Brain Injury During Transition in the Newborn With Congenital Heart Disease: Hazards of the Preoperative Period Jennifer M. Lynch, MD, PhD,* J. William Gaynor, MD,† and Daniel J. Licht, MD‡,1 Infants born with critical congenital heart disease are at risk for neurodevelopmental morbidities later in life. In-utero differences in fetal circulation lead to vulnerabilities which lead to an increased incidence of stroke, white matter injury, and brain immaturity. Recent work has shown these infants may be most vulnerable to brain injury during the early neonatal period when they are awaiting their cardiac surgeries. Novel imaging and monitoring modalities are being employed to investigate this crucial time period and elucidate the precise timing and cause of brain injury in this population. Semin Pediatr Neurol 28:60-65 C 2018 Elsevier Inc. All rights reserved.
Introduction Congenital heart defects (CHD) are the most common birth defect, affecting approximately 30,000 newborns each year. Nearly one-third of these children require cardiac surgery during the neonatal period.1 Although surgical advancements over the last several decades have improved survival, neurodevelopmental disabilities remain a significant morbidity among survivors. As a result, clinical and investigative focus has shifted from survival beyond the neonatal period toward neurologic sequelae. Magnetic resonance imaging (MRI) studies during the neonatal period in this population reveal abnormal development including microcephaly, decreased folding, and white matter immaturity.2 This immaturity leads to a high prevalence of a specific form of hypoxic-ischemic white matter injury (WMI), which is similar, if not identical to, periventricular
leukomalacia (PVL) and has identical MRI signal properties to the PVL that commonly occurs in infants born prematurely.3 School-age survivors of various forms of CHD demonstrate problems with academic achievement, fine and gross motor function, visual-spatial skills, and executive function.4,5 Newborn infants are a particular challenge to study; their examination is poorly informative and most information on brain health has to be obtained from neuromonitoring. Furthermore, neurodevelopmental testing (ie, Bayley scales of infant development) when conducted too early work poorly at predicting academic achievement of performance later in life. Thus, during early infancy, we rely on imaging which shows immaturity and injury, and infer that early abnormal findings contribute to the negative, long-term cognitive outcomes.
Brain Abnormalities From the *Division of General Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA. † Division of Cardiothoracic Surgery, The Children’s Hospital of Philadelphia, Philadelphia, PA. ‡ Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA. 1
Dr Licht is supported by grants from the NINDS, United States (R01NS72338 and RO1NS060653) and NICHD, United States (U01 HD087180-01) support from the June and Steve Wolfson Family Foundation. Address reprint requests to Jennifer M. Lynch, MD, PhD, Division of General Pediatrics, The Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104. E-mail:
[email protected]
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https://doi.org/10.1016/j.spen.2018.05.007 1071-9091/11/& 2018 Elsevier Inc. All rights reserved.
White Matter Injury The underlying cause of the neurobehavioral symptoms seen in children with CHD is believed to be the high prevalence of WMI.3 Specifically, these infants are prone to a form of hypoxic-ischemic WMI which commonly occurs in a vascular watershed zone near the lateral ventricles (Fig. 1). Vulnerability to this WMI in these full-term infants with CHD occurs as a consequence of in utero differences in cerebral oxygen delivery that result in delayed maturation of the entire fetal brain and the glial support cells including oligodendrocytes.2 Immature
Brain injury During transition in the newborn with CHD
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Figure 1 MRI of white matter injury (WMI). Axial and Sagittal T1-MRI (top) and diffusion imaging (bottom) showing injury distribution and acuity. Arrows show the T1 hyper-intensities and restriction of water diffusion, which characterize WMI.
