Neuroprotective Strategies – What Do We Really Need to Know? Francisco A. Guzmán-Pruneda, and Charles D. Fraser Jr. While preliminary data are encouraging, definitive data are lacking to conclusively demonstrate the benefit of perioperative neurologic monitoring in improving neurodevelopmental outcomes in children who require surgery for congenital heart disease. Nonetheless, in the current era, some form of perioperative neurologic monitoring is important. Strategies include bicortical near infrared spectroscopy monitoring in the pre- and postoperative periods along with bicortical near infrared spectroscopy and transcranial Doppler intraoperatively. These monitors provide real-time information concerning cerebral oxygen delivery and blood flow. These strategies will allow us to refine treatments to optimize neurodevelopmental potential in children with congenital heart disease. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 17:77-80 C 2014 Published by Elsevier Inc.



he progressive improvement in surgical mortality for children with congenital heart disease (CHD) has allowed more in depth focus on associated neurologic morbidity. Numerous investigators have documented the neurodevelopmental deficits in children after surgery for CHD.1–8 Deficits include, but are not limited to, impairments in executive functions, academic achievement, memory, and visual-spatial skills.6 Myelination is a pivotal step in brain maturation, and delayed myelination is associated with the potential for neuronal injury in the preterm neonate. Premature newborn brains exhibit changes in ultrastructure associated with the development of periventricular leukomalacia (PVL), a type of white matter injury.9,10 PVL is characterized by focal necrosis of white matter located in the walls of the lateral ventricles and diffuse injury to oligodendrocyte precursors.11 Woodward et al12 have shown a correlation between abnormal white matter findings on magnetic resonance imaging and poor cognitive and motor impairments at 2 years of age. PVL and other ischemic surrogates are frequently noted before Division of Congenital Heart Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX. Address correspondence to Charles D. Fraser, Jr., MD, FACS, Surgeon-inChief, Chief, Clayton Chair in Surgery, Donovan Chair and Chief, Congenital Heart Surgery, Texas Children’s Hospital, Professor of Surgery and Pediatrics, Baylor College of Medicine, 6621 Fannin Street, MC-WT 19345H, Houston, TX, 77030. E-mail: [email protected] 1092-9126/& 2014 Published by Elsevier Inc.

and after surgery in children with CHD. In some instances, pathogenesis may be related to an impaired circulatory physiology and preischemic state,13 including an association between untreated CHD and a decrease in baseline cerebral blood flow (CBF). The use of high-resolution magnetic resonance imaging and diffusion tensor imaging has further expanded the characterization of brain injury in this vulnerable population.14,15 Up to 40% of neonates with CHD will have preoperative imaging findings of neurological injury.16,17 Major types of acquired preoperative injury include focal stroke and PVL.13,18 Postoperative cerebral ischemia is also considered to have a dominant influence in the emergence of brain injury.19 Ultimately, more than 70% of children will have new or worsening of preexistent lesions following anatomic repair.20

Etiology of Brain Injury The understanding of the etiology of neurological injury in patients with CHD is progressing. Numerous factors are now known to play a role in the development of central nervous system morbidity.21 While the major emphasis was placed in the past on the risks of cardiopulmonary bypass (CPB), investigation has also shifted to factors associated with prenatal and perioperative brain injury. Newborn brains are vulnerable to stress-related injury, and this is especially true in infants with congenital heart defects. There is evidence that the brain of a full-term newborn with CHD resembles that of a premature neonate.21,22 Gross brain 77

F.A. Guzmán-Pruneda and C.D. Fraser Jr.

78 abnormalities may be present at birth. Patients with hypoplastic left heart syndrome and transposition of the great arteries may demonstrate alteration in central nervous system maturation comparable to a 1 month delay in structural brain development.22 Ortinau et al23 have related a decrease in cortical folding and cortical surface area to CHD. By analyzing brain microstructure and metabolism, investigators have also assessed brain maturation in this pediatric population. Compared with age-matching controls, patients with CHD demonstrated significant biochemical and imaging abnormalities indicative of widespread brain injury, according to Miller.24 In the treatment of the newborn with CHD, the brain is exposed to the potential of unsuspected iatrogenic injury. McQuillen and colleagues18 identified balloon atrial septostomy as a significant risk factor for preoperative stroke in 61% of patients with transposition of the great arteries. While our group did not find preoperative balloon atrial septostomy to be a significant risk factor in a comparable study population, it remains undeniable that children with structural CHD and intracardiac manipulation are at risk.25 Our findings were also supported by Petit and colleagues,26 who correlated the degree of perioperative brain injury with the duration of preoperative hypoxia. Genetic factors are also known to significantly influence the risk of suboptimal neurodevelopmental outcomes. Gaynor et al27 found an association between the apolipoprotein E ε2 allele and a worse neurologic outcome when patients were assessed for psychomotor development at 1 year of age.

