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Ann Thorac Surg 2006;81:S2381-S2388
© 2006 The Society of Thoracic Surgeons

Supplement

Factors Influencing Neurologic Outcome After Neonatal Cardiopulmonary Bypass: What We Can and Cannot Control

Tain-Yen Hsia, MD, Peter J. Gruber, MD, PhD *

Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

* Address correspondence to Dr Gruber, Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Suite 8527, Philadelphia, PA 19104 (Email: gruber{at}email.chop.edu).

Presented at the Symposium on Harnessing the Effects of Neonatal Cardiopulmonary Bypass at the Fourth World Congress of Pediatric Cardiology and Cardiac Surgery, Buenos Aires, Argentina, Sept 21, 2005.


   Abstract
Top
 Abstract
Introduction
 Mechanism of Brain Injury...
 Fixed Factors
 Modifiable Factors
 Perioperative Factors
 Operative Factors
 Summary
 References
 
Advances in cardiopulmonary bypass and surgical techniques have led to progress in the early repair of congenital heart defects in children. However, as increasing numbers survive their initial cardiac operation, an awareness is emerging that significant early and late neurologic morbidities continue to complicate otherwise successful operative repairs. Adverse neurologic outcomes after neonatal cardiac surgery are multifactorial and relate to both fixed and modifiable mechanisms. The purpose of this review is to (1) review mechanisms of brain injury after neonatal cardiopulmonary bypass, (2) examine risk factors, and (3) speculate on how investigations may improve our understanding of neurologic injury.


   Introduction
Top
 Abstract
 Introduction
Mechanism of Brain Injury...
 Fixed Factors
 Modifiable Factors
 Perioperative Factors
 Operative Factors
 Summary
 References
 
Advances in cardiopulmonary bypass (CPB), improvements in myocardial protection, innovative surgical techniques and instrumentation, and expansion of our knowledge of neonatal anatomy and physiology have led to considerable progress in the early repair of congenital heart defects in neonates and infants [1, 2]. Beside complex single ventricle lesions, survival after neonatal CPB is now comparable to those for older children or adults. However, as increasing numbers of neonates survive their initial cardiac operation, a growing awareness is emerging that significant early and late neurologic morbidities continue to complicate otherwise successful operative repairs.

Adverse neurologic outcomes after neonatal cardiac surgery are multifactorial and relate to both fixed and modifiable mechanisms (Table 1). Fixed factors include known genetic syndromes, structural central nervous system malformations, multiple surgeries (leading to multiple insults), socioeconomic status, and poorly defined genetic predispositions to neuroresiliency and obtunded recovery [3]. Potentially modifiable factors include preoperative hypoxia–ischemia, intraoperative events such as the use of deep hypothermic circulatory arrest (DHCA), and postoperative cardiopulmonary instability. The purpose of this review is to (1) review mechanisms of brain injury after neonatal CPB, (2) examine challenging risk factors and summarize techniques to reduce their effects, and (3) speculate on how novel investigations may improve our understanding of neurologic injury and outcome.


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  		Table 1. Factors Influencing Neurologic Injury
 

   Mechanism of Brain Injury After Cardiopulmonary Bypass
Top
 Abstract
 Introduction
 Mechanism of Brain Injury...
Fixed Factors
 Modifiable Factors
 Perioperative Factors
 Operative Factors
 Summary
 References
 
Brain injury after CPB is a devastating complication whose sequelae can range from the subtle to the profound. By some measures, neurologic dysfunction, such as stroke, seizures, choreoathetosis, altered level of consciousness, and coma, has improved from as high as 25% a decade ago to 2% to 11% today [4, 5]. As a result of such improvement, attention is now appropriately focused on more subtle neurologic injury that may lay unrecognized in the early postoperative period. Neurodevelopmental and behavioral deficits can appear later in childhood, leading to long-term functional impairments [3, 6, 7]. These subtle defects manifest as a developmental signature that includes cognitive and intellectual impairment, attention and executive function deficits, visual-spatial and visual-motor skill deficiencies, speech and language delays, and behavioral difficulties (Table 2). In addition to the reduced quality of life for the patients and their families, the need for supportive services casts a prolonged cost to society at large.


