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Improved non-invasive magnetic resonance (MR) characterisation of in vivo models of focal ischaemic insults such as transient ischaemic attack (TIA) and perinatal arterial ischaemic stroke (AIS) may assist diagnosis, outcome prediction and treatment design. The classic middle cerebral artery occlusion (MCAO) model of ischaemic stroke is well documented in MR studies but generates extensive and complex lesions involving an acute inflammatory response and de-occlusion that immediately restores circulation. By contrast, intrastriatal microinjection of the potent vasoconstrictor, endothelin-1 (ET-1), induces a focal, reversible and low-flow ischaemia in the absence of a typical inflammatory response, which gradually restores blood flow over several hours and may be more relevant to TIA and AIS pathology. This study presents the first comprehensive longitudinal MR characterisation of the real-time anatomical [T1-weighted (T1-w)/T2-weighted (T2-w)], pathophysiological [apparent diffusion coefficient (ADC), cerebral blood volume, gadolinium contrast imaging of blood-brain barrier (BBB) integrity] and metabolic [phosphorus magnetic resonance spectroscopy (31P MRS)] evolution of a purely ischaemic ET-1-induced lesion within the juvenile and adult rat brain. ET-1-induced cytotoxic oedema was visualised on T2-w magnetic resonance imaging (MRI), inconsistent with the conventional notion that it cannot be detected using anatomical MRI. There was no immunohistochemical evidence of an acute inflammatory response or loss of BBB integrity, thus excluding a vasogenic oedema contribution to the pathology. Maximal T2-w intensity correlated with the lowest ADC value in both age groups, re-emphasising the purely ischaemic nature of the lesion and the absence of vasogenic oedema. Furthermore, extensive acute T1-w hypointensity was observed in the presence of cytotoxic oedema-induced T2-w changes, whereas other authors have shown that increased T1 values following MCAO reflect vasogenic oedema. Intriguingly, the lesion border exhibited hyperintensity on T2-w and ADC MRI at later time points, and the former may be a consequence of phagocytosis-induced fatty droplet deposition by macrophages detected immunohistochemically. In spite of a chronically reduced ADC, typically associated with ischaemia-induced energy failure, a 31P MRS-detectable reduction in the phosphocreatine (PCr) to gamma adenosine triphosphate (γATP) ratio was not observed at any time point in either age group, suggesting dissociation of tissue water diffusion and metabolic changes within the ET-1-induced lesion.

Introduction: The turnover of Ringer´s solutions is greatly dependent on the physiological situation, such as the presence of dehydration or anaesthesia. The present study evaluates whether the kinetics is affected by previous infusion of colloid fluid., Methods: Ten male volunteers with a mean age of 22 years underwent three infusion experiments, on separate days and in random order. The experiments included 10 mL/kg of 6% hydroxyethyl starch 130/0.4 (Voluven™), 20 mL/kg of Ringer's acetate, and a combination of both, where Ringer´s was administered 75 minutes after the starch infusion ended. The kinetics of the volume expansion was analysed by non-linear least- squares regression, based on urinary excretion and serial measurement of blood haemoglobin concentration for up to 420 minutes., Results: The mean volume of distribution of the starch was 3.12 L which agreed well with the plasma volume (3.14 L) estimated by anthropometry. The volume expansion following the infusion of starch showed monoexponential elimination kinetics with a half-life of two hours. Two interaction effects were found when Ringer´s acetate was infused after the starch. First, there was a higher tendency for Ringer´s acetate to distribute to a peripheral compartment at the expense of the plasma volume expansion. The translocated amount of Ringer´s was 70% higher when HES had been infused earlier. Second, the elimination half-life of Ringer´s acetate was five times longer when administered after the starch (88 versus 497 minutes, P<0.02)., Conclusions: Starch promoted peripheral accumulation of the later infused Ringer´s acetate solution and markedly prolonged the elimination half-life., Trial Registration: ClinicalTrials.gov: NCT01195025.

Purpose: The purpose of the study was to assess the responses of pial artery pulsation (cc-TQ) and subarachnoid width (sas-TQ) to acetazolamide challenge in patients with chronic carotid artery stenosis and relate these responses to changes in peak systolic velocity (PSV), cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT) and time to peak response (TTP)., Methods: Fifteen patients with carotid artery stenosis ≥ 90% on the ipsilateral side and <50% on the contralateral side were enrolled into the study. PSV was assessed using colour-coded duplex sonography, CBF, CBV, MTT and TTP with perfusion computed tomography, cc-TQ and sas-TQ with near-infrared transillumination/backscattering sounding (NIR-T/BSS)., Results: Based on the ipsilateral/contralateral cc-TQ ratio after acetazolamide challenge two groups of patients were distinguished: the first group with a ratio ≥ 1 and the second with a ratio <1. In the second group increases in CBF and CBV after the acetazolamide test were significantly higher in both hemispheres (ipsilateral: +33.0% ± 8.1% vs. +15.3% ± 4.4% and +26.3% ± 6.6% vs. +14.3% ± 5.1%; contralateral: +26.8% ± 7.0% vs. +17.6% ± 5.6% and +20.0% ± 7.3% vs. +10.0% ± 3.7%, respectively), cc-TQ was significantly higher only on the ipsilateral side (+37.3% ± 9.3% vs. +26.6% ± 8.6%) and the decrease in sas-TQ was less pronounced on the ipsilateral side (-0.7% ± 1.5% vs. -10.2% ± 1.5%), in comparison with the first group. The changes in sas-TQ following the acetazolamide test were consistent with the changes in TTP., Conclusions: The ipsilateral/contralateral cc-TQ ratio following acetazolamide challenge may be used to distinguish patient groups characterized by different haemodynamic parameters. Further research on a larger group of patients is warranted.

Background: Diastolic dysfunction is the hemodynamic hallmark of hypertensive heart disease. Tau (τ) has been used to describe left ventricle relaxation. The relationship between τ and afterload has been controversial. Our goal was to demonstrate this relationship in mice, because genetically-modified mouse models have been used extensively for studies in cardiovascular diseases., Methods: Increased arterial load was produced by phenylephrine administration (50 µg/kg iv) (n = 10). A series of pressure-volume loops was recorded with a Millar conductance catheter in vivo as the left ventricle pressure reached the maximum. The arterial load was expressed as Ea (effective arterial elastance). Tau values were computed using three mathematical methods: τWeiss, τGlantz, and τLogistic., Results: A correlation plot between τ and Ea showed a biphasic relationship a flat phase I and an inclined phase II. The existence of an inflection point was proved mathematically with biphasic linear regression. Pressure-volume area (PVA), a parameter linearly related to myocardial O2 consumption (MVO2), was found to be directly proportional to Ea. The plot of τ versus PVA was also biphasic., Conclusion: We concluded that a small increase of the arterial load by phenylephrine increased PVA (index of MVO2) but had little effect on τ. However, after an inflection point, further increase of arterial load and PVA resulted in the linear increase of τ.

Aims: Erythropoietin stimulating agents (ESAs) is an active area of clinical investigation in heart failure (HF) but can cause hypertension and higher hemoglobin concentrations (Hb) that have been associated with adverse outcomes. We evaluated a dosing algorithm and potential confounders' effect on Hb and blood pressure (BP) in a clinical trial., Methods: In an ongoing randomized, placebo controlled, single blind clinical trial of ESA (epoetin alfa) in anemic patients with HF and a preserved ejection fraction (HFPEF), Hb was measured weekly as was BP, weight and concomitant medical therapy. A repeated measure mixed model evaluated determinants of weekly changes in Hb and BP., Results: Among 45 subjects (78 ± 11 years, 67% women, EF = 57 ± 9%) with a total of 780 repeated weekly Hb measures, Hb significantly increased over time in those assigned to ESA (β = 0.933, P < 0.0001), compared to placebo. Dose (β = -0.108, P < 0.0001), patient weight (β = -0.016, P = 0.0037), diuretic use (β = -0.124, P = 0.0389), and time (β = 0.003, P = 0.0331), were all significantly associated with Hb change. Increased diuretic dose and weight change were significantly inversely associated with changes in Hb. ESA administration and dose were not significant determinants of absolute BP or changes in BP from baseline., Discussion: In addition to ESA dose and duration of therapy, factors indicative of volume status including weight and diuretic use are determinants of hemoglobin levels in HF subjects., Conclusion: The currently employed dosing algorithm, which adjusts the administration of ESA based on the absolute hemoglobin and weekly change in hemoglobin increases Hb with relatively a low weekly dose of ESA without significant effects on BP., (© 2011 Blackwell Publishing Ltd.)