What to Do – Can Neuromonitoring Affect Outcomes? In a prospective, observational study of 30 neonates undergoing an arterial switch operation, we sought to determine if early improved neurological status translated into better longterm outcomes in patients undergoing neonatal ASO. Our group identified several modifiable factors that impact neurodevelopmental outcomes.25 Among them, cerebral regional oxygen saturation (rSO2) values o45% in the preoperative period correlated with lower cognitive and motor scores while intraoperative rSO2 levels o45% were associated with lower language scores. This raises the question of whether avoiding prolonged cerebral oxygen deprivation by early anatomic correction is associated with improved outcome. Furthermore, to our view, these data present convincing evidence that identifying significant perioperative brain hypoxia is important in mitigating the risk of brain injury. As such, we see the use of neuromonitoring as critical in effective management of our patients. Without question, other than timing of surgery, the intraoperative period is the time over which the surgeon exerts the most control. Thusly, given the aforementioned observations, our theory is that optimized intraoperative brain protection through delivery of appropriate CBF to both cerebral hemispheres can only be achieved through effective intra- and perioperative neuromonitoring.

The Boston Circulatory Arrest trial28 found a nonlinear relationship between duration of total arrest and the degree of brain injury, with the risk becoming significant after exceeding a 41-minute threshold. This number is not intended to represent a universal timeframe for every patient undergoing cardiac surgery, as other factors come into play such as diagnosis, age at surgery, perfusion strategy, and postoperative care. Additionally, other intraoperative factors such as lowflow CPB, a base deficit on arterial blood gas analysis during bypass, and low mean blood pressure on postoperative day 1, were associated with postoperative white matter injury.18 As noted above, without the use of some assessment of intraoperative brain physiology, the surgeon is left to wonder whether the duration of cerebral ischemia in a given patient has exceeded the threshold for irreversible ischemic insult.

Does it Matter? In an analysis of nonmodifiable, patient-related factors, Gaynor et al29 and Goff et al30 determined low birth weight, ethnicity, gender, total brain maturation score, and the presence of a genetic syndrome to be significant predictors of neurodevelopmental outcomes at 1 year of age. Gaynor and colleagues did not find the use of deep hypothermic circulatory arrest (DHCA) nor its duration, with a median of 34 minutes, to be associated with a worse neurological outcome. Recently, a prospective, randomized controlled trial by Algra et al31 compared antegrade cerebral perfusion (ACP) versus DHCA and found no difference in neurodevelopmental outcomes at 2 years of age. However, their perfusion protocol included inferior flow rates, an alpha stat perfusion strategy, lower target hematocrit, and a lack of continuous neuromonitoring to guide ACP flow intraoperatively. Conversely, research conducted at our institution25,32 revealed that potentially modifiable, perioperative factors play a pivotal role in neurodevelopmental outcomes. Our observations have been further supported by Hoffman et al,33 who revealed that visual-motor integration as well as neurodevelopmental index were normal, provided that cerebral oxygen saturation remained above 45% in the early postoperative period. These investigators also documented an association between the hours spent at rSO2 o45%–55% and poorer neurological outcomes. Our interpretation of these data, as well as our own, draws us to the conclusion that perioperative neurologic monitoring is warranted.

Neuromonitoring Tools Near infrared spectroscopy (NIRS) provides real-time, continuous, non-invasive estimates of cerebral cortical oxygenation before, during, and after cardiac surgery. Of note, conventional NIRS devices have a maximum read out upper value of 95%, which is often achieved during periods of CPB, particularly during periods of hypothermia. This leads to a legitimate concern about the potential for excessive CBF. Therefore, our group has investigated the benefit of incorporating CBF velocities measured by transcranial Doppler (TCD) and cerebral rSO2 measured by NIRS to our neuromonitoring protocol in an effort to provide optimal cerebral perfusion during CPB.34

