Systemic Hemodynamics Research Articles

Hyperosmolar Therapy in Elderly Neurosurgical Patients: Comparison of the Effect of Mannitol (20%) and Hypertonic Saline (3%) on Advanced Cardiovascular Parameters Using Transesophageal Echocardiography: A Preliminary Randomized Controlled Trial

Osmotherapeutic agents increase the intravascular volume by withdrawing water from the brain followed by relative hypovolemia due to diuresis leading to significant changes in systemic hemodynamics which might have adverse consequences in the elderly. We studied the effect of mannitol (20%) and hypertonic saline (HTS) (3%) on left ventricular outflow tract velocity time integral (LVOT-VTI) and cardiac output (CO) in elderly patients undergoing supratentorial neurosurgical procedures using transesophageal echocardiography. We recruited 28 patients aged above 65years undergoing supratentorial craniotomy who received equiosmolar solutions of 5.35ml/kg of 3% HTS (group HS, n= 14) or 5ml/kg of 20% mannitol (group M, n= 14). LVOT-VTI was recorded at baseline, 15, 30, 45, 60, and 90minutes postinfusion and CO was derived. We also recorded heart rate, blood pressure, fluid balance, brain relaxation, vasopressor use, complications, and neurological outcome. We found a significant decrease in LVOT-VTI at 45, and 60minutes in group M as compared to group HS [mean (standard deviation), 16.76 (1.81) vs. 20.78 (1.87), P<0.001, 17.4 (2.38) vs. 19.16 (2), P=0.044, respectively]. We also found a corresponding significant fall in CO [3863.16 (845.87) vs. 4745.59 (1209.33) ml/minute, P=0.034] and systolic blood pressure (P=0.039), at 45minutes in group M. Urine output was higher in group M (P<0.001). All other parameters were comparable. HTS appears to be associated with better systemic hemodynamics (LVOT-VTI, CO) while providing equivalent brain relaxation as mannitol in elderly patients. A future larger study is required to confirm our preliminary findings.

Macitentan in Adults with Sickle Cell Disease and Pulmonary Hypertension: A Proof-of-Concept Study

Pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with a mortality rate of 37%. There is an upregulation of adhesion molecules which leads to the expression of endothelin-1, a potent vasoconstrictor. A prospective, descriptive study was done to determine the safety and efficacy of macitentan in patients with SCD and PH. Continuous variables were reported as mean ± SEM or percentage where appropriate. We screened 13 patients and recruited five. All five patients were adults. Data were analyzed as appropriate by student t - test. Statistical significance was assumed at p &lt; 0.05. Baseline pulmonary hemodynamics obtained by right heart catheterization and systemic hemodynamics were (± SEM): mean pulmonary artery pressure (MPAP) 32 ± 8 mmHg, right atrial pressure (RAP) 9 ± 4 mmHg, pulmonary vascular resistance (PVR) 257 dynes-sec/cm5 and CI 3·7 ± 0.39 l/m2. Of all parameters, only PVR and 6-min walk distance changed significantly. For the group, MPAP decreased by 15.6%, PVR by 22.5% and RAP by 25.5%. The 6-minute walk distance increased over sixteen weeks except in Patient 4 who had a 3% decrease. The mean walk distance increased in the total distance, from 464 ± 158 meters to 477 ± 190 meters (p .123). In four patients, the adverse events were mild to moderate and did not lead to study drug discontinuation. Significant improvement in pulmonary hemodynamics and exercise capacity in patients with SCD-related pulmonary arterial hypertension. We found that macitentan was safe and well tolerated.

Ineffectiveness of hemoadsorption in large animals with abdominal sepsis: a randomized controlled porcine study.