The integrity of the blood-brain barrier (BBB) is critical to normal brain function. Traditional techniques for the assessment of BBB disruption rely heavily on the spatiotemporal analysis of extravasating contrast agents. However, such methods based on the leakage of relatively large molecules are not suitable for the detection of subtle BBB impairment or for the performance of repeated measurements in a short time frame. Quantification of the water exchange rate constant (WER) across the BBB using strictly intravascular contrast agents could provide a much more sensitive method for the quantification of the BBB integrity. To estimate WER, we have recently devised a powerful new method using a water exchange index (WEI) biomarker and demonstrated BBB disruption in an acute stroke model. Here, we confirm that WEI is sensitive to even very subtle changes in the integrity of the BBB caused by: (i) systemic hypercapnia and (ii) low doses of a hyperosmolar solution. In addition, we have examined the sensitivity and accuracy of WEI as a biomarker of WER using computer simulation. In particular, the dependence of the WEI-WER relation on changes in vascular blood volume, T1 relaxation of cellular magnetization and transcytolemmal water exchange was explored. Simulated WEI was found to vary linearly with WER for typically encountered exchange rate constants (1-4 Hz), regardless of the blood volume. However, for very high WER (>5 Hz), WEI became progressively more insensitive to increasing WER. The incorporation of transcytolemmal water exchange, using a three-compartment tissue model, helped to extend the linear WEI regime to slightly higher WER, but had no significant effect for most physiologically important WERs (WER < 4 Hz). Variation in cellular T1 had no effect on WEI. Using both theoretical and experimental approaches, our study validates the utility of the WEI biomarker for the monitoring of BBB integrity., (Copyright © 2012 John Wiley & Sons, Ltd.)

Background: Preservation of myocardial perfusion during general anesthesia is likely important in patients at risk for perioperative cardiac complications. Data related to the influence of general anesthesia on the normal myocardial circulation are limited. In this study, we investigated myocardial microcirculatory responses to pharmacological vasodilation and sympathetic stimulation during general anesthesia with sevoflurane in healthy humans immediately before surgical stimulation., Methods: Six female and 7 male subjects (mean age 43 years, range 28-61) were studied at baseline while awake and during the administration of 1 minimum alveolar concentration sevoflurane. Using myocardial contrast echocardiography, myocardial blood flow (MBF) and microcirculatory variables were assessed at rest, during adenosine-induced hyperemia, and after cold pressor test-induced sympathetic stimulation. MBF was calculated from the relative myocardial blood volume multiplied by its exchange frequency (β) divided by myocardial tissue density (ρT), which was set at 1.05 g·mL(-1)., Results: During sevoflurane anesthesia, MBF at rest was similar to baseline values (1.05 ± 0.28 vs 1.05 ± 0.32 mL·min(-1)·g(-1); P = 0.98; 95% confidence interval [CI], -0.18 to 0.18). Myocardial blood volume decreased (P = 0.0044; 95% CI, 0.01-0.04) while its exchange frequency (β) increased under sevoflurane anesthesia when compared with baseline. In contrast, hyperemic MBF was reduced during anesthesia compared with baseline (2.25 ± 0.5 vs 3.53 ± 0.7 mL·min(-1)·g(-1); P = 0.0003; 95% CI, 0.72-1.84). Sympathetic stimulation during sevoflurane anesthesia resulted in a similar MBF compared to baseline (1.53 ± 0.53 and 1.55 ± 0.49 mL·min(-1)·g(-1); P = 0.74; 95% CI, -0.47 to 0.35)., Conclusions: In otherwise healthy subjects who are not subjected to surgical stimulation, MBF at rest and after sympathetic stimulation is preserved during sevoflurane anesthesia despite a decrease in myocardial blood volume. However, sevoflurane anesthesia reduces hyperemic MBF, and thus MBF reserve, in these subjects.

In patients with liver cirrhosis, albumin is given to improve relative hypovolemia caused by marked splanchnic arteriolar vasodilatation. However, the volume effect of albumin is not predictable and depends also on capillary permeability, hydrostatic pressure and lymphatic ability to re-circulate albumin from interstitium to plasma. In patients with decompensated cirrhosis, the capillary permeability is increased, hydrostatic pressure is higher, and the lymphatics functions are deficient. Hence the albumin molecules are more likely to be extravasated rapidly into the interstitium and are subsequently less likely to be re-circulated back into the plasma. This would not only fail to correct circulating hypovolemia, the purpose for which it is given, but also would favor development of reverse colloid oncotic pressure and fluid movement out of the capillaries leading to development of edema. Thus, anything else which could further increase capillary permeability or hydrostatic pressure in cirrhotic patients might create more problems with albumin infusion. An increased capillary permeability is the hallmark of diabetes mellitus. Furthermore, diabetes mellitus may worsen immunodepression in cirrhotic patients thus increasing the incidence of severe infections which may further have a deleterious effect on hemodynamics and capillary permeability. A diabetic patient with advanced cirrhosis and sepsis usually has markedly increased capillary permeability, high hydrostatic pressure due to hyperdynamic circulation, and compromised lymphatic drainage capacity. Hence, using albumin infusion in them would not only fail to improve relative hypovolemia, but also would deleteriously promote extravascular accumulation of fluid, which might impair the functions of many vital organs. However, the efficacy and safety of albumin infusion in diabetic patients with advanced cirrhosis and sepsis is not known. Such data can have a great clinical implication and would necessitate search of a suitable alternative. Because albumin has relatively smaller molecular weight, synthetic colloids with a higher molecular weight might be effective in conditions of increased capillary permeability., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: To describe an animal model of rapid intravenous infusion with different volumes of crystalloid and discuss the clinical findings., Methods: Fifty six male Wistar rats were used, divided randomly in seven groups (n = 8). The rats of groups 1 to 6 received lactated Ringer's solution intravenously, in the rate of 25 ml/min, with different volumes proportional to blood volume (BV). The rats of group 0 were submitted to the same procedure, but did not receive the fluid (control group). The data included respiratory rate, heart rate, saturation of peripheral oxygen (SpO(2)) in two times (before and after the infusion), and upshots (respiratory arrest and death). Dunnett's test and ANOVA were used., Results: The clinical signs significantly changed in the 2, 2.5 and 3 fold BV groups. The respiratory arrest was observed in the 1.5, 2, 2.5 and 3 fold BV groups, but death was present only in 2.5 and 3 fold BV groups., Conclusions: The infusion of crystalloid in the same volume of blood volume did not cause significant variation in respiratory and heart rate, saturation of peripheral oxygen and did not induce respiratory arrest. The infusion of a volume of 3 fold blood volume was lethal to all animals.

Despite the widespread use of loop diuretics to treat acute decompensated heart failure (ADHF), robust data supporting their role and optimal dosing strategies are scarce. This analysis aimed to compare clinical outcomes of patients admitted with ADHF who received a diuretic dosing protocol with those who received the usual diuretic therapy. We performed an observational medical records review to compare the use of a nurse-driven diuretic dosing protocol with usual diuretic dosing for patients admitted with ADHF during a 1-year period. Using a propensity scoring model, comparisons were made between groups for total weight loss, length of stay (LOS), 30-day readmissions, in-hospital mortality, 30-day mortality, and acute kidney failure. Sixty-eight of the 596 patients admitted with ADHF during the study period received the diuretic protocol. Protocol use was associated with an additional 2.63-kg weight loss (P=.003) but a trend toward increased LOS compared with patients receiving usual care (P=.097). However, patients receiving the protocol had a significantly lower risk of 30-day readmission (odds ratio, 0.46, 95% confidence interval, 0.22-0.95). Protocol use was not associated with significant differences in kidney failure, inpatient mortality, or 30-day mortality. A diuretic dosing protocol for patients admitted with ADHF improves weight loss and may lower 30-day readmissions, at the cost of potentially increasing LOS., (© 2013 Wiley Periodicals, Inc.)

