Which of the following blood vessels would have the greatest resistance to blood flow?

Poiseuille's Law and Vascular Resistance

Energy losses in flowing blood occur either as viscous losses resulting from friction or as inertial losses related to changes in the velocity or direction of flow. The termviscosity describes the resistance to flow that arises because of the intermolecular attractions between fluid layers. Fluids with particularly strong intermolecular attractions offer a high resistance to flow and have high coefficients of viscosity. Because blood viscosity increases exponentially with increases in hematocrit, the concentration of red blood cells is the most important factor affecting the viscosity of whole blood. The viscosity of plasma is determined largely by the concentration of plasma proteins. Poiseuille's law describes the viscous energy losses that occur in an idealized flow model. This law states that the pressure gradient between two points along a tube (P1−P2) is directly proportional to the mean flow velocity

or volume flow (Q), the tube length (L), and the fluid viscosity (η), and is inversely proportional to either the second or the fourth power of the radius (r):

(8.4) P1−P2=V¯8Lηr2=Q8Lηπr4.

This equation is often simplified to (pressure = flow × resistance), where the resistance term (R) is

(8.5)R=8L ηπr4.

The hemodynamic resistance of an arterial segment increases as the flow velocity increases, provided the lumen size remains constant, and these additional energy losses are related to inertial effects or changes in kinetic energy and are proportional to the square of blood velocity (Eq. 8.3).

Vascular Resistance

Vascular resistance is commonly used in the clinical setting as an index of systemic ventricular afterload. The electrical analogue for vascular resistance is described by Ohm’s law, which applies to direct electric current circuit. For a steady flow state, the vascular resistance is derived by dividing pressure gradient by volume flow. As the systemic venous pressure is very small when compared with the mean aortic pressure, the systemic arterial resistance can be approximated as mean aortic pressure divided by cardiac output. Nonetheless, as arterial blood flow is pulsatile in nature, the use of vascular resistance alone to describe afterload is deemed inadequate.

Balancing Pulmonary and Vascular Resistance (Qp:Qs)

The anesthetic management of patients with shunting lesions who are undergoing noncardiac surgery varies with the severity of the lesion. Usually there is a component of bidirectional blood flow; however, the net amount of shunting in patients without Eisenmenger syndrome is left to right. Patients with minor shunting (e.g., a small ASD and a Qp:Qs ratio < 1.5:1) will likely require only minor anesthetic adjustments. However, for all patients with a shunting lesion, care should be taken to meticulously avoid air bubbles in all IV lines, because they can result in paradoxical emboli that can lead to heart attacks and strokes. With increasing degrees of left-to-right shunting and a Qp:Qs ratio greater than 1.5:1, it is increasingly important to manage and limit pulmonary blood flow to prevent right ventricular failure secondary to volume overload.

Modifying pulmonary and systemic vascular resistance: Some congenital heart lesions (e.g., unrestricted VSDs) are very responsive to changes in the ratio of pulmonary to systemic vascular resistance. In general, drugs and maneuvers that increase systemic vascular resistance (hypothermia, sympathetic stimulation, vasoconstrictive drugs) and lower pulmonary vascular resistance will promote left-to-right shunting. The same is true for drugs (e.g., nitric oxide, milrinone) and nonpharmacologic measures that decrease pulmonary vascular resistance. Examples of such measures include hyperventilation with a high inspired oxygen concentration, alkalosis, minimizing positive pressure ventilation or positive end-expiratory pressure (opening the chest decreasesintrapulmonary pressures intraoperatively), maintaining normothermia, and lowering catecholamine levels (deep anesthesia, avoiding pain and anxiety). These measures produce higher pulmonary blood flow (improved oxygen saturation) but also have the potential to cause CHF. In contrast, measures that increase pulmonary vascular resistance (positive pressure ventilation with room air, drugs [nitrous oxide], volatile anesthetics) or that decrease systemic vascular resistance (anesthetics agents, histamine [drugs, anaphylaxis], α-blockers, ganglionic blockers) will promote a decrease in left-to-right shunting (seeTable 7.5).

Onset of IV and inhaled agents: There is ongoing but mostly academic concern that the induction of anesthesia is altered by left-to-right shunt lesions, given the brief transit time in the pulmonary circulation. However, even in patients with highly elevated pulmonary blood flow, which could theoretically dilute IV anesthetic agents and cause slow transit to the brain because of recirculation, there is usually little or no effect on induction speed. Similarly the induction speed with volatile agents is unaffected as long as cardiac output is maintained. In contrast, patients with a right-to-left shunting lesion tend to have a more rapid onset of action after IV drug administration. Because the drug bypasses the lungs, it gets relatively less diluted and reaches its targets (e.g., brain) faster and at a higher concentration than it does in patients without a shunting lesion. The reverse is true for inhaled anesthetics, which exhibit a slower induction speed as blood concentrations rise more slowly.

