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The longitudinal effects of persistent periodic breathing on cerebral oxygenation in preterm infants
Sleep Medicine 16 (2015) 729–735
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Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Original Article
The longitudinal effects of persistent periodic breathing on cerebral oxygenation in preterm infants Pauline F.F. Decima a,b, Karinna L. Fyfe a,c, Alexsandria Odoi a, Flora Y. Wong a,c, Rosemary S.C. Horne a,c,* a
The Ritchie Centre, Monash Institute of Medical Research and Prince Henry’s Institute, Monash University, Melbourne, VIC, Australia Laboratoire PériTox, UMR-I 01 INERIS, Faculté de Médecine, Université de Picardie Jules Verne, Amiens, France c Department of Paediatrics, Monash University, Melbourne, VIC, Australia b
A R T I C L E
I N F O
Article history: Received 20 November 2014 Received in revised form 14 January 2015 Accepted 13 February 2015 Available online 14 March 2015 Keywords: Pediatric Heart rate Arterial oxygen saturation Neonate Sleep
A B S T R A C T
Objectives: Periodic breathing is common in preterm infants, but is thought to be benign. The aim of our study was to assess the incidence and impact of periodic breathing on heart rate (HR), oxygen saturation (SpO2), and brain tissue oxygenation index (TOI) over the first six months after term-equivalent age. Study design: Twenty-four preterm infants (27–36 weeks gestational age) were studied with daytime polysomnography in quiet sleep (QS) and active sleep (AS) and in both the prone and supine positions at 2–4 weeks, 2–3 months, and 5–6 months post-term corrected age. HR, SpO2, and TOI (NIRO-200 spectrophotometer) were recorded. Periodic breathing episodes were defined as greater than or equal to three sequential apneas each lasting ≥3 s. Results: A total 164 individual episodes of periodic breathing were recorded in 19 infants at 2–4 weeks, 62 in 12 infants at 2–3 months, and 35 in 10 infants at 5–6 months. There was no effect of gestational age on periodic breathing frequency or duration. Falls in HR (−21.9 ± 2.7%) and TOI (−13.1 ± 1.5%) were significantly greater at 2–3 months of age compared to 2–4 weeks of age. Conclusions: The majority of preterm infants discharged home without clinical respiratory problems had persistent periodic breathing. Although in most infants periodic breathing was not associated with significant falls in SpO2 or TOI, several infants had significant desaturations and reduced cerebral oxygenation especially during AS. The clinical significance of this on neurodevelopmental outcome is unknown and warrants further investigations. Crown Copyright © 2015 Published by Elsevier B.V. All rights reserved.
1. Introduction Worldwide, around 10% of all infants are born preterm and figures indicate that numbers have increased by 36% over the last 25 years (www.marchofdimes.com). Respiratory instability during sleep is very common in infants born preterm and is thought to be due to immaturity of the central and peripheral mechanisms that control breathing [1]. Short periods of apnea not associated with decrements in oxygenation are not problematic; however, if they are associated with significant desaturation, they can have adverse consequences [2,3]. Apneas can occur in isolation or in a repetitive pattern termed “periodic breathing” [4]. Periodic breathing is common in termborn infants in the first 2 weeks of life and significantly decreases with age [5]; however, the frequency is low, making up <1% of total
* Corresponding author. The Ritchie Centre, Level 5 Monash Medical Centre, 246 Clayton Road, Melbourne, Vic 3168, Australia. Tel.: +61 3 9594 5100; fax: +61 3 9594 6811. E-mail address: [email protected] (R.S.C. Horne). http://dx.doi.org/10.1016/j.sleep.2015.02.537 1389-9457/Crown Copyright © 2015 Published by Elsevier B.V. All rights reserved.
sleep time (TST) [5,6]. Periodic breathing is significantly more prevalent in ex-preterm infants compared to term-born infants at termequivalent age [7]. However, to date, few studies have followed expreterm infants after term-equivalent age. One early study reported an increased incidence of periodic breathing at 52 weeks postconceptional age (ie, three months post-term corrected age, CA) but a similar incidence at 64 weeks postconceptional age (ie, six months post-term CA) compared to term-born infants [7]. Because of its high prevalence, and the fact that it is thought not to be associated with significant hypoxia or bradycardia, the traditional view of periodic breathing is that it is simply due to immaturity of respiratory control and is benign [8]. The limited number of studies which have assessed the impact of periodic breathing have however found that repetitive apneas can be associated with falls in both peripheral oxygen saturation and cerebral oxygenation. A study of one preterm infant born at 27 weeks of gestation and studied at 37 weeks postconceptional age with nearinfrared spectroscopy (NIRS) showed that significant cyclical changes in cerebral blood volume were recorded during periods of periodic breathing [9]. A later study in 10 term-born infants studied at 6–8 weeks postnatal age also demonstrated that cyclical desaturation
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and reoxygenation occurred during episodes of periodic breathing [10]. To date, studies have not examined the effects of periodic breathing on the cerebral circulation longitudinally in preterm infants after term-equivalent age, nor have they assessed the influences of sleep state and sleeping position. Thus, the aim of this study was to evaluate longitudinally the incidence of periodic breathing during sleep across the six months after term-equivalent age and to assess the impact of periodic breathing on heart rate (HR), arterial oxygen saturation, and cerebral oxygenation in both active sleep (AS) and quiet sleep (QS) and in both the prone and supine positions. 2. Methods The Monash Medical Centre and Monash University Human Research Ethics Committees granted ethical approval for this project. This project arose as a number of preterm infants participating in a larger study of infant sleeping position on cerebral oxygenation [11] were identified to have persistent periodic breathing well past term-equivalent age. 2.1. Subjects In the larger study, 35 healthy preterm infants were recruited from Monash Newborn, Monash Medical Centre, and the Special Care Nursery at Jessie Macpherson Private Hospital, Melbourne, Australia. For the current study, as we were investigating the longitudinal effects of periodic breathing, only data from the 24 infants (13 M/11 F) who completed all three studies at 2–4 weeks CA, 2–3 months CA, and 5–6 months CA were analyzed. Before the study, written informed consent was obtained from parents and no monetary incentive was provided for participation. 2.2. Polysomnographic recordings Infants were studied using daytime polysomnography at the Melbourne Children’s Sleep Centre, Monash Medical Centre. All electrodes and measuring devices for polysomnography were attached during the infant’s morning feed. Infants were then allowed to sleep naturally in a pram in a darkened room at constant temperature. Infants were visually monitored continuously via an infrared camera placed above the pram and behavioral changes, such as body movements and crying, were recorded. Infants were put
to sleep in both the prone and supine sleeping positions, with the initial starting position randomized. The sleeping position was changed between morning and afternoon sleep periods that were interrupted by a midday feed. Sleep state was assessed as QS, AS, or indeterminate sleep using electroencephalogram (EEG), behavioral, HR, and breathing pattern criteria [12]. Polysomnographic recordings included continuous monitoring of EEG (C4/A1; O2/A1), electrooculogram, submental electromyogram, electrocardiogram (ECG), thoracic and abdominal breathing movements (Resp-ez Piezo-electric sensor, EPM Systems, Midlothian, VA, USA), airflow from the nose and mouth (Breathsensor, Thermal Airflow Sensor, Mortara Instruments Australia, Sydney, NSW, Australia), arterial blood oxygen saturation (SpO2) with a 2-s averaging time (Masimo Radical Oximeter, Masimo Corporation, Irvine, CA, USA), and abdominal skin temperature (ADInstruments, Sydney, NSW, Australia). In addition to the standard polysomnogram (PSG) leads, we also measured cerebral oxygenation using a NIRO-200 (NIRO-200 spectrophotometer, Hamamatsu Photonics KK, Tokyo, Japan) with optodes positioned 4 cm apart on the frontal region as previously described [13]. NIRS depends on the relative transparency of biological tissue to light in the near-infrared region of the spectrum. NIRS enables the noninvasive measurement of cerebral tissue oxygenation index (TOI). All physiological data were recorded at a sampling frequency of 512 Hz using a Compumedics E-Series Sleep Recording system with ProFusion PSG 2 software (Compumedics Limited, Abbotsford, VIC, Australia). At the completion of the study, data were exported via the European Data Format to analysis software (Chart 7.0, ADInstruments, Sydney, NSW, Australia). 2.3. Data analysis Sleep state was scored independently of periodic breathing episodes. As few epochs of indeterminate sleep were scored, these were included in AS. Periodic breathing episodes were defined as three or more sequential apneas lasting >3 s separated by no more than 20 s of normal breathing [14]. An example of periodic breathing is presented in Fig. 1. The duration of each periodic breathing episode was measured from the beginning of the first apnea until the end of the last apnea. The frequency of periodic breathing was determined for each infant as the total number of episodes recorded and also the amount of TST spent in periodic breathing. Changes in HR,
Respiratory Movements SpO2%
Oxygenated Haemoglobin
Deoxygenated Haemoglobin
Tissue Oxygen Index
1
3
2
Time (minutes) Fig. 1. An example of the effects of periodic breathing on cerebral oxygenation and peripheral arterial oxygen saturation (SpO2) in a preterm infant at 2–4 weeks post-term corrected age.
