210 SECTION IV Pediatric Critical Care Cardiovascular events, and certain congenital defects (e g , congenital diaphrag matic hernia and congenital heart disease) Regulation of Postnatal Pulmonary Vas[.]
210 S E C T I O N I V Pediatric Critical Care: Cardiovascular events, and certain congenital defects (e.g., congenital diaphragmatic hernia and congenital heart disease) Regulation of Postnatal Pulmonary Vascular Resistance After the immediate postnatal state, the pulmonary circulation is maintained in a dilated, low-resistance state Because the inflow pressure of the pulmonary circulation is quite low, there is a vertical gradation to the distribution of blood flow in the lung Hydrostatic pressure must be adjusted for vertical height above the left atrium, both at the inflow and outflow of every alveolar capillary unit For example, given a pulmonary artery mean pressure of 20 cm H2O (zeroed at the level of the left atrium), an alveolar-capillary unit 12 cm above the left atrium will face an inflow pressure of only cm H2O A left atrial pressure of cm H2O would generate no opposing outflow pressure to alveolar capillary units more than cm above the left atrium Therefore, critical closing pressure of postcapillary vessels would set outflow pressure for a unit 10 cm above the left atrium Were intrinsic vascular resistance identical throughout the lung, flow at any vertical height would be determined by hydrostatic driving pressure (inflowoutflow) and would be greatest at the base and least at the apex of the lung West et al reported that this phenomenon partitions the lung into three vertical regions (Fig 24.10).44 Zone I vessels are higher above the left atrium than pulmonary artery pressure (expressed in cm H2O) and are not perfused by the pulmonary artery Zone II vessels lie above the height defined by the hydrostatic left atrial pressure but below the height of pulmonary artery pressure These units are perfused in proportion to the driving pressure across them, which is approximately pulmonary artery pressure less vertical height (or critical closing pressure, whichever Zone I Ppa Zone II PLA LA Zone III Reference height of LA • Fig 24.10 The lung is divided vertically into three regions Zone I alveo- lar capillary units are unperfused because they see no functional inflow pressure Zone II units are perfused in proportion to their height above the left atrium (LA) Zone III vasculature is more uniformly perfused because gravity has comparable effects on inflow and outflow pressures (Modified from Fuhrman BP Regional circulation In: Fuhrman BP, Shoemaker WC, eds Critical Care: State of the Art, vol 10 Fullerton, CA: Society of Critical Care Medicine; 1989.) is higher) Zone III vessels lie at a vertical height less than outflow pressure expressed in cm H2O Driving pressure across these units is independent of height because inflow and outflow pressures are comparably influenced by gravity Of note, in a supine neonate, there is likely no zone I Small pulmonary arteries course along with the branching airways, and small pulmonary vessels are intimately related with alveoli Therefore, airway pressure can directly modulate pulmonary blood flow.45 Alveolar pressure can be loosely translated into surrounding pressure for alveolar vessels Positive airway pressure applied to the lung can impinge on alveolar vessels whenever alveolar pressure exceeds the other determinants of outflow pressure During positive-pressure ventilation, outflow pressure of the pulmonary circulation may be determined predominantly by the mechanics of ventilation The lung is partitioned into zones, but the distribution of flow becomes a complex function of alveolar pressure as well as left atrial and critical closing pressures To further complicate this view of the pulmonary circulation, lung volume and alveolar pressure both change during positivepressure ventilation During inspiration, extra-alveolar vessels are dilated by radial traction, reducing their resistance to flow, whereas alveolar vessels narrow and elongate.45 During lung inflation, alveolar surface tension rises, diminishing the transmission of alveolar pressure to alveolar vessels There is also evidence that lung stretch may directly augment pulmonary vascular tone in a manner that is dependent on calcium flux and subject to calcium channel blockade using verapamil In fact, it is clear that mechanical ventilation can have profound direct effects on the intact pulmonary circulation that depends on the waveform of airway pressure applied, not on mean airway pressure alone In heterogeneous lung disease, the application of positive airway pressure can modulate