Vascular Resistance Profile

The vascular resistance profile in the pulmonary circuit has been estimated by micropuncture studies.57,58 In zone 3 conditions, where vascular resistance is not influenced by alveolar pressure, the majority of the resistance lies in pulmonary microvessels with nearly 50% of total resistance residing in alveolar capillaries (Fig. 6-3). These results indicate that the small pulmonary arteries and capillaries account for most of the pressure drop across the pulmonary vascular bed, a finding in striking contrast to the systemic circulation, where the arterioles account for the greatest pressure drop.

Hydraulic Pressure Profile and Vascular Resistances

The decline in hydraulic pressure between the systemic vasculature and the end of the interlobular artery in both the superficial and juxtamedullary microvasculatures can be as much as 25 mm Hg at normal perfusion pressures, with most of that pressure drop occurring along the interlobular arteries (Fig. 3.6). Based on studies of the vasculature of juxtamedullary nephrons, most of the preglomerular pressure drop between the arcuate artery and the glomerulus occurs along the afferent arteriole.30,31 Approximately 70% of the postglomerular hydraulic pressure drop occurs along the efferent arterioles. The very late portion of the afferent arteriole (last 50–150 µm) and the early portion of the efferent arteriole (first 50–150 µm) provide the major fraction of the total preglomerular and postglomerular resistance (seeFig. 3.6).30,31 Multiphoton imaging studies have indicated the presence of an intraglomerular precapillary sphincter at the terminal end of afferent arterioles (Fig. 3.7).32,33 Collectively, the total resistance (RT) consists of two major sites, the afferent (Ra) and efferent (Re) arterioles and a minor contribution from the outflowing venules and veins (Rv). Accordingly, the following relationships describe the intrarenal cortical vascular resistances:

(1)RT=Ra+Re+Rv

(2)Ra=(AP−PGC)/RBF

(3)Re=(PGC−PC)/EABF

II. Key Elements of Short-Term Blood Pressure Regulation in Humans

Mean arterial pressure (MAP) is the product of cardiac output (CO) and total peripheral resistance (TPR):

TPR is a calculated variable and only MAP and CO can be measured. Whereas measuring arterial pressure is straightforward and can be done cheaply and noninvasively (with a simple blood pressure cuff, by one person with minimal training), measuring cardiac output or even obtaining a reasonably accurate, noninvasive estimate takes significant equipment and technical skill. Implicit in the earlier equation is the idea that MAP might be regulated by changing either CO or TPR (also called vascular resistance) [1–3]. If there is an acute fall in blood pressure, physiological responses that tend to maintain or improve CO occur, and the blood vessels are constricted so that vascular resistance rises. If blood pressure is raised acutely, generally opposite directional changes occur. How does this happen?

There are sensory afferents located throughout the cardiovascular system that respond to mechanical events associated with the cardiac cycle. In general there are two main groups of mechanoreceptors that play an essential role in the beat-to-beat regulation of arterial pressure so that MAP does not swing wildly with postural changes and during activities of daily living.

The carotid sinus and aortic arch possess the so-called arterial baroreceptors (these areas also possess chemoreceptors) that are innervated by cranial nerves IX and X, respectively (Fig. 1). Mechanosensitive afferents in these areas respond to changes in arterial pressure (i.e., stretch) and evoke reflex changes in heart rate and vascular resistance when there are changes in blood pressure. The arterial baroreceptors are stimulated when blood pressure is higher, with some afferents appearing more sensitive to static distention and others to phasic deformation (pulse pressure). When stimulated, the baroreceptors send signals to the brainstem cardiovascular centers that inhibit sympathetic outflow and stimulate cardiac vagal traffic, leading to vasodilation and a slower heart rate. When arterial pressure falls, afferent traffic from the baroreceptors falls; sympathetic outflow is no longer inhibited and vagal outflow is no longer stimulated. Thus, both heart rate and sympathetic vasoconstrictor tone increase. Figure 2 is an individual record of the heart rate and muscle sympathetic nerve responses to changes in arterial pressure evoked by sequential boluses of vasodilating and constricting drugs in a volunteer subject.

The thoracic cavity, great veins, and cardiac chambers are also innervated by mechanosensitive (and chemosensitive) afferents [2,3,10,11]. At least some of these afferents sense mechanical events related to cardiac filling, and in general, when active, these afferents are sympatho-inhibitory. This means that when central blood volume is high, sympathetic outflow is reduced. In general, the cardiopulmonary afferents do not play a prominent role in the regulation of heart rate, but information from them can act centrally and modify the heart rate responses to arterial baroreceptor loading and unloading. Cardiopulmonary afferents can also modulate release of fluid-regulating hormones from the hypothalamus. When central blood volume is high the afferents are stimulated, and this inhibits the activation of fluid-retaining-hormone release and other mechanisms that conserve body fluids.

