Invasive and non-invasive assessment of macro- and micro-circulatory effects of vasopressors during sevoflurane anesthesia in a pediatric experimental model: A randomized trial.

BACKGROUND: While non-invasive assessment of macro- and micro-circulation has the promise to optimize anesthesia management, evidence is lacking for the relationship between invasive and non-invasive measurements of cardiac output and microcirculatory indices. AIMS: We aimed to compare the abilities of non-invasive techniques to detect changes in macro- and micro-circulation following deep anesthesia and subsequent restoration of the compromised hemodynamic by routinely used vasopressors in a randomized experimental study. METHODS: A 20%-25% drop in mean arterial pressure was induced by sevoflurane in anesthetized mechanically ventilated just-weaned piglets (n = 12) prior to the administration of vasopressors in random order (dopamine, ephedrine, noradrenaline, and phenylephrine). Simultaneous transpulmonary thermodilution cardiac output assessment with the invasive pulse index continuous contour (PiCCO) method was compared with non-invasive estimates obtained with electrical conductivity (ICON) and echo Doppler (Cardio Q). Changes in microcirculation were characterized by sublingual red blood cell velocity, jugular cerebral venous oxygen saturation, and arterial lactate. MAIN OUTCOME MEASURES: Cardiac output indices obtained by invasive and non-invasive methods. RESULTS: Changes in cardiac output measured invasively and non-invasively correlated significantly after sevoflurane (r = .78, p = .003 and r = .76, p = .006 between PiCCO and ICON or Cardio Q, respectively). Following the administration of vasopressors, invasive and non-invasive cardiac output assessments were unrelated with significant correlations observed only between PiCCO and ICON after dopamine and ephedrine. Sevoflurane-induced hypotension decreased jugular cerebral venous oxygen saturation significantly and was recovered by all vasopressors. Sevoflurane and vasopressors had no effect on red blood cell velocity, which increased only after dopamine. No consistent changes in lactate were observed during the study period. CONCLUSIONS: The results of this study suggest that non-invasive cardiac output measurements may not accurately reflect changes in macrocirculation after hemodynamic optimization by vasopressors. Due to the incoherence between macro- and micro-circulation, monitoring microcirculation is essential to guide patient management.

Perfusion Computer Tomography Assessment of the Effect of Angiotensin II On Blood Flow Distribution in Rabbits with Intrarenal VX2 Tumors.

BACKGROUND/AIMS: Unlike other organs, which only have one set of capillary network, the renal microvasculature consists of two sets of capillary network series connected by efferent arterioles. Angiotensin II constricts the efferent glomerular artery. Hence, renal tumor blood flow (BF) distribution may be different from tumors in other organs. This study aims to investigate the effects of angiotensin II on the hemodynamics of intrarenal VX2 tumors using perfusion computed tomography(CT). METHODS: Twenty-four male New Zealand white rabbits were randomly divided into three groups: groups A (blank controls), group B (negative controls), and group C (angiotensin II-treated animals). Group B and C were established to the model of intrarenal VX2 tumors. Furthermore, perfusion CT of the kidney was performed in each group. Prior to perfusion CT scan in group C, the mean arterial blood was elevated to 150-160 mmHg by angiotensin II. The BF, blood volume (BV), mean transit time (MTT), capillary permeability-surface area product (PS), and relative permeability-surface area product (RPS) of tumors and renal tissues were calculated. RESULTS: Compared with normal renal cortex tissues in group A, the BF, BV and PS values of tumors in group B were significantly lower, MTT was prolonged and RPS increased. Compared with group B, only the RPS of these tumors increased from 83.23 ± 29.17% to 120.94 ± 31.84% by angiotensin II infusion. Angiotensin II significantly increased the RPS value of the renal cortex distant from the tumor (CDT) and the right renal cortex (RRC). CONCLUSIONS: Perfusion CT can accurately observe the influence of angiotensin II on normal and tumor BF in kidneys. This clarifies the effect of angiotensin II on intrarenal tumor hemodynamics.

Pharmacological assessment of the contribution of the arterial baroreflex to sympathetic discharge patterns in healthy humans.

