Keywords
cardiopulmonary bypass - congenital heart disease - neonates - neurology/neurologic
(deficits - disease - injury)
Introduction
Advances in surgical technique and perioperative care have led to a substantial increase
of survival for neonates with complex congenital heart disease (CHD). Despite these
improvements, neonates requiring corrective or palliative surgery are still at higher
risk of later neurodevelopmental impairment.[1]
[2]
[3] The etiology is multifactorial and related to nonmodifiable patient-specific factors
and potentially modifiable factors including surgical technique and perioperative
care. Perioperative cerebral hypoxemia might be a relevant modifiable cause.[4] Particularly white matter injury has been documented by cerebral magnetic resonance
imaging (MRI) before and after surgery in several previous studies.[5]
[6]
[7]
[8]
[9]
[10]
[11] Brain injury is usually subtle and clinical evident neurologic injury is fortunately
relatively rare. As developmental assessment can only be performed with a relatively
long period of latency, surrogate markers for clinically silent hypoxic-ischemic brain
injuries in neonates with CHD are needed. Near-infrared spectroscopy allows real-time
noninvasive measurement of cerebral tissue oxygen saturation and is frequently used
for perioperative monitoring. Previous studies have reported relationships between
perioperative cerebral oxygenation and abnormal findings on MRI or neurodevelopmental
outcomes in neonates with complex CHD.[9]
[12]
[13]
[14] A brain-specific and sensitive biomarker released into the bloodstream after cellular
damage, which permits the identification of patients at risk or even predicts long-term
developmental outcomes, would be of great value for clinical practice and to develop
strategies to improve the long-term neurologic outcome.
Among others, the glial fibrillary acid protein might be a suitable biomarker. This
protein is part of the astrocyte cytoskeleton and is thought to be specific to the
central nervous system. In previous studies, serum levels were associated with neurologic
outcome after traumatic brain injury and cardiac arrest in adults and with acute brain
injury and death in children with extracorporeal life support.[15]
[16]
[17] In addition, glial fibrillary acid protein concentrations were predictive for neurodevelopmental
outcome in neonates with perinatal asphyxia and hypoxic ischemic encephalopathy and
for the occurrence of periventricular white matter injury in premature infants.[18]
[19] Up to now there is limited data regarding glial fibrillary acid protein levels in
children with CHD.[20]
[21]
[22]
[23]
[24]
[25] Especially the value of glial fibrillary acid protein as a predictor of developmental
outcome after cardiac surgery is relatively unknown.[25]
[26]
This study aimed to determine perioperative glial fibrillary acid protein levels in
neonates undergoing cardiac surgery utilizing cardiopulmonary bypass and to evaluate
the association between serum levels and cerebral tissue oxygenation. We hypothesized
that higher glial fibrillary acid protein levels are related to impaired perioperative
cerebral oxygenation.
Methods
The study was designed as a prospective observational cohort study. Neonates with
CHD up to 28 days of age undergoing cardiac surgery utilizing cardiopulmonary bypass
were eligible for enrollment. Exclusion criteria included proven or clinically suspected
genetic syndrome, weight at surgery of less than 2500 g, history of birth asphyxia,
or preexisting brain injury.
The study protocol has been approved by the institutional research ethics committee.
Written informed consent was provided for all subjects.
All patients received standard care during the perioperative period. In terms of bypass
management, the pH-stat method was used for cooling to the desired temperature. Patients
undergoing the Norwood procedure were operated on in deep hypothermia with selective
cerebral perfusion during aortic arch reconstruction. Hemofiltration was routinely
used before weaning from bypass.
Glial Fibrillary Acidic Protein
Glial fibrillary acid protein levels were obtained before surgery as well as 0, 12,
24, and 48 hours after surgery. Blood was drawn from indwelling arterial or central
venous lines. Samples were centrifuged and aliquots stored at –20°C until analysis.