Patients with heart failure often show increased arginine vasopressin secretion and enhanced sympathetic and renin-angiotensin-aldosterone activation, which accelerate renal water reabsorption, causing water retention and volume overload. Tolvaptan is an orally active antagonist of arginine vasopressin type 2 receptors in the collecting duct of the kidney that inhibits water reabsorption without substantially affecting the electrolyte balance. Tolvaptan in combination with conventional diuretics improves fluid retention and congestive symptoms in patients with heart failure and volume overload, with minimal effects on hemodynamics and serum potassium. Tolvaptan slightly increases serum sodium concentrations, generally within the normal range. Although it does not seem to affect long-term mortality, tolvaptan does improve short-term water retention and congestive symptoms in heart failure patients with volume overload despite the use of conventional diuretics, and is approved for this indication in Japan.

Aims: Although it is known that alcohol has vasoactive properties, previous studies have not investigated the relationship between cerebral blood flow (CBF) and cerebral blood volume (CBV) after alcohol consumption. The aim of this study was to investigate effects of alcohol on CBF and CBV, both globally and regionally, in social drinkers., Methods: The method of choice was dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Eight males were scanned twice on two separate days; once after consumption of alcohol (blood-alcohol concentration (BAC) of 0.08%) and once sober., Results: The results showed an average increase of CBF after alcohol consumption, both in grey matter (GM) and in white matter (WM), with a CBF(BAC of 0.08%)/CBF(baseline) ratio of 1.2. Regional increases in CBF were seen in areas close to where the large brain-feeding blood vessels enter the brain, in the thalamus region and in the frontal brain regions. The lowest CBF changes were seen in the occipital brain regions. There was also an increase in CBV after alcohol consumption, in particular across WM regions., Conclusion: In conclusion, a BAC of 0.08% causes both an average increase in global and regional CBF. There was stronger correlation between alcohol-induced changes in CBF and CBV in WM than in GM, suggesting the vasculature in the WM to be relatively more affected than the GM. Simultaneous measurements of CBF and CBV after acute alcohol intoxication in social drinkers are important in basic human neuroscience research to elucidate and understand brain physiology in the presence of exogenous neuro-pharmaceutical manipulations.

Background: Plasma expander (PE) based on polyethylene glycol (PEG) conjugated to albumin has shown positive results maintaining blood volume during hemodilution and restoring blood volume during resuscitation from hemorrhagic shock. Polyethylene glycol conjugation to human serum albumin (HSA), PEG-HSA, increases size, weight, and colloidal osmotic pressure, with minor effects on solution viscosity., Methods: This study was designed to test the hypothesis that PEG-HSA (2 g/dL) produced by direct PEGylation chemistry improves cardiac function during 2 experimental models, (i) moderate hemodilution and (ii) resuscitation from hemorrhagic shock, compared with a conventional colloidal PE (Dextran 70 kd [Dx70], 6 g/dL). Cardiac function was studied using a miniaturized pressure volume conductance catheter implanted in the left ventricle and evaluated in terms of cardiac indices derived from the pressure volume measurements., Results: Polyethylene glycol-HSA increased cardiac output, stroke volume, and stroke work and decreased systemic vascular resistance compared with Dx70 in both experimental models. The improvements induced by PEG-HSA in cardiac function were sustained over the observation time. Polyethylene glycol-HSA cardiac mechanoenergetics changes are the result of increased energy transferred per stroke and decreased resistance of the vasculature connecting the heart. In summary, PEG-HSA decreased left ventricle ejection impedance., Conclusion: Ejection of blood diluted with PEG-HSA presented a reduced load to the heart, increased contractile function, and lowered the energy consumed per unit volume compared with Dx70. Our results emphasize the importance of heart function as a parameter to be included in the evaluation changes induced by new PEs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Mannitol is often used during intracranial surgery to improve surgical exposure. Furosemide is often added to mannitol to augment this effect. The concern exists, however, that the augmented diuresis caused by the addition of furosemide to mannitol may cause hypovolemia and hypoperfusion, hypokalemia, and hyponatremia. We examined the intraoperative safety of low-dose furosemide (0.3 mg/kg) combined with mannitol (1 g/kg)., Methods: We observed 23 patients in a double-blind, block randomized, placebo-controlled study to examine the effects of furosemide (0.3 mg/kg) when combined with mannitol (1 g/kg) on surgical brain relaxation for tumor surgery. Mannitol and the study drug (furosemide or placebo) were administered, and arterial blood gases with electrolytes (sodium, potassium, and lactic acid) and urine output volume were recorded every 30 minutes for 3 hours. Plasma sodium, potassium, and lactic acid concentrations, and interval urine outputs, were compared across time and between furosemide-placebo assignment groupings, with a P<0.01 considered significant., Results: Although mannitol produced a large volume of diuresis (1533±335 mL), the addition of a low dose of furosemide substantially increased both the rate of production of urine for the first 90 minutes after administration and the total volume of urine produced (2561±611 mL, P<0.001, compared with placebo group). The addition of furosemide did not produce a serum potassium level below 3.8±0.7 mEq/L, a serum sodium level below 128.3±3.4 mEq/L, or a serum lactic acid level above 2.4±0.9 mmol/L. There were no differences in the plasma potassium concentration, sodium concentration, or lactic acid concentration between the drug groups at any time point., Conclusions: Despite an increase in urine output by as much as 67%, adding low-dose furosemide to mannitol does not seem to produce significant electrolyte derangements or hypovolemia compared with the administration of mannitol alone.

It has been demonstrated that insulin-mediated recruitment of microvascular blood volume is associated with insulin sensitivity. We hypothesize that insulin rapidly stimulates penetration of red blood cells (RBC) and plasma into the glycocalyx and thereby promotes insulin-mediated glucose uptake by increasing intracapillary blood volume. Experiments were performed in rats; the role of the glycocalyx was assessed by enzymatic degradation using a bolus of hyaluronidase. First, the effect of insulin on glycocalyx accessibility was assessed by measuring the depth of penetration of RBCs into the glycocalyx in microvessels of the gastrocnemius muscle with Sidestream Dark-field imaging. Secondly, peripheral insulin sensitivity was determined using intravenous insulin tolerance tests (IVITT). In addition, in a smaller set of experiments, intravital microscopy of capillary hemodynamics in cremaster muscle and histological analysis of the distribution of fluorescently labeled 40 kDa dextrans (D40) in hindlimb muscle was used to evaluate insulin-mediated increases in capillary blood volume. Insulin increased glycocalyx penetration of RBCs by 0.34±0.44 µm (P<0.05) within 10 minutes, and this effect of insulin was greatly impaired in hyaluronidase treated rats. Further, hyaluronidase treated rats showed a 35±25% reduction in whole-body insulin-mediated glucose disposal compared to control rats. Insulin-mediated increases in capillary blood volume were reflected by a rapid increase in capillary tube hematocrit from 21.1±10.1% to 29.0±9.8% (P<0.05), and an increase in D40 intensity in individual capillaries of 134±138% compared to baseline at the end of the IVITT. These effects of insulin were virtually abolished in hyaluronidase treated animals. In conclusion, insulin rapidly increases glycocalyx accessibility for circulating blood in muscle, and this is associated with an increased blood volume in individual capillaries. Hyaluronidase treatment of the glycocalyx abolishes the effects of insulin on capillary blood volume and impairs insulin-mediated glucose disposal.

