Neurological Complications and Neurodevelopmental Sequelae of Pediatric Cardiac Surgery

Balu Vaidyanathan, R Krishna Kumar

Department of Pediatric Cardiology, Amrita Institute of Medical Sciences and Research Centre, Kochi

The mortality rates associated with cardiac surgery in infants has declined significantly in recent years due to advances in surgical techniques, cardiopulmonary bypass (CPB) and post-operative intensive care.1 The focus in recent years has shifted from mortality to long-term functional disability of which neurocognitive performance is an important determinant.1 Several recent studies have focused on the mechanisms of neurological injury during cardiac surgery in the infants and many strategies have been developed to prevent or minimize peri-operative brain damage.2 This review will discuss the mechanisms and the clinical consequences of peri-operative neurological injury together with the current and future neuroprotective strategies for pediatric cardiac surgery.

Neurological Injury

Prevalence: Ferry3 reported that transient and permanent neuropsychiatric injury occurs in as many as 25% of all infants undergoing hypothermic CPB with severe abnormalities in <10% cases. In complex palliative procedures such as first stage palliation for hypoplastic left heart syndrome, neurological injury can occur in as high as 45% of infants.4 A recent report, however, revealed a much lower incidence (2.3%) of acute neurological complications after pediatric cardiac surgery.5 However, it is not possible to determine the prevalence of sub-clinical forms of neurological injury with the currently available methods and it is likely that this also contributes to the adverse long-term neurodevelopmental sequelae.

Mechanisms : Neurological injury during cardiac surgery can be due to either cerebral embolic injury or global cerebral ischemia and reperfusion.6 Embolic injury can occur due to air or particulate emboli or via monitoring lines. With advances in bypass techniques, like the use of filters, it has come down significantly. Global cerebral ischemia is the most important mechanism of cerebral injury, particularly in the infants. This is mediated by the hypoxia-reperfusion injury mechanism. The cellular mechanism causing hypoxia-reperfusion injury is referred to as excitotoxicity, which is mediated by excitatory amino acids like glutamate and aspartate acting via N-methyl-Daspartate (NMDA) receptors.

Presentation : Neurological injury during infant cardiac surgery can present acutely in the post-operative period or later as long-term permanent or transient neurocognitive sequelae.7 Acute neurological disorders include seizures, cerebrovascular accidents, movement disorders (choreoathetosis), spinal cord injury and delayed recovery from anesthesia. Long-term neurodevelopmental issues include cognitive impairment, speech and language problems, impaired visual-spatial and visual-motor skills, attention deficit/hyperactivity disorder, motor delays and learning disabilities.

Seizures: Early transient post-operative seizures have been reported in 4-10% of infants with critical congenital heart disease undergoing open heart surgery. In the Boston Circulatory Arrest Trial, the incidence of clinical seizures in the first post-operative week was 6% while 20% had ictal activity on continuous electroencephalography (EEG) monitoring.8 Independent risk factors for clinical and EEG seizures were assignment to a strategy of circulatory arrest,longer duration of circulatory arrest and diagnosis of dtransposition of great arteries (d-TGA) with ventricular septal defect (VSD) in comparison with d-TGA with intact ventricular septum.9 Presence of clinical or EEG seizures in the post-operative period correlated with worse neurodevelopmental outcomes at ages 1 and 2½ years as well as neurological and magnetic resonance imaging (MRI) abnormalities at 1 year of age.10 Seizures associated with stroke carry a much worse prognosis compared to isolated “post-pump” seizures.

Cerebrovascular accidents (Stroke): Strokes are more common in patients with uncorrected congenital heart disease.11 Peri-operative mechanisms that can contribute to the development of stroke include embolic phenomenon during CPB, systemic inflammatory response triggered by bypass, vascular stasis, altered vascular surface due to presence of prosthetic material, elevated right atrial and central venous pressures (predisposing to cerebral venous thrombosis), presence of residual defects or fenestrations predisposing to right to left shunts (e.g. patent foramen ovale) and a procoagulant shift in the humoral clotting systems.12 The various mechanisms of stroke in the post-operative period include cerebral emboli, arterial or venous thrombosis or intracranial hemorrhage. The clinical presentation of stroke varies according to the age of the patient. In infants, stroke often presents as focal seizures or changes in mental status; in older children acute focal motor deficits, language and visual deficits are more common.