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SpO2, and TOI were only calculated during episodes of periodic breathing which were free of movement artifact during the 30 s prior to the episode onset (baseline) and during the entire episode. HR, SpO2, and TOI values were extracted beat to beat from LabChart. To allow for differences between individual infants, all values were calculated as a percentage change from baseline. Due to the cyclical nature of the changes in physiological parameters with the repetitive apneas as illustrated in Fig. 1, percentage changes from baseline averaged over each periodic breathing episode masked the actual changes observed. Thus, each detected nadir was used to calculate the maximal percentage change for each episode (nadir percentage change) from the baseline. 2.4. Statistical analysis Data were first tested for normality (Shapiro–Wilk test) and equal variance. The effects of the sleep state, sleep position, and postterm CA on the frequency, duration of periodic breathing, and the cardiovascular effects (baseline and nadir percentage change in HR, SpO2, and TOI) were tested with a two-way analysis of variance (ANOVA) followed by a post hoc Student–Newman–Keuls test if required. The relationship between the duration of periodic breathing episodes and gestational age (GA) and nadir percentage change in HR, SpO2, and TOI were tested with Pearson’s correlation analysis. Results are expressed as mean ± standard error of the mean (SEM), and a p value of <0.05 was considered statistically significant. 3. Results 3.1. Demographics Infants (13 M/11 F) were born between 27.3 and 36.2 weeks of GA (mean 31.2 ± 0.5 weeks, mean ± SEM) with birth weights of between 925 and 3060 g (mean 1698 ± 112 g). All of the 24 infants were born with appropriate birth weight for GA. Apgar scores ranged from 2 to 9 (median 6) at 1 min and from 4 to 10 (median 9) at 5 min. Of the 24 infants, 13 had been administered caffeine for apnea of prematurity during their hospital stay and none were on caffeine at the time of the studies. Ten infants spent between 3 and 65 days in the neonatal intensive care unit. None of the infants was diagnosed with significant intraventricular hemorrhage (IVH grades III or IV) and none were on supplemental oxygen at the time of the studies. There were no differences in age or weight between the infants in this cohort who completed all three studies and the entire cohort (21 M/14 F) who were born between 26 and 36 weeks GA (mean GA at birth 31.2 ± 0.1 weeks, mean birth weight 1697 ± 92 g). Infants were studied at 2–4 weeks CA (mean 43 ± 0.1 weeks post-conceptional age), 2–3 months (mean 51 ± 0.2 weeks post-conceptional age), and 5–6 months (mean 63 ± 0.3 weeks post-conceptional age). Mean TST at 2–4 weeks was 3.5 ± 0.1 h, at 2–3 months 2.9 ± 0.1 h, and at 5–6 months 2.3 ± 2.6 h. 3.2. Periodic breathing episodes A total of 261 individual episodes of periodic breathing were detected: 164 at study 1, 62 at study 2, and 35 at study 3. Twenty-two of the 24 infants (92%) exhibited periodic breathing during at least one of the three studies: 19 infants (79%) at 2–4 weeks CA; 12 (50%) at 2–3 months CA; and 10 (42%) at 5–6 months CA. Seven infants (29 %) exhibited epochs of periodic breathing at all three studies and 10 infants (42%) at studies 1 and 2. The two infants who did not exhibit periodic breathing were one female infant born at 27.5 weeks of gestation and one male infant born at 30.2 weeks of gestation. The frequency and duration of periodic breathing at any of the three studies were not affected by GA at birth. There were no
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Table 1 Number and mean duration of episodes of periodic breathing and baseline values for heart rate (HR), oxygen saturation (SpO2), and cerebral oxygenation (TOI). Values are mean ± SEM.
2–4 weeks Number of episodes Episode duration (s) Baseline HR (bpm) Baseline SpO2 (%) Baseline TOI (%) 2–3 months Number of episodes Episode duration (s) Baseline HR (bpm) Baseline SpO2 (%) Baseline TOI (%) 5–6 months Number of episodes Episode duration (s) Baseline HR (bpm) Baseline SpO2 (%) Baseline TOI (%) ** p < 0.01 †† p < 0.01 ‡ p < 0.05 # p < 0.05
