205CHAPTER 24 Regional Peripheral Circulation Changes in vascular tone may alter the maximum venous re turn (and thus cardiac output) attainable before venous collapse (Pc) at any given intravascular[.]
CHAPTER 24 Regional Peripheral Circulation 205 Qmax a b n sio sfu an Tr on a ti Dil l n sa io e Ba ct ag tri rrh ns mo Co He Q Qpump c d e Pc PRA Pm • Fig 24.4 Venous return curve As pump flow (Qpump) varies, right atrial pressure (Pra) is altered by redistribution of blood between arteries and veins Qpump cannot be increased above Qmax because Pra would fall below critical closing pressure (Pc) of the venous circulation Pm, Mean circulatory pressure of the vasculature at no flow Pc curve Pm II Pm PRA • Fig 24.6 Effects of changing blood volume and microvascular resistance on the venous return curve Curves a, c, and e are parallel but have different mean circulatory pressure (Pm) at zero flow Curves b, c, and d are nonparallel but have the same Pm Pc, Critical closing pressure; PRA, right atrial pressure r tu re us no Ve Q rling Sta I Pm n cu e rv PRA • Fig 24.5 Theoretical superimposition of venous return and Starling curves For any state of the heart and vasculature, these curves intersect at a point that characterizes right atrial pressure (Pra) and cardiac output (Q) Changes in vascular tone may alter the maximum venous return (and thus cardiac output) attainable before venous collapse (Pc) at any given intravascular volume At zero flow, the mean pressure in the system would relate most directly to the volume of blood within the vessels Thus, changes in vascular tone change the slope of the venous return curve (see Fig 24.6) In clinical practice, it is unusual for any of these changes in vascular mechanics to occur in isolation For instance, arteriolar dilation and dilation of other capacitance vessels often occur together Arteriolar dilation and dilation of capacitance vessels have opposite effects on the venous return curve and, consequently, different effects on cardiac output It is for this reason that vascular volume expansion is often required in combination with nitroprusside or milrinone infusions in order to ensure adequacy of cardiac output despite a reduction in afterload In patients with sepsis, intravascular volume, venous capacitance, vascular resistance, and the inotropic state of the heart can all profoundly influence cardiac output Descriptions of shock as “warm” or “cold” relate directly to the interaction of these factors For example, patients with warm shock often demonstrate adequate contractility with low vascular tone, whereas patients with cold shock may have poor contractility with increased or decreased vascular tone As such, assessments of intravascular volume are important to help guide management Critical Closing Pressure In many organs as inflow pressure is lowered, Q decreases and ceases at a pressure—the critical closing pressure (Pc)—that is higher than venous pressure The probable mechanism is the vascular waterfall or Starling resistor In 1910, Jerusalem and Starling2 described a device designed to control afterload to the left ventricle and that made possible the study of cardiac contractility.4 The device consisted of a collapsible rubber tube traversing a pressurized glass chamber (Fig 24.7) When pressure surrounding the rubber tube exceeded the outflow pressure set by the reservoir, surrounding pressure opposed the flow of blood and became the true outflow pressure of the device The physiologic counterpart of this occurs in small vessels surrounded by tissue pressure In the heart, for example, a Starling resistor effect occurs in extramyocardial coronary veins, although there is also evidence for critical closure of small arterioles No one has yet demonstrated vessel closure directly However, this might not be necessary because, as 206 S E C T I O N I V Pediatric Critical Care: Cardiovascular where R is resistance, l is tube length, r is the internal radius of the tube, and h is the fluid viscosity Blood is not a Newtonian fluid, but this fact does not affect the accuracy of calculated vascular resistance much However, vascular beds contain many “tubes” in parallel Thus, for vascular systems, a factor k is added that represents the number of vessels The equation then becomes Ps Pi Q Po • Fig 24.7 The Starling resistor is a compressible conduit exposed to surrounding pressure (Ps) When the Ps is less than the outflow pressure (Po), Ps does not oppose blood flow When the Ps is between inflow (Pi) and outflow pressures, it opposes blood