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Pharyngeal dysfunction associated with early and late onset sleep disordered breathing in children
International Journal of Pediatric Otorhinolaryngology 127 (2019) 109667
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Pharyngeal dysfunction associated with early and late onset sleep disordered breathing in children
T
Marie Lyonsa, Timothy Cooperb, Dominic Cavec, Manisha Witmansd, Hamdy El-Hakima,∗ a Pediatric Otolaryngology, Division of Pediatric Surgery & Division of Otolaryngology (Department of Surgery), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada b Division of Otolaryngology (Department of Surgery), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada c Division of Pediatric Anesthesiology (Department of Anesthesiology), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada d Division of Pediatric Pulmonology (Department of Pediatrics), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Sleep disordered breathing Airway Endoscopy Early-onset Pediatric
Objective: To compare the frequency and type of diagnoses associated with pharyngeal dysfunction (PD) in children presenting with early versus late onset sleep disordered breathing (SDB). Methods: This was a retrospective, cross-sectional study. A consecutive series of children ≤3 years old who underwent management for SDB were retrospectively identified from a prospectively kept surgical database. The early onset group was compared with two separate late onset (≥4years old) groups. Diagnoses associated with PD included gastroesophageal reflux disease (GERD), swallowing dysfunction, prematurity, asthma, and obesity. Distribution of PD diagnoses, airway lesions, syndromic conditions, pulse oximetry scores, and endoscopic pattern of airway obstruction were compared. Results: 73 patients with early onset SDB were identified (51 boys, mean age 2.25 ± 0.64 years, range 1.75–3 years) and compared with two groups of later onset SDB consisting of 75 and 72 patients with mean ages of 7.58 ± 2.40 years and 8.04 ± 3.34 years respectively (range 4–16 years). The early onset SDB group had a higher prevalence of PD diagnoses compared to the later onset group with 35 of 73 patients being diagnosed compared to 41 of 147 children (p = 0.01). Early onset SDB patients were more likely to have GERD or swallowing dysfunction (p < 0.01) while later onset patients more commonly presented with associated asthma or obesity (p < 0.01). There was no statistically significant difference in airway lesions between groups. Conclusion: Early-onset SDB is associated with conditions causing PD more often than later-onset SDB. Identifying these conditions and optimizing their management may impact outcomes in treating pediatric SDB.
1. Introduction Sleep disordered breathing (SDB) is a common and important clinical problem in children [1]. While untreated severe cases can develop pulmonary hypertension and eventually cor pulmonale [2], milder forms of the condition have been associated with poor growth and deterioration in school performance [3]. The diagnosis of SDB in clinical practice is most often based on a history of classic day and nighttime symptoms and physical examination findings [4]. Neither can reliably predict the severity of the condition, nor the morbidity anticipated during its management [5,6]. Although polysomnography is the gold standard for diagnosis, it is not routinely performed due to practical limitations related to availability of this test [7]. It is now recognized that some children will not benefit from adenotonsillectomy and have persistent SDB post-operatively [8]. In young
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children (3 years old and younger), the literature has examined the safety of tonsillectomy and adenoidectomy (T&A), accuracy of history in predicting SDB, and the likelihood of needing tonsillectomy after an initial adenoidectomy [9–11]. Collectively, T&A was claimed to be less successful [12] in this group than in older children, and to be associated with a higher risk of complications [9]. The belief that SDB is universally caused by adenotonsillar hypertrophy and anatomic obstruction must be reconsidered given the failure of resolution post T&A in a significant number of cases [8]. Pharyngeal dysfunction (PD), consisting of various permutations of altered pharyngeal sensation, and/or impaired neuro-muscular control, may have a prominent role in children presenting with SDB [13–15]. Common conditions like gastro-esophageal reflux disease (GERD), asthma, and obesity [13–15] promote pharyngeal collapsibility, inflammation and altered neuronal control. As such pharyngeal dysfunction appears to be
Corresponding author. Division of Pediatric Surgery - The Stollery Children's Hospital, 2C3.57 Walter MacKenzie centre, Edmonton, Alberta, T6G 2R7, Canada. E-mail address: [email protected] (H. El-Hakim).
https://doi.org/10.1016/j.ijporl.2019.109667 Received 31 May 2019; Received in revised form 6 August 2019; Accepted 30 August 2019 Available online 03 September 2019 0165-5876/ © 2019 Elsevier B.V. All rights reserved.
International Journal of Pediatric Otorhinolaryngology 127 (2019) 109667
M. Lyons, et al.
Depending on patient history and co-morbid factors, this may be coupled with suspension laryngoscopy and bronchoscopy performed with rigid instrumentation. The endoscopy findings were collected from the hospital charts and operative records, and reported as either obstruction only (adenoidal, tonsillar, nasal septal), collapse only (pharyngeal, lingual, or laryngeal), or mixed for any given patient. The findings for each location were allocated a dichotomous score (0 absent, 1 present with > 50% reduction of cross-sectional area). Variables collected from the database included demographic details (date of procedure, age, gender), secondary diagnoses, and procedure performed. The secondary diagnoses documented in the database were categorized into 1) airway lesions, 2) named syndromes and 3) conditions associated with PD. Our definition of PD included prematurity, swallowing dysfunction, GERD/EE, obesity, and asthma. Prematurity was defined as birth at a gestational age of less than 36 weeks. Swallowing dysfunction was diagnosed based on a history of prolonged feeding, choking with liquids and/or solids, cyanotic spells or apparent life-threatening events, and evaluation by pediatric Speech and Language pathology. The diagnosis of GERD or EE was based on history of symptoms, prior or concurrent medical treatment with response, esophagoscopy/gastroscopy findings, and/or positive pH probe and/or gastric emptying scan. Patients classified as obese were above the 95th percentile based on the Center for Disease Control and Prevention Body Mass Index [CDC BMI] - for age growth charts [21]. Asthmatic children had this diagnosis made by a pediatric pulmonologist. The presence or absence of PD was reported dichotomously. Lastly, overnight pulse oximetry data was collected and reported as previously described by Nixon et al. [22] (grading from 0 to 4). Our primary outcome measure was the proportion and types of conditions associated with PD in the early onset compared to the late onset groups (cumulative). Secondarily, we compared the early and late groups with regards to distribution of airway lesions, proportions of patients with obstruction, collapse, or mixed findings on sleep nasopharyngoscopy, pulse oximetry score, and the predictive value of PD for abnormal pulse oximetry scores.