The use of hemoadsorption (HA) has become popular in the treatment of vasoplegic states associated with massive cytokine release, including septic shock. However, this approach does not seem to be based on robust evidence, and it does not follow international guidelines. To understand the pathophysiological rationale and timing of HA, we conducted a large animal septic shock experiment. Prospective randomized large-animal peritoneal septic shock experiment. Laboratory investigation. Twenty-six anesthetized, mechanically ventilated, and instrumented pigs randomly assigned into (1) sham-operated group with HA (SHAM, n = 5); (2) sepsis animals without HA (SEPSIS, n = 5); (3) sepsis group with HA at norepinephrine initiation (EARLY, n = 8); and (4) sepsis group with HA initiated at norepinephrine rate reaching 0.5 μg/kg/min (LATE, n = 8). Peritoneal sepsis was induced by cultivated autologous feces inoculation. A CytoSorb cartridge (200 g) with a blood flow rate of 200 mL/min and heparin anticoagulation was used to perform HA. The animals received sedation and intensive organ support up to 48 h or until they experienced cardiovascular collapse. Systemic hemodynamics, multiple-organ functions, and immune-inflammatory response were measured at predefined periods. The HA treatment was not associated with any measurable benefit in terms of systemic hemodynamics and organ support. The systemic inflammatory markers were unaffected by any of the treatment timings. In contrast, the HA resulted in higher vasopressor load and decreased 36-h survival (5 animals in SHAM (100%), 4 (80%) in SEPSIS, 4 (57%) in EARLY, and 2 (25%) in LATE; p = 0.041). The HA exposure in healthy animals was associated with hemodynamic deterioration, systemic inflammatory response, and cytopenia. In this large-animal-controlled fulminant sepsis study, the HA was unable to counteract the disease progression in the early or advanced septic shock phase. However, findings from the HA-exposed sham animals suggest potential safety concerns.

Evaluation of the effectiveness and safety of erector spinae plane block during coronary artery bypass surgery: a randomized clinical trial

The search for a method of perioperative pain control after coronary bypass surgery is relevant both from the point of view of safety and effectiveness of the methods used.Aim: To evaluate the hemodynamic changes and effectiveness of erector spinae plane block (ESPB) for off-pump coronary artery bypass surgery.Methodology and research methods. The prospective randomized single-center study included 45 patients equally distributed according to the applied methods of perioperative analgesia into 3 groups: general anesthesia with epidural anesthesia (GA + EA group, n = 15), general anesthesia with ESPB (GA + ESPB group, n = 15) and general anesthesia without any regional anesthesia techniques (GA group, n = 15). Assessment of hemodynamics and severity of pain syndrome was performed during the first postoperative day.Results. The intraoperative dose of fentanyl was 0.4 (0.4–0.5) mg in the GA + EA group, and 0.4 (0.3–0.4) mg in the GA + ESPB group that is significantly less than in the GA group – 1.1 (1.0–1.1) mg (p &lt; 0.001). Postoperatively, the dose of fentanyl was 0.10±0.04 mg in the GA + EA group and 0.23±0.05 mg in the GA group (p &lt; 0.001), whereas in the ESPB group fentanyl was not used. The pain level assessed by the numeric rating scale (NRS) was 3.0 (2.0–4.0) points at one hour after tracheal extubation and 3.0 (0.5–3.5) points at the end of the first day of the postoperative period without difference between the groups. The systemic and pulmonary hemodynamics, respiratory and vasopressor support did not differ as well.Conclusion. The use of regional anesthesia (EA and ESPB) provides similar quality of perioperative analgesia like general anesthesia, but leads to reduction in opioid doses. Postoperatively, the use of ESPB does not lead to a deterioration of the hemodynamic status of the patient.

Systemic tolerance of intravenous milrinone administration for cerebral vasospasm secondary to non-traumatic subarachnoid hemorrhage

PurposeDelayed cerebral ischemia (DCI) is a severe subarachnoid hemorrhage (SAH) complication, closely related to cerebral vasospasm (CVS). CVS treatment frequently comprises intravenous milrinone, an inotropic and vasodilatory drug. Our objective is to describe milrinone's hemodynamic, respiratory and renal effects when administrated as treatment for CVS. MethodsRetrospective single-center observational study of patients receiving intravenous milrinone for CVS with systemic hemodynamics, oxygenation, renal disorders monitoring. We described these parameters' evolution before and after milrinone initiation (day – 1, baseline, day 1 and day 2), studied treatment cessation causes and assessed neurological outcome at 3–6 months. ResultsNinety-one patients were included. Milrinone initiation led to cardiac output increase (4.5 L/min [3.4–5.2] at baseline vs 6.6 L/min [5.2–7.7] at day 2, p < 0.001), Mean Arterial Pressure decrease (101 mmHg [94–110] at baseline vs 95 mmHg [85–102] at day 2, p = 0.001) norepinephrine treatment requirement increase (32% of patients before milrinone start vs 58% at day 1, p = 0.002) and slight PaO2/FiO2 ratio deterioration (401 [333–406] at baseline vs 348 [307–357] at day 2, p = 0.016). Milrinone was interrupted in 8% of patients. 55% had a favorable outcome. ConclusionIntravenous milrinone for CVS treatment seems associated with significant impact on systemic hemodynamics leading sometimes to treatment discontinuation.