oligodendrocytes have very high metabolic requirements as they prepare to become mature, myelinating oligodendrocytes.6 This high metabolic demand leaves cells vulnerable to hypoxic-ischemic cell death during periods of low oxygen saturation or poor perfusion.7 Consequently, this periventricular region of white matter is highly susceptible to hypoxicischemic injury in both preterm infants and full-term newborns with CHD. In both populations, MRI scans reveal T1-hyperintense lesions in the white matter, and whether we call the lesions PVL or WMI is subjective. As the WMI in infants with CHD never becomes cystic, like the PVL in the preterm, the term WMI has generally been accepted for these full-term infants with CHD. Furthermore, the exact timing of this injury in CHD remains unknown, though it is present in nearly 20% of CHD infants imaged with MRI before surgery and more than 50% after surgery.3,8-12 Current investigative efforts have focused on identifying perioperative risk factors for WMI and consequent neurodevelopmental disabilities. Previous studies have identified cardiac diagnosis, brain immaturity, duration of circulatory arrest, and timing of surgery as risk factors.8-10,13 Specifically, Beca et al10 in a heterogeneous population of critical CHD showed that risk for new or worsened postoperative WMI was highest in neonates with single ventricle physiology and was associated with use of and duration of deep hypothermic
circulatory arrest (DHCA). However, our group at the Children’s Hospital of Philadelphia (CHOP) found recovery of cerebral oxygen saturation or blood flow postoperatively was independent of duration of DHCA.14 Furthermore, our group found that in a homogenous population of neonates with hypoplastic left heart syndrome (HLHS) the most significant risk factor for the development of postoperative WMI was time-to-surgery.9 Increased time-to-surgery was also found to be correlated with increasing cerebral oxygen extraction during the preoperative period.9,15 The preoperative increase in oxygen extraction is likely secondary to impaired fetal circulation, although this remains a current area of investigation.
Immaturity Miller et al16 used diffusion tensor imaging and MR spectroscopy to show that the white matter of infants with CHD was structurally and biochemically immature. In a study of 42 neonates with either HLHS or transposition of the great arteries (TGA), Licht et al2 found that the brains of these full-term infants were less mature than expected. Specifically, this study investigated the total maturation store which evaluates 4 parameters of maturity: myelination, cortical infolding, involution of glial cell migration bands, and presence of
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62 germinal matrix tissue. The decrease in total maturation store in infants with congenital heart disease corresponds to a delay of approximately 1 month in development. This immaturity has also been found to be one of the most powerful predictors of preoperative WMI,8,10 though it probably is a marker of vulnerability to injury and not clearly causative.
Stroke Stroke is defined as a thrombus, or other embolic material, occluding an artery and causing injury within a discrete vascular territory. In a study on infants with TGA, McQuillen et al12 found that balloon atrial septostomy (BAS) was a significant risk factor for focal brain injury observed on preoperative MRI. This injury had characteristics consistent with embolic stroke. However, Petit et al13 also reported a study on preoperative MRI in TGA and found no incidence of stroke, but instead found that approximately 40% of the neonates had preoperative WMI. This difference in stroke rates may be due to how stroke is being defined on the images and when during the preoperative period the images are obtained. Separating perinatal stroke from preoperative stroke is a challenge. Perinatal stroke is thought to occur as a consequence of a placental thrombus embolizing to the brain. Hence, most perinatal strokes are quite large. The majority of preoperative strokes in newborns with CHD are quite small and likely represent embolic material from central access (eg, umbilical catheters), though this has not been studied.
Neuromonitoring Magnetic Resonance Imaging As mentioned above, infants with CHD are at an increased risk for developing periventricular WMI that can be detected as hyperintense lesions on T1-weighted MR images. A study by Mahle et al3 in 2002 investigated preoperative and postoperative MRIs of infants with CHD and was the first study to report preoperative WMI in 16% of subjects and new postoperative WMI in nearly half of the subjects. The finding that WMI was present before surgery, raised the possibility that surgery was not the main risk factor for neurodevelopmental challenges faced by patients with complex CHD. More recently, studies have shown that the incidence and timing of this injury are dependent on the specific cardiac diagnosis.9,12,13 MRI is the only imaging modality capable of measuring WMI, which is clinically silent in newborns and below the detection resolution of computed tomography and ultrasound. Although MRI has the ideal spatial resolution for detecting the incidence of WMI, the need for sedation and transportation to the MR suite for imaging makes its ability to identify the exact timing of this injury limited.
