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Although some of the cardiovascular responses to changes in hematocrit (Hct) are not fully quantified experimentally, available information is sufficient to build a mathematical model of the consequences of treating anemia by introducing RBCs into the circulation via blood transfusion. We present such a model, which describes how the treatment of normovolemic anemia with blood transfusion impacts oxygen (O(2)) delivery (DO(2), the product of blood O(2) content and arterial blood flow) by the microcirculation. Our analysis accounts for the differential response of the endothelium to the wall shear stress (WSS) stimulus, changes in nitric oxide (NO) production due to modification of blood viscosity caused by alterations of both hematocrit (Hct) and cell free layer thickness, as well as for their combined effects on microvascular blood flow and DO(2). Our model shows that transfusions of 1- and 2-unit of blood have a minimal effect on DO(2) if the microcirculation is unresponsive to the WSS stimulus for NO production that causes vasodilatation increasing blood flow and DO(2). Conversely, in a fully WSS responsive organism, blood transfusion significantly enhances blood flow and DO(2), because increased viscosity stimulates endothelial NO production causing vasodilatation. This finding suggests that evaluation of a patients’ pretransfusion endothelial WSS responsiveness should be beneficial in determining the optimal transfusion requirements for treating patients with anemia. NEW & NOTEWORTHY Transfusion of 1 or 2 units of blood accounts for about 3/4 of the world blood consumption of 119 million units per year, whereas a current world demand deficit is on the order of 100 million units. Therefore, factors supporting the practice of transfusing 1 unit instead of 2 are of interest, given their potential to expand the number of interventions without increasing blood availability. Our mathematical model provides a physiological support for this practice.

Compromised microcirculation and endothelial dysfunction are hallmarks of sickle cell disease (SCD). EAF PEG Haemoglobin (Hb) and EAF PEG Albumin (Alb) represent a novel class of semisynthetic colloidal supra plasma expanders that improve microcirculation. The therapeutic activity of supra plasma expanders to attenuate vaso-occlusion and restore the haemodynamic functions in patients with SCD has been investigated using NY1DD, a transgenic mouse model of mild SCD without anaemia. Vaso-occlusion and perturbation of haemodynamics are amplified in NY1DD by hypoxia-reoxygenation protocol. EAF P5K6 Alb and Alb T12 (Alb conjugated with 12 copies of antioxidant tempo) attenuate vaso-occlusion when infused at the start of reoxygenation. However, only EAF PEG Alb restores haemodynamics close to levels in control C57BL. EAF P5K6 Alb-T12, active plasma expander conjugated with antioxidant, completely clears vaso-occlusion and restores normal haemodynamics. EAF PEG Hb also completely clears vaso-occlusion and restores normal haemodynamics. Pretreating NY1DD with EAF PEG Hb protects it from hypoxia reoxygenation-induced damages. EAF P5K6 Alb T12 attenuates the endothelial dysfunction in S + S Antilles mice as reflected by the vasodilatory response of its arteries and arterioles to vaso-dilators. Active plasma expanders are novel therapeutics to restore normal haemodynamics in SCD patients to improve tissue oxygenation during episodes of painful vaso-occlusive crisis. Abbreviations: 2-IT: 2-immothiolane; Mal-T: 4-Maleimido tempo; Alb: human serum albumin (HSA); Alb-T12: human albumin conjugated with 12 copies of tempo; EAF: extension arm facilitated; EAF PEG Hb: extension arm facilitated PEGylated haemoglobin; EAF PEG Alb: extension arm facilitated PEGylated albumin; EAF P3K6 Hb: extension arm facilitated PEGylated haemoglobin conjugated with 6 copies of PEG3K; EAF P5K6 Alb T12: extension arm facilitated PEGylated albumin conjugated with 6 copies of PEG5K and 12 copies of tempo; Hb: haemoglobin; HAS: human serum albumin (Alb); PEG: polyethylene glycol; MP4: MalPEG Hb, is formulated at 4.2 g/dL in lactated Ringer's solution, a product of Sangart; SCD: sickle cell disease; NO: nitric oxide; SEC: size exclusive chromatography; Vrbc: red cell velocity; Q: volumetric flow rates, Q; SNP: sodium nitroprusside.