Nonmotor manifestations determine the life quality of patients with Parkinson's disease (PD). Identification of the nonmotor symptoms in PD as definite changes will represent a milestone in its diagnosis. Outcome measures that characterize nonmotor manifestations with specificity for dopaminergic deficiency are essential to that goal. Pain is a prevalent sensory disturbance in PD patients. The prevalence was reported to be up to 83%. Nociceptive stimuli under normal conditions elicit decreases in cerebral blood volume (CBV) in the striatum via dopaminergic neurotransmission. This nociception-induced CBV response is potentially to be defined as a characteristic of the pain symptom of PD. To validate this concept, steady-state CBV-weighted functional magnetic resonance imaging with iron oxide nanoparticles was employed to measure CBV changes in parkinsonian rats. Tyrosine hydroxylase immunohistology was used to identify the dopaminergic integrity to corroborate the imaging findings. Additional experiments that tested pain responses in parkinsonism were also carried out. The results revealed that the lesioned striatum exhibited a weakened CBV decrease in response to the nociceptive stimulus. This weakened CBV response occurred mainly in areas with dopaminergic denervation. A strong correspondence was observed between the distributions of the nociception-induced CBV responses and dopaminergic innervation. The persisting CBV signals in the striatum were abolished by the D2/D3 antagonist eticlopride. The findings of these behavioral, neuroimaging, immunohistological, and pharmacological experiments demonstrate that pain in a rat model of PD can be characterized by nociception induced striatal CBV signal changes with specificity for dopaminergic dysfunction., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Objectives: Hydroxyethyl starch (HES) 130/0.4 is considered an effective plasma expander when compared to crystalloids. There is controversy around its superiority regarding hemodynamic optimization and about possible detrimental effects on coagulation. The aim of this study was to compare the effects of HES 130/0.4 to lactated Ringer solution during hip arthroplasty in adult patients under spinal anesthesia regarding intraoperative bleeding, hemodynamic parameters, coagulation profile, transfusion requirements and clinical outcomes., Methods: In this randomized, controlled trial, 48 patients scheduled for hip arthroplasty with spinal anesthesia were randomized into two groups: 24 patients were allocated to receive a preload of 15 mL.kg(-1) of HES 130/0.4 and 24 patients received a preload of 30 mL.kg(-1) lactated Ringer solution before surgery. Hemodynamic measurements, hemoglobin concentrations, biochemical parameters and coagulation tests were evaluated in three periods during surgical procedure. Patients received medical follow-up during their hospital stay and up to postoperative 30 days. Primary outcome was the requirement of red blood cell transfusion between groups during hospital stay. Secondary outcome were hemodynamic parameters, length of hospital stay, mortality and occurrence of clinical postoperative complications., Results: Red blood cell transfusion was required in 17% of patients in the HES group and in 46% in the Ringer group (p = .029). Postoperative infections were more frequently observed in the Ringer group (17%) compared to the HES group (0), p = .037. There were no significant differences between groups in mortality, hospital length of stay and clinical complications other than infection., Conclusions: During hip arthroplasty, patients treated with hypervolemic hemodilution with hydroxyethyl starch 130/0.4 required less transfusion and presented lower infection rate compared to patients who received lactated Ringer., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Unlabelled: Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hb(mass)) and maximal oxygen uptake (v O(2 max))., Purpose: This study defined the time course of changes in Hb(mass), v O(2 max) as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field., Methods: 19 trained men received rHuEpo injections of 50 IU•kg(-1) body mass every two days for 4 weeks. Hb(mass) was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v O(2 max) and 3,000 m time trial performance were measured pre, post administration and at the end of the study., Results: Relative to baseline, running performance significantly improved by ∼6% after administration (10:30±1:07 min:sec vs. 11:08±1:15 min:sec, p<0.001) and remained significantly enhanced by ∼3% 4 weeks after administration (10:46±1:13 min:sec, p<0.001), while v O(2 max) was also significantly increased post administration (60.7±5.8 mL•min(-1)•kg(-1) vs. 56.0±6.2 mL•min(-1)•kg(-1), p<0.001) and remained significantly increased 4 weeks after rHuEpo (58.0±5.6 mL•min(-1)•kg(-1), p = 0.021). Hb(mass) was significantly increased at the end of administration compared to baseline (15.2±1.5 g•kg(-1) vs. 12.7±1.2 g•kg(-1), p<0.001). The rate of decrease in Hb(mass) toward baseline values post rHuEpo was similar to that of the increase during administration (-0.53 g•kg(-1)•wk(-1), 95% confidence interval (CI) (-0.68, -0.38) vs. 0.54 g•kg(-1•)wk(-1), CI (0.46, 0.63)) but Hb(mass) was still significantly elevated 4 weeks after administration compared to baseline (13.7±1.1 g•kg(-1), p<0.001)., Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated v O(2 max) and Hb(mass).

Background: Patients admitted to surgery may be dehydrated, which is difficult to diagnose except when it is severe (>5% Gl116 of the body weight). We hypothesized that modest dehydration can be detected by kinetic analysis of the blood hemoglobin concentration after a bolus infusion of crystalloid fluid., Methods: Four series of experiments were performed on 10 conscious, healthy male volunteers. Separated by at least 2 days, they received 5 or 10 mL/kg acetated Ringer's solution over 15 minutes. Before starting half of the IV infusions, volume depletion amounting to 1.5 to 2.0 L (approximately 2% of body weight) was induced with furosemide. The elimination clearance and the half-life of the infused fluid were calculated based on blood hemoglobin over 120 minutes. The perfusion index and the pleth variability index were monitored by pulse oximetry after a change of body position., Results: Dehydration decreased the elimination clearance of acetated Ringer's solution [median (25th-75th percentile)] from 1.84 (1.23-2.57) to 0.53 (0.41-0.79) mL/kg/min (Wilcoxon matched-pair test P < 0.001) and increased the half-life from 23 (12-37) to 76 (57-101) minutes (P < 0.001). The smaller infusion, 5 mL/kg, fully discriminated between experiments performed in the euhydrated and dehydrated states, whereas the urinary excretion provided a less-reliable indication of hydration status. Dehydration decreased the perfusion index but did not affect the pleth variability index., Conclusion: Dehydration amounting to 2% of the body weight could be detected from the elimination clearance and the half-life of an infusion of 5 mL/kg Ringer's solution.

Chronic kidney disease (CKD) is prevalent in 3%-4% of the adult population in the United States, and the vast majority of these people are hypertensive. Compared with those with essential hypertension, hypertension in CKD remains poorly controlled despite the use of multiple antihypertensive drugs. Hypervolemia is thought to be a major cause of hypertension, and diuretics are useful to improve blood pressure control in CKD. Non-osmotic storage of sodium in the skin and muscle may be a novel mechanism by which sodium may modulate hypertension; further work is need to study this novel phenomenon with diuretics. Among people with stage 4 CKD, loop diuretics are recommended over thiazides. Thiazide diuretics are deemed ineffective in people with stage 4 CKD. Review of the literature suggests that thiazides may be useful even among people with advanced CKD. They cause a negative sodium balance, increasing sodium excretion by 10%-15% and weight loss by 1-2 kg in observational studies. Observational data show improvement in seated clinic blood pressure of about 10-15 mm Hg systolic and 5-10 mm Hg diastolic, whereas randomized trials show about 15 mm Hg improvement in mean arterial pressure. Volume depletion, hyponatremia, hypokalemia, hypercalcemia, and acute kidney injury are adverse effects that should be closely monitored. Our review suggests that adequately powered randomized trials are needed before the use of thiazide diuretics can be firmly recommended in those with advanced CKD., (Published by Elsevier Inc.)

Objective: The aim of this study was to compare the effect of 6% hydroxyl ethyl starch solution with 4% gelatin and Ringer's solutions on the haemodynamic stability of patients after coronary artery bypass graft (CABG) surgery and immediately after discontinuation of cardiopulmonary bypass (CPB)., Methods: This was a randomised, double-blind clinical trial of 92 patients who were candidates for on-pump CABG. After discontinuation of CPB, all patients were transferred to the intensive care unit (ICU) and divided randomly into three groups. The first group received Ringer's solution, the second group 4% gelatin, and the third 6% hydroxyl ethyl starch (HES) solution (Voluven). Haemodynamic parameters such as heart rate, mean arterial pressure, systolic blood pressure, diastolic blood pressure, central venous pressure, cardiac output and the presence of arrhythmias were documented., Results: The volume needed for maintaining normal blood pressure and central venous pressure in the range of 10-14 mmHg was less in the HES group than in the other groups. The volume was similar however in the gelatin and Ringer's groups in the first 24 hours after surgery. Urinary output in the first four and 24 hours after surgery were significantly higher in the HES group than in the other two groups. Mean creatinine levels were significantly lower in the HES group., Conclusion: HES (6%) had a better volume-expanding effect than gelatin (4%) and Ringer's solutions, and its short-term effects on renal function were also better than gelatin and Ringer's solutions.