Hemodynamical Evaluation of a New Surgically Implanted Pulsatile Right Ventricular Assist Device Driven by a Conventional Intra-Aortic Balloon Pump Console.

Severe right heart failure, often overlooked and challenging to manage, has prompted a growing interest in innovative approaches to provide functional support. This study uses experimentation in large porcine models to introduce a novel prototype of a pulsatile mechanical circulatory support device and document its effects when deployed as a right ventricular assist device (RVAD). The pulsatile ventricular assist platform (pVAP), featuring a membrane pump driven by an intra-aortic balloon pump console, actively generates pulsatile flow to propel right ventricular blood into the pulmonary artery. This novel prototype demonstrates promising potential in addressing the challenges of right heart failure management. After preliminary in vitro assessments, the pVAP was tested on seven porcine models in a healthy state and after the induction of right ventricular failure. During the procedure, a set of standard ( ie , standard-of-care) hemodynamic measurements was obtained. Additionally, invasive pressure-volume loop analysis was employed to examine left ventricular hemodynamics. Results indicated that activation of the pVAP during right ventricular failure significantly improved systemic hemodynamics and enhanced left ventricular function. This study sheds light on the potential of the pVAP in managing right heart failure.

A mathematical model of tissue axial and radial diffusion in the microvasculature for intravascular microscopy and phosphorescence quenching data

This study aims to extend earlier Krogh Cylinder Models of an oxygen profile by considering axial diffusion and analytically solving Fick's Law Partial Differential Equation with novel boundary conditions via the separation of variables. We next prospectively collected a total of 20 animals, which were randomly assigned to receive either fresh or two-week-old stored red blood cell (RBC) transfusions and PQM oxygen data were measured acutely (90 min) or chronically (24 h). Transfusion effects were evaluated in vivo using intravital microscopy of the dorsal skinfold window chamber in Golden Syrian Hamsters. Hamsters were initially hemorrhaged by 50% of total blood volume and resuscitated 1-h post hemorrhage. PQM data were subsequently collected and fit the derived 2D Krogh cylinder model. Systemic hemodynamics (mean arterial pressure, heart rate) were similar in both pre and post-transfusion with either stored or fresh cells. Transfusion with stored cells was found to impair axial and radial oxygen gradients as quantified by our model and consistent with previous studies. Specifically, we observed a statistically significant decrease in the arteriolar tissue radial oxygen gradient after transfusion with stored RBCs at 24 h compared with fresh RBCs (0.33 ± 0.17 mmHg μ m-1 vs, 0.14 ± 0.12 mmHg μ m-1; p = 0.0280). We also observed a deficit in the arteriolar tissue oxygen gradient (0.03 ± 0.01 mmHg μ m-1 fresh vs. 0.018 ± 0.007 mmHg μ m-1 stored; p = 0.0185). We successfully derived and validated an analytical 2D Krogh cylinder model in an animal model of microhemodynamic oxygen diffusion aberration secondary to storage lesions.

Inhospital outcomes of implantation of a centrifugal left ventricular assist device in patients with endstage heart failure: experience of the Chazov National Medical Research Center of Cardiology