a common denominator in comorbid conditions of SDB such as swallowing dysfunction, GERD, eosinophilic esophagitis (EE), obesity, prematurity, and asthma. Although a cause and effect relationship has not been established between PD and SDB, these conditions may interact with other underlying factors and affect the management and natural history of SDB. Based on the assumption that adenotonsillar size peaks beyond the age of 3 years of age as part of the immunological maturation process [16,17], we hypothesized that conditions promoting PD may be more prevalent and different in type in children with early onset compared to late onset SDB. Our aim was therefore to compare the conditions associated with PD in children presenting early with SDB (≤3 years old), to children who presented later (≥4years old). 2. Materials and methods This study is a retrospective, cross-sectional, chart review. It is based on the caseload of a single pediatric otolaryngologist at a tertiary pediatric referral center (The Stollery Children's Hospital, Edmonton, Alberta, Canada). Ethics approval was obtained from the University of Alberta Hospital's Ethics Review Board (Pro 00018996). Patients were identified by searching a prospectively kept database of all surgical patients in the senior author's surgical practice (Microsoft Access® 2000). Consecutive patients were identified from the database for inclusion over a six-year period. The database contains demographic data, otolaryngological and non-otolaryngological diagnoses, method of anesthesia, urgency, procedures performed, special instrumentation and settings, and complications. Eligible children for inclusion in the study group or “early onset” group were those aged 3 years or younger at the time of intervention, who had undergone surgery and/or airway endoscopy for SDB consisting of a sleep nasopharyngoscopy and/or suspension laryngoscopy and bronchoscopy. The diagnosis of SDB was based on the documented history of persistent daily symptoms (nocturnal with or without diurnal) for at least 12 months (and score exceeding 33% on Pediatric Sleep Questionnaire [18]) in addition to physical examination and overnight pulse oximetry. A shorter duration of symptoms consistent with SDB was allowed for diagnosis in patients under one year of age. Two separate groups of ‘late onset’ SDB were also identified from the database. Each comprised of children aged between 4 and 17 years of age, who were treated surgically and/or underwent airway endoscopy consecutively for SDB. The two groups were consecutive patients identified from two randomly chosen periods (concurrent with the study group's period). The period extended from a randomly selected treatment date until an appropriate number of patients met inclusion criteria to match the total number of early SDB patients identified in the database. The two control groups will be referred to as ‘Late onset I’, and ‘Late onset II’. This use of two comparison groups would bolster the conclusions by reinforcing the direction of any effect demonstrated [19], in addition to providing a sufficient sample size. Patients with incomplete records lacking pertinent data were excluded from all groups. During the initial clinic visit regarding SDB, the senior author routinely inquiries about and documents history of prematurity, intubation, intensive care admission, swallowing dysfunction, GERD or eosinophilic esophagitis (EE), wheezing during infancy and use of bronchodilators, asthma, atopy, atypical croup, obesity, airway surgery, syndromes, family history of SDB, neuropsychiatric disorders, developmental delay and exposure to tobacco smoke. The pediatric otolaryngologist routinely performs a systematic endoscopic examination of the upper airway (from the nose to the larynx) in the operating room in those children with SDB who undergo surgical management or may require nocturnal ventilation. This is performed with a 2.2 mm flexible endoscope following induction of anesthesia with total intravenous agents (propofol and remifentanil), allowing for spontaneous ventilation as described in previous studies by the senior author [20].
2.1. Statistical analysis Descriptive statistics, Student's t-test, χ2 and Fisher's exact tests (with the Freeman Halton extension using a 2x3 table (http://faculty. vassar.edu/lowry/fisher2x3.html), and odds ratios (OR) were used as appropriate. Bivariable regression analysis was performed to explore if the presence or absence of PD predicts abnormal pulse oximetry. Statistical significance was defined as p < 0.05 in all cases. Statistical analysis was performed using SigmaStat and SigmaPlot version 3 (Systat Software Inc, San Jose, CA). 3. Results The database contained a total of 4361 patients treated by the senior author over 6 years. We identified 73 patients ≤3 years old who were treated for a primary diagnosis of SDB (the early onset group). Of these, 51 were males and 22 were females. Mean age was 2.25 ± 0.64 years, (range 0.29–3.0 years). The median McGill sleep score was 1 (range 1–4). In the first comparison group, 75 consecutive patients constituted the late onset group I. There were 39 males and 36 females. The mean age was 7.58 ± 2.40 years (range 4–16 years). The second comparison group, late onset group II was comprised of 72 consecutive patients. There were 45 males and 27 females. Their mean age was 8.04 ± 3.34 years (range 4–16 years). The median McGill sleep scores for both late onset groups were both one (range 1–4). There was no significant difference between the groups with respect to gender and sleep oximetry score (Table 1). Conditions associated with PD were diagnosed in 35 out of 73 in the early onset group and in 45 out of 147 patients in the late onset groups 2
International Journal of Pediatric Otorhinolaryngology 127 (2019) 109667
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Table 1 Demographics and pulse oximetry scores of children with early and late onset SDB. Group
Age (mean ± SD) (range)
Gender (F:M)
Median Pulse oximetry grade (range)
Early onset (n = 73) Late onset I (n = 75) Late onset II (n = 72) P value
2.25 ± 0.64 (0.29–3.0) 7.58 ± 2.4 (4.29–16.18) 8.04 ± 3.34 (4.12–16.44) < 0.05a
22:51 36:39 27:45 0.08b
1 (1–4) 1 (1–4) 1 (1–4) > 0.05c
a b c
Student t-test. Chi square test. Mann-Whitney U.
Table 2 Distribution of conditions associated with pharyngeal dysfunction in children with early and late onset SDB.
