Journal of Perinatology (2007) 27,65–67 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 www.nature.com/jp PERINATAL/NEONATAL CASE PRESENTATION Non-sinus bradyarrhythmias in very low birth weight infants

YD Gamble, WP Lutin and OP Mathew Department of Pediatrics, Sections of Neonatology and Pediatric cardiology, Medical College of Georgia, Augusta, GA, USA

min and oxygen saturation less than 85% were considered Transient occur frequently in preterm infants with apnea of clinically significant and further reviewed. Segments of the stored prematurity. However, occurrence of non-sinus bradyarrhythmias in very 24-h waveforms meeting one or both criteria were displayed, low birth weight (VLBW) infants has received very little attention. This case amplified if necessary and analyzed during the study period of 6 series documents transient bradyarrhythmias in VLBW infants. Most months. Isolated abnormal beats such as premature atrial and frequently observed was a non-sinus atrial rhythm followed by ventricular contractions were not evaluated. Only periods without junctional escape rhythm. Ventricular rhythm with wide QRS complexes artifacts were considered for analysis. Periods with movement occurred rarely. The majority of these episodes occurred in the absence of artifacts as indicated by changes in baseline, lack of clarity of EKG oxygen desaturation. Increase in vagal tone is presumed to mediate this signals due to increased muscle activity or loss of signal were response. excluded from analysis. Our ability to amplify the signal assured Journal of Perinatology (2007) 27, 65–67. doi:10.1038/sj.jp.7211623 that the quality of EKG signal was adequate for the intended Keywords: cardiac arrhythmia; prematurity; aphea purpose. Episodes of sinus , once confirmed, were not subjected to further review. Non-sinus bradyarrhythmias were classified as non-sinus atrial, junctional, ventricular and other. We Introduction also extracted demographic variables, neonatal risk factors, None of the major studies on apnea and bradycardia in preterm medications and diagnosis from individual medical records. infants1–3 have reported the occurrence of non-sinus bradyarrhythmias, although the occurrence of supraventricular escape rhythm during transient episodes of bradycardia has been Results 4 documented. Consequently, this observation has received very little Forty-one episodes of non-sinus bradyarrhythmias were attention among neonatologists and other physicians caring for documented in 11 LBW infants over a 6-month period (GA very low birth weight (VLBW) infants. In this case series, our 28.1±2.7 weeks(mean±s.d.); BW 1058±233 g). Their median experience with non-sinus bradyarrhythmias among VLBW infants Apgar scores were 7 and 8 at one and 5 min, respectively. The during a 6-month period is reported. median postnatal age at the time of bradycardia recordings was 15 days. Four infants were male and seven were females. None of the infants was receiving mechanical ventilation or nasal continuous Methods positive airway pressure (CPAP) at the time of evaluation; seven Heart rate, respiration and oxygen saturation are routinely infants were receiving oxygen through nasal cannula. Ten infants monitored and displayed on the bedside monitors and the were being treated with caffeine for apnea of prematurity. None of waveforms are captured and stored on a dedicated networked the infants were being bottle-fed during the study period. The mean computer for 72 h utilizing Neoscan software (Spacelabs medical, number of non-sinus bradyarrhythmias in these infants was Redmond, WA, USA). The frequency of sampling of 3.7±2.7 per 24 h (range 1–6). Both atrial and ventricular Electrocardiogram (EKG) signal is 224 Hz. Following Human dysrhythmias were observed. A non-sinus atrial rhythm was the Assurance Committee approval, cardiorespiratory waveforms were most frequently observed arrhythmia. This type of arrhythmia was analyzed as a part of bradycardia and desaturation protocol in seen initially in 12 episodes (Figure 1), which progressed to a VLBW infants. Only non-intubated preterm infants (p32 weeks junctional rhythm in three episodes. Junctional rhythm, with gestational age (GA)) were evaluated. Heart rate below 100 beats/ absent P waves and a narrow QRS complex, was the primary arrhythmia in 10 episodes. Retrograde atrial conduction was seen Correspondence: Dr OP Mathew, Department of Pediatrics, Section of Neonatology, Medical in three episodes with junctional rhythm (Figure 2). Ventricular College of Georgia, 1120 15th Street BIW 6033, Augusta, GA 30912, USA. E-mail: [email protected] rhythm with wide QRS complexes occurred in four episodes Received 18 May 2006; revised 7 September 2006; accepted 22 September 2006 (Figure 3). Twelve episodes were categorized as other and consisted Non-sinus bradyarrhythmias YD Gamble et al 66

