Posttransfusion Increase of Hematocrit per se Does Not Improve Circulatory Oxygen Delivery due to Increased Blood Viscosity.

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.

Severity of non-alcoholic fatty liver disease is associated with high systemic levels of tumor necrosis factor alpha and low serum interleukin 10 in morbidly obese patients.

Morbid obesity has been shown to increase the risk to develop hepatic steatosis, also referred to as non-alcoholic fatty liver disease (NAFLD). Emerging evidence suggests that the severity of NAFLD may associate with increased serum levels of inflammatory markers as well as decreased concentration of mediators with anti-inflammatory actions, such as tumor necrosis factor alpha (TNF-α) and interleukin (IL) 10, respectively. We thus examined the serum levels of TNF-α and IL-10 in 102 morbidly obese women and men (body mass index > 40 kg/m(2)), exhibiting different grades of NAFLD. Blood glucose, glycated hemoglobin, insulin, the homeostatic model assessment of insulin resistance (HOMA-IR), total cholesterol, triglycerides, high- and low-density lipoproteins, parameters of liver function, TNF-α, and IL-10 were measured in each subject. The stage of NAFLD was estimated by abdominal ultrasound imaging. In comparison with morbidly obese subjects without steatosis, morbidly obese patients with NAFLD showed increased age (39.23 ± 9.80 years), HOMA-IR (6.74 ± 1.62), total cholesterol (219.7 ± 9.58 mg/dl), aspartate aminotransferase (36.25 ± 3.24 UI/l), gamma-glutamyl transpeptidase (37.12 ± 3.41 UI/l), and TNF-α (37.41 ± 1.72 pg/ml) as well as decreased serum levels of IL-10 (61.05 ± 2.43 pg/ml). Interestingly, the systemic levels of TNF-α increased, while IL-10 decreased in accordance with the severity of NAFLD, which supports a role for systemic inflammatory mediators in promoting steatosis progression. Further clinical prospective studies need to be addressed to elucidate the role of TNF-α and IL-10 in the development of NAFLD while also establishing their clinical utility in the assessment of morbidly obese patients at higher risk to develop severe steatosis.

Replacing the Transfusion of 1-2 Units of Blood with Plasma Expanders that Increase Oxygen Delivery Capacity: Evidence from Experimental Studies.

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.

Influence of serological factors and BMI on the blood pressure/hematocrit association in healthy young men and women.

The association between mean arterial blood pressure (MAP) and hematocrit (Hct) as a surrogate for blood viscosity was investigated in a young (average 20.0±2.3 years), healthy population of 174 men and 442 women. Health status was assessed by clinical examination and serological evaluation. Individuals with severe anemia or hemoconcentration, prior traumas or major surgical intervention, smokers, and pregnant or lactating women were excluded from the study. The MAP/Hct association was positive and significant (P=0.04) for women and negative, albeit not significantly so, for men. The MAP/Hct association was also evaluated in subgroups of the same population with a progressive step-by-step exclusion of: individuals with cholesterol >200 mg/dL; triglycerides >200 mg/dL; body mass index >25 kg/m(2); and glucose >100 mg/dL. This consecutively reduced the strength of the positive MAP/Hct association in women, which became negative - although not significantly so - when all anomalously high factors were excluded. The same trend was found in men. Our study indicates that previously reported positive trends in the relationship between the MAP and Hct in the population are not present in a young, healthy population of men or women that excludes individuals with the confounding factors of above normal serological values and BMI.

Semisynthetic hybrid biopolymers for non-pharmacological intervention of the microcirculation.

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.

Plasma expander and blood storage effects on capillary perfusion in transfusion after hemorrhage.

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.

Autoregulation and mechanotransduction control the arteriolar response to small changes in hematocrit.

Here, we present an analytic model of arteriolar mechanics that accounts for key autoregulation mechanisms, including the myogenic response and the vasodilatory effects of nitric oxide (NO) in the vasculature. It couples the fluid mechanics of blood flow in arterioles with solid mechanics of the vessel wall and includes the effects of wall shear stress- and stretch-induced endothelial NO production. The model can be used to describe the regulation of blood flow and NO transport under small changes in hematocrit and to analyze the regulatory response of arterioles to small changes in hematocrit. Our analysis revealed that the experimentally observed paradoxical increase in cardiac output with small increases in hematocrit results from the combination of increased NO production and the effects of a strong myogenic response modulated by elevated levels of WSS. Our findings support the hypothesis that vascular resistance varies inversely with blood viscosity for small changes in hematocrit in a healthy circulation that responds to shear stress stimuli. They also suggest beneficial effects independent of changes in O(2) carrying capacity associated with the postsurgical transfusion of one or two units of blood.

PEG-albumin plasma expansion increases expression of MCP-1 evidencing increased circulatory wall shear stress: an experimental study.

