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Anesth Analg 2002;95:889-892
© 2002 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

A Glial-Derived Protein, S100B, in Neonates and Infants with Congenital Heart Disease: Evidence for Preexisting Neurologic Injury

Paula M. Bokesch, MD*, Elumalai Appachi, MD{dagger}, Marco Cavaglia, MD*, Emad Mossad, MD*, and Roger B.B. Mee, MB ChB, FRACS{ddagger}

Departments of *Cardiothoracic Anesthesia, {dagger}Pediatric Critical Care, and the {ddagger}Center for Congenital Heart Disease and Surgery, The Cleveland Clinic Foundation, Ohio

Address correspondence and reprint requests to Paula M. Bokesch, MD, Department of Cardiothoracic Anesthesia, G30 Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Address e-mail to bokescp{at}ccf.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The glial-derived protein S100B is a serum marker of cerebral ischemia and correlates with negative neurological outcome after cardiopulmonary bypass (CPB) in adults. We sought to characterize the S100B release pattern before and after CPB in neonates and infants with congenital heart disease and correlate it with surgical mortality. Serum was collected before surgery and at 24 postoperative h from 109 neonates and infants with congenital heart disease. All patients had presurgical transthoracic echocardiograms and CPB with or without hypothermic circulatory arrest. S100B concentrations were determined using a two-site immunoluminometric assay (Sangtec 100TM). Thirty-day surgical mortality was observed. All neonates had significantly increased S100B concentrations before surgery that decreased by 24 postoperative h. Preoperative S100B concentrations in 32 neonates with hypoplastic left heart syndrome correlated inversely with the forward flow and size of the ascending aorta and postoperative mortality (r2 = -0.63; P = 0.03). Among infants, increased pulmonary blood flow was associated with higher S100B levels before surgery than cyanosis. There was no correlation with postoperative S100B and time on CPB, hypothermic circulatory arrest, or 30-day surgical mortality. In conclusion, preoperative S100B concentrations correlate inversely with the size of the ascending aorta in hypoplastic left heart syndrome and may serve as a marker for preexisting brain injury and mortality.

IMPLICATIONS: Neonates with hypoplastic left heart syndrome and no forward flow in the ascending aorta may have brain injury at birth before heart surgery.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Improved techniques in cardiopulmonary bypass (CPB) combined with deep hypothermia and hypothermic circulatory arrest have enabled correction of complex congenital heart defects in the neonatal and early infancy periods. Although advances in technological, surgical, and anesthetic techniques have improved morbidity and mortality for these critically ill babies, developmental and neurological abnormalities in follow-up studies may still occur in neonates, infants, and children (1–3).

Neurological dysfunction after heart surgery is usually attributed to intraoperative ischemic events occurring during CPB, hypothermic circulatory arrest (HCA), and after reperfusion and rewarming (1,4). Another important factor that may contribute to the neurologic morbidity after open-heart surgery is a preexisting brain abnormality secondary to the defective cardiac anatomy and physiology in utero and at birth. Brain and developmental abnormalities are very difficult to detect in a newborn baby. Neuropsychological examinations are not useful or feasible in a critically ill neonate. Imaging techniques or cranial ultrasounds do not provide functional data. A biochemical marker of cerebral injury is highly desirable both before CPB to detect and quantify preexisting brain injury as well as to determine the extent of cerebral injury in association with CPB and HCA.

