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Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
ECMO in neonates: Neuroimaging findings and outcome Arno F.J. van Heijst, MD, PhDa,n, Amerik C. de Mol, MD, PhDb, and Hanneke IJsselstijn, MD, PhDc a
Department of Pediatrics, Division of Neonatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b Department of Pediatrics, Albert Sweitzer Hospital, Dordrecht, Rotterdam, The Netherlands c Department of Pediatric Surgery and Intensive Care, Erasmus MC—Sophia Children's Hospital, Rotterdam, The Netherlands
article info
abstract
Keywords:
Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for newborns with
ECMO
severe but reversible respiratory failure. Although ECMO has significantly improved
Brain
survival, it is associated with substantial complications, of which intracranial injuries
Cerebral utrrasound
are the most important. These injuries consist of hemorrhagic and non-hemorrhagic,
MRI
ischemic lesions. Different from the classical presentation of hemorrhages in preterm infants, hemorrhages in ECMO-treated newborns are mainly parenchymal and with a high percentage in the posterior fossa area. There are conflicting data on the predominant occurrence of cerebral lesions in the right hemisphere. The existence of intracerebral injuries and the classification of its severity are the major predictors of neurodevelopmental outcome. This section will discuss the known data on intracranial injury in the ECMO population and the effect of ECMO on the brain. & 2014 Elsevier Inc. All rights reserved.
Introduction Extracorporeal membrane oxygenation (ECMO) is used in newborns as a rescue therapy for severe but reversible respiratory insufficiency in case of failure of other, conventional, therapies.1 Since ECMO was first used in a newborn in 1975, until July 2013, over 26,000 newborns have been treated.2,3 Although survival rates in general are excellent, serious complications do arise, with intracranial injuries representing the major complications associated with ECMO treatment. The major cause of death in the newborn ECMO population is due to cerebral injury with intracranial hemorrhage (ICH) and/or infarction, with approximately half of the non-survivors having severe bleeding complications.3,4 Survival is not the only issue we should look at when determining that ECMO is a beneficial treatment method for these very sick infants. Longn
term follow-up is necessary not only to evaluate the results of this highly technical, invasive approach but also to identify infants at risk for adverse outcome and provide adequate guidance for long-term care. Feeding problems, poor somatic growth, chronic lung disease, and recurrent hospitalizations are all part of medical morbidity in survivors.5 Neurodevelopmental impairment is a significant outcome measure. These factors are covered in another chapter. This review focuses on the intracranial injuries that are related to ECMO treatment in newborns.
Intracranial injuries in ECMO ECMO-treated neonates incur a relatively high frequency of abnormalities identified on routine neuroimaging, which
Corresponding author. E-mail address: [email protected] (A.F.J. van Heijst).
0146-0005/14/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semperi.2013.11.008
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vary widely in type and severity. The incidence of abnormalities discovered in neuroimaging during or after ECMO varies according to the literature from 10% to even 59% (Table 1).6–23 The most recent report of the ELSO registry mentioned a prevalence of cerebral infarction and hemorrhage in 7.2% and 7.1% of the newborns treated with ECMO, respectively. Survival in these infants is less than in the general population (84%) with survival rates of 54% for children with infarctions and 44% for those with hemorrhages.3
Classification The types of brain injuries in ECMO-treated newborns vary to a great extent. In the 1980s Taylor proposed the following classification (Fig. 1). This is based on the type of presentation and severity of injury,14 i.e., hemorrhagic and nonhemorrhagic and major and minor. With this classification,
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he developed a systemic approach to quantify the severity of these lesions and he and Bulas later modified this score.24–26 For their scoring system, they divided intracranial lesions into four categories: hemorrhagic, non-hemorrhagic parenchymal lesions, extraaxial fluid collections, and ventricular dilatation. Based on an assumption of risk for neurologic consequences, each category was assigned a relative risk score of 1, 2, or 3, respectively, for ventricular dilatation, hemorrhage, and other parenchymal lesions. Within each category, more severe lesions were assigned a higher numeric score. Finally the abnormality score within a category was multiplied by the relative weight factor making a total score (Table 2). A subgroup of non-hemorrhagic lesions comprises the ventricular enlargement and widened interhemispheric fissure, which are both common in ECMO-treated newborns.25 Recently, we presented an alternative refined classification system of focal brain injury in ECMO-treated neonates, aiming at better understanding of the different types of
Table 1 – Studies on the prevalence of intracranial abnormalities in ECMO-treated newborns. Number of patients
Intracranial hemorrhage, n (%)
Non-hemorhagic lesions, n (%)
Bartlett et al.17
100
Not available
14/17 died 8/12 died
Bowerman et al.18 Cilley et al.20
28
In preterm infants: 17/19 (89%) In full-term infants (4 35weeks) 12/81 (15%) 8/28 (28.6%)
Not available
35
10/35 (28.6%)
Not available
Campbell et al.19 Babcock et al.8 Glass et al.6
33
6 (18.2%)
10 (of 20 studied patients) (50%)
5 of 8 in (extremely) premature infants All 8 infants o34 weeks GA had ICH Only 2 of 27 with GA 4 34 weeks No L–R hemisphere differences
50
8 (16%)
14 (28%)
No L–R hemisphere differences
42
5 (11.9%)
No L–R hemisphere differences
Taylor et al.7
207
180
43 (20.8%) 21 (10.1%) major 42 (20.2%) minor 6 (3.3%) major ischemic lesions
No L–R hemisphere differences 25% were major abnormalities
Mendoza et al.22
13 (31%) 5 (12%) major 7 (16.7%) minor 68 (32.8%) 31 (46%) major 37 (54%) minor 10 (5.5%) major hemorrhagic lesions
Griffin et al.21 Hahn et al.15
22
Non
2 cerebral atrophy (9.1%)
36
3 (8.3%)
Lazar et al.10 Bulas et al.11
74
3 (4%)
8 (22%) 19/36 ventricular dilatation and/or enlarged subarachnoidal spaces and interhemispheric fissure 16 (21.6%)
386
73 29 44 44
Ahmad et al.16 Raets et al.23
References
Other information
L 4 R for hemorrhages R 4 L for ischemia 106 (59%) had some abnormality 16 (8.9%) had major abnormalities
All hemorrhages were cerebellar Non-hemorrhagic lesions R 4 L
No L–R hemisphere differences
86 (22%) 22 (6%) major 64 (16%) minor (16)
No L–R hemisphere differences
51
(19%) (8%) major (11%) minor (11%) combined with nonhemorrhagic lesions 6 (11.8%)
12 (23%)
676
60 (8.8%)
56 (8.3%) of which 34 (5%) infarction 22 (3.3%) others
Non-hemorrhagic lesions mainly ventricular dilatation Stroke left hemisphere predominance
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lesions, their distribution, and underlying mechanisms and evaluated 667 newborns in a nationwide cohort in the Netherlands (Fig. 2).23
Localization of most common lesions The “usual” periventricular/intraventricular hemorrhage seen in a premature infant has been described in ECMO-treated neonates, but hemorrhages extending in the parenchyma occur much more frequently during ECMO than in other fullterm newborns.18 In two studies, Bulas et al.11 reported the localization of hemorrhages. In a series of 117 infants with sonographic or computer tomography (CT) evidence of hemorrhage, 64% were parenchymal and 8.5% extraaxial. In the second study, the most common site for a parenchymal bleed was the posterior fossa (27%).27 Others also described an increased risk for posterior fossa hemorrhages that rarely occur in Taylor and non-ECMO-treated newborns.7,11,14,15,27,28 29 Walker suggested that venous outflow obstruction, which occurs because of ligation and cannulation of the right internal jugular vein, causes stasis within the periventricular medullary veins. Thereby increasing the risk of rupture of these vessels. An increased venous pressure may disrupt the blood–brain barrier and alter the cerebral autoregulation curve by causing a shift from the lower end to a higher level.30,31 Venous outflow obstruction might not only be related to the increased rate of posterior fossa hemorrhages but to parenchymal hemorrhages in general. O'Conner et al.32 demonstrated that the prevalence of ICH decreased with the use of a cephalic jugular vein drainage catheter. This observation supports the role of venous obstruction in the etiology of intracranial hemorrhages in general. The most important non-hemorrhagic, non-ischemic lesion in ECMO-treated newborns is the occurrence of subarachnoidal space enlargement at the interhemispheric fissure and frontal, temporal, and parietal convexity and ventricular enlargement.33 Widened interhemispheric fissures have been well described with rates of occurrence as high as 59%.8,34 Rubin et al.35 believed this dilation is an intracranial manifestation of generalized edema. Other authors have suggested that increased sagittal sinus pressure associated with internal jugular vein ligation and
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Table 2 – Neuroimaging score.24–26 Abnormal finding
Score
Ventricular dilatation; relative weight ¼ 1 Minimal Moderate Marked
1.0 2.0 3.0
Subarachnoid space dilatation; relative weight ¼1 Wide interhemispheric fissure Large subarachnoid space
0.5 1.0
Hemorrhage; relative weight ¼ 2 Subependymal only Single petechial Scattered petechial Intraventricular Small parenchymal (r1 cm) Large parenchymal Extraaxial small Extraaxial large
0.5 0.5 1.0 1.0 1.5 3.0 0.5 1.0
Parenchymal lesions; relative weight ¼ 3 Focal PVL or hypodensity Focal atrophy Patchy PVL or hypodensity Diffuse PVL of hypodensity Mild generalized atrophy Moderate generalized atrophy Mass lesion/infarction
0.5 0.5 2.0 3.0 2.0 3.0 3.0
cannulation of the superior vena cava is the cause of this dilation due to decreased cerebrospinal fluid resorption of the arachnoid villi.29,36 In an animal model, Stolar and Reyes37 found a temporary increase in intracranial pressure associated with ligation of the jugular vein. Widened extraaxial space can develop as well following superior vena cava thrombosis.38 An increased incidence of dilation of the interhemispheric fissure and increased subarachnoid space is particularly seen following venovenous ECMO as a result of decreased venous drainage.33 Due to the potential risk of venous stasis, cephalic drainage has been developed in an attempt to prevent neurologic complications by maintaining normal cerebral blood flow and increasing ECMO oxygen delivery.39
Fig. 1 – Classification of neonatal intracranial lesions.14
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Fig. 2 – Focal brain injuries and incidence of lesions in 667 ECMO-treated newborns.23 (Four patients have more than one lesion, AC ¼ anterior cerebral artery, MCA ¼ medial cerebral artery, PCA ¼ posterior cerebral artery, AChA ¼ anterior choroidal artery, PCoA ¼ posterior communicating artery, IVH ¼ intraventricular hemorrhage).