The effects of changing hematocrit (Hct) on the rate of circulatory oxygen ( $$\hbox {O}_2$$ ) delivery were modeled analytically to describe transfusion of 0.5–3.0 units of packed red blood cells (pRBC, 300 mL/unit, 60% Hct) to anemic patients. In our model, Hct affects $$\hbox {O}_2$$ delivery to the microcirculation by changing blood $$\hbox {O}_2$$ carrying capacity and blood viscosity, which in turn affects blood flow velocity and, therefore, $$\hbox {O}_2$$ delivery. Changing blood velocity impacts the $$\hbox {O}_2$$ delivery by affecting the oxygen diffusive losses as blood transits through the arteriolar vasculature. An increase in Hct has two opposite effects: it increases the blood $$\hbox {O}_2$$ carrying capacity and decreases the flow velocity. This suggests the existence of an optimal Hct that maximizes $$\hbox {O}_2$$ delivery. Our results show that maximal $$\hbox {O}_2$$ delivery occurs in the anemic range, where $$\text {Hct} < 39$$ %. Optimal blood management is associated with transfusing enough units up to reaching maximal $$\hbox {O}_2$$ delivery. Although somewhat complex to implement, this practice would result in both substantial blood savings and improved $$\hbox {O}_2$$ delivery.

The spatial irregularities of red blood cells (RBCs) in continuous pulsing flow condition in micro-channels were investigated by analyzing the time variability of optical signatures obtained by recording transmitted light variability at specific location in micro-flow channels. Different flow conditions were filmed and analyzed by the digital particle image velocimetry (DPIV) to characterize local flow velocity across the whole micro-channel and in four sub-areas selected to study the particles behaviors close to the walls and in the micro-channel bulk. Starting from a behavioral classification based on the three flow patterns identified as {Weak Activity, Vorticity, Alignment}, an analysis to detect the spatial irregularity in the flow distribution was carried out. The velocity gradients and four nonlinear parameters (shear rate, strain rate, vorticity, divergence) were computed from the time-varying velocity maps obtained by DPIV and used to provide a quantitative characterization of the flow features. The comparison of the results obtained in the four experiments has made possible an overall understanding of the RBC movements in different conditions and, as well, the establishment of a analysis procedure for flows spatial irregularity detection.

The US Food and Drug Administration (FDA) held a workshop on red blood cell (RBC) product regulatory science on October 6 and 7, 2016, at the Natcher Conference Center on the National Institutes of Health (NIH) Campus in Bethesda, Maryland. The workshop was supported by the National Heart, Lung, and Blood Institute, NIH; the Department of Defense; the Office of the Assistant Secretary for Health, Department of Health and Human Services; and the Center for Biologics Evaluation and Research, FDA. The workshop reviewed the status and scientific basis of the current regulatory framework and the available scientific tools to expand it to evaluate innovative and future RBC transfusion products. A full record of the proceedings is available on the FDA website (http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm507890.htm). The contents of the summary are the authors' opinions and do not represent agency policy.

© 2016 Informa UK Limited, trading as Taylor & Francis Group. There is a 0.138% incidence of adverse reactions related to blood transfusion. Transfusion-related acute lung injury, immunosuppression, fever, pathogen transmission, and hemolytic transfusion reactions are the most common ones. Synthetic oxygen carriers have been developed to deal with blood shortages and for use in the field where stored blood was not available. They were also designed to be pathogen free, including unknown viruses. In this study, we used Male Golden Syrian Hamsters implemented with a dorsal window chamber to determine how infusion of three different, genetically crosslinked recombinant acellular hemoglobin (rHb) solutions with different oxygen affinities and nitric oxide kinetics affect mean arterial pressure (MAP), heart rate (HR), kidney function, and kidney structure. We found that the administration of all three rHb solutions caused mild hypertension and bradycardia 30 minutes after infusion. However, acute changes in glomerular filtration rate (GFR) were not detected, even though histological analysis was performed 72 hours after treatment revealed some structural changes. All the rHb solutions resulted in hypertension 30 minutes after a 10% topload administration. Regardless of their properties, the presence of acellular Hb causes significant alterations to kidney tissue.

The thirteen papers included in this special section focus on new biomedical device technologies. The world of biomedical devices is certainly one industrial sector that could benefit the most from microfluidics pointof- care (POC) based diagnostics. Nowadays it is well-known the potential of the POC devices to lead the shift toward the predictive, personalized and preemptive medicine. The idea behind POC devices is to perform a diagnostic test near the patient without the need of any infrastructure and trained personnel. That entails the miniaturization of complex fluids handling, from the single cell to the multi-phase flow, sample manipulation and integrated detection. The scope of this special issue was to bring together contributions focusing on new concepts in POC devices realization and investigate on their applications.

The effects of changing hematocrit (Hct) on the rate of circulatory oxygen ([Formula: see text]) delivery were modeled analytically to describe transfusion of 0.5-3.0 units of packed red blood cells (pRBC, 300 mL/unit, 60% Hct) to anemic patients. In our model, Hct affects [Formula: see text] delivery to the microcirculation by changing blood [Formula: see text] carrying capacity and blood viscosity, which in turn affects blood flow velocity and, therefore, [Formula: see text] delivery. Changing blood velocity impacts the [Formula: see text] delivery by affecting the oxygen diffusive losses as blood transits through the arteriolar vasculature. An increase in Hct has two opposite effects: it increases the blood [Formula: see text] carrying capacity and decreases the flow velocity. This suggests the existence of an optimal Hct that maximizes [Formula: see text] delivery. Our results show that maximal [Formula: see text] delivery occurs in the anemic range, where [Formula: see text]%. Optimal blood management is associated with transfusing enough units up to reaching maximal [Formula: see text] delivery. Although somewhat complex to implement, this practice would result in both substantial blood savings and improved [Formula: see text] delivery.