Neuroprotective strategies


ACP Strategy


Unfavorable neurological outcomes associated with low-flow CBP and circulatory arrest have provoked a shift toward the provision of physiologic CBF during aortic arch reconstruction. ACP was initially devised as a means of circumventing the need for DHCA and its consequential effects.35 A variety of ACP techniques have been described, and to our belief, this lack of standardization in cannulation, flow rate, and neuromonitoring strategies has made outcomes comparison challenging and is, in part, responsible for the lack of clearly documented outcomes differences when comparing ACP and DHCA. As per previous discussion, we believe that physiologic ACP can only be provided if one utilizes some form of intraoperative neurologic monitoring. Hofer et al36 have documented that at ACP flow rates of o30 cc/kg, about 10% of patients will have no detectable TCD flow signal in the left cerebral hemisphere, emphasizing that in some patients the circle of Willis flow is compromised. As such, we have noted that bicortical NIRS and TCD monitoring is essential to assure adequate flow to both hemispheres. Even in cases of standard cannulation and CPB, one cannot be entirely assured of adequate CBF to both hemispheres without monitoring.37,38 Cerebral physiological monitoring is carried out via bilateral frontal NIRS and TCD through the anterior fontanel or temporal window. Baseline mean CBF and rSO2 are established via NIRS and TCD, at 18˚ to 22˚C, during full flow CPB. Snares are placed on the brachiocephalic vessels and the descending thoracic aorta. CBF is then provided from the right innominate and right vertebral arteries, which are above the level of the snare. pH-stat acidbase management and target hematocrit of 30% to 35% are utilized in all phases of CPB.39 ACP flow rates are adjusted to achieve CBF velocity and oxygen saturation within þ 10% of the baseline values at full CPB. If the left hemispheric rSO2 decreases more than 10% below the right-sided rSO2, or to a value lower than 80% to 85%, ACP flow and hematocrit should be increased.40

1. Visconti KJ, Rimmer D, Gauvreau K, et al: Regional low-flow perfusion versus circulatory arrest in neonates: one-year neurodevelopmental outcome. Ann Thorac Surg 2006;82:2207-2211; [discussion, 2211-2213] 2. Goldberg CS, Bove EL, Devaney EJ, et al: A randomized clinical trial of regional cerebral perfusion versus deep hypothermic circulatory arrest: outcomes for infants with functional single ventricle. J Thorac Cardiovasc Surg 2007;133:880-887 3. Bellinger DC, Jonas RA, Rappaport LA, et al: Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 1995;332:549-555 4. Bellinger DC, Wypij D, duPlessis AJ, et al: Neurodevelopmental status at eight years in children with dextro-transposition of the great arteries: the Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003;126: 1385-1396 5. Bellinger DC, Wypij D, Kuban KC, et al: Developmental and neurological status of children at 4 years of age after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. Circulation 1999;100:526-532 6. Bellinger DC, Wypij D, Rivkin MJ, et al: Adolescents with d-transposition of the great arteries corrected with the arterial switch procedure: neuropsychological assessment and structural brain imaging. Circulation 2011;124:1361-1369 7. Shillingford AJ, Glanzman MM, Ittenbach RF, et al: Inattention, hyperactivity, and school performance in a population of schoolage children with complex congenital heart disease. Pediatrics 2008;121:e759-e767 8. Newburger JW, Jonas RA, Wernovsky G, et al: A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med 1993;329:1057-1064 9. Volpe JJ: Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res 2001;50:553-562 10. Volpe JJ: Brain injury in the premature infant—from pathogenesis to prevention. Brain Dev 1997;19:519-534 11. Rezaie P, Dean A: Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system. Neuropathology 2002;22:106-132 12. Woodward LJ, Anderson PJ, Austin NC, et al: Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med 2006;355:685-694 13. Licht DJ, Wang J, Silvestre DW, et al: Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects. J Thorac Cardiovasc Surg 2004;128:841-849 14. Mercuri E, Barnett A, Rutherford M, et al: Neonatal cerebral infarction and neuromotor outcome at school age. Pediatrics 2004;113:95-100 15. Soul JS, Robertson RL, Wypij D, et al: Subtle hemorrhagic brain injury is associated with neurodevelopmental impairment in infants with repaired congenital heart disease. J Thorac Cardiovasc Surg 2009;138:374-381 16. Sherlock RL, McQuillen PS, Miller SP, et al: Preventing brain injury in newborns with congenital heart disease: brain imaging and innovative trial designs. Stroke 2009;40:327-332 17. Mahle WT, Tavani F, Zimmerman RA: An MRI study of neurological injury before and after congenital heart surgery. Circulation 2002;106 (suppl 1):I109-I144 18. McQuillen PS, Barkovich AJ, Hamrick SE, et al: Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke 2007;38(suppl):736-741 19. Galli KK, Zimmerman RA, Jarvik GP, et al: Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg 2004;127:692-704 20. Dent CL, Spaeth JP, Jones BV, et al: Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg 2006;131:190-197 21. Wernovsky G: Current insights regarding neurological and developmental abnormalities in children and young adults with complex congenital cardiac disease. Cardiol Young 2006;(suppl 1):92-104

Conclusion Definitive data are lacking to conclusively demonstrate the benefit of perioperative neurologic monitoring in improving neurodevelopmental outcomes in children who require surgery for CHD. Nonetheless, in the current era, we believe some form of perioperative neurologic monitoring is important. Our current strategy includes bicortical NIRS monitoring in the pre- and postoperative periods along with bicortical NIRS and TCD intraoperatively. These monitors provide real time information concerning cerebral oxygen delivery useful in adjusting therapy. It is hoped that this strategy will allow us to continue to refine treatments to optimize neurodevelopmental potential in children with CHD. Future studies will include the use of novel methods to discern thresholds for loss of cerebral autoregulation, and will provide another opportunity for refinement of perfusion and perioperative management strategy.