and redistribute blood flow away from ventilated and toward unventilated regions of the lung by directly increasing the pulmonary vascular resistance of lung segments exposed to elevated airway pressure, that is, segments not protected by consolidation or airway obstruction.45 Two of the most important factors affecting pulmonary vascular resistance in the postnatal period are oxygen concentration and pH Decreasing oxygen tension or pH elicits pulmonary vasoconstriction of the resting pulmonary circulation.46 Alveolar hypoxia constricts pulmonary arterioles, diverting blood flow away from hypoxic lung segments and toward well-oxygenated segments.47 This enhances ventilation-perfusion matching This is a unique pulmonary vascular response to hypoxia, which is probably greater in newborns compared with adults The mechanism of alveolar hypoxic pulmonary vasoconstriction remains to be defined and is the subject of several extensive reviews Acidosis potentiates hypoxic pulmonary vasoconstriction and alkalosis reduces it.46 The exact mechanism of pH-mediated pulmonary vasoactive responses also remains incompletely understood but appears to be independent of partial pressure of arterial carbon dioxide (Paco2) Alveolar hyperoxia and alkalosis are often used to relax pulmonary vascular tone because they generally relieve pulmonary vasoconstriction while having little apparent effect on the systemic circulation as a whole However, detrimental effects of hypocarbia or respiratory alkalosis on cerebral and myocardial blood flow may occur The lung is innervated, but neural effects on pulmonary vascular resistance appear to be of little consequence on basal tone However, pulmonary neurohumoral receptors are sensitive to aadrenergic, b-adrenergic, and dopaminergic agonists Therefore, vasoactive agents that stimulate these receptors will affect the CHAPTER 24 Regional Peripheral Circulation Cerebral Circulation The brain makes up 2% of body mass, receiving approximately 14% of the cardiac output while accounting for close to 20% of the body’s O2 consumption in adults, up to 30% of cardiac output, 50% or more of total O2 usage, and up to 98% usage of produced hepatic glucose in neonates Other organ systems receive a larger percentage of the total cardiac output (e.g., the lung) and use greater amounts of O2 (e.g., skeletal muscle), but the brain is unique in its intolerance for diminished blood flow In fact, although some favorable outcomes have been reported, severe, if not irreversible, damage occurs often after just minutes of circulatory arrest under normal conditions.49 The cranium has three compartments: tissue, cerebral spinal fluid (CSF), and blood The Monro-Kellie doctrine states that these compartments occupy a relatively fixed space and that an increase in one compartment can only occur at the expense of another For example, with brain swelling, CSF and cerebral venous blood must be displaced if intracranial pressure (ICP) is to remain unchanged As the limits of CSF and blood evacuation are approached, ICP rises Raised ICP and/or venous obstruction can impede cerebral blood flow (CBF) Cerebral perfusion pressure (CPP), defined as the difference between the mean arterial pressure and the ICP, is thus a more accurate descriptor of cerebral inflow pressure CBF will decline when the CPP falls below the lower limit of the autoregulatory curve In the setting of raised ICP, this will occur even in the face of elevated systemic arterial pressures At rest, cerebral O2 consumption is surprisingly high Glucose is the primary energy substrate, although ketones can be used during periods of starvation The brain has no functional capacity to store energy; thus, it is completely dependent on a steady supply of O2, as up to 92% of its ATP production results from the oxidative metabolism of glucose.49 An important feature unique to the cerebral circulation is the presence of a blood-brain barrier (BBB) The vascular endothelium of brain capillaries forms a continuous sheet, with adjacent cells joined by tight junctions Unlike the endothelium of nonneural capillaries, there are no intercellular clefts through which water-soluble particles can traverse, and there is markedly diminished pinocytosis However, lipid-soluble substances, carbon dioxide (CO2) and O2, can freely diffuse across the endothelium Metabolically important components—such as glucose, lactate, and amino acids—depend on specific carrier proteins to facilitate their diffusion into the brain Furthermore, the BBB has a biochemical component, with high levels of degradative enzymes that protect the vascular smooth muscle and extracellular fluid from the