Diuretics are the first choice as an antihypertensive, because of its efficacy and cost, however its mechanism of action is not well understood. The aim of this work was to analyze the hemorrheological effect of the diuretics as vasodilators in patients with newly diagnosed arterial hypertension.Patients with hypertension were given diet and exercise recommendations and 25 mg of chlorthalidone per day were prescribed; Hemoglobin/hematocrit, viscosity, and basal nitric oxide (ON) were determined at 15 and 45 days and compared with healthy subjects.We included 28 patients with average age of 48 years old; systolic blood pressure in the treated patients decreased from baseline at 15 days from 130 to 119 mm Hg and at 114 mmHg at 15 to 45 days; diastolic blood pressure decreased from baseline at 15 days from 103 to 97 mm Hg, and at 93 mmHg at 15 to 45 days. The hematocrit increased in both men and women with a statistical significance of the baseline period at 15 days, after that, it remained without significative changes. The viscosity increased similarly to the hematocrit, which conditioned the ON elevation.The increase in hematocrit due to diuretic caused an increase in blood viscosity, which led to an increase in nitric oxide, resulting in lower blood pressure.Los diuréticos son la primera elección como antihipertensivo por su eficacia y costo, sin embargo su mecanismo de acción no está bien esclarecido. El objetivo de este trabajo fue analizar el efecto hemorreológico del diurético como vasodilatador en pacientes con hipertensión arterial de reciente diagnóstico.A los pacientes con hipertensión arterial se les dieron recomendaciones de dieta, ejercicio y se prescribió 25 mg de clortalidona al día; se determinaron hemoglobina/hematocrito, viscosidad y óxido nítrico (ON) basal, a los 15 y 45 días y se compararon con sujetos sanos.Se incluyeron 28 pacientes, con edad promedio de 48 años; la presión arterial sistólica en los pacientes tratados descendió de la cifra basal a los 15 días de 130 a 119 mmHg, y a 114 mmHg de los 15 a los 45 días; la presión arterial diastólica descendió de la basal a los 15 días de 103 a 97 mmHg, y a 93 mmHg de los 15 a los 45 días . El hematocrito se incrementó en ambos géneros, con significancia estadística del período basal a los 15 días de tratamiento, posteriormente permaneció sin cambios. La viscosidad se incrementó de forma similar al hematocrito, lo que condicionó elevación del ON.El incremento del hematocrito debido al diurético causó elevación de la viscosidad sanguínea, lo que condujo a incremento del óxido nítrico, repercutiendo en el descenso de la presión arterial.

SummaryObjective Our aim is to determine the effect of paced eating, exposure to an educational programme that promotes healthy eating habits and allowing the satiety reflex to limit food intake in controlling weight gain in healthy adolescents. Methods Fifty-four healthy individuals consisting of 18 adolescent girls and 36 boys aged 12 ± 2 years were given recommendations for reducing eating rate without changing diet or meal size according to the educational programme ‘good manners for a healthy future’. Each participant was provided with a 30-s portable hourglass to pace time between bites. Individuals using and not using the hourglass were placed either into an ‘adhering’ or a ‘non-adhering’ group, respectively. Control data were obtained from a similar population. Results Initially, the adhering group had higher weight compared with the non-adhering group (64.1 ± 13.2 vs. 56.2 ± 11.7 kg). Control group weight was no different from the study group at baseline (56.3 ± 10.3 kg). Weight in the adhering group decreased after the first semester of participation by 2.0 ± 5.7% and after a year by 3.4 ± 4.8%, while the non-adhering group gained weight by 5.8 ± 4.5% and 12.6 ± 8.3%. The control group increased weight after a year by 8.2 ± 6.5%. In total, 18 non-adhering and 14 adhering adolescents completed the study. Conclusions This 1-year study shows a statistically significant association between rate of food intake and weight control in adherence to an educational programme directed at developing healthy eating habits. The proposed behavioural training may serve as an option for weight control in adolescents.

Oxygen delivery capacity during profoundly anemic conditions depends on blood's oxygen-carrying capacity and cardiac output. Oxygen-carrying blood substitutes and blood transfusion augment oxygen-carrying capacity, but both have given rise to safety concerns, and their efficacy remains unresolved. Anemia decreases oxygen-carrying capacity and blood viscosity. Present studies show that correcting the decrease of blood viscosity by increasing plasma viscosity with newly developed plasma expanders significantly improves tissue perfusion. These new plasma expanders promote tissue perfusion, increasing oxygen delivery capacity without increasing blood oxygen-carrying capacity, thus treating the effects of anemia while avoiding the transfusion of blood.