Protein concentrations were determined by enzyme-linked immunosorbent assay (ELISA)
with a commercially available ELISA-platform (Abbexa, Cambridge, United Kingdom).
Samples were analyzed according to the manufacturer's instructions; all samples were
assayed in duplicates.
Due to the lack of validated reference values, these were defined based on preoperative
samples after exclusion of outliers and extreme values. Concentrations >95th percentile
were defined as elevated. For statistical analysis, cases with glial fibrillary acid
protein values in the normal range were compared with patients who had elevated concentrations
at any time after surgery.
Routine Monitoring and Near-Infrared Spectroscopy
Routine perioperative monitoring included continuous measurement of arterial oxygen
saturation and invasive arterial and central venous blood pressure (IntelliVue, Philips
Healthcare, Best, the Netherlands). Arterial blood gases, including lactate levels,
were obtained at 1 to 2-hour intervals; central venous blood gases were sampled at
4-hour intervals.
Near-infrared spectroscopy probes were placed on the patient's midline forehead and
slightly to the right of midline on the T10-L2 posterior flank. Cerebral and somatic
tissue oxygen saturations were monitored continuously (INVOS 5100, Medtronic, Minneapolis,
Minnesota, United States). Regional oxygen saturation values determined by near-infrared
spectroscopy were matched to the hemodynamic and respiratory data for 12 hours before
and 48 hours after surgery. Mean values were calculated for the 12 preoperative hours
(baseline), for the first 4 postoperative hours (early postoperative course), and
for the entire 48-hour postoperative period. The intraoperative course was divided
into five periods (pre-bypass, cooling, low-flow, rewarming, off-pump) and mean values
were calculated for each period and for the entire intraoperative course. To estimate
cerebral oxygen extraction, the difference between the arterial and the corresponding
cerebral oxygen saturation measurement was calculated. Comparisons were made between
neonates with elevated postoperative glial fibrillary acid protein and cases with
glial fibrillary acid protein in the normal range. Subgroup analyses were performed
for neonates undergoing the Norwood procedure or the arterial switch operation.
Statistics
Continuous variables are expressed as mean and standard deviation or median and interquartile
range as appropriate and categorical data as count and percentages. We employed Fisher's
exact test for analysis of categorical data. Continuous variables were compared with
the Student's t-test for two independent samples or—in case of non-normally distributed data—with
the Mann–Whitney U-Test or Kruskal–Wallis test. Correlations were calculated using the Pearson correlation
coefficient. All statistical analyses were performed with the statistical software
package SPSS (IBM SPSS Statistics for Windows, Version 22.0; IBM Corp., Armonk, New
York, United States). A value of p < 0.05 was considered statistically significant.
Results
Patients
A total of 36 neonates were enrolled in the study between May 2015 and September 2016.
Underlying diagnosis is given in [Table 1]. The diagnosis was made prenatally in 20 (55.6%) patients. Two patients (5.6%) were
born preterm, and extracardiac malformations were seen in four (11.1%) patients. Prior
to enrollment, four neonates had undergone pulmonary artery banding and another four
required a balloon atrial septostomy. With one exception, all neonates received prostaglandin-E1
infusion for maintaining ductal patency. Preoperative adverse events were noted in
six cases including clinical deterioration with signs of multiorgan failure, the need
for intubation or inotropic support, unplanned cardiac surgery, or intervention.
Table 1
Cardiac diagnosis
|
Hypoplastic left heart syndrome and other single ventricle lesions
|
16 (44.4%)
|
|
Transposition of the great arteries
|
12 (33.3%)
|
|
Ventricular septal defect + aortic arch abnormality[a]
|
4 (11.1%)
|
|
Common arterial trunk
|
2 (5.6%)
|
|
Total anomalous pulmonary venous drainage
|
1 (2.8%)
|
|
Partial anomalous pulmonary venous drainage + VSD
|
1 (2.8%)
|
Abbreviation: VSD, ventricular septal defect.
a Interrupted aortic arch (n = 1) and coarctation (n = 3).
