Neonatal Brain Protection in Cardiac Surgery and the Role of Intraoperative Neuromonitoring

Abstract

Improving mortality rates in children undergoing surgery for congenital heart disease has enabled a shift in focus to improving morbidity, particularly with respect to neurological complications. Various factors have been implicated in influencing neurological outcomes. We share our experience in formulating a customized cardiopulmonary bypass (CPB) protocol based on currently available evidence. Theoretical advantages of intraoperative neuromonitoring during CPB, specifically use of near-infrared spectroscopy, will be discussed in the context of methodologies to monitor cerebral perfusion during surgery.

Keywords

near-infrared spectroscopy cardiopulmonary bypass antegrade cerebral perfusion deep hypothermic circulatory arrest

Introduction

As operative mortality in congenital heart surgery continues to decline, there is an increased emphasis on decreasing early and late morbidity. With advancements in surgical technique and the advent of innovative technology, the vast majority of the children born with congenital heart defects (CHDs) will survive to adult life and there are now more adults than children with CHD.¹ It is apparent that these patients face considerable challenges as they progress into adult life including the risks of sudden death, reoperation, and neurocognitive complications. These neurocognitive complications often manifest early in life. Creighton et al showed that 26% of the children that had cardiac surgery as neonates had IQ <85 at five years.² Similarly, Majnemer et al showed that 49% of these children have gross motor deficits and 39% have fine motor deficits at five years.³ The risk of neurological problems is greater for those that have the more severe forms of cardiac disease and especially for those requiring surgical intervention in the neonatal period. It has been reported that the incidence of long-term neurodevelopmental outcomes after neonatal and infant congenital heart surgery ranges from 21% to 69%.^3–5

In this brief review, we discuss our approach in attempting to mitigate some of the risks of perioperative neurological injury in neonates with CHD. Specifically, we will focus on the various techniques used as elements of the cardiopulmonary bypass (CPB) protocol at Texas Children’s Hospital emphasizing particularly the use of near-infrared spectroscopy (NIRS) as the neuromonitoring strategy to aid customized CPB.

Neurological Injury in Neonates With CHD

Risk factors associated with neurological injury after cardiac surgery in children are postulated to be multifactorial with prenatal, genetic, socioeconomic, and perioperative factors being implicated. It is becoming increasingly clear that preoperative injury may be an important contributor to this effect. Miller et al showed increased white matter injury in newborns with congenital heart disease.⁶ A study from our group confirmed that brain immaturity is associated with pre- and postoperative magnetic resonance imaging (MRI) abnormailities.⁷ Limperopoulos et al reported that newborns with abnormal somatosensory-evoked potentials prior to or following open heart surgery had abnormal neurologic examinations both perioperatively and again one year after surgery.⁸ Licht et al observed smaller and structurally less developed brains among term infants with hypoplastic left heart syndrome and transposition of great arteries. They concluded that these patients are susceptible to periventricular leukomalacia (PVL) in the perioperative period.⁹ Periventricular leukomalacia is cerebral white matter necrosis adjacent to lateral ventricles, resulting from injury to immature oligodendrocytes. Galli et al reported PVL in over 50% of the neonates in their study population after cardiac surgery, a finding not observed in older infants.¹⁰ In relation to genetic susceptibility to neurologic injury, Gaynor et al described an association between certain polymorphisms of apolipoprotein E genotype and low Psychomotor Development Index scores at one year after infant cardiac surgery.¹¹ It is in this complex environment that efforts are ongoing to optimize individual neurodevelopmental potential. To us, it is logical that efforts to reduce intraoperative cerebral malperfusion or unrecognized ischemia should have a net positive effect on long-term neurodevelopmental potential.

Refining CPB Strategies

Despite considerable progress in the development of CPB strategies for small children, significant challenges remain, particularly, when one considers the potential for brain injury. There have been a number of experimental and clinical studies examining neurological outcomes associated with various CPB strategies. The period of support with CPB is, of course, one element of the continuum of risk that these children face, which the surgeon can strongly influence. As such, it is critical for the operating surgeon to carefully assess currently available data and methodologies as they relate to the potential for impacting neurodevelopmental outcomes.