flow No flow is possible when Ps exceeds Pi small vessels narrow when they are compressed, the wall becomes convoluted and blood cells might become obstructed by the folds even when externally the vessel does not appear to be closed Autoregulation In all organs, when inflow pressure is suddenly raised or lowered while oxygen (O2) consumption remains constant, flow rises or falls transiently but then returns to its former value; the phenomenon is termed autoregulation Several mechanisms, particularly related to O2 sensing, have been implicated in this response, but the precise mechanisms are likely complex and multifactorial For example, studies have described a role for nitric oxide (NO) carried to the tissues by hemoglobin in the form of S-nitrosohemoglobin.5–7 Other locally produced gases, such as hydrogen sulfide8 and carbon monoxide,9,10 may also play a role Importantly, some autoregulatory mechanisms are specific to individual microcirculations (e.g., macula densa signaling in the renal circulation) Distensibility and Compliance The distensibility of a vessel is defined as the change in volume as a proportion of the initial volume for a given change in pressure: Distensibility V P V where V is volume and P is pressure Veins are much thinner than arteries and are about eight times more distensible Multiplying distensibility by volume yields DV/DP, which is the definition of compliance Because venous volume is usually more than three times arterial volume, venous compliance is about 20- to 30-fold greater than arterial compliance As a result, whenever fluids are infused, the veins accommodate the bulk of the fluid volume Vascular Resistance Under normal circumstances, vascular resistance is the major control of organ flow and can be understood by considering the resistance of a Newtonian liquid passing through a rigid tube as defined by the Hagen-Poiseuille equation: 8 1 R r 8 R kr Because the length and number of vessels and blood viscosity are relatively constant at any one time, change in vessel radius is the major factor responsible for a dynamic change in vascular resistance Because of the fourth power factor, small changes in radius cause large changes in resistance Vessel radius is influenced by vascular elasticity and transmural pressure but is mainly regulated by changes in vessel wall smooth muscle tone Vascular Impedance Resistance is strictly a steady-state concept In a pulsatile system, the factors affecting the relationship of pressure dissipation to flow are resistance due to friction and viscosity, fluid inertia, and vessel wall compliance, which combine to produce an impedance to flow that varies with frequency At zero frequency, steady-state resistance is approximated by the change in mean pressure overflow, but there are substantial contributions made by the first three harmonics that are ignored by this calculation Local Regulatory Mechanisms Regions of the circulation may differ markedly in their patterns of vascular regulation A regulatory stimulus can have multiple effects that differ from one location to another An agent that potently regulates vascular resistance in one region of the circulation may have no effect in another For example, during hemorrhagic shock, flow is preserved to the heart and brain at the expense of muscle, the kidneys, and the gut Vascular tone is strongly influenced by several mechanisms: (1) innervation and neural processes, (2) circulating endocrine and neuroendocrine mediators, (3) local metabolic products, (4) blood gas composition, (5) endothelial-derived factors, and (6) myogenic processes Innervation and Neural Processes Receptors responsive to neural products (e.g., norepinephrine and acetylcholine) are found throughout the circulation Nevertheless, innervation and receptor distribution are organ specific, allowing rapid patterned, coordinated redistribution of blood flow and an orchestrated response to events, such as hypoxia, changes in posture, and hemorrhage Although these receptors respond to circulating agonists (including adrenal epinephrine), as well as to those liberated locally, they are generally associated with innervation by autonomic nerves In general, presynaptic a-adrenergic stimulation causes norepinephrine reuptake, whereas postsynaptic a-adrenergic stimulation causes norepinephrine release and vasoconstriction b-Adrenergic stimulation generally causes vasodilation Cholinergic stimulation (whether sympathetic or parasympathetic) generally causes vasodilation (see Chapters 31 and 123) Circulating