To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside (NTP) and phenylephrine (PE) and measured action potential (AP) patterns with wavelet-based methodology. We hypothesized that 1) baroreflex unloading (NTP) would increase firing of low-threshold axons and recruitment of latent axons and 2) baroreflex loading (PE) would decrease firing of low-threshold axons. Heart rate (HR, ECG), arterial blood pressure (BP, brachial catheter), and muscle sympathetic nerve activity (MSNA, microneurography of peroneal nerve) were measured at baseline and during steady-state systemic, intravenous NTP (0.5-1.2 µg·kg-1·min-1, n = 13) or PE (0.2-1.0 µg·kg-1·min-1, n = 9) infusion. BP decreased and HR and integrated MSNA increased with NTP ( P < 0.01). AP incidence (326 ± 66 to 579 ± 129 APs/100 heartbeats) and AP content per integrated burst (8 ± 1 to 11 ± 2 APs/burst) increased with NTP ( P < 0.05). The firing probability of low-threshold axons increased with NTP, and recruitment of high-threshold axons was observed (22 ± 3 to 24 ± 3 max cluster number, 9 ± 1 to 11 ± 1 clusters/burst; P < 0.05). BP increased and HR and integrated MSNA decreased with PE ( P < 0.05). PE decreased AP incidence (406 ± 128 to 166 ± 42 APs/100 heartbeats) and resulted in fewer unique clusters (15 ± 2 to 9 ± 1 max cluster number, P < 0.05); components of an integrated burst (APs or clusters per burst) were not altered ( P > 0.05). These data support a hierarchical pattern of sympathetic neural activation during manipulation of baroreceptor afferent activity, with rate coding of active neurons playing the predominant role and recruitment/derecruitment of higher-threshold units occurring with steady-state hypotensive stress. NEW & NOTEWORTHY To study how changes in baroreceptor afferent activity affect patterns of sympathetic neural activation, we manipulated arterial blood pressure with intravenous nitroprusside and phenylephrine and measured sympathetic outflow with wavelet-based methodology. Baroreflex unloading increased sympathetic activity by increasing firing probability of low-threshold axons (rate coding) and recruiting new populations of high-threshold axons. Baroreflex loading decreased sympathetic activity by decreasing the firing probability of larger axons (derecruitment); however, the components of an integrated burst were unaffected.

Defining uremic arterial functional abnormalities in patients recently started on haemodialysis: combined in vivo and ex vivo assessment.

Endothelial dysfunction is a key initiating event in vascular disease in chronic kidney disease (CKD) patients and haemodialysis (HD) patients exhibit significant vascular abnormalities. To understand this further, we examined how ex vivo intrinsic function in isolated arteries correlates with in vivo assessments of cardiovascular status in HD patients. Abdominal fat biopsies were obtained from 11 HD patients and 26 non-uremic controls. Subcutaneous arteries were dissected and mounted on a wire myograph, and cumulative concentration-response curves to noradrenalin, endothelin-1, a thromboxane A2 agonist (U46619), angiotensin II, vasopressin, bradykinin (BK), acetylcholine (ACh) and sodium nitroprusside (SNP) were constructed. Pulse wave velocity and blood pressure were measured in HD patients. Enhanced (P<0.05-0.0001) maximal contractile responses (Rmax) to all spasmogens (particularly vasopressin) were observed in arteries from HD patients compared to controls, and this effect was more pronounced in arteries with an internal diameter>600 µm. The potency (pEC50) of U46619 (P<0.01) and vasopressin (P<0.001) was also increased in arteries>600 µm of HD patients. The maximal relaxant response to the endothelium-dependent dilators ACh and BK were lower in HD patients (P<0.01-P<0.0001) (worse for ACh than BK); however the endothelium-independent dilator SNP was similar in both groups. PWV was significantly correlated with the vasoconstrictor response to vasopressin (P = 0.042) in HD patients. HD patients are primed for hypertension and end organ demand ischaemia by a highly sensitised pressor response. The failure of arterial relaxation is mediated by endothelial dysfunction. Intrinsic vascular abnormalities may be important in sensitising HD patients to recurrent cumulative ischaemic end organ injury.