Aim. To study the inhospital outcomes of implantation of a centrifugal left ventricular assist device (LVAD) in patients with end-stage heart failure (HF).Material and methods. There were following inclusion criteria: estimated body surface area &gt;1,2 m2, end-stage HF, LV ejection fraction &lt;30%, cardiac index &lt;2,2 l/min, long-term optimal therapy for HF. Patients were considered for implantation of a centrifugal (LVAD) as part of the final therapy, but subsequent heart transplantation was not ruled out if appropriate.Results. LVAD was implanted in 23 patients. All patients were men (mean age, 59,1±10 years; mean body mass index, 26±4,6 kg/m2). Ten patients had dilated cardiomyopathy, while 13 — ischemic one. Diabetes was revealed on in 3 (13%) patients, while chronic kidney disease and cancer — in 3 (13%) and 4 (17%) patients, respectively. The mean value of the six-minute walk test (6MWT) upon admission to the hospital was 257±71 meters. In one patient with gastric cancer, the device was implanted as a part of bridging therapy strategy. Thirty-day mortality was 9% (n=2). One of the deceased patients had a long history of end-stage heart failure, body weight deficiency, and frailty with severe muscle weakness. The second death was the result of early postoperative right ventricular failure. At discharge, patients had optimal LVAD performance based on anthropometric characteristics and physical activity. According to echocardiography, the criteria for unloading the left heart chambers have been achieved. The distance of 6MWT at discharge was 298±78 meters.Conclusion. Inhospital outcomes of implantation of a centrifugal LVAD in patients with end-stage HF demonstrate high efficiency in supporting systemic hemodynamics with an acceptable safety profile in patients with extremely high perioperative risk.

Effects of furosemide, acetazolamide and amiloride on renal cortical and medullary tissue oxygenation in non-anaesthetised healthy sheep.

It has been proposed that diuretics can improve renal tissue oxygenation through inhibition of tubular sodium reabsorption and reduced metabolic demand. However, the impact of clinically used diuretic drugs on the renal cortical and medullary microcirculation is unclear. Therefore, we examined the effects of three commonly used diuretics, at clinically relevant doses, on renal cortical and medullary perfusion and oxygenation in non-anaesthetised healthy sheep. Merino ewes received acetazolamide (250mg; n=9), furosemide (20mg; n=10) or amiloride (10mg; n=7) intravenously. Systemic and renal haemodynamics, renal cortical and medullary tissue perfusion and , and renal function were then monitored for up to 8h post-treatment. The peak diuretic response occurred 2h (99.4±14.8mL/h) after acetazolamide, at which stage cortical and medullary tissue perfusion and were not significantly different from their baseline levels. The peak diuretic response to furosemide occurred at 1h (196.5±12.3mL/h) post-treatment but there were no significant changes in cortical and medullary tissue oxygenation during this period. However, cortical tissue fell from 40.1±3.8mmHg at baseline to 17.2±4.4mmHg at 3h and to 20.5±5.3mmHg at 6h after furosemide administration. Amiloride did not produce a diuretic response and was not associated with significant changes in cortical or medullary tissue oxygenation. In conclusion, clinically relevant doses of diuretic agents did not improve regional renal tissue oxygenation in healthy animals during the 8h experimentation period. On the contrary, rebound renal cortical hypoxia may develop after dissipation of furosemide-induced diuresis.

Association of left ventricular diastolic dysfunction with inflammatory activity, renal dysfunction, and liver-related mortality in patients with cirrhosis and ascites.

Left ventricular diastolic dysfunction (LVDD) is the predominant cardiac abnormality in cirrhosis. We investigated the association of LVDD with systemic inflammation and its impact on renal function, occurrence of hepatorenal syndrome (HRS) and survival in patients with cirrhosis and ascites. We prospectively enrolled 215 patients with cirrhosis and ascites. We evaluated the diagnosis and grading of LVDD by Doppler echocardiography, inflammatory markers, systemic hemodynamics, vasoactive factors, radioisotope-assessed renal function and blood flow, HRS development and liver-related mortality. LVDD was diagnosed in 142 (66%) patients [grade 2/3: n = 61 (43%)]. Serum lipopolysaccharide-binding protein (LBP), plasma renin activity (PRA) and glomerular filtration rate (GFR) were independently associated with the presence of grade 2/3 LVDD and the severity of diastolic dysfunction. Serum tumor necrosis factor-α, cardiac output and plasma noradrenaline were also independently associated with the presence of grade 2/3 LVDD. The diastolic function marker E/e' was strongly correlated with serum LBP (r = 0.731; P < 0.001), PRA (r = 0.714; P < 0.001) and GFR (r = -0.609; P < 0.001) among patients with LVDD. The 5-year risk of HRS development and death was significantly higher in patients with grade 2/3 LVDD compared to those with grade 1 (35.5 vs. 14.4%; P = 0.01 and 53.3 vs. 28.2%; P = 0.03, respectively). The occurrence and severity of LVDD in patients with cirrhosis and ascites is closely related to inflammatory activity. Advanced LVDD is associated with baseline circulatory and renal dysfunction, favoring HRS development, and increased mortality.

