372 SECTION IV Pediatric Critical Care Cardiovascular microemboli, and cause retrograde flow in the venous line if the vacuum apparatus malfunctions or becomes occluded 44,45 Con siderations for safe[.]
372 S E C T I O N I V Pediatric Critical Care: Cardiovascular microemboli, and cause retrograde flow in the venous line if the vacuum apparatus malfunctions or becomes occluded.44,45 Considerations for safe VAVD operation include using a pressure monitor to maintain a venous line pressure between to 240 mm Hg (gravity siphon will typically provide 25 to 215 mm Hg), adding both positive and negative pressure relief valves to the sealed venous reservoir, being vigilant to recognize and ask the surgeon to correct sources of venous line air, including a moisture trap in the vacuum kit, and only using the minimal amount of vacuum to achieve full arterial flow.46–49 When on total CPB, the mean arterial pressure (MAP) and CVP should confirm that the heart is empty by showing a flat tracing However, the many anatomic variations of the congenital patient can lead to blood returning to the heart despite adequate drainage Variations such as a patent ductus arteriosus, major aortopulmonary collateral arteries, an unrecognized left SVC draining to the coronary sinus, and aortic insufficiency can return blood to the heart and should be considered when evaluating venous drainage Assessment of adequate venous drainage and perfusion flow rate is critical before proceeding to the surgical repair A poorly positioned venous or arterial cannula can restrict optimal perfusion flow; addressing this issue during the aortic cross-clamp period would waste unnecessary myocardial ischemic time Once cannula placement is deemed acceptable, full perfusion flow is achieved, and oxygenation from the oxygenator is confirmed, the anesthesiologist can turn off the ventilator Determining and Monitoring Effective Perfusion Flow Rate The fundamental goals of bypass are to meet the metabolic demands of all tissues and to attenuate the deleterious pathophysiologic effects of artificially supporting a patient Once the patient is transitioned to CPB, several management techniques are used to safely optimize the level of support Perfusion flow rate, which represents the cardiac output during CPB, is altered to meet the O2 consumption needs of the patient Global adequacy of flow is estimated in real time by the display of O2 saturation by a sensor in the venous return line Assessing regional O2 consumption to the brain, kidneys, or bowel, for instance, is a challenge Additionally, owing to age-related differences of body surface area (BSA)-to-blood volume ratios, flow rate indexes are higher in neonates than adults The optimal effective flow rate or cardiac index for any size patient remains unclear Considering that the perfusion flow rate is not fixed during the different phases of CPB, several variables are helpful in determining a safe minimal rate Initial normothermic target rates are calculated for CPB initiation by weight and BSA At Children’s Health Dallas, in addition to the CPB initiation flow rates calculated by weight, the perfusionist calculates several cardiac indexes ranging from 2.4 to 3.0 L/min per m2 Factors such as the degree of hypothermia, acid-base balance, depth of anesthesia and neuromuscular blockade, hematocrit, venous saturation, lactate level, urine output, and near infrared saturation trends are used to guide perfusion flow rates Patient temperature is the greatest factor affecting perfusion flow; rates as low as 40 to 50 mL/kg are routinely used at core temperatures in the 20°C range A growing area of concern is the avoidance and early detection of acute kidney injury (AKI) in congenital heart disease patients While traditional diagnostic approaches have not been thoroughly validated in children, it has been widely reported that there is a 40% to 50% incidence of AKI in congenital heart disease patients, and 64% incidence in neonatal patients.50–52 The kidneys perceive nonpulsatile flow or a decrease in arterial flow as hypovolemia, and the resultant neurohormonal cascade is thought to trigger the AKI complex Since most perioperative risk factors, such as younger age and the incidence of higher surgical complexity, are nonmodifiable, therapeutic strategies have focused on optimally managing perfusion flow rate, arterial pressure, and hematocrit.53 Arterial Pressure The MAP will slowly lose its pulsatile trace and flatten out as the heart empties on CPB Though the MAP is calculated by factoring the systolic and diastolic pressures, the value of the flat tracing is referred to as the MAP and perfusion pressure during CPB The transition to CPB often leads to hypotension; in contrast to adult cases, vasopressors (e.g., phenylephrine) are not typically administered in the early phase of CPB in young