Chikungunya: un reto para los servicios de salud de la República Dominicana / Chikungunya: a challenge for the Dominican Republic's health services

Desde diciembre de 2013, la Región de las Américas se enfrenta por primera vez a una epidemia de chikungunya. Los casos iniciales se registraron en el Caribe francés y, debido al comercio y la movilización de personas, esta epidemia no tardó en llegar a la República Dominicana, cuya población es de 10 millones de habitantes y comparte con Haití la isla La Española. En este artículo se difunde información extraída de diversos artículos y documentos oficiales sobre el virus, la infección y la epidemia de chikungunya, que han sido de gran ayuda para orientar la respuesta en la República Dominicana y pueden ser útiles para mejorar tanto el conocimiento como las actuaciones frente a la epidemia de los trabajadores del sector salud de la Región. Se destaca la importancia que revisten las investigaciones realizadas en países y territorios afectados del océano Índico, como la isla de Reunión, durante la epidemia declarada entre 2005 y 2007, cuando se registró una tasa de ataque mayor de 30%, se identificaron los grupos de riesgo, las formas graves y atípicas de la infección, la transmisión vertical del virus, las formas crónicas, que pueden provocar dolores recurrentes durante tres años, y las defunciones directa o indirectamente relacionadas con el virus chikungunya. Por su alta tasa de ataque, el virus chikungunya se convierte en un reto sin precedentes para los ministerios de salud, que exige una adecuada organización de los servicios de salud, la priorización de la atención a los grupos de riesgo y a los pacientes con formas graves de la enfermedad, así como una adecuada comunicación social y respuesta intersectorial.

The Region of the Americas has been affected since December 2013 by a chikungunya epidemic for the first time. Although the first cases were recorded in the French Caribbean, the epidemic quickly spread to the Dominican Republic due to trade and people movements. The Dominican Republic, which shares the island of Hispaniola with Haiti, has a population of 10 million. This article contains information from a range of different publications and official documents about the chikungunya virus infection and epidemic. These papers were extremely helpful for guiding the response to the epidemic in the Dominican Republic and may also be useful for enhancing knowledge of the virus and responses among health workers elsewhere in the region. Particular attention is drawn to the important research undertaken in countries and territories affected by the epidemic in the Indian Ocean area. This is the case, for example, of the island of La Réunion, where the epidemic had an attack rate of more than 30% between 2005 and 2007. Researchers were able to identify risk groups, severe and atypical forms of the infection, cases of vertical transmission, chronic disease causing recurrent pain over three years, and directly- or indirectly-related deaths from the virus. Given its high attack rate, the chikungunya virus has emerged as an exceptional challenge for health ministries and calls for appropriate organized responses from the health services, prioritization of care for risk groups and patients exhibiting severe forms of the disease, and effective social communication and intersectoral actions.

In vitro assessment of mouse fetal abdominal aortic vascular function.

Fetal growth restriction (FGR) affects 3-8% of human pregnancies. Mouse models have provided important etiological data on FGR; they permit the assessment of treatment strategies on the physiological function of both mother and her developing offspring. Our study aimed to 1) develop a method to assess vascular function in fetal mice and 2) as a proof of principle ascertain whether a high dose of sildenafil citrate (SC; Viagra) administered to the pregnant dam affected fetal vascular reactivity. We developed a wire myography methodology for evaluation of fetal vascular function in vitro using the placenta-specific insulin-like growth factor II (Igf2) knockout mouse (P0; a model of FGR). Vascular function was determined in abdominal aortas isolated from P0 and wild-type (WT) fetuses at embryonic day (E) 18.5 of gestation. A subset of dams received SC 0.8 mg/ml via drinking water from E12.5; data were compared with water-only controls. Using wire myography, we found that fetal aortic rings exhibited significant agonist-induced contraction, and endothelium-dependent and endothelium-independent relaxation. Sex-specific alterations in reactivity were noted in both strains. Maternal treatment with SC significantly attenuated endothelium-dependent and endothelium-independent relaxation of fetal aortic rings. Mouse fetal abdominal aortas reproducibly respond to vasoactive agents. Study of these vessels in mouse genetic models of pregnancy complications may 1) help to delineate early signs of abnormal vascular reactivity and 2) inform whether treatments given to the mother during pregnancy may impact upon fetal vascular function.