Surgeries and Postoperative Course
The 36 neonates underwent 38 surgical procedures ([Table 2]). Postoperative complications were noted after 14 (36.8%) surgeries, mostly within
the first 48 hours. Transient rhythm disturbances (n = 5) were most common, others included sepsis, low-cardiac output, and shunt thrombosis.
Clinically overt neurological complications were not noted in any case. Two patients
died within the study period. One patient deceased 91 days after the Norwood procedure
due to shunt thrombosis, another with the borderline left heart structures 28 days
after a biventricular repair approach.
Table 2
Surgical data and postoperative course
|
Type of surgery
|
|
Norwood procedure
|
15
|
(39.5%)
|
|
Arterial switch operation
|
12
|
(31.6%)
|
|
Aortic arch repair (+VSD closure)
|
6
|
(15.8%)
|
|
Others[a]
|
5
|
(13.2%)
|
|
Surgical data
|
|
Age at surgery (d)
|
5
|
(3–7)
|
|
Weight at surgery (kg)
|
3.42
|
±0.44
|
|
Cardiopulmonary Bypass (min)
|
139
|
±37
|
|
Aortic cross-clamp (min)
|
68
|
±30
|
|
Selective cerebral perfusion[b] (min)
|
43
|
±12
|
|
Temperature nadir (°C)
|
22.0
|
±4.3
|
|
Primary chest closure (n)
|
32
|
(84.2%)
|
|
Postoperative course
|
|
Mechanical ventilation (h)
|
87
|
(61–118)
|
|
Duration of inotropic support (h)
|
26
|
(18–73)
|
|
Intensive care unit stay (d)
|
11
|
(6–33)
|
|
Hospital stay (d)
|
25
|
(12–49)
|
Abbreviation: VSD, ventricular septal defect.
a Others: repair of anomalous pulmonary venous return (n = 2), repair of common arterial trunk (n = 2), atrioseptectomy and pulmonary artery banding (n = 1).
b Selective cerebral perfusion (n = 17).
Perioperative Glial Fibrillary Acid Protein Serum Concentrations
[Fig. 1] shows pre- and postoperative glial fibrillary acid protein serum concentrations.
No samples were available after three procedures. Compared with preoperative baseline
values, median postoperative serum concentrations were not significantly different
at any time point. [Table 3] compares values between cases undergoing the arterial switch operation, the Norwood
procedure, or other surgeries, respectively.
Table 3
Perioperative GFAP serum concentrations (µg/L)
|
Time of sampling
|
Single ventricle (n = 16)
|
Transposition (n = 12)
|
Others (n = 7)
|
p-Value
|
|
Preoperative
|
0.97
|
(0.33–1.36)
|
1.39
|
(0.75–12.87)
|
7.34
|
(0.89–17.09)
|
0.246
|
|
0h postoperative
|
1.73
|
(0.75–5.53)
|
2.30
|
(1.14–6.95)
|
4.21
|
(1.02–19.30)
|
0.484
|
|
12h postoperative
|
1.48
|
(0.85–4.61)
|
3.20
|
(1.09–5.01)
|
3.86
|
(1.73–20.09)
|
0.356
|
|
24h postoperative
|
1.48
|
(0.63–9.53)
|
3.92
|
(1.67–5.26)
|
2.06
|
(1.43–19.57)
|
0.440
|
|
48h postoperative
|
1.46
|
(0.25–12.86)
|
2.25
|
(0.95–14.30)
|
1.26
|
(0.90–7.78)
|
0.876
|
Abbreviation: GFAP, glial fibrillary acid protein.
Fig. 1 Pre- and postoperative glial fibrillary acid protein (GFAP) serum concentrations
(n = 35). Whiskers above and below the box represent the largest and smallest data points
that are <1.5 box lengths (interquartile range) away from the end of the box; circles
highlight data points >1.5 box lengths (outliers) and asterisks data points >3 box
lengths away (extreme values). The red line represents the 95th percentile of preoperative
GFAP values after exclusion of outliers and extreme values.