patients The goal in the early phase of CPB is to cool the patient and reduce the metabolic demands Low perfusion pressure, 20 to 30 mm Hg, is accepted during the cooling phase, and vasodilators (e.g., phentolamine) are used to reduce arterial tone and increase uniformity of perfusion and improve cooling Vasodilation has been shown to improve temperature distribution and reduce lactate production in pediatric deep hypothermic CPB.54 Hemodilution, hypocalcemia, and the inflammatory response are also factors that cause hypotension at the onset of CPB Hemodilution will lower the perfusion pressure because of the viscosity reduction, and hemoconcentration performed by the perfusionist with the hemoconcentrator can easily increase perfusion pressure by raising the hematocrit The systemic inflammatory response is triggered by the foreign surface contact of blood and bypass circuitry This response releases many vasoactive mediators, which can quickly drop the perfusion pressure, and highlights the importance of minimizing circuit surface area for the pediatric patient The decrease in pressure in an adult patient with coronary or carotid stenosis would likely be treated with a vasopressor, while increasing perfusion flow is the preferred method in young patients Arterial and Venous Oxygen Saturation Most O2 saturation monitoring techniques are noninvasive, inexpensive, and can be used in real time Changing perfusion flow rate and O2 delivery will have immediate and direct effects on O2 saturation levels Pulse oximetry is a clinical mainstay used to monitor O2 delivery to the extremities during the preoperative and postoperative periods However, due to the nonpulsatile flow pattern generated during CPB, this technology is ineffective As mentioned earlier, a mainstay monitoring technique during CPB is to track the O2 saturation of the venous line blood draining into the venous reservoir As a general guideline, perfusion flow rate is adjusted to maintain this mixed venous O2 saturation (Svo2) greater than 70% While this guideline is helpful during “normal” physiologic conditions, the many nonphysiologic variables of CPB cause shifts in the oxyhemoglobin dissociation curve (Fig 35.7); these venous O2 saturations may fail to represent satisfactory O2 delivery to the tissues Leftward shifts in the curve prevent O2 from being released from hemoglobin, which could deceivingly demonstrate an acceptable Svo2 in the presence of tissue hypoxia As the patient is cooled during CPB, regional deoxygenation has been shown to occur despite a normal or rising Svo2 without increasing perfusion flow rate.55 Hypothermia not only strengthens the hemoglobin O2 affinity but also creates an alkaline blood pH and causes a further leftward oxyhemoglobin CHAPTER 35 Pediatric Cardiopulmonary Bypass 100 80 Oxygen saturation (%) • BOX 35.1 Methods to Improve Cerebral Near- Left shift: Decreased 2,3-DPG Fetal hemoglobin Hypothermia Hypocarbia Alkalosis 90 70 60 Infrared Spectroscopy Values Increase perfusion flow rate Increase hematocrit pH-stat blood gas strategy Decrease temperature Increase mean arterial pressure; vasopressor Verify adequate superior vena cava drainage Right shift: Increased 2,3-DPG Hyperthermia Hypercarbia Acidosis 50 40 30 20 10 10 20 30 373 40 50 60 PO2 (mm Hg) 70 80 90 100 • Fig 35.7 The oxyhemoglobin dissociation curve 2,3-DPG, 2,3-Diphosphoglycerate; Po2, partial pressure of oxygen shift In this situation, it is important to cool and warm patients methodically to minimize the temperature gradient between the blood and tissues and maintain perfusion flow so that the Svo2 does not trend downward As tissue temperature decreases, venous line Svo2 can be used to help guide the reduction of perfusion flow rate In addition to hypothermia, other factors—such as third spacing, myocardial dysfunction, and hemodilution—may reduce O2 delivery and lead to cellular hypoxia Therefore, it is common practice to augment O2 delivery using higher fraction of inspired O2 settings and maintaining a partial arterial oxygen pressure (Pao2) above normal physiologic values, with the goal of increasing the O2 gradient between capillaries and tissue beds However, the O2 tension strategy must be carefully managed to avoid the generation of systemic reactive O2 species, systemic inflammation, O2 radicals, and end-organ injury This paradox is especially pronounced in patients with cyanotic defects owing to their physiologic sensitivity to oxidative stress.56 While the literature does not clearly delineate what Pao2 value is considered high or hyperoxic, it is suggested that CPB should be initiated by controlling oxygenation in a slow, graded manner and to not exceed Pao2 values of 350 mm Hg.57,58 It is especially critical to meet the metabolic needs of brain tissue, and global Svo2 values may misrepresent regional O2 