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In our large cohort of 667 newborns, the incidence of brain injury in The Netherlands over the past two decades was 17.3%.23 In accordance with previous reports, the survival rate was lower in patients with abnormalities (54.7%) than in those without abnormalities on cerebral ultrasound (75.5%). Stroke (hemorrhagic and/or ischemic) was documented in 94 infants (13.9%). Primary hemorrhage, seen in 60 infants (8.8% of all), was the commonest type of lesion. Intraventricular hemorrhage (IVH) was the most frequent subtype of hemorrhage. Ischemic strokes caused by vessel occlusion had an incidence of 34 in 676 infants (5%); four had thrombosis in the superior sagittal sinus and 30 were diagnosed with arterial ischemic stroke (located on the left in 70%). Injuries other than stroke were also seen, including symmetrical post-asphyxial damage in 2.2%. Only 5 of the 676 patients (0.7%) had documented intracranial lesions prior to the ECMO procedure.23
Lateralization of intracranial lesions Since the introduction of ECMO, there has been concern about the effect of ligation of the right common carotid artery and right internal jugular vein on the perfusion of the brain. Conflicting data exist on the predominant occurrence of cerebral lesions in the right hemisphere related to this ligation.6,7,19,22,40–42 Especially some older studies with small series noted an increase in injuries to the right hemisphere in infants who underwent ligation of the right carotid artery.9,15,22 Predominance for ischemic lesions in the right hemisphere was demonstrated by several authors.9,15,19,22 Schumacher et al.40 found an increase in left-sided seizures and lateralized neuromotor findings. Lott et al.41 who used other techniques to evaluate lateralization, demonstrated long-lasting decreased blood flow in the right internal carotid artery and a reduction in amplitude of right hemispheric long latency-evoked potentials. Mendoza et al.22 demonstrated that hemorrhagic lesions occurred more often in the left hemisphere. Later other larger studies did not reveal any hemisphere predominance for cerebral lesions but instead an equal distribution on neuroimaging studies, no lateralized neurologic findings, and satisfactory collateral flow on Doppler flow studies.6,7,26,42,43 In a series of 355 infants, using ultrasound, CT, magnetic resonance imaging (MRI), or clinical evaluation, Graziani et al.13 also demonstrated no preference for lesions in the right hemisphere as compared with the left. In a cohort of 31 infants treated with ECMO and evaluated by MRI, there was no lateralization of major brain lesions. However, focal brain lesions were significantly associated with an asymmetric cerebrovascular response to carotid ligation of the right versus left middle cerebral artery as detected by magnetic resonance angiography.44 Roelants-van Rijn et al.45 studied brain metabolism in the basal ganglia using proton MRI and spectroscopy in nine neonates following ECMO and also found no difference in right or left basal ganglia, suggesting that ligation of the
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carotid artery did not produce persistent changes in this small group. For ischemic lesions, Schumacher et al.40 has argued that no lateralization among ECMO-treated neonates is indicative of increased vulnerability of the right hemisphere, since the literature suggest that lateralizing hypoxic–ischemic brain injury in neonates without vessel ligation is usually located in the left hemisphere. Our recent study on 667 newborns did find differences in lesions between both hemispheres, namely a striking leftside predominance for lobar bleeding (12 of 15 located on the left) and ischemic stroke.23 Side predominance of lobar bleeding was not found in term neonates not treated with ECMO.46–48 We hypothesized that this left-side predominance could be related to asymmetrical brain venous drainage and a shift of blood volume to the left hemisphere after cannulation of the right internal jugular vein. The predominance for ischemic stroke in the left hemisphere was unexpected in view of ligation of the right common carotid artery. As described earlier conflicting data are reported on this issue. Several authors reported that stroke in a non-ECMO population has a discrete preference for the left hemisphere.19,49–52 The mechanism behind this vulnerability is not clear. Important in this is the role of the circle of Willis. A competent circle grants blood flow to the right hemisphere. We examined 10 infants during cannulation for VA-ECMO with Doppler ultrasound and Near Infrared Spectrophotometry (NIRS) and found changes in cerebral oxygenation and hemodynamics but no difference between right and left hemisphere due to competence of the circle of Willis.53 Therefore we assume that a different pathogenesis must explain predominance of left-sided acute ischemic stroke in our study. We speculate that, despite continuous heparinization during ECMO, thrombosis may occur on catheters lying in the aortic arch. Compensatory high flow through the left carotid and basilar arteries, with embolic complications, will tend to occur in areas of left brain arteries. Bulas and Glass54 discussed right hemisphere vulnerability. They stated that although there is discussion about whether or not there is structural vulnerability to the right hemisphere, there is evidence for vulnerability at a functional level. They identified 24 children with neuro-radiographically documented unilateral neonatal brain injury, and compared, at age of 5 years, the performance of children with left-sided lesions (n ¼ 12) with those having right-sided lesions (n ¼ 12) on selected tasks reported to be predominantly mediated by the left hemisphere (language comprehension and production and right hand function) or by the right hemisphere (visual pattern discrimination and left hand function). There was a significant association between the pattern of neuropsychological deficit and the side of lesion, such that 75% of the left-lesion group children were more likely to have lower scores on the left hemisphere testing items and 81% of the right-lesion group children were more likely to have lower scores for the right hemisphere test items. In their discussion, they concluded that the data demonstrate that the neuropsychological profile of the ECMO cohort seems to vary according to brain injury severity, rather than a
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dominance of functional deficits associated with the right hemisphere.
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series described by Hardart et al.65 besides lower gestational age, sepsis, coagulopathy, and acidosis were all associated with a higher incidence of intracranial hemorrhage.61
Timing of intracranial brain injury in relation to ECMO Biehl et al.55 studied the timing of intracranial hemorrhages in relation to the start of ECMO and found that 50% of ICH occurred in the first 24 h, 75% by 48 h, and 85% within 72 h of initiation of bypass. Others also found that the majority of cases of ICH occurred within 72 h after the start of ECMO.14,23,56–58 On the other hand, Bulas et al.11 found that the risk for ischemic lesions was not the greatest in the first days but increased with a longer ECMO run time. During ECMO, systemic heparinization is warranted and (small) existing hemorrhages may worsen and new ones develop, reason thus for repeated control.