Circadian and Diurnal Regulation of Cerebral Blood Flow.

Circadian and diurnal variation in cerebral blood flow directly contributes to the diurnal variation in the risk of stroke, either through factors that trigger stroke or due to impaired compensatory mechanisms. Cerebral blood flow results from the integration of systemic hemodynamics, including heart rate, cardiac output, and blood pressure, with cerebrovascular regulatory mechanisms, including cerebrovascular reactivity, autoregulation, and neurovascular coupling. We review the evidence for the circadian and diurnal variation in each of these mechanisms and their integration, from the detailed evidence for mechanisms underlying the nocturnal nadir and morning surge in blood pressure to identifying limited available evidence for circadian and diurnal variation in cerebrovascular compensatory mechanisms. We, thus, identify key systemic hemodynamic factors related to the diurnal variation in the risk of stroke but particularly identify the need for further research focused on cerebrovascular regulatory mechanisms.

Analgesic efficacy and safety of regional anesthesia methods in the perioperative period of surgical treatment of unstable spinal fractures: a randomized study

INTRODUCTION: Perioperative anesthesia in spinal surgery is important areas of anesthesiology. Comparison of spine-straightening muscle block (Erector spinae plane block, ESP block) and epidural anesthesia (EA) during spinal surgery may access its effectiveness and safety. OBJECTIVE: To evaluate the efficacy and safety of a single and extended ESP block compared with epidural analgesia in the perioperative period of treatment of unstable vertebral fractures. MATERIALS AND METHODS: A prospective trial involved 110 patients. Three groups of patients were identified: group 1 (n = 35) — with bonuses P block; group 2 (n = 30) — with prolonged ESP block, group 3 (n = 45) — with prolonged epidural analgesia. Systemic hemodynamics, total opioid consumption, pain intensity, complications, the need for additional analgesia were evaluated. RESULTS: There were no differences in hemodynamics and opioid consumption in the intraoperative period. Six hours after surgery the groups with prolonged ESP block (group 2) and prolonged epidural analgesia (group 3) had lower pain indicators on the VAS scale than for group 1. The need for anesthesia (tramadol) for group 1 was significantly higher than for other groups, and amounted to 78 %. The need of opioid was 3 % for group 1, in other groups it was not required. PTR was present in a small percentage in each of the groups, but no statistical differences were found (p = 0.45). In the group with EA, there were 3 cases of urinary retention, 1 case of hip paresthesia. CONCLUSIONS: The use of ESP block allows to achieve effective and safe analgesia during spinal surgery for unstable vertebral fractures. Longer analgesia is provided by prolonged use of the ESP block than by its single use. When compared with prolonged EA, no significant differences were found in the effectiveness of analgesia, the consumption of opioids and the frequency of PTR.

Effect of plasma exchange with albumin replacement on albumin functionality and organ dysfunction in acute-on-chronic liver failure