consumption It has been shown that considerable regional differences exist and Svo2 can overestimate regional saturations from the brain.59 The majority of venous blood analyzed by the venous line Svo2 comes from IVC cannula, and IVC saturation is notoriously misleading as an estimate of O2 consumption owing to “contamination” by highly saturated renal venous blood Though the Svo2 does have its place in guiding perfusion flow rate, more specific, regional oxygenation assessment is currently recommended to ensure adequate perfusion flow distribution, particularly for the brain Near-Infrared Spectroscopy Near-infrared spectroscopy (NIRS) is a noninvasive optical sensor that can measure cerebral and somatic tissue oxygenation NIRS monitoring is gaining considerable popularity because sensor pads may be placed over various regional tissue beds, particularly both cerebral hemispheres, and display real-time results Somatic monitoring sites—such as flank, abdominal, and muscle—are suggested to help broaden the assessment of systemic hypoperfusion The technology works by bouncing various wavelength arcs of near-infrared light from a sensor emitter and detector These photodetectors allow for selective measurement of tissue oxygenation This technology is widely used in the operating room and intensive care unit, although interpreting the results has been a topic of debate A validation study performed at Children’s Health Dallas demonstrated that cerebral NIRS values accurately predicted the O2 saturation in the SVC on CPB and that flank NIRS values were significantly associated with IVC saturation.60 As increasing evidence validates tissue oximetry against invasive measurements, NIRS monitoring has shown its value in quickly detecting regional low flow.61–64 At Children’s Health Dallas, the perfusionists use NIRS trends and values to guide perfusion flow rate, hematocrit, blood gas strategy, temperature, and vasomotor tone (Box 35.1) It is important to note that NIRS helps to guide rather than dictate perfusion management The upper limits and critical lower values reported by NIRS are poorly defined Considering the regional O2 oxygen saturation variations of the neonatal and infant cardiac surgical patients, NIRS provides valuable information and early detection of poor perfusion in critical organs NIRS has been particularly useful as a real-time monitor on patients with hypoplastic left heart syndrome, for example Cerebral O2 saturation measured after stage I palliation has been shown to strongly correlate with hemodynamic parameters and help to identify early postoperative complications.62,65 Hoffman et al.66 found that avoiding cerebral hypoxia with the use of NIRS monitoring was the most significant factor in improving childhood neurodevelopmental outcomes Additionally, Sood et al.67 demonstrated that perioperative NIRS monitoring was useful in predicting neurodevelopmental outcomes, especially when evaluating the percent decrease of cerebral O2 saturation from baseline values during the intraoperative period Methods to Optimize Physiologic Management Target Hematocrit and Ultrafiltration Despite the progress of reducing the pediatric circuit prime volume, hemodilution during CPB remains difficult to avoid.68 Hemodilution can cause edema, coagulopathy, blood and colloid osmotic pressure reduction, and the need to transfuse blood products Blood product transfusion is the most straightforward solution to address these complications; however, the risk-benefit assessment of blood transfusion must be considered Transfusionrelated complications include increased postoperative morbidity and mortality, prolonged mechanical ventilation and hospital stay, 374 S E C T I O N I V Pediatric Critical Care: Cardiovascular exacerbation of the inflammatory response, and infection.69–72 Modern blood bank testing and donor screening have significantly reduced infectious complications, but noninfectious risk remains a major concern In addition, smaller patients are exposed to a higher transfusion risk because the transfusion effects may be more pronounced than in adult patients With a goal of minimizing hemodilution and donor blood exposure, the cardiac team must implement a transfusion algorithm and define a target hematocrit during CPB Perioperative and developmental outcomes data reported from clinical trials at the Boston Children’s Hospital demonstrate that, when compared with target CPB hematocrit values of 30%, hematocrit values at or below 20% are associated with adverse outcomes and that the benefits of hematocrit values higher than 25% should be further investigated.73,74 The protocol at Children’s Health Dallas is to maintain a hematocrit of at least 30% during CPB Reducing circuit prime volume and incorporating an ultrafiltration device can significantly reduce donor blood exposure Originally, a