AS supine
AS prone
QS supine
QS prone
35 65 ± 9 134 ± 2 98.7 ± 0.1 64.4 ± 1.5***
20 45 ± 5 137 ± 2 †† 98.6 ± 0.2 48.1 ± 3.8
23 44 ± 5 135 ± 2 *** 97.9 ± 0.4** 62.8 ± 1.6
10 59 ± 12 146 ± 2 99.2 ± 0.2 58.5 ± 1.4
17 47 ± 2 128 ± 2 ‡ 98.8 ± 0.3†† 52.6 ± 4.9‡
14 46 ± 8 133 ± 2 98.9 ± 0.5†† 47.1 ± 2.2
6
1
35 ± 5 131 ± 1 ‡ 96.6 ± 0.3 52.4 ± 4.0‡
34 123 93.9 41.6
16 32 ± 2 128 ± 2 97.6 ± 0.2 59.6 ± 1.5
3
6
31 ± 4 126 ± 8 98.2 ± 0.4 55.1 ± 3.0
35 ± 7 116 ± 3 # 96.7 ± 0.2 56.1 ± 3.2
0 -
***p < 0.001 prone versus supine. AS versus QS. 2–4 weeks versus 2–3 months. 2–3 months versus 5–6 months.
statistically significant differences in periodic breathing frequency at any age studied; however, periodic breathing was least common in QS in the prone position with 10 episodes being recorded at 2–4 weeks CA, one at 2–3 months CA, and none at 5–6 months CA. Episodes of periodic breathing were most common in AS in the supine position with 35 episodes recorded at 2–4 weeks CA, 17 at 2–3 months CA, and 16 at 5–6 months CA (Table 1). The duration of periodic breathing episodes was not affected by post-term age in either position (data were only tested in AS) (Table 1). Overall, the periodic breathing frequency declined with increasing postnatal age (p < 0.05) (Table 1); however, this was not the case in all infants (Fig. 2). Of note, one infant who had only two episodes of periodic breathing recorded at study 1 and none at study 2 had 14 episodes recorded at study 3. The amount of time spent in periodic breathing at each study was calculated as a percentage of TST. Although this fell with age, 6.9 ± 2.4% at study 1, 3.6 ± 1.8% at study 2, and 1.3 ± 0.6% at study 3, this did not achieve statistical significance. There was considerable variability between infants across the three studies as illustrated in Fig. 2. 3.3. Effects of post-term CA on HR, SpO2, and TOI during periodic breathing Of the total number of events detected, 151 episodes (58%) contained no movement artifact and were analyzed: 88 at 2–4 weeks CA, 38 at 2–3 months CA, and 25 at 5–6 months CA. The effects of sleep state, sleep position, and postnatal age on baseline HR, SpO2, and TOI are presented in Table 1. At 2–4 weeks baseline, HR and SpO2 were significantly higher in the prone position compared to the supine position in QS and HR was lower in AS compared to QS when infants slept prone while SpO2 was higher in AS compared to QS when infants slept supine. TOI was higher in the supine compared to the prone position in both sleep states and this reached statistical significance in AS. At 2–3 months of age in both the prone and supine positions, SpO2 was higher in AS compared with QS. The effects of postnatal age on baseline HR, SpO2, and TOI are also presented in Table 1. HR and TOI were significantly lower at 2–3 months compared to 2–4 weeks in both AS and QS when infants
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2-4 weeks
total sleep time spent PB (%)
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Baby
2-3 months
total sleep time spent PB (%)
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Baby
5-6 months
total sleep time spent PB (%)
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Baby Fig. 2. Percent total sleep time individual preterm infants spent in periodic breathing (PB) at 2–4 weeks, 2–3 months, and 5–6 months corrected age.
slept supine. HR was also significantly lower at 5–6 months compared to 2–3 months in QS in the supine position. There were no effects of sleep state or sleep position on the nadir in percentage change in either SpO2, HR, or TOI at any of the three ages studied (Fig. 3A, 3B, and 3C). There were no effects of postnatal age on SpO2 in either sleep state or sleep position (Fig. 3A). In the majority of infants, periodic
breathing was not associated with desaturation during individual periodic breathing episodes, with a mean of 1.7 ± 0.8 s (range 0–46.8 s) spent <90% at study 1, 0.8 ± 0.3 s (range 0–9.7 s) at study 2, and 0.5 ± 0.3 s (range 0–4.6 s) at study 3. However, when infants were examined individually, infant 12 who spent <5% of his TST in periodic breathing spent 108.3 s with an SpO2 <90%, 94.0 s with an SpO2 <85%, and 78.8 s with an SpO2 <80% at study 1. At study 2, he spent
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Fig. 3. Effects of postnatal age on (A) peripheral oxygen saturation (SpO2), (B) percentage nadir in heart rate (HR), and (C) tissue oxygenation index (TOI).
15.7 s with an SpO2 <90% and 8.9 s with an SpO2 <85%. By contrast, infants 4 and 14 who spent over 25% of their sleep time in periodic breathing at study 1 spent no time with an SpO2 <90% and infant 16 spent only 2.9 s with an SpO2 <90%. Fig. 3B shows that the nadir in percentage fall in HR in AS in the prone position was significantly greater at study 2 (−21.9 ± 2.7%) compared to study 1 (−14.1 ± 2.3%, p < 0.05) and the nadir at study 2 was significantly greater than at study 3 (−5.4 ± 5.9%, p < 0.05). There were no differences in nadir change in HR in AS in the supine position or in QS in either position. Fig. 3C shows that in AS, the mean nadir percentage change in TOI was less in study 1 (−7.0 ± 1.2%) compared to study 2 (−13.1 ± 1.5%, p < 0.01) in the prone position and also in the supine position (−7.1 ± 0.9 c.f. −11.6 ± 1.4%, p < 0.01). In the supine position, the nadir in TOI was also significantly less at study 1 than at study 3 (−11.7 ± 1.4%, p < 0.05). In QS, mean nadir percentage change in TOI in the supine position was significantly less at study 1 (−5.3 ± 0.7%) compared to both study 2 (−11.3 ± 2.4%) and study 3 (−15.8 ± 1.3%, p < 0.001 for both). The effects in the prone position were not tested due to the infrequency of periodic breathing in QS in this position. This analysis identified three infants who had falls in HR, SpO2, and TOI with falls of 50%, 40%, and 36% during individual periodic breathing episodes, respectively. These changes were not related to the periodic breathing episode duration. All three infants were male and had been born at 27.3, 31.5, and 30.6 weeks of gestation with birth weights of 1087 g, 1660 g, and 1546 g, respectively. They had been ventilated for 50 days, six days, and one day, respectively (range for the whole group 0–63 days, median one day). There was nothing in the clinical history of these three infants which would distinguish them from the rest of the cohort.
When all data were combined at each age, there was no significant correlation between mean nadir percentage change in SpO2 or TOI and periodic breathing episode duration at any of the three studies. Mean nadir percentage change in HR was significantly correlated with periodic breathing episode duration at 2–3 months CA (p < 0.01).
4. Discussion In our longitudinal study of preterm infants who had been discharged home with no clinical concerns of respiratory instability, we observed that 92% of infants exhibited at least one episode of periodic breathing during a daytime nap study during the first 6 months after term CA. The incidence decreased with increasing postnatal age with 79% exhibiting periodic breathing at 2–4 weeks postterm CA, 50% at 2–3 months, and then 42% at 5–6 months. In contrast to apnea of prematurity, the incidence and duration of individual episodes of periodic breathing were not related to GA at birth. Although overall the duration of episodes of periodic breathing was not correlated with significant falls in HR, SpO2, or TOI, we did identify three infants in whom there were significant falls in these parameters. Because of its high prevalence, and the fact that periodic breathing is thought not to be associated with significant hypoxia or bradycardia, the traditional view of periodic breathing is that it is simply due to immaturity of respiratory control and is benign [8]. Overall, we found minimal consequences of periodic breathing and the duration of periodic breathing episodes was not related to peripheral desaturation. However, there were a number of episodes
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where SpO2 fell by >4% and some infants spent extended periods with an SpO2 <90%. These falls in SpO2 were similar to those reported by Poets and Southall [15] in preterm infants studied at around term-equivalent age and emphasize that periodic breathing is not always benign in nature. Similarly, we demonstrated that there was no significant bradycardia in most episodes and that the duration of periodic breathing episodes was not related to the severity of bradycardia. As with SpO2, there were, however, a number of episodes where HR fell by >20%. With regard to cerebral hemodynamics, we showed that episodes of periodic breathing were associated with significant falls in TOI, which again were not related to episode duration. Interestingly, our study identified that these falls in TOI were least at 2–4 weeks of age and more pronounced at 2–3 months of age. Arithmetically, the higher percentage fall in TOI could be in part due to the lower baseline cerebral TOI at 2–3 months of age, which, as in this study, has also been identified in previous studies by our group in both term [13] and preterm infants [11]. Physiologically, we have previously suggested that this agerelated progression is due to maturation of cerebral blood flow– metabolism coupling during this period, at 2–3 months CA in combination with rapid growth of the brain and accompanying increases in cerebral oxygen requirements [13]. Accordingly, a mismatch between cerebral metabolic demands and cerebral oxygen delivery at this age leads to a nadir in TOI. In addition, there is a physiological anemia also occurring at this age [16], further increasing the cerebral oxygen extraction in order to meet the metabolic demand. Thus, any reduction in SpO2 and cardiac output (as indicated by falls in HR) as occurs during periodic breathing is likely to have a more marked effect on TOI. Clinically, our findings suggest that infants with periodic breathing at 2–3 months of age would warrant close observation and further studies with neurodevelopmental follow-up in this population would be required. Previous studies have examined changes in cerebral hemodynamics associated with apnea of prematurity and have identified that cerebral blood volume [17,18] and cerebral blood flow velocity [19] decrease during a single apnea. However, to date, there has only been one study in healthy term-born infants on the effects of periodic breathing on cerebral hemodynamics. This study [10] showed that periodic breathing episodes >1 min in duration were associated with cyclical variations in the hemoglobin oxygenation index. Changes in cerebral blood volume occurred in 42% of episodes and these were correlated with changes in HR. Animal studies have shown that repeated episodes of hypoxemia can cause brain injury [20]. Furthermore, low regional cerebral oxygenation levels while in the neonatal unit have been associated with poorer neurodevelopmental outcomes at 18 months [21]. Repetitive apneas have been shown to impair growth and development [22,23], be a source of oxidative stress which is associated with pro-inflammatory mechanisms that could contribute to lung and airway alterations [3], alter cardiovascular regulation [3], and lower neurodevelopmental outcomes [24,25]. To date, no studies have examined the effects of prolonged apnea and bradycardia during infancy on neurodevelopmental outcomes. However, it is known that the repetitive hypoxia associated with obstructive sleep apnea in childhood is associated with both behavioral and neurocognitive deficits [26]. The concept of loop gain has been used to understand the mechanisms that predispose infants to periodic breathing [8]. Periodic breathing is favored by a hypersensitive chemoreceptor response, a low lung gas store, a delay in sensory information reaching the chemoreceptors, and a large arterial-inspired gradient for oxygen and carbon dioxide which lead to large changes in the ratio of arterial partial pressure of oxygen to the arterial partial pressure of carbon dioxide [8]. In term infants, periodic breathing is likely due to a hypersensitivity of the carotid bodies; however, in preterm infants the other factors listed above also likely play a role [8].