Early onset (n = 73) Late onset I (n = 75) Late onset II (n = 72) P value a OR 95% CI
GERD/EE
History of prematurity
Swallowing dysfunction
Asthma
Obesity
22 2 2 < 0.001 15.42 (5.1–46.9)
2 0 0 0.11 NA
9 0 0 < 0.001 NA
0 12 4 0.001 NA
2 11 14 0.001 7.3 (1.7–31.6)
CI = confidence interval; GERD = gastroesophageal reflux disease; EE = eosinophilic esophagitis; OR = odds ratio. a Fisher exact test.
(chi square, P = 0.012, OR 2.087, 95% CI: 1.172–3.72) (Table 2). This difference was statistically significant. That held true even when syndromic children are excluded from the groups. The causes of PD differed significantly between the groups. Obesity and asthma were common in the late onset group (25 and 16 respectively), and present in two and none in the early onset group (Table 2). On the other hand, GERD/EE and swallowing dysfunction were much more common in the early onset group (22 and 9 respectively), with only 4 and none diagnosed in the later onset children (Table 2). There was no statistically significant difference in airway lesions between the early onset group (10/73) and the late onset groups (9/ 147) (Chi square test P = 0.06, OR 2.43, 95% CI: 0.94–6.28). The number and types of airway lesions in each group are outlined in Table 3. Laryngomalacia was the most common airway lesion in all groups. Syndromes were not significantly more common in younger children (8/73) as compared to older children (10/147) (Chi square test P = 0.30 OR 1.67, 95% CI: 0.64–4.47). Within the early onset group, two children had a diagnosis of 22q11 deletion syndrome and one child was diagnosed with each of Sanfillipo syndrome, achondroplasia, pseudohypoparathyroidism, CHARGE, cerebral palsy, and ambiguous genitalia. The syndromic diagnoses in the late onset groups included four patients with Down syndrome, two with Rubenstein-Taybi syndrome, and one with each of McCune-Albright syndrome, Cri du chat syndrome, cerebral palsy, and congenital muscle disproportion. Sleep nasopharyngoscopy findings are outlined in Table 4. The proportions of findings were different amongst the early and late SDB groups. The early onset group was more likely than the later onset patients to have a dynamic collapse pattern without significant obstruction. This difference was statistically significant (Freeman–Halton extension of Fisher exact test P = 0.011.) On regression analysis, the presence of PD significantly predicted abnormal overnight oximetry (coefficient of regression of 0.548, Standard error 0.156, p = 0.004).
Table 4 Comparison of endoscopic findings between early and late onset SDB groups.
Early Onset (n = 73) Late onset I (n = 75) Late onset II (n = 72)
Obstruction
Collapse
Mixed
42 33 36
11 4 6
20 38 30
(Fisher's exact test, p = 0.011).
4. Discussion This study systematically examines the diagnostic profile of young children with SDB compared to their older peers. As compared to other studies that have examined individual causes of PD, our concern was to elucidate a final common pathway to all these conditions. This study's results suggest that conditions associated with PD are more common in patients with earlier onset SDB. In addition, the distribution of types of PD differed markedly between the early and late onset SDB groups. GERD/EE was more common in younger patients, and asthma and obesity predominated in the older ones. Interestingly, the number of syndromic children did not differ significantly between the groups. Congenital airway lesions were also twice as common in young snorers, although this did not reach statistical significance. Finally, the presence of PD significantly predicted abnormal overnight oximetry. Prior studies have shown a relationship between GERD and SDB, particularly in early presentations. In a series by Leonardis et al. [23], 70% of infants and neonates diagnosed with SDB were treated for GERD. McCormick et al. [24] found that approximately 8% of children ≤3 years of age undergoing T&A were also diagnosed with GERD, but that GERD was also a predictor of post-operative complications in this group. Simultaneous pH probe monitoring and polysomnography has shown an association between reflux and arousals in an infant population [25].
Table 3 Airway lesions encountered in early and late onset SDB groups.
Early Onset (n = 73) Late onset I (n = 75) Late onset II (n = 72)
Laryngomalacia
Tracheomalacia
Laryngeal cleft
Sub-mucous cleft palate
Laryngeal paralysis
6 3 2
1 1 0
1 0 0
1 0 1
1 1 1
3
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5. Conclusions
The association between asthma and SDB has been documented in numerous prior studies which are well characterized by the systematic review by Brockmann et al. [26]. Of note, the mean age of patients cumulatively examined in the review was 8.6 years, similar to that of our late onset group. Obesity has also been well documented as a risk factor for SDB [27–29]. While obesity affects all age groups and its prevalence is highly population specific, it more commonly affects older children and adolescents as opposed to infants and pre-school aged children [30,31]. As such, we would expect to have a higher prevalence in our later onset SDB group. There is also a notion that the age of onset of SDB may reflect a group of underlying conditions, which would produce different endoscopic findings. It has already been suggested that the airway acts as a Starling resistor [32] and that defects in the dynamic state (i.e. forces tending to collapse the airway exceeding dilatational forces) will lead to collapse during sleep. It is believed that young children's pharyngeal airway is less collapsible than older individuals [13]. The higher proportion of dynamic collapse in children with early onset SDB in this series may be associated with the increased prevalence of conditions related to PD in this group. The current literature supports that patient history related to the presence or absence of classic symptoms are a poor predictor of the severity of SDB [5]. On regression analysis, the presence of comorbid PD conditions largely elicited on history was predictive of the severity of pulse oximetry abnormalities. This may assist in triaging appropriate investigations including sleep studies and predicting postoperative monitoring requirements. However, it must be acknowledged that the relationship between SDB, comorbid PD conditions, and pulse oximetry scores is complex and that conditions associated with PD such as asthma may independently affect pulse oximetry scores. Our study also found a notable number of patients with congenital lesions of the larynx in the study group. Laryngomalacia predominated and this was diagnosed using sleep nasopharyngoscopy. Recent studies have demonstrated that laryngomalacia can present primarily with SDB and that resolution of symptoms is achievable after supraglottoplasty [33–36]. This study further demonstrates the utility of airway endoscopy in the evaluation of children presenting with SDB in identifying secondary airway abnormalities beyond adenotonsillar hypertrophy. This study has several limitations. Firstly, it was conducted retrospectively. As such, we are unable to make any conclusions regarding the cause and effect relationship between PD and SDB. The diagnosis of conditions associated with PD was based mainly on the history and the investigations of other physicians involved in the patient's care. As such, uniform diagnostic evaluation was not performed for each comorbid condition. Due to lack of availability of polysomnography, overnight pulse oximetry studies were used to assess the severity of SDB. Although polysomnography may be considered the gold standard to diagnose OSA, access to this diagnostic study is limited at our center, like many others [22,37]. Lastly, the relationship between PD and treatment outcomes was not examined. However, the numbers in the study are large, affording a significant power, and we used the dual comparison group tactic to reduce bias as much as possible. The pulse oximetry score used had also been validated previously and shown to correlate well with polysomnography [22]. More importantly, it represents a real life amenable and available screening tool. Overnight pulse oximetry studies are performed regularly in practice and are used in routine clinical decision, giving this data clinical relevance to practicing otolaryngologists. Future research prospectively examining post-operative SDB outcomes in children with and without PD would be of significant value. In addition, further evaluation of the effect of medical management of PD in relation to SDB measures may reduce the need for or allow for the delay of surgical intervention in patients presenting with early-onset SDB.
