Published online May 1, 2006
PEDIATRICS
Vol. 117
No. 5
May 2006, pp.
1814-1817
(doi:10.1542/peds.2005-1992)
Sudden Cardiac Arrest in an Intubated Premature Infant With Cerebellar and Brainstem Injury: Is There a Link?
R. Victoria Chen, MD and
Jeffrey Perlman, MB, ChB
Department of Pediatrics, Weill Medical College of Cornell University, New York, New York
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ABSTRACT
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The ventilated premature infant frequently exhibits unprovoked desaturation episodes accompanied by bradycardia. In most instances, these episodes are short-lived and recover spontaneously or with minimal interventions. However, in some infants these episodes may be more profound and require substantial interventions to restore cardiorespiratory status. Here we present the case of a ventilated premature infant who had experienced prolonged, multiple daily desaturation episodes accompanied by bradycardia that required significant interventions. Postoperatively, after placement of a tracheotomy and despite a patent airway, the infant developed acute bradycardia that progressed rapidly to sudden death. At autopsy, significant cerebellar and brainstem injury was noted. We hypothesize that the specific cerebellum and brainstem injury may have contributed to autonomic dysfunction and sudden death.
Key Words: cardiopulmonary resuscitation • premature infant • cerebellar injury
Abbreviations: DOL, day of life • SIDS, sudden infant death syndrome
The ventilated premature infant frequently exhibits unprovoked desaturation episodes accompanied by bradycardia. Mostly, these episodes are of short duration, and infants recover spontaneously or with minimal interventions. However, in some infants, these episodes may be more significant and require substantial interventions to restore cardiorespiratory status. Here we present the case of a ventilated premature infant who had experienced prolonged, multiple daily desaturation episodes accompanied by bradycardia that required significant interventions. Postoperatively, after placement of a tracheotomy and despite a patent airway, the infant developed acute bradycardia that rapidly progressed to sudden death. At autopsy, significant cerebellar and brainstem injury was noted. We hypothesize that the specific cerebellum and brainstem injury may have contributed to autonomic dysfunction and the sudden death.
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CASE REPORT
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B.H. was a 30-week appropriate-for-gestational-age 1586-g premature male infant born to a 28-year-old gravida 2 para 0 mother after a pregnancy complicated by preterm labor. The infant was delivered vaginally, and the Apgar scores at 1 and 5 minutes were 9 and 9, respectively. The early clinical course was characterized by respiratory distress syndrome, for which the infant received surfactant, and seizure-like activity on day of life (DOL) 1 that was treated with phenobarbital. A cranial sonogram performed on DOL 2 revealed a grade 2 intraventricular hemorrhage. The subsequent course was pertinent for continued ventilator requirement. Because of the inability to wean from the ventilator, the infant was transferred to this institution on DOL 75. On admission, the upper airway was examined by direct laryngoscopy, and marked vocal cord swelling, which involved the subglottic area as well, was noted. The edema was attributed to possible gastroesophageal reflux and the prolonged intubation. The infant was started on antireflux therapy and transpyloric feedings. The respiratory course was characterized by frequent desaturation episodes that often were acute and unprovoked and often accompanied by bradycardia. Many of these episodes required substantial interventions (ie, bag/mask ventilation, replacement of the endotracheal tube, and aerosol therapy to restore cardiorespiratory status). The infant underwent 2 additional cranial sonograms; the first was interpreted as normal, and the second revealed small areas of increased echogenicity in the basal ganglia as well as mild ventriculomegaly. An electroencephalogram performed on DOL 84 was interpreted as normal. An ophthalmic examination revealed bilateral optic atrophy. The neurologic examination during this time was significant for diffuse peripheral hypertonia and hyperreflexia. On DOL 98, the patient went to the operating room for evaluation of the airway by direct laryngoscopy and bronchoscopy. The findings included laryngeal edema involving the vocal folds, epiglottis, and arytenoids and bilateral vocal cord granulation, but normal motility of the cords was noted. There was no subglottic narrowing or laryngomalacia, and the trachea was patent. A tracheotomy was performed, and a 3.0 tracheostomy tube was inserted. Approximately 12 hours later, while on the ventilator and in a quiet state and immediately after a suctioning procedure, the infant developed an episode of acute desaturation and bradycardia, with his heart rate decreasing to 80 beats per minute, that was unresponsive to positive-pressure ventilation. The tracheotomy was evaluated emergently by an otolaryngologist and was found to be appropriately positioned and patent. On auscultation of the heart immediately after the fiber-optic examination, it was noted that the infant had pulseless electrical activity. He was administered cardiorespiratory resuscitation and given 2 doses of epinephrine but was unresponsive and expired.