hemoconcentrator added to the CPB circuit was used primarily to remove plasma water and raise the hematocrit This process is referred to as conventional ultrafiltration (CUF) and its initial use was met with a few limitations Perfusionists were accustomed to using diuretics to help increase the hematocrit; however, this strategy offered little control and required adequate kidney perfusion during CPB When ultrafiltration emerged as a CPB technique in the mid-1980s, hemoconcentrators were viewed as an expensive option for removing excess circuit volume Also, while fluid is removed from the circuit during CUF, the volume in the venous reservoir level diminishes and CUF must be stopped before the reservoir is emptied, which would have catastrophic consequences Thus, the amount of fluid removed during CUF is dependent on available volume in the venous reservoir, which limits the ability to effectively raise the hematocrit In 1991, a report described a modified ultrafiltration (MUF) technique performed after weaning the patient from CPB that enabled the perfusionist to concentrate the entire circuit and return most of that volume back to the patient.75 During this era, pediatric circuit prime volume was still rather high; various MUF techniques proved to be a valuable resource for reducing total body water post-CPB As the prime volumes of CPB circuits have become increasingly smaller relative to the blood volume of the patient, perfusionists have begun to abandon the cumbersome MUF technique in favor of preventing hemodilution rather than reversing hemodilution.76–77 The early popularity of MUF led investigators to explore the potential reduction of proinflammatory mediators during ultrafiltration An additional ultrafiltration technique, zero balance ultrafiltration (ZBUF), emerged as an alternate method to attenuate the inflammatory response ZBUF is performed by removing the ultrafiltration effluent from the circuit during CPB while administering a replacement solution (e.g., Plasma-Lyte A) to the venous reservoir in a 1:1 ratio The highvolume filtration of fluid that is able to be exchanged allows the perfusionist to control electrolyte and glucose levels (e.g., high potassium levels after delivering cardioplegia) and more effectively remove inflammatory mediators The increasing acceptance of ultrafiltration during CPB led to developing many technique variations during the preoperative, perioperative, and postoperative phases, which can be categorized into two groups: blood concentration and blood filtration In preparation for neonatal CPB at Children’s Health Dallas, for example, the perfusionist adds approximately 300 mL of PRBCs to the venous reservoir after priming the circuit with Plasma-Lyte A The circuit volume is recirculated through the hemoconcentrator, and volume is removed until the reservoir is almost empty The circuit prime is then “washed” by adding approximately 500 mL of Plasma-Lyte A and then removing that volume This process is known as prebypass ultrafiltration (PreBUF) In addition to concentrating the circuit, Pre-BUF has been shown to reduce high potassium, glucose, lactate, citrate, and bradykinin levels found in PRBCs CUF is then performed during the early phase of CPB to remove any excess circuit volume and maintain a hematocrit of 30% During the warming phase of CPB, the perfusionist performs CUF and ZBUF This combined ultrafiltration strategy, coupled with a miniaturized circuit, allows the perfusionist to filter the blood and exceed or meet baseline hematocrit values before weaning from CPB Hypothermia Deep Hypothermic Circulatory Arrest vs Antegrade Cerebral Perfusion The therapeutic potential of hypothermia has been known for centuries and has been routinely used in cardiac surgery since its inception This concept relies on the fundamental physiologic relationship between O2 consumption and temperature In 1950, Bigelow and colleagues78 compared the use of normothermia and topical cooling on dogs and reported superior ischemic tolerance by surface cooling after 15 minutes of circulatory arrest The first clinical application in cardiac surgery was reported in 1953 by Lewis and Taufic, who described the successful repair of an ASD in a 5-year-old girl using topical cooling and total body hypothermia.2 To achieve this, patients were submerged in an ice bath to reduce their temperature to approximately 28°C Then, the defect was closed with the aid of inflow occlusion In 1958, Sealy and colleagues79 successfully reported the use of hypothermia in conjunction with CPB The use of CPB with various degrees of hypothermia or deep hypothermic circulatory arrest (DHCA) dramatically increased the “safe” period of support, which enabled surgeons to repair increasingly complex anomalies and allowed cardiac surgery to flourish Hypothermia suppresses metabolic activity, preserves