EDITORIALS nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350:2645–2653. 13. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med 2009;360:2445–2454. 14. Kunisaki KM. Will expanded ART use reduce the burden of HIVassociated chronic lung disease? Curr Opin HIV AIDS 2014;9: 27–33.

15. Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and Cushing’s syndrome secondary to an interaction between ritonavir and fluticasone: a review of the literature. HIV Med 2008;9: 389–396.

Copyright © 2014 by the American Thoracic Society

Former Preterm Infants, Caffeine Was Good for You, But Now Beware of Snoring! Extremely premature infants are surviving and reaching adulthood as a result of tremendous advancement in the field of medicine. This was unthinkable a few decades ago. However, they are not only surviving but also presenting with challenges and health-related issues, which are still not defined or characterized clearly. Recent data suggest that adults who were born at a premature gestational age may present with conditions similar to chronic obstructive pulmonary disease (1). We know very little about the effect of the therapies we use saving these premature infants during an extremely vulnerable time of growth, and even less is known about the long-term effects of the therapies. This becomes more relevant as the infants approach young adulthood. There is a critical need to assess the long-term effects of interventions applied to this vulnerable population as they grow older. One such intervention is the use of caffeine in premature infants. Caffeine, in different forms, is used throughout the human age spectrum for various reasons and has significant effects on neuronal circuitry and functions such as sleep. In this issue of the Journal, Marcus and colleagues (pp. 791– 799) report results of a cross-sectional study on the long-term effects of therapeutic caffeine on sleep characteristics in a subgroup of 201 infants who participated in the Caffeine for Apnea of Prematurity (CAP) study (2). This was a large, randomized controlled trial investigating the neurodevelopmental effects of caffeine citrate in 2,006 infants of less than 1,251 g birth weight. In the present followup study, patients underwent polysomnography and actigraphy at age 5–12 years to investigate the potential long-term effects of caffeine on sleep architecture and obstructive sleep apnea syndrome (OSAS). The authors report no significant differences in sleep quality or quantity or OSAS between the groups. Given that the incidence of OSAS in children born at term is around 1–4% (3, 4), the authors found a high prevalence of OSAS: 10% had polysomnographyconfirmed OSAS and 26% had either an elevated apnea/hypopnea index or a history of prior adenotonsillectomy. The authors also discovered an increased prevalence of periodic leg movements in both groups, irrespective of the use of caffeine. The strengths of this study include a high rate of successfully performed home polysomnographies (98%) and a large sample size. But what follows from its findings? Basically, there is good and bad news in these data. The bad news, as already shown with less sophisticated methodology or in much smaller patient samples (3, 5), is that infants born preterm have a 3–5 times higher risk of developing obstructive sleep apnea later in childhood. Is this plausible?


OSAS is more likely to develop in patients with a narrow upper airway and/or reduced muscle tone. Traditionally, preterm infants often develop a narrow face and an arched palate, perhaps related to their being intubated or constantly lying in a prone position during their first postnatal weeks in the neonatal intensive care unit (6). They may also suffer from disturbed chemoreceptor functioning, at least if they also develop bronchopulmonary dysplasia (7). Thus, if the association between preterm birth and a high risk of obstructive sleep apnea were biologically plausible, what would be the consequences? Both preterm birth and OSAS are risk factors for developing metabolic syndrome. Recent data suggest that insulin levels of preterm infants are increased if they are measured in cord blood (8), making it unlikely that OSAS serves as an intervening variable for developing metabolic syndrome in former preterm infants, but suggesting instead that both are additive risk factors. Moreover, preterm birth and sleep-disordered breathing are both associated with poor academic achievements (9, 10), and although the contribution of the former is probably difficult to avoid, that of the latter should be preventable, but only if detected and treated early (11, 12). Identifying OSAS early after its occurrence is probably also important to prevent its recurrence when reaching adult age. Recent data show that children with OSAS have impaired twopoint discrimination in their tongue and hard palate, suggesting the permanent vibrations caused by their snoring may result in permanent nerve damage to their upper airway, potentially forming the basis for the recurrence of OSAS in adult life (13). Taken together, these data strongly suggest that sleepdisordered breathing in children, particularly those born preterm, should be identified, characterized, and treated (e.g., by antiinflammatory drugs or adenotomy) (14) to prevent long-term consequences extending into adulthood. The good news in the study by Marcus and colleagues (2) is that neonatal caffeine citrate treatment, recently shown to exert positive effects on motor development that extend into middle childhood (15), does not appear to come at the expense of poor sleep quality or quantity. This is particularly reassuring, given the fact that caffeine ranks third among drugs most commonly used in the neonatal intensive care unit (16). Thus, these new data provide further reassurance for a considerable proportion of children born preterm that neonatal caffeine administration is safe. Nonetheless, several open questions remain. For example, although it has recently been shown that caffeine

American Journal of Respiratory and Critical Care Medicine Volume 190 Number 7 | October 1 2014