The glial-derived protein S100B is a serum marker of cerebral ischemia. Patients suffering from stroke, subarachnoid hemorrhage, and head trauma release S100B into the cerebrospinal fluid and blood (5,6). In adults, serum concentrations of S100B after CPB correlate with detrimental neurological outcome (7). We sought to characterize the S100B release pattern before and after CPB in neonates and infants and determine its relationship to patient mortality.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After IRB approval and parental informed consent, 109 term neonates or infants undergoing elective cardiac surgery using CPB were sequentially enrolled in this study. Patients with Down syndrome and neonates who suffered a cardiac arrest, hypotension, or severe acidosis, with a pH value <7.2, within 24 h before surgery were excluded. Patients were grouped by type of repair: Stage I repair of hypoplastic left heart syndrome (HLHS, Group 1), transposition of the great arteries (Group 2), tetralogy of Fallot (Group 3), bi-directional cavopulmonary anastomosis (Group 4), or ventricular septal defects (VSD, Group 5). All neonates had preoperative renal and head ultrasounds before surgery as per standard procedure at Cleveland Clinic Foundation. Only those with normal ultrasounds were included in this study. All patients had preoperative echocardiograms that determined chamber and valve size and antegrade or retrograde flow in the aorta. Demographic, intra-, and postoperative data on each patient were collected from patient records. Surgical mortality for 30 days after surgery was documented.

After the induction of anesthesia, all patients had 4.5–5.0F double-lumen catheters placed in the internal jugular vein as per standard procedure for monitoring, drug infusion, and blood sample collection. In most patients, a right atrial catheter inserted by the surgeon replaced this catheter at the end of surgery. These catheters were used for venous sampling to assay S100B concentrations. One milliliter of venous blood was obtained from all patients before the incision and 24 h after arrival in the pediatric intensive care unit (ICU). The samples were immediately centrifuged and the serum stored at -80°C until analysis.

Serum S100B concentrations were determined using a monoclonal two-site immunoluminometric assay according to the manufacturer’s directions (LIA-MAT Sangtec 100TM, AB Sangtec Medical, Bromma, Sweden). The precision was <10.0% coefficient of variation. The lower level of detection was 0.1 µg/L, and the upper level was 20.0 µg/L.

If not otherwise stated, all data are presented as mean ± SEM. Data were analyzed using SigmaStatTM (Jandel Scientific, San Rafael, CA). For comparisons of means, continuous variables were analyzed with Student’s t-tests if the sample was large or had a normal distribution. Otherwise, a nonparametric test was used (Mann-Whitney). Regression analysis was performed using the least square method with case-wise deletion of missing data. Correlation coefficients were determined using the Pearson Product Moment Correlation. A P value <0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The pre- and postoperative serum concentrations of S100B are presented in Table 1. Group 1 patients with HLHS had the largest mean S100B concentrations before and 24 h after surgery compared with all other groups (P < 0.01). Preoperative S100B concentrations correlated significantly (P = 0.003) and inversely (r2 = -0.64) with the size of the ascending aorta and the presence of forward flow through the aortic valve documented by transthoracic echocardiography (Fig. 1). All patients who died (n = 5) had preoperative serum concentrations >=3.6 µg/L and small ascending aorta diameters without forward flow. None of these patients were acidotic at the time of sampling or within 24 h of surgery. If these patients were excluded from data analysis, the mean preoperative S100B concentration was 1.75 ± 1.7 µg/L, which was similar to Group 2 patients.


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  		Table 1. Pre- and Postoperative Serum S100B Concentrations
 


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  		Figure 1. Preoperative [S100B] versus ascending aorta diameter normalized to body surface area. Dark squares (5) are neonates who died after Stage I repair of HLHS. r2 = -0.64; P = 0.003; n = 32 Stage I repair of HLHS.

 
As with Group 1, Group 2 patients with transposition of the great arteries also had increased preoperative S100B, as compared with Groups 3 and 4, that decreased 24 h after surgery (Table 1). Within this group, patients with VSD (n = 17) did not have preoperative concentrations of S100B significantly different from patients with intact ventricular septum (1.95 ± 1.7 µg/L versus 2.2 ± 1.4 µg/L, respectively; P = 0.3). All infants (Groups 3 and 4) had significantly smaller preoperative concentrations of S100B than patients in Groups 1 and 2 (P < 0.01). However, among infants, cyanotic infants (Groups 3 and 4) had significantly smaller preoperative S100B concentrations than noncyanotic infants with VSD and increased pulmonary circulation (Group 5; P < 0.05).