Prematurity as a risk factor for brain injury It is most likely that the cerebral injuries that occur in ECMOtreated newborns originate from a combination of factors, namely pre-ECMO-, patient-, and disease related factors as well as factors related to the ECMO treatment itself. Two reviews describing these factors have been published recently.59,60 Despite the exclusion of small premature infants from ECMO, studies have shown that younger infants continue to have statistically significant increased risk of hemorrhage.11,20,23,61 Taylor et al.7 for instance found that in a series of 207 infants, preterm infants were at higher risk for developing intracranial abnormalities than term or near-term infants, 56% against 40%, respectively. We recently also demonstrated that the incidence of lesions was significantly higher in preterm (o37 weeks) compared with term infants (Z37 weeks), 28 of 89 (31.5%) versus 83 of 571 (14.5%), respectively (p o 0.01).23 The ELSO registry supports a worse outcome in preterm infants (o35 weeks) with 61% survival while it is 83% in term infants.3 These findings support the current practice of setting the age limit at 34 weeks' gestational age. Ramachandrappa et al.62 in a review of ELSO's registry data demonstrated that late preterm infants (34–36 weeks gestational age) had the highest mortality rate (26.2%) and highest incidence of IVH (12.3%) against 3.6% in full-term newborns. Although ECMO is generally not offered to infants below 34 weeks of gestation in view of the risk for ICH, the earlier mentioned Dutch cohort counted three infants treated under 34 weeks gestational age. Two of them indeed developed ICH.23 On the other hand, in an analysis of ECMO in preterm infants, Hirshl et al.63 demonstrated that survival tended to decrease with decreasing gestational age and that the incidence of ICH increased with decreasing gestational age. Interestingly, however, it was not possible to give a clear cut off point for gestational age above or below which survival and ICH incidence really differed. This would make a sharp limit of 34 weeks as the lower limit of treatment arbitrary. Infants with sepsis are also at high risk for ICH hemorrhage likely due to additional problems with coagulopathy.64 In a
Neuroimaging In general, head ultrasound (HUS) is used as the preferred technique for the routine detection of intracranial abnormalities in ECMO-treated newborns. Although the incidence of intracranial abnormalities is low in ECMO candidates, it is advised to perform a pre-ECMO HUS because the presence of a large ICH is a contraindication for ECMO initiation. HUS has been sensitive in the evaluation of large ICH. Bulas et al.11 demonstrated that over 90% of major ICH, lesions that most determine further treatment, could successfully be identified with HUS. As the risk of ICH is greatest in the first few days of ECMO, daily HUS has been recommended for the potential identification of a developing bleed. The question as to how often daily sonograms should be performed has been reviewed by Biehl et al.55 who found daily HUS cost-effective only during the first 3 days on ECMO. Large parenchymal hemorrhages are usually easily identified with HUS as focal regions of increased echogenicity of hypoechogenic areas due to decreased coagulation. As stated earlier, the general location of ICH is not in the germinal matrix as is seen in preterm infants. It is thus crucial to look carefully within the peripheral parenchyma and posterior fossa for hemorrhagic lesions. HUS is less useful for the detection of ischemic lesions. It is important to be aware that ischemic lesions before ECMO seem to be related to an increased risk of subsequent major intracranial complications.66 Several authors have demonstrated that CT scan can identify intracranial lesions that earlier were not seen with HUS, sometimes even major ones. Additional information was found with CT/MRI scans in 72– 93%. Especially infarctions, diffuse edema, and atrophy are lesions that were detected in CT scans/MRI in children with normal HUS.10,11,14,36,54,67–70 Recently, Rollins et al.71 studied 50 neonates with MRI done after ECMO, before discharge and compared the results with HUS done during ECMO. HUS was abnormal in 24% during ECMO whereas MRI after ECMO was abnormal in 62%. All patients with abnormal HUS had an abnormal MRI. However, of the patients with a normal HUS, 50% had an abnormal MRI. Most of the lesions unrecognized on HUS were nonhemorrhagic.
Outcome What is generally known about long-term follow-up? Taking into account the relatively high rate of neuroimaging abnormalities that are present in ECMO-treated neonates, neurodevelopmental outcome studies are important to define the impact on later functioning. A more extensive overview of outcome data is described elsewhere in this journal. This
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chapter focuses on the association of neuroimaging abnormalities and neurodevelopmental outcome. Mild to major neurodevelopmental impairment is described in 15–25% of neonatal ECMO survivors.6,9,12,72–79 Impairment involves abnormal cognitive and psychomotor development. However, more subtle signs of neurological involvement appear to occur at higher rates. Learning problems at school age appear to be as high as 50% and parents report behavioral problems more often than in normal controls. By the end of the first grade, even non-retarded ECMO children are still more than twice as likely to be receiving special educational services.9,12,73,75–77,80,81 The specific impact of perinatal brain injury in ECMO patients on neurodevelopment was the subject of many studies. In the 1980s, Taylor et al.25 used the neuroimaging score described above (Table 1) to study the relation between this score and neurodevelopment as tested with mental and psychomotor development index of the Bayley Scales of Infant Development (BSID) in 46 newborns with mean age of 11.8 months (range: 6–16 months). He reported that infants with normal development had more favorable neuroimaging scores than infants with delayed development and that there was a significant inverse correlation between the neuroimaging score and mental and psychomotor development indexes. However, it was not possible to predict individual outcomes based on neuroimaging scores because there were children with low scores and adverse outcome but also with high scores and normal outcome. This suggests that there are mechanisms in the infantile brain to compensate for structural damage.54 This relative neuroplasticity of the immature brain has also been confirmed by the study by Bulas and Glass54 who showed that 6 of 14 (43%) and 8 of 12 (67%) with severe and moderate intracranial lesions on HUS and CT in the neonatal period, respectively, had developed without significant disability at the age of 5 years. In another study by von Allmen et al.66 they studied 42 1year-old ECMO survivors. Some kind of neuroimaging abnormality during ECMO was seen in 78% of the infants with neurodevelopmental delay; this was 28% in the subgroup of infants with normal development. IVH, especially major lesions, was associated with poor neurodevelopmental outcome; it was present in 56% of infants with developmental delay in 26% of the suspect group and in 20% of the infants who had normal development at 1 year. Griffin et al.21 showed that absence of ICH, cerebral infarct, or cerebral atrophy correlated with normal short-term neurodevelopment in 22 newborns evaluated with BSID at 3, 6, 12, and 24 months. Vaucher et al.78 studied a large cohort of 139 ECMO survivors aged 4–24 months looking at neuromotor, developmental, and neurosensory outcome. Neuromotor outcome was categorized as normal, suspect (hypotonia, hypertonia, or asymmetry), or abnormal (cerebral palsy); developmental outcome was defined as normal when motor and mental developmental scores were 483 and neurosensory outcome was considered abnormal in children with hearing loss who required amplification or in those with severe visual impairment. Brain abnormalities were classified as normal, mild (mild ventriculomegaly, grade I or II IVH, and subarachnoid hemorrhage), moderate (moderate ventriculomegaly and
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grade III IVH), and severe (severe ventriculomegaly, porencephaly, grade IV IVH, cerebral infarction, and cystic leukomalacia). Vaucher showed that moderate or severe neuroimaging abnormality during ECMO was an independent predictor for suspect or abnormal neurologic outcome at age over 12 months (OR ¼ 5.10, 95% CI: 1.55–17.09), for cerebral palsy (OR ¼ 10.30, 95% CI: 1.56–67.87), for motor developmental index o84 (OR ¼ 6.30, 95% CI: 1.72–23.32), and for adverse neuromotor, neurosensory, or developmental outcome (OR ¼ 6.43, 95% CI: 1.89–21.89). Glass et al.12 published a large follow-up study in 152 children aged 5 years and additional data were published in a second paper.54 Extensive neuropsychological and neurobehavioral testing was done. Outcome was related to the severity of brain injury on neonatal neuroimaging for which the earlier described neuroimaging score was used, based on HUS and CT scan made within 3 weeks after ECMO, and imaging was scored as no lesion (in 88 children), mild lesion (in 38 children), moderate lesion (in 12 children), and severe lesion (in 14 children). The outcome measures included intellectual status, pre-academic skills, neuropsychological deficits, and neuromotor dysfunction. One or more major disability conditions were seen in 17% of children, of whom 14% had mental retardation or a severe learning disability and 5% had a motor disability. Severity of the injury expressed as a higher neuroimaging score was associated with the presence of disability at the age 5 years. The prevalence of any kind of disability ranged from 10% in ECMO survivors without intracranial lesions up to 57% in those with severe abnormalities. The odds ratio for disability at age 5 years after moderate or severe lesion was 26.00 (95% CI: 2.6– 263.0) and 69.33 (95% CI: 7.3–653.9), respectively. Even children with mild brain injuries had lower IQ scores relative to ECMO children without an identified brain injury. Both of these ECMO subgroups demonstrated mild but consistent functional deficits relative to the normal control group of healthy children. The grip strength (left hand and right hand) and dexterity (left hand) were significantly related with injury severity. The fact that a large proportion of children with moderate to severe neuroimaging abnormalities develop without significant disabilities suggests that neuroimaging in the neonatal period may be helpful to predict neurodevelopmental outcome but long-term follow-up is still important. Moreover, despite normal intelligence, many children may experience (subtle) learning disabilities, which will be discussed in another chapter.82 Hahn et al.15 and Bulas et al.26 state that the risk of adverse neurodevelopment outcome might be more related to major non-hemorrhagic lesions or combined lesions than to major hemorrhagic lesions. A few studies, however, did not reveal a relation between neuroimaging results and neurodevelopmental outcome. In their study on 31 newborns aged 6 and 12 months, Lago et al.44 found no relation between the presence of major brain lesions including parenchymal hemorrhages, infarctions or combinations, and Bayley test scores. However, enlarged cerebrospinal fluid spaces were associated with lower motor and performance developmental indexes. Eight patients in the study by Glass et al.12 had post-decannulation CT scan
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evidence of widened interhemispheric fissure. The mean fullscale IQ score was 84 for these children, and all 8 of them had lower verbal than performance IQ scores. This might suggest that the presence of a widened interhemispheric fissure may not be benign. The study by Rollins et al.71 also found no relation between neurodevelopmental index and enlargement of subarachnoid space and also between neurodevelopmental impairment and findings on HUS or MRI. Rollins questioned the predictive value of neuroimaging results after ECMO for developmental outcome. This because in the study by Glass et al.12 43% of children with severe and 67% with moderate brain injury on neuroimaging were later noted to have no disability at 5-year follow-up. Furthermore, Lazar et al.10 found that 13.5% had delayed neurological development despite no evidence of anatomic injury on serial HUS or follow-up imaging.