highenergy phosphate stores, and reduces the reaction rate of biochemical reactions Several factors are used in determining the type and degree of hypothermia during CPB The most significant factor is the degree of surgical difficulty and anticipated CPB support time Complex surgical repairs requiring lengthy support times would benefit from more pronounced hypothermia The degree of hypothermia varies greatly and is typically classified as mild, moderate, deep, and profound (Table 35.5) Deep hypothermia might be seen as desirable when low flow (#50 mL/kg per minute) or DHCA is desired, as is the case in operations involving complete aortic arch reconstruction Circulatory arrest is a process in which the perfusion flow is turned off and the TABLE Hypothermia Classifications in Cardiac Surgery 35.5 Category Core Temperature Mild 32°C–34°C Moderate 25°C–32°C Deep 15°C–25°C Profound #15°C Oxygen consumption (mL· min–1· m–2) CHAPTER 35 Pediatric Cardiopulmonary Bypass 150 37 °C 100 30 °C 25 °C 50 20 °C 15 °C 0.0 0.5 1.0 1.5 2.0 Perfusion flow rate (L · min–1· m–2) 2.5 • Fig 35.8 Nomogram relating oxygen consumption to perfusion flow rate and temperature (From Kirklin JW, Barratt-Boyes BG Hypothermia, circulatory arrest, and cardiopulmonary bypass In: Kirklin JW, Barratt-Boyes BG, eds Cardiac Surgery 2nd ed New York: Churchill-Livingstone; 1993:91.) patient’s blood volume is allowed to drain into the venous reservoir This dramatic application provides an asanguineous and completely motionless surgical field, facilitating complex repairs In very small patients, the venous cannula may be obstructive and DHCA is required in order to remove the cannula and access the surgical site Hypothermia also facilitates exposure of the surgical field by allowing decreased perfusion flow rates, which reduces the amount of collateral blood returning to the heart via the pulmonary veins (Fig 35.8) Patients with pulmonary blood flow restrictions (e.g., tetralogy of Fallot, pulmonary atresia) can develop major aortopulmonary collateral arteries; these collaterals can flood the heart during the aortic cross-clamp period if CPB flow is maintained This excessive blood return not only obscures the surgical site but may also warm the cold arrested myocardium or wash out cardioplegia from the coronary arteries Hypothermia and perfusion flow rate reduction can attenuate this collateral flow while maintaining adequate oxygenation to the patient The rate of cooling varies greatly between different tissue beds; thus, multiple measurement sites are recommended to ensure uniform cooling distribution (Fig 35.9) The optimal temperature measurement site is controversial, but choosing sites that closely reflect tissue temperatures of vital organs, particularly the brain, is widely accepted At Children’s Health Dallas, the patient’s nasopharyngeal, rectal, and bladder temperatures are monitored during surgery Nasopharyngeal temperature closely correlates with brain temperature; however, it may underestimate the global core temperature considering the slower cooling rates of other tissue beds For this reason, rectal and bladder temperature monitoring sites with slower rates of cooling are typically used to guide cooling end points The concept of a “safe” circulatory arrest time is controversial, and most guidelines are met with a degree of uncertainty A nomogram focused on neurologic protection has been devised that estimates safe circulatory arrest times, but values should not be used as absolutes (Fig 35.10) The historic incidence of perioperative cerebral injury during DHCA has led investigators to explore alternative techniques to protect the brain during complex repairs Antegrade cerebral perfusion (ACP, also known as selective cerebral perfusion) uses a cannulation technique that directs perfusion flow to only the brain with the theoretic advantage of 375 protecting it from hypoxic ischemic injury Though this technique has been adopted among many surgical centers, investigations comparing DHCA and ACP have failed to definitively demonstrate superiority of either technique,80–82 and not all of this work is focused only on neurologic issues Recent literature has suggested that during ACP, the resultant partial perfusion from collateral vessels provides better protection to abdominal organs than DHCA.83,84 In addition, the ideal temperature during ACP remains unknown However, recent reports have demonstrated superior results using moderate to mild hypothermia, in the 25°C to 30°C range, rather than deep levels of hypothermia.85,86 Considering the coagulopathy, inflammatory response, and the vascular and organ dysfunction associated with deep hypothermia, investigators have been prompted to explore warmer or normothermic high-flow CPB Recent studies have shown that high-flow normothermic CPB is as safe as