Background: This study aims to study changes in blood volume after 1 litre infusions of Gelofusine(®) [4% succinylated gelatine in 0.7% saline, weight-average molecular weight (MWw) 30 kDa] and Voluven(®) (6% hydroxyethyl starch in 0.9% saline, MWw 130 kDa) in the presence of increased capillary permeability., Methods: In this randomized double-blind study, adults undergoing laparoscopic cholecystectomy received 1 litre of Gelofusine(®) (n=12) or Voluven(®) (n=13) over 1 h at the induction of anaesthesia. No other fluids were given. Haematocrit, serum electrolytes, and osmolality were measured before infusion and hourly thereafter for 4 h. Changes in blood volume were calculated from changes in haematocrit. The urinary albumin:creatinine ratio (ACR) was measured before and after operation., Results: Baseline parameters before the two infusions were similar (P>0.050). The urinary ACR increased significantly after operation after Gelofusine(®) (P=0.011) and Voluven(®) (P=0.002), indicating increased capillary permeability. Voluven(®) produced a greater increase in serum chloride concentration (P=0.028) and a larger decrease in strong ion difference (P=0.009) than Gelofusine(®). There were no significant differences in changes in haematocrit (P=0.523) and blood volume (P=0.404) over the study period when the two infusions were compared, nor were there any differences in serum sodium, potassium, bicarbonate, and albumin concentrations (P>0.050). Urine output, sodium concentration, and osmolality were similar after the two infusions (P>0.050)., Conclusions: The blood volume-expanding effects of the two colloids were not significantly different, despite the increase in postoperative urinary ACR and the 100 kDa difference in MWw.

Objective: New volumetric variables of preload, such as total end-diastolic volume index (TEDVI) and active circulation volume index (ACVI) and central blood volume index (CBVI), may represent good indicators of preload and predictors of fluid responsiveness. During acute changes of intravascular volume these variables would allow a more accurate intervention., Aim: The aim of the present study was to investigate the changes in TEDVI, ACVI, CBVI in a juvenile model of hemorrhagic shock and resuscitation., Methods: Twelve anaesthetized ponies (3-8 months of age) were studied at normovolaemia (BASE), after blood withdrawal to mean arterial pressure (MAP) of 40 mmHg (HEMO), after infusion of norepinephrine to reach a MAP of ± 10% of baseline (HE-NE), and after retransfusion of shed blood (RESU). TEDVI, ACVI, CBVI were measured by Ultrasound Dilution (UD) technology with CoStatus device. Data were analyzed using 1-way (ANOVA) followed by Bonferroni's multiple pairwise comparisons. Evaluation of dependence between CoStatus volumetric variables and stroke volume index (SVI) were performed using the linear regression analysis and calculating the r(2) coefficient of determination., Results: TEDVI and ACVI changed significantly during HEMO and RESU status. NE administration induced MAP and CVP significant changes, whereas TEDVI and ACVI remained unchanged. CBVI showed high variability and seemed to be inconsistent on the identification of the volume status. In the correlation analysis, only TEDVI consistently correlated with SVI and volume induced SVI changes., Conclusions: In this animal model, TEDVI and ACVI were superior to CBVI in consistently reflecting hemorrhage. TEDVI but not ACVI and CBVI correlated with volume-induced changes in SVI. NE administration did not affect this correlation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The hemoglobin vesicle (Hb-vesicle) is a cellular-type artificial oxygen carrier showing a resuscitative effect comparable to that of blood transfusion in several animal models. However, the efficacy of Hb-vesicles for resuscitation when the hemorrhage cannot be controlled remains unclear. Therefore, we used Hb-vesicles in a rat hemorrhagic shock model caused by continuous bleeding. For inducing uncontrolled hemorrhage, animals were heparinized and bled from the caudal artery. Fluid resuscitation was subsequently performed with five materials: Hb-vesicle suspension in a 5% albumin (Alb) solution (HbV), washed red blood cells (wRBC) in a 6% hydroxyethyl starch (HES) solution, 5% Alb, 6% HES, and saline (Sal). During the experiment, all animals in the HbV and wRBC groups survived, whereas all those in the Alb and HES groups died. In the Sal group, five of seven animals died. In the HbV and wRBC groups, the heart rate, mean arterial pressure, and blood lactic acid levels were stabilized during resuscitation. Meanwhile, the hematocrit levels of the HbV, Alb, and HES groups showed sharp decreases (HbV: 6.8% ± 1.7%, Alb: 6.8% ± 0.8%, HES: 5.5% ± 0.7% at 100% total circulated blood volume; final hematocrit of the HbV group: 1.5% ± 0.5%). These results suggest that shocked animals can survive longer when the Hb-vesicle supply is maintained and that HbV showed a similar effect to wRBC in maintaining the circulating volume and oxygen metabolism. Continuous infusion of Hb-vesicles may extend the survival of trauma victims with uncontrolled hemorrhage until they have reached a trauma center.

The cerebrovascular effects of nimodipine are still poorly understood even in the healthy condition; in particular, its effects on tissue oxygenation have never been investigated. The aim of the present study was to investigate changes in cerebral oxygenation and blood volume upon oral administration of nimodipine (90 mg) in the healthy condition. In eight subjects, changes in cerebral tissue oxygenation and blood volume were determined simultaneously with changes in blood velocity of the middle cerebral artery (VMCA) by using, respectively, near infrared spectroscopy (NIRS) and transcranial Doppler ultrasonography (TCD). The subjects also underwent noninvasive assessment of arterial blood pressure (ABP) and end-tidal CO2. TCD and NIRS CO2 reactivity indices were al-so extracted. Nimodipine significantly reduced ABP (11±13%) and increased heart rate, as well as NIRS oxygenation(6.0±4.8%) and blood volume indices (9.4±10.1%), while V(MCA) was not significantly decreased (2.0±3.5%). Nimodipine slightly but significantly reduced the V(MCA) response to changes in pCO2 whereas the CO2 reactivity of NIRS parameters was improved. The observed changes in cerebral tissue oxygenation and blood volume indicate nimodipine-induced cerebrovascular dilation and increased perfusion, while the effect on V(MCA)possibly results from dilation of the insonated artery. The present results cast doubt on the putative nimodipine-induced impairment of CO2 reactivity.