Elevated Preoperative Glial Fibrillary Acid Protein Concentrations
Preoperative glial fibrillary acid protein levels were above the 95th percentile (>
4 µg/L) in seven cases. Six patients (transposition of the great arteries, n = 4; common arterial trunk with interrupted aortic arch, n = 1; ventricle septum defect with aortic arch hypoplasia and coarctation, n = 1) had markedly elevated glial fibrillary acid protein concentrations ([Fig. 1], extreme values). Preoperative cerebral oxygen saturation was not different between
cases with elevated glial fibrillary acid protein and those in the normal range (60 ± 12%
vs. 67 ± 9%, p = 0.163).
There was no association between elevated preoperative GFAP and clinical factors including
the need for septostomy in patients with transposition of the great arteries.
Elevated Postoperative Glial Fibrillary Acid Protein Concentrations
Elevated postoperative glial fibrillary acid protein concentrations were found after
18 surgeries, including all seven cases with elevated preoperative values. Glial fibrillary
acid protein was elevated after the arterial switch operation in 7 of 12 cases, after
5 of 15 Norwood procedures, and after other operations in 6 of 8 cases (p = 0.144). Median age at surgery was higher in patients with elevated postoperative
glial fibrillary acid protein. The duration of cardiopulmonary bypass, aortic cross
clamp, and selective cerebral perfusion were not different. No differences in variables
of the postoperative course were noticed ([Table 4]).
Table 4
Surgical data and postoperative course
|
GFAP normal (n = 17)
|
GFAP elevated (n = 18)
|
p-Value
|
|
Surgical data
|
|
Age at surgery (d)
|
4
|
(2–5)
|
6
|
(4–7)
|
0.009
|
|
Weight at surgery (kg)
|
3.51
|
±0.45
|
3.32
|
±0.41
|
0.205
|
|
Cardiopulmonary bypass (min)
|
143
|
±38
|
140
|
±35
|
0.807
|
|
Aortic cross-clamp[a](min)
|
61
|
±27
|
76
|
±30
|
0.127
|
|
Selective cerebral perfusion[b] (min)
|
42
|
±9
|
46
|
±15
|
0.574
|
|
Temperature nadir (°C)
|
21.7
|
±4.8
|
22.4
|
±3.8
|
0.624
|
|
Postoperative course
|
|
Mechanical ventilation (h)
|
88
|
(58–116)
|
80
|
(58–116)
|
0.961
|
|
Inotropic support (h)
|
22
|
(16–55)
|
46
|
(18–88)
|
0.143
|
|
Intensive care unit stay (d)
|
22
|
(8–38)
|
11
|
(6–29)
|
0.245
|
|
Hospital stay (d)
|
42
|
(13–60)
|
20
|
(11–49)
|
0.365
|
Abbreviation: GFAP, glial fibrillary acid protein.
a Aortic cross clamp, n = 16 versus 17;
b selective cerebral perfusion, n = 10 versus 7.
[Fig. 2] compares pre-, intra-, and postoperative cerebral oxygen saturation readings between
cases with elevated postoperative glial fibrillary acid protein and those with concentrations
in the normal range. Preoperative cerebral oxygen saturation values were not different.
Mean intraoperative cerebral oxygen saturation was lower in patients with elevated
glial fibrillary acid protein ([Table 5]). Specifically, cerebral oxygen saturations during cooling (72 ± 13% vs. 80 ± 8%,
p = 0.045) and while on bypass until rewarming (76 ± 15% vs. 85 ± 7%, p = 0.029) were lower in cases with elevated glial fibrillary acid protein ([Fig. 2]). No differences were observed in postoperative cerebral and somatic tissue oxygen
saturations ([Fig. 2], [Table 4]). Routine monitoring data showed no differences between groups ([Table 5]).