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  		Table 2. Developmental Signature of Neurologic Injury After Congenital Heart Surgery
 
But what are the pathophysiologic mechanisms that result in these deficiencies? Early in life, the brain undergoes an intensive period of neuronal development and axonal growth. A number of predispositions, including its fragile vasculature, high metabolic activity, and immature cerebral autoregulation, make the immature brain particularly susceptible to ischemia–reperfusion injury. Differentiating oligodendrocytes myelinate developing axons in the cerebrum, cerebellum, brainstem, and the spinal cord. With its expanding network of neuronal growth and ongoing myelination, the white matter is particularly vulnerable to ischemic insult. Perturbation to this process leads to myelination deficiencies, failure of white matter expansion, and development of ventricular enlargement [8].

Periventricular leukomalacia (PVL), the necrosis of the deep white matter adjacent to the lateral ventricles owing to injury to immature oligodendroglial cells, occurs in greater than 50% of neonates after cardiac surgery by magnetic resonance imaging [9]. Described by neuropathologists Banker and Larroche, PVL was initially thought to be specifically associated with preterm neonates; it is now known to occur in term infants with congenital heart disease (CHD), or after insults such as hypoxia, hypoglycemia, and meningitis [10, 11]. Despite the strong association of PVL with similar neurodevelopmental deficits as those seen after neonatal CPB, a causative link between the two has yet to be firmly established. Although mature oligodendrocytes tend to be more resistant to ischemic injury, immature oligodendrocytes and their progenitors have been shown to be susceptible not only to hypoxic injury but also to proinflammatory cytokines, either circulating or in situ produced inflammatory mediators through a variety of mechanisms [8, 12, 13]. The injurious effect of cytokines may be related to vasomotor or vasoocclusive effects [14, 15]. Alternatively (or additionally), defects in glutamate transport [16] or accumulation result in oligodendrocyte toxicity [17]. Undoubtedly, a combination of multiple mechanisms is responsible for injuries on this axis. Only by addressing this complexity directly can we begin to unravel these mechanisms, a prerequisite for rational therapeutic strategies.

Neonatal CPB with or without modifications such as DHCA or regional low-flow cerebral perfusion is a clear risk factor for neurologic complications [18, 19]. Although different pathophysiologic mechanisms are at work at different times, fixed or preexisting risk factors, intraoperative cerebral hypoxia–ischemia, and insults sustained during the vulnerable early perioperative period all play a cumulative role in the pathogenesis of CPB-related neurologic dysfunction [7, 20, 21]. We will address each of these aspects in turn below.


   Fixed Factors
Top
 Abstract
 Introduction
 Mechanism of Brain Injury...
 Fixed Factors
Modifiable Factors
 Perioperative Factors
 Operative Factors
 Summary
 References
 
Fixed factors are those about which we have little control. Despite our current inability to influence these factors, understanding these risks may be important in stratifying high-risk patients—an important task for families and providers alike. Unrecognized structural brain abnormalities are a key example. For example, newborns with CHD have a substantially higher incidence of cerebral dysgenesis than the general population [7]. Additionally, a postmortem series of 41 infants with hypoplastic left heart syndrome recently identified that 29% harbored major or minor central nervous system abnormalities: 10% had gross structural malformation such as agenesis of the corpus callosum and holoprosencephaly, 27% had micrencephaly, and 21% had abnormal cortical mantle formation [22]. Another preoperative neuroimaging study suggested that more than half of neonates with congenital heart defects have evidence of congenital or acquired cerebral lesions, including microcephaly, incomplete closure of the operculum, PVL, and other ischemic lesions.

In addition to structural defects, there may be other susceptibilities. For example, more than 50% of neonates have magnetic resonance imaging evidence of PVL after CPB compared with less than 5% of older infants, suggesting that the neonatal brain is particularly vulnerable to CPB-related injuries [23]. In patients with PVL, cerebral blood flow is reduced and autoregulatory circuits are blunted [24]. Whether these deleterious effects of CPB on the immature brain are the result of inflammatory responses, primary cerebral ischemia, developmental metabolic differences, or subtle structural brain malformations remains unclear. Low birth weight has long been identified as an increased risk for developmental disability typically characterized by subtle learning and behavioral problems. Some of the common problems have similar developmental signature as those seen in patients after neonatal or infant open heart surgery [25–27]. Thus low birth weight and prematurity are potential independent predictors of poor neurologic outcome and late developmental deficits after CPB [4].

