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Anesth Analg 2004;98:1267-1272
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000111114.48702.59


PEDIATRIC ANESTHESIA

Is Bilateral Monitoring of Cerebral Oxygen Saturation Necessary During Neonatal Aortic Arch Reconstruction?

Dean B. Andropoulos, MD*,{dagger},{ddagger}, Laura K. Diaz, MD*,{ddagger}, Charles D. Fraser, Jr., MD||, E. Dean McKenzie, MD||, and Stephen A. Stayer, MD*,{dagger},{ddagger}

Departments of *Anesthesiology, {dagger}Pediatrics, and ||Surgery, Baylor College of Medicine, Houston, Texas; and Divisions of {ddagger}Pediatric Cardiovascular Anesthesiology and ¶Congenital Heart Surgery, Texas Children’s Hospital, Houston, Texas

Address correspondence and reprint requests to Dean B. Andropoulos, MD, 6621 Fannin, WT 19345H, Houston, TX 77030. Address e-mail to dra{at}bcm.tmc.edu


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this study, we measured cerebral oxygenation in both cerebral hemispheres by using near-infrared spectroscopy before, during, and after regional low-flow cerebral perfusion (RLFP) to determine whether bilateral monitoring was necessary. Neonates undergoing aortic arch reconstruction with RLFP were studied. The bilateral regional cerebral oxygenation index was measured and recorded at 1-min intervals during the following periods: 1) before bypass, 2) during bypass before RLFP, 3) during RLFP, 4) on bypass after RLFP, and 5) post-bypass. Before bypass and on bypass before RLFP, the correlation (r = 0.979 and 0.852) and agreement (mean bias, right versus left, 0 and +2) between hemispheres were excellent. During RLFP, however, correlation (r = 0.35) and agreement (mean bias of the right versus left side, +6.3) worsened and only partially returned to baseline values after RLFP. Nine of 19 patients had sustained differences in cerebral oxygen saturation of >10%, always with the left side values less than the right. Bilateral monitoring detects desaturation in the left cerebral hemisphere during RLFP. The long-term consequences of lower saturations on the left side of the brain are unclear.

IMPLICATIONS: Left-sided cerebral hemisphere oxygen saturation, measured with near-infrared spectroscopy, was less than right-sided cerebral oxygen saturation during regional low-flow cerebral perfusion used for neonatal aortic arch reconstruction.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Complex neonatal cardiac surgery has traditionally required the use of deep hypothermic circulatory arrest (DHCA) to provide a bloodless operating field. Prolonged periods of DHCA are associated with neurologic morbidity, such as choreoathetosis, seizures, and long-term adverse cognitive developmental effects (1–3). Selective cerebral perfusion has been described; this provides blood flow to the brain during bypass while maintaining a bloodless operating field, thereby reducing the duration of DHCA or eliminating it altogether (4,5). One such technique is regional low-flow cerebral perfusion (RLFP), which uses a 3- to 3.5-mm polytetrafluoroethylene (PTFE) graft sutured to the right innominate artery as the source of arterial inflow during cardiopulmonary bypass. During aortic reconstruction, only the brain and right arm (via the right subclavian artery) are perfused through the graft, with the brachiocephalic vessels and descending thoracic aorta snared to produce a bloodless field. The brain receives direct unilateral perfusion via the right common carotid artery and right vertebral artery.

Near-infrared spectroscopy (NIRS) has been used to measure cerebral oxygenation during RLFP and as a guide to determine adequate flow during cardiopulmonary bypass (6). Although NIRS has successfully demonstrated adequate oxygen delivery to the right cerebral hemisphere, the adequacy of blood flow to the left cerebral hemisphere has been questioned (6), because cerebral blood flow occurs through the right carotid and vertebral arteries and blood must traverse the circle of Willis to reach the left hemisphere.

