Sleep apnoea profile in preterm infants recovering

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1 Arhives of Disease in hildhood, 1985, 6, Sleep apnoea profile in preterm infants reovering from respiratory distress syndrome K H P BENTELE, M ALBANI, BUDDE, AND F J UniversitatsKinderklinik, HamburgEppendorf, Germany SHULTE SUMMARY Polygraphi reordings ere made on 1 preterm infants reovering from respiratory distress syndrome and 1 healthy preterm ontrol infants at 4, 5, and 64 eeks' oneptual age to study the influene of respiratory distress syndrome on the development of the sleep apnoea profile. To signifiant differenes ere found: infants ith respiratory distress syndrome not only had a loer inidene of nonobstrutive apnoea and periodi breathing at 4 eeks but also a persistently higher inidene of obstrutive and mixed apnoea at 5 and 64 eeks' oneptual age; the latter finding being related to nonrapid eye movement sleep only. While the loer inidene of both types of apnoea at 4 eeks suggests an advaned maturation of respiratory drive, the persistene of obstrutive and mixed apnoea related to nonrapid eye movement sleep may reflet the impat of respiratory distress syndrome on airay strutures. Prematurity and lo birtheight are knon to be distress syndrome on the development of respiratory assoiated ith an inreased inidene of the sudden ontrol, hih in ertain aspets is mirrored by the infant death syndrome (SIDS).1 When respiratory sleep apnoea profile,7 polygraphi reordings ere distress syndrome in preterm infants is ompliated obtained at 4, 5, and 64 eeks' oneptional age by bronhopulmonary dysplasia, the risk of sudden in to groups of preterm infantsone group ho infant death is reported to be further inreased, ere healthy and the other reovering from respiratory distress syndrome. resulting in a umulative inidene of up to 34%.3 This inreased rate of mortality from sudden infant death syndrome in preterm infants reovering from Patients and methods respiratory distress syndrome and bronhopulmonary dysplasia, hoever, annot be explained solely Infant populations. The study group omprised 1 on the basis of various lung funtion abnormalities. preterm infants reovering from respiratory distress These abnormalities, although more pronouned syndrome, defined by linial and radiologial ith bronhopulmonary dysplasia, ere found in riteria. A synopsis of these infants' birth harateristis is given in Table 1. The parameters of preterm infants ith and ithout evidene of this disorder after respiratory distress syndrome.4 mehanial ventilation (expressed as mean and Thus, in addition to an impairment of upper and loer airays, disturbed or possibly defetive development of the regulatory mehanisms of Table 1 Birth harateristis of healthy preterm infants breathing needs onsideration in preterm infants and those reovering from respiratory distress surviving respiratory distress syndrome. It has been syndrome (RDS) suggested that prematurity per se, refleted in a Preterm ith RDS Healthy preterm partiular and different development of the sleep (n= 1) (n=1) apnoea profile during the first six months of life is Gestational age (ks). assoiated ith a maturational delay of respiratory mean (range) 3 (834) 35 (336) drive.5 Furthermore, in omparison ith preterm Birtheight (kg). mean infants ithout apnoea, those ith apnoea ere (range) 154 (1.15) 1 (17348) Apgar sore at 5 min=6 6 found to exhibit not only immature respiratory aesarian setion 5 4 reflexes but also redued respiratory entre Tin birth 4 9 Sex, boy:girl 5:5 6:6 ativity.6 To study the influene of respiratory 547 Arh Dis hild: first published as 1.36/ad on 1 June Donloaded from on November 18 by guest. Proteted by opyright.