hypothermic CPB during low-risk procedures, and may reduce postoperative inotropic and respiratory support, shorten length of stay, and reduce intraoperative blood transfusion.87,88 pH and Partial Pressure of Arterial Carbon Dioxide Strategy CO2 concentration and pH are primary determinants of cerebral blood flow As body temperature decreases, the solubility of CO2 increases, resulting in a decreased partial pressure of arterial CO2 (Paco2) and increased pH Manipulating the acid-base management during hypothermic bypass can be classified by two mechanisms of control: a-stat or pH-stat Both mechanisms have been studied intensely in reptiles (ectotherms) and hibernating mammals (endotherms), looking at their adaptive blood pH alterations that allow them to withstand extreme temperature fluctuations pH-stat acid-base management is practiced by hibernating mammals, accomplished by decreasing ventilatory rate and raising Paco2 while maintaining a constant pH during hypothermic conditions Maintaining pH while varying temperature during hibernation is thought to preserve O2 stores by decreasing metabolic activity Alternatively, reptiles use a-stat and allow their pH to enter an alkaline state by reducing Paco2 The perfusionist can maintain a pH-stat or “temperature-corrected” acid-base strategy during CPB by allowing CO2 to passively rise or actually adding CO2 to the CPB circuit Cerebral blood flow has been shown to decrease during hypothermia using the a-stat strategy and demonstrates a linear relationship to the increased Paco2 when a pH-stat strategy is used.89 In addition to preserving cerebral blood flow during hypothermia, a pH-stat strategy induces a rightward shift of the oxyhemoglobin dissociation curve (see Fig 35.7) potentially allowing for increased O2 off-loading from hemoglobin at the capillary level Whether pH-stat or a-stat acid-base management during hypothermic CPB demonstrates clear benefits on clinical outcomes has been difficult to demonstrate However, it is suggested that a pH-stat strategy is optimal for pediatric patients, and a-stat is the optimal strategy for adult patients.90 Myocardial Protection Myocardial protection refers to the strategies and techniques employed to allow the surgeon to work on the heart in a bloodless and motionless field yet recover the best possible postischemic myocardial function and cardiac output for the patient Strategies for both adults and children attempt to reduce cardiac workload and minimize the metabolic demands and consequences of O2 376 S E C T I O N I V Pediatric Critical Care: Cardiovascular Cooling Rewarming 41 40 39 38 37 36 35 34 33 32 31 30 29 28 Temperature (± SEM) ° Centigrade 27 26 Arterial cannula 25 Myocardial 24 Brain 23 Nasopharyngeal 22 21 Rectal 20 P < 05 19 18 17 16 15 14 13 12 11 10 10 20 30 40 10 20 30 40 Time (minutes) 50 60 70 80 90 • Fig 35.9 Relationships of temperatures measured at various sites over time during cooling and warming from cardiopulmonary bypass (From Stefaniszyn HJ, Novick RJ, Keith FM, et al Is the brain adequately cooled during deep hypothermic cardiopulmonary bypass? Curr Surg 1983;40:294–297.) deprivation during ischemia Reducing afterload and emptying the heart by initiating CPB is a myocardial protection technique during beating heart procedures (e.g., palliative shunts, bidirectional Glenn procedure) When the heart needs to be stopped and opened for intracardiac repairs, the aorta is cross-clamped and cardioplegia is delivered to the coronary circulation to cause prolonged asystole Cardioplegia is a myocardial arrest-producing solution that is formulated to prolong myocardial tolerance to ischemia There are many techniques to protect the myocardium, but cardioplegia strategies are often the focus when discussing protection techniques In North America, high-potassium depolarizing solutions are the most common type of cardioplegia used.34 Universal agreement on an optimal myocardial protective technique is widely debated; most strategies are guided by surgeon or institutional preference After the first successful cardiac surgical correction using CPB in 1953, surgeons explored a variety of techniques to support the patient during the repair It did not take long for them to realize ... oxyhemoglobin dissociation curve 2,3-DPG, 2,3-Diphosphoglycerate; Po2, partial pressure of oxygen shift In this situation, it is important to cool and warm patients methodically to minimize the temperature... help guide the reduction of perfusion flow rate In addition to hypothermia, other factors—such as third spacing, myocardial dysfunction, and hemodilution—may reduce O2 delivery and lead to cellular... generation of systemic reactive O2 species, systemic inflammation, O2 radicals, and end-organ injury This paradox is especially pronounced in patients with cyanotic defects owing to their physiologic