The purpose of this study was to compare cerebral oxygenation in both cerebral hemispheres by using NIRS during neonatal aortic arch reconstruction using RLFP to determine whether bilateral monitoring is necessary. Our hypothesis was that both hemispheres have equivalent oxygen delivery with this technique and, thus, that bilateral cerebral oxygen saturation values would correlate closely, rendering bilateral monitoring unnecessary.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After IRB approval, infants undergoing aortic arch reconstruction were considered eligible. Parental consent was deemed not necessary because the neurologic monitoring was routine care at our institution, and our study was observation only, without invention. Patients undergoing the Norwood operation for hypoplastic left heart syndrome or a variant and those undergoing aortic arch advancement for interrupted aortic arch or severe arch hypoplasia were studied if a period of RLFP was planned. The anesthetic technique consisted of fentanyl 100–200 µg/kg, midazolam 0.3–1.0 mg/kg, and pancuronium or vecuronium for neuromuscular blockade. Isoflurane (<1%) was used to supplement the anesthetic before bypass. Isoflurane up to 2% was used on bypass for vasodilation and was always discontinued before rewarming. Arterial blood pressure monitoring consisted of an umbilical or femoral arterial catheter. In addition, a catheter was placed in the left radial artery for patients undergoing the Norwood operation and in the right radial artery for patients undergoing aortic arch advancement.

Cerebral physiologic monitoring included NIRS (INVOS 5100; Somanetics Corp., Troy MI) to measure a regional cerebral oxygen saturation index (rSO2i). This method uses near-infrared light at 730- and 810-nm wavelengths to measure the absorption spectra of the total hemoglobin and deoxyhemoglobin in the frontal cerebral cortex (7). One light-emitting diode and 2 detectors, spaced 3 and 4 cm from the light-emitting diode, are used. The 3-cm detector is assumed to measure primarily the light passing through shallow structures such as the skull, skin, and soft tissues. The 4-cm detector is assumed to measure light passing through both the shallow structures and a deeper banana-shaped path in the frontal cerebral cortex. A subtraction algorithm is used to correct for the signal from the extracranial tissues, and a percentage rSO2i is displayed; this is derived as the ratio of oxyhemoglobin to total hemoglobin x 100 (8). The monitor is self-calibrating before measurement begins, and if signal strength is inadequate, a "poor signal quality" error message is displayed. Bilateral sensors were applied to the forehead just to the right and left of the midline.

Transcranial Doppler (TCD) pulsed-wave ultrasound (EME Companion; Nicolet Biomedical, Madison, WI) of the right middle cerebral artery was used to measure cerebral blood flow velocity (CBFV). A 2-MHz probe was placed over the right temporal area, and the depth of sample volume and angle of insonation were adjusted until a biphasic CBFV signal was obtained, signifying sampling at the bifurcation of the middle and anterior cerebral arteries (9). Right-sided CBFV was monitored continuously throughout the surgery. A left-sided TCD probe was also placed, and left CBFV was assessed before, during, and after RLFP (see below) during the bypass period to ensure adequate blood flow to the left side.

For all patients, bypass was initiated through an 8F or 10F aortic cannula inserted into the distal end of a 3- or 3.5-mm PTFE graft, with the proximal end anastomosed into the distal right innominate artery. The right innominate artery was occluded during the anastomosis of the PTFE graft, potentially causing right-sided cerebral ischemia, and the TCD was used to monitor CBFV during this procedure.

Bypass was instituted at a flow of 150–200 mL · kg–1· min–1. Phenoxybenzamine 0.25 mg/kg was administered to all Norwood patients on initiation of bypass. Phenoxybenzamine 0.25–1 mg/kg or phentolamine 0.3–1 mg/kg was administered to all other patients during bypass to achieve a mean arterial blood pressure of 30–40 mm Hg at a minimum flow of 150 mL · kg–1 · min–1 throughout the bypass. Extracorporeal cooling to a nasopharyngeal temperature of 18°C was achieved over no less than 20 min. The target hematocrit was 25%–30% during the period of hypothermia. A pH-stat blood gas strategy was used during all phases of the bypass period. RLFP was instituted by snaring the base of the right innominate, left common carotid, and left subclavian arteries, along with the descending thoracic aorta distal to the coarctation; perfusion was then initiated via the PTFE graft to the right innominate artery throughout the period of aortic reconstruction. Bypass flow was adjusted as described below. DHCA was used only for brief periods for atrial septectomy or changing the aortic cannula from the PTFE graft to the neoaorta in Norwood patients. Bypass flow during RLFP was adjusted to match CBFV to within ±10% of the baseline values measured during full-flow hypothermic bypass at 18°C, as previously described (10).