Shear stress generated by blood flow is transmitted to endothelial cells lining blood vessels through the cell free layer at the blood/vessel interface, consisting of a blood plasma zone and the glycocalyx, a gel-like lining of the endothelium, composed of polysaccharides attached to the cell wall. This multilayered system determines how flow is sensed and converted into biochemical responses by the endothelium by mechanotransduction. Analysis of flow profiles in this system using particle velocimetry is not possible since the gel-like structure affects particle trajectories, precluding obtaining information on shear stress. Likewise using numerical simulations of flow and transport is not viable for fully resolving the mechanical effects within the glycocalyx and their transmission to the endothelial surface, and understanding how shear stress is sensed by the endothelium requires complex and expensive in vivo and in vitro experimentation. Equivalent microfluidic models/circuits would allow to explicitly study the impact of glycocalyx topology on shear stress in controlled systems at a fraction of the cost. We propose a continuum scale model that treats the glycocalyx as a porous medium with known porosity and permeability, while accounting for varying blood viscosity. The model is amenable to analytical solution for the time-averaged velocity profile within and above the glycocalyx, and its predictions match in vivo data, providing a framework to design microfluidic systems using micro patterns designed to simulate the macroscopic effects of the biological glycocalyx.

BACKGROUND: Blood transfusion is used to treat acute anemia with the goal of increasing blood oxygen-carrying capacity as determined by hematocrit (Hct) and oxygen delivery (DO2). However, increasing Hct also increases blood viscosity, which may thus lower DO2 if the arterial circulation is a rigid hydraulic system as the resistance to blood flow will increase. The net effect of transfusion on DO2 in this system can be analyzed by using the relationship between Hct and systemic blood viscosity of circulating blood at the posttransfusion Hct to calculate DO2 and comparing this value with pretransfusion DO2. We hypothesized that increasing Hct would increase DO2 and tested our hypothesis by mathematically modeling DO2 in the circulation. METHODS: Calculations were made assuming a normal cardiac output (5 L/min) with degrees of anemia ranging from 5% to 80% Hct deficit. We analyzed the effects of transfusing 0.5 or more units of 300 cc of packed red blood cells (PRBCs) at an Hct of 65% and calculated microcirculatory DO2 after accounting for increased blood viscosity and assuming no change in blood pressure. Our model accounts for O2 diffusion out of the circulation before blood arriving to the nutritional circulation and for changes in blood flow velocity. The immediate posttransfusion DO2 was also compared with DO2 after the transient increase in volume due to transfusion has subsided. RESULTS: Blood transfusion of up to 3 units of PRBCs increased DO2 when Hct (or hemoglobin) was 60% lower than normal, but did not increase DO2 when administered before this threshold. CONCLUSIONS: After accounting for the effect of increasing blood viscosity on blood flow owing to increasing Hct, we found in a mathematical simulation of DO2 that transfusion of up to 3 units of PRBCs does not increase DO2, unless anemia is the result of an Hct deficit greater than 60%. Observations that transfusions occasionally result in clinical improvement suggest that other mechanisms possibly related to increased blood viscosity may compensate for the absence of increase in DO2.

The key points in the design of microfluidic Lab-On-a-Chips for blood tests are the simplicity of the microfluidic chip geometry, the portability of the monitoring system and the ease on-chip integration of the data analysis procedure. The majority of those, recently designed, have been used for blood separation, however their introduction, also, for pathological conditions diagnosis would be important in different biomedical contexts. To overcome this lack is necessary to establish the relation between the RBCs flow and blood viscosity changes in micro-vessels. For that, the development of methods to analyze the dynamics of the RBCs flows in networks of micro-channels becomes essential in the study of RBCs flows in micro-vascular networks. A simplification in the experimental set-up and in the approach for the data collection and analysis could contribute significantly to understand the relation between the blood non-Newtonian properties and the emergent behaviors in collective RBCs flows. In this paper, we have investigated the collective behaviors of RBCs in a micro-channel in unsteady conditions, using a simplified monitoring set-up and implementing a 2D image processing procedure based on the digital particle image velocimetry. Our experimental study consisted in the analysis of RBCs motions freely in the micro-channel and driven by an external pressure. Despite the equipment minimal complexity, the advanced signal processing method implemented has allowed a significant qualitative and quantitative classification of the RBCs behaviors and the dynamical characterization of the particles velocities along both the horizontal and vertical directions. The concurrent causes for the particles displacement as the base solution-particles interaction, particle-particle interaction, and the external force due to pressure gradient were accounted in the results interpretation. The method implemented and the results obtained represent a proof of concept toward the realization of a general-purpose microfluidic LOC device for in-vitro flow analysis of RBCs collective behaviors.