Endocrine and Neuroendocrine Mediators Humoral regulators of vascular tone include angiotensin, arginine vasopressin, bradykinin, histamine, and serotonin Of less certain CHAPTER 24 Regional Peripheral Circulation significance are aldosterone, thyroxine, antinatriuretic peptide, and various reproductive hormones Most of these have both direct effects and secondary effects, which tend to be organ specific or regional in nature Angiotensin plays a special role in the homeostasis of blood pressure and is produced in hemorrhagic or hypovolemic shock It causes generalized vasoconstriction in both systemic and pulmonary circulations; however, locally, it stimulates the release of vasodilating prostaglandins in the lungs and kidney Bradykinin is a potent pulmonary and systemic vasodilator released locally by the action of proteolytic enzymes on kallikrein after tissue injury Histamine is released by mast cells in response to injury and is also a potent vasodilator in most regions of the circulation, but it causes vasoconstriction in the lung Local Metabolic Products Local metabolic regulation of vasomotor tone provides an ideal homeostatic mechanism whereby metabolic demand can directly influence perfusion The precise mechanisms underlying the coupling of blood flow with metabolic activity remain unclear One theory holds that as the metabolic rate increases, so too does the formation of some vasodilating substance Thus, the regional vasculature relaxes, allowing more O2 to be delivered in support of this work As flow rises, the metabolites are washed out, restoring their concentration to normal Adenosine, for instance, which accumulates locally when tissue metabolism is high and tissue oxygenation is marginal, causes pronounced vasodilation in the coronary, striated muscle, splanchnic, and cerebral circulations Another example is potassium, which is released from muscle in response to increased work, ischemia, and hypoxia Hypokalemia causes vasoconstriction; hyperkalemia, within the physiologic range, causes vasodilation An increasing amount of data demonstrate the importance of the local redox state on the regulation of blood flow through the microcirculation Reactive oxygen species, such as superoxide, hydrogen peroxide, and peroxynitrite, have been shown to influence normal regulatory processes and participate in the pathophysiology of a wide array of cardiovascular disorders For example, the rapid reaction of NO with the superoxide anion results in the formation of peroxynitrite, a potent oxidant Although peroxynitrite is known to have cytotoxic properties, under normal conditions peroxynitrite inhibits leukocyte adherence and platelet aggregation without evidence of cellular injury.11 In disease states, however, peroxynitrite can lead to protein nitration and DNA damage In addition, elevated levels of superoxide may decrease the bioavailability of NO, leading to abnormal vasomotion.12 Blood Gas Composition Tissue levels of O2 and carbon dioxide have been shown to reflect adequacy of perfusion and O2 delivery.13 These blood gases are potent determinants of regional blood flow and have effects that differ from one region of the circulation to another They also have a more general effect mediated by carotid chemoreceptors Endothelial-Derived Factors The vascular endothelial cells are capable of producing a variety of vasoactive substances, which participate in the regulation of normal vascular tone These substances, such as NO, carbon monoxide (CO), hydrogen sulfide, and endothelin-1 (ET-1), are capable of producing vascular relaxation and/or constriction, modulating the propensity of the blood to clot, and inducing and/or inhibiting smooth muscle migration and replication14 (Fig 24.8) Understanding the role of the vascular endothelium and the factors 207 that it produces in regulating blood flow in health and disease has resulted in several treatment strategies that target, mimic, or augment endothelial processes Therapies that have been used with variable success include inhaled NO for pulmonary hypertension; L-arginine supplementation for coronary artery disease and the pulmonary vasculopathy of sickle cell disease; phosphodiesterase inhibitors, which prevent the breakdown of cyclic guanosine monophosphate (cGMP) for pulmonary hypertensive disorders; endothelin receptor antagonists for pulmonary hypertensive disorders and vasospasm following subarachnoid hemorrhage; and NO inhibitors for refractory hypotension secondary to sepsis.15–20 Indeed, many older therapies used to