bradycardia. A change in P wave morphology with shortening of PR interval was the most commonly observed EKG change, which progressed in some cases to a junctional escape rhythm with or without retrograde P wave conduction. The results of the present study are consistent with our current understanding of bradyarrhythmias in the fetus, preterm and term neonates.5–7 7 Figure 1 Note the development of non-sinus atrial rhythm during the Southall et al. monitored electrocardiograms continuously for episode of bradycardia. Decreasing PR interval can be seen during the 24 h in 134 full-term neonates. Junctional escape rhythm was episode. observed in 25 infants. Sinus arrest was observed in 7% of infants. Valimaki and Tarlo6 reported nodal escape beats in 2/30 preterm infants monitored. The 11 VLBW infants in the present study constitute approximately 15% of VLBW infants admitted to our unit during the study period. Our data underestimate actual prevalence, since all our VLBW infants were not evaluated. Andriessen et al.4 documented the occurrence of supraventricular escape rhythm in 8/19 (42%) preterm infants during transient episodes of bradycardia. This is consistent with our own preliminary data from Figure 2 Development of junctional rhythm with narrow QRS an ongoing study showing the majority of VLBW infants develop complexes with retrograde conduction of P wave. Note the sudden these bradyarrhythmias.8 Yet, classical clinical studies on apnea decrease in heart rate from approximately 150/min during the sinus and bradycardia have not reported non-sinus bradyarrhythmias.1–3 rhythm to 70 over a 2-s period. The reason for the discrepancy is unclear. Short recording time as well as the difference in methodology presumably account for this difference. Most polygraphic studies were being recorded at speeds that preclude any detailed analysis of the EKG. On the other hand, the long computerized monitoring period coupled with our ability to amplify the signal and expand the time base enabled us to detect and analyze these episodes in greater detail. Lack of movement artifact during the analyzed events makes it likely that these events occurred primarily during sleep or quiet wakefulness. However, because of the lack of sleep state monitoring, this latter conclusion Figure 3 changes to a junctional rhythm with narrow should be interpreted with caution. QRS complex for one beat followed by the development of wide QRS Occurrence of these escape rhythms during transient episodes of complexes for the next three beats. bradycardia in VLBW infants may be explained on the basis of physiological changes during development. If the sinus node is suppressed, an escape depolarization will originate from the next primarily of sinus arrest. Seven infants developed more than one highest hierarchical tissue which is the atrial myocardium. Atrio- type of arrhythmia. Instantaneous heart rate (based on RR ventricular (AV) nodal escape rhythm develops when both sinus interval) was generally less than 75 beats/min, often in the 40–60 nodal tissue and atrial myocardium are suppressed. Myocardial range at the time of arrhythmia and was not markedly different for cells in the chick embryo resemble cells in the adult sinus node,9 different types of . Oxygen saturation recordings were indicating that both atrial and ventricular cells possess available in 24 episodes. The mean saturation at the onset of automaticity when they are young. One can only speculate on the arrhythmia was 90.5±10.9%. The majority of these episodes etiology of these transient bradyarrhythmias. All infants had occurred in the absence of desaturation; in fact, 20 episodes had clinically significant apnea of prematurity, and all, but one, were oxygen saturation levels >90% and two had oxygen saturation being treated with caffeine. None of these infants had hyperkalemia levels between 85 and 90%. Only in two episodes were oxygen or being treated with drugs such as calcium channel blockers or saturation levels below 85%. had evidence of clinically significant ischemic events that could be implicated in the development of bradyarrhythmias. Valimarki and Tarlo6 investigated the relationship between cardiac arrhythmia Discussion and apnea in neonates. These investigators observed that nodal Our results indicate that non-sinus bradyarrhythmia is not an escape was associated with apnea but not its duration. This finding infrequent occurrence among VLBW infants with apnea and suggests that hypoxia may not be responsible for the development