Conclusion Intracranial abnormalities, hemorrhagic and non-hemorrhagic, are the major complications of ECMO in newborns. They do occur in a substantial number of these infants and influence survival and affect later neurodevelopmental outcome. On the other hand, some children with severe intracranial injuries have a normal development suggestive of plasticity of the brain. To investigate in detail the consequences of brain damage in ECMO-treated infants, adequate longterm, structured follow-up in large patient groups is necessary. As such, it is important to understand the underlying pathophysiologic mechanisms that are involved in the etiology of brain injury.
re fe r en ces
1. UK Collaborative ECMO Trail Group. UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation. Lancet. 1996;348(9020):75–82. 2. Bartlett RH. Esperanza. Presidential address. Trans Am Soc Artif Intern Organs. 1985;31:723–726. 3. ELSO. ELSO registry data. ELSO; 2013. 4. Stolar CJ, Snedecor SM, Bartlett RH. Extracorporeal membrane oxygenation and neonatal respiratory failure: experience from the extracorporeal life support organization. J Pediatr Surg. 1991;26(5):563–571. 5. P Glass AW, Coffman CE. Outcome and follow up of neonates treated with ECMO. In: Zwischenberger JB, BB, ed. ECMO Extracorporeal Cardiopulmonary Support in Critical Care. Ann Arbor: Extracorporeal Life Support Organization; 1995. 327–340. 6. Glass P, Miller M, Short B. Morbidity for survivors of extracorporeal membrane oxygenation: neurodevelopmental outcome at 1 year of age. Pediatrics. 1989;83(1):72–78. 7. Taylor GA, Short BL, Fitz CR. Imaging of cerebrovascular injury in infants treated with extracorporeal membrane oxygenation. J Pediatr. 1989;114(4 Pt 1):635–639. 8. Babcock DS, Han BK, Weiss RG, Ryckman FC. Brain abnormalities in infants on extracorporeal membrane oxygenation: sonographic and CT findings. Am J Roentgenol. 1989;153(3): 571–576.
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9. Hofkosh D, Thompson AE, Nozza RJ, Kemp SS, Bowen A, Feldman HM. Ten years of extracorporeal membrane oxygenation: neurodevelopmental outcome. Pediatrics. 1991;87(4): 549–555. 10. Lazar EL, Abramson SJ, Weinstein S, Stolar CJ. Neuroimaging of brain injury in neonates treated with extracorporeal membrane oxygenation: lessons learned from serial examinations. J Pediatr Surg. 1994;29(2):186–190. 11. Bulas DI, Taylor GA, O'Donnell RM, Short BL, Fitz CR, Vezina G. Intracranial abnormalities in infants treated with extracorporeal membrane oxygenation: update on sonographic and CT findings. Am J Neuroradiol. 1996;17(2):287–294. 12. Glass P, Bulas DI, Wagner AE, et al. Severity of brain injury following neonatal extracorporeal membrane oxygenation and outcome at age 5 years. Dev Med Child Neurol. 1997;39(7):441–448. 13. Graziani LJ, Gringlas M, Baumgart S. Cerebrovascular complications and neurodevelopmental sequelae of neonatal ECMO. Clin Perinatol. 1997;24(3):655–675. 14. Taylor GA, Fitz CR, Miller MK, Garin DB, Catena LM, Short BL. Intracranial abnormalities in infants treated with extracorporeal membrane oxygenation: imaging with US and CT. Radiology. 1987;165(3):675–678. 15. Hahn JS, Vaucher Y, Bejar R, Coen RW. Electroencephalographic and neuroimaging findings in neonates undergoing extracorporeal membrane oxygenation. Neuropediatrics. 1993; 24(1):19–24. 16. Ahmad A, Gangitano E, Odell RM, Doran R, Durand M. Survival, intracranial lesions, and neurodevelopmental outcome in infants with congenital diaphragmatic hernia treated with extracorporeal membrane oxygenation. J Perinatol. 1999;19(6 Pt 1):436–440. 17. Bartlett RH, Gazzaniga AB, Toomasian J, et al. Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failure. 100 cases. Ann Surg. 1986;204(3):236–245. 18. Bowerman RA, Zwischenberger JB, Andrews AF, Bartlett RH. Cranial sonography of the infant treated with extracorporeal membrane oxygenation. Am J Roentgenol. 1985;145(1):161–166. 19. Campbell LR, Bunyapen C, Holmes GL, Howell CG Jr, Kanto WP Jr. Right common carotid artery ligation in extracorporeal membrane oxygenation. J Pediatr. 1988;113(1 Pt 1):110–113. 20. Cilley RE, Zwischenberger JB, Andrews AF, Bowerman RA, Roloff DW, Bartlett RH. Intracranial hemorrhage during extracorporeal membrane oxygenation in neonates. Pediatrics. 1986;78(4):699–704. 21. Griffin MP, Minifee PK, Landry SH, Allison PL, Swischuk LE, Zwischenberger JB. Neurodevelopmental outcome in neonates after extracorporeal membrane oxygenation: cranial magnetic resonance imaging and ultrasonography correlation. J Pediatr Surg. 1992;27(1):33–35. 22. Mendoza JC, Shearer LL, Cook LN. Lateralization of brain lesions following extracorporeal membrane oxygenation. Pediatrics. 1991;88(5):1004–1009. 23. Raets MMA, Dudink J, IJsselstijn H, et al. Brain injury associated with neonatal ECMO in the Netherlands. A nationwide evaluation spanning two decades. PCCM, DOI:10.1097/PCC. 0b013e3182a555ac in press. 24. Taylor GA, Fitz CR, Glass P, Short BL. CT of cerebrovascular injury after neonatal extracorporeal membrane oxygenation: implications for neurodevelopmental outcome. Am J Roentgenol. 1989;153(1):121–126. 25. Taylor GA, Glass P, Fitz CR, Miller MK. Neurologic status in infants treated with extracorporeal membrane oxygenation: correlation of imaging findings with developmental outcome. Radiology. 1987;165(3):679–682. 26. Bulas DI, Glass P, O'Donnell RM, Taylor GA, Short BL, Vezina GL. Neonates treated with ECMO: predictive value of early CT and US neuroimaging findings on short-term neurodevelopmental outcome. Radiology. 1995;195(2):407–412.