effects of circulating vasoactive substances, such as catecholamines Thus, as a result of the BBB, the cerebral vasculature responds differently from other vascular beds to humoral stimuli However, humoral stimuli can significantly alter the vascular tone of large cerebral arteries and can affect blood flow to parts of the brain that lack a complete BBB, such as the choroid plexus, median eminence, and area postrema.50 It has been recognized for nearly 80 years that CBF remains constant over a wide range of mean systemic arterial pressures (Fig 24.11).51 Constant CBF is maintained in the face of increasing inflow pressures by compensatory vasoconstriction Conversely, in the setting of low systemic arterial pressures (i.e., low inflow pressures) the cerebral vasculature dilates in order to maintain steady CBF At systemic arterial pressures outside the autoregulatory range, further dilation or constriction can no longer maintain blood flow At high pressures, disruption of the BBB ensues, with subsequent edema and even hemorrhage from ruptured cerebral vessels At low pressures, CBF begins to fall—with continued decreases leading to ischemia and, ultimately, brain death.52 Importantly, normal cerebral autoregulation can be impaired in the setting of disease Traumatic brain injury, subarachnoid hemorrhage, and stroke, for example, can all abolish or impair the normal autoregulatory response.53,54 The brain’s ability to autoregulate flow is well established, but the mechanisms underlying it are not completely understood A myogenic response appears to be especially important in the setting of raised CPP Large- and medium-sized cerebral arteries, including the internal carotid artery (ICA), have been shown to constrict both in vitro and in vivo in response to elevated transmural pressures Although small arteries and arterioles primarily modulate cerebral resistance during normotension, at higher pressures the large cranial vessels dominate Thus, at high perfusion pressures, smaller, more delicate vessels are protected by changes in upstream resistance AUTOREGULATION OF CEREBRAL BLOOD FLOW 100 90 80 Cerebral blood flow (mL/100 g/min) vascular tone of both the pulmonary and systemic circulations The degree of pulmonary to systemic alterations induced by these agents is variable and often dictated by the relative tone of each vascular bed Therefore, the response of these agents is difficult to predict in an individual critically ill patient A selective pulmonary vasodilator was long sought for treatment of pulmonary hypertension because, with the exception of O2, the response of the pulmonary circulation to humoral vasoactive agents is generally similar to that of the systemic circulation To date, inhaled NO is the most commonly used agent for selective pulmonary vascular dilation It is noteworthy that its selectivity is not based on a differential effect in the pulmonary and systemic circulations Rather, when delivered as an inhaled gas, NO is rapidly bound to hemoglobin and inactivated, thus, limiting its effects on the pulmonary circulation Inhaled prostacyclin is another agent that offers relative pulmonary vascular selectivity owing to its rapid metabolism.48 211 70 60 50 40 30 20 10 0 25 50 75 100 125 150 175 200 Mean cerebral perfusion pressure (mm Hg) • Fig 24.11 Cerebral blood flow (CBF) autoregulates at perfusion pressures between 50 and 160 mm Hg Below 50 mm Hg, CBF falls Above 160 mm Hg, CBF rises (Modified from Fuhrman BP Regional circulation In: Fuhrman BP, Shoemaker WC, eds Critical Care: State of the Art, vol 10 Fullerton, CA: Society of Critical Care Medicine; 1989.) 212 S E C T I O N I V Pediatric Critical Care: Cardiovascular In marked contrast to other vascular beds, neural stimuli have relatively little effect on basal CBF Cerebral vessels display extensive perivascular innervation, especially by the sympathetic nerves arising from the superior cervical sympathetic ganglia, but the brain is well protected from circulating catecholamines by the BBB Thus, many of the vasoactive agents used in the critical care setting (a- and b-adrenergic agonists) have minimal effects of resting cerebral vascular tone Mild to moderate electrical stimulation, as well as surgical resection of both the sympathetic and parasympathetic nervous systems, does not alter cerebral vascular tone under resting conditions However, vigorous sympathetic stimulation, as would occur with strenuous exercise or hypertension, does result in vasoconstriction of large- and medium-sized cerebral vessels Thus, while a neurogenic mechanism may not mediate cerebral vascular resistance under normal conditions, it does