Effects of dehydration on reptilian embryonic cardiovascular function are unknown. Here, we present the first morphological and physiological data quantifying the cumulative effects of four acute dehydration events on the embryonic American alligator, Alligator mississipiensis. We hypothesized that dehydration would alter embryonic morphology, reduce blood volume and augment the response to angiotensin II (Ang II), a key osmotic and blood volume regulatory response element in adult vertebrates. Drying events at 30%, 40%, 50%, and 60% of embryonic incubation reduced total egg water content by 14.43 ± 0.37 g, a 3.4 fold increase relative to controls. However, embyronic blood volume was greater in the dehydration group at 70% of embryonic incubation compared to controls (0.39 ± 0.044 mLg(-1) and 0.22 ± 0.03 mLg(-1), respectively), however, both groups were similar at 90% of incubation (0.18 ± 0.02 mLg(-1) in the controls and 0.23 ± 0.03 mLg(-1) in the dehydrated group). Dehydration altered the morphological phenotype and resulted in an overall reduction in embryonic mass at both incubation time points measured. Dehydration also altered the physiological phenotype, resulting in embryonic alligators that were relatively bradycardic at 90% of incubation. Arterial Ang II injections resulted in a dose dependent hypertension, which increased in intensity over the span of incubation studied. While progressive incubation altered the Ang II response, dehydration had no impact on the cardiovascular responses to the peptide. Quantification of Ang II type-1 receptor protein using western blot analysis illustrated that dehydration condition and incubation time point did not alter protein quantity. Collectively, our results show that dehydration during embryonic development of the American alligator alters embryonic morphology and baseline heart rate without altering arterial pressure and response to Ang II., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Isotonic crystalloids play a central role in perioperative fluid management. Isooncotic preparations of colloids (for example, human albumin or hydroxyethyl starch) remain nearly completely intravascular when infused to compensate for acute blood losses. Recent data were interpreted to indicate a comparable intravascular volume effect for crystalloids, challenging the occasionally suggested advantage of using colloids to treat hypovolemia. General physiological knowledge and clinical experience, however, suggest otherwise., Methods: In a prospective study, double-tracer blood volume measurements were performed before and after intended normovolemic hemodilution in ten female adults, simultaneously substituting the three-fold amount of withdrawn blood with Ringer's lactate. Any originated deficits were substituted with half the volume of 20% human albumin, followed by a further assessment of blood volume. To assess significance between the measurements, repeated measures analysis of variance (ANOVA) according to Fisher were performed. If significant results were shown, paired t tests (according to Student) for the singular measurements were taken. P < 0.05 was considered to be significant., Results: A total of 1,097 ± 285 ml of whole blood were withdrawn (641 ± 155 ml/m(2) body surface area) and simultaneously replaced by 3,430 ± 806 ml of Ringer's lactate. All patients showed a significant decrease in blood volume after hemodilution (-459 ± 185 ml; P < 0.05) that did not involve relevant hemodynamical changes, and a significant increase in interstitial water content (+2,157 ± 606 ml; P < 0.05). The volume effect of Ringer's lactate was 17 ± 10%. The infusion of 245 ± 64 ml of 20% human albumin in this situation restored blood volume back to baseline values, the volume effect being 184 ± 63%., Conclusions: Substitution of isolated intravascular deficits in cardiopulmonary healthy adults with the three-fold amount of Ringer's lactate impedes maintenance of intravascular normovolemia. The main side effect was an impressive interstitial fluid accumulation, which was partly restored by the intravenous infusion of 20% human albumin. We recommend to substitute the five-fold amount of crystalloids or to use an isooncotic preparation in the face of acute bleeding in patients where edema prevention might be advantageous.

Background: Mannitol has traditionally been the mainstay of medical therapy for intracranial hypertension in patients with head injury. We previously demonstrated that mannitol reduces brain volume in patients with cerebral edema, although whether this occurs because of a reduction in brain water, blood volume, or both remains poorly understood., Objective: To test the hypothesis that mannitol acts by lowering blood viscosity leading to reflex vasoconstriction and a fall in cerebral blood volume (CBV)., Methods: We used O positron emission tomography to study 6 patients with traumatic brain injuries requiring treatment for intracranial hypertension. Cerebral blood flow (CBF), CBV, and cerebral metabolic rate for oxygen (CMRO2) were measured before and 1 hour after administration of 1.0 g/kg 20% mannitol., Results: CBV rose from 4.1 ± 0.4 to 4.2 ± 0.2 mL/100 g (P = .3), while intracranial pressure fell from 21.5 ± 4.9 to 13.7 ± 5.1 mm Hg (P < .003) after mannitol. Blood pressure, PaCO2, oxygen content, CBF, and CMRO2 did not change., Conclusion: A single bolus of 1 g/kg of 20% mannitol does not acutely lower CBV. Another mechanism, such as a reduction in brain water, may better explain mannitol's ability to lower intracranial pressure and reduce mass effect.

Background: Multiple studies have shown that cerebral tissue oxygen saturation (Sct(O(2))) is decreased after phenylephrine treatment. We hypothesized that the negative impact of phenylephrine administration on Sct(O(2)) is affected by arterial blood carbon dioxide partial pressure (Pa(CO(2))) because CO(2) is a powerful modulator of cerebrovascular tone., Methods: In 14 anaesthetized healthy patients, i.v. phenylephrine bolus was administered to increase the mean arterial pressure ~20-30% during hypocapnia, normocapnia, and hypercapnia. Sct(O(2)) and cerebral blood volume (CBV) were measured using frequency domain near-infrared spectroscopy, a quantitative technology. Data collection occurred before and after each treatment., Results: Phenylephrine caused a significant decrease in Sct(O(2)) during hypocapnia [ΔSct(O(2)) =-3.4 (1.5)%, P<0.001], normocapnia [ΔSct(O(2)) =-2.4 (1.5)%, P<0.001], and hypercapnia [ΔSct(O(2)) =-1.4 (1.5)%, P<0.01]. Decreases in Sct(O(2)) were significantly different between hypocapnia, normocapnia, and hypercapnia (P<0.001). Phenylephrine also caused a significant decrease in CBV during hypocapnia (P<0.01), but not during normocapnia or hypercapnia., Conclusion: The negative impact of phenylephrine treatment on Sct(O(2)) and CBV is intensified during hypocapnia while blunted during hypercapnia.

The deactivation of the inhibitory mechanisms with injections of moxonidine (α2-adrenoceptor/imidazoline receptor agonist) into the lateral parabrachial nucleus (LPBN) increases hypertonic NaCl intake by intra- or extracellular dehydrated rats. In the present study, we investigated the changes in the urinary sodium and volume, sodium balance, and plasma vasopressin and oxytocin in rats treated with intragastric (i.g.) 2 M NaCl load (2 ml/rat) combined with injections of moxonidine into the LPBN. Male Holtzman rats (n=5-12/group) with stainless steel cannulas implanted bilaterally into LPBN were used. Bilateral injections of moxonidine (0.5 nmol/0.2 μl) into the LPBN decreased i.g. 2 M NaCl-induced diuresis (4.6±0.7 vs. vehicle: 7.4±0.6 ml/120 min) and natriuresis (1.65±0.29 vs. vehicle: 2.53±0.17 mEq/120 min), whereas the previous injection of the α2-adrenoceptor antagonist RX 821002 (10 nmol/0.2 μl) into the LPBN abolished the effects of moxonidine. Moxonidine injected into the LPBN reduced i.g. 2 M NaCl-induced increase in plasma oxytocin and vasopressin (14.6±2.8 and 2.2±0.3 vs. vehicle: 25.7±7 and 4.3±0.7 pg/ml, respectively). Moxonidine injected into the LPBN combined with i.g. 2 M NaCl also increased 0.3 M NaCl intake (7.5±1.7 vs. vehicle: 0.5±0.2 mEq/2 h) and produced positive sodium balance (2.3±1.4 vs. vehicle: -1.2±0.4 mEq/2 h) in rats that had access to water and NaCl. The present results show that LPBN α2-adrenoceptor activation reduces renal and hormonal responses to intracellular dehydration and increases sodium and water intake, which facilitates sodium retention and body fluid volume expansion., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

Pharmacologic MRI (phMRI) uses functional MRI techniques to provide a noninvasive in vivo measurement of the hemodynamic effects of drugs. The cerebral blood volume change (ΔCBV) serves as a surrogate for neuronal activity via neurovascular coupling mechanisms. By assessing the location and time course of brain activity in mouse mutant studies, phMRI can provide valuable insights into how different behavioral phenotypes are expressed in deferring brain activity response to drug challenge. In this report, we evaluate the utility of three different intravascular ultrasmall superparamagnetic iron oxide (USPIO) contrast agents for phMRI using a gradient-echo technique, with temporal resolution of one min at high magnetic field. The tissue half-life of the USPIOs was studied using a nonlinear detrending model. The three USPIOs are candidates for CBV weighted phMRI experiments, with r(2)/r(1) ratios ≥ 20 and apparent half-lives ≥ 1.5 h at the described doses. An echo-time of about 10 ms or longer results in a functional contrast to noise ratio (fCNR) > 75 after USPIO injection, with negligible decrease between 1.5-2 h. phMRI experiments were conducted at 7 T using cocaine as a psychotropic substance and acetazolamide, a global vasodilator, as a positive control. Cocaine acts as a dopamine-serotonin-norepinephrine reuptake inhibitor, increasing extracellular concentrations of these neurotransmitters, and thus increasing dopaminergic, serotonergic and noradrenergic neurotransmission. phMRI results showed that CBV was reduced in the normal mouse brain after cocaine challenge, with the largest effects in the nucleus accumbens, whereas after acetazolamide, blood volume was increased in both cerebral and extracerebral tissue., (Copyright © 2011 John Wiley & Sons, Ltd.)