12Movement disorders (Choreoathetosis):This has been reported in 0.5-19% of children undergoing open heart surgery. Wong et al.13 identified age beyond infancy, cyanotic congenital heart disease with systemic to pulmonary collaterals and shorter duration of cooling prior to hypothermic circulatory arrest as risk factors for choreoathetosis. Two forms have been identified according to severity; a mild transient form confined to distal extremities is commoner in infants under 10 months and a more severe, progressive form that involves the proximal extremities is more often seen in children above 1 year of age. Prognosis for the distal form is generally benign while the proximal form is associated with mortality that is reported to be as high as 40% with a very high incidence of persistent neurodevelopmental defects.

12Spinal cord injury: Spinal cord injury resulting in paraplegia is usually associated with surgery of the descending thoracic aorta (e.g. coarctation of aorta). Brewer et al.14 in a series of 12,532 coarctectomies reported a 0.41% incidence of paraplegia. This complication is usually seen in patients who have poorly developed collateral circulation as seen in infants, pre-subclavian coarctation, stenosis of left subclavian artery and in re-repair. Risk factors for development of spinal cord injury include longer duration of aortic cross clamping, hyperthermia, higher level of aortic clamping, upper body hypotension and elevated intraspinal pressure.15 Various techniques employed for prevention of paraplegia include hypothermia, cerebrospinal fluid drainage, localized cooling of spinal cord and pharmacological agents like corticosteroids, naloxone and papaverine. Specialized perfusion techniques like temporary ascending to descending aorta bypass have been employed to prevent this complication in patients with poorly developed collateral circulation with excellent results.

16 Peri-operative Risk Factors for Neurological Injury

These can be broadly divided into three groups: (i) preoperative factors, (ii) intra-operative factors, and (iii) postoperative factors.

Pre-operative factors: Few studies have systematically evaluated the role of pre-operative factors in the genesis of neurological complications associated with pediatric cardiac surgery. The role of some of the pre-operative factors known to be associated with neurological complications is discussed below.

Age: Neurological injury associated with open heart surgery is common in younger patients. Galli et al.17 reported a very high incidence of peri-ventricular leukomalacia on followup MRI scans in neonates compared to infants (54% v. 4%) undergoing open heart surgery utilizing CPB with or without hypothermic circulatory arrest. The oligodendrogliocytes in the neonatal brain are immature and rapidly differentiating compared to the mature oligodendrogliocytes in older infants and this makes the neonatal brain more vulnerable to the toxic effects of hypoxia-reperfusion and immune-mediated insults associated with CPB.

18Pre-operative neurological status: Limperopoulos et al.19 detected a very high prevalence of neurological abnormalities pre-operatively in both newborns (> 50%) and infants (38%) undergoing open heart surgery. Their study showed a very significant relationship between preoperative and post-operative neurological status with only 14% of newborns and 12% of infants developing fresh neurological complications after surgery. The major findings on pre-operative neurological evaluation were hypotonia, jitteriness, motor asymmetries, microcephaly and seizures (7%). Neuroimaging revealed abnormal findings like ventriculomegaly, intraventricular hemorrhage, cerebral atrophy and aqueductal stenosis. This study emphasized the role of a thorough pre-operative neurological assessment in all newborns and infants undergoing major open heart surgery.

Oxygen saturation: It is widely believed that persistent hypoxia is a risk factor for neurological damage in cardiac surgery patients. Limperopoulos et al.19 found that the presence of oxygen saturation <85% was associated with a significantly higher neurological abnormalities in infants compared to those with saturation >85%. This underlines the need to perform corrective surgery at a younger age to prevent the deleterious effects of chronic hypoxia.

Cardiac diagnosis: Clancy et al.20 classified infants with congenital heart disease into 4 groups according to perioperative physiology – Class 1: Two ventricles without arch obstruction; Class 2: Two ventricles with arch obstruction; Class 3: Single ventricle without arch obstruction; Class 4: Single ventricle with arch obstruction. Patients with hypoplastic left heart syndrome complex (Class 4) have the highest risk of peri-operative cerebral injury and long-term neurodevelopmental sequelae.

21,22 Genetic factors: Forbess et al.21 reported the association of velocardiofacial syndrome (partial deletion of chromosome 21) as a significant risk factor for poor neurodevelopmental outcome after open heart surgery in infants. Gaynor et al.23 recently reported the association between a particular apolipoprotein E genotype (Ee2 allele) and post-operative neurodevelopmental dysfunction.

Intra-operative factors: On the basis of several studies done on the role of various techniques of CPB and neurodevelopmental sequelae, various factors during surgery, which can affect the long-term neurological outcome, are discussed below.

