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University of Groningen Congenital heart disease : the timing of brain injury Mebius, Mirthe Johanna

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Congenital heart disease : the timing of brain injury

Mebius, Mirthe Johanna

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

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Publication date: 2018

Link to publication in University of Groningen/UMCG research database

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Mebius, M. J. (2018). Congenital heart disease : the timing of brain injury. [S.n.].

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the first 72 h after birth in infants

diagnosed prenatally with congenital

heart disease

Mirthe J. Mebius, Michelle E. van der Laan, Elise A. Verhagen,

Marcus T.R. Roofthooft, Arend F. Bos, Elisabeth M.W. Kooi

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Abstract

Background: Evidence suggests that hypoxic-ischemic brain injury in infants with

congenital heart disease already occurs during early life. The aim of our study was, therefore, to assess the course of regional cerebral oxygen saturation (rcSO2) and fractional tissue oxygen extraction (FTOE) during the first 72 h after birth in infants with prenatally diagnosed duct-dependent congenital heart disease. In addition, we identified clinical parameters that were associated with rcSO2.

Materials and methods: We included 56 infants with duct-dependent congenital heart

disease. We measured arterial oxygen saturation (SpO2) and rcSO2 during the first 72 h after birth. Simultaneously, we calculated FTOE.

Results: We observed median rcSO2 values of approximately 60%, a decreasing FTOE from 0.34 on day 1 to 0.28 on day 3 and stable preductal SpO2 values around 90%. Several clinical variables were associated with rcSO2. In a multiple linear regression model only type of CHD and preductal SpO2 were significant predictors of rcSO2 during the first three days after birth. Infants with a duct-dependent pulmonary circulation had up to 12% lower rcSO2 values than infants with a duct-dependent systemic circulation.

Conclusion: We demonstrated that, during the first three days after birth, cerebral oxygen

saturation is low in infants with duct-dependent congenital heart disease. Furthermore, this study provides preoperative reference values of rcSO2 and FTOE in infants with duct-dependent CHD.

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Introduction

Neurodevelopmental impairments are common in infants with congenital heart disease (CHD) and occur across a wide spectrum of domains, such as intelligence, language, attention, executive functioning, and fine and gross motor skills.1,2 Accumulating evidence

suggests that brain injury that leads to neurodevelopmental impairments already occurs during early postnatal life in infants with CHD. Abnormal neurological physical examination or abnormalities on preoperative MRI-scans are reported in up to 53% of infants with CHD.3-7

Many of the brain abnormalities seen on preoperative MRI-scans are associated with cerebral hypoxia and/or ischemia and include periventricular leukomalacia and stroke followed by white matter injury.3 However, little is known about cerebral oxygenation during early

postnatal life in infants with CHD.

Near-infrared spectroscopy (NIRS) is a reliable and non-invasive method to continuously assess cerebral oxygen saturation (rcSO2) during early postnatal life.8,9 When transcutaneous

arterial oxygen saturation (SpO2) is measured simultaneously with rcSO2, fractional tissue oxygen extraction (FTOE) can be calculated.10 Both r

cSO2 and FTOE are indicators of cerebral

hypoxia and ischemia. Most studies on rcSO2 in infants with CHD cover the intraoperative or postoperative period.11-14 There are only a few studies that mention preoperative r

cSO2

values.15-17 These studies, however, measured r

cSO2 during the immediate preoperative

period with a maximum of 24 h before cardiac surgery. Furthermore, they only measured rcSO2 for a short period of time.15,16 Given that infants with CHD are at risk of developing

hypoxic-ischemic brain injury during early postnatal life, it is important to know whether cerebral oxygen saturation is low during the first days after birth. In addition, in order to monitor the effect of interventions or to interpret intraoperative and postoperative rcSO2 values we need solid preoperative reference values.

Therefore, our aim was to assess the course of cerebral oxygen saturation and extraction during the first 72 h after birth in infants with prenatally diagnosed duct-dependent congenital heart disease.