This study demonstrates a high prevalence of conditions associated with PD in young children diagnosed with SDB. Children 3 years old and younger had a significantly higher prevalence of PD in comparison to older children diagnosed with SDB. As such, younger children are a distinct cohort with additional comorbid conditions which may influence their presentation and outcomes. Conditions associated with PD may be contributing factors in patients with persistent SDB following adenotonsillectomy. Further studies to validate these findings and examine post-operative sleep outcomes in patients with and without PD are needed. Conflicts of interest None. Disclosure of finance None. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijporl.2019.109667. References [1] N.J. Ali, D.J. Pitson, J.R. Stradling, Snoring, sleep disturbance, and behaviour in 4-5 year olds, Arch. Dis. Child. 68 (3) (1993) 360–366, https://doi.org/10.1136/adc. 68.3.360. [2] R.S. Amin, T.R. Kimball, J.A. Bean, et al., Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea, Am. J. Respir. Crit. Care Med. 165 (10) (2002) 1395–1399, https://doi.org/ 10.1164/rccm.2105118. [3] S. Blunden, K. Lushington, D. Kennedy, J. Martin, D. Dawson, Behavior and neurocognitive performance in children aged 5-10 years who snore compared to controls, J. Clin. Exp. Neuropsychol. 22 (5) (2000) 554–568, https://doi.org/10.1076/ 1380-3395(200010)22:5;1-9;FT554. [4] Z. Sargi, R.T. Younis, Pediatric obstructive sleep apnea: current management, ORL J. Otorhinolaryngol. Relat. Spec. 69 (6) (2007) 340–344, https://doi.org/10.1159/ 000108365. [5] S.E. Brietzke, E.S. Katz, D.W. Roberson, Can history and physical examination reliably diagnose pediatric obstructive sleep apnea/hypopnea syndrome? A systematic review of the literature, Otolaryngol. Head Neck Surg. 131 (6) (2004) 827–832, https://doi.org/10.1016/j.otohns.2004.07.002. [6] Standards and indications for cardiopulmonary sleep studies in children. American Thoracic Society, Am. J. Respir. Crit. Care Med. 153 (2) (1996) 866–878, https:// doi.org/10.1164/ajrccm.153.2.8564147. [7] R.A. Weatherly, E.F. Mai, D.L. Ruzicka, R.D. Chervin, Identification and evaluation of obstructive sleep apnea prior to adenotonsillectomy in children: a survey of practice patterns, Sleep Med. 4 (4) (2003) 297–307 http://www.ncbi.nlm.nih.gov/ pubmed/14592302 , Accessed date: 19 May 2019. [8] M. Friedman, M. Wilson, H.-C. Lin, H.-W. Chang, Updated systematic review of tonsillectomy and adenoidectomy for treatment of pediatric obstructive sleep apnea/hypopnea syndrome, Otolaryngol. Head Neck Surg. 140 (6) (2009) 800–808, https://doi.org/10.1016/j.otohns.2009.01.043. [9] M.M. Statham, R.G. Elluru, R. Buncher, M. Kalra, Adenotonsillectomy for obstructive sleep apnea syndrome in young children: prevalence of pulmonary complications, Arch. Otolaryngol. Head Neck Surg. 132 (5) (2006) 476–480, https:// doi.org/10.1001/archotol.132.5.476. [10] A.H. Werle, P.J. Nicklaus, D.J. Kirse, D.E. Bruegger, A retrospective study of tonsillectomy in the under 2-year-old child: indications, perioperative management, and complications, Int. J. Pediatr. Otorhinolaryngol. 67 (5) (2003) 453–460 http:// www.ncbi.nlm.nih.gov/pubmed/12697346 , Accessed date: 19 May 2019. [11] H.E. Montgomery-Downs, D. Gozal, Sleep habits and risk factors for sleep-disordered breathing in infants and young toddlers in Louisville, Kentucky, Sleep Med. 7 (3) (2006) 211–219, https://doi.org/10.1016/j.sleep.2005.11.003. [12] K. Liukkonen, P. Virkkula, E.T. Aronen, T. Kirjavainen, A. Pitkäranta, All snoring is not adenoids in young children, Int. J. Pediatr. Otorhinolaryngol. 72 (6) (2008) 879–884, https://doi.org/10.1016/j.ijporl.2008.02.018. [13] M. Alkhalil, E. Schulman, J. Getsy, Obstructive sleep apnea syndrome and asthma: what are the links? J. Clin. Sleep Med. 5 (1) (2009) 71–78 http://www.ncbi.nlm. nih.gov/pubmed/19317386 , Accessed date: 19 May 2019. [14] M. Bortolotti, L. Gentilini, C. Morselli, M. Giovannini, Obstructive sleep apnoea is improved by a prolonged treatment of gastrooesophageal reflux with omeprazole, Dig. Liver Dis. 38 (2) (2006) 78–81, https://doi.org/10.1016/j.dld.2005.09.018.