Low-flow CPB and the use of deep hypothermic circulatory arrest (DHCA) are frequently employed strategies to aid in the conduct of complex congenital cardiac corrections, but some reports suggest that these strategies have been associated with neurologic complications and/or neurodevelopmental abnormalities in up to 50% of patients.^12–14 In a piglet model of low-flow hypothermic CPB, Loepke et al observed that neuronal injury occurred predominantly in deep neocortex and in the hippocampus. Factors mitigating injury were higher arterial carbon dioxide, hematocrit (Hct), and blood glucose levels.¹⁵ One of several important findings from the Boston Circulatory Arrest Trial was the observation that the duration of continuous DHCA did not adversely affect the neurological outcome unless it exceeded 41 minutes.¹⁶ In a study looking at the outcomes of neonatal arterial switch operations performed with hypothermic full-flow CPB (150 mL/kg per min), alpha-stat pH management, and minimal periods of hypothermic circulatory arrest, Karl et al observed that the incidence of all perioperative neurologic abnormalities was 20%. Based on the evaluation at late follow-up, they concluded that not all survivors could be considered neurodevelopmentally normal but that the risk of important impairment was low.¹⁷ Pouard et al published their findings regarding the use of normothermic CPB for neonatal arterial switch operations. They compared the results with hypothermic CPB and concluded that not only was normothermic CPB a feasible option but also allowed a faster recovery time.¹⁸ Controversy persists as to the optimal strategy of acid–base and arterial blood gas management during the various phases of CPB. Two commonly used strategies are the pH-stat and the alpha-stat strategy. Studies have shown lower morbidity and shorter recovery for patients managed with pH-stat versus alpha-stat strategy.¹⁹ Kurth et al studied a piglet model of CPB with deep hypothermnic circulatory arrest. They reported that cortical deoxygenation during hypothermic arrest was slower after pH-stat CPB and that the pH-stat strategy of blood gas management was associated with improved neurologic outcomes when compared with the alpha-stat strategy.^20,21

Core Principles and Practices of CPB at Texas Children’s Hospital

We follow two basic principles to guide CPB technique at our institution. We aim to deliver “adequate” amounts of oxygenated blood to both cerebral hemispheres during all phases of CBP. Second, we try to avoid or minimize the use of any technique that violates the first core principle.

Our strategy is based primarily on the use of full-flow CPB (≥150 mL/kg per min). We aim to minimize and eliminate wherever possible the use of low-flow CPB and DHCA. For procedures that could alternatively be performed utilizing DHCA, such as aortic arch reconstruction and Norwood stage I palliation, we favor continuous bypass with selective antegrade cerebral perfusion (ACP) during the arch reconstruction. The basic technique, now uniformly adopted, was described by Pigula et al as a means of reducing circulatory arrest time and maintaining cerebral blood volume and oxygen saturation.²² We have modified the original technique with some critical differences relating to flow rates and cerebral physiologic monitoring.²³ We use bilateral NIRS and transcranial Doppler (TCD) ultrasound to guide ACP. Flow rates used during ACP at our institution are almost double the rates that others have reported.^24–26 Our strategy is highly influenced by the observation that flow rates of <30 mL/kg per min may not provide adequate cerebral blood flow to some patients.²⁷ Pigula and associates studied a cohort of patients that had undergone a stage I Norwood palliation with either regional low-flow perfusion of the brain (ACP) or DHCA. Neurodevelopmental outcomes were not significantly different for the two groups at one year.²⁸ This was a nonrandomized study. We believe that the ACP flow rates used in this study (30-40 mL/kg per min) may be less than optimal for some patients.

