD. However, compared to saline controls, SV and CO in SNP-treated animals increased significantly during rewarming in response to afterload reduction displayed as reduced SVR, mean arterial- and end-systolic pressures. The cardiac contractility variable PRSW was equally reduced after rewarming in both groups. CONCLUSION: When rewarming the present model of HCD a significant increase in SVR takes place. In this context, pharmacologic intervention aimed at reducing SVR show clear positive results on CO and SV. However, a reduction in SVR alone is not sufficient to fully alleviate CO during HCD, and indicate the need of additional inotropic support.

Sodium Nitroprusside in Patients With Mixed Pulmonary Hypertension and Left Heart Disease: Hemodynamic Predictors of Response and Prognostic Implications.

BACKGROUND: Mixed pulmonary hypertension (PH) in heart failure (HF) is defined by transpulmonary gradient ≥ 12 and/or pulmonary vascular resistance (PVR) ≥ 240 dyne/s/cm(-5), but diastolic pressure gradient (DPG) ≥ 7 mmHg has been proposed more recently. We evaluated the acute hemodynamic response to sodium nitroprusside (SNP) specifically in relation to the proposed DPG criterion ≥7 mmHg and the prognostic significance of response to SNP in patients with mixed PH and advanced HF. METHODS: Ninety-eight consecutive patients with advanced HF and mixed PH underwent cardiac catheterization and acute SNP infusion. Baseline hemodynamic parameters included transpulmonary gradient, PVR, DPG, and pulmonary capacitance (PCap). Hemodynamic response to SNP was defined as a reduction in PVR of at least 20%. The composite endpoint was death/heart transplantation/mechanical circulatory support. RESULTS: Sixty of the 98 patients were SNP responders. SNP resulted in significant reductions in filling pressures and PVR and increase in stroke volume and PCap. DPG (not baseline PVR) was significantly associated with hemodynamic response to SNP on logistic regression analysis. The sensitivity and specificity of a DPG ≥7 mmHg to identify nonresponders to SNP were 74% and 97%, respectively. At median follow-up of 218 (148-324) days, 13 and 19 patients of the SNP responders and nonresponders, respectively, met the composite endpoint (P = .021 by log-rank test). Hemodynamic response to SNP and PCap were independently associated with the composite outcome of survival free from transplantation/mechanical circulatory support. CONCLUSION: Baseline DPG ≥ 7 mmHg is associated with poor PVR response to SNP. PVR response to SNP and PCap are associated with a more favorable prognosis in patients with advanced HF and mixed PH.

The effect of sodium nitroprusside on psychotic symptoms and spatial working memory in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia. METHOD: This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18-60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 µg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later. RESULTS: SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo. CONCLUSIONS: Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.

Altered cardiovascular function at birth in growth-restricted preterm lambs.

BACKGROUND: Cardiovascular dysfunction at birth may underlie poor outcomes after fetal growth restriction (FGR) in neonates. We compared the cardiovascular transition between FGR and appropriately grown (AG) preterm lambs and examined possible mechanisms underlying any cardiovascular dysfunction in FGR lambs. METHODS: FGR was induced in ewes bearing twins at 0.7 gestation; the twin was used as an internal control (AG). At 0.8 gestation, lambs were delivered and either euthanized with their arteries isolated for in vitro wire myography, or ventilated for 2 h. At 60 min, inhaled nitric oxide (iNO) was administered in a subgroup for 30 min. Molecular assessment of the nitric oxide (NO) pathway within lung tissue was conducted. RESULTS: FGR lambs had lower left ventricular output and cerebral blood flow (CBF) and higher systemic vascular resistance compared with AG lambs. INO administration to FGR lambs rapidly improved cardiovascular and systemic hemodynamics but resulted in decreased CBF in AG lambs. Isolated arteries from FGR lambs showed impaired sensitivity to NO donors, but enhanced vasodilation to Sildenafil and Sodium nitroprusside, and altered expression of components of the NO pathway. CONCLUSION: Cardiovascular dysfunction at birth may underlie the increased morbidity and mortality observed in preterm FGR newborns. Impaired NO signaling likely underlies the abnormal vascular reactivity.