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The aim of this study was to examine cardiorespiratory control in infants presenting with an apparent life-threatening event (ALTE). We performed six to eight 45° head-up tilts in 10 ALTE infants (age, 14 ± 3 weeks) and 12 age-matched control subjects during slow wave sleep and rapid eye movement sleep (REM). All infants underwent full overnight polygraphic sleep recordings with noninvasive measurement of beat-to-beat blood pressure. All control infants had normal sleep breathing. In contrast, 5 of the 10 ALTE infants had more than two obstructive apneas per hour of sleep, with short hypoxic episodes (obstructive sleep apnea [OSA]). In slow wave sleep, in response to the tilt, the ALTE infants with OSA showed a reduced heart rate response, and three of the five showed a marked postural hypotension. The ALTE infants with OSA also had altered heart rate and blood pressure variability and an increased arousal threshold in REM (p = 0.0002). By contrast, those ALTE infants with normal sleep breathing had cardiovascular and arousal responses similar to those of the control infants. We conclude that a number of ALTE infants with OSA have abnormal cardiovascular autonomic control that, combined with their decreased arousability in REM, may provide an explanation for the ALTE episodes.
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Keywords: autonomic nervous system; infant; sleep apnea, obstructive
Infants presenting with an apparent life-threatening event (ALTE) are reported to have had an acute and unexpected change in behavior that has severely alarmed the caregiver. In some cases the caregiver thinks the child has died. Usually such an event involves a combination of color change (pallid or cyanotic), usually limpness, and apnea, choking, or gagging (1). It is thought that between 0.05 and 6.0% of the general population have experienced an ALTE (2).
A number of studies have shown that a high percentage of ALTE infants exhibit sleep-disordered breathing with obstructive breathing episodes (3-5), lower heart rate variability (6), altered autonomic control during sleep (7, 8), increased arousal thresholds (9), and fewer body movements in sleep (10) when compared with aged-matched control subjects. These findings are suggestive of a subtle cardiovascular autonomic control.
Given these findings it is important to establish whether there is any association between ALTE, sleep-disordered breathing, and autonomic dysfunction. To date, autonomic cardiovascular function in infants has been assessed primarily on the basis of heart rate parameters alone because of the difficulty of obtaining continuous blood pressure measurements. However, it is now possible to measure beat-to-beat blood pressure in infants using the Portapres device (11-13), and this has enabled a fuller characterization of infant autonomic responses.
The purpose of the present study was to examine cardiovascular autonomic function, using a noninvasive measure of blood pressure. We measured the response to a 45° head-up tilt in ALTE infants while asleep and assessed whether there was any association between an abnormality of autonomic cardiovascular control and sleep-disordered breathing in these infants.
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Subjects
Ten infants, 14 ± 3 weeks of age, who had a history of an ALTE, were enrolled in the study. For the purposes of this study, an ALTE was defined as an apneic episode occurring during sleep, which involved some color change and/or limpness that severely alarmed the caregiver. Before the sleep study, clinical evaluation of these infants did not reveal any abnormality.
Control Subjects
Twelve full-term, healthy infants (13 ± 2 weeks of age) were studied. All infants enrolled in the study had a normal clinical examination on the third day of life and before the study. A family history of ALTE or sudden infant death syndrome was excluded.
Written parental consent was obtained in all cases. The study protocol was approved by the Sydney Children's Hospital (Sydney, Australia) Ethics Review Committee.
Study Protocol
The protocol has been described previously (13). All infants were admitted for full overnight polygraphic sleep studies. Polysomnography was performed with the Compumedics S series system (Compumedics, Melbourne, Australia). Heart rate (HR) was assessed by continuous electrocardiograph recording. As described previously, continuous, noninvasive arterial blood pressure (BP) measurement was performed with the Portapres device (TNO Biomedical Instrumentation, Amsterdam, The Netherlands), with the inflatable cuff being placed around the infant's wrist. During slow wave sleep (SWS) and rapid eye movement sleep (REM), eight consecutive 45° head-up tilts were performed with at least a 1-minute control period between each tilt. Further details about the protocol are provided in the online data supplement.
