215CHAPTER 24 Regional Peripheral Circulation related to the low right ventricular systolic pressure and to the fact that alterations in aortic pressure change coronary perfusing pres sure without alt[.]
CHAPTER 24 Regional Peripheral Circulation related to the low right ventricular systolic pressure and to the fact that alterations in aortic pressure change coronary perfusing pressure without altering right ventricular pressure If the normal right ventricle is acutely distended by pulmonary embolism, for example, there will eventually be right ventricular failure; the increased wall stress increases its O2 consumption, but the raised systolic pressure reduces the coronary flow Therefore, when supply cannot match demand, there will be right ventricular myocardial ischemia.91 Raising aortic perfusing pressure mechanically or with a-adrenergic agonists increases right ventricular myocardial blood flow, relieves ischemia, and restores right ventricular function to normal Improved coronary flow is not the only mechanism of this improvement; the increased left ventricular afterload moves the ventricular septum toward the right ventricle and improves left ventricular performance.92 If right ventricular pressure is chronically elevated so that there is right ventricular hypertrophy—as in pulmonic stenosis, many forms of cyanotic congenital heart disease, and some chronic lung diseases—then right ventricular myocardial blood flow behaves in the same way as left ventricular blood flow, with one exception.93–95 If aortic pressure is lowered, left ventricular pressure also decreases, as left ventricular work and O2 consumption In the right ventricle, however, the workload may not be reduced (if there is no ventricular septal defect) Thus, an imbalance between myocardial O2 supply and demand may occur The worst imbalance occurs when aortic systolic pressure is maintained but coronary perfusing pressure decreases This can occur in a child with tetralogy of Fallot who has too large an aortopulmonary anastomosis The high aortic and left ventricular systolic pressures mandate an equally high right ventricular systolic pressure, but the low diastolic aortic pressure reduces coronary perfusion pressure in diastole and can cause both left and right ventricular ischemia and failure.96 Gastrointestinal Circulation The maintenance of adequate splanchnic blood flow in critically ill patients is important In a globally compromised circulation, the gastrointestinal system is particularly prone to injury, impairing its two chief functions: the digestion and absorption of nutrients and the maintenance of a barrier to the translocation of enteric antigens.97–99 Moreover, splanchnic ischemia has been associated with multiple-organ failure and increased morbidity and mortality in these patients.100,101 The gastrointestinal circulation has multiple levels of regulation Broadly, these can be divided into intrinsic and extrinsic mechanisms Intrinsic mechanisms include local metabolic processes, locally produced vasoactive substances, and myogenic reflexes Extrinsic factors include circulating vasoactive substances, neural innervation, and general hemodynamic forces.102 Blood flow to the intestinal circulation, like other vascular beds, is autoregulated such that O2 delivery remains fairly constant, with inflow pressures varying from 30 to 120 mm Hg.102 O2, CO2, H1 ions, and adenosine are important local metabolic mediators of this process Other important vasoactive mediators of intestinal blood flow include serotonin, histamine, bradykinin, and prostaglandin, although their role in autoregulation is unclear.103,104 Finally, various gastrointestinal hormones and peptides released from the intestinal mucosa and intestinal glands—including gastrin, vasoactive intestinal polypeptide, cholecystokinin, secretin, glucagon, enkephalins, somatostatin, and kallidin—are known to have vasoactive properties A phenomenon unique to the gastrointestinal circulation is the increase in flow following the consumption of nutrients 215 This postprandial intestinal hyperemia appears to involve multiple factors However, the composition of the chyme is particularly important In fact, luminal distention, mechanical stimulation, and extrinsic neural stimulation are not necessary for the response to occur Lipids in combination with bile salts are the most potent triggers for postprandial hyperemia Glucose is the most potent single stimulus for this response Blood flow to skin and skeletal muscle decreases and cardiac output increases during postprandial hyperemia Furthermore, nutrients that induce the largest increase in blood flow elicit the largest O2 debt within the intestinal villi Interestingly, this postprandial hyperemia may be protective in some instances of low blood flow to the intestinal mucosa Glucose has been shown to ameliorate mucosal ischemia in models of septic and hemorrhagic shock; early enteral feeding has been advocated in human studies as well.106 Conversely, enteral feeding has also been associated with bowel ischemia and injury in some patients, such as premature infants, complicating decisions around enteral feeding during or following low-flow states.107 Increasing data demonstrate a large role for NO in the regulation of gastrointestinal blood flow NO, at least in part, mediates basal mesenteric and hepatic blood flow A number of studies implicate endothelial dysfunction, and aberrations in NO signaling in particular, in portal hypertension and cirrhosis.108–110 NO also participates in the maintenance of mucosal barrier function; it is further protective by virtue of its inhibitory effect on platelet and leukocyte adhesion.111 Furthermore, postprandial hyperemia has been shown to involve adenosine-mediated NO release.112 Finally, neuronal NO synthase and inducible NO synthase are important in both normal and abnormal gastrointestinal motility and gastrointestinal inflammatory disorders, respectively.113–115 ET-1 is another important mediator of intestinal blood