Fig. 2 Comparison of pre-, intra-, and postoperative cerebral tissue oxygen saturations
(ScO2) between patients with normal (n = 17, green line) and elevated (n = 18, red line) postoperative glial fibrillary acid protein (GFAP) concentrations.
The intraoperative course was divided into five periods: pre-bypass (A), cooling (B), low-flow (C), rewarming (D), and off-pump (E). p-Values refer to the comparison of mean values between groups in the outlined
perioperative period (highlighted in yellow). Mean ScO2 values during cooling and low-flow were significantly lower in cases with postoperative
elevated GFAP (asterisks).
Table 5
Near-infrared spectroscopy and routine monitoring data
|
GFAP normal (n = 17)
|
GFAP elevated (n = 18)
|
p-Value
|
|
Preoperative course
|
|
ScO2 (%)
|
68
|
±8
|
62
|
±10
|
0.109
|
|
SsO2 (%)
|
67
|
±8
|
62
|
±7
|
0.060
|
|
ΔSacO2 (%)
|
25
|
±9
|
27
|
±9
|
0.551
|
|
SaO2 (%)
|
92
|
±3
|
89
|
±6
|
0.102
|
|
MAP (mm Hg)
|
50
|
±4
|
48
|
±4
|
0.229
|
|
paCO2 (mm Hg)
|
43
|
±10
|
43
|
±6
|
0.907
|
|
paO2 (mm Hg)
|
55
|
±22
|
52
|
±21
|
0.634
|
|
Lactate (mmol/L)
|
1.5
|
±0.6
|
1.5
|
±0.5
|
0.681
|
|
Intraoperative data (entire period)
|
|
ScO2 (%)
|
77
|
±7
|
70
|
±10
|
0.029
|
|
SsO2 (%)
|
77
|
±8
|
78
|
±11
|
0.800
|
|
Early postoperative course (first 4 h)
|
|
ScO2 (%)
|
57
|
±4
|
56
|
±13
|
0.834
|
|
SsO2 (%)
|
86
|
±9
|
85
|
±15
|
0.791
|
|
SaO2 (%)
|
90
|
±7
|
93
|
±8
|
0.222
|
|
MAP (mm Hg)
|
54
|
±6
|
52
|
±6
|
0.422
|
|
paCO2 (mm Hg)
|
37
|
±6
|
39
|
±7
|
0.540
|
|
paO2 (mm Hg)
|
82
|
±52
|
105
|
±57
|
0.226
|
|
SvO2 (%)
|
72
|
±11
|
70
|
±10
|
0.479
|
|
Lactate (mmol/L)
|
6.7
|
±2.2
|
5.6
|
±1.9
|
0.120
|
|
Entire postoperative course
|
|
ScO2 (%)
|
70
|
±13
|
72
|
±10
|
0.654
|
|
SsO2 (%)
|
77
|
±11
|
77
|
±11
|
0.881
|
|
ΔSacO2 (%)
|
20
|
±9
|
23
|
±7
|
0.269
|
|
SaO2 (%)
|
88
|
±7
|
93
|
±7
|
0.072
|
|
MAP (mmHg)
|
50
|
±4
|
49
|
±3
|
0.175
|
|
paCO2 (mmHg)
|
42
|
±4
|
44
|
±3
|
0.273
|
|
paO2 (mmHg)
|
72
|
±38
|
99
|
±47
|
0.066
|
|
SvO2 (%)
|
72
|
±10
|
72
|
±7
|
0.918
|
|
Maximum lactate (mmol/L)
|
7.9
|
±2.2
|
6.5
|
±1.9
|
0.055
|
Abbreviations: GFAP, glial fibrillary acid protein; MAP, mean arterial pressure; paCO2, arterial carbon dioxide tension; paO2, arterial oxygen tension; ΔSacO2, arterial–cerebral saturation difference; SaO2, arterial oxygen saturation; ScO2, cerebral tissue oxygen saturation; SsO2, somatic tissue oxygen saturation;; SvO2, central venous saturation.