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Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Pharyngeal dysfunction associated with early and late onset sleep disordered breathing in children
T
Marie Lyonsa, Timothy Cooperb, Dominic Cavec, Manisha Witmansd, Hamdy El-Hakima,∗ a Pediatric Otolaryngology, Division of Pediatric Surgery & Division of Otolaryngology (Department of Surgery), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada b Division of Otolaryngology (Department of Surgery), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada c Division of Pediatric Anesthesiology (Department of Anesthesiology), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada d Division of Pediatric Pulmonology (Department of Pediatrics), The Stollery Children's Hospital & University of Alberta Hospitals, Edmonton, Alberta, Canada
A R T I C LE I N FO
A B S T R A C T
Keywords: Sleep disordered breathing Airway Endoscopy Early-onset Pediatric
Objective: To compare the frequency and type of diagnoses associated with pharyngeal dysfunction (PD) in children presenting with early versus late onset sleep disordered breathing (SDB). Methods: This was a retrospective, cross-sectional study. A consecutive series of children ≤3 years old who underwent management for SDB were retrospectively identified from a prospectively kept surgical database. The early onset group was compared with two separate late onset (≥4years old) groups. Diagnoses associated with PD included gastroesophageal reflux disease (GERD), swallowing dysfunction, prematurity, asthma, and obesity. Distribution of PD diagnoses, airway lesions, syndromic conditions, pulse oximetry scores, and endoscopic pattern of airway obstruction were compared. Results: 73 patients with early onset SDB were identified (51 boys, mean age 2.25 ± 0.64 years, range 1.75–3 years) and compared with two groups of later onset SDB consisting of 75 and 72 patients with mean ages of 7.58 ± 2.40 years and 8.04 ± 3.34 years respectively (range 4–16 years). The early onset SDB group had a higher prevalence of PD diagnoses compared to the later onset group with 35 of 73 patients being diagnosed compared to 41 of 147 children (p = 0.01). Early onset SDB patients were more likely to have GERD or swallowing dysfunction (p < 0.01) while later onset patients more commonly presented with associated asthma or obesity (p < 0.01). There was no statistically significant difference in airway lesions between groups. Conclusion: Early-onset SDB is associated with conditions causing PD more often than later-onset SDB. Identifying these conditions and optimizing their management may impact outcomes in treating pediatric SDB.
1. Introduction Sleep disordered breathing (SDB) is a common and important clinical problem in children [1]. While untreated severe cases can develop pulmonary hypertension and eventually cor pulmonale [2], milder forms of the condition have been associated with poor growth and deterioration in school performance [3]. The diagnosis of SDB in clinical practice is most often based on a history of classic day and nighttime symptoms and physical examination findings [4]. Neither can reliably predict the severity of the condition, nor the morbidity anticipated during its management [5,6]. Although polysomnography is the gold standard for diagnosis, it is not routinely performed due to practical limitations related to availability of this test [7]. It is now recognized that some children will not benefit from adenotonsillectomy and have persistent SDB post-operatively [8]. In young
∗
children (3 years old and younger), the literature has examined the safety of tonsillectomy and adenoidectomy (T&A), accuracy of history in predicting SDB, and the likelihood of needing tonsillectomy after an initial adenoidectomy [9–11]. Collectively, T&A was claimed to be less successful [12] in this group than in older children, and to be associated with a higher risk of complications [9]. The belief that SDB is universally caused by adenotonsillar hypertrophy and anatomic obstruction must be reconsidered given the failure of resolution post T&A in a significant number of cases [8]. Pharyngeal dysfunction (PD), consisting of various permutations of altered pharyngeal sensation, and/or impaired neuro-muscular control, may have a prominent role in children presenting with SDB [13–15]. Common conditions like gastro-esophageal reflux disease (GERD), asthma, and obesity [13–15] promote pharyngeal collapsibility, inflammation and altered neuronal control. As such pharyngeal dysfunction appears to be
Corresponding author. Division of Pediatric Surgery - The Stollery Children's Hospital, 2C3.57 Walter MacKenzie centre, Edmonton, Alberta, T6G 2R7, Canada. E-mail address: [email protected] (H. El-Hakim).
https://doi.org/10.1016/j.ijporl.2019.109667 Received 31 May 2019; Received in revised form 6 August 2019; Accepted 30 August 2019 Available online 03 September 2019 0165-5876/ © 2019 Elsevier B.V. All rights reserved.
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Depending on patient history and co-morbid factors, this may be coupled with suspension laryngoscopy and bronchoscopy performed with rigid instrumentation. The endoscopy findings were collected from the hospital charts and operative records, and reported as either obstruction only (adenoidal, tonsillar, nasal septal), collapse only (pharyngeal, lingual, or laryngeal), or mixed for any given patient. The findings for each location were allocated a dichotomous score (0 absent, 1 present with > 50% reduction of cross-sectional area). Variables collected from the database included demographic details (date of procedure, age, gender), secondary diagnoses, and procedure performed. The secondary diagnoses documented in the database were categorized into 1) airway lesions, 2) named syndromes and 3) conditions associated with PD. Our definition of PD included prematurity, swallowing dysfunction, GERD/EE, obesity, and asthma. Prematurity was defined as birth at a gestational age of less than 36 weeks. Swallowing dysfunction was diagnosed based on a history of prolonged feeding, choking with liquids and/or solids, cyanotic spells or apparent life-threatening events, and evaluation by pediatric Speech and Language pathology. The diagnosis of GERD or EE was based on history of symptoms, prior or concurrent medical treatment with response, esophagoscopy/gastroscopy findings, and/or positive pH probe and/or gastric emptying scan. Patients classified as obese were above the 95th percentile based on the Center for Disease Control and Prevention Body Mass Index [CDC BMI] - for age growth charts [21]. Asthmatic children had this diagnosis made by a pediatric pulmonologist. The presence or absence of PD was reported dichotomously. Lastly, overnight pulse oximetry data was collected and reported as previously described by Nixon et al. [22] (grading from 0 to 4). Our primary outcome measure was the proportion and types of conditions associated with PD in the early onset compared to the late onset groups (cumulative). Secondarily, we compared the early and late groups with regards to distribution of airway lesions, proportions of patients with obstruction, collapse, or mixed findings on sleep nasopharyngoscopy, pulse oximetry score, and the predictive value of PD for abnormal pulse oximetry scores.