We favor the use of a pH-stat strategy of acid–base management in neonates in all phases of CPB. Some centers still use alpha-stat management and although there are pros and cons to both techniques, pH-stat has been shown by some to be associated with reduced perioperative morbidity in infants when compared with alpha-stat.¹⁹

We use Hct levels ranging from 30% to 35% on CPB. Jonas et al demonstrated in a single-center randomized trial that neonates who were maintained at Hct of around 20% during hypothermic CPB had poorer perioperative and developmental outcomes than those maintained at Hct of about 30%.²⁹

We emphasize slow cooling over no <20 minutes to deep hypothermia (18°C-20°C). Figure 1 demonstrates a typical NIRS recording obtained during a case conducted using the above-mentioned CPB protocol in our institution. A study published by our group on 20 neonates that underwent aortic arch reconstruction using this CPB strategy showed excellent short-term survival and clinical outcomes. Bilateral NIRS showed regional cerebral oxygenation saturation (rSO₂) of 87% to 95% during ACP.³⁰ Table 1 summarizes the CPB strategy used in our institution.

Figure 1.

A near-infrared spectroscopy (NIRS) graph showing regional cerebral saturation of oxygen index (rSO₂i) in a neonate with an unbalanced complete common atrioventricular canal defect (left ventricular dominance) and infradiaphragmatic total anomalous pulmonary venous return. This patient underwent four periods of deep hypothermic circulatory arrest (DHCA) at 18°C of 3, 12, 26, and 1 minute duration, respectively, for a total of 42 minutes. We used hematocrit (Hct) >30%, slow cooling over >20 minutes, pH-stat, full-flow CPB at 150 mL/kg per min and rSO₂ was kept above 90% before DHCA. The rSO₂i was not allowed to fall beyond baseline levels during the entire period from initiation of CPB to end of support.

Table 1.

Core Practices of the CPB Strategy in Texas Children’s Hospital

Full CPB flow of 150 mL/kg per min at all possible times

Minimize or eliminate low-flow CPB

Minimize or eliminate DHCA (exception TAPVR)

ACP for aortic arch reconstruction

“Adequate” ACP flow rate guided by NIRS and TCD

pH-stat management during all phases of CPB

Hematocrit of 30%-35% on CPB

Slow deep cooling over no <20 minutes to deep hypothermia

Abbreviations: CPB, cardiopulmonary bypass; DHCA, deep hypothermic circulatory arrest; TAPVR, total anomalous pulmonary venous return; ACP, antegrade cerebral perfusion; NIRS, near-infrared spectroscopy; TCD, transcranial Doppler.

NIRS Monitoring of Cerebral Oxygen Saturation during CPB

Near-infrared spectroscopy is a noninvasive optical technique used to monitor brain tissue oxygenation. Near-infrared spectroscopy monitoring tools for pediatric patients use different algorithms than those used for adults. Near-infrared light at 730 and 810 nm wavelengths is used to estimate relative amounts of oxygenated and deoxygenated hemoglobin (Hb) in the cerebral blood. Also, there is a subtraction algorithm for the thinner pediatric skull and extracranial tissue compared with adults.³¹ One light-emitting diode is used that emits near-infrared light to a portion of the frontal cerebral cortex and is detected through two detectors placed three and four centimeters from the emitter. The device that we use is the Somanetics INVOS system which is US Food and Drug Administration (FDA) approved. It displays a numerical result as rSO₂ index (rSO₂i). This index is a ratio of oxygenated Hb to total Hb in the light pathway and is reported as a percentage ranging from 15% to 95%.