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27. Bulas DI, Taylor GA, Fitz CR, Revenis ME, Glass P, Ingram JD. Posterior fossa intracranial hemorrhage in infants treated with extracorporeal membrane oxygenation: sonographic findings. Am J Roentgenol. 1991;156(3):571–575. 28. Wiznitzer M, Masaryk TJ, Lewin J, Walsh M, Stork EK. Parenchymal and vascular magnetic resonance imaging of the brain after extracorporeal membrane oxygenation. Am J Dis Child. 1990;144(12):1323–1326. 29. Taylor GA, Walker LK. Intracranial venous system in newborns treated with extracorporeal membrane oxygenation: Doppler US evaluation after ligation of the right jugular vein. Radiology. 1992;183(2):453–456. 30. Mayhan WG, Heistad DD. Role of veins and cerebral venous pressure in disruption of the blood–brain barrier. Circ Res. 1986;59(2):216–220. 31. McPherson RW, Koehler RC, Traystman RJ. Effect of jugular venous pressure on cerebral autoregulation in dogs. Am J Physiol. 1988;255(6 Pt 2):H1516–H1524. 32. O'Connor TA, Haney BM, Grist GE, Egelhoff JC, Snyder CL, Ashcraft KW. Decreased incidence of intracranial hemorrhage using cephalic jugular venous drainage during neonatal extracorporeal membrane oxygenation. J Pediatr Surg. 1993;28 (10):1332–1335. 33. Brunberg JA, Kewitz G, Schumacher RE. Venovenous extracorporeal membrane oxygenation: early CT alterations following use in management of severe respiratory failure in neonates. Am J Neuroradiol. 1993;14(3):595–603. 34. Canady AI, Fessler RD, Klein MD. Ultrasound abnormalities in term infants on ECMO. Pediatr Neurosurg. 1993;19(4):202–205. 35. Rubin DA, Gross GW, Ehrlich SM, Alexander AA. Interhemispheric fissure width in neonates on ECMO. Pediatr Radiol. 1990;21(1):12–15. 36. Matamoros A, Anderson JC, McConnell J, Bolam DL. Neurosonographic findings in infants treated by extracorporeal membrane oxygenation (ECMO). J Child Neurol. 1989;4(suppl):S52–61. 37. Stolar CJ, Reyes C. Extracorporeal membrane oxygenation causes significant changes in intracranial pressure and carotid artery blood flow in newborn lambs. J Pediatr Surg. 1988;23 (12):1163–1168. 38. McLaughlin JF, Loeser JD, Roberts TS. Acquired hydrocephalus associated with superior vena cava syndrome in infants. Childs Nerv Syst. 1997;13(2):59–63. 39. Weber TR, Kountzman B. The effects of venous occlusion on cerebral blood flow characteristics during ECMO. J Pediatr Surg. 1996;31(8):1124–1127. 40. Schumacher RE, Barks JD, Johnston MV, et al. Right-sided brain lesions in infants following extracorporeal membrane oxygenation. Pediatrics. 1988;82(2):155–161. 41. Lott IT, McPherson D, Towne B, Johnson D, Starr A. Long-term neurophysiologic outcome after neonatal extracorporeal membrane oxygenation. J Pediatr. 1990;116(3):343–349. 42. Taylor GA, Short BL, Glass P, Ichord R. Cerebral hemodynamics in infants undergoing extracorporeal membrane oxygenation: further observations. Radiology. 1988;168(1):163–167. 43. Adolph V, Ekelund C, Smith C, Starrett A, Falterman K, Arensman R. Developmental outcome of neonates treated with extracorporeal membrane oxygenation. J Pediatr Surg. 1990;25(1):43–46. 44. Lago P, Rebsamen S, Clancy RR, et al. MRI, MRA, and neurodevelopmental outcome following neonatal ECMO. Pediatr Neurol. 1995;12(4):294–304. 45. Roelants-van Rijn AM, van der GJ, de Vries LS, Groenendaal F. Cerebral proton magnetic resonance spectroscopy of neonates after extracorporeal membrane oxygenation. Acta Paediatr. 2001;90(11):1288–1291. 46. Sandberg DI, Lamberti-Pasculli M, Drake JM, Humphreys RP, Rutka JT. Spontaneous intraparenchymal hemorrhage in full-
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term neonates. Neurosurgery. 2001;48(5):1042–1048 [discussion 8-9]. Huang AH, Robertson RL. Spontaneous superficial parenchymal and leptomeningeal hemorrhage in term neonates. Am J Neuroradiol. 2004;25(3):469–475. Dale ST, Coleman LT. Neonatal alloimmune thrombocytopenia: antenatal and postnatal imaging findings in the pediatric brain. Am J Neuroradiol. 2002;23(9):1457–1465. Mannino FL, Trauner DA. Stroke in neonates. J Pediatr. 1983; 102(4):605–610. Mantovani JF, Gerber GJ. Idiopathic neonatal cerebral infarction. Am J Dis Child. 1984;138(4):359–362. Ment LR, Duncan CC, Ehrenkranz RA. Perinatal cerebral infarction. Semin Perinatol. 1987;11(2):142–154. Levy MS, Share JC, Fauza DO, Wilson JM. Fate of the reconstructed carotid artery after extracorporeal membrane oxygenation. J Pediatr Surg. 1995;30(7):1046–1049. Van Heijst A, Liem D, Hopman J, Van Der Staak F, Sengers R. Oxygenation and hemodynamics in left and right cerebral hemispheres during induction of veno-arterial extracorporeal membrane oxygenation. J Pediatr. 2004;144(2):223–228. Bulas D, Glass P. Neonatal ECMO: neuroimaging and neurodevelopmental outcome. Semin Perinatol. 2005;29(1):58–65. Biehl DA, Stewart DL, Forti NH, Cook LN. Timing of intracranial hemorrhage during extracorporeal life support. ASAIO J. 1996;42(6):938–941. De Sanctis JT, Bramson RT, Blickman JG. Can clinical parameters help reliably predict the onset of acute intracranial hemorrhage in infants receiving extracorporeal membrane oxygenation? Radiology. 1996;199(2):429–432. Dela Cruz TV, Stewart DL, Winston SJ, Weatherman KS, Phelps JL, Mendoza JC. Risk factors for intracranial hemorrhage in the extracorporeal membrane oxygenation patient. J Perinatol. 1997;17(1):18–23. Khan AM, Shabarek FM, Zwischenberger JB, et al. Utility of daily head ultrasonography for infants on extracorporeal membrane oxygenation. J Pediatr Surg. 1998;33(8):1229–1232. de Mol AC, Liem KD, van Heijst AF. Cerebral aspects of neonatal extracorporeal membrane oxygenation: a review. Neonatology. 2013;104(2):95–103 [Epub 2013/07/03]. Short BL. The effect of extracorporeal life support on the brain: a focus on ECMO. Semin Perinatol. 2005;29(1):45–50. Hardart GE, Fackler JC. Predictors of intracranial hemorrhage during neonatal extracorporeal membrane oxygenation. J Pediatr. 1999;134(2):156–159. Ramachandrappa A, Rosenberg ES, Wagoner S, Jain L. Morbidity and mortality in late preterm infants with severe hypoxic respiratory failure on extra-corporeal membrane oxygenation. J Pediatr. 2011;159(2):192–198 [e3]. Hirschl RB, Schumacher RE, Snedecor SN, Bui KC, Bartlett RH. The efficacy of extracorporeal life support in premature and low birth weight newborns. J Pediatr Surg. 1993;28(10): 1336–1340 [discussion 41]. Zimmerman JJ, Dietrich KA. Current perspectives on septic shock. Pediatr Clin North Am. 1987;34(1):131–163. Hardart GE, Hardart MKM, Arnold JH. Intracranial hemorrhage in premature neonates treated with extracorporeal membrane oxygenation correlates with conceptional age. J Pediatr. 2004;145(2):184–189. von Allmen D, Babcock D, Matsumoto J, et al. The predictive value of head ultrasound in the ECMO candidate. J Pediatr Surg. 1992;27(1):36–39. Garber SJ, Stewart DL, Cook LN, Bond SJ. Evaluation of post extracorporeal membrane oxygenation follow-up testing. ASAIO J. 1998;44(3):171–174. Silverboard G, Horder MH, Ahmann PA, Lazzara A, Schwartz JF. Reliability of ultrasound in diagnosis of intracerebral
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76. Khambekar K, Nichani S, Luyt DK, et al. Developmental outcome in newborn infants treated for acute respiratory failure with extracorporeal membrane oxygenation: present experience. Arch Dis Child Fetal Neonatal Ed. 2006;91(1): F21–F25. 77. Rais-Bahrami K, Wagner AE, Coffman C, Glass P, Short BL. Neurodevelopmental outcome in ECMO vs near-miss ECMO patients at 5 years of age. Clin Pediatr. 2000;39(3):145–152. 78. Vaucher YE, Dudell GG, Bejar R, Gist K. Predictors of early childhood outcome in candidates for extracorporeal membrane oxygenation. J Pediatr. 1996;128(1):109–117. 79. Wildin SR, Landry SH, Zwischenberger JB. Prospective, controlled study of developmental outcome in survivors of extracorporeal membrane oxygenation: the first 24 months. Pediatrics. 1994;93(3):404–408. 80. Van Meurs KP, Robbins ST, Reed VL, et al. Congenital diaphragmatic hernia: long-term outcome in neonates treated with extracorporeal membrane oxygenation. J Pediatr. 1993;122(6):893–899. 81. Schumacher RE, Palmer TW, Roloff DW, LaClaire PA, Bartlett RH. Follow-up of infants treated with extracorporeal membrane oxygenation for newborn respiratory failure. Pediatrics. 1991;87(4):451–457. 82. Madderom MJ, Reuser JJCM, Utens EMWJ, et al. Neurodevelopmental, educational and behavioral outcome at 8 years after neonatal ECMO: a nationwide multicenter study. Intensive Care Med. 2013;39(9):1584–1593.
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Available online at www.sciencedirect.com
www.elsevier.com/locate/semperi
ECMO in neonates: Neuroimaging findings and outcome Arno F.J. van Heijst, MD, PhDa,n, Amerik C. de Mol, MD, PhDb, and Hanneke IJsselstijn, MD, PhDc a
Department of Pediatrics, Division of Neonatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands b Department of Pediatrics, Albert Sweitzer Hospital, Dordrecht, Rotterdam, The Netherlands c Department of Pediatric Surgery and Intensive Care, Erasmus MC—Sophia Children's Hospital, Rotterdam, The Netherlands
article info
abstract
Keywords:
Extracorporeal membrane oxygenation (ECMO) is a rescue therapy for newborns with
ECMO
severe but reversible respiratory failure. Although ECMO has significantly improved
Brain
survival, it is associated with substantial complications, of which intracranial injuries
Cerebral utrrasound
are the most important. These injuries consist of hemorrhagic and non-hemorrhagic,
MRI
ischemic lesions. Different from the classical presentation of hemorrhages in preterm infants, hemorrhages in ECMO-treated newborns are mainly parenchymal and with a high percentage in the posterior fossa area. There are conflicting data on the predominant occurrence of cerebral lesions in the right hemisphere. The existence of intracerebral injuries and the classification of its severity are the major predictors of neurodevelopmental outcome. This section will discuss the known data on intracranial injury in the ECMO population and the effect of ECMO on the brain. & 2014 Elsevier Inc. All rights reserved.