2 548 Bentele, Albani, Budde, and Shulte (range)) ere as follos: total duration of intubation, 16 (3 to 43) days; ontrolled ventilation, 5.5 (1 to 14) days; intermittent mandatory ventilation and ontinuous positive airay pressure, 1 (1 to 8) days; and inspiratory oxygen onentration exeeding *4, 6 ( to 336) hours. Three of the preterm infants ere small for gestational age (birtheight belo 3rd entile); four presented ith linial and ehoardiographi signs of a patent dutus arteriosus, hih as ligated in to; seven had reeived antibiotis beause of suspeted infetion until ultures proved to be negative; seven had reurrent sleep apnoea or bradyardia, or both, for some days after extubation; and to developed bronhopulmonary dysplasia. At the time of the first reording all of the 1 infants ere breathing spontaneously and did not require supplementary oxygen. None had reeived theophylline or affeine during the eek before the first reording. All infants ere free of signs of intraranial haemorrhage and had normal real time ultrasound sans. The ontrol group omprised 1 healthy preterm infants hose birth harateristis are also shon in Table 1. Exept for prematurity none had other peri or postnatal ompliations. The study of this ontrol group as also part of a larger projet hih, in some aspets, has been reported elsehere.5 Four ontrol infants ere lost to follo up at 5 eeks (1) and 64 eeks (3), and to infants died from SIDS (both ere tins, seond in birth order, and had not at that time been under home apnoea surveillane). Informed onsent as obtained from the parents of all infants inluded in the study. Parents ere alloed to feed their infants before and oasionally during the reordings. Methods. All infants underent polygraphi sleep reordings during at least one omplete sleep yle. A detailed desription of our reording tehniques has been given in previous reports First reordings ere obtained ithin the eek of the expeted date of delivery, alulated from the first day of the mother's last menstrual period. While at 4 eeks' oneptual age reordings ere made either late in the morning or early in the afternoon; at 5 and 64 eeks' oneptual age all infants ere investigated at the same time of day; that is beteen 8 pm and midnight. All reordings ere analysed visually and the different types of sleep apnoea as ell as the episodes of periodi breathing ere identified in relation to sleep states aording to established riteria desribed in detail previously.5 81 Undifferentiated sleep as not evaluated in respet of the different apnoea variables, sine in most instanes it as less than 1 minutes of the total sleep time reorded. Apnoea density as alulated by dividing the total amount of a given type of apnoea by the total time spent in a speifi sleep state multiplied by 1. This gave the apnoea density for 1 minutes rapid and nonrapid eye movement sleep separately. In this ay the density of periodi breathing related to sleep state as also obtained. Duration of the different types of apnoea and episodes of periodi breathing ere alulated by dividing the total time spent in a speifi type of apnoea or in periodi breathing by the time spent in a speifi sleep state multiplied by 1. Mean duration of a given type of apnoea or episodes of periodi breathing as alulated by dividing the total duration of apnoei episodes during a speifi sleep state by the total number of these events. Due to the ide intersubjet variation and obviously uneven distribution of the apnoea variables, the median values and the interquartile ranges ere alulated for the various apnoea measures at the three age levels studied. For graphial presentation of the median and interquartile range the 'box and hiskers' graphs of Tukey'1 ere used. The Mann and Whitney U test1 as used for statistial omparison beteen the to groups. Results At 4 eeks' oneptual age, preterm infants reovering from respiratory distress syndrome experiened onsiderably less nonobstrutive apnoea than the ontrol group. This differene as observed in terms of both the density and duration of nonobstrutive apnoea related to both sleep states, but as more pronouned during nonrapid eye movement sleep (Tables and 3, Fig. 1). The same pattern (ith redued density and duration) as also shon for longer episodes of nonobstrutive apnoea (six seonds or more), but this did not, hoever, reah statistial signifiane at 4 eeks' oneptual age (Tables and 3). At 4 eeks the density and total and mean duration of periodi breathing ere found to be signifiantly dereased in the study group. Moreover, the number of infants experiening periodi breathing at 4 eeks' oneptual age as signifiantly loer in the study group, partiularly during nonrapid eye movement sleep. While only 1% of the study group infants shoed periodi breathing during nonrapid eye movement sleep this type of breathing as experiened by 5% of the ontrols (Fig. ). With regard to rapid eye movement sleep at 4 eeks, this ratio Arh Dis hild: first published as 1.36/ad on 1 June Donloaded from on November 18 by guest. Proteted by opyright.