The infant was tilted manually from the horizontal position to a 45° angle within 2-3 seconds. This position was maintained for between 20 and 60 seconds. If the tilt resulted in a transient arousal, sigh, or apnea, these data were excluded from the hemodynamic analysis, but were included in the assessment of arousal response. An arousal was defined as a full cortical arousal, as evidenced by the electroencephalogram polygraph, which was maintained for more than 3 seconds. Subcortical arousals were not noted.
Data and Statistical Analysis
Sleep staging was done according to the criteria of Guilleminault and Souquet (14). Apneas were recorded if there was a pause in breathing of greater than or equal to two respiratory cycles with or without oxygen desaturation. Apneas were divided into central, obstructive, and mixed apneas. An obstructive respiratory disturbance index of greater than two was considered to be abnormal (9).
A 30-second mean reference period was calculated before each tilt. Maximum values (and standard deviations) for diastolic blood pressure, systolic blood pressure, and HR were then calculated for every 5-second epoch throughout the pretilting reference period and tilting period and expressed as the maximum percentage change from the reference period. The ratio of the average time between R-wave peaks (R-R interval changes) was calculated by comparing the minimum R-R interval seen after the tilt with the maximum R-R interval within 25 beats of the postural change.
Arousal responses were calculated as a percentage of the number of tilt tests to cause a sleep state change as evidenced by the electroencephalogram.
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All control data have been presented previously (13). The mean duration of sleep recordings was 477 (± 56) minutes for control subjects and 501 (± 49) minutes for ALTE infants (no significant difference), and the mean number of sleep cycles for that duration was 32 (± 3.7) for control subjects and 36 (± 2.6) for the ALTE infants (p < 0.05). All control infants had normal sleep breathing. In contrast, the ALTE group had an obstructive respiratory disturbance index of eight (± 8). Five ALTE infants had obstructive sleep apnea (OSA) (the ALTE-OSA group) with a mean obstructive respiratory disturbance index of 15 (± 6), and 5 ALTE infants had normal sleep breathing (the ALTE-no OSA group) with an obstructive respiratory disturbance index of 1 (± 0.5).
Although these two groups were easily divided on the basis of their sleep breathing, it was not possible to distinguish these two groups on the basis of the clinical history of the ALTE episode. In both groups three of the five infants were cyanotic, and all five ALTE-OSA infants and four of the ALTE-no OSA infants were reported to be floppy. Cardiopulmonary resuscitation was performed on three of the five ALTE-OSA infants, but only one of the five ALTE no-OSA infants needed cardiopulmonary resuscitation. This may indicate the severity of the episode, but of itself was not sufficient to distinguish the two groups.
As a group, the ALTE infants had a significantly increased heart rate (p < 0.05) in SWS compared with the control subjects. The ALTE-OSA group had a significantly higher heart rate in both SWS and REM compared with the control subjects (p < 0.05), whereas the ALTE-no OSA group had a heart rate similar to that of the control subjects in both sleep states (Figure 1A).
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Heart rate variability (HRV) was significantly lowered in SWS in the ALTE group as a whole (coefficient of variation, 2.6 ± 0.9%), and in the ALTE-OSA group (2.0 ± 0.7%), compared with the control group (3.6 ± 0.7%), although this difference was not observed in REM. The HRV of the ALTE-no OSA group in both sleep states was similar to that of the control infants.
There was a significant rise in both systolic BP and diastolic BP from SWS to REM, p < 0.05 (Figures 1B and 1C) in the control group. Although this difference was not evident in the ALTE group as a whole, the ALTE-no OSA infants showed a rise similar to that of the control subjects in BP between SWS and REM whereas the ALTE-OSA infants showed a slight, although not significant, decrease in BP during REM compared with SWS (Figures 1B and 1C).