In a previous dose escalation study our group found that combining 90μg/kg rFVIIa with HBOC-201 reduced blood loss and improved physiologic parameters compared to HBOC alone. In this follow-up study in a swine liver injury model, we found that while there were no adverse hematology effects and trends observed in the previous study were confirmed, statistical significance could not be reached. Additional pre-clinical studies are indicated to identify optimal components of a multifunctional blood substitute for clinical use in trauma.

l-Arginine (L-arg) is an amino acid precursor to nitric oxide (NO). Dietary supplements containing L-arg have been marketed with the purpose of increasing vasodilation, thereby elevating blood flow to the exercising muscle and enhancing the metabolic response to exercise. Our goal was to identify the acute effect of L-arg supplementation on biceps strength performance, indicators of NO production (nitrite and nitrate - NOx), and muscle blood volume (Mbv) and oxygenation (Mox) during recovery from 3 sets of resistance exercise. Fifteen males participated in a randomized, double-blind, placebo-controlled study. After withdrawing resting blood samples, the subjects were supplemented with 6 g of L-arg (ARG) or placebo (PLA). Monitoring of Mbv and Mox with near-infrared spectroscopy began 30 min after supplementation and lasted for 60 min. The exercise protocol (3 sets of 10 maximal voluntary contractions of isokinetic concentric elbow extension at 60°·s(-1), 2-min rest between sets) was initiated 80 min after supplementation. Blood samples were drawn at 30, 60, 90, and 120 min after supplementation. Repeated measures ANOVA showed that Mbv significantly (p ≤ 0.05) increased in ARG compared with the PLA during the recovery period of each set of resistance exercise. NOx, Mox, peak torque, total work, and set total work were not significantly different between groups. We found that acute L-arg supplementation increases Mbv during recovery from sets of resistance exercise with no increase in strength performance. It is still premature to recommend nutritional supplements containing L-arg as an ergogenic aid to increase muscle strength during resistance training in healthy subjects.

Aims: This study evaluated the hypothesis that exogenous nitric oxide (NO) supplementation during acute hemodilution with plasma expander (PE) provides beneficial effects on cardiac function., Main Methods: Acute hemodilution in golden Syrian hamsters was induced by a 40% of blood volume exchange with dextran 70 kDa. Intravascular NO supplementation after hemodilution was accomplished with a NO donor, diethylenetriamine NONOate (DETA NONOate). The test group was treated with DETA NONOate, while the control group received only vehicle. Left ventricular cardiac function was studied using pressure-volume measurements obtained with a miniaturized conductance catheter., Key Findings: Cardiac output increased to 122±5% and 107±1% of the baseline in the group treated with NO donor and the vehicle group, respectively. Stroke work per stroke volume (SW/SV) after hemodilution reduced to 90% of the baseline and the NO donor significantly reduced SW/SV compared to the vehicle. The minimum rate of pressure change (dP/dt(min)) was significantly lower in animals treated with the NO donor compared to vehicle treated animals. Systemic vascular resistance (SVR) decreased to 62±5% of the baseline in the NO donor group whereas the vehicle group SVR decreased to 83±5% of the baseline. Using intravital microscopy analysis of microvessel in the dorsal skinfold window chamber, we established that the NO donor group induced significant vasodilation compared to the vehicle group., Significance: NO supplementation in an acute hemodilution with PE has beneficial effects on cardiac performance. However, the NO supplementation effects with a NO donor are dose-independent and short-lasting., (Copyright © 2011 Elsevier Inc. All rights reserved.)

During prolonged exercise, fluid and salt losses through sweating reduce plasma volume which leads to heart rate drift in association with hyperthermia and reductions in performance. Oral rehydration with water reduces the loss of plasma volume and lessens heart rate drift and hyperthermia. Moreover, the inclusion of sodium in the rehydration solution to levels that double those in sweat (i.e., around 90 mmol/l Na(+)) restores plasma volume when ingested during exercise, and expands plasma volume if ingested pre-exercise. Pre-exercise salt and fluid ingestion with the intention of expanding plasma volume has received an increasing amount of attention in the literature in recent years. In four studies, pre-exercise salt and fluid ingestion improved performance, measured as time to exhaustion, either during exercise in a thermoneutral or in a hot environment. While in a hot environment, the performance improvements were linked to lowering of core temperatures and heart rate, the reasons for the improved performance in a thermoneutral environment remain unclear. However, when ingesting pre-exercise saline solutions above 0.9% (i.e., > 164 mmol/l Na(+)), osmolality and plasma sodium increase and core temperature remain at dehydration levels. Thus, too much salt counteracts the beneficial effects of plasma volume expansion on heat dissipation and hence in performance. In summary, the available literature suggests that pre-exercise saline ingestion with concentrations not over 164 mmol/l Na(+) is an ergogenic aid for subsequent prolonged exercise in a warm or thermoneutral environment., (Copyright © 2012 S. Karger AG, Basel.)

Objectives: To investigate the ratio of enzyme inhibitor volume to blood volume in angiotensin II (Ang II) blood collection tubes., Design and Methods: Whole blood was mixed with known volumes of inhibitor prior to angiotensin II analysis., Results: Imunoreactive Ang II levels increased at low blood volume to high inhibitor volume ratios, due to interference by o-phenanthroline., Conclusion: To prevent falsely elevated Ang II levels in low volume blood samples an appropriate volume of inhibitor solution must be used., (Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia., Measurements and Main Results: Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ≤ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ≤ .05), consistent with adrenal suppression., Conclusions: In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.

History and Admission Findings: A 70-year-old female patient was admitted with progressive dyspnea and peripheral edema. The patient had a medical history of myocardial hypertrophy, diastolic dysfunction and concomitant pulmonary hypertension (PH)., Investigations: The physical exam was suggestive of cardiac decompensation. Echocardiography showed myocardial hypertrophy, an enlarged left atrium as well as enlarged right-sided heart chambers. A prominent tricuspid regurgitation jet was present, and the estimated systolic right ventricular pressure was 65 mmHg. Invasive hemodynamic measurements showed a marked pressure elevation in the pulmonary circulation (mean PAP 51 mmHg), combined with an elevated left ventricular end-diastolic pressure (LVEDP) of 30 mmHg and a profound increase in the transpulmonary gradient (TPG, 21 mmHg)., Treatment and Course: The synopsis of these findings led to the diagnosis of postcapillary PH with a prominent precapillary involvement and cardiac decompensation. Due to signs of volume overload, an adequate diuretic therapy was initiated. The patient was recompensated and lost 7 kg of weight, which was associated with substantial clinical improvement. At invasive follow-up hemodynamic measurement, the patient's PAP was substantially decreased and almost reached normal values. The previously diagnosed precapillary involvement had disappeared., Conclusion: PH is a frequent phenomenon in patients with systolic and diastolic heart failure, and might initially appear as a combination of pre- and postcapillary involvement. The patients' volume status has a major influence on pulmonary hemodynamics. An adequate therapy of the underlying heart failure, especially an adequate diuresis, may have marked beneficial effects on pulmonary hemodynamics. Hemodynamic measurements should always be performed in compensated status., (© Georg Thieme Verlag KG Stuttgart · New York.)

There is evidence that in cardiac failure, there is defective baroreceptor reflex control of sympathetic nerve activity. Often, cardiac failure is preceded by a state of cardiac hypertrophy in which there may be enhanced performance of the heart. This study investigated whether in two different models of cardiac hypertrophy, there was an increased contribution of nitric oxide (NO) to the low-pressure baroreceptor regulation of renal sympathetic nerve activity (RSNA) and nerve-dependent excretory function. Administration of a volume load, 0.25* body wt/min saline for 30 min, in normal rats decreased RSNA by 40* and increased urine flow by some 9-fold. Following nitro-L-arginine methyl ester (L-NAME) administration, 10 μg·kg(-1)·min(-1) for 60 min, which had no effect on blood pressure, heart rate, or RSNA, the volume load-induced renal sympathoinhibitory and excretory responses were markedly enhanced. In cardiac hypertrophy states induced by 2 wk of isoprenaline/caffeine or 1 wk thyroxine administration, the volume challenge failed to suppress RSNA, and there were blunted increases in urine flow in the innervated kidneys, but following L-NAME infusion, the volume load decreased RSNA by 30-40* and increased urine flow by some 20-fold in the innervated kidneys, roughly to the same extent as observed in normal rats. These findings suggest that the blunted renal sympathoinhibition and nerve-dependent diuresis to the volume load in cardiac hypertrophy are related to a heightened production or activity of NO within either the afferent or central arms of the reflex.