Subgroup Analysis
Patients undergoing the Norwood procedure or the arterial switch operation were analyzed
separately. The arterial switch operation was performed earlier compared with the
Norwood procedure (median age 4 [2–5] days vs. 6 [4–7] days, p = 0.032). Duration of cardiopulmonary bypass was not different, but aortic cross-clamp
time was longer for the arterial switch operation (158 ± 23 vs. 151 ± 21 minutes,
p = 0.445 and 101 ± 16 vs. 46 ± 11 minute, p < 0.001). The temperature nadir was higher during the arterial switch operation (24.8 ± 2.4°C
vs. 18.5 ± 1.2°C, p < 0.001). Mean intraoperative cerebral oxygen saturation was not different between
subgroups (Norwood: 75 ± 8% vs. arterial switch operation: 75 ± 10%, p = 0.923). However, cerebral oxygen saturation during hypothermic bypass was lower
(78 ± 12% vs. 87 ± 6%, p = 0.040), while cerebral oxygen saturations after termination of cardiopulmonary
bypass were higher in the arterial switch operation group (79 ± 10% vs. 62 ± 12%,
p = 0.001). The frequency of cases with elevated postoperative glial fibrillary acid
protein was not different between subgroups (Norwood: 5/15 vs. arterial switch operation:
7/12, p = 0.194).
Glial Fibrillary Acid Protein after the Arterial Switch Operation
Preoperative cerebral (55 ± 9% vs. 64 ± 4%, p = 0.048) and somatic tissue oxygen saturations (59 ± 8% vs. 70 ± 6%, p = 0.025) as well as arterial oxygen saturations (86 ± 5% vs. 92 ± 4%, p = 0.03) and arterial partial pressure of oxygen (38 ± 5 mm Hg vs. 45 ± 5 mm Hg, p = 0.046) were lower in cases with elevated glial fibrillary acid protein. Median
age at surgery was 2 (2–3) days compared with 4 (3–6) days in patients with elevated
glial fibrillary acid protein (p = 0.149). Duration of cardiopulmonary bypass and aortic cross-clamp and intraoperative
tissue oxygen saturations was not different between cases with normal or elevated
glial fibrillary acid protein values (cerebral oxygen saturation: 73 ± 13% vs. 77 ± 5%,
p = 0.507 and somatic oxygen saturation: 86 ± 6% vs. 85 ± 4%, p = 0.905). Routine monitoring and near-infrared spectroscopy data of the postoperative
course showed no differences.
Glial Fibrillary Acid Protein after the Norwood Procedure
Median age at Norwood procedure was 7 (6–8) days in cases with elevated glial fibrillary
acid protein compared with 5 (4–6) days with serum levels in the normal range (p = 0.028). The duration of selective cerebral perfusion tended to be longer in patients
with elevated glial fibrillary acid protein (53 ± 10 vs. 42 ± 9 minutes, p = 0.056). There were no differences in duration of cardiopulmonary bypass (146 ± 11
vs. 154 ± 24 minutes, p = 0.463). The mean intraoperative cerebral tissue oxygen saturation was 72 ± 3% compared
with 77 ± 8% in cases with glial fibrillary acid protein in the normal range (p = 0.208). There were no differences in perioperative routine monitoring or near-infrared
spectroscopy data.
Discussion
Perioperative hypoxemia may be an important modifiable risk factor for developmental
impairment in children with complex CHD requiring corrective or palliative surgery
during the neonatal period. Our pilot study evaluated the relation between cerebral
oxygenation derived by near-infrared spectroscopy and serum concentrations of the
astrocyte protein glial fibrillary acid protein, a potential biomarker for brain injury.
In our cohort, postoperative glial fibrillary acid protein concentrations were elevated
in about every second patient. Overall, neonates with elevated glial fibrillary acid
protein were operated later and had lower intraoperative cerebral tissue oxygen saturations.