Blood pressure variability (BPV) was significantly higher (coefficient of variation, 3.1 ± 0.9%) in SWS in the ALTE group compared with the control infants (2.1 ± 0.5%), and this difference was further accentuated when just the ALTE-OSA infants were considered (3.3 ± 0.9%). There was no difference between BPV in the ALTE-no OSA infants and the control infants. BPV increased in all groups between SWS and REM, but there was no significant difference in BPV in REM between the groups. Characteristics of the different study groups and individual results are provided in the online data supplement.
45° Head-up tilting. A number of the 45° head-up tilting maneuvers had to be discarded because of artifacts, with the greater number of tests being discarded from the control group (50 ± 25%) compared with the ALTE infants (37 ± 37%).
All control infants showed a characteristic biphasic HR and BP response to the head-up tilt in both SWS and REM (Figure 2A, top panel and Figure 3A, top panel). On tilting, the control infants had an increase, followed by a decrease, in both HR and BP (Tables 1 and 2). Peak values of HR and BP were attained within six to eight heart beats from the initiation of the tilt and a return to pretilt values occurred within about 10 seconds (Figure 4A). This increase in HR, followed by a decrease, was reflected in the R-R interval changes in response to the tilt, with the maximum-to-minimum R-R interval ratio being greater than one in all control subjects (Table 1). Figure 4A shows a typical example of the HR and BP response to the head-up tilt in a control infant.
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The biphasic response was also evident in the ALTE group (Figure 2A, bottom panel and Figure 3A, bottom panel), although the extent of the HR and BP responses was significantly reduced in both sleep states. In SWS, the ALTE group showed a mean maximal increase in HR of only 9%, (compared with 16% in the control group) followed by a mean maximal drop in HR of 13% (compared with 21% in the control group) (Table 1). This reduced heart rate response was reflected in the maximum-to-minimum R-R ratio, with the ratio being significantly reduced in this group compared with the control subjects. Systolic BP and diastolic BP showed a similar attenuated response (Table 2). Both HR and BP returned to pretilt values within the same time frame as the control group. A similar reduced response was also evident in REM.
When the ALTE group was further subdivided into those infants with OSA and those without OSA, the reduced biphasic response was not evident in the ALTE-no OSA group. Indeed, the increases in HR, R-R interval ratio, and BP were of the same order as the control group in both sleep states (Tables 1 and 2; Figure 2B, bottom panel and Figure 3B, bottom panel).
However, the hemodynamic response in the ALTE-OSA group to the head-up tilt was significantly different qualitatively and quantitatively (Figure 2B, top panel and Figure 3B, top panel) from both the control and ALTE-no OSA groups. In SWS, all five of the infants in the ALTE-OSA group showed either no HR response or only a minimal HR response, and in two of these infants the maximum-to-minimum R-R interval was less than one. Four of the five infants had either no BP rise or only a minimal rise followed by a sustained decrease in BP for the duration of the tilt (Tables 1 and 2), and three of these four infants had a greater than 10% decrease in BP throughout the duration of the tilt (Figure 4B). The fifth infant in this group had a sustained increase in BP of 20% throughout the duration of the tilt, again with no change in HR (Figure 4C). In REM, the ALTE-OSA infants again showed a minimal HR response; however, whereas the BP response was also minimal, there was not a sustained decrease in BP.
In both sleep states, on lowering the infant back to the supine position, the control infants showed a transient increase in HR and BP. The HR and BP response was not as marked as at the initiation of the tilt and was more variable (Figure 2A, top panel and Figure 3A, top panel). The re-establishment of pretilt values took slightly longer in this second phase of the test compared with the initial phase (25 seconds compared with 15 seconds).
The ALTE group, as a whole, had a similar hemodynamic response to the return to the supine position as the control group. The ALTE-OSA group also showed this same profile, but the ALTE-no OSA group showed a marked transient decrease in BP on return to the supine position, which was not evident in any of the other groups.