EDITORIALS citrate also reduces intermittent hypoxia in more mature infants than in those studied in the CAP trial (17), it is yet unclear what its effects on neurodevelopmental outcomes are in this age group. Also, why caffeine improved outcome is unclear, as the CAP trial did not record information on apneas or (more relevant) episodes of intermittent hypoxia/bradycardia. This requires more data on the neurocognitive consequences of intermittent hypoxia in early life, which hopefully will soon come out of analyses of the data from recent trials of oxygen targeting in extremely low gestational age infants (18) currently being conducted. Although the current study does not show any harmful effects on sleep, does it mean we need to take a closer look at the long-term potential effect of caffeine on sleep disturbances, using more sophisticated methods, including spectral analysis of the EEG or cyclic alternating pattern that can suggest increased arousability and so forth? In the meantime, although caffeine use in infants at risk for intermittent hypoxia or so-called apnea of prematurity seems comparatively safe, we are reminded that close follow-up is mandatory in this vulnerable population, not least to identify and treat OSAS early in these patients. n Author disclosures are available with the text of this article at www.atsjournals.org. Christian F. Poets, M.D. Department of Neonatology Tubingen ¨ University Hospital Tubingen, ¨ Germany Salman Raza Khan, M.D. Division of Pulmonology and Sleep Medicine Children’s Hospital of Los Angeles Los Angeles, California

References 1. Brostrom ¨ EB, Akre O, Katz-Salamon M, Jaraj D, Kaijser M. Obstructive pulmonary disease in old age among individuals born preterm. Eur J Epidemiol 2013;28:79–85. 2. Marcus CL, Meltzer LJ, Roberts RS, Traylor J, Dix J, D’ilario J, Asztalos E, Opie G, Doyle LW, Biggs SN, et al.; Caffeine for Apnea of Prematurity–Sleep Study. Long-term effects of caffeine therapy for apnea of prematurity on sleep at school age. Am J Respir Crit Care Med 2014;190:791–799. 3. Raynes-Greenow CH, Hadfield RM, Cistulli PA, Bowen J, Allen H, Roberts CL. Sleep apnea in early childhood associated with preterm birth but not small for gestational age: a population-based record linkage study. Sleep 2012;35:1475–1480.


4. Urschitz MS, Brockmann PE, Schlaud M, Poets CF. Population prevalence of obstructive sleep apnoea in a community of German third graders. Eur Respir J 2010;36:556–568. 5. Rosen CLLE, Larkin EK, Kirchner HL, Emancipator JL, Bivins SF, Surovec SA, Martin RJ, Redline S. Prevalence and risk factors for sleep-disordered breathing in 8- to 11-year-old children: association with race and prematurity. J Pediatr 2003;142:383–389. 6. Pohlandt F. Hypothesis: myopia of prematurity is caused by postnatal bone mineral deficiency. Eur J Pediatr 1994;153:234–236. 7. Katz-Salamon M, Jonsson B, Lagercrantz H. Blunted peripheral chemoreceptor response to hyperoxia in a group of infants with bronchopulmonary dysplasia. Pediatr Pulmonol 1995;20:101–106. 8. Wang G, Divall S, Radovick S, Paige D, Ning Y, Chen Z, Ji Y, Hong X, Walker SO, Caruso D, et al. Preterm birth and random plasma insulin levels at birth and in early childhood. JAMA 2014;311:587–596. 9. Poets CF, Wallwiener D, Vetter K. Risks associated with delivering infants 2 to 6 weeks before term—a review of recent data. Dtsch Arztebl Int 2012;109:721–726. 10. Urschitz MS, Guenther A, Eggebrecht E, Wolff J, Urschitz-Duprat PM, Schlaud M, Poets CF. Snoring, intermittent hypoxia and academic performance in primary school children. Am J Respir Crit Care Med 2003;168:464–468. 11. Bonuck K, Freeman K, Chervin RD, Xu L. Sleep-disordered breathing in a population-based cohort: behavioral outcomes at 4 and 7 years. Pediatrics 2012;129:e857–e865. 12. Friedman BC, Hendeles-Amitai A, Kozminsky E, Leiberman A, Friger M, Tarasiuk A, Tal A. Adenotonsillectomy improves neurocognitive function in children with obstructive sleep apnea syndrome. Sleep 2003;26:999–1005. 13. Tapia IE, Bandla P, Traylor J, Karamessinis L, Huang J, Marcus CL. Upper airway sensory function in children with obstructive sleep apnea syndrome. Sleep 2010;33:968–972. 14. Kuhle S, Urschitz MS. Anti-inflammatory medications for obstructive sleep apnea in children. Cochrane Database Syst Rev 2011;19: CD007074. 15. Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A, et al.; Caffeine for Apnea of Prematurity (CAP) Trial Investigators. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA 2012;307:275–282. 16. Hsieh EM, Hornik CP, Clark RH, Laughon MM, Benjamin DK Jr, Smith PB; Best Pharmaceuticals for Children Act—Pediatric Trials Network. Medication use in the neonatal intensive care unit. Am J Perinatol 2014;31:811–822. 17. Rhein LM, Dobson NR, Darnall RA, Corwin MJ, Heeren TC, Poets CF, McEntire BL, Hunt CE; Caffeine Pilot Study Group. Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial. JAMA Pediatr 2014;168:250–257. 18. Schmidt B, Whyte RK, Asztalos EV, Moddemann D, Poets C, Rabi Y, Solimano A, Roberts RS; Canadian Oxygen Trial (COT) Group. Effects of targeting higher vs lower arterial oxygen saturations on death or disability in extremely preterm infants: a randomized clinical trial. JAMA 2013;309:2111–2120.

Copyright © 2014 by the American Thoracic Society


Former preterm infants, caffeine was good for you, but now beware of snoring!

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