Quantitative assessment of brain microvascular and tissue oxygenation during cardiac arrest and resuscitation in pigs.

Cardiac arrest is associated with a very high rate of mortality, in part due to inadequate tissue perfusion during attempts at resuscitation. Parameters such as mean arterial pressure and end-tidal carbon dioxide may not accurately reflect adequacy of tissue perfusion during cardiac resuscitation. We hypothesised that quantitative measurements of tissue oxygen tension would more accurately reflect adequacy of tissue perfusion during experimental cardiac arrest. Using oxygen-dependent quenching of phosphorescence, we made measurements of oxygen in the microcirculation and in the interstitial space of the brain and muscle in a porcine model of ventricular fibrillation and cardiopulmonary resuscitation. Measurements were performed at baseline, during untreated ventricular fibrillation, during resuscitation and after return of spontaneous circulation. After achieving stable baseline brain tissue oxygen tension, as measured using an Oxyphor G4-based phosphorescent microsensor, ventricular fibrillation resulted in an immediate reduction in all measured parameters. During cardiopulmonary resuscitation, brain oxygen tension remained unchanged. After the return of spontaneous circulation, all measured parameters including brain oxygen tension recovered to baseline levels. Muscle tissue oxygen tension followed a similar trend as the brain, but with slower response times. We conclude that measurements of brain tissue oxygen tension, which more accurately reflect adequacy of tissue perfusion during cardiac arrest and resuscitation, may contribute to the development of new strategies to optimise perfusion during cardiac resuscitation and improve patient outcomes after cardiac arrest.

Microcirculatory alterations in patients with severe sepsis: impact of time of assessment and relationship with outcome.

OBJECTIVES: Sepsis induces microvascular alterations that may play an important role in the development of organ dysfunction. However, the relationship of these alterations to systemic variables and outcome is still not well defined. We investigated which factors may influence microcirculatory alterations in patients with severe sepsis and whether these are independently associated with mortality. DESIGN: Analysis of prospectively collected data from previously published studies by our group. SETTING: A 36-bed, medicosurgical university hospital Department of Intensive Care. PATIENTS: A total of 252 patients with severe sepsis in whom the sublingual microcirculation was visualized using orthogonal polarization spectral or sidestream darkfield imaging techniques. MEASUREMENTS AND MAIN RESULTS: Microcirculatory measurements were obtained either early, within 24h of the onset of severe sepsis (n = 204), or later, after 48h (n = 48). When multiple measurements were obtained, only the first was considered. Although global hemodynamic variables were relatively preserved (mean arterial pressure 70 [65-77] mm Hg, cardiac index 3.3 [2.7-4.0] L/min.m, and SvO2 68.3 [62.8-74.7]%), microvascular variables were markedly altered (proportion of perfused small vessels 65 [50-74]%, microvascular flow index 2.15 [1.80-2.60], and heterogeneity of proportion of perfused small vessels 35 [20-50]%). Among microcirculatory variables, proportion of perfused small vessels was the strongest predictor of outcome (receiver operating characteristic curve area 0.818 [0.766-0.871], p < 0.001). Survival rates decreased markedly with severity of alterations in the proportion of perfused small vessels (70% and 75% in the two upper proportion of perfused small vessel quartiles compared with 3% and 44% in the two lower quartiles, p < 0.0001). Multivariable analysis identified proportion of perfused small vessels and sequential organ failure assessment score as independent predictors of outcome. Microcirculatory alterations were less severe in the later than in the earlier (proportion of perfused small vessels, 74 [57-82]% vs. 63 [48-71]%, p = 0.004) phase of sepsis. In multivariable analysis focused on the early period of sepsis, proportion of perfused small vessels and lactate were independent predictors of outcome. CONCLUSIONS: Microcirculatory alterations are stronger predictors of outcome than global hemodynamic variables.

Assessment of an uncalibrated pressure waveform device's ability to track cardiac output changes due to norepinephrine dose adjustments in patients with septic shock: a comparison with Doppler echocardiography.