Introduction Extracorporeal membrane oxygenation (ECMO) is used in newborns as a rescue therapy for severe but reversible respiratory insufficiency in case of failure of other, conventional, therapies.1 Since ECMO was first used in a newborn in 1975, until July 2013, over 26,000 newborns have been treated.2,3 Although survival rates in general are excellent, serious complications do arise, with intracranial injuries representing the major complications associated with ECMO treatment. The major cause of death in the newborn ECMO population is due to cerebral injury with intracranial hemorrhage (ICH) and/or infarction, with approximately half of the non-survivors having severe bleeding complications.3,4 Survival is not the only issue we should look at when determining that ECMO is a beneficial treatment method for these very sick infants. Longn
term follow-up is necessary not only to evaluate the results of this highly technical, invasive approach but also to identify infants at risk for adverse outcome and provide adequate guidance for long-term care. Feeding problems, poor somatic growth, chronic lung disease, and recurrent hospitalizations are all part of medical morbidity in survivors.5 Neurodevelopmental impairment is a significant outcome measure. These factors are covered in another chapter. This review focuses on the intracranial injuries that are related to ECMO treatment in newborns.
Intracranial injuries in ECMO ECMO-treated neonates incur a relatively high frequency of abnormalities identified on routine neuroimaging, which
Corresponding author. E-mail address: [email protected] (A.F.J. van Heijst).
0146-0005/14/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.semperi.2013.11.008
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vary widely in type and severity. The incidence of abnormalities discovered in neuroimaging during or after ECMO varies according to the literature from 10% to even 59% (Table 1).6–23 The most recent report of the ELSO registry mentioned a prevalence of cerebral infarction and hemorrhage in 7.2% and 7.1% of the newborns treated with ECMO, respectively. Survival in these infants is less than in the general population (84%) with survival rates of 54% for children with infarctions and 44% for those with hemorrhages.3
Classification The types of brain injuries in ECMO-treated newborns vary to a great extent. In the 1980s Taylor proposed the following classification (Fig. 1). This is based on the type of presentation and severity of injury,14 i.e., hemorrhagic and nonhemorrhagic and major and minor. With this classification,
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he developed a systemic approach to quantify the severity of these lesions and he and Bulas later modified this score.24–26 For their scoring system, they divided intracranial lesions into four categories: hemorrhagic, non-hemorrhagic parenchymal lesions, extraaxial fluid collections, and ventricular dilatation. Based on an assumption of risk for neurologic consequences, each category was assigned a relative risk score of 1, 2, or 3, respectively, for ventricular dilatation, hemorrhage, and other parenchymal lesions. Within each category, more severe lesions were assigned a higher numeric score. Finally the abnormality score within a category was multiplied by the relative weight factor making a total score (Table 2). A subgroup of non-hemorrhagic lesions comprises the ventricular enlargement and widened interhemispheric fissure, which are both common in ECMO-treated newborns.25 Recently, we presented an alternative refined classification system of focal brain injury in ECMO-treated neonates, aiming at better understanding of the different types of
Table 1 – Studies on the prevalence of intracranial abnormalities in ECMO-treated newborns. Number of patients
Intracranial hemorrhage, n (%)
Non-hemorhagic lesions, n (%)
Bartlett et al.17
100
Not available
14/17 died 8/12 died
Bowerman et al.18 Cilley et al.20
28
In preterm infants: 17/19 (89%) In full-term infants (4 35weeks) 12/81 (15%) 8/28 (28.6%)
Not available
35
10/35 (28.6%)
Not available
Campbell et al.19 Babcock et al.8 Glass et al.6
33
6 (18.2%)
10 (of 20 studied patients) (50%)
5 of 8 in (extremely) premature infants All 8 infants o34 weeks GA had ICH Only 2 of 27 with GA 4 34 weeks No L–R hemisphere differences
50
8 (16%)
14 (28%)
No L–R hemisphere differences
42
5 (11.9%)
No L–R hemisphere differences
Taylor et al.7
207
180
43 (20.8%) 21 (10.1%) major 42 (20.2%) minor 6 (3.3%) major ischemic lesions
No L–R hemisphere differences 25% were major abnormalities
Mendoza et al.22
13 (31%) 5 (12%) major 7 (16.7%) minor 68 (32.8%) 31 (46%) major 37 (54%) minor 10 (5.5%) major hemorrhagic lesions
Griffin et al.21 Hahn et al.15
22
Non
2 cerebral atrophy (9.1%)
36
3 (8.3%)
Lazar et al.10 Bulas et al.11
74
3 (4%)
8 (22%) 19/36 ventricular dilatation and/or enlarged subarachnoidal spaces and interhemispheric fissure 16 (21.6%)
386
73 29 44 44
Ahmad et al.16 Raets et al.23
References
Other information
L 4 R for hemorrhages R 4 L for ischemia 106 (59%) had some abnormality 16 (8.9%) had major abnormalities
All hemorrhages were cerebellar Non-hemorrhagic lesions R 4 L
No L–R hemisphere differences
86 (22%) 22 (6%) major 64 (16%) minor (16)
No L–R hemisphere differences
51
(19%) (8%) major (11%) minor (11%) combined with nonhemorrhagic lesions 6 (11.8%)
12 (23%)
676
60 (8.8%)
56 (8.3%) of which 34 (5%) infarction 22 (3.3%) others
Non-hemorrhagic lesions mainly ventricular dilatation Stroke left hemisphere predominance
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lesions, their distribution, and underlying mechanisms and evaluated 667 newborns in a nationwide cohort in the Netherlands (Fig. 2).23
Localization of most common lesions The “usual” periventricular/intraventricular hemorrhage seen in a premature infant has been described in ECMO-treated neonates, but hemorrhages extending in the parenchyma occur much more frequently during ECMO than in other fullterm newborns.18 In two studies, Bulas et al.11 reported the localization of hemorrhages. In a series of 117 infants with sonographic or computer tomography (CT) evidence of hemorrhage, 64% were parenchymal and 8.5% extraaxial. In the second study, the most common site for a parenchymal bleed was the posterior fossa (27%).27 Others also described an increased risk for posterior fossa hemorrhages that rarely occur in Taylor and non-ECMO-treated newborns.7,11,14,15,27,28 29 Walker suggested that venous outflow obstruction, which occurs because of ligation and cannulation of the right internal jugular vein, causes stasis within the periventricular medullary veins. Thereby increasing the risk of rupture of these vessels. An increased venous pressure may disrupt the blood–brain barrier and alter the cerebral autoregulation curve by causing a shift from the lower end to a higher level.30,31 Venous outflow obstruction might not only be related to the increased rate of posterior fossa hemorrhages but to parenchymal hemorrhages in general. O'Conner et al.32 demonstrated that the prevalence of ICH decreased with the use of a cephalic jugular vein drainage catheter. This observation supports the role of venous obstruction in the etiology of intracranial hemorrhages in general. The most important non-hemorrhagic, non-ischemic lesion in ECMO-treated newborns is the occurrence of subarachnoidal space enlargement at the interhemispheric fissure and frontal, temporal, and parietal convexity and ventricular enlargement.33 Widened interhemispheric fissures have been well described with rates of occurrence as high as 59%.8,34 Rubin et al.35 believed this dilation is an intracranial manifestation of generalized edema. Other authors have suggested that increased sagittal sinus pressure associated with internal jugular vein ligation and
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Table 2 – Neuroimaging score.24–26 Abnormal finding
Score
Ventricular dilatation; relative weight ¼ 1 Minimal Moderate Marked
1.0 2.0 3.0
Subarachnoid space dilatation; relative weight ¼1 Wide interhemispheric fissure Large subarachnoid space
0.5 1.0
Hemorrhage; relative weight ¼ 2 Subependymal only Single petechial Scattered petechial Intraventricular Small parenchymal (r1 cm) Large parenchymal Extraaxial small Extraaxial large
0.5 0.5 1.0 1.0 1.5 3.0 0.5 1.0
Parenchymal lesions; relative weight ¼ 3 Focal PVL or hypodensity Focal atrophy Patchy PVL or hypodensity Diffuse PVL of hypodensity Mild generalized atrophy Moderate generalized atrophy Mass lesion/infarction
0.5 0.5 2.0 3.0 2.0 3.0 3.0
cannulation of the superior vena cava is the cause of this dilation due to decreased cerebrospinal fluid resorption of the arachnoid villi.29,36 In an animal model, Stolar and Reyes37 found a temporary increase in intracranial pressure associated with ligation of the jugular vein. Widened extraaxial space can develop as well following superior vena cava thrombosis.38 An increased incidence of dilation of the interhemispheric fissure and increased subarachnoid space is particularly seen following venovenous ECMO as a result of decreased venous drainage.33 Due to the potential risk of venous stasis, cephalic drainage has been developed in an attempt to prevent neurologic complications by maintaining normal cerebral blood flow and increasing ECMO oxygen delivery.39
Fig. 1 – Classification of neonatal intracranial lesions.14
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Fig. 2 – Focal brain injuries and incidence of lesions in 667 ECMO-treated newborns.23 (Four patients have more than one lesion, AC ¼ anterior cerebral artery, MCA ¼ medial cerebral artery, PCA ¼ posterior cerebral artery, AChA ¼ anterior choroidal artery, PCoA ¼ posterior communicating artery, IVH ¼ intraventricular hemorrhage).