promote vascular relaxation, such as nitrovasodilators, affect endothelial function NO is a labile humoral factor produced by NO synthase from L-arginine in the vascular endothelial cell NO diffuses into the smooth muscle cell and produces vascular relaxation by increasing concentrations of cGMP via the activation of soluble guanylate cyclase NO is released in response to a variety of factors, including shear stress (flow) and the binding of certain endothelium-dependent vasodilators (such as acetylcholine, adenosine triphosphate [ATP], and bradykinin) to receptors on the endothelial cell Basal NO release is an important mediator of both resting pulmonary and systemic vascular tone in the fetus, newborn, and adult, as well as a mediator of the fall in pulmonary vascular resistance normally occurring at the time of birth.21 Dynamic changes in NO release are fundamental to the regulation of all vascular beds CO is a labile humoral factor produced by the action of hemoxygenase on heme in many tissues, including endothelial cells Hemoxygenase-1 is constitutive and hemoxygenase-2 is inducible CO interacts with NO, is an independent stimulator of cGMP, relaxes smooth muscle, inhibits its replication, and has powerful antithrombotic and antiinflammatory effects It is beginning to enter the field of clinical medicine.10,22 Hydrogen sulfide is produced in most tissues by a variety of mechanisms and may be the ultimate sensor that is stimulated by O2 deficit or excess.8 ET-1 is a 21 amino acid polypeptide also produced by vascular endothelial cells.23 The vasoactive properties of ET-1 are complex; studies have shown varying hemodynamic effects on different vascular beds However, its most striking property is its sustained hypertensive action In fact, ET-1 is the most potent vasoconstricting agent discovered, with a potency 10 times that of angiotensin II The hemodynamic effects of ET-1 are mediated by at least two distinctive receptor populations, ETA and ETB The ETA receptors are located on vascular smooth muscle cells and mediate vasoconstriction, whereas the ETB receptors may be located on endothelial cells and mediate both vasodilation and vasoconstriction Individual endothelins occur in low levels in the plasma, generally below their vasoactive thresholds This suggests that they are primarily effective at the local site of release Even at these levels, they may potentiate the effects of other vasoconstrictors, such as norepinephrine and serotonin.24 The role of endogenous ET-1 in the regulation of normal vascular tone is presently unclear Nevertheless, alterations in endothelin-1 have been implicated in the pathophysiology of a number of disease states.25 Endothelial-derived hyperpolarizing factor (EDHF), a diffusible substance that causes vascular relaxation by hyperpolarizing the smooth muscle cell, is another important endothelial factor EDHF has not yet been identified, but current evidence suggests that the action of EDHF is dependent on potassium (K1) channels (see Fig 24.8) Activation of K1 channels in the vascular smooth muscle results in cell membrane hyperpolarization, 208 S E C T I O N I V Pediatric Critical Care: Cardiovascular Dilation Constriction PLA2 AA COX1 COX2 PGI2 EC EDHF L-Arg L-Cit TXA2 BigET ECE NOS ETB ET-1 NO K+ sGC AC K+ SMC ATP cAMP PKA GTP cGMP Ca2+ PKG PreProET ETA ETB PLC IP3 DAG Ca2+ Ca2+ • Fig 24.8 Schematic of some endogenous vasoactive agents produced by the vascular endothelium. AA, Arachidonic acid; AC, adenylate cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; COX, cyclooxygenase; DAG, diacylglycerol; EC, endothelial cell; ECE, endothelin-converting enzyme; EDHF, endothelial-derived hyperpolarizing factor; ET-1, endothelin-1; GTP, guanosine triphosphate; IP3, inositol 1,4,5, triphosphate; L-arg, L-arginine; L-cit, L-citrulline; NO, nitric oxide; NOS, nitric oxide synthase; PGI2, prostacyclin; PKA, protein kinase A; PKC, protein kinase C; PLA, phospholipase A2; sGC, soluble guanylate cyclase; SMC, smooth muscle cell; TXA2, thromboxane A2 closure of voltage-dependent calcium (Ca21) channels, and, ultimately, vasodilation K1 channels are also present in endothelial cells Activation within the endothelium results in changes in calcium flux and may be important in the release of NO, prostacyclin, and EDHF K1 channel subtypes include ATP-sensitive K1 channels, Ca21-dependent K1 channels, voltage-dependent K1 channels, and inward-rectifier K1 channels The breakdown of phospholipids within vascular endothelial cells results in the production