Near-infrared spectroscopy can accurately estimate cerebral oxygenation during cardiac operations.³² Blood in the cerebral circulation is predominantly venous and this accounts for the relationship of the rSO₂ measured by NIRS to the oxygen saturation in the jugular venous bulb. Daubeney et al reported a comparison between the two and showed excellent correlation.³² However, as Tortoriello et al reported, although NIRS can predict trends in cerebral oxygen saturation quite well, it cannot predict absolute values of systemic venous oxygen saturation (SvO₂) solely through measurement of rSO₂.³³

In a study of cerebral oxygenation during pediatric cardiac surgery with deep hypothermic circulatory arrest in 26 patients, Kurth et al observed that postoperative neurologic status was abnormal in three (12%) patients. The cerebrovascular hemoglobin oxygen saturation (SCO₂) increase during deep hypothermic CPB was less in these three patients than in the remaining study population. There were no other significant SCO₂ differences between outcome groups.³⁴ Hoffman et al investigated potential relationships between SvO₂ following the Norwood stage 1 procedure and childhood neurodevelopmental outcomes. Participants scored significantly below the population mean for motor, visual–motor integration, and composite neurodevelopmental outcomes at age of four years.³⁵ The five (of 13) patients with abnormal outcomes had significantly lower postoperative SvO₂ values than those with normal outcomes (46% ± 8% vs 56% ± 6%, P = .024). Standard hemodynamic parameters did not differentiate patient outcomes. The risk of abnormal outcome increased with increasing time at a SvO₂ of <40% (P < .001).

A study by Dent et al involving brain imaging by MRI after Norwood stage I palliation showed that nine of the ten neonates with rSO₂ <45% for >180 minutes during the perioperative period had new ischemic MRI lesions.²⁵ Austin et al reported a benefit associated with multimodality neurophysiologic monitoring during pediatric cardiac surgery in a cohort of 250 patients. Obvious neurologic sequelae occurred in 7% of patients for whom monitoring had not detected noteworthy changes in cerebral perfusion or metabolism, and 6% in whom noteworthy changes were followed by an intervention that altered patient management. In contrast to this, obvious neurologic sequelae occurred in 26% of patients in whom changes were detected by monitoring but were not followed by an intervention.³⁶

Near-infrared spectroscopy may be very sensitive in detecting altered perfusion and oxygen delivery and thus may help to avert disasters during operation, particularly in neonates and infants. Sakamoto et al reported on the detection of cerebral ischemia caused by an obstructed superior vena cava cannula with the help of NIRS, which could not be identified by other monitoring modalities.³⁷ Gottlieb et al reported on the recognition of aortic cannula displacement during cardiac surgery through bilateral NIRS monitoring of rSO₂. The authors felt that the aortic cannula malposition would not have been detected using standard monitors.³⁸

In our institution, we employ bilateral NIRS in all aortic arch repairs as a guide to ACP. We have earlier shown the efficacy of ACP to provide comparable blood flow to both cerebral hemispheres with bilateral NIRS and TCD as guides to adequacy of the flow.^30,39 We also use NIRS in cases that require DHCA to guide our strategy of minimizing the duration of DHCA and to help assess adequacy of perfusion during the cooling phase of CPB prior to DHCA. We use NIRS to help confirm proper cannula positioning and also for monitoring during closed heart procedures such as coarctation repairs and placement of systemic to pulmonary artery shunts.

Bilateral NIRS as a Guide to ACP

Antegrade cerebral perfusion is a technique devised to avoid or minimize DHCA during procedures such as aortic arch reconstruction and Norwood stage I palliation in neonates (Figure 2 ). Pigula et al demonstrated that with ACP use there is blood flow both to the brain and to subdiaphragmatic structures.^22,40 As discussed earlier, the ACP technique that we use is a modification of their strategy; the critical differences being the neurophysiologic monitoring with bilateral NIRS and ACP flow rate. We have good success in terms of outcomes for our patients that require aortic arch repair on ACP.⁴¹

Figure 2.

Depiction of the operative field during aortic arch recontruction with antegrade cerebral perfusion (ACP). Arterial inflow is through the cannulated three to four mm polytetrafluoroethylene (PTFE) graft following anastomosis of the graft to the innominate artery. Exposure is maintained by gentle retraction on the brachiocephalic vessel snares and a snare or clamp on the descending aorta and the right atrial cannula.

