Beatriz Y. Salazar Vázquez

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 Ringers 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.

The Effect of Small Changes in Hematocrit on Nitric Oxide Transport in Arterioles

We report the development of a mathematical model that quantifies the effects of small changes in systemic hematocrit (Hct) on the transport of nitric oxide (NO) in the microcirculation. The model consists of coupled transport equations for NO and oxygen (O2) and accounts for both shear-induced NO production by the endothelium and the effect of changing systemic Hct on the rate of NO production and the rate of NO scavenging by red blood cells. To incorporate the dependence of the plasma layer width on changes in Hct, the model couples the hemodynamics of blood in arterioles with NO and O2 transport in the plasma layer. A sensitivity analysis was conducted to determine the effects of uncertain model parameters (the thicknesses of endothelial surface layers and diffusion coefficients of NO and O2 in muscle tissues and vascular walls) on the models predictions. Our analysis reveals that small increases in Hct may raise NO availability in the vascular wall. This finding sheds new light on the experimental data that show that the blood circulation responds to systematic increases of Hct in a manner that is consistent with increasing NO production followed by a plateau.

Blood pressure directly correlates with blood viscosity in diabetes type 1 children but not in normals

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 21 (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.

The variability of blood pressure due to small changes of hematocrit

The hematocrit (Hct) of awake hamsters was lowered to 90% of baseline by isovolemic hemodilution using hamster plasma to determine the acute effect of small changes in Hct and blood viscosity on systemic hemodynamics. Mean arterial blood pressure increased, reaching a maximum of about 10% above baseline (8.6 +/- 5.5 mmHg) when Hct decreased 8.4 +/- 1.9% (P < 0.005). Cardiac output increased continuously with hemodilution. These conditions were reached at approximately 60 min after exchange transfusion and remained stationary for 1 h. Peripheral vascular resistance was approximately constant up to a decrease of Hct of about 10% and then fell continuously with lowering Hct. Vascular hindrance or vascular resistance independent of blood viscosity increased by about 20% and remained at this level up to an Hct decrease of 20%, indicating that the vasculature constricted with the lowered Hct. The results for the initial 2-h period are opposite but continuous with previous findings with small increases in Hct. In conclusion, limited acute anemic conditions increase mean arterial blood pressure during the initial period of 2 h, an effect that is quantitatively similar but opposite to the acute increase of Hct during the same period.

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 patients 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.

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.

Blood pressure and blood viscosity are not correlated in normal healthy subjects

The relationship between blood viscosity, hematocrit (Hct), and mean arterial blood pressure (MAP) was studied in a healthy population of 91 men and 66 women with an average age of 30.6 ± 8.0 years, from the city of Victoria de Durango (1800 m elevation). In women and men, Hct values were 42.4% ± 2.9% and 47.2% ± 2.3%, blood viscosities were 4.5 ± 0.7 and 6.1 ± 1.0 cP, and MAP was 83.0 ± 6.8 and 88.0 ± 6.1 mmHg, respectively. The correlation between blood viscosity and Hct was linear and positive (r2 = 0.48) and identical to that of previous studies reported in the literature when men and women are taken as a single group. Separating the data by gender yielded positive, linear correlations (r2 = 0.18 and 0.10, respectively) with identical slopes, however blood viscosity for men was 1.2 cP greater than in women (P = 0.02). MAP and blood viscosity (and Hct) were not statistically associated when men and women were analyzed separately and were weakly positively correlated (r2 = 0.08, P < 0.02) when treated as a group. The present results suggest that studies that show a positive correlation between MAP and blood viscosity (and Hct) do not differentiate data according to gender, or involve populations that do not compensate for increased blood viscosity and potentially increased shear stress.

Vasoactive hemoglobin solution improves survival in hemodilution followed by hemorrhagic shock

Objective: To compare survival after exchange transfusion followed by hemorrhage using: 1) the vasoactive, oxygen-carrying, bovine hemoglobin-based blood substitute Oxyglobin (Biopure, 12.9 g hemoglobin/dL); and 2) the hydroxyethyl starch plasma expander Hextend (high molecular weight and low degree of substitution, 6%). Design: Comparison between treatments. Setting: Laboratory. Subjects: Awake hamster chamber window model. Interventions: Fifty percent blood volume exchange transfusion followed by a 60% hemorrhage over 1 hr, followed by 1 hr of observation. Measurement of blood gases, mean arterial blood pressure, functional capillary density, arteriolar and venular diameter, and Po2 tension distribution. Measurements and Main Results: Survival with Oxyglobin was 100% and only 50% for the Hextend group. Vasoconstriction was evident in the microcirculation. Mean arterial pressure was higher in the Oxyglobin group. Functional capillary density was significantly reduced, although to a lesser extent by Oxyglobin. There was no difference in microvascular Po2 distribution after 1 hr of shock between groups. Conclusions: Higher mean arterial pressure during the initial stages of hemorrhage could be due to vasoconstriction in the Oxyglobin group as compared to the Hextend group. It is concluded that the pressor effect due to a vasoactive oxygen carrier may be beneficial in maintaining perfusion in conditions of severe hemodilution followed by hypovolemia.

Hematocrit and mean arterial blood pressure in pre- and postmenopause women

The relationship between mean arterial blood pressure (MAP) and hematocrit (Hct) was studied in pre- and postmenopause women in the city of Durango, Mexico. Premenopause women show a negative trend between parameters that is not statistically significant. MAP and Hct are directly related in postmenopause women (p < 0.01). It is proposed that that this MAP/Hct relationship is in part due to differences in endothelial function where menopause decreases the capacity of the endothelium to respond to increased blood viscosity and shears stress, leading to the increased production of vasodilator mediators to compensate for changes in blood viscosity due to changes in Hct. Comparison with a large group of postmenopause women in the city of Stockholm showed identical trends.