Methods

Patients

This was a retrospective study conducted at Beatrix Children’s Hospital, a tertiary cardiac and neonatal intensive care unit of University Medical Center Groningen, The Netherlands. All infants with a gestational age of > 36 weeks, who were born between December 2007 and August 2014 and who had been diagnosed prenatally with duct-dependent CHD, were considered for inclusion. Of these infants only those who had been treated with prostaglandin E1 and in whom rcSO2 had been measured for at least 24 h during the first 72 h after birth were selected for inclusion. Infants with major chromosomal abnormalities were excluded from participation. The institutional review board of the University Medical Center Groningen approved the study.

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Near-infrared spectroscopy

For this study, we used INVOS 4100c and 5100c near-infrared spectrometers (Covidien, Mansfield, MA, USA) in combination with neonatal or pediatric SomaSensors (Covidien). The SomaSensor was placed on the frontoparietal side of the head and rcSO2 was measured continuously during the first 72 h after birth according to local protocol. Simultaneously with rcSO2, we measured preductal transcutaneous SpO2 (Nellcor, Covidien) and calculated FTOE as follows: FTOE = (SpO2 − rcSO2) / SpO2. The rcSO2 and SpO2 data were directly obtained from the INVOS and Philips monitor, respectively, and were stored for offline analysis at 0.2 Hz. For the purpose of this study we calculated mean rcSO2, SpO2, and FTOE values per infant per day.

Clinical characteristics

We collected all available clinical and biochemical parameters that might influence the course of rcSO2. From the patients’ medical files, we collected type of CHD, gestational age, birth weight, Apgar score at 5 min, respiratory support, whether the infant received blood transfusion during the study period, mean airway pressure and treatment with inotropes and sedatives. For type of CHD we distinguished between infants with mainly a duct-dependent systemic circulation and those with mainly a duct-dependent pulmonary circulation. Infants with transposition of the great arteries, pulmonary atresia or critical pulmonary valve stenosis were considered to have a duct-dependent pulmonary circulation. Infants with hypoplastic left heart syndrome, coarctation of the aorta or critical aortic valve stenosis were considered to have a duct-dependent systemic circulation. Furthermore, we collected serum lactate and hemoglobin from the first drawn venous blood sample and pH, pCO2, and pO2 from the first arterial, venous or capillary blood gas measurement within 72 h after birth.

Statistical analysis

For statistical analysis, we used SPSS 22.0 (IBM Corp., Armonk, NY, USA). We displayed the course of rcSO2, FTOE, and SpO2 graphically per day for all infants. To analyze differences in rcSO2, FTOE, and SpO2 between subsequent days we used the Wilcoxon signed rank test. To find associations between clinical and biochemical parameters and cerebral oxygen saturation and extraction we used the Spearman’s rank order correlation test or the Mann Whitney U test where appropriate. Finally, we used multiple linear regression analyses (enter method) to determine which clinical and biochemical parameters could predict rcSO2 most accurately. For this analysis, we selected only those variables with a P-value < 0.05 in univariate regression analysis. P-values of < 0.05 were considered to be statistically significant.

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Results

Patient characteristics

We identified 77 infants with prenatally diagnosed duct-dependent CHD who were treated with prostaglandin E1 between December 2007 and August 2014. Fifty-six patients met the inclusion criteria. Reasons for exclusion were < 24 h of NIRS-measurements (eighteen infants), a gestational age of < 36 weeks (one infant), the circulation of only one lung being duct-dependent (one infant) and major chromosomal abnormalities (one infant). The fifty-six infants had a median (range) gestational age of 39.1 weeks (36.6–41.7 weeks) and a median birth weight of 3343 g (1960–4400 g). Thirteen infants died within one month after birth as a consequence of their congenital heart disease. Patient characteristics are presented in Table 1.