The design of microfluid Lab-On-a-Chip for blood tests requires the simplicity of chip, the portability of the monitoring system and the easy data analysis procedure. In this work is presented a method to investigate the red blood cells (RBCs) collective behavior in a micro-channel, by using a simplified set-up and implementing an analysis procedure based on digital particle image velocimetry (DPIV). The method adopted and the results obtained represent a proof of concept toward the realization of a general-purpose microfluidic LOC device for in-vitro analysis of RBCs flow.

Objective: Our primary goal is to investigate the effects of nonNewtonian blood properties on wall shear stress in microvessels. The secondary goal is to derive a correction factor for the Poiseuillelaw-based indirect measurements of wall shear stress. Methods: The flow is assumed to exhibit two distinct, immiscible and homogeneous fluid layers: an inner region densely packed with RBCs, and an outer cell-free layer whose thickness depends on discharge hematocrit. The cell-free layer is assumed to be Newtonian, while rheology of the RBC-rich core is modeled using the Quemada constitutive law. Results: Our model provides a realistic description of experimentally observed blood velocity profiles, tube hematocrit, core hematocrit, and apparent viscosity over a wide range of vessel radii and discharge hematocrits. Conclusions: Our analysis reveals the importance of incorporating this complex blood rheology into estimates of WSS in microvessels. The latter is accomplished by specifying a correction factor, which accounts for the deviation of blood flow from the Poiseuille law.

At least a third of the blood supply in the world is used to transfuse 1–2 units of packed red blood cells for each intervention and most clinical trials of blood substitutes have been carried out at this level of oxygen carrying capacity (OCC) restoration. However, the increase of oxygenation achieved is marginal or none at all for molecular hemoglobin (Hb) products, due to their lingering vasoactivity. This has provided the impetus for the development of “oxygen therapeutics” using Hb-based molecules that have high oxygen affinity and target delivery of oxygen to anoxic areas. However it is still unclear how these oxygen carriers counteract or mitigate the functional effects of anemia due to obstruction, vasoconstriction and under-perfusion. Indeed, they are administered as a low dosage/low volume therapeutic Hb (subsequently further diluted in the circulatory pool) and hence induce extremely small OCC changes. Hyperviscous plasma expanders provide an alternative to oxygen therapeutics by increasing the oxygen delivery capacity (ODC); in anemia they induce supra-perfusion and increase tissue perfusion (flow) by as much as 50%. Polyethylene glycol conjugate albumin (PEG-Alb) accomplishes this by enhancing the shear thinning behavior of diluted blood, which increases microvascular endothelial shear stress, causes vasodilation and lowering peripheral vascular resistance thus facilitating cardiac function. Induction of supra-perfusion takes advantage of the fact that ODC is the product of OCC and blood flow and hence can be maintained by increasing either or both. Animal studies suggest that this approach may save a considerable fraction of the blood supply. It has an additional benefit of enhancing tissue clearance of toxic metabolites.

The microcirculation presents functional organic structures in the range of 1-100 micrometers, commensurate with the upper end of nanotechnology constructs. When devices are designed and deployed to deliver treatment via the circulation they ultimately contend with the smallest dimensions of both healthy and impaired microvessels, particularly the capillary system whose ability to sustain the tissue is assessed by measuring "functional capillary density" (FCD). FCD is directly determined by hydrostatic and osmotic pressures and indirectly by the effect of cardiovascular regulators, particularly the bioavailability of nitric oxide (NO) resulting from fluid mechanical effects and transport in the submicroscopic cell free plasma layer (CFL) located between blood and microvascular wall. Macromolecules using colloids as templates that are surface decorated with polyethylene glycol (PEG) become immuno-invisible and can be introduced into the circulation to manipulate the NO environment in blood and the endothelium. PEG-albumin is a class of molecules with novel plasma expansion properties that directly interacts with the microcirculation via CFL related effects. The principal application of this technology is in transfusion medicine and the plasma expanders used to treat blood losses and concomitant effects on microvascular function due to related acute inflammatory conditions and ischemia.