Previous studies of the occurrence of apnea of prematurity in preterm infants have highlighted that the incidence increases with decreasing GA at birth and is maximal at 30–31 weeks of gestation with approximately half of infants being affected [27]. By contrast, we found that periodic breathing incidence and duration was not related to GA at birth. Previous studies of the incidence of periodic breathing recorded prior to discharge (33–37 weeks GA) also did not find an association with subject characteristics including GA at birth, birth weight, or GA at testing [28]. Several studies have examined the incidence of periodic breathing in preterm infants prior to hospital discharge. Globtzbach et al. [29] found that all of the 66 preterm infants studied prior to discharge from hospital had episodes of periodic breathing. Similarly, Razi et al. [28] also found that all 343 infants born between 27 and 34 weeks GA and studied at 33–37 weeks GA exhibited episodes of periodic breathing. Earlier studies have also identified that the incidence of periodic breathing at term-equivalent age is higher in preterm compared to termborn infants [7]. Our finding that periodic breathing occurred in all but two of 24 infants (92%) over the first six months after termequivalent age expands these findings and highlights the increased incidence of periodic breathing in preterm infants. The majority of studies of the longitudinal changes in periodic breathing incidence have been in term-born infants. These studies have shown that although periodic breathing is common in the first 2 weeks of life occurring in 78% of infants, the incidence falls to 29% in infants aged 39–52 weeks [5]. In term infants, the percentage of TST spent in periodic breathing is low with reference values of a median of 1.1 % (maximum 10.4%) at one month and median 1% (maximum 4.6%) at 3 months in 37 infants [6]. Our study found that overall the percentage of TST spent in periodic breathing was low; however, at 2–4 weeks CA four infants spent >20% of TST periodic breathing, and at 2–3 months two infants spent > 15% of TST in periodic breathing. These times spent in periodic breathing far exceed those reported in term infants [6]. Our study also considered the effects of sleep state and sleeping position on periodic breathing longitudinally as these factors have been shown to influence the incidence of periodic breathing in preterm infants before term-equivalent [30] and also after termequivalent age [7,31]. Similar to previous studies, we found that periodic breathing was more common in AS and in the supine position and least common in QS in the prone position. Previous studies have identified that respiratory instability is higher in AS compared to QS and is also more common in the supine compared to the prone position in preterm infants [32]. It has been suggested that this increased instability in AS may result from overall immaturity of respiratory control components and from the phasic inhibitory–excitatory mechanisms inherent in this sleep state [33], and it is also known that carotid body activity is elevated in AS [34]. We found that the frequency but not duration of periodic breathing decreased with increasing post-conceptional age. Previous studies have also reported that the frequency of periodic breathing decreases with increasing postnatal age in both term [5–7,31] and preterm infants [7,31]. In contrast to previous studies, we did not identify any effect of postnatal age on periodic breathing episode duration. Wilkinson et al. [31] reported that periodic breathing episode duration decreased from a mean of 18.3 s at 36–38 weeks GA to 9.8 s at 5–6 months CA. These results are probably due to differences between the studies, with Wilkinson et al. [31] expressing their data as post-conceptional age and also having an earlier study time prior to term. We acknowledge that the major limitation to this study was the small sample size of 24 infants and the wide GA at which they were born. However, our analysis showed that GA did not affect the incidence of periodic breathing and our study design allowed repeatedmeasures analysis to examine the effects of sleep state and sleeping position on the physiological variables of interest.
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5. Conclusions Periodic breathing induces repetitive decreases in HR, arterial oxygenation, and cerebral oxygenation over the first six months after term CA in preterm infants. While most infants spent a small percentage of TST in periodic breathing and had minimal or no associated hypoxia, a minority of infants had significant hypoxia, bradycardia, and decreased cerebral oxygenation, which would have otherwise gone undetected. The clinical significance of this is unknown but has the potential to influence neurodevelopmental outcomes. Further research to elucidate the effects, if any, of significant periodic breathing, on growth and development is required.
Conflict of interest The authors have no financial relationships relevant to this article to disclose. Funding for this project was provided by The National Health and Medical Research Council of Australia APP1006647 the Victorian Government’s Operational Infrastructure Support Program and The Lullaby Trust (UK). The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.02.537.