Table 1 Patient characteristics

N = 56

Gestational age (weeks) 39.1 (36.6 - 41.7)

Birth weight (grams) 3343 (1960 - 4400)

Male 29 (51) Diagnosis - TGA - HLHS - Pulmonary stenosis - Pulmonary atresia - Interrupted aortic arch - Coarctation of the aorta - Aortic valve stenosis

19 (33) 14 (25) 8 (14) 8 (14) 3 (5) 3 (5) 1 (2) Apgar at 5 minutes 9 (4 - 10) MABP day 1 (n=23) 48 (36 - 63) MABP day 2 (n=24) 48 (35 - 65) MABP day 3 (n=25) 48 (39 - 92)

Respiratory support day 1

- None/low flow - CPAP - NIMV/SiPAP - SIMV/SIPPV 30 (53) 7 (12) 2 (4) 18 (31)

Respiratory support day 2

- None/low flow - CPAP - NIMV/SiPAP - SIMV/SIPPV 30 (52) 6 (11) 1 (2) 20 (35)

Respiratory support day 3

- None/low flow - CPAP - NIMV/SiPAP - SIMV/SIPPV 32 (56) 8 (14) 1 (2) 16 (28)

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N = 56

Mean airway pressure day 1 10.1 (7.8 - 11.3)

Mean airway pressure day 2 9.7 (7.6 - 10.9)

Mean airway pressure day 3 9,4 (7.7 - 11.5)

Hba (n=42) 11.0 (7.9 - 14.4)

pHa(n=42) 7.29 (6.84 - 7.59)

Lactatea (n=33) 3.9 (1.2 - 13.4)

pCO2a (n=42) 7.1 (2.5 - 10.4)

pO2a (n=19) 4.0 (2.6 - 11.7)

Blood transfusion during study period 9 (16)

Data represent either median (range) or number of patients (percentage). TGA, transposition of the great arteries; HLHS, hypoplastic left heart syndrome; MABP, mean arterial blood pressure; CPAP, continuous positive airway pressure; NIMV, nasal intermittent mandatory ventilation; SiPAP, synchronized intermittent positive airway pressure; SIMV, synchronized intermittent mandatory ventilation; SIPPV, synchronized intermittent positive pressure ventilation .a indicates first measurement within 72 hours after birth.

The course of rcSO2, FTOE and SpO2 for all infants

Fifty infants had rcSO2 and FTOE values on all three days after birth, two infants did not have rcSO2 and FTOE values on day 1 and four infants did not contribute to day 3. The course of rcSO2, FTOE and SpO2 is presented in Figure 1. Median (range) rcSO2 ranged from 58.5% (45%–81%) on day 1 to 62.5% (49%–86%) on day 2 to 61.5% (49%–92%) on day 3. Cerebral oxygen saturation was significantly higher on day 2 and day 3 than on day 1 (P = 0.004 and < 0.001, respectively) and decreased from day 2 to day 3 (P=0.01). Median (range) FTOE decreased during the first three days after birth from 0.34 (0.11–0.50) on day 1 to 0.29 (0.06–0.44) on day 2 and 0.28 (0.02–0.47) on day 3. Median (range) SpO2 ranged from 90% (73%–99%) on day 1 to 91% (73%–100% and 75%–100%, respectively) on days 2 and 3. There were no significant differences in SpO2 between subsequent days.

Association with clinical and biochemical parameters

First venous blood samples were drawn on day 1 in 64%, on day 2 in 24% and on day 3 in 12% of the cases. Blood gas measurements were arterial in 25%, venous in 30% and capillary in 45% of the cases. The vast majority of infants had blood gas measurements on day 1 (83%).