We use bilateral NIRS to guide ACP during cardiac surgery. This strategy stems from the published studies that demonstrated lower rSO₂ on the left side of brain compared with the right side, while on ACP. The reasons for this disparity may be multiple, including the fact that all blood flow to the left side during ACP is through the circle of Willis. Other reasons for these findings may include anatomic variations, obstructed left-sided venous drainage or positioning of the patient.^30,39,42 Hence, without left-sided monitoring strategy, left-sided desaturations may go undetected.

Future Neuroprotection Studies

Studies are currently underway examining novel techniques to improve neurological outcomes after neonatal cardiac surgery. One of these studies includes looking at the role of erythropoietin (EPO) at improving neurodevelopmental outcomes at one, three, and five years of age. Erythropoietin has been shown to have multiple biologic roles including neurological and cardioprotective effects.⁴³ Neonates are ideal candidates for this therapy as the timing of the neurologic insult is known, thus allowing appropriate time for the effect of EPO to occur.

In the recent past, there has been concern about the use of anesthesia and its effect on neurodevelopment on neonates.⁴⁴ On the other hand, it is also known that anesthetics like ketamine that antagonize N-methyl-d-aspartate receptors can block influx of calcium ions as a response to ischemic injury and thus may have a protective effect with regard to neurologic injury.⁴⁵ A clinical trial is currently underway to determine the advantages in neurological outcomes, if any, associated with the use of ketamine in children.

An ongoing study by our group is using brain MRI, electroencephalogram, and neurodevelopmental outcomes to assess the effects of our high-flow CPB and increased oxygen delivery strategy on new hypoxic brain injury after cardiac surgery in neonates. The hypothesis is that our CPB strategy may reduce the incidence of hypoxic–ischemic brain lesions postoperatively compared to that in previously published reports. Early results have shown a strong relationship of postoperative white matter injury to preoperative brain injuries and single-ventricle anatomy. No association of brain injury has so far been established between the gestational age at birth, use of ACP versus full-flow CPB or rSO₂ <45% for >240 minutes in the perioperative period. The study is currently enrolling patients and will include planned follow-up evaluations out to five years.

Conclusion

Although our CPB strategy has not been conclusively demonstrated to be superior to others, considerable evidence exists that can help in formulating a successful customized CPB protocol. Inadequate cerebral blood flow has been strongly associated with poor neurological outcomes and providing adequate blood flow during all phases of CPB is the goal of most strategies. We believe that this is facilitated by continuous monitoring of cerebral perfusion, which can be reliably achieved through the application of bilateral NIRS and TCD. Our CPB strategy has shown promise and we are encouraged by our preliminary outcomes. However, further studies looking at long-term neurological outcomes are required and are currently underway.

Footnotes

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Presented at the Fourth Annual Symposium of the Walter Sisulu Paediatric Cardiac Centre for Africa, Johannesburg, South Africa; March 23–24, 2011.

Abbreviations and Acronyms

References

Williams

Pearson

Barst

. Report of the national heart, lung, and blood institute working group on research in adult congenital heart disease. J Am Coll Cardiol. 2006;47(4):701–707.

Creighton

Robertson

Sauve

. Neurocognitive, functional, and health outcomes at 5 years of age for children after complex cardiac surgery at 6 weeks of age or younger. Pediatrics. 2007;120(3):e478–e486.

Majnemer

Limperopoulos

Shevell

Rosenblatt

Rohlicek

Tchervenkov

Long-term neuromotor outcome at school entry of infants with congenital heart defects requiring open-heart surgery. J Pediatr. 2006;148(1):72–77.

Wernovsky

Shillingford

Gaynor

JW.

Central nervous system outcomes in children with complex congenital heart disease. Curr Opin Cardiol. 2005;20(2):94–99.

Bellinger

Wypij

duDuplessis

. 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(5):1385–1396.

Miller

McQuillen

Hamrick

. Abnormal brain development in newborns with congenital heart disease. N Engl J Med. 2007;357(19):1928–1938.