Genetic factors undoubtedly play a key factor in these predispositions to injury. Evaluations of long-term neurodevelopmental outcomes in children after neonatal cardiac surgery have demonstrated individual variables that may predispose patients to poorer performance. These risk factors include the underlying congenital defects (ie, presence of a ventricular septal defect or aortopulmonary collaterals), lower socioeconomic status, and genetic polymorphisms [19, 21]. For example, carriers of the apolipoprotein E2 allele have significantly lower 1-year Psychomotor Development Index after neonatal CPB, suggesting that impairment of neuronal regeneration after injury increases the likelihood of neurodevelopmental dysfunction [21]. This area is clearly understudied, and the application of evolving global genomic technologies provides a rich source of hope for the future.


   Modifiable Factors
Top
 Abstract
 Introduction
 Mechanism of Brain Injury...
 Fixed Factors
 Modifiable Factors
Perioperative Factors
 Operative Factors
 Summary
 References
 
What are the potentially modifiable factors in brain injury with CHD? These risks are more obvious because patients suffering from, and treated for, CHD undergo the extremes of physiology with multiple, iatrogenic interventions. For convenience, we will discuss these factors as either perioperative or operative, although these groups are clearly not mutually exclusive.


   Perioperative Factors
Top
 Abstract
 Introduction
 Mechanism of Brain Injury...
 Fixed Factors
 Modifiable Factors
 Perioperative Factors
Operative Factors
 Summary
 References
 
Newborns with CHD have the potential for preoperative systemic deficits that may adversely affect early and late neurologic recovery. It is common for patients with complex heart defects to present with severe acidosis, hypoxemia, and varying degrees of end-organ impairments such as renal and hepatic dysfunction. Many patients require preoperative intensive medical care during which indwelling catheters and mechanical ventilation are frequently used with their well-known concomitant risks. Preoperative sepsis, often delaying neonatal surgery, may also be an independent risk factor for unfavorable neurologic outcome. Primary neurologic problems such as intracranial hemorrhage or seizures present additional risks [28]. The high incidence of preoperative PVL on neuroimaging suggests that in some of these patients, there is ongoing cerebral ischemia before CPB [24]. High brain lactate levels are detected in more than 50% of neonates with congenital heart defects before surgical palliation, despite a general lack of specific focal ischemic lesions [29]. All these risks emphasize the primacy of a concerted interdisciplinary effort to maximize the health of the preoperative patient.

Similarly, postoperative care undoubtedly plays a key role in the outcome of patients undergoing treatment for CHD. The recovering postischemic neonatal brain that is repaying its hypoxemic debt is particularly vulnerable to injuries caused by hemodynamic, acid–base, and oxygenation disturbances [13, 23]. It is important to maintaining adequate cardiac output, cerebral perfusion pressure, oxygen delivery, and neutral pH milieu in the immediate postoperative period. Hypotension and hypoxemia in the intensive care unit are strong predictors of PVL after neonatal and infant CPB [9]. Adequate cardiac output and optimization of oxygen delivery are important. Cardiac support may need to be provided either by pharmacologic or mechanical methods. For example, delayed sternal closure can temporize the effects of edema and transitory, postoperative cardiopulmonary dysfunction. As an example, some have adopted a strategy of routine postoperative mechanical ventricular assistance after the Norwood operation. One group reported 89% survival in 18 consecutive patients and normal neurodevelopmental testing in all survivors at 4 to 6 months [30, 31]. Although these techniques need to be balanced by consideration of the considerable risks of extracorporeal membrane oxygenation itself, the concept of preserved cardiac output is an important one.

Cardiopulmonary bypass is a suboptimal, artificial circulatory arrangement that leads to a number of iatrogenic injuries: gaseous and particulate emboli, induced cerebral ischemia, and profound systemic inflammatory response. Logically, much of the early CPB modifications were focused on minimizing iatrogenic brain injury. Improvements such as thin-walled cannulas with superior flow dynamics, smaller circuits with inline filters, identifying sufficient perfusion rates, and maintaining adequate anticoagulation have all contributed to better results. More recently, modified ultrafiltration, pH-stat blood gas management, and hemodilution have been studied for their ability to modulate adverse effects of CPB [32, 33]. We will now examine each of these aspects briefly below, summarizing the current knowledge and objective evidence.