Several clinical and biochemical parameters were associated with rcSO2 during the first three days after birth. On day 1, rcSO2 correlated positively to preductal SpO2 (rho 0.56,

P≤0.001), and tended to be positively correlated to Hb (rho 0.29, P=0.06) and Apgar score at

5 min (rho 0.26, P=0.05). There was a negative correlation between rcSO2 and birth weight (rho − 0.29, P=0.04). Furthermore, infants who were treated with inotropes or sedatives had significantly lower rcSO2 values (P=0.03 and P=0.04, respectively). On day 2 there was a positive correlation between rSO and preductal SpO (rho 0.29, P=0.03). On day 3 there

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                                                                                               Figur e 1 The course of rc SO 2 , FT OE and SpO 2 dur ing the first 72 hours af ter bir th. Data ar e sho wn in bo x-and-whisk er plots . Cir cles repr esent outliers . Rc SO 2 , r eg ional cer ebral o xy gen saturation; FT OE, frac tional tissue o xy gen ex trac tion; SpO 2 , pr educ tal ar ter ial o xy gen saturation.

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was a positive correlation between rcSO2 and preductal SpO2 (rho 0.42, P=0.003) and there tended to be a positive correlation between rcSO2 and gestational age (rho 0.24, P=0.09).

During the first three days after birth, infants with a duct-dependent pulmonary circulation had lower rcSO2 values than infants with a duct-dependent systemic circulation. The median difference in rcSO2 between both types of CHD ranged from 6% to 12%.

Multiple linear regression analysis

Based on the significance level from the univariate linear regression analyses, type of CHD and preductal SpO2 were selected as predictors on day 1, day 2 and day 3 after birth (Table 2). Following the enter method, type of CHD and preductal SpO2 remained significant on day 1 and day 2. On day 3, only type of CHD remained significant in the model. The multivariate model explained 38% of the variance on day 1 and 31% on day 2 and day 3 (Table 3).

Table 2 Linear regression analysis for rcSO2 and clinical and biochemical parameters

B Std. error β t P-value 95% CI Day 1 Birth weight -0.05 0.003 -0.27 -1.97 0.05 -0.11 to 0.00 Gestational age 1.59 1.33 0.17 1.20 0.24 -1.08 to 4.26 Apgar at 5 minutes 1.62 1.10 0.21 1.49 0.15 -0.58 to 3.83 Type of CHD -9.36 2.07 -0.54 -4.53 <0.001 -13.51 to -5.21 Respiratory support -1.72 0.84 -0.28 -2.05 0.05 -3.41 to -0.03 Preductal SpO2 0.76 0.19 0.49 3.99 <0.001 0.38 to 1.14 mABP 0.19 0.23 0.14 0.83 0.41 -2.81 to 0.67 Hb 1.69 0.96 0.27 1.76 0.09 -0.25 to 3.64 pH 13.13 11.97 0.17 1.10 0.28 -11.07 to 37.32 Lactate -0.06 0.59 -0.02 -0.11 0.91 -1.26 to 1.13 pCO2 -0.71 0.69 -0.16 -1.03 0.31 -2.11 to 0.69 Sedatives -4.49 2.42 -0.26 -1.85 0.07 -9.38 to 0.39 Inotropes -11.40 5.85 -0.27 -1.95 0.06 -23.16 to 0.36 Day 2 Birth weight 0.56 1.28 0.06 0.44 0.67 -2.02 to 3.13 Gestational age -0.00 -0.00 -0.13 -0.96 0.34 -0.01 to 0.00 Apgar at 5 minutes 1.46 1.04 0.19 1.40 0.17 -.64 to 3.55 Type of CHD -6.32 2.12 -0.38 -2.99 <0.001 -10.57 to -2.07 Respiratory support -1.15 0.78 -0.20 -1.47 0.15 -2.71 to 0.42 mABP 0.03 0.20 0.02 0.15 0.88 -0.37 to 0.40 Preductal SpO2 0.73 0.19 0.49 3.96 <0.001 0.36 to 1.10 Hb 0.37 0.91 0.06 0.40 0.69 -1.47 to 2.21 pH -1.71 10.62 -0.03 -0.16 0.87 -23.18 to 19.76 Lactate -0.45 0.46 -0.17 -0.97 0.34 -1.38 to 0.49 pCO2 -0.18 0.61 -0.01 -0.03 0.98 -1.26 to 1.22 Sedatives -4.66 2.53 -0.25 -1.85 0.07 -9.73 to 0.41