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5 1 L 4'1 4, 1 8j r O 6 '.4 i x ". i Sleep apnoea profile in preterm infants reovering from respiratory distress syndrome I, IN Postoneptuol age (eeks) Fig. 1 Density ofnonobstrutive apnoea (3 seonds) in relation to sleep states and postoneptual age in healthy preterm infants and those reovering from respiratory distress syndrome. orresponding data for 1 normal term infants inluded in a former studys are also given for omparison. The median and interquartile range are shon by the 'box and hisker' graphs of Tukey. 1 S=signifiant at the 5 level. REM=rapid eye movement; nonrem=nonrapid eye movement. as 3:7% for the study and ontrol infants respetively. At 5 and 64 eeks, the density and duration of nonobstrutive apnoea and periodi breathing ere no longer signifiantly different beteen the groups (Tables and 3, Fig. 1). ery fe infants in either group still experiened periodi breathing during nonrapid eye movement sleep at these ages (Fig. ). With regard to obstrutive and mixed apnoea, the study group infants exhibited a loer density and duration at 4 eeks' oneptual age than the ontrols. This differene as only observed during nonrapid eye movement sleep and did not reah statistial signifiane (Tables, 3, and 4). At 5 and 64 eeks, hoever, infants reovering from respiratory distress syndrome had signifiantly more and longer episodes of obstrutive and mixed apnoea than the ontrols (Tables and 3, Fig. 3). As shon in Table 4 the mean duration of obstrutive and mixed apnoea at 5 and 64 eeks as also signifiantly longer in the study group. This aounts for z. OA 8 Preterm ontrols E] Study group tn n_ 6 * * O = HPI 4 5 Postoneptual age (eeks) 64 Fig. Number of infants in eah group ho suffered episodes ofperiodi breathing in relation to sleep states and postoneptual age. The orresponding data for 1 normal term infants5 are given for omparison. Bars represent the number of infants ith periodi breathing given as a perentage of the total number of infants in eah group. 3: s 1 a. atioo* : n 8' p '. 16 9: s Preterm ontrols Study group I Term ontrols s s n 4 5 Postoneptual age (eeks) Fig. 3 Density of obstrutive and mixed apnoea (:3 seonds) in relation to sleep states and postoneptual age in study and ontrol infants and, for omparison, in 1 normal term infants." The median and interquartile range are shon by the 'box and hisker' graphs of Tukey. l S=signifiant at the 5 level. 64 Arh Dis hild: first published as 1.36/ad on 1 June Donloaded from on November 18 by guest. Proteted by opyright.

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7 Sleep apnoea profile in preterm infants reovering from respiratory distress syndrome 553 an even greater number of longer (6 seonds or more) episodes of apnoea in this group. At both 5 and at 64 eeks, differenes beteen density and total and mean duration of obstrutive and mixed apnoea ere related to nonrapid eye movement sleep only (Tables, 3, and 4, Fig. 3). Disussion The present study shos to main differenes beteen the sleep apnoea profiles of healthy preterm infants and those reovering from respiratory distress syndrome during the first 6 months after normal term. Firstly, there as a loer inidene (that is a loer density and duration) of nonobstrutive apnoea and periodi breathing at 4 eeks and, seondly, a higher inidene of obstrutive and mixed apnoea at 5 and 64 eeks' oneptual age in the study groupboth findings being losely related to nonrapid eye movement sleep. Thus, an already remarkably loer inidene of apnoea at 4 eeks suggesting an advaned development of respiratory ontrol mehanisms in the study group ontrasts ith the nearly stable persistene of obstrutive and mixed apnoea during nonrapid eye movement sleep in these same infants at 5 and 64 eeks' oneptual age. Aording to the findings of urzidasalova et al, 13 neither the loer mean gestational age and birtheight nor the