80 22. Licht DJ, Shera DM, Clancy RR, et al: Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg 2009;137:529-536; [discussion, 536-537] 23. Ortinau C, Alexopoulos D, Dierker D, et al: Cortical folding is altered before surgery in infants with congenital heart disease. J Pediatr 2013;163: 1507-1510 24. Miller SP, McQuillen PS, Hamrick S, et al: Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007;357: 1928-1938 25. Andropoulos DB, Easley RB, Brady K, et al: Changing expectations for neurological outcomes after the neonatal arterial switch operation. Ann Thorac Surg 2012;94:1250-1255; [discussion, 1255-1256] 26. Petit CJ, Rome JJ, Wernovsky G, et al: Preoperative brain injury in transposition of the great arteries is associated with oxygenation and time to surgery, not balloon atrial septostomy. Circulation 2009;119:709-716 27. Gaynor JW, Gerdes M, Zackai EH, et al: Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg 2003;126:1736-1745 28. Wypij D, Newburger JW, Rappaport LA, et al: The effect of duration of deep hypothermic circulatory arrest in infant heart surgery on late neurodevelopment: The Boston Circulatory Arrest Trial. J Thorac Cardiovasc Surg 2003;126:1397-1403 29. Gaynor JW, Wernovsky G, Jarvik GP, et al: Patient characteristics are important determinants of neurodevelopmental outcome at one year of age after neonatal and infant cardiac surgery. J Thorac Cardiovasc Surg 2007;133:1344-1353 30. Goff DA, Shera DM, Tang S, et al: Risk factors for preoperative periventricular leukomalacia in term neonates with hypoplastic left heart syndrome are patient related. J Thorac Cardiovasc Surg 2013. http://dx.; [Epub ahead of print] 31. Algra SO, Jansen N, van der Tweel I, et al: Neurological injury after neonatal cardiac surgery: a randomized controlled trial of two perfusion techniques. Circulation 2014;129:224-233

F.A. Guzmán-Pruneda and C.D. Fraser Jr. 32. Andropoulos DB, Easley RB, Brady K, et al: Neurodevelopmental outcomes after regional cerebral perfusion with neuromonitoring for neonatal aortic arch reconstruction. Ann Thorac Surg 2013;95:648-654; [discussion, 654-655] 33. Hoffman GM, Brosig CL, Mussatto KA, et al: Perioperative cerebral oxygen saturation in neonates with hypoplastic left heart syndrome and childhood neurodevelopmental outcome. J Thorac Cardiovasc Surg 2013;146: 1153-1164 34. Andropoulos DB, Stayer SA, McKenzie ED, et al: Novel cerebral physiologic monitoring to guide low-flow cerebral perfusion during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg 2003;125: 491-499 35. Pigula F, Nemoto EM, Griffith BP, et al: Regional low-flow perfusion provides cerebral circulatory support during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg 2000;119:331-339 36. Hofer A, Haizinger B, Geiselseder G, et al: Monitoring of selective antegrade cerebral perfusion using near infrared spectroscopy in neonatal aortic arch surgery. Eur J Anaesthesiol 2005;22:293-298 37. Gottlieb EA, Fraser CD Jr., Andropoulos DB, et al: Bilateral monitoring of cerebral oxygen saturation results in recognition of aortic cannula malposition during pediatric congenital heart surgery. Paediatr Anaesth 2006;16:787-789 38. Austin EH 3rd, Edmonds HL Jr., Auden SM, et al: Benefit of neurophysiologic monitoring for pediatric cardiac surgery. J Thorac Cardiovasc Surg 1997;114:707-715; 717; [discussion, 715-716] 39. Jonas RA, Wypij D, Roth SJ, et al: The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg 2003;126: 1765-1774 40. Fraser CD Jr., Andropoulos DB: Principles of antegrade cerebral perfusion during arch reconstruction in newborns/infants. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2008;11:61-68

Neuroprotective strategies--what do we really need to know?

While preliminary data are encouraging, definitive data are lacking to conclusively demonstrate the benefit of perioperative neurologic monitoring in ...
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