   Operative Factors
Top
 Abstract
 Introduction
 Mechanism of Brain Injury...
 Fixed Factors
 Modifiable Factors
 Perioperative Factors
 Operative Factors
Summary
 References
 
Deep Hypothermic Circulatory Arrest
The introduction of DHCA was an important development in the history of the treatment of CHD, allowing the approach of previously unrepairable lesions. More recently, suggestions that DHCA should always be avoided in favor of continuous CPB strategies have not been consistently supported by clinical evidence [19, 34, 35]. Recognition of the clear, deleterious effects of DHCA on cerebral function has been followed by intensive investigations into factors that may improve neurologic outcome. Disagreement remains as to the precise relationship between duration of DHCA and cognitive performance, but generally, more than 40 to 45 minutes of DHCA increases risks of late cognitive impairment [7]. Some interventions that may limit brain injury from DHCA include (1) preoperative steroids and aprotinin, (2) hyperoxygenation before DHCA, (3) allowing at least 20 minutes of cooling duration to ensure adequate cerebral protection, (4) packing the head in ice, (5) intermittent cerebral perfusion between 15- to 20-minute periods of DHCA, and (6) modified ultrafiltration after CPB [36–41]. Definitive confirmation of neuroprotective benefits of any adjunct strategy in neonatal and infant DHCA will eventually require further, well-designed prospective randomized investigations.

Embolic Injury
Cerebral embolization during CPB is a major cause of neurologic morbidity [42, 43]. Although the pathogenesis in the pediatric population is largely distinct from adults, it is still a considerable risk. Conventional embolic cerebral injury is the result of arterial occlusion with subsequent ischemia and infarction. However, recent investigations have shown that passage, not only enlodgement, of a deformable embolus, such as air, fat, or clot, can also lead to endothelial damage as it traverses through a vessel. A single microbubble or lipid microembolus can initiate a cascade of events that causes the disruption of the blood–brain barrier. This in turn produces cerebral swelling, intracranial hypertension, and expansion of a lesion initiated by a separate, larger occlusive embolism [42]. Therefore, one must practice extreme diligence to avoid delivery of emboli of any size or composition into the cerebral circulation [42, 44–46]. One randomized study of 100 patients undergoing routine CPB used a 40-µm arterial filter to significantly reduce the amount of gaseous microembolism; this intervention was associated with reduced postoperative neuropsychological deficits [45]. Debubbling the CPB circuit components is an important method to reduce gaseous microemboli that requires the constant vigilance among surgeons, nurses, and perfusionists. Besides the tubing, membrane oxygenators are a constant source of trapped air. New-generation microporous hollow-fiber oxygenators (ie, Optimin, Cobe CV, Arvada, CO) designed specifically for neonatal CPB can still entrain air into the blood and produce air emboli if negative pressure develops on the blood side of the membrane. After cannulation, back-bleeding the arterial cannula with a syringe can provide an additional level of security that no air is introduced into the system, as well as removing any air that may have accumulated at the arterial cannulation site through alternative sources. More recently, a dynamic bubble trap placed between the arterial filter and aortic cannula in adult CPB has been shown to eliminate 81% of the microbubbles in patients undergoing coronary artery bypass grafting operation [47].

Once CPB is initiated, entrainment of air into the CPB circuit through the venous cannula can be an ongoing hazard, especially if vacuum-assisted drainage is adopted. Frequently, this can be remedied by applying a second pursestring suture around the venous cannula or by snaring both cavae if bicaval venous drainage is used. Recently, a randomized study of adult valve surgery suggested that the old technique (Gott VA, personal communication, 1999) of flooding the mediastinum with carbon dioxide reduces air microembolism [48]. Importantly, adequate removal of air must be achieved after the completion of repair. Although the optimal technique for removing air from the cardiac chambers remains surgeon-dependent, minimizing the ejection of air after the conclusion of cross-clamp or circulatory arrest period continues to be the most important controllable measure against cerebral air embolism. Methods for this include inversion of atrial appendices, aspiration of the left ventricular apex, rotation of the surgical table, low-suction or needle venting of the ascending aorta, and manual cardiac jostling.

In the event that air embolism occurs and is recognized, attempts to reduce its size should be aggressively pursued. These may include reestablishment of hypothermic CPB, retrograde cerebral perfusion, or in select cases postoperative hyperbaric oxygen therapy. Each of these techniques has been reported with varying degrees of success in the adult population [49]. Although practiced by some groups, published experiences with these methods in congenital cardiac surgery are limited.