OBJECTIVES: The FloTrac Vigileo (FTV) estimates cardiac output (CO) on the basis of an uncalibrated arterial pressure waveform. To assess the ability of the third-generation of FTV (v.3.02) to track changes in CO following norepinephrine dose adjustment in patients with septic shock, we performed a comparative study using Doppler echocardiography (DE). STUDY DESIGN: Prospective observational study. PATIENTS: We prospectively included 20 mechanically ventilated patients receiving norepinephrine and monitored with the FTV. Five minutes after each change in norepinephrine dose (decided by the attending physician), CO was measured simultaneously with the FTV (CO(FTV)) and DE (CO(DE)). The changes in CO were compared. ROC curves were built to assess the ability of FTV to detect significant changes in CO(DE) of at least 15%. RESULTS: Ninety pairs of CO variations measurements were made. The intertechnique correlation coefficient for changes in CO of at least 15% was r=0.59; P=0.0009. The AUC of a ROC curve built to test the FTV's ability to detect a CO(DE) increase of 15% or more was 0.783 (±0.083) (P=0.005). A CO(FTV) threshold value of 15% had a sensitivity of 54% (25-81) and a specificity of 87% (77-94). For a CO(DE) decrease of 15% or more, the ROC curve had an AUC of 0.616 (±0.075) (P=0.12) and a CO(FTV) threshold value of 13% yielded a sensitivity of 53% (27-79) and a specificity of 72% (60-82). CONCLUSIONS: The FTV was unable to accurately track changes in CO following norepinephrine dose adjustments in critically ill patients with septic shock.

The CAM-LDPI method: a novel platform for the assessment of drug absorption.

OBJECTIVES: This study aimed to explore the use of the chicken chorioallantoic membrane (CAM) with laser doppler perfusion imaging (LDPI) as a platform to assess absorption of vasoactive drugs. METHODS: The optimal age of the CAM to be employed in the test and the indicator of vasoactivity were first established. Test substances that included common solvents and vasoactive drugs were tested on the CAM surface to determine their irritancy and blood perfusion effects. KEY FINDINGS: Insignificant changes in blood perfusion were observed with deionized water, 0.9% w/v soldium chloride and 5% w/v glucose monohydrate, as well as theophylline and glucagon. Complex changes in blood perfusion were detected with ethanol, N-methyl-2-pyrrolidone, glycerin and propranolol. Both caffeine and glyceryl trinitrate resulted in a drop in blood perfusion. CONCLUSIONS: It was concluded that the LDPI offers a rapid and non-invasive method to measure blood perfusion in the CAM. The latter provides a potentially useful platform in formulation studies to evaluate the effects of additives on drug absorption using caffeine or glyceryl trinitrate as model drugs.

Perioperative assessment of terlipressin infusion during living donor liver transplantation.

OBJECTIVE: To investigate the safety and efficacy of infusion of terlipressin during living donor liver transplantation (LDLT). METHODS: Patients undergoing LDLT with low systemic vascular resistance index (SVRI) and pulmonary vascular resistance index (PVRI) (n=41) were randomly allocated into control (n=20) and terlipressin groups (n=21). Terlipressin was infused at 1.0-4.0 µg/kg per h in the terlipressin group during surgery. Controls received generally accepted inotropic and vasopressor agents. RESULTS: Terlipressin infusion induced significantly higher SVRI and PVRI at 60 min after drug infusion, produced significantly greater hourly urine output during the anhepatic phase, and was related to significantly shorter stays in the postoperative intensive care unit (ICU) compared with control treatment (mean±SD ICU stay 5.7±1.5 versus 6.9±1.5 days, respectively). Patients given a terlipressin infusion>2.0 µg/kg per h during the preanhepatic phase had a median ICU stay of <6 days (sensitivity 90.0%; specificity 89.0%). CONCLUSIONS: Terlipressin infusion improved low SVRI and PVRI during LDLT and may have contributed to better renal function and shorter ICU stays.

[Efficacy, safety and cost of sedation with sevoflurane in intensive care unit]. / Efficacité, tolérance et coût d'une sédation par sévoflurane en réanimation.