provide protection during times of stress.55 Indeed, patients with chronic hypertension have been shown to have a rightward shift of the autoregulatory curve As in other vascular beds, it appears that CBF is coupled to changes in metabolism.56 For example, hypothermia decreases the cerebral metabolic rate of oxygen (CMRO2) and therefore CBF, in both animal and human studies.57–59 Seizure activity and fever both increase the CMRO2 and CBF, which explains the deleterious consequences of both conditions for patients with raised ICP.60 The mechanisms underlying this coupling of blood flow and metabolism are still unclear A number of substances have been shown to affect cerebrovascular tone These include CO2, O2, hydrogen ions, lactic acid, histamine, potassium ions, prostaglandin, ET-1, NO, and adenosine CO2 plays a critical role in the regulation of CBF In fact, a linear increase in CBF is seen with increasing Paco2, making CO2 one of the most potent known cerebral vasodilators.61 CO2 exerts its effect via a reduction of the perivascular pH Whereas arterial H1 cannot cross the BBB, CO2 can easily diffuse into the brain Carbonic anhydrase facilitates the reaction between CO2 and H2O, forming carbonic acid with subsequent dissociation producing H1 ions Perivascular acidosis dilates the cerebral vasculature, while alkalosis leads to vasoconstriction.62 In this way, the cerebral vasculature is distinct in that respiratory acidosis and alkalosis will alter tone and CBF, while metabolic acidosis and alkalosis will not.61,63 Interestingly, abnormal CO2 reactivity has been associated with several disease processes, including traumatic brain injury, subarachnoid hemorrhage, stroke, carotid stenosis, and congestive heart failure.53,54 Indeed, abnormal CO2 vasoreactivity has been used as a means to prognosticate in some disease states.54 Several studies have demonstrated that the cerebral vasculature adapts in the setting of chronically elevated Paco2 with changes in the pH of the brain extracellular fluid This has obvious implications for the clinician attempting to treat raised ICP with chronic hyperventilation Partial pressure of arterial oxygen (Pao2) also participates in the regulation of CBF Arterial hypoxia dilates cerebral vessels at Pao2 below 40 to 50 mm Hg The relation between CBF and arterial oxygen content is almost linear, and cerebral O2 delivery can be maintained unless arterial O2 content falls below vol% Hyperoxia does not appear to be a potent stimulus for vasoconstriction, however The mechanisms of hypoxic vasodilation are not completely understood, but it is known that adenosine and both Ca21-activated and ATP-activated K1 channels are particularly important Adenosine, which leads to vasodilation through an increase in cAMP, has been found to increase by more than fivefold with hypoxia.64 A large body of evidence, both in animals and humans, implicates NO in a number of important processes within the cerebral circulation.65–67 Vasodilation in response to acetylcholine, oxytocin, substance P, histamine, ET-1, ADP, ATP, and prostaglandin has been shown to be NO dependent in all cases Clinically, it is noteworthy that nitroprusside and other NO-donor compounds can dilate cerebral vessels.68 This greatly complicates the management of hypertension in patients with increased ICP In that setting, nitroprusside, for example, may reduce arterial pressure but raise both cerebral blood flow and blood volume, causing herniation to occur In addition, impaired NO signaling is important in the pathophysiology of subarachnoid hemorrhage in which endothelial dysfunction has been well documented, leading to the important clinical problem of vasospasm ET-1 also mediates cerebrovascular tone.69 Both ETA and ETB receptors have been identified in the cerebral vasculature When given in high concentrations, ET-1 constricts cerebral vessels, probably via ETA receptor activation In low concentrations, however, ET-1 relaxes cerebral vessels via endothelial cell ETB receptor activation, a response that is NO dependent Sarafotoxin 6c (a selective ETB agonist) causes cerebral vasodilation However, ETA and combined receptor antagonists not alter basal cerebrovascular tone Recently, ET-1 has been identified as an important mediator of vasospasm following subarachnoid hemorrhage ET-1 levels are increased following subarachnoid hemorrhage Associated with this increase, ETA receptor levels, smooth muscle cell ETB receptor levels (which mediate vasoconstriction), and endothelin-converting enzyme activity are increased The potential clinical use of ET receptor antagonists following subarachnoid hemorrhage is under