For many years it was assumed that the cardiopulmonary afferents served as an early warning system so that small reductions in central blood volume subtly deactivated the cardiopulmonary afferents and evoked increases in sympathetic outflow before the arterial baroreceptors sensed a fall in arterial pressure (Fig. 3). However, this view has been challenged by studies in humans showing that small changes in central blood volume affect mechanical events that are likely sensed by the arterial receptors (for discussion, see [11]). This highlights the difficulty of studying blood pressure regulation in humans. First, for anatomical reasons, in humans it is difficult to isolate all but the carotid receptors for selective stimulation. Second, any reflex responses evoked by “selective” activation of one afferent pool evoke changes in systemic hemodynamic variables that are sensed by the other afferent pools, which then (in turn) evoke additional compensatory responses that make it difficult to interpret the overall behavior of the system.

In summary, arterial and perhaps cardiopulmonary receptors play a key role in the short-term regulation of arterial pressure in humans. Stimulation of these receptors by stretch associated with increased arterial pressure or central blood volume inhibits sympathetic outflow to blood vessels and stimulates vagal outflow to the heart. When blood pressure falls, there is less baroreceptor afferent activity and therefore more sympathetic outflow to vessels and withdrawal of vagal tone to the heart; responses that tend to maintain or increase arterial pressure.

5.5.2 Vascular resistance

Vascular resistance is actively regulated by the vascular endothelium. The endothelium plays a central role in orchestrating the microvascular response that promotes tissue perfusion and oxygenation primarily by acting as a transducer of local shear stress (Ellis et al., 2005, Vallet, 2002). Both blood flow and viscosity are responsible for generating the shear stress sensed by the endothelium. With hemodilution blood viscosity and local shear stress are reduced, which in turn leads to vasoconstriction, maldistribution of microvascular blood flow, and tissue hypoxia (Salazar Vazquez et al., 2010). An increase in blood flow attenuates the loss of local shear stress, thus maintaining the vasodilated state in the microvasculature. However, with progressively higher levels of hemodilution, the decrease of viscosity-mediated shear stress gradually decreases the local release of vasodilators by the endothelium causing vasoconstriction and a decrease in microvascular blood flow (Tsai et al., 1998). Normalizing plasma viscosity in extreme hemodilution conditions with high-viscosity plasma expanders maintains FCD and microvascular blood flow at near normal levels (Cabrales and Tsai, 2006, Cabrales et al., 2005b, 2006, 2008, de Wit et al., 1997, Salazar Vazquez et al., 2010, Tsai and Intaglietta, 2001, Tsai et al., 1998). Maintenance of adequate microvascular blood flow and tissue oxygenation with progressive hemodilution appears to require the maintenance of a given level of shear stress at the capillary level.

A structural feature of the vascular endothelium that contributes to microvascular resistance is the glycocalyx (Pries and Secomb, 2005). The glycocalyx is an extension on the luminal side of the endothelium composed of glycoproteins, proteoglycans and plasma proteins, and forms the interface between the plasma layer of the blood and the endothelium. This structure has been shown to play an important role in a variety of vascular functions, including maintenance of vascular permeability, mediation of shear stress-dependent vasodilatation, local RBC flow distribution, and exclusion of leukocytes, platelets and cytokines from the endothelial surface (Kim et al., 2009, Levick and Michel, 2010, Pries and Kuebler, 2006, Pries and Secomb, 2005). The glycocalyx is in a dynamic equilibrium with plasma such that the thickness and composition depends on plasma composition, especially albumin levels (Pries and Secomb, 2005). Degradation of the glycocalyx results in impaired regulation of microvascular blood flow, activation of inflammatory pathways, tissue edema, and the reductions in FCD (Cabrales et al., 2007, Chappell et al., 2009, De Backer et al., 2009). Conditions known to cause degradation of the glycocalyx include inflammation, ischemia-reperfusion, acute hyperglycemia, and hemodilution (Cabrales et al., 2007, Pries et al., 1998). Loss of the endothelial glycocalyx has been associated with edema formation and renal injury in a number of clinical conditions (Henrich et al., 2010, Singh et al., 2007, Snoeijs et al., 2010, van den Berg et al., 2003).