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B Std. error β t P-value 95% CI Day 3 Birth weight 2.34 1.56 0.21 1.50 0.14 -0.80 to 5.48 Gestational age -0.00 0.00 -0.14 -0.97 0.34 -0.10 to 0.00 Apgar at 5 minutes 2.11 1.19 0.25 1.77 0.08 -0.29 to 4.51 Type of CHD -10.34 2.38 -0.53 -4.35 <0.001 -15.11 to -5.56 Respiratory support -1.51 0.98 -0.22 -1.54 0.13 -3.49 to 0.46 mABP 0.00 0.15 0.00 0.00 1.00 -0.30 to 0.31 Preductal SpO2 0.71 0.23 0.41 3.09 <0.001 0.25 to 1.17 Hb 0.34 1.20 0.05 0.28 0.78 -2.09 to 2.76 pH 6.67 12.72 0.08 0.52 0.60 -19.07 to 32.40 Lactate 0.17 0.59 0.05 0.30 0.77 -1.02 to 1.37 pCO2 -0.86 0.73 -0.19 -1.17 0.25 -2.35 to 0.62 Sedatives -2.51 3.36 -0.11 -0.75 0.46 -9.26 to 4.25 Inotropes 2.37 6.87 0.05 0.35 0.73 -11.45 to 16.19

B, un-standardized coefficient; std. error, standard error; β, standardized coefficient; SpO2, preductal arterial oxygen saturation; mABP, mean arterial blood pressure.

Table 3 Multiple linear regression models for rcSO2 and clinical and biochemical parameters

B Std. error β t P-value 95% CI Day 1 Constant 15.890 17.80 0.89 0.38 -19.93 to 51.70 Type of CHD -6.15 2.17 -0.36 -2.83 0.01 -10.51 to -1.78 Preductal SpO2 0.55 0.19 0.37 2.86 0.01 0.16 to 0.93 Day 2 Constant 12.45 17.98 0.69 0.49 -23.74 to 48.63 Type of CHD -4.51 2.19 -0.27 -2.06 0.04 -8.92 to -0.11 Preductal SpO2 0.60 0.19 0.40 3.08 <0.001 0.21 to 0.98 Day 3 Constant 71.64 1.92 37.41 <0.001 67.79 to 75.49 Type of CHD -10.85 2.37 -0.56 -4.58 <0.001 -15.61 to -6.08

B, un-standardized coefficient; std. error, standard error; β, standardized coefficient; SpO2, preductal arterial oxygen saturation.

Type of CHD

As type of CHD was a significant predictor in the multivariate regression model during the first three days after birth and rcSO2 was significantly lower in infants with a duct-dependent pulmonary circulation, we explored this difference in depth. Infants with a duct-dependent pulmonary circulation had significantly lower SpO2 values than infants with a duct-dependent systemic circulation during the first three days after birth. Furthermore, they had lower Hb values and tended to have a lower Apgar score at 5 min. There were no other differences in clinical and biochemical parameters between infants with a duct-dependent

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pulmonary circulation and infants with a duct-dependent systemic circulation (Table 4).