a common denominator in comorbid conditions of SDB such as swallowing dysfunction, GERD, eosinophilic esophagitis (EE), obesity, prematurity, and asthma. Although a cause and effect relationship has not been established between PD and SDB, these conditions may interact with other underlying factors and affect the management and natural history of SDB. Based on the assumption that adenotonsillar size peaks beyond the age of 3 years of age as part of the immunological maturation process [16,17], we hypothesized that conditions promoting PD may be more prevalent and different in type in children with early onset compared to late onset SDB. Our aim was therefore to compare the conditions associated with PD in children presenting early with SDB (≤3 years old), to children who presented later (≥4years old). 2. Materials and methods This study is a retrospective, cross-sectional, chart review. It is based on the caseload of a single pediatric otolaryngologist at a tertiary pediatric referral center (The Stollery Children's Hospital, Edmonton, Alberta, Canada). Ethics approval was obtained from the University of Alberta Hospital's Ethics Review Board (Pro 00018996). Patients were identified by searching a prospectively kept database of all surgical patients in the senior author's surgical practice (Microsoft Access® 2000). Consecutive patients were identified from the database for inclusion over a six-year period. The database contains demographic data, otolaryngological and non-otolaryngological diagnoses, method of anesthesia, urgency, procedures performed, special instrumentation and settings, and complications. Eligible children for inclusion in the study group or “early onset” group were those aged 3 years or younger at the time of intervention, who had undergone surgery and/or airway endoscopy for SDB consisting of a sleep nasopharyngoscopy and/or suspension laryngoscopy and bronchoscopy. The diagnosis of SDB was based on the documented history of persistent daily symptoms (nocturnal with or without diurnal) for at least 12 months (and score exceeding 33% on Pediatric Sleep Questionnaire [18]) in addition to physical examination and overnight pulse oximetry. A shorter duration of symptoms consistent with SDB was allowed for diagnosis in patients under one year of age. Two separate groups of ‘late onset’ SDB were also identified from the database. Each comprised of children aged between 4 and 17 years of age, who were treated surgically and/or underwent airway endoscopy consecutively for SDB. The two groups were consecutive patients identified from two randomly chosen periods (concurrent with the study group's period). The period extended from a randomly selected treatment date until an appropriate number of patients met inclusion criteria to match the total number of early SDB patients identified in the database. The two control groups will be referred to as ‘Late onset I’, and ‘Late onset II’. This use of two comparison groups would bolster the conclusions by reinforcing the direction of any effect demonstrated [19], in addition to providing a sufficient sample size. Patients with incomplete records lacking pertinent data were excluded from all groups. During the initial clinic visit regarding SDB, the senior author routinely inquiries about and documents history of prematurity, intubation, intensive care admission, swallowing dysfunction, GERD or eosinophilic esophagitis (EE), wheezing during infancy and use of bronchodilators, asthma, atopy, atypical croup, obesity, airway surgery, syndromes, family history of SDB, neuropsychiatric disorders, developmental delay and exposure to tobacco smoke. The pediatric otolaryngologist routinely performs a systematic endoscopic examination of the upper airway (from the nose to the larynx) in the operating room in those children with SDB who undergo surgical management or may require nocturnal ventilation. This is performed with a 2.2 mm flexible endoscope following induction of anesthesia with total intravenous agents (propofol and remifentanil), allowing for spontaneous ventilation as described in previous studies by the senior author [20].
2.1. Statistical analysis Descriptive statistics, Student's t-test, χ2 and Fisher's exact tests (with the Freeman Halton extension using a 2x3 table (http://faculty. vassar.edu/lowry/fisher2x3.html), and odds ratios (OR) were used as appropriate. Bivariable regression analysis was performed to explore if the presence or absence of PD predicts abnormal pulse oximetry. Statistical significance was defined as p < 0.05 in all cases. Statistical analysis was performed using SigmaStat and SigmaPlot version 3 (Systat Software Inc, San Jose, CA). 3. Results The database contained a total of 4361 patients treated by the senior author over 6 years. We identified 73 patients ≤3 years old who were treated for a primary diagnosis of SDB (the early onset group). Of these, 51 were males and 22 were females. Mean age was 2.25 ± 0.64 years, (range 0.29–3.0 years). The median McGill sleep score was 1 (range 1–4). In the first comparison group, 75 consecutive patients constituted the late onset group I. There were 39 males and 36 females. The mean age was 7.58 ± 2.40 years (range 4–16 years). The second comparison group, late onset group II was comprised of 72 consecutive patients. There were 45 males and 27 females. Their mean age was 8.04 ± 3.34 years (range 4–16 years). The median McGill sleep scores for both late onset groups were both one (range 1–4). There was no significant difference between the groups with respect to gender and sleep oximetry score (Table 1). Conditions associated with PD were diagnosed in 35 out of 73 in the early onset group and in 45 out of 147 patients in the late onset groups 2
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Table 1 Demographics and pulse oximetry scores of children with early and late onset SDB. Group
Age (mean ± SD) (range)
Gender (F:M)
Median Pulse oximetry grade (range)
Early onset (n = 73) Late onset I (n = 75) Late onset II (n = 72) P value
2.25 ± 0.64 (0.29–3.0) 7.58 ± 2.4 (4.29–16.18) 8.04 ± 3.34 (4.12–16.44) < 0.05a
22:51 36:39 27:45 0.08b
1 (1–4) 1 (1–4) 1 (1–4) > 0.05c
a b c
Student t-test. Chi square test. Mann-Whitney U.
Table 2 Distribution of conditions associated with pharyngeal dysfunction in children with early and late onset SDB.