Electroencephalography Electroencephalography (EEG) has been one of the mainstays of neuromonitoring but has been used primarily as a seizure
detector in pediatric critical care. EEG employs a differential amplifier to enhance electrical fields between electrodes placed on the scalp. The electrical fields are generated by the pyramidal cells of the cortex of the brain. EEG data has excellent temporal resolution and good spatial resolution, which make it an attractive tool for neuromonitoring. However, EEG’s strengths of temporal and spatial resolution is offset by the the need for trained personnel to interpret the data. Nonetheless EEG serves as an important tool for seizure detection for at risk populations, especially in newborns where seizures are likely to be electrographic only (ie, no clinical signs).17-19 The potential of EEG to detect early ischemia or as a predictor of cardiac arrest is under active investigation.20,21 As the incidence of preoperative seizures is low, the use of EEG in the preoperative period in newborns with CHD has been limited. However, EEG patterns in premature infants have been well described and there are distinct patterns associated with stages of maturation from the very premature to term birth.22 Thus, preoperative EEG could likely be a good determinant of brain immaturity and hence risk for WMI, however, this has yet to be studied.
Diffuse Optical Spectroscopies Assuring adequate tissue perfusion to match oxygen demand is central for support in these patients. To that end, measurements of cerebral oxygen extraction and oxygen delivery are imperative for prevention of white matter injury. Oxygen extraction can be approximated from the difference between the saturation of arterial blood received by the brain and saturation of the venous blood leaving the brain. However, the gold standard for measurement of cerebral venous saturation remains a highly invasive procedure: central venous catheterization followed by direct measurement of oxygen saturation in the jugular bulb by oximetry.23 Although jugular catheters are commonly placed in adult critical care patients, these catheters pose substantial challenges in neonates. Thus, noninvasive modalities for measuring venous oxygen saturation are required. Near-infrared spectroscopy (NIRS) is a widely accepted noninvasive method for measuring cerebral tissue oxygen saturation. However, most commercially available oximeters are only capable of monitoring trends in oxygen saturation and are inaccurate as absolute measurements of oxygenation. Moreover, these commercial NIRS devices may also be inaccurate trend monitors as well in certain low perfusion states such as during deep hypothermic circulatory arrest,24 for which they are often used in this patient population. Frequency domain NIRS is a more sophisticated modality that is capable of quantifying oxygen saturation and blood volume.25-27 Although monitoring cerebral oxygen saturation in highrisk critical care populations is standard clinical practice in some institutions, few modalities exist for measuring cerebral blood flow (CBF). Current established tools for measuring CBF include various forms of MRI, transcranial Doppler ultrasound (TCD), positron emission tomography and Xenon
Brain injury During transition in the newborn with CHD enhanced computer tomography. A major disadvantage of most of these techniques is that they can only be used as spot measurements of CBF, that is, they cannot be employed for continuous monitoring. This situation presents a significant limitation for neuromonitoring in neonates infants with CHD, because they may be susceptible to white matter injury during long preoperative, operative and postoperative time periods. Although TCD can be used for noninvasive monitoring of cerebral hemodynamics, assumptions about the cerebral vessel diameters can cause large errors in measurements of CBF velocity. TCD is also unable to measure regional variations in CBF. Additionally, positron emission tomography and Xe-133 expose the patient to radiation, which can be particularly harmful to neonates. Diffuse correlation spectroscopy (DCS) is a novel optical technique that is capable of continuous and noninvasive quantification of CBF at the bedside. Although DCS has been validated in this patient population,28 its use has yet to be implemented clinically. However, combined with frequency-domain NIRS, DCS offers the ability for continuous, noninvasive quantification of cerebral oxygen metabolism at the bedside,14,28 and is a valuable tool in assessing risk for injury in this patient population.9,14,15