different number of tins in our study group an aount for the differenes in the apnoea profile beteen study and ontrol groups at 4 eeks. On the ontrary, the loer mean gestational age and loer number of tins in the study group ould more probably have led to an inreased rather than a dereased inidene of nonobstrutive apnoea at 4 eeks. In a previous study5 e shoed that at 4 eeks' oneptual age normal preterm infants ompared ith term ontrols experiened signifiantly more episodes of apnoea, and that at 5 eeks the onverse as true. It as suggested that this sleep apnoea profile of healthy preterm infants indiated maturational delay of the respiratory drive at 4 eeks hih seemed to be folloed by inreased respiratory drive, and thus a probably overadaptive maturation of respiratory ontrol, at 5 eeks. In our study, infants ho ere reovering from respiratory distress syndrome experiened apnoea of both types and periodi breathing to almost as lo a degree as that observed in normal term infants (Figs. 1 and ), partiularly during nonrapid eye movement sleep. An advaned maturational proess of respiratory drive may therefore be assumed in these infants. Hoppenbrouers et al, 14 studying the development of sleep state distribution of normal preterm infants and those suffering episodes of apnoea, found that at 44 eeks' oneptual age infants ith apnoea ere not different from normal term ontrols, indiating that 'stress produed by apnoea in the premature infant appeared to aelerate development of sleep state distribution toard normal term patterns'. Although e did not investigate sleep state distribution, different peri and postnatal onditions produing different amounts of hypoxaemi 'stress' in preterm infants ith and ithout respiratory distress syndrome ould have influened the development of the apnoea profile in the study group toards that of normal term infants at 4 eeks. Like siblings of SIDS vitims ho olletively shoed not only a redued inidene of apnoea but also an advaned development of eletroenephalographi poer spetral patterns suggesting an aelerated entral nervous system maturation,' preterm infants reovering from respiratory distress syndrome may have experiened onsiderably more environmental stimulation and episodes of hypoxaemia than healthy preterm ontrols. As Quattrohi et al have reported,'6 there is no inreasing anatomial evidene supporting our assumption. Takashima and oorkers'7 shoed signifiant differenes in the development of axodendriti synaptogenesis of neuronal strutures in the medulla oblongata involved in respiratory ontrol in different infant populations. Whereas SIDS vitims almost uniformly had a notieable delay in the development of these respiratory neurons, a group of ventilator dependant preterm infants ho died from ompliations of respiratory distress syndrome shoed a developmental status indiating an advaned, but in ertain aspets possibly abnormal, maturation in omparison ith age mathed ontrols ho died from other auses. The seemingly loer degree of obstrutive and mixed apnoea during nonrapid eye movement sleep observed at 4 eeks' oneptual age in the study group is onsistent ith the signifiantly loer inidene of nonobstrutive apnoea and periodi breathing in these infants, suggesting an advaned maturation of respiratory ontrol. Sine a higher degree of obstrutive and mixed apnoea during nonrapid eye movement sleep at 4 eeks as the major differene beteen normal preterm and normal term ontrol infants this as onsidered to be a marker of developmental delay.5 From this point of vie the omparably lo level of this type of apnoea in the urrent study group at 4 eeks may be looked at as an indiator of an advaned maturation of respiratory drive. onsequently the persistene of obstrutive and mixed apnoea related to nonrapid eye movement sleep an no longer Arh Dis hild: first published as 1.36/ad on 1 June Donloaded from on November 18 by guest. Proteted by opyright.