In addition to gaseous emboli, particulate emboli pose an additional risk. Although atherosclerotic debris is generally not a problem in neonatal cardiac surgery, fibrin and platelet thrombi can form downstream from the arterial filter. Continuous monitoring and maintenance of adequate anticoagulation during CPB is the most important prevention against particulate cerebral embolism. Insufficient heparinization can lead to intravascular thrombosis, procoagulant factor and natural coagulation inhibitor consumption, and post-CPB bleeding and thrombotic complications [50]. Although many centers use the weight-based normogram for heparin dosing, the patient-specific directly calculated dose-response curve system (Hepcon Hemostasis Management System, Medtronics Inc, Minneapolis, MN) may provide improved anticoagulation management on CPB [51, 52]. One prospective randomized study of 26 infants and children undergoing CPB demonstrated that an individualized anticoagulation protocol reduced coagulation activation, fibrinolysis, blood loss, and transfusion requirement when compared with a standard weight-based regiment [52].

A confounding factor for neonatal and infant CPB is the presence of congenital prothrombotic disorders that can affect the anticoagulation management. These include deficiencies in antithrombin III, proteins C and S, plasminogen, and tissue plasminogen activator. Even in healthy newborns, administration of fresh-frozen plasma may be necessary inasmuch as neonates have only half as much antithrombin-III as adults and standard heparin dose may not be adequate [38].

Improved Monitoring
Whereas myocardial protection and systemic oxygen delivery is continuously monitored during neonatal CPB, adequate cerebral perfusion has traditionally been evaluated by surrogate markers such as perfusion pressure, mixed venous oxygen saturation, or base deficit and lactate levels. However, there are now real-time intraoperative cerebral monitoring devices that are available for clinical use, the potential benefits of which are becoming more widely recognized [53–61].

The Bispectral index monitor (Aspect Medical Systems, Natick, MA) uses spectral analysis to analyze electroencephalographic patterns to recognize burst suppressions or electrical silence that may be helpful in guiding adequacy of neuroprotection in DHCA. Its clinical use has recently been supplanted by more sophisticated and sensitive technologies such as transcranial Doppler ultrasound and near-infrared spectroscopy [53]. Transcranial Doppler ultrasound allows sensitive, real-time measurement of cerebral blood flow and monitoring of emboli during congenital heart surgery. Using a pulse-wave ultrasound at 2 MHz, the middle cerebral artery through the temporal window is most consistently monitored. In small infants, an alternative site through the anterior fontanel can be interrogated to investigate the internal carotid artery. Near-infrared spectroscopy uses 204 wavelengths of near-infrared light at 700 to 1,000 nm to monitor brain tissue oxygenation. The Somanetics INVOS system (Somanetics, Troy, MI) produces the regional cerebral oxygen saturation index that is the ratio of oxyhemoglobin to total hemoglobin. Significant desaturation is noted when regional cerebral venous oxygen saturation falls below the baseline value obtained before CPB. A newer device, Hamamatsu NIRO 300 (Hamamatsu Photonics, Hamamatsu, Japan) not only measures cerebral oxygenation, but also the redox state of cytochrome isoforms, giving a direct indication of oxygenation within mitochondria [54].

Bispectral index electroencephalogram, transcranial Doppler ultrasound, and near-infrared spectroscopy may individualize cerebral protection strategies by indicating minimally acceptable flow rates, adequate level of hypothermia, or maximal allowable duration for DHCA [18, 44]. In a retrospective study of the benefits of intraoperative neurophysiologic monitoring in 250 pediatric cardiac operations (all three modalities were used,) interventions in response to noted deficiencies in cerebral perfusion or oxygenation led to decreased postoperative adverse neurologic events and reduce the length of stay [54]. Although promising, prospective studies need to be completed in a rigorous fashion before advocating the wholesale adoption of a single technique.

Optimize Cardiopulmonary Bypass Circuit
In the neonatal brain, where the intrinsic vascular autoregulation that modulates cerebral blood flow is impaired during hypothermia [20, 39], even small disturbances to cerebral blood flow can result in significant deleterious effects. Inadequate venous drainage can quickly reduce cerebral blood flow and impede cooling. Obstructions as a result of oversized caval cannulas, suboptimal cannula placement, insufficient bed height in gravity drainage, small tubing or connector diameter, and air locks within the circuit need to be avoided. Using vacuum-assisted drainage can ameliorate some of these problems.