Andropoulos

Hunter

Nelson

. Brain immaturity is associated with brain injury before and after neonatal cardiac surgery with high-flow bypass and cerebral oxygenation monitoring. Thorac Cardiovasc Surg. 2010;139(3):543–556.

Limperopoulos

Majnemer

Rosenblatt

Shevell

Rohlicek

Tchervenkov

Multimodality evoked potential findings in infants with congenital heart defects. J Child Neurol. 1999;14(11):702–707.

Licht

Shera

Clancy

. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg. 2009;137(3):529–536; discussion 536–537.

10.

Galli

Zimmerman

Jarvik

. Periventricular leukomalacia is common after neonatal cardiac surgery. J Thorac Cardiovasc Surg. 2004;127(3):692–704.

11.

Gaynor

Gerdes

Zackai

. Apolipoprotein E genotype and neurodevelopmental sequelae of infant cardiac surgery. J Thorac Cardiovasc Surg. 2003;126(6):1736–1745.

12.

Ehyai

Fenichel

Bender

Incidence and prognosis of seizures in infants after cardiac surgery with profound hypothermia and circulatory arrest. JAMA. 1984;252(22):3165–3167.

13.

Hammon

Stump

Butterworth

Moody

DM.

Approaches to reduce neurologic complications during cardiac surgery. Semin Thorac Cardiovasc Surg. 2001;13(2):184–191.

14.

Hickey

PR.

Neurologic sequelae associated with deep hypothermic circulatory arrest. Ann Thorac Surg. 1998;65(6 suppl):S65–S69; discussion S69–S70, S74–S76.

15.

Loepke

Golden

McCann

Kurth

CD.

Injury pattern of the neonatal brain after hypothermic low-flow cardiopulmonary bypass in a piglet model. Anesth Analg. 2005;101(2):340–348.

16.

Wypij

Newburger

Rappaport

. 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(5):1397–1403.

17.

Karl

Hall

Ford

. Arterial switch with full-flow cardiopulmonary bypass and limited circulatory arrest: neurodevelopmental outcome. J Thorac Cardiovasc Surg. 2004;127(1):213–222.

18.

Pouard

Mauriat

. Normothermic cardiopulmonary bypass and myocardial cardioplegic protection for neonatal arterial switch operation. Eur J Cardiothorac Surg. 2006;30(5):695–699.

19.

du Plessis

Jonas

Wypij

. Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg. 1997;114(6):991–1000; discussion 1000–1001.

20.

Kurth

O’Rourke

O’Hara

IB.

Comparison of pH-stat and alpha-stat cardiopulmonary bypass on cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets. Anesthesiology. 1998;89(1):110–118.

21.

Priestley

Golden

O’Hara

McCann

Kurth

CD.

Comparison of neurologic outcome after deep hypothermic circulatory arrest with alpha-stat and pH-stat cardiopulmonary bypass in newborn pigs. J Thorac Cardiovasc Surg. 2001;121(2):336–343.

22.

Pigula

Nemoto

Griffith

Siewers

RD.

Regional low-flow perfusion provides cerebral circulatory support during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg. 2000;119(2):331–339.

23.

Fraser

Jr Andropoulos

DB.

Principles of antegrade cerebral perfusion during arch reconstruction in newborns/infants. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2008;11(1):61–68.

24.

McQuillen

Barkovich

Hamrick

. Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke. 2007;38(2 suppl):736–741.

25.

Dent

Spaeth

Jones

. Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg. 2005;130(6):1523–1530.

26.

Tweddell

Hoffman

Mussatto

. Improved survival of patients undergoing palliation of hypoplastic left heart syndrome: lessons learned from 115 consecutive patients. Circulation. 2002;106(12 suppl 1):I82–I89.

27.

Hofer

Haizinger

Geiselseder

Mair

Rehak

Gombotz

Monitoring of selective antegrade cerebral perfusion using near infrared spectroscopy in neonatal aortic arch surgery. Eur J Anaesthesiol. 2005;22(4):293–298.

28.