of the important by-products of arachidonic acid, including prostacyclin (PGI2) and thromboxane (TXA2) PGI2 activates adenylate cyclase, resulting in increased cyclic adenosine monophosphate (cAMP) production and subsequent vasodilation, whereas TXA2 results in vasoconstriction via phospholipase C signaling (see Fig 24.8) Other prostaglandins and leukotrienes also have potent vasoactive properties Myogenic Processes In 1902, Bayliss described an intrinsic increase in vascular tone in response to elevated intravascular pressure.26 This myogenic response results in alterations in vascular tone following changes in transmural pressure or stretch This response is especially important at the arteriolar level and is thought to participate in regional autoregulation Increases in intravascular pressure and/or stretch result in an increase in arteriolar smooth muscle tone, while decreasing pressures have the reverse effect The precise mechanisms mediating this response are unclear, but a role for dynamic changes in intracellular Ca21 and myosin light-chain phosphorylation has been documented.27 More recent work has focused on the role of tyrosine phosphorylation pathways, ENaC, transient receptor potential (TRP) channels, K1 channels, and alterations in Ca21 sensitivity in this response.28–32 Moreover, the myogenic response varies between the regional circulations and vessels within a given circulation.33 Regional Circulations Pulmonary Circulation Maldevelopment and/or maladaptation of the pulmonary vascular bed are important components of several neonatal and infant disease states (i.e., chronic lung disease, persistent pulmonary hypertension of the newborn, and congenital heart disease) In addition, strategies aimed at altering postnatal pulmonary vascular resistance are commonly used in the management of these patients Therefore, an understanding of the regulation of postnatal pulmonary vascular tone is important The morphologic development of the pulmonary circulation affects the physiologic changes that occur in the perinatal period In the fetus and neonate, small pulmonary arteries have thicker muscular coats than similarly located arteries in the adult This muscularity is responsible, in large part, for the pulmonary vascular reactivity and high resistance found in the fetus Within the Changes in the Pulmonary Circulation at Birth After birth, with initiation of ventilation by the lungs and the subsequent increase in pulmonary and systemic arterial blood O2 tensions, pulmonary vascular resistance decreases and pulmonary blood flow increases by 8- to 10-fold to match systemic blood flow This large increase in pulmonary blood flow increases pulmonary venous return to the left atrium, increasing left atrial pressure Then, the valve of the foramen ovale closes, preventing any significant atrial right-to-left shunting of blood In addition, the ductus arteriosus constricts and closes functionally within several hours after birth, effectively separating the pulmonary and systemic circulations Mean pulmonary arterial pressure decreases and, by 24 hours of age, is approximately 50% of mean systemic arterial pressure Adult values are reached to weeks after birth39,40 (Fig 24.9) The decrease in pulmonary vascular resistance with ventilation and oxygenation at birth is regulated by a complex and incompletely understood interplay between metabolic and mechanical factors, which, in turn, are triggered by the ventilatory and circulatory changes that occur at birth Physical expansion of the fetal lamb lung without changing O2 tension increases fetal pulmonary Pulmonary arterial mean pressure (mm Hg) Normal Fetal Circulation In the fetus, normal gas exchange occurs in the placenta and pulmonary blood flow is low, supplying only nutritional requirements for lung growth and performing some metabolic functions Pulmonary blood flow in near-term lambs is between 8% and 10% of total output of the heart.36 Pulmonary blood flow is low despite the dominance of the right ventricle, which, in the fetus, ejects about two-thirds of total cardiac output Most of the right ventricular output is diverted away from the lungs through the widely patent ductus arteriosus to the descending thoracic aorta, from which a large proportion reaches the placenta through the umbilical circulation for oxygenation Fetal pulmonary arterial pressure increases with advancing gestation At term, mean pulmonary arterial pressure is about 50 mm Hg, generally exceeding mean descending aortic pressure by to mm Hg.37 Pulmonary vascular