At autopsy, the endotracheal tube was within the trachea and was patent. The lung parenchyma showed some patchy firm areas of consolidation but the bronchial, pulmonary trees, and lung lobation appeared normal in situ. There was chronic ischemic cerebral damage including organizing infarction involving predominantly the distribution of the posterior circulation (ie, brainstem, thalamus, cerebellum, and occipital lobe). The brain was significant for marked atrophy of the right lateral cerebellar hemisphere, which was approximately half the size of the left hemisphere. There were organizing infarcts in the areas of the medulla, thalamus, and right occipital lobe consistent with chronic ischemic damage. The areas particularly affected included the right inferior olive and pyramid. The contralateral inferior olive also showed subtotal gliosis and neuronal loss.
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DISCUSSION
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This case demonstrates an acute fatal bradyarrhythmia in a ventilated premature infant in the absence of airway obstruction and in whom significant cerebellum and brainstem injury was demonstrated at autopsy. We postulate that the cerebellar and brainstem injury may have contributed to the sudden death via a mechanism of autonomic dysfunction.
Premature infants have been noted to be at higher risk for sudden death compared with term infants both in isolation and in association with underlying pathologic states, in particular bronchopulmonary dysplasia.1 Sudden infant death syndrome (SIDS) beyond the neonatal period is the most common cause of death in infancy; however, the mechanism(s) remains largely unknown. There are some clearly identified epidemiologic risk factors such as sleeping prone, sleeping on soft bedding, and prenatal and postnatal cigarette smoke exposure.2,3 Less well-documented associations include high core or environmental temperatures and profuse sweating.4,5 Despite extensive research, the precise mechanisms that link these risk factors to adverse physiologic responses so as to increase the risk for sudden death remain unclear. One pathway that has been suggested includes the development of sleep apnea, airway occlusion, and failure of the arousal responses.6 In our case, the infant was being ventilated, and there was no antemortem or postmortem evidence of airway obstruction. Thus, the acute fatal bradycardia with progression to pulseless electrical activity is likely secondary to another mechanism.
Recent experimental and clinical studies have implicated disordered autonomic control as a novel potential mechanism of sudden death. This concept of autonomic dysfunction stems from data by Ledwidge et al7 obtained during a sleep study of a 5-month-old infant with a history of recurrent acute life-threatening events. During the study the infant never developed apnea, which made airway dysfunction an unlikely cause of the acute life-threatening events. Rather, there was a failure of the infant's compensatory mechanisms to maintain blood pressure and heart rate parameters at baseline when the body was changed from the horizontal to the upright position during deep sleep. Thus, the infant developed profound hypotension and bradycardia with change in position, which ultimately proved to be fatal. Home recordings of 5 other infants who died suddenly from SIDS also showed sudden bradycardia rather than apnea as the predominant final event.8 Autonomic dysfunction has often been described in adults and is attributed to an inappropriate peripheral vasomotor response to a postural challenge. Thus, in the presence of a reduction in central venous return, blood pressure continues to fall without a compensatory tachycardia because of poor peripheral vasomotor control.9 This state is referred to as neurocardiogenic or vasovagal syncope.