Background: Free tissue transplantations are lengthy procedures that result in prolong tissue ischemia. Restoral of blood flow is essential for free flap recovery; however, upon reperfusion tissue that is viable may continue to be nonperfused. To further elucidate this pathophysiology skeletal muscle microcirculation was investigated during reperfusion following 4-hour single arteriole occlusion. Materials and methods: A blunt micropipette probe was use to compress a single arteriole in the unanesthetized hamster (N = 20) dorsal skinfold chamber. Arteriole (n = 20), capillary (n = 97), and postcapillary venule (n = 16) diameters and blood flow were analyzed at 0, 30, 60, 120, 240 min and 24 hours of reperfusion after 4 hour occlusion. Results: Feeding arcade arterioles exhibited a brief (

We studied the extreme hemodilution to a hematocrit of 11% induced by three plasma expanders: polyethylene glycol (PEG)-conjugated albumin (PEG-Alb), 6% 70-kDa dextran, and 6% 500-kDa dextran. The experimental component of our study relied on microelectrodes and cardiac output to measure both the rheological properties of plasma-expander blood mixtures and nitric oxide (NO) bioavailability in vessel walls. The modeling component consisted of an analysis of the distribution of wall shear stress (WSS) in the microvessels. Our experiments demonstrated that plasma expansion with PEG-Alb caused a state of supraperfusion with cardiac output 40% above baseline, significantly increased NO vessel wall bioavailability, and lowered peripheral vascular resistance. We attributed this behavior to the shear thinning nature of blood and PEG-Alb mixtures. To substantiate this hypothesis, we developed a mathematical model of non-Newtonian blood flow in a vessel. Our model used the Quemada rheological constitutive relationship to express blood viscosity in terms of both hematocrit and shear rate. The model revealed that the net effect of the hemodilution induced by relatively low-viscosity shear thinning PEG-Alb plasma expanders is to reduce overall blood viscosity and to increase the WSS, thus intensifying endothelial NO production. These changes act synergistically, significantly increasing cardiac output and perfusion due to lowered overall peripheral vascular resistance.

BACKGROUND: Treating hemorrhage with blood transfusions in subjects previously hemodiluted with different colloidal plasma expanders, using fresh autologous blood or blood that has been stored for 2 weeks, allows identifying the interaction between type of plasma expander and differences in blood storage. STUDY DESIGN AND METHODS: Studies used the hamster window chamber model. Fresh autologous plasma, 130-kDa starch-based plasma expander (hydroxyethyl starch [HES]), or 4% polyethylene glycol–conjugated albumin (PEG-Alb) was used for 20% of blood volume (BV) hemodilution. Hemodilution was followed by a 55% by BV 40-minute hemorrhagic shock period, treated with transfusion of fresh or blood that was stored for 2 weeks. Outcome was evaluated 1 hour after blood transfusion in terms of microvascular and systemic variables. RESULTS: Results were principally dependent on the type of colloidal solution used during hemodilution, 4% PEG-Alb yielding the best microvascular recovery evaluated in terms of the functional capillary density. This result was consistent whether fresh blood or stored blood was used in treating the subsequent shock period. Fresh blood results were significantly better in systemic and microvascular terms relative to stored blood. HES and fresh plasma hemodilution yielded less favorable results, a difference that was enhanced when fresh versus stored blood was compared in their efficacy of correcting the subsequent hemorrhage. CONCLUSION: The type of plasma expander used for hemodilution influences the short-term outcome of subsequent volume resuscitation using blood transfusion, 4% PEG-Alb providing the most favorable outcome by comparison to HES or fresh plasma.

Cell free layer (CFL), a plasma layer bounded by the red blood cell (RBC) core and the endothelium, plays an important physiological role. Its width affects the effective blood viscosity as well as the scavenging and production of nitric oxide (NO). Measurements of the CFL and its spatio-temporal variability are highly uncertain, exhibiting random fluctuations. Yet traditional models of blood flow and NO scavenging treat the CFL's bounding surfaces as deterministic and smooth. We investigate the effects of the endothelium roughness and uncertain (random) spatial variability on blood flow and the estimates of effective blood viscosity.

Background: Infusion of large volume of fluid is practiced in the treatment of hemorrhagic shock although resuscitation with small fluid volumes reduces the risks associated with fluid overload. We explored the hypothesis that reduced Ringer's lactate (RL) volume restoration in hemorrhage is significantly improved by increasing its viscosity, leading to improved microvascular conditions. Methods: Awake hamsters were subjected to a hemorrhage of 50% of blood volume followed by a shock period of 1 hour. They were resuscitated with conventional RL (n = 6) or with RL whose viscosity was increased by the addition of 0.3% alginate (RL-HV) (n = 6). In both cases, the volume infused was 200% of shed blood. Results: After resuscitation, blood and plasma viscosities were 1.9 cp ± 0.18 cp and 1.0 cp ± 0.03 cp in RL and 2.5 cp ± 0.34 cp and 1.6 cp ± 0.05 cp in RL-HV. Mean arterial pressure was lower than baseline in RL. Arteriolar diameter and arteriolar and venular flow were significantly higher in RL-HV. Functional capillary density was significantly higher in RL-HV than RL. After 90 minutes of resuscitation, functional capillary density was lower than baseline in RL, whereas it was maintained in RL-HV. Arteriolar Po2 was higher in RL-HV than RL. Microcirculation O2 delivery and tissue Po2 were significantly higher in RL-HV. Conclusions: Increasing blood and plasma viscosities in resuscitation from hemorrhagic shock with increased viscosity RL improves microvascular hemodynamics and oxygenation parameters.