Although S100B concentrations were larger at 24 h than before surgery in Group 4, all of these infants were extubated and discharged from the ICU on the first postoperative day. As expected, all of these patients had significantly (P < 0.01) increased pressure in the superior vena cava on arrival in the ICU (12.2 ± 2 mm Hg versus 5.6 ± 1 mm Hg before CPB). There was no correlation between the 24-h postoperative S100B concentrations and the duration of CPB or HCA, aortic cross-clamp time, or survival in any of the groups.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
S100B has been established as a useful serum marker of cerebral injury caused by minor and major head trauma, global anoxia, focal ischemia, metastatic malignant melanoma, and cardiac surgery (5–7). All of these conditions involve disruption of the blood-brain barrier. Johnsson et al. (8) first reported the relationship of increased S100B and cerebral complications after cardiac surgery in adults. These authors and others subsequently determined that shed mediastinal blood collected during surgery by cardiotomy suction also contained high levels of S100B as well as chest tube blood that was used for autotransfusion after surgery (9). Therefore, earlier reports that correlated serum S100B levels immediately after pediatric cardiac operations with duration of CPB and HCA may have been contaminated by extra-cerebral sources of S100B (10,11).

Our study did not find any relationship between CPB duration, cross-clamp time, or use of HCA and serum concentrations of S100B 24 hours after surgery. Also, serum concentrations of S100B at 24 hours after surgery did not correlate with 30-day surgical mortality. Unlike adult studies, neonates and infants had smaller concentrations of S100B at 24 hours after surgery than before surgery. However, this finding may reflect dilution of the protein in serum from postoperative blood, colloid, and crystalloid infusions in small babies.

Although neonates in Groups 1 and 2 had larger S100B levels than previously reported in adults, these values were not necessarily abnormal. Age-related serum S100B concentrations before surgery have been described in children with congenital heart disease with the highest values in neonates (12,13). Erb et al. (14) reported serum concentrations of 1.97 µg/L in 12 healthy neonates on the day of birth. Maschmann et al. (15) reported serum S100B concentrations in 66 term newborns to be 0.66–3.33 µg/L in the first week of life. Newborns with signs of hypoxic-ischemic encephalopathy after perinatal acidosis had increased serum concentrations of S100B >4.0 µg/L in the first week of life. However, compared with serum levels of adult patients (usually <0.2 µg/L), even nonacidotic newborns have significantly larger S100B concentrations. The reason for the higher S100B serum levels in healthy newborns is unclear. Some possibilities are immaturity of the blood-brain barrier with subsequent leakage of S100B from the brain into the blood, extracerebral sources of S100B such as brown fat, or decreased elimination by immature kidneys. In adults, S100B is eliminated, unchanged by the kidneys with a half-life of 25.3 ± 5.1 minutes after CPB, and is not affected by a moderate decrease in glomerular filtration rate (9).

The most intriguing observation in our study was the relationship between preoperative S100B concentrations and the size of the ascending aorta normalized to body surface area in neonates undergoing the Norwood operation (Stage I repair of HLHS). Smaller ascending aorta correlated with larger concentrations of S100B (Fig. 1; P = 0.003). Patients with Shone’s complex (mitral stenosis and aortic stenosis without atresia) and other variants of HLHS, who had forward flow through their aortic valve (confirmed by preoperative echocardiography), had smaller preoperative concentrations of S100B. These data suggest that neonates with little or no forward flow in the ascending aorta have brain injury before surgery. None of these neonates were acidotic or hypotensive at this time.

Group 5 infants had a similar finding as Group 1 neonates, namely decreased forward flow in the ascending aorta. Patients with VSDs have excessive pulmonary circulation through the VSD, thereby decreasing forward flow in the ascending aorta. Age-matched cyanotic patients with normal or increased flow patterns in the ascending aorta (Groups 3 and 4) had smaller preoperative S100B concentrations.

Group 4 infants were all previous Stage I repair of HLHS and its variants. At 5.8 ± 2 months of age, these infants had significantly smaller concentrations of S100B before surgery than they did as neonates. The significant increase of S100B after surgery in this group may reflect the increased pressure in the superior vena cava, although more patients are required to determine if this correlation is consistent.