Visconti

Rimmer

Gauvreau

. Regional low-flow perfusion versus circulatory arrest in neonates: one-year neurodevelopmental outcome. Ann Thorac Surg. 2006;82(6):2207–2211; discussion 2211–2213.

29.

Jonas

Wypij

Roth

. The influence of hemodilution on outcome after hypothermic cardiopulmonary bypass: results of a randomized trial in infants. J Thorac Cardiovasc Surg. 2003;126(6):1765–1774.

30.

Andropoulos

Stayer

McKenzie

Fraser

Jr . Regional low-flow perfusion provides comparable blood flow and oxygenation to both cerebral hemispheres during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg. 2003;126(6):1712–1717.

31.

Fraser

Jr Andropoulos

DB.

Neurologic monitoring for special cardiopulmonary bypass techniques. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2004;7(1):125–132.

32.

Daubeney

Pilkington

Janke

Charlton

Smith

Webber

SA.

Cerebral oxygenation measured by near-infrared spectroscopy: comparison with jugular bulb oximetry. Ann Thorac Surg. 1996;61(3):930–934.

33.

Tortoriello

Stayer

Mott

. A noninvasive estimation of mixed venous oxygen saturation using near-infrared spectroscopy by cerebral oximetry in pediatric cardiac surgery patients. Paediatr Anaesth. 2005;15(6):495–503.

34.

Kurth

Steven

Nicolson

SC.

Cerebral oxygenation during pediatric cardiac surgery using deep hypothermic circulatory arrest. Anesthesiology. 1995;82(1):74–82.

35.

Hoffman

Mussatto

Brosig

. Systemic venous oxygen saturation after the Norwood procedure and childhood neurodevelopmental outcome. J Thorac Cardiovasc Surg. 2005;130(4):1094–1100.

36.

Austin

3rd Edmonds

Jr Auden

. Benefit of neurophysiologic monitoring for pediatric cardiac surgery. J Thorac Cardiovasc Surg. 1997;114(5):707-715–717; discussion 715–716.

37.

Sakamoto

Duebener

Laussen

Jonas

RA.

Cerebral ischemia caused by obstructed superior vena cava cannula is detected by near-infrared spectroscopy. J Cardiothorac Vasc Anesth. 2004;18(3):293–303.

38.

Gottlieb

Fraser

Jr Andropoulos

Diaz

LK.

Bilateral monitoring of cerebral oxygen saturation results in recognition of aortic cannula malposition during pediatric congenital heart surgery. Paediatr Anaesth. 2006;16(7):787–789.

39.

Andropoulos

Stayer

McKenzie

Fraser

Jr . Novel cerebral physiologic monitoring to guide low-flow cerebral perfusion during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg. 2003;125(3):491–499.

40.

Pigula

Gandhi

Siewers

Davis

Webber

Nemoto

EM.

Regional low-flow perfusion provides somatic circulatory support during neonatal aortic arch surgery. Ann Thorac Surg. 2001;72(2):401–406; discussion 406–407.

41.

Morales

DLS

Scully

Braud

. Interrupted aortic arch repair: aortic arch advancement without a patch minimizes arch intervention. Ann Thorac Surg. 2006;82(5):1577–1584.

42.

Andropoulos

Diaz

Fraser

Jr McKenzie

Stayer

SA.

Is bilateral monitoring of cerebral oxygen saturation necessary during neonatal aortic arch reconstruction?

Anesth Analg. 2004;98(5):1267–1272.

43.

McPherson

Juul

SE.

Recent trends in erythropoietin-mediated neuroprotection. Int J Dev Neurosci. 2008;26(1):103–111. Review.

44.

Rappaport

Mellon

Simone

Woodcock

Defining safe use of anesthesia in children. N Engl J Med. 2011;364(15):1387–1390.

45.

Hudetz

Pagel

PS.

Neuroprotection by ketamine: a review of the experimental and clinical evidence. Cardiothorac Vasc Anesth. 2010;24(1):131–142.