The effect of low and high viscosity hemodilution with plasma expanders on the extent of the cell free layer (CFL) width was analyzed in the microcirculation of the exteriorized cremaster muscle preparation of Sprague-Dawley male rats. Anesthetized animals were subjected to 40% hemodilution by blood volume, using 5% human serum albumin (HSA) or 6% Hetastarch (hydroxyethyl starch 670 kDa). Arterioles (n=5 for each treatment) were investigated. Mean arterial pressure, heart rate, vessel flow velocity and CFL width were measured at baseline and 5, 20 and 40 min post-exchange transfusion. Blood and plasma viscosity was determined from terminal blood collections. CFL width and pseudoshear rate, diameter and flow, normalized to baseline, were significantly elevated at all post-exchange assessments. Peripheral vascular resistance decreased. The increase of the CFL width was greater with HSA by comparison with Hetastarch hemodilution (p

Objective: To determine the relationship between mean arterial blood pressure (MAP) and blood viscosity in diabetic type 1 children and healthy controls to investigate whether MAP is independent of blood viscosity in healthy children, and vice versa. Research design and methods: Children with diabetes type 1 treated by insulin injection were studied. Controls were healthy children of both sexes. MAP was calculated from systolic and diastolic pressure measurements. Blood viscosity was determined indirectly by measuring blood hemoglobin (Hb) content. The relationship between Hb, hematocrit (Hct) and blood viscosity was determined in a subgroup of controls and diabetics selected at random. Results :2 1 (10.6 ± 2.5 years) type 1 diabetic children treated with insulin and 25 healthy controls age 9.6 ± 1.7 years were studied. Hb was 13.8 ± 0.8 g/dl in normal children vs. 14.3 ± 0.9 g/dl in the diabetic group ( p< 0.05). MAP was 71.4 ± 8.2 in the normal vs. 82.9 ± 7.2 mmHg in the diabetic group ( p< 0.001). Glucose was 89.3 ± 10.6 vs. 202.4 ± 87.4 mg/dl respectively. Diabetics had a positive MAP/Hb correlation (p = 0.007), while normals showed a non significant (p = 0.2) negative correlation. The blood viscosity/Hb relationship was studied in a subgroup of 8 healthy controls and 8 diabetic type 1 children. There was no significant difference in Hb and Hct between groups. Diabetics showed a trend of increasing blood viscosity (+7%, p = 0.15). Conclusions: Normal children compensate for the increase in vascular resistance due to increased blood viscosity (increased Hb and Hct) while diabetic children do not, probably due to endothelial dysfunction.

Introduction This study analyzed the systemic and microvascular hemodynamic changes related to increased nitric oxide (NO) availability during the early phase of hemorrhagic shock. Hemodynamic responses to hemorrhagic shock were studied in the hamster window chamber. Materials and Methods Exogenous NO was administered in the form of nitrosothiols (nitrosylated glutathione, GSNO) and was given prior the onset of hemorrhage. Moderate hemorrhage was induced by arterial controlled bleeding of 50% of the blood volume, and the hypovolemic shock was followed over 90 min. Results Animals pre-treated with GSNO maintained systemic and microvascular conditions during hypovolemic hemorrhagic shock, when compared to animal treated with glutathione (GSH) or the Sham group. Low concentrations of NO released during the early phase of hypovolemic shock from GSNO mitigated arteriolar vasoconstriction, increased capillary perfusion and venous return, and improved cardiac function (recovered of blood pressure and stabilized heart rate). GSNO's effect on resistance vessels influenced intravascular pressure redistribution and blood flow, preventing tissue ischemia. Discussion Increases in NO availability during the early phase of hypovolemic shock could preserve cardiac function and microvascular perfusion, sustaining organ function. Direct translation into a clinical scenario may be limited, although the pathophysiological importance of NO in the early phase of hypovolemia is clearly highlighted here.

Purpose of review: Plasma expanders are reviewed to determine their ability to restore microvascular function as a means for extending the transfusion trigger and delaying the use of blood transfusions. This outcome is currently achievable because of the emergence of a new understanding of optimal tissue function that prioritizes maintenance of functional capillary density, which results from the normalization of blood viscosity via the increase in plasma viscosity with new viscogenic colloids. Recent findings: Use of viscous plasma expanders in experimental models of extreme hemodilution, hemorrhagic shock and endotoxemia shows that the limiting factor in anemia is not oxygen-carrying capacity but the decline of microvascular function due to the lowering of functional capillary density. In support of this hypothesis, we find that viscogenic colloids including high-molecular-weight starches, dextrans, polyvinylpyrrolidone, keratin and polyethylene glycol-conjugated albumin maintain or restore microvascular function in extreme hemodilution, polyethylene glycol-conjugated albumin yielding the best results. Summary: Preclinical studies show that polyethylene glycol-conjugated albumin at concentrations in the range of 2-4% extends the transfusion trigger, providing the more extended and complete microvascular and systemic recovery from hemorrhagic shock, extreme hemodilution and endotoxemia, postponing the need of reestablish intrinsic blood oxygen-carrying capacity to hemoglobin concentrations lower than those associated with accepted transfusion triggers.