Prenatal and Postnatal Circulation The topic of fetal and transitional circulation in CHD is covered in detail elsewhere in this special edition. Briefly, studies have investigated in utero CBF and compensatory mechanisms and the relationship of these with specific congenital heart defects and fetal circulation.29 Prenatal studies using Doppler ultrasound have shown fetuses with HLHS have lower than normal cerebral vascular resistance (CVR).30,31 Lower fetal CVR is likely due to decreased oxygen delivery to the brain caused by the altered anatomy that results from ductal dependent CBF.29,30 Doppler ultrasound in fetuses with TGA also demonstrates a decrease in fetal CVR, reflecting a deficit in oxygen delivery that is due to the lower oxygen saturations caused by the transposed great vessels.29,32 Sustained decrease in CVR during fetal life could exhaust the compensatory mechanisms that are needed to increase CBF during postnatal life in response to increasing oxygen demand. After birth, the rise in the partial pressure of oxygen in the blood that occurs with the baby’s first breath of air causes changes in pulmonary and ductal tissue. Pulmonary vasculature experiences an instant vasodilation, with a precipitous fall in pulmonary vascular resistance, whereas ductal tissue experiences vasoconstriction. Closure of the ductus arteriosis separates the pulmonary and systemic circulations in normal infants but may cause catastrophic circulatory failure for infants with critical heart defects where the ductus was vital for mixing the two circulations. In 1976, Olley et al33 published the use of prostaglandins to prevent the closure of the ductus arteriosis, allowing palliation of the abnormal circulations that resulted from critical heart
63 deformities. With this revolutionary therapy, babies with critical heart lesions could be kept alive for weeks after birth. However, the continued connection between pulmonary and systemic circulations may expose the cerebral and systemic circulations to the effects of a dramatically lower pulmonary vascular resistance.
Preoperative Risk for Brain Injury Although studies have traditionally focused on investigating risk factors for brain injury in critical CHD related to surgery and the use of cardiopulmonary bypass, a growing body of evidence supports the notion that preoperative risks may be more significant. This was first observed in infants with TGA. In a study on preoperative brain injury in 22 neonates with TGA, McQuillen et al12 observed that 41% of these neonates had evidence of brain injury on preoperative MRI. Additionally, this study reported that the need for BAS was a risk factor for this brain injury. However, in another study on 26 neonates with TGA, Petit et al13 found that the incidence of WMI on preoperative MRI was not associated with BAS but was correlated with lower preoperative systemic oxygen saturations and longer time from birth to surgery (referred to hereafter as “time-to-surgery”). Longer time-to-surgery has also been shown to be a significant risk factor for white matter injury in infants with HLHS. In infants with HLHS, the prevalence of white matter injury appears to be greater on postoperative MR images than on preoperative scans, which has focused the majority of studies on risk factors for injury in this population on the operative and postoperative time periods.10,14 However, in a study performed by our group on 37 neonates with HLHS, time-to-surgery was the most significant risk factor for the development of new or worsened white matter injury on postoperative MRIs. This study also reported that preoperative CBF and cerebral oxygen saturation were risk factors for the development of postoperative WMI, further highlighting the importance of the preoperative period, even in a population for which the majority of imaging evidence for injury is seen only postoperatively (Fig. 1). Timing of surgery has also been found to be a significant risk factor in neonates with congenital heart disease who are diagnosed during the prenatal period compared to those diagnosed after birth. In a study of 216 neonates with HLHS, Mahle et al34 reported that infants with prenatal diagnosis went to surgery at a shorter time-to-surgery and had fewer adverse perioperative neurologic events, including seizure or coma than infants diagnosed postnatally. Furthermore, studies have found that earlier surgeries lead to improved clinical outcomes and reduced costs.35,36 Specifically, Anderson et al35 found that infants with TGA who underwent the arterial switch operation after 3 days of life had an increased risk of major morbidity such as cardiac and infectious morbidities as well as neurologic morbidities including seizure and stroke. In a separate study, Anderson et al36 reported that infants with HLHS had an increase risk of morbidity with delay of their stage 1 palliation.