flow The intestinal vasculature displays increased vasoconstriction in response to ET-1 compared with other vascular beds This has particular importance for gastrointestinal blood flow in critically ill patients, as ET-1 levels have been found to be elevated following surgery and in association with a number of disease states, including hypoxia, pancreatitis, and sepsis ET receptor antagonism ameliorates ischemic injury to the bowel in several models of low-flow states.116,117 Finally, it should be remembered that drugs used to augment systolic blood pressure and/or to enhance cardiac output could have various effects on the gastrointestinal circulation Fenoldopam, a dopamine-1 receptor agonist, has been shown to improve intestinal perfusion during hemorrhage.118 However, findings on more common agents—such as norepinephrine, dopamine, and vasopressin—have had mixed results depending on the doses used and the models or clinical situations studied.119–121 Investigations continue to target the determination of an optimum strategy to improve overall cardiac output and O2 delivery without compromising flow to specific organs, such as the bowel Renal Circulation Blood flow to the kidneys greatly exceeds the metabolic needs of the organs themselves In a 70-kg adult, combined renal blood flow is approximately 1200 mL/min, accounting for just over 20% of total cardiac output supplying organs that represent under 0.5% of total body weight.122 This high renal blood flow is necessary in order to support glomerular filtration, which maintains solute and fluid homeostasis Blood is supplied to the kidneys by the renal arteries, which branch to form the interlobar, arcuate, and interlobular arteries 216 S E C T I O N I V Pediatric Critical Care: Cardiovascular Interlobular arteries progress to form the afferent arterioles, which lead to the glomerular capillaries within the glomerulus, the site of fluid and solute filtration The distal glomerular capillaries reform into the efferent arterioles, which then lead to a second capillary system, the peritubular capillaries An elevated hydrostatic pressure within the glomerular capillaries supports filtration, whereas a much lower pressure within the peritubular capillary system supports absorption.122 Alterations in the resistance of the afferent and efferent arterioles regulate these pressures and allow for dynamic changes in renal function in response to overall fluid and solute needs Renal blood flow is determined by the difference between renal artery pressure (which is generally equivalent to systemic arterial pressure) and renal vein pressure over the renal vascular resistance In general, three vascular segments limit renal vascular resistance: the interlobular arteries, afferent arterioles, and efferent arterioles Regulation of renal vascular resistance can be broadly divided into extrinsic mechanisms and intrinsic mechanisms Extrinsic mechanisms, which include the sympathoadrenal system, atrial natriuretic system, and renin-angiotensin-aldosterone axis, modulate renal blood flow by alterations in intrarenal vascular tone, mesangial tone, intravascular volume, and systemic vascular resistance.122 Intrinsic mechanisms, which primarily alter afferent arteriolar resistance, are responsible for the autoregulation of renal blood flow in response to changes in renal perfusion pressure The juxtaglomerular apparatus, which includes the afferent and efferent arterioles, macula densa, and glomerular mesangium, is an important site in the regulation of renal perfusion and glomerular filtration Glomerular filtration is largely a function of glomerular filtration pressure, which, in turn, is dependent on renal perfusion pressure and, importantly, the balance between afferent arteriolar and efferent arteriolar tone Increased efferent arteriolar tone increases glomerular filtration by increasing glomerular pressure, whereas increased afferent arteriolar tone has the opposite effect Endogenous epinephrine and norepinephrine derived from sympathetic neural input have various effects on renal perfusion and glomerular filtration Mild sympathetic output preferentially constricts the efferent arterioles, thereby increasing glomerular pressure and filtration.123 However, intense sympathetic discharge results in afferent arteriolar constriction, which decreases glomerular filtration Furthermore, sympathetic stimulation of afferent arterioles results in renin release, which leads to increased sodium reabsorption and fluid retention Sympathetic stimulation can affect renal blood flow more generally by alterations in systemic arterial pressure Clinically, norepinephrine has been shown to increase renal perfusion and renal function (measured by changes in creatinine clearance) in patients with septic shock Angiotensin II, produced by cleavage of angiotensin I by the enzyme angiotensin-converting enzyme, also has important effects on renal perfusion Like catecholamine stimulation, the effects of angiotensin II are dose related At low levels, angiotensin II results in efferent arteriolar constriction, whereas at high levels both the afferent and efferent arterioles are constricted.123 Angiotensin II alters renal blood flow further by alterations in intravascular volume through aldosterone and arginine vasopressin and by increasing systemic vascular resistance Arginine vasopressin (AVP) is synthesized in the anterior hypothalamus and released from the posterior pituitary gland It plays a critical role in maintaining serum osmolality within a narrow range Both V1 and V2 receptors have been identified V2 receptors are located on the renal collecting ducts; stimulation results in increased reabsorption of water Activation of V1 receptors on systemic vessels results in vasoconstriction Interestingly, V1 receptor activation in the pulmonary vasculature results in vasodilation, at least in part via NO production Triggers for AVP release include changes in serum osmolality, hypovolemia, and hypotension Patients with septic shock