Journal of Perinatology Non-sinus bradyarrhythmias YD Gamble et al 67 of bradyarrhythmia, which is supported by our finding that the vast 2 Henderson-smart DJ, Butcher-Puech MC, Edwards DA. Incidence and majority of transient arrhythmia was developed in the absence of mechanism of bradycardia during apnoea in preterm infants. Arch Dis Child oxygen desaturation. Similar findings were documented by 1986; 61: 227–232. Andriessen et al.4 as well. If so, what is the likely mechanism for its 3 Upton CJ, Milner AD, Stokes GM. Episodic bradycardia in preterm infants. development? The relative immaturity of sympathetic efferents Arch Dis Child 1992; 67: 831–834. compared to parasympathetic efferents predisposes the newborn 4 Andriessen P, Koolen AM, Bastin FH, Lafeber HN, Meijler FL. human infant and experimental animals to bradycardia.10 In this Supraventricular escape rhythms during transient episodes of bradycardia in preterm infants. Cardiol Young 2001; 11: 626–631. context, it is interesting to note that bradycardia, with or without 5 Park MK. Pediatric Cardiology for Practitioners, 4th edn. Mosby Inc.: escape beats, can be induced in preterm infants by compressing the St Louis, 2002. 11 fontanel, the eye ball or the carotid sinus. Increased negative 6 Valimaki I, Tarlo PA. Heart rate patterns and apnea in newborn infants. Am pressure changes during obstructed inspiratory efforts are known to J Obstet Gynecol 1971; 110: 343–349. increase the afferent activity of the superior laryngeal nerve, a 7 Southall DP, Richards J, Brown DJ, Johnston PG, de Swiet M, Shinebourne branch of the vagus nerve,12 which has potent inhibitory effects on EA. 24-Hour tape recordings of ECG and respiration in the newborn infant cardiorespiratory control.13 The vast majority of episodes of apnea with findings related to sudden death and unexplained brain damage in in preterm infants are mixed or obstructive in nature.14 infancy. Arch Dis Child 1980; 55: 7–16. Furthermore, the site of obstruction in the vast majority of episodes 8 Gamble Y, Mathew OP. Bradyarrhythmias in premature infants: does vagal is at the level of the pharynx.15 Occurrence of nocturnal inhibitory reflexes play a role [abstract]. PAS 57: 1233. arrhythmias in adults with obstructive sleep apnea is well 9 Sperelakis N, Pappano AJ. Physiology and pharmacology of developing heart documented.16 Hence, the sudden development of bradyarrhythmia cells. Pharmacol Ther 1983; 22: 1–39. 10 Church SC, Morgan BC, Oliver Jr TK, Guntheroth WG. Cardiac arrhythmias (see Figure 2) and the pattern of its development is consistent with in premature infants: an indication of autonomic immaturity? J Pediatr transient increase in vagal tone. 1967; 71: 542–546. Congenital long QT syndrome is associated with life-threatening 11 Phillips SJ, Agate Jr FJ, Silverman WA, Steiner P. cardiac reactivity in arrhythmias. Defects in the cardiac sodium channel (SCN5A premature infants. Biol Neonat 1964; 6: 225–249. mutations), which account for 5% of this syndrome, have been 12 Mathew OP, Sant’Ambrogio G, Fisher JT, Sant’Ambrogio FB. Respiratory implicated in a subset of sudden infant death syndrome (SIDS) afferent activity in the superior laryngeal nerves. Respir Physiol 1984; 58: victims.17 Ackerman and co-workers have also provided molecular 41–50. evidence implicating mutations of K channel in SIDS victims.18 We 13 Haddad GG. Respiratory Control in the Newly Born Infant: Comparative believe that the transient bradyarrhythmias reported here reflect Physiology and Clinical Disorders. In: Mathew OP (ed). Respiratory Control immaturity of the cardiorespiratory control systems and may be a and Disorders in the Newborn. Marcel Dekker Inc: New York, 2003, marker of delayed maturation of ionic channels in the heart. pp 1–15. Whether a delay in maturation of these channels predisposes the 14 Miller MJ, Martin RJ. Pathophysiology of apnea of prematurity. In: Polin RA, Fox WW, Abman SH (eds). Fetal and Neonatal Physiology. Saunders: infants to life-threatening events or SIDS is not known. Since Philadelphia, 2004, pp 905–918. preterm infants constitute a group of infants at high risk for SIDS, 15 Mathew OP, Roberts JL, Thach BT. Pharyngeal airway obstruction in preterm it is tempting to postulate the development of fatal infants during mixed and obstructive apnea. J Pediatr 1982; 100: 964–968. bradyarrhythmia during sudden surge in vagal tone among infants 16 Mehra R, Benjamin EJ, Shahar E, Gottlieb DJ, Nawabit R, Kirchner HL et al. with maturational delay of cardiac ionic channels. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006; 173: 910–916. 17 Ackerman MJ, Siu BL, Sturner WQ, Tester DJ, Valdivia CR, Makielski JC et al. Postmortem molecular analysis of SCN5A defects in sudden infant death References syndrome. JAMA 2001; 286: 2264–2269. 1 Dransfield DA, Spitzer AR, Fox WW. Episodic airway obstruction in 18 Tester DJ, Ackerman MJ. Sudden infant death syndrome: how significant are premature infants. Am J Dis Child 1983; 137: 441–443. the cardiac channelopathies? Cardiovasc Res 2005; 67: 388–396.

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