Hemodilution decreases concentration of the plasma proteins, particualrly albumin, which are required to maintain the integrity of the glycocalyx structure (Jacob et al., 2007). Breakdown of the glycocalyx structure decreases flow resistance and enhances RBC flow (Cabrales et al., 2007, Pries and Secomb, 2005, Pries et al., 1998). Although the increase in RBC flow would appear to benefit tissue oxygenation, the observed reduction in FCD associated with the loss of the glycocalyx would suggest an overall inability to maintain or sustain microvascular blood flow, and thus be detrimental to tissue oxygenation. There is evidence of glycocalyx degradation during CPB (Rehm et al., 2007, Svennevig et al., 2008). It is unclear if the extent of hemodilution contributed to the degradation or if the degradation contributed to patient morbidity and mortality post-CPB. Further studies are required to determine the role of the glycocalyx in maintaining FCD and microvascular blood flow during hemodilution and CPB.

Intact Fish

Measuring vascular resistance in unanesthetized fish is the most technically challenging procedure. Under anesthesia, blood pressure cannulas are placed in the ventral aorta to record central arterial blood pressure (PVA), the dorsal aorta to record systemic arterial blood pressure (PDA), and the ductus Cuvier to record central venous pressure (PVEN). A flow probe is placed around the ventral aorta to measure cardiac output (Q; Figure 3). The fish is then revived and returned to the water, usually with minimal restraint, while pressure and flow parameters are measured at rest, following either injection of drugs or during other experimental manipulations such as swimming. Gill resistance (RG) is calculated from the equation RG = (PVA − PDA)/Q, and systemic resistance (RS) is calculated from the equation RS = (PDA − PVEN)/Q. Typically, all of these parameters are recorded simultaneously (Figure 4).

Role of Nitric Oxide

Basal vascular resistance, which determines the regional gastrointestinal blood flow, depends on the delicate balance between the constrictor and dilator forces that are acting upon the vascular smooth muscle. Nitric oxide is the major dilator that counterbalances the constrictive effect of the endothelin 1 and the intrinsic contractile response of smooth vascular muscle. Under basal conditions, nitric oxide is continuously produced by endothelial cell nitric oxide synthase (constitutive isoform) from l-arginine. It relaxes vascular smooth muscle by decreasing cytosolic free calcium via increased cyclic guanosine monophosphate (cGMP).24,25 In rats, acute administration of a nitric oxide synthase inhibitor (L-NNA) reduces basal intestinal blood flow.26 Nitric oxide production can increase markedly after chemical or mechanical stimulation of nitric oxide synthase (induced or stimulated isoform). Methylene blue, a guanylate cyclase inhibitor, abolishes intestinal vasodilation resulting from administration of sodium nitroprusside, a nitric oxide donor.27 After ischemia with reperfusion, exogenous nitric oxide sources (SIN-1, CAS-754, and nitroprusside) and l-arginine reduce mu­cosal barrier dysfunction without improving intestinal blood flow, suggesting that nitric oxide may have a modulating effect on microvascular permeability.28

The fetal circulation has an increased basal production of nitric oxide compared with the adult.29 In late-gestation sheep fetus, nitric oxide was shown to play an important role in contributing to low vascular resistance and increased blood flow throughout the gastrointestinal tract, as well as in redistribution of intestinal blood flow between intestinal segments.30 Inhibition of endogenous nitric oxide in midgestation fetal sheep results in substantial blood flow reduction across all segments of the gastrointestinal tract, implying that nitric oxide plays a major vasodilator role at such an early stage of gastrointestinal circulation development.31 Sustained inhibition of nitric oxide synthase in utero results in vasoconstriction of fetal blood vessels, but no evidence of injury to the gastrointestinal tract exists.32 A lack of nitric oxide synthesis appears to be causative in neonatal hypertrophic pyloric stenosis,33 but this effect is mediated by the neuronal (not the endothelial) isoform of nitric oxide synthase based on gene knockout studies.34

Blood Vessels

Total peripheral vascular resistance is decreased with pregnancy. This involves two processes, remodeling of the arterial and arteriolar walls and active vasodilation of arterioles. The degree to which veins are remodeled, or made more compliant, in response to the changing hormonal environment is controversial. Because venous distension in the legs, varicose veins, hemorrhoids and ankle swelling are common complaints in pregnant women, but not before conception or after delivery, it is obvious that veins are more compliant as an adaptation to pregnancy (Edouard et al., 1998). Edouard et al. (1998) have argued that veins in the lower extremities are more affected than those in upper extremities. This remains to be seen. What is not controversial is the increase in a number of vasoactive agents in the maternal circulation. These include estrogen, nitric oxide, relaxin, and calcitonin gene-related peptide. It has been recognized for decades that the blood pressure elevating effects of angiotensin II (Ang II) are attenuated during pregnancy. This is likely due to a decrease in the ratio of type 1 angiotensin receptors (AT1R) to type 2 (AT2R) expressed in vascular smooth muscle. It is also true that arteries in pregnant animals are less constricted by alpha adrenergic agonists than in non-pregnant animals.