Table 4 Differences between infants with a dependent systemic and infants with a

duct-dependent pulmonary circulation

Duct-dependent

pulmonary circulation systemic circulationDuct-dependent P-value

Gestational age (weeks) 39.1 (37.6-41.7) 39.1 (36.6-40.6) 0.95

Birth weight (grams) 3380 (2690-4400) 3240 (1960-4180) 0.12

Apgar score at 5 minutes 8.5 (4-10) 9 (8-10) 0.06

Head circumference (cm) 34.5 (31.5-37.5) 33.5 (30.5-37.2) 0.10 SpO2 Day 1 88.5 (73-99) 93.5 (83-98) 0.002 SpO2 Day 2 90.0 (73-100) 94.0 (82-99) 0.006 SpO 2 Day 3 87.5 (75-100) 94.0 (86-98) <0.001 RcSO2 Day 1 57.0 (45-79) 64.0 (53-81) <0.001 RcSO2 Day 2 60.5 (49-86) 66.5 (54-82) 0.003 RcSO2 Day 3 59.5 (49-92) 71.5 (61-87) <0.001 Hb# 10.3 (7.9-13.8) 11.4 (9.3-14.4) 0.02 pH# 7.29 (6.84-7.59) 7.31 (7.22-7.49) 0.37 pCO2# 7.1 (2.5-10.4) 6.4 (3.6-9.1) 0.73 Lactate# 3.5 (1.2-13.4) 3.95 (1.7-8.0) 0.89

Mechanical ventilation Day 1 16 (46) 2 (10) 0.01

Mechanical ventilation Day 2 17 (49) 3 (19) 0.05

Mechanical ventilation Day 3 13 (37) 3 (14) 0.08

Data represent either median (minimum-maximum) or number (percentage). # indicates first measurement within 72 hours after birth, SpO2, preductal arterial oxygen saturation; rcSO2, regional cerebral oxygen saturation.

Discussion

The present study shows the course of rcSO2 and FTOE in infants with duct-dependent CHD during the first three days after birth. Furthermore, our study indicates that cerebral oxygen saturation was low during the first 72 h after birth in infants with prenatally diagnosed duct-dependent congenital heart disease. To our knowledge this is the first study to describe cerebral oxygen saturation and extraction during the first 72 h after birth in infants with prenatally diagnosed duct-dependent CHD.

Compared to healthy term infants, we found rcSO2 values that were approximately 20% lower in our cohort during the first days after birth. Previous studies reported mean rcSO2 values to be between 77% and 78% in healthy term infants during the first days after birth.18,19

Based on a piglet study performed by Kurth et al.,20 one might even suggest that some of

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thresholds for functional impairment to be between 33% and 44%.20 These r

cSO2 values,

however, were measured with a different type of sensor than the sensors we used for our study. The pediatric and neonatal SomaSensors display values approximately 10% higher than other pediatric or adult sensors.21,22 Taking this into account, a significant number of

infants in our study approached the hypoxia-ischemia thresholds during the first days after birth.

Our results are in accordance with the few studies that also reported on preoperative rcSO2 values in various types of CHD.15-17 These studies, however, only measured r

cSO2 during

the immediate preoperative period or for a very short period of time. Furthermore, they did not address the early postnatal period as they studied infants up to seven years of age.16,17

There are several explanations for the low rcSO2 values. First, hypoxemia might have led to hypoxia of the cerebral tissue. The infants in our study had median preductal SpO2 around 90% during the first three days after birth. As expected, there was a positive correlation between SpO2 and rcSO2 during the first three days after birth. Second, the infants could have suffered from ischemia of the cerebral tissue. FTOE, which reflects the balance between oxygen supply and oxygen consumption, was indeed relatively high in our cohort. Finally, other clinical and biochemical parameters could have influenced rcSO2 values. Cerebral oxygen saturation was associated with Hb, use of sedatives and inotropes. Hb however, was within the normal range in our study population and the association between use of sedatives and rcSO2 was opposite from the association as described in previous literature. Furthermore, the association between use of inotropes and rcSO2 was only based on two infants with a high illness severity who were treated with inotropes.