Bilateral rSO2i was recorded by the software of the INVOS 5100 in 1-min intervals throughout the entire case and was saved to computer disk after the case for further analysis. Data collection was divided into 5 periods: 1) before bypass (from just after the induction of anesthesia to the initiation of bypass), 2) on bypass before RLFP, 3) during RLFP, 4) on bypass after RLFP, and 5) after bypass (from termination of bypass until leaving the operating room). Bypass data reported in Table 1 were collected after cooling to 18°C at 3 time periods: just before RLFP during full-flow bypass, during RLFP, and just after RLFP on full-flow bypass through the reconstructed aorta.


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Table 1. Bypass Data at 18°C (n = 19)
 
Data analysis was performed with SigmaStat Version 2.3 (SPSS, Chicago, IL). Linear regression analysis was used to correlate right- and left-sided rSO2i measurements. Bland-Altman analysis was used to determine the level of agreement in individual data points between sides for measuring cerebral saturation and is reported as bias (difference in mean values, right side versus left, for each time period) and precision (±2 SD from the mean values for each individual paired measurement). One-way repeated-measures analysis of variance was used to compare values for bypass data before, during, and after RLFP. Normally distributed data are expressed as mean ± SD and nonnormally distributed data as median with 25%–75% interquartile ranges. Paired Student’s t-tests were used to compare bilateral CBFV values before, during, and after RLFP. P values <0.05 were considered statistically significant.

Our primary outcome variable was the mean difference in all rSO2i values between cerebral hemispheres during RLFP. We chose a mean difference of 10% (in absolute rSO2i values; e.g., rSO2i of 50% versus 60% is a 10% difference) as clinically significant on the basis of NIRS data using the INVOS system in 2 clinical studies that demonstrated a more frequent incidence of acute neurologic change with a relative change of 20% in baseline rSO2i (11,12). An absolute change of 10% at the rSO2i ranges in our patients corresponds to the <=20% relative change seen in these studies. We chose a 10% absolute difference as clinically relevant because, in our experience, the clinician would want to know and possibly treat at this level of decreased rSO2i. On the basis of our previous study of RLFP using an identical protocol, in which the right-sided rSO2i in 34 patients was 88% ± 8% during RLFP (10), we calculated that a sample size of 12 patients was necessary to detect a difference of 10% between cerebral hemispheres with a power of 80% and an {alpha} of 0.05. We chose to study 20 patients to account for the possibility of increased variability of rSO2i measurements when both cerebral hemispheres were monitored.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Twenty patients were enrolled in the study; however, case data were not saved for 1 patient, leaving 19 patients with complete data sets. Patient data are reported in Tables 1 and 2. There were no in-hospital deaths within 30 days of operation and no new neurologic deficits detected by clinical examination during a follow-up period of 2–14 mo.


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Table 2. Patient Data (n = 19)
 
Correlation of rSO2i values between cerebral hemispheres at the five time periods is reported in Table 3. Before bypass, rSO2i on both sides exhibited strong correlation (r = 0.979), an identical mean value (bias of 0%), and a precision of 10.8%. In the bypass period before RLFP, r was 0.852, bias was +2.0%, and precision was 6.6%. During RLFP, there was a worsening in correlation (r = 0.350) and agreement, with a bias of +6.3% and a precision of 17.6% (Fig. 1). Only 10 of the 19 patients maintained rSO2i values within 10% on both sides during the entire RLFP period. The remaining nine had a difference of >=10% for at least 3 min, always with the left-sided rSO2i less than the right. The largest single difference was one patient who exhibited a 5-min period of right-sided rSO2i of 92%–94% and left-sided rSO2I of 60%–64%. This left-sided rSO2i value of 60% represents the lowest value recorded during RLFP for the entire study in all patients. In all patients, rSO2i values on both sides during RLFP were higher than the preincision values observed during periods of stable hemodynamics. Two patients underwent some DHCA during the RLFP period, accounting for the few individual low rSO2i values displayed in Figure 1. In the post-RLFP period, correlation improved to 0.730, bias to +1.7%, and precision to 7.1%. After bypass there was once again a strong correlation between values (r = 0.925), but bias was still +3.6%, with a precision of 4.7%. Figure 2 displays the individual plots of two patients’ rSO2i versus time: one with strong correlation and agreement between cerebral hemispheres during RLFP and one with poor correlation and agreement.