The tilting maneuver caused a number of arousals. Infants aroused a significantly greater number of times in REM compared with SWS in both the control (p < 0.005) and ALTE groups (p < 0.05), although the ALTE infants, as a group, aroused less frequently in REM than did the control infants. However, the ALTE-OSA infants displayed no difference in their arousability in REM compared with SWS, arousing an equal number of times in either sleep state, whereas the arousability of the ALTE-no OSA infants matched that of the control group (Figure 5).
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The main findings of this study are that a significant number of the ALTE infants in this study who had OSA also had altered cardiovascular variability as well as postural hypotension during SWS in response to a postural challenge concomitant with depressed arousal responses. There are a number of studies that have shown the presence of obstructive apneas in sleep in infants who have presented with an ALTE (14-16). In a study by Guilleminault and coworkers, who performed nocturnal polygraphic recordings on 346 ALTE infants over a period of 10 years, 57% were found to have obstructive breathing episodes during sleep (4). This figure is similar to the results of a study by Kurz and associates (3), which showed that 17 of 28 infants presenting with ALTE had sleep apnea syndrome. Although ours is only a small sample, our finding that 50% of the ALTE infants had disordered sleep breathing is consistent with these previous reports.
Baseline HR, HRV, BP, and BPV were higher in REM than in SWS for both groups. Previous studies have shown that ALTE infants, as a group, have higher heart rates and reduced HRV than control infants (6, 17). Our study confirmed this finding, with two major differences. First, there was a clear demarcation between the ALTE infants with and without OSA. Indeed, those ALTE infants without OSA had an HR and HRV comparable to those of the control group, and it was only those infants with OSA who exhibited a higher HR and reduced HRV. This reduced HRV was only evident in SWS, a fact that supports previous research (6). Second, infants with OSA have significantly increased BPV in SWS compared with control subjects.
Altered cardiovascular variability has been observed in adults with OSA (18). Adults suffering from moderate-severe OSA have a reduced HR, an attenuated HRV, and increased BPV. The fact that this altered cardiovascular variability pattern was also observed in our group of ALTE infants with OSA may well indicate that the repetitive sympathetic activation consequent to apneic episodes may cause an impairment of baroreflex and other cardiovascular reflex functions.
Another important finding of this study is the change in BP due to sleep states in ALTE infants. We have previously shown (13) that BP is elevated in REM compared with SWS in normal infants. However, in this study, we found that four of the five infants with OSA did not have an increased BP in REM, and in fact, in two of these infants there was a slight decrease in BP in REM, although this was not significant. Blunting of the normal decline in BP during sleep has been described in adults with OSA (19), which may be due to either the constant high level of sympathetic activity present with the recurrent obstructive apneas and hypoxia or to an ineffective parasympathetic response.
The ALTE infants with OSA in this study appear to be vulnerable as a result of both their depressed arousal responses and their altered cardiovascular variability.
As reported previously, there is a characteristic biphasic response to the 45° head-up tilt in control infants (13) that follows the pattern well described in adults (20, 21). This characteristic profile was observed in all control infants and in the ALTE infants without OSA. However, none of the ALTE infants with OSA had this characteristic response. In SWS, three of the five infants had sustained hypotension (> 10% decrease in BP) (7, 22) and one had sustained hypertension throughout the duration of the tilt with little, if any, HR change. A number of previous studies have shown that some ALTE infants have different HR and BP responses to head-up tilt (7, 8, 22, 23) compared with control infants. Indeed, a number of these studies have shown that some ALTE infants have minimal, if any, HR change (8), as well as postural hypotension. However, these previous studies of infants have been confined to either HR alone or to HR and intermittent BP measurements, which have not allowed for the observation of immediate, beat-to-beat hemodynamic changes. Moreover, previous studies have not performed full overnight polysomnography, and therefore were unable to determine whether the infant had obstructed breathing during sleep. Recently, evidence of abnormal autonomic responses has been found in adults with some form of sleep-disordered breathing. Guilleminault and coworkers have found that some young adults with the high upper airway resistance syndrome also had postural hypotension (24).