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In our large cohort of 667 newborns, the incidence of brain injury in The Netherlands over the past two decades was 17.3%.23 In accordance with previous reports, the survival rate was lower in patients with abnormalities (54.7%) than in those without abnormalities on cerebral ultrasound (75.5%). Stroke (hemorrhagic and/or ischemic) was documented in 94 infants (13.9%). Primary hemorrhage, seen in 60 infants (8.8% of all), was the commonest type of lesion. Intraventricular hemorrhage (IVH) was the most frequent subtype of hemorrhage. Ischemic strokes caused by vessel occlusion had an incidence of 34 in 676 infants (5%); four had thrombosis in the superior sagittal sinus and 30 were diagnosed with arterial ischemic stroke (located on the left in 70%). Injuries other than stroke were also seen, including symmetrical post-asphyxial damage in 2.2%. Only 5 of the 676 patients (0.7%) had documented intracranial lesions prior to the ECMO procedure.23
Lateralization of intracranial lesions Since the introduction of ECMO, there has been concern about the effect of ligation of the right common carotid artery and right internal jugular vein on the perfusion of the brain. Conflicting data exist on the predominant occurrence of cerebral lesions in the right hemisphere related to this ligation.6,7,19,22,40–42 Especially some older studies with small series noted an increase in injuries to the right hemisphere in infants who underwent ligation of the right carotid artery.9,15,22 Predominance for ischemic lesions in the right hemisphere was demonstrated by several authors.9,15,19,22 Schumacher et al.40 found an increase in left-sided seizures and lateralized neuromotor findings. Lott et al.41 who used other techniques to evaluate lateralization, demonstrated long-lasting decreased blood flow in the right internal carotid artery and a reduction in amplitude of right hemispheric long latency-evoked potentials. Mendoza et al.22 demonstrated that hemorrhagic lesions occurred more often in the left hemisphere. Later other larger studies did not reveal any hemisphere predominance for cerebral lesions but instead an equal distribution on neuroimaging studies, no lateralized neurologic findings, and satisfactory collateral flow on Doppler flow studies.6,7,26,42,43 In a series of 355 infants, using ultrasound, CT, magnetic resonance imaging (MRI), or clinical evaluation, Graziani et al.13 also demonstrated no preference for lesions in the right hemisphere as compared with the left. In a cohort of 31 infants treated with ECMO and evaluated by MRI, there was no lateralization of major brain lesions. However, focal brain lesions were significantly associated with an asymmetric cerebrovascular response to carotid ligation of the right versus left middle cerebral artery as detected by magnetic resonance angiography.44 Roelants-van Rijn et al.45 studied brain metabolism in the basal ganglia using proton MRI and spectroscopy in nine neonates following ECMO and also found no difference in right or left basal ganglia, suggesting that ligation of the
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carotid artery did not produce persistent changes in this small group. For ischemic lesions, Schumacher et al.40 has argued that no lateralization among ECMO-treated neonates is indicative of increased vulnerability of the right hemisphere, since the literature suggest that lateralizing hypoxic–ischemic brain injury in neonates without vessel ligation is usually located in the left hemisphere. Our recent study on 667 newborns did find differences in lesions between both hemispheres, namely a striking leftside predominance for lobar bleeding (12 of 15 located on the left) and ischemic stroke.23 Side predominance of lobar bleeding was not found in term neonates not treated with ECMO.46–48 We hypothesized that this left-side predominance could be related to asymmetrical brain venous drainage and a shift of blood volume to the left hemisphere after cannulation of the right internal jugular vein. The predominance for ischemic stroke in the left hemisphere was unexpected in view of ligation of the right common carotid artery. As described earlier conflicting data are reported on this issue. Several authors reported that stroke in a non-ECMO population has a discrete preference for the left hemisphere.19,49–52 The mechanism behind this vulnerability is not clear. Important in this is the role of the circle of Willis. A competent circle grants blood flow to the right hemisphere. We examined 10 infants during cannulation for VA-ECMO with Doppler ultrasound and Near Infrared Spectrophotometry (NIRS) and found changes in cerebral oxygenation and hemodynamics but no difference between right and left hemisphere due to competence of the circle of Willis.53 Therefore we assume that a different pathogenesis must explain predominance of left-sided acute ischemic stroke in our study. We speculate that, despite continuous heparinization during ECMO, thrombosis may occur on catheters lying in the aortic arch. Compensatory high flow through the left carotid and basilar arteries, with embolic complications, will tend to occur in areas of left brain arteries. Bulas and Glass54 discussed right hemisphere vulnerability. They stated that although there is discussion about whether or not there is structural vulnerability to the right hemisphere, there is evidence for vulnerability at a functional level. They identified 24 children with neuro-radiographically documented unilateral neonatal brain injury, and compared, at age of 5 years, the performance of children with left-sided lesions (n ¼ 12) with those having right-sided lesions (n ¼ 12) on selected tasks reported to be predominantly mediated by the left hemisphere (language comprehension and production and right hand function) or by the right hemisphere (visual pattern discrimination and left hand function). There was a significant association between the pattern of neuropsychological deficit and the side of lesion, such that 75% of the left-lesion group children were more likely to have lower scores on the left hemisphere testing items and 81% of the right-lesion group children were more likely to have lower scores for the right hemisphere test items. In their discussion, they concluded that the data demonstrate that the neuropsychological profile of the ECMO cohort seems to vary according to brain injury severity, rather than a
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dominance of functional deficits associated with the right hemisphere.
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series described by Hardart et al.65 besides lower gestational age, sepsis, coagulopathy, and acidosis were all associated with a higher incidence of intracranial hemorrhage.61
Timing of intracranial brain injury in relation to ECMO Biehl et al.55 studied the timing of intracranial hemorrhages in relation to the start of ECMO and found that 50% of ICH occurred in the first 24 h, 75% by 48 h, and 85% within 72 h of initiation of bypass. Others also found that the majority of cases of ICH occurred within 72 h after the start of ECMO.14,23,56–58 On the other hand, Bulas et al.11 found that the risk for ischemic lesions was not the greatest in the first days but increased with a longer ECMO run time. During ECMO, systemic heparinization is warranted and (small) existing hemorrhages may worsen and new ones develop, reason thus for repeated control.
Prematurity as a risk factor for brain injury It is most likely that the cerebral injuries that occur in ECMOtreated newborns originate from a combination of factors, namely pre-ECMO-, patient-, and disease related factors as well as factors related to the ECMO treatment itself. Two reviews describing these factors have been published recently.59,60 Despite the exclusion of small premature infants from ECMO, studies have shown that younger infants continue to have statistically significant increased risk of hemorrhage.11,20,23,61 Taylor et al.7 for instance found that in a series of 207 infants, preterm infants were at higher risk for developing intracranial abnormalities than term or near-term infants, 56% against 40%, respectively. We recently also demonstrated that the incidence of lesions was significantly higher in preterm (o37 weeks) compared with term infants (Z37 weeks), 28 of 89 (31.5%) versus 83 of 571 (14.5%), respectively (p o 0.01).23 The ELSO registry supports a worse outcome in preterm infants (o35 weeks) with 61% survival while it is 83% in term infants.3 These findings support the current practice of setting the age limit at 34 weeks' gestational age. Ramachandrappa et al.62 in a review of ELSO's registry data demonstrated that late preterm infants (34–36 weeks gestational age) had the highest mortality rate (26.2%) and highest incidence of IVH (12.3%) against 3.6% in full-term newborns. Although ECMO is generally not offered to infants below 34 weeks of gestation in view of the risk for ICH, the earlier mentioned Dutch cohort counted three infants treated under 34 weeks gestational age. Two of them indeed developed ICH.23 On the other hand, in an analysis of ECMO in preterm infants, Hirshl et al.63 demonstrated that survival tended to decrease with decreasing gestational age and that the incidence of ICH increased with decreasing gestational age. Interestingly, however, it was not possible to give a clear cut off point for gestational age above or below which survival and ICH incidence really differed. This would make a sharp limit of 34 weeks as the lower limit of treatment arbitrary. Infants with sepsis are also at high risk for ICH hemorrhage likely due to additional problems with coagulopathy.64 In a
Neuroimaging In general, head ultrasound (HUS) is used as the preferred technique for the routine detection of intracranial abnormalities in ECMO-treated newborns. Although the incidence of intracranial abnormalities is low in ECMO candidates, it is advised to perform a pre-ECMO HUS because the presence of a large ICH is a contraindication for ECMO initiation. HUS has been sensitive in the evaluation of large ICH. Bulas et al.11 demonstrated that over 90% of major ICH, lesions that most determine further treatment, could successfully be identified with HUS. As the risk of ICH is greatest in the first few days of ECMO, daily HUS has been recommended for the potential identification of a developing bleed. The question as to how often daily sonograms should be performed has been reviewed by Biehl et al.55 who found daily HUS cost-effective only during the first 3 days on ECMO. Large parenchymal hemorrhages are usually easily identified with HUS as focal regions of increased echogenicity of hypoechogenic areas due to decreased coagulation. As stated earlier, the general location of ICH is not in the germinal matrix as is seen in preterm infants. It is thus crucial to look carefully within the peripheral parenchyma and posterior fossa for hemorrhagic lesions. HUS is less useful for the detection of ischemic lesions. It is important to be aware that ischemic lesions before ECMO seem to be related to an increased risk of subsequent major intracranial complications.66 Several authors have demonstrated that CT scan can identify intracranial lesions that earlier were not seen with HUS, sometimes even major ones. Additional information was found with CT/MRI scans in 72– 93%. Especially infarctions, diffuse edema, and atrophy are lesions that were detected in CT scans/MRI in children with normal HUS.10,11,14,36,54,67–70 Recently, Rollins et al.71 studied 50 neonates with MRI done after ECMO, before discharge and compared the results with HUS done during ECMO. HUS was abnormal in 24% during ECMO whereas MRI after ECMO was abnormal in 62%. All patients with abnormal HUS had an abnormal MRI. However, of the patients with a normal HUS, 50% had an abnormal MRI. Most of the lesions unrecognized on HUS were nonhemorrhagic.