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[11] Fyfe KL, Yiallourou SR, Wong FY, Odoi A, Walker AM, Horne RSC. Cerebral oxygenation in preterm infants. Pediatrics 2014;134:435–45. [12] Anders TF, Emde R, Parmelee A. A manual of standardized terminology, techniques and criteria for scoring of states of sleep and wakefulness in newborn infants. Los Angeles: UCLA Brain Information Services/BRI Publications Office; 1971. [13] Wong FY, Witcombe NB, Yiallourou SR, et al. Cerebral oxygenation is depressed during sleep in healthy term infants when they sleep prone. Pediatrics 2011;127:e558–65. [14] Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2012;8:597–619. [15] Poets CF, Southall DP. Patterns of oxygenation during periodic breathing in preterm infants. Early Hum Dev 1991;26:1–12. [16] Strauss RG. Anaemia of prematurity: pathophysiology and treatment. Blood Rev 2010;24:221–5. [17] Pichler G, Schmolzer G, Muller W, Urlesberger B. Body position-dependent changes in cerebral hemodynamics during apnea in preterm infants. Brain Dev 2001;23:395–400. [18] Urlesberger B, Kaspirek A, Pichler G, Muller W. Apnoea of prematurity and changes in cerebral oxygenation and cerebral blood volume. Neuropediatrics 1999;30:29–33. [19] Perlman JM, Volpe JJ. Episodes of apnea and bradycardia in the preterm newborn: impact on cerebral circulation. Pediatrics 1985;76:333–8. [20] Back SA, Han BH, Luo NL, et al. Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci 2002;22:455–63. [21] Alderliesten T, Lemmers PM, van Haastert IC, et al. Hypotension in preterm neonates: low blood pressure alone does not affect neurodevelopmental outcome. J Pediatr 2014;[epub date 2014/02/04.]. [22] Groothuis JR, Rosenberg AA. Home oxygen promotes weight gain in infants with bronchopulmonary dysplasia. Am J Dis Child 1987;141:992–5. [23] Riordan LL, Kelly DH, Shannon DC. Slow weight gain is associated with increased periodic breathing in healthy infants. Pediatr Pulmonol 1994;17:22–5. [24] Janvier A, Khairy M, Kokkotis A, Cormier C, Messmer D, Barrington KJ. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol 2004;24:763–8. [25] Hunt CE, Corwin MJ, Baird T, et al. Cardiorespiratory events detected by home memory monitoring and one-year neurodevelopmental outcome. J Pediatr 2004;145:465–71. [26] Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 2002;11:1–16. [27] Henderson-Smart DJ. The effect of gestational age on the incidence and duration of recurrent apnoea in newborn babies. Aust Paediatr J 1981;17:273–6. [28] Razi NM, DeLauter M, Pandit PB. Periodic breathing and oxygen saturation in preterm infants at discharge. J Perinatol 2002;22:442–4. [29] Glotzbach SF, Baldwin RB, Lederer NE, Tansey PA, Ariagno RL. Periodic breathing in preterm infants: incidence and characteristics. Pediatrics 1989;84:785–92. [30] Heimler R, Langlois J, Hodel DJ, Nelin LD, Sasidharan P. Effect of positioning on the breathing pattern of preterm infants. Arch Dis Child 1992;67:312–14. [31] Wilkinson MH, Skuza EM, Rennie GC, et al. Postnatal development of periodic breathing cycle duration in term and preterm infants. Pediatr Res 2007;62:331– 6. [32] Elder DE, Campbell AJ, Larsen PD, Galletly D. Respiratory variability in preterm and term infants: effect of sleep state, position and age. Respir Physiol Neurobiol 2011;175:234–8. [33] Gaultier C, Gallego J. Development of respiratory control: evolving concepts and perspectives. Respir Physiol Neurobiol 2005;149:3–15. [34] Chardon K, Telliez F, Bach V, et al. Effects of warm and cool thermal conditions on ventilatory responses to hyperoxic test in neonates. Respir Physiol Neurobiol 2004;140:145–53.
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Sleep Medicine j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / s l e e p
Original Article
The longitudinal effects of persistent periodic breathing on cerebral oxygenation in preterm infants Pauline F.F. Decima a,b, Karinna L. Fyfe a,c, Alexsandria Odoi a, Flora Y. Wong a,c, Rosemary S.C. Horne a,c,* a
The Ritchie Centre, Monash Institute of Medical Research and Prince Henry’s Institute, Monash University, Melbourne, VIC, Australia Laboratoire PériTox, UMR-I 01 INERIS, Faculté de Médecine, Université de Picardie Jules Verne, Amiens, France c Department of Paediatrics, Monash University, Melbourne, VIC, Australia b
A R T I C L E
I N F O
Article history: Received 20 November 2014 Received in revised form 14 January 2015 Accepted 13 February 2015 Available online 14 March 2015 Keywords: Pediatric Heart rate Arterial oxygen saturation Neonate Sleep
A B S T R A C T
Objectives: Periodic breathing is common in preterm infants, but is thought to be benign. The aim of our study was to assess the incidence and impact of periodic breathing on heart rate (HR), oxygen saturation (SpO2), and brain tissue oxygenation index (TOI) over the first six months after term-equivalent age. Study design: Twenty-four preterm infants (27–36 weeks gestational age) were studied with daytime polysomnography in quiet sleep (QS) and active sleep (AS) and in both the prone and supine positions at 2–4 weeks, 2–3 months, and 5–6 months post-term corrected age. HR, SpO2, and TOI (NIRO-200 spectrophotometer) were recorded. Periodic breathing episodes were defined as greater than or equal to three sequential apneas each lasting ≥3 s. Results: A total 164 individual episodes of periodic breathing were recorded in 19 infants at 2–4 weeks, 62 in 12 infants at 2–3 months, and 35 in 10 infants at 5–6 months. There was no effect of gestational age on periodic breathing frequency or duration. Falls in HR (−21.9 ± 2.7%) and TOI (−13.1 ± 1.5%) were significantly greater at 2–3 months of age compared to 2–4 weeks of age. Conclusions: The majority of preterm infants discharged home without clinical respiratory problems had persistent periodic breathing. Although in most infants periodic breathing was not associated with significant falls in SpO2 or TOI, several infants had significant desaturations and reduced cerebral oxygenation especially during AS. The clinical significance of this on neurodevelopmental outcome is unknown and warrants further investigations. Crown Copyright © 2015 Published by Elsevier B.V. All rights reserved.
1. Introduction Worldwide, around 10% of all infants are born preterm and figures indicate that numbers have increased by 36% over the last 25 years (www.marchofdimes.com). Respiratory instability during sleep is very common in infants born preterm and is thought to be due to immaturity of the central and peripheral mechanisms that control breathing [1]. Short periods of apnea not associated with decrements in oxygenation are not problematic; however, if they are associated with significant desaturation, they can have adverse consequences [2,3]. Apneas can occur in isolation or in a repetitive pattern termed “periodic breathing” [4]. Periodic breathing is common in termborn infants in the first 2 weeks of life and significantly decreases with age [5]; however, the frequency is low, making up <1% of total
* Corresponding author. The Ritchie Centre, Level 5 Monash Medical Centre, 246 Clayton Road, Melbourne, Vic 3168, Australia. Tel.: +61 3 9594 5100; fax: +61 3 9594 6811. E-mail address: [email protected] (R.S.C. Horne). http://dx.doi.org/10.1016/j.sleep.2015.02.537 1389-9457/Crown Copyright © 2015 Published by Elsevier B.V. All rights reserved.