In summary, preoperative serum concentrations of S100B are increased in neonates and infants with congenital heart disease. Preoperative serum S100B concentrations correlate inversely with the forward flow and size of the ascending aorta in HLHS and may serve as an indicator of preoperative brain injury and a predictor of survival.


   Footnotes
 
Presented by Dr. Julie Tome, Department of Cardiothoracic Anesthesia, at the Annual Meeting of the American Society of Anesthesiologists, New Orleans, LA, October 2001.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. 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: 526–32.[Abstract/Free Full Text]
  2. Hovels-Gurich HH, Seghaye MC, Dabritz S, et al. Cognitive and motor development in preschool and school-aged children after neonatal arterial switch operation. J Thorac Cardiovasc Surg 1997; 114: 578–85.[Abstract/Free Full Text]
  3. Miller G, Eggli KD, Contant C, et al. Postoperative neurologic complications after open heart surgery on young infants. Arch Pediatr Adolesc Med 1995; 149: 764–8.[Abstract]
  4. Taylor KM. Central nervous system effects of cardiopulmonary bypass. Ann Thorac Surg 1998; 66: S20–4.[Abstract/Free Full Text]
  5. Raabe A, Grolms C, Sorge O, et al. Serum S-100B protein in severe head injury. Neurosurgery 1999; 45: 477–83.[ISI][Medline]
  6. Wunderlich MT, Ebert AD, Kratz T, et al. Early neurobehavioral outcome after stroke is related to release of neurobiochemical markers of brain damage. Stroke 1999; 30: 1190–5.[Abstract/Free Full Text]
  7. Georgiadis D, Berger A, Kowatschev E, et al. Predictive value of S100B and neuron-specific enolase serum levels for adverse neurologic outcome after cardiac surgery. J Thorac Cardiovasc Surg 2000; 119: 138–47.[Abstract/Free Full Text]
  8. Johnsson P, Lundqvist C, Lindgren A, et al. Cerebral complications after cardiac surgery assessed by S-100 and NSE levels in blood. J Cardiothorac Vasc Anesth 1995; 9: 694–9.[ISI][Medline]
  9. Jonsson H, Johnsson P, Hoglund P, et al. Elimination of S100B and renal function after cardiac surgery. J Cardiothorac Vasc Anesth 2000; 14: 698–701.[ISI][Medline]
  10. Taggart DP, Mazel JW, Bhattacharya K, et al. Comparison of serum S-100B levels during CABG and intracardiac operations. Ann Thorac Surg 1997; 63: 492–6.[Abstract/Free Full Text]
  11. Abdul-Khaliq H, Blasig IE, Baur MO, et al. Release of the cerebral protein S-100B into blood after reperfusion during cardiac operations in infants: is there a relation to oxygen radical-induced lipid peroxidation? J Thorac Cardiovasc Surg 1999; 117: 1027–8.[Free Full Text]
  12. Lindberg L, Olsson AK, Anderson K, Joegi P. Serum S-100 protein levels after pediatric cardiac operations: a possible new marker for postperfusion cerebral injury. J Thorac Cardiovasc Surg 1998; 116: 281–5.[Abstract/Free Full Text]
  13. Jensen E, Sandstroem K, Andreasson S, et al. Increased levels of S-100 protein after cardiac surgery with cardiopulmonary bypass and general surgery in children. Paediatr Anaesth 2000; 10: 297–302.[ISI][Medline]
  14. Erb MA, Heinemann MK, Wendel HP, et al. S100 after correction of congenital heart defects in neonates: is it a reliable marker for cerebral damage? Ann Thorac Surg 2000; 69: 1515–9.[Abstract/Free Full Text]
  15. Maschmann J, Erb MA, Ziemer G, Speer CP. Evaluation of S-100 serum concentrations in healthy newborn and seven newborns with perinatal acidosis. Acta Paediatr 2000; 89: 553–5.[Medline]
Accepted for publication June 3, 2002.




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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