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Table 3. Comparison of Right- and Left-Sided rSo2i
 


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Figure 1. Regional low-flow cerebral perfusion (RLFP) period. A, Linear regression analysis of left versus right cerebral hemisphere regional cerebral oxygenation index. B, Bland-Altman analysis of the agreement between measurements of cerebral oxygenation of the left and right cerebral hemispheres. rSO2i L = regional cerebral oxygenation index, left cerebral hemisphere; rSO2i R = regional cerebral oxygenation index, right cerebral hemisphere. All numerical data are expressed as percentage rSO2i. Solid line = mean bias; dashed lines = 2 SD greater and less than the mean bias.

 


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Figure 2. A, Neonate undergoing Norwood operation with a nearly identical regional cerebral oxygen saturation index (rSO2i) during regional low-flow cerebral perfusion (RLFP). The prebypass period was during Minutes 0–95; the pre-RLFP period on bypass was Minutes 90–140; the RLFP period was Minutes 140–230; the post-RLFP period on bypass was Minutes 230–275; and the postbypass period was after 275 min. B, Another neonate undergoing Norwood operation with divergent rSO2i during most of the bypass period, but especially during RLFP. Pre-bypass was during Minutes 0–75; pre-RLFP was during Minutes 76–125; RLFP was during Minutes 125–190; post-RLFP was during Minutes 191–260; and postbypass was after 260 min. R= right; L = left.

 
CBFV measurements compared during the 3 time periods after cooling to 18°C were 20 ± 8 cm/s (mean ± SD) on the right and 20 ± 10 cm/s on the left; during RLFP, they were 22 ± 8 cm/s on the right and 23 ± 8 cm/s on the left; and after RLFP, they were 18 ± 7 cm/s on the right and 19 ± 12 cm/s on the left (all P > 0.05 with the paired Student’s t-test). In the nine patients with sustained decreased rSO2i on the left during RLFP, there was no correlation with changes in CBFV; four patients were within 25% of pre-RLFP values, two patients were >=25% lower, and three patients were >=25% above baseline values.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
This study demonstrates that, for the entire study group, the mean difference in rSO2i during RLFP was 6.3% higher in the right cerebral hemisphere. Although this did not meet our criteria for clinical significance, nearly half of the patients studied had sustained differences of >=10%, always less on the left side. Thus, our data suggest that bilateral monitoring of rSO2i is useful to detect left hemisphere desaturation in these patients during neonatal aortic arch reconstruction using RLFP. Detecting lower rSO2i on the left side allows clinicians to make adjustments that increase rSO2i, thereby allowing for a greater margin of safety. Maneuvers that may increase low rSO2i include increasing the bypass flow rate, increasing PaCO2, increasing hemoglobin, and decreasing the patient’s temperature (12). Without left-sided monitoring, lower rSO2i in the left cerebral hemisphere is undetected.

Previous reports have demonstrated the utility of bilateral NIRS monitoring in adult patients when perfusion to the brain occurs through only one carotid artery. In a study of 100 patients undergoing carotid endarterectomy with regional anesthesia, Samra et al. (11) demonstrated that carotid occlusion decreased rSO2i more in patients who exhibited neurologic symptoms (from a mean of 63% to 51% versus 66% to 61% in those exhibiting no symptoms). A relative decrease in rSO2i of <20% with carotid clamping had a high negative predictive value of 97.4%. That study demonstrated a high degree of individual patient variability with this monitoring technology. Janelle et al. (13) reported a case of bilateral NIRS monitoring during emergency repair of a DeBakey Type I aortic dissection. An abrupt decrease in right rSO2i from 65% to <20% allowed recognition of an aortic dissection extending to the right common carotid artery during hypothermic bypass, requiring a change in the perfusion and operative strategy to immediately address the carotid dissection.