Early onset (n = 73) Late onset I (n = 75) Late onset II (n = 72) P value a OR 95% CI
GERD/EE
History of prematurity
Swallowing dysfunction
Asthma
Obesity
22 2 2 < 0.001 15.42 (5.1–46.9)
2 0 0 0.11 NA
9 0 0 < 0.001 NA
0 12 4 0.001 NA
2 11 14 0.001 7.3 (1.7–31.6)
CI = confidence interval; GERD = gastroesophageal reflux disease; EE = eosinophilic esophagitis; OR = odds ratio. a Fisher exact test.
(chi square, P = 0.012, OR 2.087, 95% CI: 1.172–3.72) (Table 2). This difference was statistically significant. That held true even when syndromic children are excluded from the groups. The causes of PD differed significantly between the groups. Obesity and asthma were common in the late onset group (25 and 16 respectively), and present in two and none in the early onset group (Table 2). On the other hand, GERD/EE and swallowing dysfunction were much more common in the early onset group (22 and 9 respectively), with only 4 and none diagnosed in the later onset children (Table 2). There was no statistically significant difference in airway lesions between the early onset group (10/73) and the late onset groups (9/ 147) (Chi square test P = 0.06, OR 2.43, 95% CI: 0.94–6.28). The number and types of airway lesions in each group are outlined in Table 3. Laryngomalacia was the most common airway lesion in all groups. Syndromes were not significantly more common in younger children (8/73) as compared to older children (10/147) (Chi square test P = 0.30 OR 1.67, 95% CI: 0.64–4.47). Within the early onset group, two children had a diagnosis of 22q11 deletion syndrome and one child was diagnosed with each of Sanfillipo syndrome, achondroplasia, pseudohypoparathyroidism, CHARGE, cerebral palsy, and ambiguous genitalia. The syndromic diagnoses in the late onset groups included four patients with Down syndrome, two with Rubenstein-Taybi syndrome, and one with each of McCune-Albright syndrome, Cri du chat syndrome, cerebral palsy, and congenital muscle disproportion. Sleep nasopharyngoscopy findings are outlined in Table 4. The proportions of findings were different amongst the early and late SDB groups. The early onset group was more likely than the later onset patients to have a dynamic collapse pattern without significant obstruction. This difference was statistically significant (Freeman–Halton extension of Fisher exact test P = 0.011.) On regression analysis, the presence of PD significantly predicted abnormal overnight oximetry (coefficient of regression of 0.548, Standard error 0.156, p = 0.004).
Table 4 Comparison of endoscopic findings between early and late onset SDB groups.
Early Onset (n = 73) Late onset I (n = 75) Late onset II (n = 72)
Obstruction
Collapse
Mixed
42 33 36
11 4 6
20 38 30
(Fisher's exact test, p = 0.011).
4. Discussion This study systematically examines the diagnostic profile of young children with SDB compared to their older peers. As compared to other studies that have examined individual causes of PD, our concern was to elucidate a final common pathway to all these conditions. This study's results suggest that conditions associated with PD are more common in patients with earlier onset SDB. In addition, the distribution of types of PD differed markedly between the early and late onset SDB groups. GERD/EE was more common in younger patients, and asthma and obesity predominated in the older ones. Interestingly, the number of syndromic children did not differ significantly between the groups. Congenital airway lesions were also twice as common in young snorers, although this did not reach statistical significance. Finally, the presence of PD significantly predicted abnormal overnight oximetry. Prior studies have shown a relationship between GERD and SDB, particularly in early presentations. In a series by Leonardis et al. [23], 70% of infants and neonates diagnosed with SDB were treated for GERD. McCormick et al. [24] found that approximately 8% of children ≤3 years of age undergoing T&A were also diagnosed with GERD, but that GERD was also a predictor of post-operative complications in this group. Simultaneous pH probe monitoring and polysomnography has shown an association between reflux and arousals in an infant population [25].
Table 3 Airway lesions encountered in early and late onset SDB groups.
Early Onset (n = 73) Late onset I (n = 75) Late onset II (n = 72)
Laryngomalacia
Tracheomalacia
Laryngeal cleft
Sub-mucous cleft palate
Laryngeal paralysis
6 3 2
1 1 0
1 0 0
1 0 1
1 1 1
3
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5. Conclusions
The association between asthma and SDB has been documented in numerous prior studies which are well characterized by the systematic review by Brockmann et al. [26]. Of note, the mean age of patients cumulatively examined in the review was 8.6 years, similar to that of our late onset group. Obesity has also been well documented as a risk factor for SDB [27–29]. While obesity affects all age groups and its prevalence is highly population specific, it more commonly affects older children and adolescents as opposed to infants and pre-school aged children [30,31]. As such, we would expect to have a higher prevalence in our later onset SDB group. There is also a notion that the age of onset of SDB may reflect a group of underlying conditions, which would produce different endoscopic findings. It has already been suggested that the airway acts as a Starling resistor [32] and that defects in the dynamic state (i.e. forces tending to collapse the airway exceeding dilatational forces) will lead to collapse during sleep. It is believed that young children's pharyngeal airway is less collapsible than older individuals [13]. The higher proportion of dynamic collapse in children with early onset SDB in this series may be associated with the increased prevalence of conditions related to PD in this group. The current literature supports that patient history related to the presence or absence of classic symptoms are a poor predictor of the severity of SDB [5]. On regression analysis, the presence of comorbid PD conditions largely elicited on history was predictive of the severity of pulse oximetry abnormalities. This may assist in triaging appropriate investigations including sleep studies and predicting postoperative monitoring requirements. However, it must be acknowledged that the relationship between SDB, comorbid PD conditions, and pulse oximetry scores is complex and that conditions associated with PD such as asthma may independently affect pulse oximetry scores. Our study also found a notable number of patients with congenital lesions of the larynx in the study group. Laryngomalacia predominated and this was diagnosed using sleep nasopharyngoscopy. Recent studies have demonstrated that laryngomalacia can present primarily with SDB and that resolution of symptoms is achievable after supraglottoplasty [33–36]. This study further demonstrates the utility of airway endoscopy in the evaluation of children presenting with SDB in identifying secondary airway abnormalities beyond adenotonsillar hypertrophy. This study has several limitations. Firstly, it was conducted retrospectively. As such, we are unable to make any conclusions regarding the cause and effect relationship between PD and SDB. The diagnosis of conditions associated with PD was based mainly on the history and the investigations of other physicians involved in the patient's care. As such, uniform diagnostic evaluation was not performed for each comorbid condition. Due to lack of availability of polysomnography, overnight pulse oximetry studies were used to assess the severity of SDB. Although polysomnography may be considered the gold standard to diagnose OSA, access to this diagnostic study is limited at our center, like many others [22,37]. Lastly, the relationship between PD and treatment outcomes was not examined. However, the numbers in the study are large, affording a significant power, and we used the dual comparison group tactic to reduce bias as much as possible. The pulse oximetry score used had also been validated previously and shown to correlate well with polysomnography [22]. More importantly, it represents a real life amenable and available screening tool. Overnight pulse oximetry studies are performed regularly in practice and are used in routine clinical decision, giving this data clinical relevance to practicing otolaryngologists. Future research prospectively examining post-operative SDB outcomes in children with and without PD would be of significant value. In addition, further evaluation of the effect of medical management of PD in relation to SDB measures may reduce the need for or allow for the delay of surgical intervention in patients presenting with early-onset SDB.