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Figure 2 Preoperative cerebral oxygenation as a function of time-tosurgery in a study of 37 neonates with HLHS.9 The solid line represents the best-fit line to the data (R2 ¼ 0.17, P ¼ 0.03, slope ¼ −2.7 ± 1.2). The grey ribbon denotes the 95% CI for the mean ScO2. The symbols represent whether or not the subject acquired a large amount of new or worsened postoperative PVL. (Color version of the figure available online.)
The pathophysiology responsible for the effect of longer time-to-surgery on risk for white matter brain injury is still not fully understood. A study by our group at CHOP investigating preoperative cerebral hemodynamics in infants with TGA and HLHS has revealed that oxygen demand is increasing during the preoperative period and that this demand is not compensated for by increasing oxygen delivery (Fig. 2) (Fig. 3).15 This increase in extraction may be due in part to the relative brain immaturity. An increase in oxygen demand would be expected to cause a corresponding increase in oxygen delivery. The absence of CBF compensation suggests a failure of compensatory mechanisms, for example a failure of cerebrovascular reactivity. The use of prostaglandins during the preoperative period may also play a role. Cerebral oxygen metabolism (quantified as the cerebral metabolic rate of oxygenation, or CMRO2) has been shown to increase during the first few weeks of life in premature infants who have similar brain maturation and risk for WMI as full-term infants with complex CHD.2,37 Thus, monitoring of CMRO2 during the vulnerable preoperative period may be imperative to preventing injury in this patient population.
Anticipatory Management Aimed at Neuroprotection As longer time between birth and surgery is a risk factor for WMI, it is imperative to identify reasons for delayed timing of
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Figure 3 Time profile of preoperative ScO2 in a study of infants with HLHS (red, n ¼ 24) and TGA (blue, n ¼ 24).15 Each thin line represents measurements for a single subject. Thick lines represent linear trends derived from a mixed effects model. (Color version of the figure available online.)
surgery. Timing of surgery may be delayed due to postnatal diagnosis, and consequently prenatal diagnosis has been shown to improve neurologic morbidities.34 Prenatal diagnosis also allows for earlier treatment with prostaglandins to prevent circulatory failure and there is ample evidence on how this has mitigated some brain injury.38 However, prostaglandins now appear to be a double-edged sword, as clinicians have become comfortable with their use and have used them to extend the time from birth to surgery. As stated above, multiple studies have reported increase in morbidity with increasing time-to-surgery for both TGA and HLHS.9,13,35,36 What, then, determines a patient′s time-tosurgery? These surgeries are usually scheduled for day-of-life 3 or later to allow time for pulmonary vascular resistance to fall. However after 3 days, the time-to-surgery varies greatly between institutions. In a study by our group at CHOP on 37 infants with HLHS, time-to-surgery was largely based on the day of the week during which the patient was born.9 For instance, the subjects born on a Wednesday had an average time-to-surgery of 5.1 ± 1.6 days, whereas the subjects born on a Monday had an average time-to-surgery of 3.7 ± 2.2 days.9 This is believed to be due in large part to the fact that at our institution, these cardiac surgeries are scheduled for the weekdays only. Thus, a patient born on a Wednesday would usually wait until at least the following Monday for their surgery. To mitigate this, either operative scheduling needs to be modified to allow for surgeries on weekends, or, in instances of induction of labor or cesarean section, scheduling deliveries on Wednesdays and Thursdays should be avoided. In addition to timing deliveries or performing surgeries on the weekends, time-to-surgery can be decreased if instead of surgeons being assigned to a patient prentatally, the surgeon who is available on the predetermined day of surgery is the one assigned to the case, similar to the laborist model widely adopted in the obstetric community.
Brain injury During transition in the newborn with CHD
Summary There is a growing body of evidence that the preoperative period carries the greatest risk for development of WMI and consequent neurodevelopmental disabilities. Furthermore, a time-to-surgery of 3-4 days appears to be a threshold beyond which the risk for neurologic morbidity increases.9,35 This optimal time for surgery needs to be validated in different cardiac diagnoses and also across different institutions with varying preoperative, perioperative, and postoperative care strategies. Once confirmed, these cardiac surgeries need to be treated as urgent, if not emergent, care, with surgery being performed earlier than 4 days after birth.
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