Systemic and microvascular hemodynamic responses to hemorrhagic shock volume resuscitation with hypertonic saline followed by infusion of polymerized bovine hemoglobin (PBH) at different concentrations were studied in the hamster window chamber model to determine the role of plasma oxygen-carrying capacity and vasoactivity during resuscitation. Moderate hemorrhagic shock was induced by arterial controlled bleeding of 50% of blood volume (BV), and a hypovolemic state was maintained for 1 h. Volume was restituted by infusion of hypertonic saline (7.5% NaCl), 3.5% of BV, followed by 10% of BV of PBH at 2 different concentrations. Resuscitation was followed for 90 min and was carried out using 13 gPBH/dL (PBH13), PBH diluted to 4 gPBH/dL in albumin solution at matching colloidal osmotic pressure (PBH4), and an albumin-only solution at matching colloidal osmotic pressure (PBH0). Systemic parameters, microvascular hemodynamics, and functional capillary density were determined during hemorrhage, hypovolemic shock, and resuscitation. The PBH13 caused higher arterial pressure without reverting vasoconstriction and hypoperfusion. The PBH4 and PBH0 had lower MAP and partially reverted vasoconstriction. Only treatment with PBH4 restored perfusion and functional capillary density when compared with PBH13 and PBH0. Blood gas parameters and acid-base balance recovered proportionally to microvascular perfusion. Tissue PO2 was significantly improved in the PBH4 group, showing that limited restoration of oxygen-carrying capacity is beneficial and compensates for the effects of vasoactivity, a characteristic of molecular hemoglobin solutions proposed as blood substitutes.

This review discusses the cell-free layer at the wall of the microcirculatory vessels with emphasis on the influence of blood rheological parameters on its formation as well as its possible effects on microvascular functions. Understanding cell-free layer characteristics in the microcirculation has been of increased interest for its possible influence on physiological function. The availability of better imaging and measurement techniques in recent years has created an excellent opportunity for researchers to examine the cell-free layer in much greater detail than possible previously. The most recent approach enables capturing spatial and temporal information of cell-free layer characteristics which can provide new insights to how cell-free layer width and its variations can impact physiological function. Cell-free layer formation is dependent on diameter of the vessel, flow rate, and rheological properties of blood including hematocrit, red blood cell aggregation, and deformability. Specifically in microvessels, its formation can also be affected by the presence of the glycocalyx layer that lines the luminal surface of the vessel wall. As the cell-free layer is omnipresent in microcirculatory vessels, its formation at the vessel wall could affect function throughout the microvascular network by altering wall shear stress, local hematocrit, flow distribution, effective viscosity and nitric oxide production as well as its scavenging by red blood cells.

Ischemia reperfusion (IR) injury, occurring during heart attacks, hemorrhagic shock, and bypass and transplant surgeries, impairs microcirculatory function and nitric oxide (NO) synthesis. We report the regulation of endothelial and inducible NO synthase (eNOS and iNOS) proteins as a consequence of the application of continuous mode diagnostic frequency ultrasound application following IR injury.Animals were assigned to one of five groups for microcirculatory assessment or Western blot analysis (WB) as follows: (1) IR+iNOS inhibition (1400W); and (2) IR+1400W+ultrasound for microcirculatory assessment, (3) Control; (4) IR; and (5) IR+ultrasound for WB. Functional capillary density and microvascular diameter, flow velocity, and flow were monitored for microcirculatory assessment. Skin tissue samples were harvested for WB. 2.49MHz continuous ultrasound was used for application.Both the inhibition of iNOS alone and iNOS inhibition with ultrasound irradiation positively influenced the microcirculation of observed animals relative to baseline values. Ultrasound exposure resulted in a significant production of eNOS protein in skin tissue harvested 24h into reperfusion (p0.01). iNOS levels from the same tissue of ultrasound exposed animals were found to be significantly decreased 0.5h into reperfusion (p0.05).Protection from lasting IR injury effects in the microcirculation, with continuous mode diagnostic frequency ultrasound, results from augmented eNOS protein levels during late reperfusion. Ultrasound inhibited iNOS protein production during early reperfusion may also confer protection from IR injury.