Infants with a duct-dependent pulmonary circulation had significantly lower rcSO2 values than infants with a duct-dependent systemic circulation. This difference may have been caused by a difference in SpO2. As expected, infants with a duct-dependent pulmonary circulation had significantly lower SpO2 values. This group consisted of infants with cyanotic congenital heart lesions that go hand in hand with tissue hypoxia. The majority of the group with a duct-dependent systemic circulation, however, suffered from HLHS, which induces cyanosis as well. Furthermore, even when correcting for preductal SpO2, type of CHD remained a significant predictor of rcSO2. Therefore, SpO2 cannot fully explain the difference in rcSO2 between both CHD-subgroups.

Another explanation for the difference in rcSO2 between both CHD-subgroups might be a difference in Hb. Infants with a duct-dependent pulmonary circulation had a significantly lower Hb during the first blood gas measurement within 72 h after birth. Hb, however, only tended to be associated with rcSO2 during the first day after birth and was not significant in the multiple linear regression model. Therefore, Hb also cannot fully explain the difference in rcSO2 between both CHD-subgroups. A third explanation might be the type of CHD itself.

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The present study provides solid reference values of pre-operative rcSO2 and FTOE in infants with prenatally diagnosed duct-dependent CHD. This allows us to interpret the effect of preoperative interventions or intra- and postoperative rcSO2 and FTOE values.

There are several limitations to our study. First, this study was a retrospective study, which could have induced selection bias. The most important reason for non-inclusion was < 24 h of NIRS measurements. This happened primarily due to logistic issues and was not based on a clinical decision. NIRS devices were not readily available at the beginning of the study. We believe, therefore, that selection bias did not influence our results to a large extent. Second, the retrospective and observational design of the study was associated with missing values on clinical and biochemical parameters. As a consequence, we were only able to correlate the first blood gas measurement within 72 h after birth to rcSO2 instead of single values for each day. Third, we did not include a control group. Healthy term infants are usually discharged very soon after birth or even born at home. Therefore, it would have been impossible to obtain full datasets of healthy term infants. For this reason, we chose to compare our results with reference values from healthy term infants from literature.18-19 Finally, we did not have

data on neurodevelopmental outcome for these infants yet. Therefore, we were unable to specify the relation between low rcSO2 values and neurodevelopmental outcome. Previous studies using intraoperative or postoperative NIRS, however, found significant associations between low rcSO2 values and neurodevelopmental outcome at two to five years of age.23-24

The association between early postnatal rcSO2 values and neurodevelopmental outcome later in life should be the focus of prospective research. Furthermore, large (multicenter) prospective studies should be conducted to address the differences in cerebral oxygen saturation between different types of CHD and the association between clinical and biochemical parameters and cerebral oxygen saturation and extraction.

In conclusion, cerebral oxygen saturation is low in infants with prenatally diagnosed duct-dependent congenital heart disease. Furthermore, infants with a duct-dependent pulmonary circulation have up to 12% lower cerebral oxygen saturation values than infants with a duct-dependent systemic circulation. In addition, we provide preoperative reference values to monitor interventions or to interpret perioperative cerebral oxygen saturation values.

Acknowledgements

We would like to thank the nurses and staff of the neonatal intensive care unit for their help with the NIRS measurements. This study was part of the research program of the Graduate School of Medical Sciences, Research Institutes BCN-BRAIN and GUIDE, University of Groningen. M.J. Mebius and M.E. van der Laan were financially supported by the Junior Scientific Master Class of the University of Groningen (13-35).

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1. Marino BS, Lipkin PH, Newburger JW et al. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association. Circulation 2012;126:1143-1172.

2. Martinez-Biarge M, Jowett VC, Cowan FM et al. Neurodevelopmental outcome in children with congenital heart disease. Semin Fetal Neonatal

Med 2013;18:279-285.

3. Donofrio MT, Massaro AN. Impact of congenital heart disease on brain development and neurodevelopmental outcome. Int J Pediatr 2010;2010:10.1155/2010/359390. Epub 2010. 4. McQuillen PS, Goff DA, Licht DJ. Effects of

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