8 554 Bentele, Albani, Budde, and Shulte point to a ontinuing maturational delay. More probably it reflets strutural lesions of the larger and terminal airays as a ompliation of respiratory distress syndrome and its treatment, fators hih are more likely to produe funtional abnormalities during nonrapid eye movement sleep sine in this sleep state, ith a predominantly autonomi ontrol of breathing, healthy preterm infants at 5 and 64 eeks exhibit virtually no obstrutive and mixed apnoea. An inreased frequeny of obstrutive and mixed apnoea in preterm infants surviving respiratory distress syndrome as also reported by Fontan et al,18 hose study group, hoever, omprised infants of different oneptional ages and hose study results ere not related to sleep states. Persistently inreased amounts of obstrutive and mixed apnoea, knon to ause onsiderable oxygen desaturation,19 may thus ompromise respiration during nonrapid eye movement sleep ith its tendeny to hypoventilation, and hallenge preterm infants to overome the impat of respiratory distress syndrome by breathing at a more mature level. This demand for a more mature level of respiratory drive seems to be indiated by the early redution in episodes of apnoea and periodi breathing in the study group. Under the additional influene of multiple aggravating intrinsi (developmental hanges of sleep state distribution) and environmental fators (that is upper respiratory trat infetions, anaemia et) these infants, hose breathing is already ompromised, may suffer an inreased risk of SIDS, hih has been reported.13 As has been pointed out by Hoppenbrouers and Hodgman,' the hallenge for a fored respiratory drive may allo demands to be met for some time and 'initially be adaptive but ultimately ause a depletion of the infant's reserve'. We thank Mrs R Klingsporn for tehnial assistane. The present study as supported by a grant from the Deutshe Forshungsgemeinshaft (Be 91/). Referenes Standfast SJ, Jereb S, Aliferis D, Janerih DT. In: Tildon JT, Roeder LM, Steinshneider A, eds. Sudden infant death syndrome. London: Aademi Press, Werthammer J, Bron E, Neff RK, Taeush HW. Sudden infant death syndrome in infants ith bronhopulmonary dysplasia. Pediatris 198;69: Bron ER, Purohit DM. Sudden death among infants ith bronhopulmonary dysplasia after disharge from the neonatal intensive are unit. Pediatr Res 1983;18:35A. 4Watts JL, Ariagno RL, Brady JP. hroni pulmonary disease in neonates after artifiial ventilation: distribution of ventilation and pulmonary interstitial emphysema. Pediatris 1977;6:73. Albani M, Bentele KHP, Budde, Shulte FJ, Infant sleep apnea profile: preterm vs. term infants. Eur J Pediatr 1985;173: Gerhardt T, Banalari E. Apnea of prematurity: I. Lung funtion and regulation of breathing. Pediatris 1984;74:586. 7Hoppenbrouers T, Hodgman JE, Harper RM, Hofman E, Sterman MB, MGinty DJ. Polygraphi studies of normal infants during the first six months of life: III. Inidene of apnea and periodi breathing. Pediatris 1977;6:4185. Shulte FJ, Lasson U, Parl U, Nolte R, Jurgens U. Brain and behavioural maturation in neborn infants of diabeti mothers. Neuropadiatrie 1969;1: Gabriel M, Albani M, Shulte FJ. Apnei spells and sleep states in preterm infants. 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Eletroenephalogr lin Neurophysiol 198;53: Quattrohi JJ, Baba N, Liss L, Adrion W. Sudden infant death syndrome (SIDS): a preliminary study of retiular dendriti spines in infants ith SIDS. Brain Res 198;181: Takashima S, Mito T. Neuronal development of the medullary retiular formation in sudden infant death syndrome and premature infants. Neuropediatris 1985;16:769. "1 Fontan JP, Haood S, Heldt GP, Tooley WH. Polysomnographi findings at disharge in infants born at less than 3 eeks of gestational age (GA). Pediatr Res 1984;18:A Kahn A, Blum D, Watershoot P, Engelman E, Smets P. Effets of obstrutive sleep apneas on transutaneous oxygen pressure in ontrol infants, siblings of sudden infant death syndrome vitims, and near miss infants: omparison ith the effets of entral sleep apneas. Pediatris 198;7:856. Bekith JB. The sudden infant death syndrome. urr Probl Pediatr 1973;3: Hoppenbrouers T, Hodgman JE. Sudden infant death syndrome (SIDS): an integration of ontogeneti, pathologi, physiologi and epidemiologi fators. Neuropediatris 198;13:Supplement. orrespondene to Dr K H P Bentele, UniversitatsKinderklinik, Martinistrasse 5, Hamburg, Germany. Reeived 3 January 1984 Arh Dis hild: first published as 1.36/ad on 1 June Donloaded from on November 18 by guest. Proteted by opyright.