A major area of interest in SIDS has been to determine which specific brain structures are recruited to restore either breathing or to help the body recover from severe hypotension. Arousal is the main mechanism for recovery with these functions immediately restored, mediated by compensatory forebrain pathways. To assist both respiratory and cardiac function, and particularly when arousal does not occur, other neural areas, particularly in the brainstem and cerebellum, seem to assume this role. The evidence for this sequence stems from functional magnetic resonance studies in normal subjects and in children afflicted with congenital central hypoventilation syndrome, as well as experimental electrophysiological recordings. Indeed, experimental data suggest that cerebellar mechanisms are particularly recruited during extreme challenges rather than during routine regulatory processes.10–12 Furthermore, functional MRI studies have shown that ventilatory and pressor challenges elicit significant changes in regional signal intensity in areas within the cortex, hypothalamus, and cerebellum and pons.12 Within the cerebellum, several areas have been shown to be more important in the regulation and modulation of response to both blood pressure and oxygen tension changes. In particular, the fastigial nucleus seems to be crucial. Thus, bilateral lesions in this region lead to a fatal decompensation after the lowering of blood pressure or apnea in animal models.13 It has been shown also that lesions in this area result in profound reduction in respiratory responses such as decreased minute ventilation, tidal volume, respiratory frequency, and peak of integrated diaphragm activity in response to hypoxia.13 It is postulated that the fastigial nucleus facilitates and/or disinhibits the respiratory response to hypoxia via interactions with peripheral chemoreceptor input such as from the carotid body. The compensatory response to blood pressure changes is likely mediated through afferent activity from the inferior olivary nucleus. The input comes via Purkinje cells to the fastigial nucleus of the cerebellum, which then sends output impulses to the vestibular sympathetic pathways and somatomotor regions of the brain.13–15
The influence of the cerebellum is particularly important during certain vulnerable states such as rapid-eye-movement sleep, when there is a loss of descending forebrain influences on brainstem cardiovascular and breathing mechanisms.16 The importance of body position and control of the autonomic nervous system for maintaining homeostasis during sleep has been demonstrated by Kleitman.17
This case demonstrated striking abnormalities in the areas that have been implicated as being crucial for cerebellar modulation of cardiovascular control. Key affected areas included both left and right olives, with one side showing an organizing infarction and the contralateral area demonstrating subtotal gliosis and neuronal loss. The inferior olive provides major input to the cerebellum. Autopsy reports in some infants whose deaths were attributed to SIDS have also demonstrated significant gliosis, particularly in the inferior olive.18 In addition, cases of profound respiratory dysfunction or congenital apnea have been linked to inferior olive hypoplasia.19 Finally, clinical and neuropathological studies in 5 infants have suggested a relationship between brainstem and/or cerebellar infarctions and respiratory-control abnormalities during infancy that resulted in sudden death.20 It is possible that in this case a simple event such as positioning for suctioning may have triggered a cardiovascular event with bradycardia for which the infant was unable to compensate secondary to the profound cerebellar/brainstem injury.
The potential importance of these observations as it relates to the very low birth weight infant stems from the recent recognition of vulnerability of the cerebellum to hypoxia and/or ischemia. Thus, MRI performed at term before discharge in very low birth weight infants demonstrates smaller cerebellar volumes, as compared with term controls, as well as infarction and distant hemorrhage in some of the infants.21 It is tempting to postulate that evolving cerebellar injury may contribute to the repeated acute and often unprovoked desaturation episodes as well as the bradycardia observed in a substantial number of ventilated premature infants, as in our case.
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FOOTNOTES
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Accepted Oct 24, 2005.
Address correspondence to Jeffrey Perlman, MB, ChB, Department of Pediatrics, Weill Medical College of Cornell University, 525 E 68th St, New York, NY 10021. E-mail: jmp2007{at}med.cornell.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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