have been shown to have decreased levels of AVP, which has led to the clinical use of AVP supplementation Unlike catecholamines and angiotensin II, high levels of AVP appear to preferentially constrict efferent arterioles, which preserves glomerular filtration ET-1 has diverse effects on the kidney.124 In general, endothelin results in vasoconstriction, decreased renal perfusion, and decreased glomerular filtration ET-1 constricts both the afferent and efferent arterioles ET-1 has also been shown to stimulate cell proliferation within the kidney Conversely, ET-1 may also promote natriuresis through ETB-receptor activation Furthermore, alterations in ET-1 signaling have been implicated in a host of renal diseases, including acute and chronic renal failure, essential hypertension, glomerulonephritis, renal fibrosis, and renal transplant rejection.124 Important vasodilators within the renal circulation include prostaglandins and atrial natriuretic peptide (ANP) The vasodilating prostaglandins (D2, E2, and I2) are synthesized from arachidonic acid by the enzyme phospholipase A2 Most of the important vasoconstricting factors—such as catecholamines, angiotensin II, and AVP—stimulate the release of prostaglandins, promoting increased renal perfusion and glomerular filtration ANP is produced within the atrial myocytes and is released in response to increased atrial stretch Through cGMP signaling, ANP results in afferent arteriolar dilation and increased renal perfusion and glomerular filtration ANP also antagonizes the actions of endogenous catecholamines, angiotensin II, and AVP Like other organ systems, renal blood flow is autoregulated via mechanisms intrinsic to the renal vasculature.122 Early studies demonstrate that renal blood flow and glomerular filtration remain constant at renal artery perfusion pressures of between 80 and 180 mm Hg.125 Importantly, urinary flow rate is not constant within the autoregulatory range but rather changes as a function of renal perfusion pressure The precise mechanisms underpinning this autoregulation are unclear However, recent evidence indicates that the mechanisms are likely complex, involving interactions between tubuloglomerular feedback and myogenic processes that protect the kidney from damage in the setting of hypertension and regulate renal function.126–128 A number of disease states that affect critically ill patients result in the loss of renal autoregulation Acute tubular necrosis, septic shock, hepatic failure, and cardiopulmonary bypass have all been associated with renal dysfunction and a loss of renal autoregulation Conflicting Needs of Regional Circulations The cardiovascular system is composed of the heart and the regional circulations In order to maintain homeostasis in health and disease, the circulations operate in concert while preserving O2 delivery to the individual organs that they supply In certain disease states, however, the regional circulations CHAPTER 24 Regional Peripheral Circulation or the needs of different organ systems may conflict Critical care providers must be aware of these conflicts in order to mitigate the consequences For example, a neonate with a patent ductus arteriosus may suffer from inadequate systemic perfusion (e.g., kidneys and gut) when pulmonary vascular resistance falls, increasing systemic to pulmonary shunting A given ventilation strategy would be expected to have different consequences for the brain and lungs in a patient suffering from head trauma with raised ICP and severe lung injury (i.e., with standard goals being mild hyperventilation or normal ventilation for brain injury and permissive hypercapnia in lung injury) In a patient with single-ventricle physiology and a superior cavopulmonary anastomosis (Glenn), the pulmonary and cerebral vascular resistance both impact pulmonary blood flow, but CO2 affects each in an opposite manner (i.e., hypercarbia increases pulmonary and decreases cerebral vascular resistance) Vasoactive medications in the setting of pulmonary hypertension are variably effective, in large part depending on the degree to which they impact the pulmonary to systemic vascular resistance ratio These examples illustrate that unsuccessful arbitration among regional circulations may contribute to the genesis of the syndrome of multiple-organ system failure (see Chapter 111) It is hoped that an increasing understanding of the mechanisms that regulate regional microcirculatory blood flow will lead to new and improved treatments that optimize blood flow and allow the intensivist to successfully arbitrate the regional blood flow “conflict of interests” and improve outcomes for critically ill children 217 Key References Aird WC Phenotypic heterogeneity of the endothelium: I Structure, function, and mechanisms Circ Res 2007;100:158-173 Aird WC Phenotypic heterogeneity of the endothelium: II Representative vascular beds Circ Res 2007;100:174-190 Cai H, Harrison DG Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress Circ Res 2000;87:840-844 Cannon RO III, 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510-512 101 Kirton OC, Windsor J, Wedderburn R, et al Failure of splanchnic resuscitation in the acutely injured trauma patient correlates with multiple organ system failure and length of stay in the ICU Chest 1998;113:1064-1069 102 Matheson PJ, Wilson MA, Garrison RN Regulation of intestinal blood flow J Surg Res 2000;93:182-196 ... peritubular capillaries An elevated hydrostatic pressure within the glomerular capillaries supports filtration, whereas a much lower pressure within the peritubular capillary system supports absorption.122... urinary flow rate is not constant within the autoregulatory range but rather changes as a function of renal perfusion pressure The precise mechanisms underpinning this autoregulation are unclear... released from the posterior pituitary gland It plays a critical role in maintaining serum osmolality within a narrow range Both V1 and V2 receptors have been identified V2 receptors are located on the