Effective treatments for acute-on-chronic liver failure (ACLF) are a major unmet need. This proof-of-concept pilot study was aimed at evaluating the effects of plasma exchange (PE) with albumin 5% (PE-A5%) on albumin functional capacity and organ dysfunction in patients with ACLF. Ten adult patients were enrolled in a single-center phase II, prospective, open-label, non-controlled study. Six PE-A5% sessions were performed in 10 days followed by a 1-month follow-up visit. Albumin functional capacity and circulatory function were assessed, as were renal, cerebral, and liver function, and systemic inflammation. The main safety variable was the percentage of PE sessions associated with at least one procedure-related adverse event (AE). Patients with ACLF showed lower albumin binding capacity, lower antioxidant capacity, and lower levels of albumin with preserved structure compared to healthy donors (n= 19). From baseline to day 11, PE-A5% treatment increased albumin levels and improved albumin binding capacity to Sudlow site II (15.3±1.6mg/ml to 18.9±1.7mg/ml; p= 0.003), fatty acid-binding capacity (8.2±1.4μM to 3.1±1.5μM; p= 0.013) and antioxidant capacity (human mercaptalbumin 9.5±1.5mg/ml to 14.6±1.6mg/ml; p= 0.001). Native albumin levels were increased throughout day 1-11PE-A5% sessions (6.5±1.0mg/ml to 10.2±1.4mg/ml; p= 0.035). PE-A5% improved systemic hemodynamics (mean arterial pressure, heart rate, cardiac index), renal function (creatinine level, blood urea nitrogen), cerebral function (hepatic encephalopathy grade), liver parameters (transaminases, bilirubin) and inflammatory parameters (C-reactive protein, leukocyte count). All patients had at least one of the 78 AEs reported, mostly mild (product/procedure-related: 36%). Sixteen serious AEs were reported in eight patients (procedure/product-related: none). PE-A5% was a safe procedure associated with positive effects on albumin functionality, and circulatory, renal, cerebral, and liver function in patients with ACLF. Acute-on-chronic liver failure (ACLF) is a clinical condition characterized by severe systemic inflammation, organ failure, and high mortality. Plasma exchange removes patient's plasma containing pathogenic substances, replacing it with 5% albumin and fresh frozen plasma (PE-A5%). In this study, cirrhotic patients with ACLF were treated with PE-A5%, which was a safe procedure that increased binding and antioxidant capacity of patients' albumin, while improving circulatory, kidney, brain, and liver functions. These beneficial effects could impact survival in ACLF. NCT01201720. 2010-021360-15.

Modern approaches to perioperative management of patients undergoing carotid endarterectomy in acute period of ischemic stroke

This article presents the Moscow Botkin Hospital experience of using combination of general and superficial cervical plexus regional anesthesia during carotid endarterectomy performed in patients in the acute period of atherothrombotic genesis ischemic stroke. The result of reliable antinociceptive protection of the body from the activation of the sympatho-adrenal system against the background of surgical manipulations was the prevention of episodes of critical hypertension and ensuring normalization of systemic hemodynamics. By reducing the need for opioids, patients’ awakening is accelerated, and their time in the operating room is minimized. In addition, the time of necessary observation in the intensive care unit and the need for anesthesia at the immediate postoperative period, is also reduced. The above factors, as well as a multidisciplinary approach to the patient, allowed not only to provide reliable prevention of recurrent vascular incidents in the acute period of ischemic stroke, but also to improve the neurological outcomes.

Systemic Hemodynamics, Cardiac Mechanics, and Signaling Pathways Induced by Extracorporeal Membrane Oxygenation in a Cardiogenic Shock Model.

Peripheral venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used in patients suffering from refractory cardiogenic shock (CS). Although considered life-saving, peripheral VA-ECMO may also be responsible for intracardiac hemodynamic changes, including left ventricular overload and dysfunction. Venoarterial extracorporeal membrane oxygenation may also increase myocardial wall stress and stroke work, possibly affecting the cellular cardioprotective and apoptosis signaling pathways, and thus the infarct size. To test this hypothesis, we investigated the effects of increasing the peripheral VA-ECMO blood flow (25-100% of the baseline cardiac output) on systemic and cardiac hemodynamics in a closed-chest CS model. Upon completion of the experiment, the hearts were removed for assessment of infarct size, histology, apoptosis measurements, and phosphorylation statuses of p38 and protein Kinase B (Akt), and extracellular signal-regulated kinase mitogen-activated protein kinases (ERK-MAPK). Peripheral VA-ECMO restored systemic perfusion but induced a significant and blood flow-dependent increase in left ventricular preload and afterload. Venoarterial extracorporeal membrane oxygenation did not affect infarct size but significantly decreased p38-MAPK phosphorylation and cardiac myocyte apoptosis in the border zone.

Intravenous Ganaxolone: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability in Healthy Adults.

Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20mg) or 5 minutes (10 or 30mg), ganaxolone was detected in plasma with a median Tmax of 5 minutes, whereas a 60-minute infusion (10 or 30mg) or a bolus (6mg over 5minutes) followed by infusion (20mg/h) for 4 hours achieved a median Tmax of approximately 1 and 3 hours, respectively. Cmax was dose and administration-time dependent, ranging from 73.8ng/mL (10mg over 5minutes) to 1240ng/mL (30mg over 5minutes). Bolus doses above 10mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.