Support strategy-low flow cardiopulmonary bypass (LF-CPB) versus deep hypothermic circulatory arrest (DHCA):The nature of neurological injury is different with these two strategies of circulatory support. DHCA causes a dosedependent hypoxia-reperfusion injury while LF-CPB results in a generalized inflammatory response causing cerebral damage.1 The Boston Circulatory Arrest Study was a randomized control study comparing these two forms of circulatory support strategies in patients with diagnosis of d-TGA undergoing arterial switch operation. Several reports describing the immediate and long-term outcomes of this study have been published.8.9.24-26 The findings of this landmark study are summarized in Table 1.

Other studies have also documented worse neurodevelopmental outcomes associated with longer duration of circulatory arrest.21,27 An uncontrolled study from All India Institute of Medical Sciences, New Delhi reported that use of circulatory arrest was not associated with significantly reduced mental performance on followup.28 Current evidences neither support nor reject the use of either DHCA or LF-CPB as a preferred strategy for infant cardiac repair.1 There is no difference in the long-term outcomes between the two strategies with respect to neurocognitive outcome. Both strategies, however, result in inferior long-term neurodevelopmental outcome compared with normal population.

Optimal pH strategy: alpha stat versus pH stat: Two strategies for pH management are used for hypothermic circulatory arrest and low flow-CPB: alpha stat and pH stat.29 Alpha stat strategy aims at maintenance of pH at 7.4 as measured at 37°C and not corrected to patients’ temperature while pH stat maintains pH at 7.4 corrected to patients’ temperature. The pH stat strategy results in a more acidotic environment; it causes a luxury cerebral perfusion and a more homogenous cerebral cooling at the cost of a higher risk of cerebral emboli. A prospective trial comparing the two strategies in patients undergoing open heart surgery under DHCA showed that the pH stat strategy was associated with lower incidence of EEG seizures, shorter time to first EEG activity, lower peri-operative morbidity and mortality, shorter intensive care unit (ICU) stay and better cardiac output in post-operative period.30 However, on longer follow-up at 2-4 years there was no significant difference in psychomotor development index between the two groups.31 Use of pH stat strategy is currently recommended for operations involving DHCA especially in patients with aortopulmonary collaterals while alpha stat is favored for operations involving moderate hypothermia.

Optimal hematocrit : Hemodilution has been widely applied for hypothermic CPB for many years, primarily because of the belief that reduced viscosity would help in countering harmful effects of deep hypothermia. However, by shifting the oxygen dissociation curve to left, hemodilution may impair oxygen delivery. Shin'oka et al.32 demonstrated that extreme hemodilution (hematocrit < 10%) causes inadequate oxygen delivery during early cooling and higher hematocrit (30%) achieved with blood prime results in improved cerebral recovery after circulatory arrest.32 A recent single-centre randomized trial33 comparing two hemodilution protocols during hypothermic CPB in infants showed better psychomotor scores at 1 year follow-up in the higher hematocrit group.

Optimal temperature and post-operative hyperthermia: Hypothermia is one of the most powerful neuroprotective mechanisms during DHCA. This is because with decrease in temperature, when the cerebral blood flow (CBF) falls linearly, the cerebral metabolic rate for oxygen (CMRO2) falls exponentially, resulting in a progressive increase in CBF: CMRO2 ratio. The effect of rate of cooling and rewarming on long-term neurodevelopmental outcome is uncertain. Certain studies have shown that gradual cooling prior to circulatory arrest reduces the neurological complications compared to rapid cooling.28,34 Hyperthermia in the rewarming phase significantly increases neurological damage.35 A recent study36 showed that a strategy aiming at maintenance of normothermia in the post-operative period could reduce the incidence of neurological injury.

Pulsatile versus non-pulsatile flow: It has been suggested that the critical opening pressure of the capillary bed is lower with pulsatile than with non-pulsatile flow. Also, animal studies have shown that CBF is higher during pulsatile pump flow over a wide range of mean arterial pressure at normothermia. However, in younger patients cerebrovascular resistance is lower and hence, pulsatile flow, which decreases mean arterial pressure may not hold any advantage. Pediatric literature has no evidence in favor of pulsatile flow system with regard to superior cerebral hemodynamics or neurological outcomes.

7Post-operative factors: The role of post-operative factors on neurological outcome has not been studied in detail. Available studies have documented longer ICU stay (as a surrogate marker for complications like low cardiac output,infection, end organ failure etc.) as a risk factor for longterm neurodevelopmental sequelae.21,27 The presence of clinical or EEG seizures in the immediate post-operative period has been shown to adversely affect neurological outcome on follow-up.10 A recent study17 identified diastolic hypotension and significant hypoxemia in the postoperative period as risk factor for development of periventricular leukomalacia in neonates.