Treatment of blood loss with plasma expanders lowers blood viscosity, increasing cardiac output. However, increased flow velocity by conventional plasma expanders does not compensate for decreased viscosity in maintaining vessel wall shear stress (WSS), decreasing endothelial nitric oxide (NO) production. A new type of plasma expander using polyethylene glycol conjugate albumin (PEG-Alb) causes supra-perfusion when used in extreme hemodilution and is effective in treating hemorrhagic shock, although it is minimally viscogenic. An acute 40% hemodilution/exchange-transfusion protocol was used to compare 4% PEG-Alb to Ringer's lactate, Dextran 70 kDa and 6% Hetastarch (670 kDa) in unanesthetized CD-1 mice. Serum cytokine analysis showed that PEG-Alb elevates monocyte chemotactic protein-1 (MCP-1), a member of a small inducible gene family, as well as expression of MIP-1α, and MIP-2. MCP-1 is specific to increased WSS. Given the direct link between increased WSS and production of NO, the beneficial resuscitation effects due to PEG-Alb plasma expansion appear to be due to increased WSS through increased perfusion and blood flow rather than blood viscosity.

Integration of cardiovascular regulation by the blood/endothelium cell-free layer.

The cell-free layer (CFL) width separating red blood cells in flowing blood from the endothelial cell membrane is shown to be a regulator of the balance between nitric oxide (NO) production by the endothelium and NO scavenging by blood hemoglobin. The CFL width is determined by hematocrit (Hct) and the vessel wall flow velocity gradient. These factors and blood and plasma viscosity determine vessel wall shear stress which regulates the production of NO in the vascular wall. Mathematical modeling and experimental findings show that vessel wall NO concentration is a strong nonlinear function of Hct and that small Hct variations have comparatively large effects on blood pressure regulation. Furthermore, NO concentration is a regulator of inflammation and oxygen metabolism. Therefore, small, sustained perturbations of Hct may have long-term effects that can promote pro-hypertensive and pro-inflammatory conditions. In this context, Hct and its variability are directly related to vascular tone, peripheral vascular resistance, oxygen transport and delivery, and inflammation. These effects are relevant to the analysis and understanding of blood pressure regulation, as NO bioavailability regulates the contractile state of blood vessels. Furthermore, regulation of the CFL is a direct function of blood composition therefore understanding of its physiology relates to the design and management of fluid resuscitation fluids. From a medical perspective, these studies propose that it should be of clinical interest to note small variations in patient's Hct levels given their importance in modulating the CFL width and therefore NO bioavailability. WIREs Syst Biol Med 2011 3 458-470 DOI: 10.1002/wsbm.150

Nonlinear cardiovascular regulation consequent to changes in blood viscosity.

Increasing blood and plasma viscosity is generally associated with pathological conditions, and increased cardiovascular risk, a perception based in part on studies where blood viscosity is increased to extreme values attained by hemoconcentration. Present studies, supported by epidemiological studies in humans, show that moderate increases in Hct improve cardiovascular function and vice versa. This result is due to the nonlinear regulation of peripheral vascular resistance arising from the increased production of nitric oxide following the increase of shear stress on the vascular wall due to increasing blood viscosity. Similar effects are found in when plasma viscosity is increased in the extremely hemodiluted circulation. In both cases there is an effect at the arteriolar/capillary level, leading to a condition of improved microvascular function and supra perfusion that facilitates clearance of metabolic waste products, while maintaining oxygen delivery. Application of these findings to the design of viscogenic plasma expanders suggests a new approach for the treatment of hemorrhage that in part replaces the use of blood transfusions, making it feasible to lower the transfusion trigger to levels below than normally considered safe.

Microcirculatory effects of intravenous fluids in critical illness: plasma expansion beyond crystalloids and colloids.

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.

Microvascular experimental evidence on the relative significance of restoring oxygen carrying capacity vs. blood viscosity in shock resuscitation.

The development of volume replacement fluids for resuscitation in hemorrhagic shock comprises oxygen carrying and non carrying fluids. Non oxygen carrying fluids or plasma expanders are used up to the transfusion trigger, and upon reaching this landmark either blood, and possibly in the near future oxygen carrying blood substitutes, are used. An experimental program in hemorrhagic shock using the hamster chamber window model allowed to compare the relative performance of most fluids proposed for shock resuscitation. This model allows investigating simultaneously the microcirculation and systemic reactions, in the awake condition, in a tissue isolated from the environment. Results from this program show that in general plasma expanders such as Ringer's lactate and dextran 70 kDa do not sufficiently restore blood viscosity upon reaching the transfusion trigger, causing microvascular collapse. This is in part restored by a blood transfusion, independently of the oxygen carrying capacity of red blood cells. These results lead to the proposal that effective blood substitutes must be designed to prevent microvascular collapse, manifested in the decrease of functional capillary density. Achievement of this goal, in combination with the increase of oxygen affinity, significantly postpones the need for a blood transfusion, and lowers the total requirement of restoration of intrinsic oxygen carrying capacity.

Increased hematocrit and reduced blood pressure following control of glycemia in diabetes.