Outcome What is generally known about long-term follow-up? Taking into account the relatively high rate of neuroimaging abnormalities that are present in ECMO-treated neonates, neurodevelopmental outcome studies are important to define the impact on later functioning. A more extensive overview of outcome data is described elsewhere in this journal. This
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chapter focuses on the association of neuroimaging abnormalities and neurodevelopmental outcome. Mild to major neurodevelopmental impairment is described in 15–25% of neonatal ECMO survivors.6,9,12,72–79 Impairment involves abnormal cognitive and psychomotor development. However, more subtle signs of neurological involvement appear to occur at higher rates. Learning problems at school age appear to be as high as 50% and parents report behavioral problems more often than in normal controls. By the end of the first grade, even non-retarded ECMO children are still more than twice as likely to be receiving special educational services.9,12,73,75–77,80,81 The specific impact of perinatal brain injury in ECMO patients on neurodevelopment was the subject of many studies. In the 1980s, Taylor et al.25 used the neuroimaging score described above (Table 1) to study the relation between this score and neurodevelopment as tested with mental and psychomotor development index of the Bayley Scales of Infant Development (BSID) in 46 newborns with mean age of 11.8 months (range: 6–16 months). He reported that infants with normal development had more favorable neuroimaging scores than infants with delayed development and that there was a significant inverse correlation between the neuroimaging score and mental and psychomotor development indexes. However, it was not possible to predict individual outcomes based on neuroimaging scores because there were children with low scores and adverse outcome but also with high scores and normal outcome. This suggests that there are mechanisms in the infantile brain to compensate for structural damage.54 This relative neuroplasticity of the immature brain has also been confirmed by the study by Bulas and Glass54 who showed that 6 of 14 (43%) and 8 of 12 (67%) with severe and moderate intracranial lesions on HUS and CT in the neonatal period, respectively, had developed without significant disability at the age of 5 years. In another study by von Allmen et al.66 they studied 42 1year-old ECMO survivors. Some kind of neuroimaging abnormality during ECMO was seen in 78% of the infants with neurodevelopmental delay; this was 28% in the subgroup of infants with normal development. IVH, especially major lesions, was associated with poor neurodevelopmental outcome; it was present in 56% of infants with developmental delay in 26% of the suspect group and in 20% of the infants who had normal development at 1 year. Griffin et al.21 showed that absence of ICH, cerebral infarct, or cerebral atrophy correlated with normal short-term neurodevelopment in 22 newborns evaluated with BSID at 3, 6, 12, and 24 months. Vaucher et al.78 studied a large cohort of 139 ECMO survivors aged 4–24 months looking at neuromotor, developmental, and neurosensory outcome. Neuromotor outcome was categorized as normal, suspect (hypotonia, hypertonia, or asymmetry), or abnormal (cerebral palsy); developmental outcome was defined as normal when motor and mental developmental scores were 483 and neurosensory outcome was considered abnormal in children with hearing loss who required amplification or in those with severe visual impairment. Brain abnormalities were classified as normal, mild (mild ventriculomegaly, grade I or II IVH, and subarachnoid hemorrhage), moderate (moderate ventriculomegaly and
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grade III IVH), and severe (severe ventriculomegaly, porencephaly, grade IV IVH, cerebral infarction, and cystic leukomalacia). Vaucher showed that moderate or severe neuroimaging abnormality during ECMO was an independent predictor for suspect or abnormal neurologic outcome at age over 12 months (OR ¼ 5.10, 95% CI: 1.55–17.09), for cerebral palsy (OR ¼ 10.30, 95% CI: 1.56–67.87), for motor developmental index o84 (OR ¼ 6.30, 95% CI: 1.72–23.32), and for adverse neuromotor, neurosensory, or developmental outcome (OR ¼ 6.43, 95% CI: 1.89–21.89). Glass et al.12 published a large follow-up study in 152 children aged 5 years and additional data were published in a second paper.54 Extensive neuropsychological and neurobehavioral testing was done. Outcome was related to the severity of brain injury on neonatal neuroimaging for which the earlier described neuroimaging score was used, based on HUS and CT scan made within 3 weeks after ECMO, and imaging was scored as no lesion (in 88 children), mild lesion (in 38 children), moderate lesion (in 12 children), and severe lesion (in 14 children). The outcome measures included intellectual status, pre-academic skills, neuropsychological deficits, and neuromotor dysfunction. One or more major disability conditions were seen in 17% of children, of whom 14% had mental retardation or a severe learning disability and 5% had a motor disability. Severity of the injury expressed as a higher neuroimaging score was associated with the presence of disability at the age 5 years. The prevalence of any kind of disability ranged from 10% in ECMO survivors without intracranial lesions up to 57% in those with severe abnormalities. The odds ratio for disability at age 5 years after moderate or severe lesion was 26.00 (95% CI: 2.6– 263.0) and 69.33 (95% CI: 7.3–653.9), respectively. Even children with mild brain injuries had lower IQ scores relative to ECMO children without an identified brain injury. Both of these ECMO subgroups demonstrated mild but consistent functional deficits relative to the normal control group of healthy children. The grip strength (left hand and right hand) and dexterity (left hand) were significantly related with injury severity. The fact that a large proportion of children with moderate to severe neuroimaging abnormalities develop without significant disabilities suggests that neuroimaging in the neonatal period may be helpful to predict neurodevelopmental outcome but long-term follow-up is still important. Moreover, despite normal intelligence, many children may experience (subtle) learning disabilities, which will be discussed in another chapter.82 Hahn et al.15 and Bulas et al.26 state that the risk of adverse neurodevelopment outcome might be more related to major non-hemorrhagic lesions or combined lesions than to major hemorrhagic lesions. A few studies, however, did not reveal a relation between neuroimaging results and neurodevelopmental outcome. In their study on 31 newborns aged 6 and 12 months, Lago et al.44 found no relation between the presence of major brain lesions including parenchymal hemorrhages, infarctions or combinations, and Bayley test scores. However, enlarged cerebrospinal fluid spaces were associated with lower motor and performance developmental indexes. Eight patients in the study by Glass et al.12 had post-decannulation CT scan
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evidence of widened interhemispheric fissure. The mean fullscale IQ score was 84 for these children, and all 8 of them had lower verbal than performance IQ scores. This might suggest that the presence of a widened interhemispheric fissure may not be benign. The study by Rollins et al.71 also found no relation between neurodevelopmental index and enlargement of subarachnoid space and also between neurodevelopmental impairment and findings on HUS or MRI. Rollins questioned the predictive value of neuroimaging results after ECMO for developmental outcome. This because in the study by Glass et al.12 43% of children with severe and 67% with moderate brain injury on neuroimaging were later noted to have no disability at 5-year follow-up. Furthermore, Lazar et al.10 found that 13.5% had delayed neurological development despite no evidence of anatomic injury on serial HUS or follow-up imaging.
Conclusion Intracranial abnormalities, hemorrhagic and non-hemorrhagic, are the major complications of ECMO in newborns. They do occur in a substantial number of these infants and influence survival and affect later neurodevelopmental outcome. On the other hand, some children with severe intracranial injuries have a normal development suggestive of plasticity of the brain. To investigate in detail the consequences of brain damage in ECMO-treated infants, adequate longterm, structured follow-up in large patient groups is necessary. As such, it is important to understand the underlying pathophysiologic mechanisms that are involved in the etiology of brain injury.
re fe r en ces
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