Role of Peri-Operative Neurophysiologic Monitoring The concept of multi-modality neurophysiologic monitoring has emerged in recent years as a pro-active measure to reduce neurological complications associated with cardiac surgery. Techniques like transcranial Doppler (TCD) and Near InfraRed Spectroscopy (NIRS) are particularly useful for determining the minimum acceptable flow rates in LF-CPB or maximum acceptable duration of DHCA.

37Various components of this monitoring are: (i) Functional neurodiagnostic studies: This includes EEG (cortex), visual, auditory and somatosensory-evoked potentials and electromyography, (ii) CBF velocity measurement: This can be done using transcranial Doppler ultrasonography of the middle cerebral artery. A 50% reduction from baseline flow velocity is considered as significant, (iii) Measurement of cerebral oxygenation: The techniques used for this purpose include jugular venous bulb saturation and NIRS. Recent studies38 using NIRS have shown its potential for non-invasive bedside monitoring of cerebral oxygenation, and (iv) Biochemical Markers: Various biochemical markers of central nervous system (CNS) injury in use include CPK-BB, lactate, neuron-specific enolase, S-100 protein and myelin basic protein.39 Lactate and CK-BB values correlate with periods of cerebral ischemia during CPB. S-100 protein levels correlate with duration of CPB, and when combined with neuron-specific enolase, identifies patients with CNS dysfunction after cardiac surgery.

Austin et al.40 reported the use of multi-modality neurophysiologic monitoring during pediatric cardiac surgery. Patients were divided into three groups – those with (i) no change in monitoring parameters, (ii) abnormalities on monitoring where appropriate therapeutic interventions were made, (iii) abnormalities where no intervention was made. The incidence of neurological complications was similar in the first two groups (7% v. 6%) while in group (iii) it was significantly higher (26%). The authors concluded that appropriate therapeutic interventions based on neurophysiologic monitoring could reduce neurological complications associated with pediatric cardiac surgery.

Neuroprotective Strategies The term neuroprotection refers to inhibition of biochemical and metabolic cascade after ischemia to prevent neuronal death. The various neuroprotective strategies to prevent neurological injury after pediatric cardiac surgery can be broadly categorized as under.

Optimal use of cardiopulmonary support techniques: Most of our current neuroprotective strategies revolve around optimal utilization and conduct of various cardiopulmonary support techniques.41 Current recommendations for circulatory support management are summarized in Table 2.

Neuroprotective drugs: Cellular mechanisms mediating ischemia reperfusion injury revolve around role of excitatory amino acids like glutamate (excitotoxicity), oxygen-derived free radicals and various inflammatory mediators like intracellular cell adhesion molecules (ICAM).43 Various drugs (both conventional and experimental) tried to mitigate pathophysiological cascade of neuronal injury are summarized in Table 3.

Strategies of selective cerebral perfusion: Retrograde cerebral perfusion (RCP): This technique, in which the brain is perfused retrograde via superior vena cava, is primarily used in adults undergoing aortic arch reconstruction. The technique has limited application in children during arch reconstruction since even small amounts of blood returning into field retrograde will result in unsatisfactory exposure.48

Cerebroplegia: Cerebroplegia solutions incorporating neuroprotective agents (e.g.: University of Wisconsin solution containing adenosine which is an NMDA blocker) can potentially reduce the excitotoxicity associated with ischemia-reperfusion injury.49 No randomized controlled trials of this strategy have been done in children.

Regional low-flow cerebral perfusion: This is also known as selective cerebral perfusion or antegrade cerebral perfusion. In this technique, right innominate artery selectively perfuses the brain (by placement of special small aortic cannula) while the other brachiocephalic vessels and descending aorta are snared. This approach reduces or eliminates the need for DHCA for operations like Norwood stage I palliation or aortic arch advancement and preserves brain function with potentially improved neurological outcomes.50

Conclusions

The tremendous advances in the peri-operative care of children undergoing cardiac surgery have resulted in the shift of the paradigm from reduction of peri-operative mortality to prevention of long-term neurodevelopmental complications. A careful pre-operative neurological evaluation is recommended for all children with complex heart disease since a large number of these patients have evidence of pre-operative neurological complications. Careful neuropsychological monitoring and adherence to the current recommendations of circulatory management during CPB can reduce the incidence of postoperative neurological complications. The immediate postoperative period is a potentially sensitive period where alterations in cardiorespiratory homeostasis can result in serious brain injury. Finally, survivors of complex cardiac surgery should undergo periodic neurodevelopmental surveillance for early detection of neurocognitive impairment so that rehabilitation can be instituted early.

Correspondence:


Dr R Krishna Kumar,
Chief Pediatric Cardiologist,
Amrita Institute of Medical Sciences and Research Centre,
PO Elamakkara,
Kochi 682026.
e-mail: rkrishnakumar@aimshospital.org
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