Decreased rSO2i on the left side during RLFP has been noted by other investigators. Hofer et al. (14) studied the effects on rSO2i of varying the RLFP flow from 10 to 30 mL · kg–1 · min–1 and found lower left-sided rSO2i values (mean, 6%–8% lower). These authors used lower RLFP flow rates compared with our average flow rate (63 mL · kg–1 · min–1). Their rSO2i values were lower (66%–78% on the right side) than those in our present study, and this likely reflects the lower RLFP flow rates. These investigators used TCD of the left middle cerebral artery and, interestingly, could detect no cerebral blood flow with this methodology in 2 of 10 patients at an RLFP flow rate of 20 mL · kg–1 · min–1 and in 6 of 10 patients at 10 mL · kg–1 · min–1. This finding suggests that RLFP at these low flow rates may produce ischemia to the left cerebral hemisphere in some patients, similar to DHCA.

There are several possible explanations for the decreased left-sided cerebral oxygen saturation seen in many individual patients during RLFP. The first is inadequate flow across the circle of Willis secondary to anatomic variations or abnormalities. Although it is assumed that the cerebral circulation is intact in the newborn infant, 10% of healthy full-term neonates exhibited deviations from normal flow patterns in a study of color Doppler patterns in 53 patients (15). Additionally, CBFV is not identical to cerebral blood flow. Changes in cerebral vascular resistance (e.g., increased resistance) may result in the same CBFV with a decrease in blood flow. Arguing against anatomic problems in the circle of Willis is the finding that in our patients, we demonstrated adequate CBFV on the left side during RLFP with intermittent assessments; seven of nine patients with rSO2i differences of >10% had CBFV the same or greater than the pre-RLFP values. We also demonstrated an intact circle of Willis by demonstrating unchanged CBFV on the right side before RLFP during test occlusion of the right innominate artery during PTFE graft placement.

In this study group, the discrepancy in rSO2i between right- and left-sided monitors actually began before RLFP, with the initiation of cardiopulmonary bypass. A possible explanation for the observed decrease in rSO2i on the left side at the onset of bypass is compromised cerebral venous drainage from the left cerebral hemisphere. Our institutional practice is to retract the left innominate vein with a silastic vessel loop to facilitate surgical access. This maneuver could occlude the vein, potentially decreasing cerebral venous drainage and resulting in an accumulation of desaturated venous blood in the left cerebral hemisphere. NIRS measures saturation in both the arterial and venous systems, and because the cerebral blood volume is 75%–85% (16) of venous blood in children, this could explain the lower rSO2i seen on the left side. The persistence of a lower rSO2i after bypass could also be explained by this maneuver, because the innominate vein remains retracted until just before sternal closure.

There are several limitations to this study. The significance of a "low" rSO2i value in any individual patient is unknown. Although there are some data suggesting that prolonged low rSO2i leads to acute neurologic changes in children undergoing open heart surgery with cardiopulmonary bypass (12), the long-term outcome of patients with abnormal rSO2i values has not been studied. Also, although studies in adults and children (11,12) have demonstrated that a relative decrease in rSO2i of 20% from baseline is associated with acute neurologic change, the baseline rSO2i in those studies was 60%–70%. During RLFP in our study, the baseline right-sided rSO2i was more than 80% in most patients, with the lowest value for rSO2i during RLFP at 60%, which is more than the baseline preincision value for nearly all of these patients. Therefore, although we can demonstrate an absolute difference of >10% in many patients, the effect of this difference at higher rSO2i on neurologic outcome is not clear and is likely to be less than for lower rSO2i values. It should be emphasized that these relatively high rSO2i values were obtained with our high-flow, pH-stat management, {alpha}-receptor blockade protocol, which yielded RLFP flow rates of 64 mL · kg–1 · min–1. It cannot be assumed that the lower RLFP flow rates of 10–30 mL · kg–1 · min–1, as reported in other studies, will result in left-sided rSO2i values that are more than baseline (6,14).

In conclusion, this study provides evidence that bilateral NIRS monitoring of cerebral oxygenation is useful during neonatal aortic arch reconstruction using RLFP. Bilateral monitoring detects otherwise unrecognizable cerebral desaturation in the left cerebral hemisphere, allowing timely corrective maneuvers to be performed. The long-term consequences of lower saturations on the left side of the brain are unclear.