Typical CPB flow rates for neonates, like adults, are based on weight. Because the normal cardiac index is 3.5 to 4.0 L · min–1 · m–2, in a newborn whose body surface area is greater relative to weight, weight-derived perfusion may result in an inadequate flow index [44]. Thus, higher CPB flow may need to be considered for premature or very small infants. Furthermore, neonates have higher metabolic rates than adults (1.5 to 2.5 times) and require proportionally higher flow, especially during normothermic CPB [62].

Collateral Steal
In patients with cyanotic lesions, bronchial and aortopulmonary collaterals can reroute up to 30% to 40% of the pump flow and return it directly to the left heart [44]. Although many of these collaterals are small and insignificant, some can be quite large. This is a particular risk in patients with pulmonary atresia or in reoperations for single ventricle physiology. Aortopulmonary collaterals, especially when arising from the head and neck vessels, are associated with increased risk of choreoathetosis after DHCA [61]. In addition, decreased rate of cerebral cooling and increased post-DHCA cerebral metabolic derangements were observed in a piglet model [62]. Collaterals steal not only from systemic perfusion, but the increased return to the left side can cause left heart distension and pulmonary venous congestion. Lowering CPB flow to prevent flooding of the operative field further reduces cerebral perfusion. Addressing this important source of runoff either intraoperatively or by preoperative coil embolization may be desirable to minimize collateral steal. Despite these theoretical advantages, two prospective studies in patients undergoing Fontan completion failed to conclusively show improved neurologic outcomes [63, 64].

Avoid Hemodilution
Hemodilution to CPB hematocrit of 20% or less was introduced as a way to minimize the use of exogenous blood products [65]. However, as modern pediatric CPB circuits have reduced the need for a large priming volume, the theoretical rationale for hemodilution has been improved microcirculation during hypothermia [32, 66]. However, more recent studies have begun to reveal some deleterious effects of hemodilution. These include reduced plasma protein and clotting factors, lower colloid osmotic pressure that facilitates interstitial edema, pronounced electrolyte imbalance, and accentuated inflammatory response [49, 67, 68]. One prospective randomized study of infants undergoing CPB demonstrated the negative effects of lower hematocrit (20% versus 30%) in both perioperative outcomes and 1-year neurodevelopmental score [32]. Although the optimal level of hematocrit for neonatal CPB remains uncertain, it is clear that temperature and flow rates are important confounding variables. During warming when the oxygen demand rises and the brain is particularly susceptible to injury owing to impaired autoregulation, there is some evidence that higher levels of hematocrit may be beneficial to provide optimal systemic oxygen delivery [49, 60].

pH Management
When blood cools, the oxyhemoglobin dissociation curve shifts to the left, resulting in a more alkaline state. This in turn reduces cerebral blood flow, increases cerebral oxygen demand, and decreases oxygen availability. Therefore, maintenance of pH neutrality during CPB, especially when profound hypothermia is used, is important in cerebral protection. Two distinct strategies of blood gas management are commonly used: alpha-stat (temperature-uncorrected) and pH-stat (temperature-corrected). Alpha-stat maintains a pH of 7.40 without correcting for the temperature effect of pH, ie, normal pH at all temperatures and total carbon dioxide is unchanged. This potentially preserves cerebral autoregulation and reduces cerebral blood flow and swelling [66]. In the temperature-corrected method, carbon dioxide is actively added continuously to achieve normal pH at the expense of intracellular acidity and disruption of cellular electrical balance. In a number of experimental studies, pH-stat appears to be superior to alpha-stat [69–72]. Some of these advantages include enhanced cerebral perfusion, more homogeneous cooling during CPB, and increased oxygen offloading.

Despite the theoretical and laboratory-demonstrated advantages, clinical correlation of these findings remains mixed. In one randomized trial of infants undergoing cardiac operation with DHCA, du Plessis and associates [73] in Boston observed improved perioperative outcomes with pH-stat management. However, there was no consistent benefit of the pH-stat strategy in 1-year developmental evaluation or in 2- to 4-year parental follow-ups [74]. Nonetheless, on the basis of the perceived advantages supported by laboratory studies, many centers have switched to pH-stat strategy for neonatal CPB when deep hypothermia with or without circulatory arrest is used.