resistance early in gestation is extremely high relative to that in the infant and adult, probably due to the low number of small arteries Pulmonary vascular resistance falls progressively during the last half of gestation, new arteries develop, and crosssectional area increases However, baseline pulmonary vascular resistance is still much higher than after birth.37,38 60 50 40 30 20 10 Pulmonary blood flow (mL/kg/min) first several weeks after birth, the medial smooth muscle involutes, and the thickness of the media of the small pulmonary arteries decreases rapidly and progressively.34 Following this perinatal transition, the medial layers of the proximal pulmonary vascular bed are completely encircled by smooth muscle Moving distally, muscularization becomes incomplete (arranged in a spiral or helix) and disappears completely from the most peripheral arterioles.35 In these arterioles, an incomplete pericyte layer is found within the endothelial basement membrane Smooth muscle precursor cells reside in the nonmuscular portions of the partially muscular pulmonary arteries Under certain conditions, such as hypoxia, these cells may rapidly differentiate into mature smooth muscle cells Subsequently, from infancy to adolescence, the arteries undergo progressive peripheral muscularization In the adult, complete circumferential muscularization extends peripherally such that the majority of small pulmonary arteries are completely muscularized 160 120 80 40 Pulmonary vascular resistance (mm Hg/mL/min/kg) CHAPTER 24 Regional Peripheral Circulation 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 209 Birth -7 -5 -3 -1 Weeks • Fig 24.9 Changes in mean pulmonary arterial pressure, pulmonary blood flow, and pulmonary vascular resistance at birth. (Data from Morin FC III, Egan E Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension J Appl Physiol 1993;73:213–218; and Soifer SJ, Morin FC III, Kaslow DC, et al The developmental effects of prostaglandin D2 on the pulmonary and systemic circulations in the newborn lamb J Dev Physiol 1983;5:237–250.) blood flow and decreases pulmonary vascular resistance, but not to newborn values.41 Mechanical factors include the replacement of fluid in the alveoli with gas, which allows unkinking of the small pulmonary arteries, and radial traction on extra-alveolar vessels that maintain their patency.42 Physical expansion of the lung also releases vasoactive substances, such as PGI2 Ventilation of the fetus without oxygenation produces partial pulmonary vasodilation, while ventilation with air or oxygen produces complete pulmonary vasodilation The exact mechanisms of oxygen-induced pulmonary vasodilation during the transitional circulation remain unclear The increase in alveolar or arterial O2 tension may decrease pulmonary vascular resistance by either directly dilating the small pulmonary arteries or indirectly stimulating the production of vasodilator substances such as PGI2 or NO Therefore, there are at least two components to the decrease in pulmonary vascular resistance with the initiation of ventilation and oxygenation Both components are necessary for the successful transition to extrauterine life Control of the perinatal pulmonary circulation reflects a balance between factors producing pulmonary vasoconstriction (low O2, leukotrienes, and other vasoconstricting substances) and those producing pulmonary vasodilation (high O2, PGI2, NO, and other vasodilating substances) The dramatic increase in pulmonary blood flow with the initiation of ventilation and oxygenation at birth reflects a shift from active pulmonary vasoconstriction in the fetus to active pulmonary vasodilation in the newborn Failure of the pulmonary circulation to undergo this normal fall in pulmonary vascular resistance at birth (persistent pulmonary hypertension of the newborn) is associated with a variety of conditions, including aspiration syndromes, sepsis, in utero stress ... to elevated intravascular pressure.26 This myogenic response results in alterations in vascular tone following changes in transmural pressure or stretch This response is especially important... channels, and alterations in Ca21 sensitivity in this response.28–32 Moreover, the myogenic response varies between the regional circulations and vessels within a given circulation.33 Regional Circulations... period In the fetus and neonate, small pulmonary arteries have thicker muscular coats than similarly located arteries in the adult This muscularity is responsible, in large part, for the pulmonary