Background: The increase in remifentanil concentration during haemorrhagic shock and the difference between this effect and that for propofol are not fully understood. We investigated the influence of haemorrhage on the pseudo-steady-state remifentanil concentration in a porcine model and compared the changes with those for propofol., Methods: After infusion of remifentanil (0.5 µg kg⁻¹ min⁻¹) and propofol (6 mg kg⁻¹ h⁻¹ after 2 mg kg⁻¹ bolus infusion) for 60 min, nine swine [mean (standard deviation) body weight=26.3 (1.3) kg] were studied using a stepwise haemorrhage model (10% of estimated blood volume removed every 30 min until 1.5 h, and stepwise removal of 5% every 30 min thereafter until circulatory collapse). Haemodynamic and metabolic variables and plasma remifentanil and propofol concentrations were measured at every step., Results: A mean volume of 913 (82) ml of blood was drained before reaching circulatory collapse. The increases in plasma concentrations from the prehaemorrhagic value fitted the following equations: % increase in remifentanil=2.1 × cumulative blood loss (% of initial blood volume) and % increase in propofol = 0.7 × cumulative blood loss during compensated shock; and % increase in remifentanil = 27.4 × cumulative blood loss-897 and % increase in propofol = 9.5 × cumulative blood loss-306 during uncompensated shock. Remifentanil concentrations were highly correlated with the reciprocal of cardiac output., Conclusions: During haemorrhage, the plasma remifentanil concentration showed a three-fold greater increase than that of propofol in administration by continuous infusion.

The Irukandji syndrome is caused by the sting of some small jellyfish species. The syndrome has severe life-threatening consequences. The exacerbating pain and cardiovascular symptoms (tachycardia and hypertension) are hard to control in many cases. We suggest a way to experiment a new possible therapy with an FDA approved analgesic, ziconotide, a synthetic derivative from a marine cone snail (Conus magus) venom component, which is administrated intravenously. The proposed experimental plasma concentration of ziconotide for rats is in the range of 0-6μgml(-1). Based on a molecular biological scenario of the venom action mechanism at cellular level, we suggest that the proposed method should be functional in re-establishing the normal cardiovascular parameters of the experimental animals and concomitantly it should abolish the severe pain caused by envenomation. We expect that positive experimental results in agreement with our theory will lead to the possibility of a new therapy for the Irukandji syndrome and possibly for other envenomations with similar ethyology., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Volume retention is the hallmark of progressive heart failure, both systolic and diastolic (heart failure with preserved ejection fraction). It represents the cause of the main symptoms (dyspnea, edema, liver synthesis) and also the main target of drug therapy. Antagonizing excessive volume retention is also the most important therapy element. Many patients can be stabilized with sequential nephron blockade (thiazide + loop diuretics) combined with afterload reduction [blockade of the RAAS (renin-angiotensin-aldosterone) system]. Personal patient coaching combined with telemetric components (weight, blood pressure) has evolved as another cornerstone of treatment in heart failure patients. If these measures are insufficient to control volume retention, renal replacement therapy is effective and can improve quality of life. More specifically, aquaresis via peritoneal dialysis has been shown to be effective and adequate to control volume overload. Many patients may qualify for this evolving therapy as it effectively prevents repeat hospitalization for heart failure decompensation, can be performed in an out-patient setting and has a low complication rate, thus significantly improving quality of life.

Purpose: To examine the effect of acetazolamide, known to increase cerebral blood flow (CBF) and glyceryl trinitrate (GTN), known to increase cerebral blood volume (CBV) on the blood oxygenation level-dependent (BOLD) response in humans using 3 T magnetic resonance imaging (MRI), and to evaluate how pharmacological agents may modulate cerebral hemodynamic and thereby possibly the BOLD signal., Materials and Methods: Six subjects were randomly allocated to receive acetazolamide, GTN, or placebo in a double-blind three-way crossover controlled study. Before, during, and after drug administration we recorded the BOLD response during visual stimulation with reversing checkerboard., Results: We found that acetazolamide caused significant depression of the BOLD response (P = 0.0066). The maximum decrease occurred at 5 minutes after infusion and was 51.9% (95% confidence interval [CI], 22.03-81.76). GTN did not influence the BOLD response (P = 0.55)., Conclusion: The BOLD response is decreased during increased CBF by acetazolamide, suggesting an inverse relationship between global CBF and the BOLD response. GTN does not change the BOLD response. This indicates that GTN exerts an effect on the large vessels only and that CBV changes in the microvascular system are necessary to alter the BOLD response., (Copyright © 2011 Wiley-Liss, Inc.)

Sodium nitrite (NaNO(2)) was evaluated in a 55% EBV hemorrhage swine model to mitigate the increased blood pressure due to HBOC-201. Animals were resuscitated by three 10 ml/kg infusions of either HBOC-201 or Hextend with and without NaNO(2). All vital signs, coagulation and blood chemistry were measured for 2 hr. HBOC-201-vasoconstriction was attenuated only after the first 10.8 μmol/kg NaNO(2) infusion. Complete abolition was obtained with the highest 3 NaNO(2) dose, but side effects were observed. There was no reduction in platelet function due to NaNO(2). NaNO(2) ability to reduce HBOC-201 vasoactivity was transient and 10.8 μmol/kg NaNO(2) seems an acceptable dose for further investigation.

Questions Under Study: recombinant activated factor VII (rFVIIa) is used off-label for massive bleeding. There is no convincing evidence of the benefits of this practice and the minimal effective dose is unknown. The aim of the study was to evaluate our in-house guideline recommending a low dose of 60 μg/kg for off-label use of rFVIIa., Methods: observational cohort study at the Inselspital Bern, a tertiary care University Hospital in Switzerland. All patients with massive bleeding treated off-label with rFVIIa between January 2005 and December 2007 were included. Survival, change of bleeding and transfusion rates, coagulation parameters and complications were analysed., Results: seventy-three patients received rFVIIa. Severe haemorrhage was documented by a bleeding rate of 1000 mL/h (median; interquartile range 350-3000) and total volume replacement of 11.9 L (6.6-15.2) before administration of rFVIIa. The median rFVIIa-dose was 64 μg/kg (56-71). rFVIIa was administered once in 79% patients, twice in 18%. The bleeding rate was reduced in 82% of the patients. Transfused packed red blood cells decreased from 14 units (8-22) over 4.9 h (2.5-8.8) before rFVIIa to 2 (0-6) in 24 h thereafter, platelet concentrates from 2 units (1-3) to 1 (0-2) and FFP from 11 units (6-16) to 2 (0-9). In-hospital mortality was 14% within 24 h and 32% at day 30. There were two arterial thromboembolic complications possibly related to rFVIIa., Conclusion: a single injection of 60 μg/kg rFVIIa, a lower dose than usually recommended, appears to be efficacious in controlling massive bleeding with a very low complication rate.

Light scattering in the normally white sclera prevents diagnostic imaging or delivery of a focused laser beam to a target in the underlying choroid layer. In this study, we examine optical clearing of the sclera and changes in blood flow resulting from the application of glycerol to the sclera of rabbits. Recovery dynamics are monitored after the application of saline. The speed of clearing for injection delivery is compared to the direct application of glycerol through an incision in the conjunctiva. Although, the same volume of glycerol was applied, the sclera cleared much faster (5 to 10 s) with the topical application of glycerol compared to the injection method (3 min). In addition, the direct topical application of glycerol spreads over a larger area in the sclera than the latter method. A diffuse optical spectroscopy system provided spectral analysis of the remitted light every two minutes during clearing and rehydration. Comparison of measurements to those obtained from phantoms with various absorption and scattering properties provided estimates of the absorption coefficient and reduced scattering coefficient of rabbit eye tissue.