In neonates with transposition of the great arteries undergoing arterial switch operation,
preoperative cerebral and somatic oxygen saturations, as well as arterial oxygen saturations
and partial pressures of oxygen were lower in those with elevated postoperative glial
fibrillary acid protein. In neonates undergoing the Norwood procedure, only older
age at surgery was associated with elevated glial fibrillary acid protein. For cases
who had a Norwood procedure, no relation between perioperative cerebral oxygenation
and postoperative glial fibrillary acid protein was observed.
Glial fibrillary acid protein is part of the astrocyte cytoskeleton and is thought
to be specific to the nervous system. After astrocyte injury, glial fibrillary acid
protein and its breakdown products can be detected in the peripheral blood. Circulating
glial fibrillary acid protein levels were predictive of abnormal brain MRI and neurodevelopmental
outcome in neonates with hypoxic ischemic encephalopathy and for the occurrence of
periventricular white matter injury in premature infants.[18]
[19] Glial fibrillary acid protein has also been evaluated in neonates and infants undergoing
surgery for CHD in previous studies.[20]
[21]
[22]
[23]
[24]
[25]
[26] However, in these reports samples were often limited to the intraoperative period.
Up to now, only one study evaluated the relation between intraoperative cerebral oxygenation
derived by near-infrared spectroscopy and glial fibrillary acid protein concentrations.[20] The association between pre- or postoperative cerebral oxygenation and postoperative
glial fibrillary acid protein release has not been previously studied.
In our cohort, preoperative glial fibrillary acid protein concentrations were found
to be elevated in ∼20% and postoperative values in ∼50%. Similar frequencies have
been reported for the prevalence of pre- and postoperative white matter injury seen
on MRI in neonates with complex CHD.[5]
[6]
[7]
[8]
[9]
[10]
[11] In contrast to our results, preoperative glial fibrillary acid protein levels were
usually undetectable or very low in previous studies, which seem to be inconsistent
with the prevalence of white matter injury based on MRI data. However, the protein
was also detectable in the majority of patients after initiation of cardiopulmonary
bypass.[20]
[21]
[22]
[23]
[24]
[25]
[26] Highest values were usually noticed at the end of bypass.[20]
[21]
[22]
[23] Unfortunately, up to now methodological heterogeneity in glial fibrillary acid protein
assessments with different ELISA-platforms hinders comparability of absolute values.
Two studies reported postoperative concentrations in the range of 2 ng/mL in patients
with transposition of the great arteries or in cases undergoing the Norwood operation.[20]
[22]
Among others, glial fibrillary acid protein concentrations were related to the duration
of cardiopulmonary bypass, lower temperature nadir, lower oxygen delivery while on
bypass, and intraoperative cerebral saturations below 45% in previous reports.[20]
[21]
[22]
[23] In our cohort, mean intraoperative cerebral oxygen saturations were lower in patients
with elevated postoperative glial fibrillary acid protein, especially during cooling
and hypothermic cardiopulmonary bypass. During hypothermic bypass relatively high
cerebral oxygen saturations are usually achieved, which are well above accepted threshold
of 40 to 45%. Prolonged periods of low cerebral oxygen saturation are rarely seen
if circulatory arrest is avoided. In a previous study, brain MRI abnormalities in
terms of hemosiderin foci were associated with lower mean cerebral oxygen saturation
in neonates and infants undergoing corrective surgery for CHD.[11] On average, cerebral oxygen saturations were all well above widely accepted thresholds
for both patients with or without imaging abnormalities.[11] Thresholds for adequate cerebral oxygenation may vary according to specific bypass
conditions, particularly during hypothermia. It is also likely that additional factors
increase the susceptibility to intra- or postoperative injury. Among others, experimental
data suggest that preoperative hypoxia increases the vulnerability of developing white
matter to ischemia and reperfusion injury.[27] Patients with complex CHD are at risk of cerebral hypoxemia before surgery.[6]
[28]
[29]
[30]
[31]
[32] Due to hemodynamic alterations of cerebral blood flow, fetuses with complex CHD
might develop brain injury even before birth. Brain development often is delayed and
may itself result in greater vulnerability to cerebral white matter injury.[33]
[34] The majority of patients in our study had the underlying diagnosis transposition
of the great arteries or hypoplastic left heart syndrome. For both, abnormal findings
on MRI before surgery, particularly white matter injury, have been reported.[5]
[7]
[10]
[31]
[35] In one study, neonates with transposition of the great arteries diagnosed with periventricular
leukomalacia were more hypoxemic and time to surgery was longer compared with those
without white matter injury.[32] In addition, Lim et al evaluated 45 infants with transposition of the great arteries
using pre- and postoperatively MRI. Surgery beyond 2 weeks of age was associated with
impaired brain growth and neurodevelopment. The underlying mechanisms were unclear.