OBJECTIVES: To study efficacy, systemic and cerebral haemodynamic, and cost of sedation with sevoflurane after midazolam failure. STUDY DESIGN: Prospective observational study in a mixed intensive care unit. PATIENTS AND METHODS: Mechanically ventiled patients in whom deep sedation failed (Ramsay score<5 despite midazolam 10mg/h and fentanyl 400µg/h) were enrolled. Sedation with sevoflurane and fentanyl (200µg/h) was performed during 48 hours. Sevoflurane was administered with a dedicated filter (AnaConDa™) and sevoflurane infusion rate was adjusted in order to achieve a Ramsay score ≥5. Ramsay score, mean arterial blood pressure, norepinephrine dose/24h, intracranial pressure and cerebral perfusion pressure in patients with brain injury were measured. Directs costs for sedation were calculated. An analysis of variance for repeated measures compared values between D0 (intravenous sedation), D1 and D2 (inhaled sedation). RESULTS: Twenty-five patients (age=51 [38-63], SAPS II=43 [33-49]) were enrolled. Ramsay score was 4 [4,5] at D0 and 6 [6] at D1 and D2 (P<0.05 vs D0). Mean arterial pressure was significantly lower at D1 (80 [73-86] mmHg) as compared to D0 (84 [77-92] mmHg) and D2 (84 [78-91] mmHg) (P<0,05). Norepinephrine consumption was lower at D2 as compared to D1 (P<0,05). Intracranial pressure was lower at D1 (9 [5-13] mmHg) and D2 (11 [7-15] mmHg) as compared to D0 (12 [7-17] mmHg) (P<0.05). PPC was stable at D1 and increased at D2. Directs costs were significantly increased with sevoflurane. CONCLUSION: Sevoflurane is an effective and safe alternative to midazolam in ICU patients associated with a moderate increase in costs.

Assessment of endothelial function of large, medium, and small vessels: a unified myograph.

Endothelial dysfunction precedes the development of morphological atherosclerotic changes and can also contribute to lesion development in cardiovascular diseases. Currently, there is a lack of a single method to determine endothelial function of the entire range of vessel dimensions from aorta to arterioles. Here we assessed endothelial function of a large range of size arteries using a unified isovolumic myograph method. The method maintains a constant volume of fluid in the lumen of the vessel during contraction and relaxation, which are characterized by an increase and a decrease of pressure, respectively. Segments of six aortas, six common femoral arteries, and six mesenteric arteries from rats; six carotid arteries from mice; and six coronary and carotid arteries from pigs were used. The endothelium-dependent dose-response vasorelaxation was determined with endothelium-dependent vasodilators while arterial preconstriction was induced with vasoconstrictors at a submaximal dose. The circumferential midtension during vascular reactivity varied from 43.1 ± 7.9 to 2.59 ± 0.46 mN/mm (from large to small arteries), whereas the circumferential midstress showed a much smaller variation from 217 ± 23.5 to 123 ± 15.3 kPa (in the same range of vessels). We also found that overinflation and axial overelongation compromised endothelium-dependent vasorelaxation to underscore the significance of vessel preload. In conclusion, an isovolumic myograph was used to unify arterial vasoreactivity from large to small arteries and shows the uniformity of wall stress and %tension throughout the range of vessel sizes.

Tissue viability imaging for assessment of pharmacologically induced vasodilation and vasoconstriction in human skin.