In this study we determine the effects of reducing blood glucose on mean arterial blood pressure (MAP) and hematocrit (Hct) in patients with type 2 diabetes who are not responding to conventional treatment in an intensive treatment program 1 year after initiation of treatment. Data on MAP, glucose and Hct was obtained from 21 diabetic type 2 individuals subjected to personalized treatment and compared (paired statistics) to pretreatment conditions. Exclusion criteria were severe retinopathy, diabetic nephropathy, amputation of diabetic foot and increased glucose>50 mg/dl. Treatment was the combined administration of glibenclamide and metformin dosed to obtain a reduction of glucose levels. Exercise and strict adherence to a prescribed diet were prescribed in all cases. One year after initiation of therapy, glucose decreased from 219 +/- 87 to 158+/-51 mg/dl (p<0.002), Hct increased from 41.6 +/- 3.2 to 44.7+/-2.9% (p<0.001) and MAP decreased from 100.6 +/- 11.0 to 94.3+/-7.2 mmHg (p<0.001). There were no statically significant changes in cholesterol and triglyceride concentrations. The patients lost weight (72.5+/-12.6 to 70.3+/-13.0 kg, p<0.001) and lowered blood creatinine concentration from 1.04+/-0.24 to 0.95+/-0.25 mg/dl, p<0.05. The increase in Hct should correspond to an increase in blood viscosity of about 12%, however blood pressure, and presumably vascular resistance, decreased by 6%. It is proposed that these effects are in part related to improved kidney function resulting in increased Hct and blood viscosity which increases vascular wall shear stress and NO bioavailability leading to a vasodilator effect.

Lowering of blood pressure by increasing hematocrit with non nitric oxide scavenging red blood cells.

Isovolemic exchange transfusion of 40% of the blood volume in awake hamsters was used to replace native red blood cells (RBCs) with RBCs whose hemoglobin (Hb) was oxidized to methemoglobin (MetHb), MetRBCs. The exchange maintained constant blood volume and produced different final hematocrits (Hcts), varying from 48 to 62% Hct. Mean arterial pressure (MAP) did not change after exchange transfusion, in which 40% of the native RBCs were replaced with MetRBCs, without increasing Hct. Increasing Hct with MetRBCs lowered MAP by 12 mm Hg when Hct was increased 12% above baseline. Further increases of Hct with MetRBCs progressively returned MAP to baseline, which occurred at 62% Hct, a 30% increase in Hct from baseline. These observations show a parabolic "U" shaped distribution of MAP against the change in Hct. Cardiac index, cardiac output divided by body weight, increased between 2 and 17% above baseline for the range of Hcts tested. Peripheral vascular resistance (VR) was decreased 18% from baseline when Hct was increased 12% from baseline. VR and MAP were above baseline for increases in Hct higher than 30%. However, vascular hindrance, VR normalized by blood viscosity (which reflects the contribution of vascular geometry), was lower than baseline for all the increases in Hct tested with MetRBC, indicating prevalence of vasodilation. These suggest that acute increases in Hct with MetRBCs increase endothelium shear stress and stimulate the production of vasoactive factors (e.g., nitric oxide [NO]). When MetRBCs were compared with functional RBCs, vasodilation was augmented for MetRBCs probably due to the lower NO scavenging of MetHb. Consequently, MetRBCs increased the viscosity related hypotension range compared with functional RBCs as NO shear stress vasodilation mediated responses are greater.

Blood pressure and hematocrit in diabetes and the role of endothelial responses in the variability of blood viscosity.

OBJECTIVE: To investigate the relationship between mean arterial blood pressure and hematocrit in a population of treated diabetic patients and a control population of healthy individuals. RESEARCH DESIGN AND METHODS: Data on hematocrit and blood pressure were obtained from 129 diabetic subjects (87 women and 42 men) and 103 healthy subjects (76 women and 27 men) enrolled in a cross-sectional study. Alcohol consumption, ischemic heart disease, stroke, neoplasia, renal, hepatic, and chronic inflammatory disease were exclusion criteria. RESULTS: The hematocrit of diabetic patients ranged from 0.35 to 0.52, and blood pressure had a bimodal distribution described by a second-order polynomial (P < 0.001), whereby elevated pressures correlated with low and high hematocrit, while the minimum average pressure was at hematocrit 0.43. Hematocrit of normal control subjects (range 0.28-0.55) was uncorrelated to blood pressure (averaged 99.7 +/- 9.7 mmHg). High blood pressure, low hematocrit diabetic subjects up to the minimum average hematocrit of 0.43 had a negative correlation (P < 0.0001) between these variables. CONCLUSIONS: Our findings are compatible with the hypothesis that diabetic patients present normal responses to hematocrit variation and therefore blood viscosity and shear stress in mediating the release of vasodilators and lack the ability to autoregulate blood pressure relative to differences in hematocrit by comparison to nondiabetic subjects. These findings also suggest that the treatment of diabetes should target maintaining an optimal hematocrit in order to lower cardiovascular risk.