Effect of Acute Vasodilator Testing Using Oxygen in Pulmonary Hypertension Due to Left Heart Disease.

Pulmonary vasodilators, including oxygen, have not shown consistent beneficial effects on pulmonary hypertension due to valvular heart disease (PH-VHD). Therefore, the study aimed to assess the effect of 100% fractional inspiration of oxygen (FiO2) on pulmonary and systemic hemodynamics in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) and isolated post-capillary pulmonary hypertension (IpcPH) due to PH-VHD. This prospective study was conducted among patients with PH-VHD undergoing mitral or aortic valve replacement or repair. The study was conducted after induction of anesthesia and pulmonary artery catheterization. Cardiac output was obtained using thermodilution and all direct, and derived hemodynamic variables were obtained at 30% and 100% FiO2. The patients were stratified a priori into responders {(≥10mmHg fall in mean pulmonary artery pressure (MPAP)} and non-responders. Fifty-seven patients completed the acute vasodilator test. The mean age and body mass index of the study population was 41.8 ± 14.1years and 21.4 ± 4.6kg/m2, respectively. There was a significant decrease in MPAP (40.77 ± 12.07mmHg vs 36.74 ± 13.3mmHg; P < .001) and pulmonary vascular resistance (PVR) {(median; Interquartile range (IQR); 388; 371 vs 323; 362dynes sec.cm-5; P < .001) at 100% FiO2. Transpulmonary gradient (TPG) and diastolic pulmonary gradient (DPG) also decreased significantly (P < .001 and P < .001). Cardiac output did not change significantly. The magnitude of decrease in MPAP, PVR, TPG, DPG, and pulmonary artery compliance (PAC) between CpcPH and IpcPH was comparable. Responders did not show a significantly greater fall in MPAP, PVR, TPG, DPG, and PAC after surgery. Hyperoxia may lead to reduction in MPAP and PVR in both hemodynamic phenotypes of PH-VHD. A larger sample size is required to support or refute the findings of this study.

Interaction between Nuclear Receptor and Alpha-Adrenergic Agonist Subtypes in Metabolism and Systemic Hemodynamics of Spontaneously Hypertensive Rats.

Partial and full PPAR-γ agonists have shown promising effects and antihypertensive and antidiabetic agents through increased plasma adiponectin concentration. This study is aimed at examining the role of PPAR-γ, alpha-adrenoceptors, and adiponectin receptors in the modulation of vasopressor responses to angiotensin II (Ang II) and adrenergic agonists, after a subset treatment of partial and full PPAR-γ agonists, each individually, and also when coupled with adiponectin in SHRs. The antioxidant potential and metabolic indices for these animals were also determined. Group I (WKY) and group II (SHR) were designated as normotensive control and hypertensive control, respectively. Groups III (SHR) and IV (SHR) received irbesartan (30 mg/kg) and pioglitazone (10 mg/kg) orally for 28 days, and groups V (SHR), VI (SHR), and VII (SHR) were treated with adiponectin (2.5 μg/kg) intraperitoneally alone, in combination with irbesartan, and in combination with pioglitazone, respectively, from days 21 to 28 only. On day 29, sodium pentobarbitone (60 mg/kg) was used to anesthetize all test animals, and systemic hemodynamic and plasma adiponectin concentrations and in vitro and in vivo antioxidant potential were measured. As compared to the WKY control, the SHR control group's noninvasive blood pressure and basal mean arterial pressure were significantly greater, along with increased arterial stiffness, lower plasma nitric oxide, adiponectin concentration, and antioxidant enzyme levels (all P < 0.05). However, they were gradually normalized by single drug treatments in all groups, and to a greater extent in the SHR + Irb + Adp group (P < 0.05). In the acute study, the dose dependant mean arterial pressure responses to intravenously administered adrenergic agonists and angiotensin-II were significantly larger in SHRs as compared to WKY by 20-25%. Adiponectin alone and in combination significantly blunted vasopressor responses to these alpha-adrenergic agonists in the SHR + Pio + Adp group by 63%, whereas attenuated responses to ANG-II administration to 70% in SHR + Irb + Adp. In conclusion, the combined treatment of adiponectin with PPAR-agonists reduced the systemic vascular responses to adrenergic agonists and improved arterial stiffness. This an evidence of the interaction of adiponectin receptors, PPAR-γ, alpha-adrenoceptors, and ANG-II in the systemic vasculature of SHRs. A significant level of synergism has also been proved among full PPAR-γ agonists and adiponectin receptors.