Tissue viability imaging (TIVI) is a novel polarization spectroscopy method for assessing dermal vascular viability. The purpose of the present study was to compare TIVI with laser Doppler flowmetry (LDF) for assessment of pharmacologically induced vasodilation and vasoconstriction in human skin. Eight individual skin sites on the backs of seven healthy volunteers were randomized to receive an intradermal injection of prostaglandin E2 (PGE2, 10(-6) to 10(-9)M), norepinephrine (NE, 10(-5) to 10(-7)M), or vehicle. Vascular responses were measured by TIVI and LDF at the injection sites at 1-min intervals starting 2min before and ending 15min after the skin challenge. TIVI and LDF demonstrated significant dose-dependent and time-related vasodilator responses to PGE2 and vasoconstrictor responses to NE, respectively (p<0.001). The time course and dose-response functions for LDF and TIVI showed notable differences. Dose-response data showed a significant reduction in TIVI signal with NE 10-7M (10(-6) NE with LDF) whereas PGE2 10(-6)M was required to elicit a significant increase in TIVI signal (10(-8)M PGE2 with LDF). TIVI demonstrated relative vascular response changes of 0.79 to 1.63 of baseline values at 15min with NE 10(-5)M or PGE2 10(-6)M compared to values of 0.59 to 8.38 with LDF. There was a modest though significant correlation between relative changes in vascular responses measured by the two methods (p<0.0001, r(2)=0.521). A Bland-Altman difference plot demonstrated significant underestimation of relative increase versus baseline measured by TIVI (r(2)=0.99, p<0.0001). We conclude that TIVI polarization spectroscopy is a sensitive method for measurement of NE-induced vascular responses but that it is less sensitive than LDF for measurement of the PGE2-induced reactions.

Ethnic differences in resistance artery contractility of normotensive pregnant women.

Black women are at a greater risk to develop hypertension during pregnancy, with a 4.5 times higher rate of fatal preeclampsia than white women. Therefore, it is important to identify factors that may affect this risk. Our group previously proposed that high activity of the central regulatory enzyme of energy metabolism, creatine kinase (CK), may increase ATP-buffering capacity and lead to enhanced vascular contractility and reduced nitric oxide bioavailability. Therefore, we assessed microvascular contractility characteristics in isolated resistance arteries from self-defined black and white normotensive pregnant women using a Mulvany-Halpern myograph. Additionally, morphology was assessed with electron microscopy. Resistance-sized arteries obtained from omentum donated during cesarean sections (11 black women and 20 white women, mean age: 34 yr) studied in series showed similar morphology but significantly greater maximum contractions to norepinephrine (10(-5) M) in blacks [14.0 mN (1.8 SE)] compared with whites [8.9 mN (1.4 SE), P = 0.02]. Furthermore, we found greater residual contractility after the specific CK inhibitor dinitrofluorobenzene (10(-6) M) in black women [55% (6 SE)] compared with white women [28% (4 SE), P = 0.001] and attenuated vasodilation after bradykinin (10(-7) M) in black women [103% (6 SE)] compared with white women [84% (5 SE), P = 0.023], whereas responses to sodium nitroprusside (10(-4) M) and amlodipine (10(-6) M) were similar. We conclude that compared with white women, normotensive pregnant black women display greater resistance artery contractility and evidence of higher vascular CK activity with attenuated nitric oxide synthesis. These findings in normotensives may imply that the black population is at risk for a further incline in pregnancy-related hypertensive disorders.

Economic evaluation of four angiotensin II receptor blockers in the treatment of hypertension.

OBJECTIVE: To evaluate the cost effectiveness of achieving JNC 7 blood pressure goals with angiotensin II receptor blockers (ARBs). RESEARCH DESIGN AND METHODS: Cost effectiveness of olmesartan, losartan, valsartan, and irbesartan was compared with real world patient chart and claims data from a large US health plan. Patients 18 and older with >or=2 claims for an ARB between May 1, 2002 and December 31, 2005 were identified from the claims database. Patients with a diagnosis of hypertension in the 6-month baseline period before the first (index) ARB claim and ARB-free during baseline were included. Medical charts were randomly sampled from the cohort of identified patients; effectiveness data were obtained from charts and linked to healthcare claims and costs. These data were used to populate the decision analytic model. MAIN OUTCOME MEASURES: All-cause and hypertension-attributable costs to achieve JNC 7 goals were measured. Comparisons were made within low and high-dose strata and pooled across ARB doses. RESULTS: 121 472 patients were identified, and charts were randomly abstracted for 1600. Of these, 1293 patients were hypertensive at index. Baseline patient characteristics for the chart group were modestly different from the larger cohort. More patients treated with olmesartan (77.8%) than with losartan (66.5%), valasartan (68.8%), or irbesartan (68.8%) achieved JNC 7 BP goals. In pooled-dose comparisons, cost per patient reaching BP goal was $8964 (all-cause) and $2704 (hypertension-attributable) for olmesartan; compared with $10 848 and $3291 for losartan; $10 557 and $3577 for valsartan; and $13395 and $4325 for irbesartan, respectively. The trend was similar for the dose stratification analysis, except in the comparison between high-dose losartan and olmesartan, where losartan had a lower cost-effectiveness ratio. CONCLUSION: Overall olmesartan was the most effective and cost-saving treatment option compared to losartan, valsartan, and irbesartan for the achievement of JNC 7 BP goals in this managed-care population.