    Acknowledgments
 
The authors thank Debora East, RN, Research Nurse, Division of Pediatric Cardiovascular Anesthesiology, Texas Children’s Hospital/Baylor College of Medicine, and E. O’Brian Smith, PhD, Biostatistician, Department of Pediatrics, Baylor College of Medicine, Children’s Nutrition Research Center.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Hickey PR. Neurologic sequelae associated with deep hypothermic circulatory arrest. Ann Thorac Surg 1998; 65: S65–9.[Abstract/Free Full Text]
  2. Bellinger DC, Wernovsky G, Rappaport LA, et al. Cognitive development of children following early repair of transposition of the great arteries using deep hypothermic circulatory arrest. Pediatrics 1991; 87: 701–7.[Abstract/Free Full Text]
  3. Wong PC, Barlow CF, Hickey PR, et al. Factors associated with choreoathetosis after cardiopulmonary bypass in children with congenital heart disease. Circulation 1992; 86: II118–26.[Medline]
  4. Asou T, Kado H, Imoto Y, et al. Selective cerebral perfusion technique during aortic arch repair in neonates. Ann Thorac Surg 1996; 61: 1546–8.[Abstract/Free Full Text]
  5. Pigula FA, Siewers RD, Nemoto EM. Regional perfusion of the brain during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg 1999; 117: 1023–4.[Free Full Text]
  6. Pigula FA, 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: 331–9.[Abstract/Free Full Text]
  7. Yoshitani K, Kawaguchi M, Tatsumi K, et al. A comparison of the INVOS 4100 and the NIRO 300 near-infrared spectrophotometers. Anesth Analg 2002; 94: 586–90.[Abstract/Free Full Text]
  8. Dullenkopf A, Frey B, Baenziger O, et al. Measurement of cerebral oxygenation state in anaesthetized children using the INVOS 5100 cerebral oximeter. Paediatr Anaesth 2003; 13: 384–91.[Web of Science][Medline]
  9. Fischer AQ, Truemper EJ. Applications in the neonate and child. In: Babikian VL, Wechsler LR, eds. Transcranial doppler ultrasonography. St. Louis: Mosby, 1993: 355–75.
  10. Andropoulos DB, Stayer SA, McKenzie ED, Fraser CD. Novel cerebral physiologic monitoring to guide low-flow cerebral perfusion during neonatal aortic arch reconstruction. J Thorac Cardiovasc Surg 2003; 125: 491–9.[Abstract/Free Full Text]
  11. Samra SK, Dy EA, Welch K, et al. Evaluation of a cerebral oximeter as a monitor of cerebral ischemia during carotid endarterectomy. Anesthesiology 2000; 93: 964–70.[Web of Science][Medline]
  12. Austin EH III, Edmonds HL Jr, Auden SM, et al. Benefit of neurophysiologic monitoring for pediatric cardiac surgery. J Thorac Cardiovasc Surg 1997; 114: 707–15.[Abstract/Free Full Text]
  13. Janelle GM, Mnookin S, Gravenstein N, et al. Unilateral cerebral oxygen desaturation during emergent repair of a DeBakey type 1 aortic dissection: potential aversion of a major catastrophe. Anesthesiology 2002; 96: 1263–5.[Web of Science][Medline]
  14. Hofer AA, Haizinger B, Geiselseder G, et al. Near infrared spectroscopy to monitor cerebral oxygenation during antegrade cerebral perfusion in neonates undergoing cardiosurgical repair [abstract]. Anesthesiology 2002; 96: A1284.
  15. Mitchell DG, Merton DA, Mirsky PJ, et al. Circle of Willis in newborns: color Doppler imaging of 53 healthy full-term infants. Radiology 1989; 172: 201–5.[Abstract/Free Full Text]
  16. Watzman HM, Kurth CD, Montengro LM, et al. Arterial and venous contributions to near-infrared cerebral oximetry. Anesthesiology 2000; 93: 947–53.[Web of Science][Medline]
Accepted for publication November 13, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press