investigation, with promising preliminary results.16 Coronary Circulation Right and left coronary arteries arise from sinuses of Valsalva and course over the surface of the heart Nutrient branches penetrate the myocardium to supply both superficial (epicardial) and deep (subendocardial) layers of the muscle Venous blood drains primarily to the coronary sinus, although some returns by way of anterior coronary veins to the right atrium or via sinusoids directly to the ventricles Myocardial workload (which sets myocardial oxygen demand) is determined by not only the needs of the heart but also the demands of the body Furthermore, the heart is required to generate its own perfusion pressure Accordingly, regulation of myocardial perfusion is tailored to match regional myocardial oxygen supply to demand over the widest possible range of cardiac workload and under conditions fashioned not so much for maximal cardiac efficiency but rather for benefit of the body Myocardial perfusion over a cardiac cycle is approximately the same per gram of tissue in the outer (subepicardial), mid-, and inner (subendocardial) layers of the left ventricle However, the dynamics during the cardiac cycle are complicated At the end of diastole, when the ventricle is relaxed and tissue pressures are generally less than 10 mm Hg in any layer of the left ventricle, pressures in the intramural arteries are similar to each other and to aortic pressure At the beginning of systole, tissue pressure rises to equal intracavitary pressure in the subendocardium but then falls off linearly across the wall to about 10 mm Hg in the subepicardium These pressures are added to those inside the vessels for an instant because the vessels walls are not rigid As a result, intravascular pressures in subendocardial arteries exceed aortic pressures, but aortic pressures are higher than pressures in subepi- Aortic pressure (mm Hg) CHAPTER 24 Regional Peripheral Circulation 120 100 80 100 Phasic coronary blood flow (mL/min) 80 60 40 20 Left coronary artery 15 10 Right coronary artery 0.6 Time (s) • Fig 24.12 Myocardial blood flow is modulated by ventricular wall tension Most of the perfusion of the left ventricular myocardium occurs in diastole (Modified from Berne RM, Levy MN Cardiovascular Physiology 7th ed St Louis: Mosby; 1997.) cardial arteries These pressure gradients and the greater shortening of subendocardial than subepicardial muscle fibers during systole compress the subendocardial vessels and squeeze blood out of them both forward into the coronary sinus and backward toward the epicardium In fact, narrowing of the subendocardial vessels facilitates thickening and shortening of the myocytes.70 This backflow enters the subepicardial arteries to supply their systolic flow In systole, there is indeed some forward flow into the orifices of the coronary arteries, but this does not perfuse the myocardium; it merely fills the extramyocardial arteries.71 In fact, there is often reverse flow in the epicardial coronary arteries In early diastole, blood flows first into the subepicardial vessels that have not been compressed but takes longer to refill the narrowed subendocardial vessels Given enough time and perfusing pressure, all the myocardium will be perfused However, if diastole is too short or perfusion pressure too low, subendocardial ischemia occurs Right ventricular myocardium, on the other hand, is normally perfused in both systole and diastole (Fig 24.12) because of lower tissue pressures We would expect perfusion of the hypertrophied right ventricle of severe pulmonic stenosis or tetralogy of Fallot to resemble that of the left ventricle.72 Myocardial Oxygen Demand-Supply Relationship The left ventricle extracts most of the O2 from the blood passing through the myocardium; coronary sinus O2 saturation is normally about 30% Therefore, increases in myocardial O2 demand must be met by increases in myocardial blood flow At rest, left ventricular myocardial blood flow is about 80 to 100 mL/100 g per minute, and with maximal exertion, left ventricular O2 213 consumption increases about fourfold, as does left ventricular blood flow in normal people and animals.73 If coronary perfusion pressure does not change during exertion, the increased flow has to be achieved by a decrease in coronary vascular resistance The response is termed metabolic regulation Coronary vascular resistance has three components: a basal low resistance in the arrested heart with maximally dilated vessels, an added resistance when vessels have tone, and a phasic resistance added whenever the ventricle contracts.74 In the beating heart with vessels maximally dilated by a