Validation of spontaneous assessment of baroreceptor reflex sensitivity and its relation to heart rate variability in the ovine fetus pre- and near-term.

Assessment of baroreceptor reflex sensitivity (BRS) in the ovine fetus provides insight into autonomic cardiovascular regulation. Currently, assessment of BRS relies on vasoactive drugs, but this approach is limited by feasibility issues and by the nonphysiologic nature of the stimulus. Thus we aimed to validate the method of spontaneous BRS assessment against the reference method of using vasoactive drugs in preterm (0.76 gestation, n = 16) and near-term (0.86 gestation, n = 16) chronically instrumented ovine fetuses. The BRS measures derived from the spontaneous and reference methods correlated at both gestational ages (R = 0.67 +/- 0.03). The sequence method of spontaneous BRS measures also correlated both to the root mean square of standard deviations (RMSSD), which is a measure of fetal heart rate variability reflecting vagal modulation (R = 0.69 +/- 0.03), and to fetal body weight (R = 0.65 +/- 0.03), which is a surrogate for growth trajectory of each fetus. The methodology presented may aid in developing new models to study BRS and cardiovascular control in ovine fetus in the last trimester of pregnancy.

In vitro assessment of mouse uterine and fetoplacental vascular function.

Adequate blood flow provision through alterations in maternal vascular function is essential during pregnancy for optimal fetal development. Abnormal uterine vasculature adaptation, resulting in aberrant blood flow to the placenta, has been implicated as a possible cause of fetal growth restriction (FGR). Our study aimed to develop strategies to evaluate murine vascular function in pregnancy using wire myography. Main uterine artery loop and branch vessels isolated from near-term pregnant mice showed significant contraction to phenylephrine (PE). Endothelial-dependent relaxation was noted with acetylcholine (ACH). U46619 elicited significant contraction of umbilical arteries and veins, but relaxation was only demonstrable with the nitric oxide (NO) donor sodium nitroprusside (SNP). In conclusion, our data suggest that murine uteroplacental and fetoplacental arteries show distinct responses to vasoactive agents. Furthermore, this study indicates that wire myography represents a robust technique for the assessment of murine uteroplacental and fetoplacental vascular function, which will aid evaluation of mouse genetic models of FGR.

Intrarenal resistance index for the assessment of early renal function impairment in patients with liver cirrhosis.

BACKGROUND: Renovascular vasoconstriction in patients with hepatorenal syndrome can be quantified by the renal arterial resistance index (RI). We investigated the value of RI measurement in detection of renal function impairment in patients with different stages of chronic liver disease. METHODS: Subjects were divided into 4 groups containing 21 patients with liver cirrhosis and ascites, 25 patients with liver cirrhosis without ascites, 35 patients with fatty liver disease and 78 control subjects. All patients underwent abdominal ultrasound examination with renal RI measurement and correlation with laboratory results for renal function. RESULTS: RI was significantly higher in ascitic patients compared to non-ascitic patients (0.74 vs. 0.67, p<0.01) and in non-ascitic patients with liver cirrhosis than in control subjects (0.67 vs. 0.62, p<0.01). 48% (19/40) of patients with liver cirrhosis and normal serum creatinine concentration showed elevated RI levels. There were no significant differences in RI levels between patients with fatty liver disease and controls (0.63 vs. 0.62). CONCLUSIONS: Intrarenal RI measurement is a predictor of renal vasoconstriction and serves to detect early renal function impairment in cirrhotic patients. The diagnosis of elevated RI may be taken into account in the clinical management of these patients.