The hemodynamic changes observed in three of the ALTE infants with OSA (sustained hypotension with minimal HR changes) are not dissimilar from those described in patients with adrenergic failure (25). During upright tilt, these patients have a marked and progressive reduction in BP and pulse pressure, and the HR is typically attenuated, but in patients whose cardiac adrenergic innervation is spared the HR response is intact and may be increased.
Although this description adequately indicates what happened to the infants with OSA in our study, the picture is somewhat more complex given their apparent high level of sympathetic activity during normal sleep. Although it is known that sympathetic efferents control arteriolar tone and thus peripheral vascular resistance, the central mechanisms by which this occurs are only now beginning to be understood in adults (26, 27); there are, however, few data available for infants. A high resting level of peripheral sympathetic activity has been shown to occur in adult patients with OSA (28), and is likely the mechanism of systemic hypertension known to be associated with OSA.
The pattern of HR and BP responses to the postural challenge in normal infants is consistent with that described in older subjects; however, the rapidity of the response (maximum values of HR and BP achieved within six to eight heart beats) is not. It has been suggested that perhaps this immediate rise in BP is the result of the initial action of the rapidly acting vestibular system, with baroreceptor regulation having a secondary and more gradual effect (13). Harper (29) has suggested that the neural compensatory mechanisms involved in hypo- or hypertension may well be mediated through afferent activity from the inferior olivary nucleus to the fastigial nucleus of the cerebellum, and then via efferent activity to the central sympathetic neural control regions.
If the immediate cardiovascular responses to postural change are mediated through the vestibular system, then the infants with OSA may have some impairment of this compensatory mechanism, perhaps as a result of the hypoxic episodes caused either by recurrent obstructed breaths or by the ALTE episode itself, with the output to the sympathetic pathways consequently being impaired. Certainly, histopathological work (30) has revealed that portions of the inferior olive, a major input relay to the cerebellum involved in vestibular responses, show significant gliosis in infants with severe respiratory dysfunction and abnormalities of the ventral medullary surface, including the inferior olive, have also been found in victims of sudden infant death syndrome (31).
Our finding of an infant with OSA who had sustained high blood pressure throughout the duration of the tilt could be the result of an apnea-induced high sympathetic output (analogous to adult sleep apnea) with an abnormal central integration of vestibular and baroreceptor inputs.
Interestingly, in REM the infants did not display sustained hypotension, although it took slightly longer for BP to return to pre-tilt BP values, when compared with the control subjects. The reason for this is unknown but probably it is due to the different BP regulation between the two major sleep states (32).
The present study also shows that infants with OSA have significantly depressed arousal responses, in this case, to a postural challenge. Further, this reduced arousal was particularly evident in REM. The finding of a clear differential in the arousal thresholds between SWS and REM in the control and the ALTE-no OSA groups is in accord with data from Galland and associates (33), who also found differential arousal responses to the head-up tilt in control infants in the different sleep states.
A number of previous studies have provided evidence that infants with ALTE have defective arousal responses to hypoxia (34-36), fewer arousals from sleep, and fewer body movements (9, 10, 37), although the reason for this is unknown. It has also been shown that infants with OSA have fewer spontaneous arousals during sleep compared with normal infants and that treatment of their OSA with nasal continuous positive airway pressure normalizes their spontaneous arousals during sleep (38). Other studies have shown that babies born to smoking mothers have a higher arousal threshold to auditory challenges as well as altered autonomic function (39, 40). The present study provides evidence that OSA may play a significant role in reducing arousability to certain stimuli and suggests that this depression of arousability is most marked in REM. The fact that obstructive apnea in infants is typically worse, or only present, in REM suggests that selective REM-linked apnea produces a selective REM-linked decrement of arousability.