Inflammatory Response Modulation
Cardiopulmonary bypass produces a profound, systemic inflammatory response through a complex interplay of cellular and humoral mechanisms, resulting in capillary leakage, tissue edema, and end-organ dysfunction [75]. Inciting factors such as cellular activation attributable to contact with the circuit and oxygenator, surgical trauma, tissue ischemia–reperfusion, mechanical shear stress, hemodilution, and pharmaceutical administration all contribute. The consequence of any of these events is the stimulation and propagation of a complex cascade of interconnected cellular and humoral responses. These responses include activation of the complement, coagulation, and fibrinolytic pathways; cytokine release; endothelial activation and expression of leukocyte adhesion molecules; neutrophil, monocyte, and platelet activation; production of nitric oxide; and release of cytotoxic molecules such as oxygen free radicals, proteolytic enzymes, and superoxides [60, 76–78].

Despite laboratory data suggesting a causal relationship between inflammation and post-CPB neurologic dysfunction, clinical correlation is mixed [36, 75, 79–81]. In piglet studies, leukocyte-depleting filters and preoperative high-dose methylprednisolone appeared to attenuate the cerebral response to DHCA by improving cerebral blood flow and cerebral oxygen metabolism. However, when a large panel of inflammatory, coagulation, and fibrinolysis markers was examined in 100 children after CPB, no correlation was found between the level of inflammatory response to postoperative cognitive performances [75]. Similarly, although most studies report antiinflammatory effects of modified ultrafiltration, a prospective randomized study of children undergoing CPB failed to reveal decreased proinflammatory cytokine levels after modified ultrafiltration [82]. Modified ultrafiltration also did not improve post-DHCA neurologic recovery or neuronal injury in piglets [81].

Other potential means of modulation and control of systemic inflammation include heparin-bonded circuits to reduced complement activation; serine protease inhibition with aprotinin, and antiinflammatory agents such as corticosteroids. Heparin-bonded oxygenators have been shown to reduce proinflammatory markers and cytokines in children. In a prospective randomized adult study, heparin-bonded circuits decreased postoperative cerebral dysfunction after CPB [83]. Whether this benefit can be translated to the neonatal or infant population remains to be examined [84]. Similarly, preoperative dexamethasone (intravenously 1 hour before CPB) reduced post-CPB cytokines, promoted pulmonary and renal recovery, and advanced clinical course in children [85]. However, the effects of neurologic outcome were not examined in these studies, inhibiting our ability to confidently translate this evidence to pediatric practice.


   Summary
Top
 Abstract
 Introduction
 Mechanism of Brain Injury...
 Fixed Factors
 Modifiable Factors
 Perioperative Factors
 Operative Factors
 Summary
References
 
As survival after neonatal cardiac surgery improves, the continuing early and late hazard for neurologic impairment remains a cause for concern. The problem is multifactorial, and we have examined some of the causative mechanisms and factors. Simple manageable measures such as diligent practice of sound left heart air-removal techniques, application of new cerebral monitoring technology, avoidance of hemodilution, and minimizing postoperative cardiopulmonary derangements are clearly valuable to improving neurologic outcomes. Other proposed adjunctive strategies including using antiinflammatory agents, adopting pH-stat blood gas management as opposed to alpha-stat, modified ultrafiltration, and preoperative hyperoxygenation for DHCA have not been demonstrated to be conclusively beneficial.

Unfortunately, the artificial circulatory arrangement produced by CPB is inherently harmful to the neonatal brain. We certainly have not yet defined all the iatrogenic problems. In addition, there are risk factors and conditions that predispose some patients to the ill effects on the developing brain. Some of these can be modified, such as diligent guarding against prolonged preoperative hypoxemia. Others, such as associated structural brain defects and lower socioeconomic class, are potentially insuperable challenges.

Contemporary CPB is safer and more efficient for neonates undergoing cardiac surgery. Satisfactory neurologic function is now as important a marker of outcome as survival. Our understanding of the mechanisms of CPB-related brain injury and methods of cerebral protection are evolving. Current work with circuit miniaturization to reduce transfusion appears promising. Continued investigations with newer classes of inflammation modulators, such as anti-cytokines and anti-adhesion molecule therapy, may add to our armamentarium against perioperative cerebral injury. Future challenges include identifying additional genetic and molecular markers that predispose post-CPB neurologic dysfunction, and means to modify these and other risks. As clinicians, families, and society continue to grasp the enormity of this problem, sustained efforts to refine neonatal CPB and ways to protect the brain will lead to better neurologic outcomes for children suffering from CHD.


   References
Top
 Abstract
 Introduction
 Mechanism of Brain Injury...
 Fixed Factors
 Modifiable Factors
 Perioperative Factors
 Operative Factors
 Summary
 References
 

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