sleep time (TST) [5,6]. Periodic breathing is significantly more prevalent in ex-preterm infants compared to term-born infants at termequivalent age [7]. However, to date, few studies have followed expreterm infants after term-equivalent age. One early study reported an increased incidence of periodic breathing at 52 weeks postconceptional age (ie, three months post-term corrected age, CA) but a similar incidence at 64 weeks postconceptional age (ie, six months post-term CA) compared to term-born infants [7]. Because of its high prevalence, and the fact that it is thought not to be associated with significant hypoxia or bradycardia, the traditional view of periodic breathing is that it is simply due to immaturity of respiratory control and is benign [8]. The limited number of studies which have assessed the impact of periodic breathing have however found that repetitive apneas can be associated with falls in both peripheral oxygen saturation and cerebral oxygenation. A study of one preterm infant born at 27 weeks of gestation and studied at 37 weeks postconceptional age with nearinfrared spectroscopy (NIRS) showed that significant cyclical changes in cerebral blood volume were recorded during periods of periodic breathing [9]. A later study in 10 term-born infants studied at 6–8 weeks postnatal age also demonstrated that cyclical desaturation
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and reoxygenation occurred during episodes of periodic breathing [10]. To date, studies have not examined the effects of periodic breathing on the cerebral circulation longitudinally in preterm infants after term-equivalent age, nor have they assessed the influences of sleep state and sleeping position. Thus, the aim of this study was to evaluate longitudinally the incidence of periodic breathing during sleep across the six months after term-equivalent age and to assess the impact of periodic breathing on heart rate (HR), arterial oxygen saturation, and cerebral oxygenation in both active sleep (AS) and quiet sleep (QS) and in both the prone and supine positions. 2. Methods The Monash Medical Centre and Monash University Human Research Ethics Committees granted ethical approval for this project. This project arose as a number of preterm infants participating in a larger study of infant sleeping position on cerebral oxygenation [11] were identified to have persistent periodic breathing well past term-equivalent age. 2.1. Subjects In the larger study, 35 healthy preterm infants were recruited from Monash Newborn, Monash Medical Centre, and the Special Care Nursery at Jessie Macpherson Private Hospital, Melbourne, Australia. For the current study, as we were investigating the longitudinal effects of periodic breathing, only data from the 24 infants (13 M/11 F) who completed all three studies at 2–4 weeks CA, 2–3 months CA, and 5–6 months CA were analyzed. Before the study, written informed consent was obtained from parents and no monetary incentive was provided for participation. 2.2. Polysomnographic recordings Infants were studied using daytime polysomnography at the Melbourne Children’s Sleep Centre, Monash Medical Centre. All electrodes and measuring devices for polysomnography were attached during the infant’s morning feed. Infants were then allowed to sleep naturally in a pram in a darkened room at constant temperature. Infants were visually monitored continuously via an infrared camera placed above the pram and behavioral changes, such as body movements and crying, were recorded. Infants were put
to sleep in both the prone and supine sleeping positions, with the initial starting position randomized. The sleeping position was changed between morning and afternoon sleep periods that were interrupted by a midday feed. Sleep state was assessed as QS, AS, or indeterminate sleep using electroencephalogram (EEG), behavioral, HR, and breathing pattern criteria [12]. Polysomnographic recordings included continuous monitoring of EEG (C4/A1; O2/A1), electrooculogram, submental electromyogram, electrocardiogram (ECG), thoracic and abdominal breathing movements (Resp-ez Piezo-electric sensor, EPM Systems, Midlothian, VA, USA), airflow from the nose and mouth (Breathsensor, Thermal Airflow Sensor, Mortara Instruments Australia, Sydney, NSW, Australia), arterial blood oxygen saturation (SpO2) with a 2-s averaging time (Masimo Radical Oximeter, Masimo Corporation, Irvine, CA, USA), and abdominal skin temperature (ADInstruments, Sydney, NSW, Australia). In addition to the standard polysomnogram (PSG) leads, we also measured cerebral oxygenation using a NIRO-200 (NIRO-200 spectrophotometer, Hamamatsu Photonics KK, Tokyo, Japan) with optodes positioned 4 cm apart on the frontal region as previously described [13]. NIRS depends on the relative transparency of biological tissue to light in the near-infrared region of the spectrum. NIRS enables the noninvasive measurement of cerebral tissue oxygenation index (TOI). All physiological data were recorded at a sampling frequency of 512 Hz using a Compumedics E-Series Sleep Recording system with ProFusion PSG 2 software (Compumedics Limited, Abbotsford, VIC, Australia). At the completion of the study, data were exported via the European Data Format to analysis software (Chart 7.0, ADInstruments, Sydney, NSW, Australia). 2.3. Data analysis Sleep state was scored independently of periodic breathing episodes. As few epochs of indeterminate sleep were scored, these were included in AS. Periodic breathing episodes were defined as three or more sequential apneas lasting >3 s separated by no more than 20 s of normal breathing [14]. An example of periodic breathing is presented in Fig. 1. The duration of each periodic breathing episode was measured from the beginning of the first apnea until the end of the last apnea. The frequency of periodic breathing was determined for each infant as the total number of episodes recorded and also the amount of TST spent in periodic breathing. Changes in HR,
Respiratory Movements SpO2%
Oxygenated Haemoglobin
Deoxygenated Haemoglobin
Tissue Oxygen Index
1
3
2
Time (minutes) Fig. 1. An example of the effects of periodic breathing on cerebral oxygenation and peripheral arterial oxygen saturation (SpO2) in a preterm infant at 2–4 weeks post-term corrected age.
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SpO2, and TOI were only calculated during episodes of periodic breathing which were free of movement artifact during the 30 s prior to the episode onset (baseline) and during the entire episode. HR, SpO2, and TOI values were extracted beat to beat from LabChart. To allow for differences between individual infants, all values were calculated as a percentage change from baseline. Due to the cyclical nature of the changes in physiological parameters with the repetitive apneas as illustrated in Fig. 1, percentage changes from baseline averaged over each periodic breathing episode masked the actual changes observed. Thus, each detected nadir was used to calculate the maximal percentage change for each episode (nadir percentage change) from the baseline. 2.4. Statistical analysis Data were first tested for normality (Shapiro–Wilk test) and equal variance. The effects of the sleep state, sleep position, and postterm CA on the frequency, duration of periodic breathing, and the cardiovascular effects (baseline and nadir percentage change in HR, SpO2, and TOI) were tested with a two-way analysis of variance (ANOVA) followed by a post hoc Student–Newman–Keuls test if required. The relationship between the duration of periodic breathing episodes and gestational age (GA) and nadir percentage change in HR, SpO2, and TOI were tested with Pearson’s correlation analysis. Results are expressed as mean ± standard error of the mean (SEM), and a p value of <0.05 was considered statistically significant. 3. Results 3.1. Demographics Infants (13 M/11 F) were born between 27.3 and 36.2 weeks of GA (mean 31.2 ± 0.5 weeks, mean ± SEM) with birth weights of between 925 and 3060 g (mean 1698 ± 112 g). All of the 24 infants were born with appropriate birth weight for GA. Apgar scores ranged from 2 to 9 (median 6) at 1 min and from 4 to 10 (median 9) at 5 min. Of the 24 infants, 13 had been administered caffeine for apnea of prematurity during their hospital stay and none were on caffeine at the time of the studies. Ten infants spent between 3 and 65 days in the neonatal intensive care unit. None of the infants was diagnosed with significant intraventricular hemorrhage (IVH grades III or IV) and none were on supplemental oxygen at the time of the studies. There were no differences in age or weight between the infants in this cohort who completed all three studies and the entire cohort (21 M/14 F) who were born between 26 and 36 weeks GA (mean GA at birth 31.2 ± 0.1 weeks, mean birth weight 1697 ± 92 g). Infants were studied at 2–4 weeks CA (mean 43 ± 0.1 weeks post-conceptional age), 2–3 months (mean 51 ± 0.2 weeks post-conceptional age), and 5–6 months (mean 63 ± 0.3 weeks post-conceptional age). Mean TST at 2–4 weeks was 3.5 ± 0.1 h, at 2–3 months 2.9 ± 0.1 h, and at 5–6 months 2.3 ± 2.6 h. 3.2. Periodic breathing episodes A total of 261 individual episodes of periodic breathing were detected: 164 at study 1, 62 at study 2, and 35 at study 3. Twenty-two of the 24 infants (92%) exhibited periodic breathing during at least one of the three studies: 19 infants (79%) at 2–4 weeks CA; 12 (50%) at 2–3 months CA; and 10 (42%) at 5–6 months CA. Seven infants (29 %) exhibited epochs of periodic breathing at all three studies and 10 infants (42%) at studies 1 and 2. The two infants who did not exhibit periodic breathing were one female infant born at 27.5 weeks of gestation and one male infant born at 30.2 weeks of gestation. The frequency and duration of periodic breathing at any of the three studies were not affected by GA at birth. There were no
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Table 1 Number and mean duration of episodes of periodic breathing and baseline values for heart rate (HR), oxygen saturation (SpO2), and cerebral oxygenation (TOI). Values are mean ± SEM.