This study has shown that some infants with OSA have abnormal autonomic cardiovascular control and decreased arousal
responses. All these features were coincident in a number of
infants who presented with an ALTE. From this study, it is not
known whether OSA plays a causal or a consequential role
indeed, there may well be a common cause for both the obstructive apnea and the autonomic cardiovascular abnormalities.
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Footnotes |
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Correspondence and requests for reprints should be addressed to C. Harrington, B.Sc., David Read Laboratory, University of Sydney, Missenden Road, Camperdown, Sydney, Australia 2006. E-mail: cth{at}med.usyd.edu.au
(Received in original form February 16, 2001 and accepted in revised form January 9, 2002).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.orgAcknowledgments: Supported by NH&MRC grant 107471.
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  B. Bollen, M. Bouslama, B. Matrot, Y. Rotrou, G. Vardon, F. Lofaso, O. Van den Bergh, R. D'Hooge, and J. Gallego Cold stimulates the behavioral response to hypoxia in newborn mice Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2009; 296(5): R1503 - R1511. [Abstract] [Full Text] [PDF]
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 T Saiki, H Rao, F Landolfo, A P R Smith, S Hannam, G F Rafferty, and A Greenough Sleeping position, oxygenation and lung function in prematurely born infants studied post term Arch. Dis. Child. Fetal Neonatal Ed., March 1, 2009; 94(2): F133 - F137. [Abstract] [Full Text] [PDF]
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 M.-K. Yum, J.-T. Kim, and H.-S. Kim Increased non-stationarity of heart rate during general anaesthesia with sevoflurane or desflurane in children Br. J. Anaesth., June 1, 2008; 100(6): 772 - 779. [Abstract] [Full Text] [PDF]
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 P. S. Zeskind and J. L. Gingras Maternal Cigarette-Smoking During Pregnancy Disrupts Rhythms in Fetal Heart Rate J. Pediatr. Psychol., January 1, 2006; 31(1): 5 - 14. [Abstract] [Full Text] [PDF]
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 K. A. Waters and K. D. Tinworth Habituation of Arousal Responses after Intermittent Hypercapnic Hypoxia in Piglets Am. J. Respir. Crit. Care Med., June 1, 2005; 171(11): 1305 - 1311. [Abstract] [Full Text] [PDF]
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 T. Kirjavainen, S. Viskari, O. Pitkanen, and E. Jokinen Infants with univentricular heart have reduced heart rate and blood pressure responses to side motion and altered responses to head-up tilt J Appl Physiol, February 1, 2005; 98(2): 518 - 525. [Abstract] [Full Text] [PDF]
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 M Vennelle, P E Brander, R N Kingshott, K Rees, P M Warren, J W Keeling, and N J Douglas Is there a familial association between obstructive sleep apnoea/hypopnoea and the sudden infant death syndrome? Thorax, April 1, 2004; 59(4): 337 - 341. [Abstract] [Full Text] [PDF]
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E. Durand, F. Lofaso, S. Dauger, G. Vardon, C. Gaultier, and J. Gallego Intermittent hypoxia induces transient arousal delay in newborn mice J Appl Physiol, March 1, 2004; 96(3): 1216 - 1222. [Abstract] [Full Text] [PDF]
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I. Kato, P. Franco, J. Groswasser, S. Scaillet, I. Kelmanson, H. Togari, and A. Kahn Incomplete Arousal Processes in Infants Who Were Victims of Sudden Death Am. J. Respir. Crit. Care Med., December 1, 2003; 168(11): 1298 - 1303. [Abstract] [Full Text] [PDF]
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C. Harrington, T. Kirjavainen, A. Teng, and C. E. Sullivan nCPAP improves abnormal autonomic function in at-risk-for-SIDS infants with OSA J Appl Physiol, October 1, 2003; 95(4): 1591 - 1597. [Abstract] [Full Text] [PDF]
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M. J. Tobin Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, and Pulmonary Function Testing in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 306 - 318. [Full Text] [PDF]
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M. J. Tobin Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 333 - 344. [Full Text] [PDF]
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