However, the authors assumed that extended periods of cyanosis and pulmonary over-circulation
may be causative.[35] In our cohort, neonates with transposition of the great arteries and elevated postoperative
glial fibrillary acid protein were also exposed to a greater degree of hypoxemia in
the preoperative course. They had lower cerebral and somatic oxygen saturation values
as well as lower arterial oxygen saturations and partial pressure of oxygen levels
on blood gases. For patients with transposition of the great arteries, lower preoperative
cerebral saturations were also related to neurodevelopmental outcome in a previous
study.[14] Similar observations were made in patients with hypoplastic left heart syndrome.
Lynch et al observed a large amount of new or worsened postoperative white matter
injury in ∼50% of the patients. The risk of injury increased with longer time to surgical
repair and cases with white matter injury tended to have lower preoperative cerebral
tissue oxygen saturations.[31] In our study, time to surgery was also longer in patients undergoing a Norwood procedure
presenting with high postoperative glial fibrillary acid protein.
Postoperative glial fibrillary acid protein levels have not yet been evaluated together
with brain imaging in children with CHD. However, one study showed a relation between
impaired neurodevelopment assessed 18 months after surgery with the Vineland Adaptive
Behavior Scales (VABS-I) and increased glial fibrillary acid protein levels during
cardiac surgery.[25] In addition, higher postoperative GFAP levels were independently associated with
decreased motor scores in a study evaluating neurodevelopmental outcomes 12 months
after neonatal cardiac surgery with the Bayley Scales of Infant and Toddler Development
third edition.[26]
Developmental outcomes and the relation to perioperative glial fibrillary acid protein
will be determined in our cohort.
Limitations
The sample size of this pilot study was relatively small and statistical power reduced,
especially for subgroup analysis. Multivariate analysis was not applicable due to
small sample size. The generalizability of our results is therefore limited. Methodological
heterogeneity in glial fibrillary acid protein assessments and the lack of reliable
reference data for commercially available ELISA-platforms hinder comparability. Normal
values were derived from preoperative values from diseased children rather than from
a healthy control group. Cerebral MRI was not performed in the perioperative course
and no association between glial fibrillary acid protein or cerebral tissue oxygenation
and evidence of hypoxic brain injury can be provided. In this observational study,
near-infrared spectroscopy monitoring was not used for a goal-directed therapy.
Conclusions
Our pilot study evaluated the astrocyte component glial fibrillary acid protein as
a potential biomarker for brain injury in neonates with complex CHD. Elevated postoperative
glial fibrillary acid protein concentrations were noted in about every second patient
and were related to older age at surgery and intraoperative cerebral oxygenation.
In patients with transposition of the great arteries, elevated glial fibrillary acid
protein levels were associated with preoperative hypoxemia. Neurodevelopmental outcome
still has to be determined, but glial fibrillary acid protein as a brain biomarker
after neonatal cardiac surgery warrants further investigation.