pharmacologic dilator, the second of these resistances is absent Perfusion of the left ventricular myocardium then produces a steep pressure-flow relation that is linear at higher flows but usually curvilinear at low pressures and flows (Fig 24.13A) Because the vessels are maximally dilated, flow is uncoupled from metabolism and depends only on driving pressure and resistance If heart rate is increased, maximal flow at any perfusion pressure decreases because the heart is in a relaxed state for a smaller proportion of each minute If tone is allowed to return to the coronary vessels, then the pressure-flow relationship can be assessed at different perfusion pressures after cannulating the left coronary artery It is necessary to this because, when cardiac metabolism and blood flow are coupled, increasing aortic blood pressure will increase coronary flow not only by increasing perfusion pressure but also by increasing myocardial O2 demand Under normal conditions, coronary blood flow is autoregulated such that if perfusion pressure is raised or lowered from its normal value, there is a range over which there is almost no change in flow; a rise in pressure has caused vasoconstriction, and a fall in pressure has caused vasodilation At perfusion pressures above some upper limit, flow increases, probably because the pressure overcomes the constriction More importantly, at pressures below about 40 mm Hg (but varying, as discussed later), flow decreases predominantly in the deep subendocardial muscle (see Fig 24.13A), indicating that some vessels have reached maximal vasodilation and can no longer decrease resistance to compensate for the decreased perfusion pressure In these vessels, flow and pressure are directly related If this pressure dependency occurs, then further decrease in perfusion pressure decreases local blood flow below its required amount, or if myocardial O2 demands increase at the same low perfusion pressure (as will occur if the ventricle becomes dilated), the requisite increase in flow will not occur These two conditions cause subendocardial ischemia At any given pressure, the difference between autoregulated and maximal flows is termed coronary flow reserve.75–77 Coronary flow reserve can be measured in units of mL/min but can also be assessed by a dimensionless flow reserve ratio derived by dividing maximal flow by resting flow Flow reserve depends on perfusion pressure because of the steepness of the pressure-flow relation in maximally dilated vessels Coronary flow reserve indicates how much extra flow the myocardium can get at a given pressure to meet increased demands for O2 If reserve is much reduced, then flow cannot increase sufficiently to meet demands and myocardial ischemia will occur What the figure does not show is that coronary flow reserve is normally lower in the subendocardium than in the subepicardium and that decreases in coronary flow reserve are always more profound in the subendocardium than in the subepicardium If autoregulated flow is normal but maximal flow is decreased, as indicated by the decreased slope of the pressure-flow relation during maximal dilation (Fig 24.13B), then coronary flow reserve will be reduced Such a change can occur with marked 214 S E C T I O N I V Pediatric Critical Care: Cardiovascular Normal maximal flow 600 Normal maximal flow Normal maximal flow Flow (mL/min) 500 400 300 R1 R2 R1 200 R2 Normal autoregulated flow 0 40 80 Increased autoregulated flow R1 R2 100 A Reduced maximal flow 120 160 Perfusion pressure (mm Hg) B 40 80 Normal autoregulated flow Normal autoregulated flow 120 160 Perfusion pressure (mm Hg) C 40 80 120 160 Perfusion pressure (mm Hg) • Fig 24.13 (A) Normal pressure-flow relations in the left coronary artery during normal autoregulated flow and maximal vasodilation Values are appropriate for a left ventricle weighing approximately 100 g R1, R2, coronary flow reserve measurements at two different coronary perfusing pressures (B) Effect on coronary flow reserve of a reduced maximal flow At the same coronary perfusing pressure, flow reserve is reduced from the normal R1 to R2 (C) Effect on coronary flow reserve of an increased autoregulated flow Reserve is reduced from R1 to R2 tachycardia; a decrease in the number of coronary vessels due to small-vessel disease, as in some collagen vascular diseases, especially systemic lupus erythematosus; increased resistance to flow in one or more large coronary vessels because of embolism, thrombosis, atheroma, or spasm; impaired myocardial relaxation due to ischemia; myocardial edema; a marked increase in left ventricular diastolic pressure; marked increase in left ventricular