2–4 weeks Number of episodes Episode duration (s) Baseline HR (bpm) Baseline SpO2 (%) Baseline TOI (%) 2–3 months Number of episodes Episode duration (s) Baseline HR (bpm) Baseline SpO2 (%) Baseline TOI (%) 5–6 months Number of episodes Episode duration (s) Baseline HR (bpm) Baseline SpO2 (%) Baseline TOI (%) ** p < 0.01 †† p < 0.01 ‡ p < 0.05 # p < 0.05
AS supine
AS prone
QS supine
QS prone
35 65 ± 9 134 ± 2 98.7 ± 0.1 64.4 ± 1.5***
20 45 ± 5 137 ± 2 †† 98.6 ± 0.2 48.1 ± 3.8
23 44 ± 5 135 ± 2 *** 97.9 ± 0.4** 62.8 ± 1.6
10 59 ± 12 146 ± 2 99.2 ± 0.2 58.5 ± 1.4
17 47 ± 2 128 ± 2 ‡ 98.8 ± 0.3†† 52.6 ± 4.9‡
14 46 ± 8 133 ± 2 98.9 ± 0.5†† 47.1 ± 2.2
6
1
35 ± 5 131 ± 1 ‡ 96.6 ± 0.3 52.4 ± 4.0‡
34 123 93.9 41.6
16 32 ± 2 128 ± 2 97.6 ± 0.2 59.6 ± 1.5
3
6
31 ± 4 126 ± 8 98.2 ± 0.4 55.1 ± 3.0
35 ± 7 116 ± 3 # 96.7 ± 0.2 56.1 ± 3.2
0 -
***p < 0.001 prone versus supine. AS versus QS. 2–4 weeks versus 2–3 months. 2–3 months versus 5–6 months.
statistically significant differences in periodic breathing frequency at any age studied; however, periodic breathing was least common in QS in the prone position with 10 episodes being recorded at 2–4 weeks CA, one at 2–3 months CA, and none at 5–6 months CA. Episodes of periodic breathing were most common in AS in the supine position with 35 episodes recorded at 2–4 weeks CA, 17 at 2–3 months CA, and 16 at 5–6 months CA (Table 1). The duration of periodic breathing episodes was not affected by post-term age in either position (data were only tested in AS) (Table 1). Overall, the periodic breathing frequency declined with increasing postnatal age (p < 0.05) (Table 1); however, this was not the case in all infants (Fig. 2). Of note, one infant who had only two episodes of periodic breathing recorded at study 1 and none at study 2 had 14 episodes recorded at study 3. The amount of time spent in periodic breathing at each study was calculated as a percentage of TST. Although this fell with age, 6.9 ± 2.4% at study 1, 3.6 ± 1.8% at study 2, and 1.3 ± 0.6% at study 3, this did not achieve statistical significance. There was considerable variability between infants across the three studies as illustrated in Fig. 2. 3.3. Effects of post-term CA on HR, SpO2, and TOI during periodic breathing Of the total number of events detected, 151 episodes (58%) contained no movement artifact and were analyzed: 88 at 2–4 weeks CA, 38 at 2–3 months CA, and 25 at 5–6 months CA. The effects of sleep state, sleep position, and postnatal age on baseline HR, SpO2, and TOI are presented in Table 1. At 2–4 weeks baseline, HR and SpO2 were significantly higher in the prone position compared to the supine position in QS and HR was lower in AS compared to QS when infants slept prone while SpO2 was higher in AS compared to QS when infants slept supine. TOI was higher in the supine compared to the prone position in both sleep states and this reached statistical significance in AS. At 2–3 months of age in both the prone and supine positions, SpO2 was higher in AS compared with QS. The effects of postnatal age on baseline HR, SpO2, and TOI are also presented in Table 1. HR and TOI were significantly lower at 2–3 months compared to 2–4 weeks in both AS and QS when infants
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2-4 weeks
total sleep time spent PB (%)
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Baby
2-3 months
total sleep time spent PB (%)
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Baby
5-6 months
total sleep time spent PB (%)
30 25 20 15 10 5 0 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Baby Fig. 2. Percent total sleep time individual preterm infants spent in periodic breathing (PB) at 2–4 weeks, 2–3 months, and 5–6 months corrected age.
slept supine. HR was also significantly lower at 5–6 months compared to 2–3 months in QS in the supine position. There were no effects of sleep state or sleep position on the nadir in percentage change in either SpO2, HR, or TOI at any of the three ages studied (Fig. 3A, 3B, and 3C). There were no effects of postnatal age on SpO2 in either sleep state or sleep position (Fig. 3A). In the majority of infants, periodic
breathing was not associated with desaturation during individual periodic breathing episodes, with a mean of 1.7 ± 0.8 s (range 0–46.8 s) spent <90% at study 1, 0.8 ± 0.3 s (range 0–9.7 s) at study 2, and 0.5 ± 0.3 s (range 0–4.6 s) at study 3. However, when infants were examined individually, infant 12 who spent <5% of his TST in periodic breathing spent 108.3 s with an SpO2 <90%, 94.0 s with an SpO2 <85%, and 78.8 s with an SpO2 <80% at study 1. At study 2, he spent
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Fig. 3. Effects of postnatal age on (A) peripheral oxygen saturation (SpO2), (B) percentage nadir in heart rate (HR), and (C) tissue oxygenation index (TOI).
15.7 s with an SpO2 <90% and 8.9 s with an SpO2 <85%. By contrast, infants 4 and 14 who spent over 25% of their sleep time in periodic breathing at study 1 spent no time with an SpO2 <90% and infant 16 spent only 2.9 s with an SpO2 <90%. Fig. 3B shows that the nadir in percentage fall in HR in AS in the prone position was significantly greater at study 2 (−21.9 ± 2.7%) compared to study 1 (−14.1 ± 2.3%, p < 0.05) and the nadir at study 2 was significantly greater than at study 3 (−5.4 ± 5.9%, p < 0.05). There were no differences in nadir change in HR in AS in the supine position or in QS in either position. Fig. 3C shows that in AS, the mean nadir percentage change in TOI was less in study 1 (−7.0 ± 1.2%) compared to study 2 (−13.1 ± 1.5%, p < 0.01) in the prone position and also in the supine position (−7.1 ± 0.9 c.f. −11.6 ± 1.4%, p < 0.01). In the supine position, the nadir in TOI was also significantly less at study 1 than at study 3 (−11.7 ± 1.4%, p < 0.05). In QS, mean nadir percentage change in TOI in the supine position was significantly less at study 1 (−5.3 ± 0.7%) compared to both study 2 (−11.3 ± 2.4%) and study 3 (−15.8 ± 1.3%, p < 0.001 for both). The effects in the prone position were not tested due to the infrequency of periodic breathing in QS in this position. This analysis identified three infants who had falls in HR, SpO2, and TOI with falls of 50%, 40%, and 36% during individual periodic breathing episodes, respectively. These changes were not related to the periodic breathing episode duration. All three infants were male and had been born at 27.3, 31.5, and 30.6 weeks of gestation with birth weights of 1087 g, 1660 g, and 1546 g, respectively. They had been ventilated for 50 days, six days, and one day, respectively (range for the whole group 0–63 days, median one day). There was nothing in the clinical history of these three infants which would distinguish them from the rest of the cohort.
When all data were combined at each age, there was no significant correlation between mean nadir percentage change in SpO2 or TOI and periodic breathing episode duration at any of the three studies. Mean nadir percentage change in HR was significantly correlated with periodic breathing episode duration at 2–3 months CA (p < 0.01).