This study demonstrates a high prevalence of conditions associated with PD in young children diagnosed with SDB. Children 3 years old and younger had a significantly higher prevalence of PD in comparison to older children diagnosed with SDB. As such, younger children are a distinct cohort with additional comorbid conditions which may influence their presentation and outcomes. Conditions associated with PD may be contributing factors in patients with persistent SDB following adenotonsillectomy. Further studies to validate these findings and examine post-operative sleep outcomes in patients with and without PD are needed. Conflicts of interest None. Disclosure of finance None. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.ijporl.2019.109667. References [1] N.J. Ali, D.J. Pitson, J.R. Stradling, Snoring, sleep disturbance, and behaviour in 4-5 year olds, Arch. Dis. Child. 68 (3) (1993) 360–366, https://doi.org/10.1136/adc. 68.3.360. [2] R.S. Amin, T.R. Kimball, J.A. Bean, et al., Left ventricular hypertrophy and abnormal ventricular geometry in children and adolescents with obstructive sleep apnea, Am. J. Respir. Crit. Care Med. 165 (10) (2002) 1395–1399, https://doi.org/ 10.1164/rccm.2105118. [3] S. Blunden, K. Lushington, D. Kennedy, J. Martin, D. Dawson, Behavior and neurocognitive performance in children aged 5-10 years who snore compared to controls, J. Clin. Exp. Neuropsychol. 22 (5) (2000) 554–568, https://doi.org/10.1076/ 1380-3395(200010)22:5;1-9;FT554. [4] Z. Sargi, R.T. Younis, Pediatric obstructive sleep apnea: current management, ORL J. Otorhinolaryngol. Relat. Spec. 69 (6) (2007) 340–344, https://doi.org/10.1159/ 000108365. [5] S.E. Brietzke, E.S. Katz, D.W. Roberson, Can history and physical examination reliably diagnose pediatric obstructive sleep apnea/hypopnea syndrome? A systematic review of the literature, Otolaryngol. Head Neck Surg. 131 (6) (2004) 827–832, https://doi.org/10.1016/j.otohns.2004.07.002. [6] Standards and indications for cardiopulmonary sleep studies in children. American Thoracic Society, Am. J. Respir. Crit. Care Med. 153 (2) (1996) 866–878, https:// doi.org/10.1164/ajrccm.153.2.8564147. [7] R.A. Weatherly, E.F. Mai, D.L. Ruzicka, R.D. Chervin, Identification and evaluation of obstructive sleep apnea prior to adenotonsillectomy in children: a survey of practice patterns, Sleep Med. 4 (4) (2003) 297–307 http://www.ncbi.nlm.nih.gov/ pubmed/14592302 , Accessed date: 19 May 2019. [8] M. Friedman, M. Wilson, H.-C. Lin, H.-W. Chang, Updated systematic review of tonsillectomy and adenoidectomy for treatment of pediatric obstructive sleep apnea/hypopnea syndrome, Otolaryngol. Head Neck Surg. 140 (6) (2009) 800–808, https://doi.org/10.1016/j.otohns.2009.01.043. [9] M.M. Statham, R.G. Elluru, R. Buncher, M. Kalra, Adenotonsillectomy for obstructive sleep apnea syndrome in young children: prevalence of pulmonary complications, Arch. Otolaryngol. Head Neck Surg. 132 (5) (2006) 476–480, https:// doi.org/10.1001/archotol.132.5.476. [10] A.H. Werle, P.J. Nicklaus, D.J. Kirse, D.E. Bruegger, A retrospective study of tonsillectomy in the under 2-year-old child: indications, perioperative management, and complications, Int. J. Pediatr. Otorhinolaryngol. 67 (5) (2003) 453–460 http:// www.ncbi.nlm.nih.gov/pubmed/12697346 , Accessed date: 19 May 2019. [11] H.E. Montgomery-Downs, D. Gozal, Sleep habits and risk factors for sleep-disordered breathing in infants and young toddlers in Louisville, Kentucky, Sleep Med. 7 (3) (2006) 211–219, https://doi.org/10.1016/j.sleep.2005.11.003. [12] K. Liukkonen, P. Virkkula, E.T. Aronen, T. Kirjavainen, A. Pitkäranta, All snoring is not adenoids in young children, Int. J. Pediatr. Otorhinolaryngol. 72 (6) (2008) 879–884, https://doi.org/10.1016/j.ijporl.2008.02.018. [13] M. Alkhalil, E. Schulman, J. Getsy, Obstructive sleep apnea syndrome and asthma: what are the links? J. Clin. Sleep Med. 5 (1) (2009) 71–78 http://www.ncbi.nlm. nih.gov/pubmed/19317386 , Accessed date: 19 May 2019. [14] M. Bortolotti, L. Gentilini, C. Morselli, M. Giovannini, Obstructive sleep apnoea is improved by a prolonged treatment of gastrooesophageal reflux with omeprazole, Dig. Liver Dis. 38 (2) (2006) 78–81, https://doi.org/10.1016/j.dld.2005.09.018.
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