systolic pressure if coronary perfusion pressure is not also increased, as in aortic stenosis or incompetence; and an increase in blood viscosity, most commonly seen with hematocrits over 65% Coronary flow reserve can also be reduced if maximal flows are normal, but autoregulated flows increase (Fig 24.13C) Increased myocardial flows above normal values can occur with exercise, tachycardia, anemia, CO poisoning, leftward shift of the hemoglobin O2 dissociation curve (as in infants with a high proportion of fetal hemoglobin), hypoxemia, thyrotoxicosis, acute ventricular dilation (because of increased wall stress), inotropic stimulation by catecholamines, and acquired ventricular hypertrophy When hypertrophy occurs a few months after birth, ventricular muscle mass increases without a concomitant increase in conducting coronary blood vessels Ventricular hypertrophy returns wall stress to normal, and myocardial flow per minute per gram of muscle is approximately normal Therefore, total left ventricular flow is increased in proportion to ventricular mass, but because maximal flow per ventricle is usually unchanged, the coronary flow reserve is diminished Often, autoregulated flow is increased and maximal flows are reduced at the same time (e.g., with severe tachycardia or cyanotic heart disease with hypoxemia, ventricular hypertrophy, and polycythemia) Under these circumstances, coronary flow reserve can be drastically reduced A third mechanism that reduces coronary flow reserve is a shift to the right of the pressure-flow line If with maximally dilated vessels, diastolic coronary flow is measured at different mean diastolic perfusion pressures, a pressure-flow line is obtained that is linear at higher pressures but curved in the low pressure-flow region.78,79 Zero flow occurs at a pressure of about to 12 mm Hg; this is the critical closing pressure that is above right atrial pressure.80,81 The whole pressure-flow line can be shifted to the right by several factors, most important of which are pericardial tamponade, a rise in right or left ventricular diastolic pressures, and a-adrenergic stimulation Such a rightward shift decreases flow reserve It is important to note that because the line of maximal pressure-flow relations slopes up and to the right, any decrease in that slope (Fig 24.13B), any increase in autoregulated flow (Fig 24.13C), or any rightward shift of the slope raises the pressure at which autoregulation fails to compensate for decreased perfusing pressure It is also important to reemphasize that any decrease in coronary flow reserve affects the subendocardium predominantly Thus, autoregulation will fail first and ischemia will occur in the subendocardium before these changes occur in the subepicardium.82 The predominant reduction in subendocardial flow and reserve is particularly marked when left ventricular diastolic pressure is high The interactions between myocardial blood flow and ventricular function are of particular importance when there is ventricular hypertrophy Myocardial wall stress is regulated within a fairly narrow range, with or without myocardial hypertrophy Consequently, myocardial blood flow per unit mass is fairly constant at about mL/min per gram of left ventricle at rest.83–88 Strauer has shown a close relationship between peak wall stress in systole and the ratio of left ventricular mass to volume.85–87,89,90 If there is no hypertrophy, coronary flow reserve is normal, but it is reduced if the left ventricular mass is increased Should the heart dilate acutely, then the mass-tovolume ratio decreases, wall stress and myocardial O2 consumption increase, and coronary flow reserve falls If ventricular dilation is marked, there can be subendocardial ischemia Decreasing ventricular dilation by afterload and preload reduction reverses these unfavorable events and is another reason for the resulting improvement in ventricular function Right ventricular myocardial blood flow follows the general principles regarding coronary blood flow, but there are differences ... the epicardium In fact, narrowing of the subendocardial vessels facilitates thickening and shortening of the myocytes.70 This backflow enters the subepicardial arteries to supply their systolic... deleterious consequences of both conditions for patients with raised ICP.60 The mechanisms underlying this coupling of blood flow and metabolism are still unclear A number of substances have been shown... Perivascular acidosis dilates the cerebral vasculature, while alkalosis leads to vasoconstriction.62 In this way, the cerebral vasculature is distinct in that respiratory acidosis and alkalosis will alter