Lyophilized recombinant human brain natriuretic peptide: A promising therapy in patients with chronic heart failure.

Lyophilized recombinant brain natriuretic peptide (BNP) is an exogenous peptide synthesized by artificial recombination technology, with a similar structure and similar physiological effects with the endogenous natriuretic peptide secreted by the human body. It's main mechanism of action is to increase cyclic guanosine monophosphate by binding with its corresponding receptor in the body, regulating, thus, the imbalance of the vascular system and cardiac hemodynamics, improving the heart's pumping capacity, and inhibiting sympathetic excitability and myocardial remodeling. Moreover, it can promote mitochondrial metabolism and enhance the use of adenosine triphosphate in cardiomyocytes. In the present study, 102 chronic heart failure (HF) patients were randomly assigned to a control and an observation group consisting of 51 patients each. Patients of the control group were treated with standard HF therapy for 3 d including oral metoprolol tartrate tablets, spironolactone, and olmesartanate while patients of the observation group were administered the recombinant human BNP injection for the same time-period, plus the standard HF therapy. The recombinant human BNP group (observation group) demonstrated better physical, emotional, social, and economic scores, as well as cardiac and inflammatory biomarkers such as serum hypersensitive C-reactive protein, N-terminal pro BNP and troponin I levels, compared to the control group. Moreover, cardiac function was also improved, as left ventricular ejection fraction and stroke volume were significantly higher in the observation group than in the control group. Interestingly, adverse reactions were not different between the 2 groups. However, these results are not generalizable and the need of large multicenter randomized controlled trials examining the safety and efficacy of recombinant human BNP in HF patients is of major importance.

Impact of blood pressure targets on central hemodynamics during intensive care after out-of-hospital cardiac arrest

ObjectivesThe aim was to investigate the advanced hemodynamic effects of the two MAP-targets during intensive care on systemic hemodynamics in comatose patients after cardiac arrest. DesignSecondary analysis of a randomized controlled trial. SettingPrimary vasopressor used was per protocol norepinephrine. Hemodynamic monitoring was done with pulmonary artery catheters (PAC) and measurements were made on predefined time points. The primary endpoint of this substudy was the difference in cardiac index within 48 h from a repeated measurements-mixed model. Secondary endpoints included systemic vascular resistance index (SVRI), heart rate, and stroke volume index. PatientsComatose survivors after out-of-hospital cardiac arrest. InterventionsThe “Blood pressure and oxygenations targets after out-of-hospital cardiac arrest (BOX)”-trial was a randomized, controlled, double-blinded, multicenter-study comparing targeted mean arterial pressure (MAP) of 63 mmHg (MAP63) vs 77 mmHg (MAP77). Measurements and main resultsAmong 789 randomized patients, 730 (93%) patients were included in the hemodynamic substudy. From PAC-insertion (median 1 hours after ICU-admission) and the next 48 hours, the MAP77-group received significantly higher doses of norepinephrine (mean difference 0.09 µg/kg/min, 95% confidence interval (CI) 0.07–0.11, pgroup < 0.0001). Cardiac index was significantly increased (0.20 L/min/m2 (CI 0.12–0.28), pgroup < 0.0001) as was SVRI with an overall difference of (43 dynes m2/s/cm5 (CI 7–79); pgroup = 0.02). Heart rate was increased in the MAP77-group (4 beats/minute; CI 2–6, pgroup < 0.003), but stroke volume index was not (pgroup = 0.10). ConclusionsTargeted MAP at 77 mmHg compared to 63 mmHg resulted in a higher dose of norepinephrine, increased cardiac index and SVRI. Heart rate was also increased, but stroke volume index was not affected by a higher blood pressure target.