4. Discussion In our longitudinal study of preterm infants who had been discharged home with no clinical concerns of respiratory instability, we observed that 92% of infants exhibited at least one episode of periodic breathing during a daytime nap study during the first 6 months after term CA. The incidence decreased with increasing postnatal age with 79% exhibiting periodic breathing at 2–4 weeks postterm CA, 50% at 2–3 months, and then 42% at 5–6 months. In contrast to apnea of prematurity, the incidence and duration of individual episodes of periodic breathing were not related to GA at birth. Although overall the duration of episodes of periodic breathing was not correlated with significant falls in HR, SpO2, or TOI, we did identify three infants in whom there were significant falls in these parameters. Because of its high prevalence, and the fact that periodic breathing is thought not to be associated with significant hypoxia or bradycardia, the traditional view of periodic breathing is that it is simply due to immaturity of respiratory control and is benign [8]. Overall, we found minimal consequences of periodic breathing and the duration of periodic breathing episodes was not related to peripheral desaturation. However, there were a number of episodes
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where SpO2 fell by >4% and some infants spent extended periods with an SpO2 <90%. These falls in SpO2 were similar to those reported by Poets and Southall [15] in preterm infants studied at around term-equivalent age and emphasize that periodic breathing is not always benign in nature. Similarly, we demonstrated that there was no significant bradycardia in most episodes and that the duration of periodic breathing episodes was not related to the severity of bradycardia. As with SpO2, there were, however, a number of episodes where HR fell by >20%. With regard to cerebral hemodynamics, we showed that episodes of periodic breathing were associated with significant falls in TOI, which again were not related to episode duration. Interestingly, our study identified that these falls in TOI were least at 2–4 weeks of age and more pronounced at 2–3 months of age. Arithmetically, the higher percentage fall in TOI could be in part due to the lower baseline cerebral TOI at 2–3 months of age, which, as in this study, has also been identified in previous studies by our group in both term [13] and preterm infants [11]. Physiologically, we have previously suggested that this agerelated progression is due to maturation of cerebral blood flow– metabolism coupling during this period, at 2–3 months CA in combination with rapid growth of the brain and accompanying increases in cerebral oxygen requirements [13]. Accordingly, a mismatch between cerebral metabolic demands and cerebral oxygen delivery at this age leads to a nadir in TOI. In addition, there is a physiological anemia also occurring at this age [16], further increasing the cerebral oxygen extraction in order to meet the metabolic demand. Thus, any reduction in SpO2 and cardiac output (as indicated by falls in HR) as occurs during periodic breathing is likely to have a more marked effect on TOI. Clinically, our findings suggest that infants with periodic breathing at 2–3 months of age would warrant close observation and further studies with neurodevelopmental follow-up in this population would be required. Previous studies have examined changes in cerebral hemodynamics associated with apnea of prematurity and have identified that cerebral blood volume [17,18] and cerebral blood flow velocity [19] decrease during a single apnea. However, to date, there has only been one study in healthy term-born infants on the effects of periodic breathing on cerebral hemodynamics. This study [10] showed that periodic breathing episodes >1 min in duration were associated with cyclical variations in the hemoglobin oxygenation index. Changes in cerebral blood volume occurred in 42% of episodes and these were correlated with changes in HR. Animal studies have shown that repeated episodes of hypoxemia can cause brain injury [20]. Furthermore, low regional cerebral oxygenation levels while in the neonatal unit have been associated with poorer neurodevelopmental outcomes at 18 months [21]. Repetitive apneas have been shown to impair growth and development [22,23], be a source of oxidative stress which is associated with pro-inflammatory mechanisms that could contribute to lung and airway alterations [3], alter cardiovascular regulation [3], and lower neurodevelopmental outcomes [24,25]. To date, no studies have examined the effects of prolonged apnea and bradycardia during infancy on neurodevelopmental outcomes. However, it is known that the repetitive hypoxia associated with obstructive sleep apnea in childhood is associated with both behavioral and neurocognitive deficits [26]. The concept of loop gain has been used to understand the mechanisms that predispose infants to periodic breathing [8]. Periodic breathing is favored by a hypersensitive chemoreceptor response, a low lung gas store, a delay in sensory information reaching the chemoreceptors, and a large arterial-inspired gradient for oxygen and carbon dioxide which lead to large changes in the ratio of arterial partial pressure of oxygen to the arterial partial pressure of carbon dioxide [8]. In term infants, periodic breathing is likely due to a hypersensitivity of the carotid bodies; however, in preterm infants the other factors listed above also likely play a role [8].
Previous studies of the occurrence of apnea of prematurity in preterm infants have highlighted that the incidence increases with decreasing GA at birth and is maximal at 30–31 weeks of gestation with approximately half of infants being affected [27]. By contrast, we found that periodic breathing incidence and duration was not related to GA at birth. Previous studies of the incidence of periodic breathing recorded prior to discharge (33–37 weeks GA) also did not find an association with subject characteristics including GA at birth, birth weight, or GA at testing [28]. Several studies have examined the incidence of periodic breathing in preterm infants prior to hospital discharge. Globtzbach et al. [29] found that all of the 66 preterm infants studied prior to discharge from hospital had episodes of periodic breathing. Similarly, Razi et al. [28] also found that all 343 infants born between 27 and 34 weeks GA and studied at 33–37 weeks GA exhibited episodes of periodic breathing. Earlier studies have also identified that the incidence of periodic breathing at term-equivalent age is higher in preterm compared to termborn infants [7]. Our finding that periodic breathing occurred in all but two of 24 infants (92%) over the first six months after termequivalent age expands these findings and highlights the increased incidence of periodic breathing in preterm infants. The majority of studies of the longitudinal changes in periodic breathing incidence have been in term-born infants. These studies have shown that although periodic breathing is common in the first 2 weeks of life occurring in 78% of infants, the incidence falls to 29% in infants aged 39–52 weeks [5]. In term infants, the percentage of TST spent in periodic breathing is low with reference values of a median of 1.1 % (maximum 10.4%) at one month and median 1% (maximum 4.6%) at 3 months in 37 infants [6]. Our study found that overall the percentage of TST spent in periodic breathing was low; however, at 2–4 weeks CA four infants spent >20% of TST periodic breathing, and at 2–3 months two infants spent > 15% of TST in periodic breathing. These times spent in periodic breathing far exceed those reported in term infants [6]. Our study also considered the effects of sleep state and sleeping position on periodic breathing longitudinally as these factors have been shown to influence the incidence of periodic breathing in preterm infants before term-equivalent [30] and also after termequivalent age [7,31]. Similar to previous studies, we found that periodic breathing was more common in AS and in the supine position and least common in QS in the prone position. Previous studies have identified that respiratory instability is higher in AS compared to QS and is also more common in the supine compared to the prone position in preterm infants [32]. It has been suggested that this increased instability in AS may result from overall immaturity of respiratory control components and from the phasic inhibitory–excitatory mechanisms inherent in this sleep state [33], and it is also known that carotid body activity is elevated in AS [34]. We found that the frequency but not duration of periodic breathing decreased with increasing post-conceptional age. Previous studies have also reported that the frequency of periodic breathing decreases with increasing postnatal age in both term [5–7,31] and preterm infants [7,31]. In contrast to previous studies, we did not identify any effect of postnatal age on periodic breathing episode duration. Wilkinson et al. [31] reported that periodic breathing episode duration decreased from a mean of 18.3 s at 36–38 weeks GA to 9.8 s at 5–6 months CA. These results are probably due to differences between the studies, with Wilkinson et al. [31] expressing their data as post-conceptional age and also having an earlier study time prior to term. We acknowledge that the major limitation to this study was the small sample size of 24 infants and the wide GA at which they were born. However, our analysis showed that GA did not affect the incidence of periodic breathing and our study design allowed repeatedmeasures analysis to examine the effects of sleep state and sleeping position on the physiological variables of interest.
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5. Conclusions Periodic breathing induces repetitive decreases in HR, arterial oxygenation, and cerebral oxygenation over the first six months after term CA in preterm infants. While most infants spent a small percentage of TST in periodic breathing and had minimal or no associated hypoxia, a minority of infants had significant hypoxia, bradycardia, and decreased cerebral oxygenation, which would have otherwise gone undetected. The clinical significance of this is unknown but has the potential to influence neurodevelopmental outcomes. Further research to elucidate the effects, if any, of significant periodic breathing, on growth and development is required.
Conflict of interest The authors have no financial relationships relevant to this article to disclose. Funding for this project was provided by The National Health and Medical Research Council of Australia APP1006647 the Victorian Government’s Operational Infrastructure Support Program and The Lullaby Trust (UK). The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.02.537.
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