One of the most frequent indications for tonsillectomy in children is for management of sleep-disordered breathing due to airway obstruction.1–4 Sleep-disordered breathing and obstructive sleep apnea (OSA) are often associated with obesity, which has become pandemic.5–7 With the need to preserve medical resources, increasing numbers of procedures are conducted on an outpatient basis; this has created the perfect storm where children may be incompletely assessed before their anesthetic and cared for as an outpatient with inadequate postoperative observation. This is of particular concern with the opioid sensitivity reported in children with OSA, i.e., what would be considered a normal dose of opioid may be a relative overdose in OSA children.8
The American Society of Anesthesiologists (ASA) proposed practice guidelines and a risk identification scoring system to assess potential OSA patients who may require more extensive postanesthesia observation.9 Likewise, pediatric otolaryngologists published guidelines regarding the need for increased vigilance.10 Unfortunately, some children have died or suffered neurologic injury as a result of apnea after tonsillectomy. We conducted a 2-stage investigation: (1) a survey of members of the Society for Pediatric Anesthesia and (2) a query from the ASA Closed Claims Project to investigate factors associated with adverse events in children undergoing tonsillectomy.
An anonymous electronic survey (Partners Human Research IRB exemption, Protocol #2010-P-002757/1; Massachusetts General Hospital, Boston, MA) was e-mailed to members of the Society for Pediatric Anesthesia (1995 active, 34 affiliates, 102 fellows, 106 residents, 22 retired, and 118 international). Two rounds of follow-up surveys were sent at 2-month intervals, including an added question which asked if the first survey was completed, so as to exclude duplicates. In addition, a formal query was conducted using the ASA Closed Claims Project database (University of Washington IRB #21618 and #43939; written patient consent waived by IRB) for cases involving otolaryngology procedures from 1990 to 2011. Summaries of 45 cases were compared with survey cases (age, gender, year of event, cause of event) to identify possible duplicates from the 2 data sources.
Inclusion criteria for electronic survey cases were those in which a child died or nearly died after tonsillectomy. Inclusion criteria for case selection from the ASA Closed Claims Project were tonsillectomy or tonsillectomy with adenoidectomy with death or adverse event due to surgical hemorrhage or adverse anesthetic event, or with death or adverse event at home or in hospital. Cases with inadequate information were excluded.
Definition of Variables
The ASA’s Practice Guidelines for the Perioperative Management of Patients with Obstructive Sleep Apnea9 (Appendix 1, see Supplemental Digital content 1, https://links.lww.com/AA/A550) was used to categorize children potentially at risk for OSA from survey reports and the ASA Closed Claims Project unless they were already labeled as having OSA by the surgeon, family, or anesthesiologist; factors such as obesity (≥95th percentile for age using standard gender-specific growth curves) + history of snoring + 1 other risk factor fulfilled our interpretation of the ASA OSA criteria. If a child’s weight was provided, we used standard growth curves to determine that the child was ≥95th percentile for age and gender. Children whose ASA OSA risk score was ≥5 were categorized as at risk for OSA for comparison with “all others,” i.e., children judged not to be at risk for OSA.
Events were classified as surgical, anesthesia, or nursing related. All events reported as hemorrhage were considered surgical. Postextubation respiratory events or events during the conduct of anesthesia were attributed to anesthetic management. If an event occurred in the postanesthesia care unit (PACU) or on the floor that was attributed to apnea, this was classified as a PACU or floor nursing observation problem.
At risk for OSA cases were compared with all others by Fisher exact test for proportions and t test for age using Levene test for equality of variances. For cross-tabulation tables with any cell having an expected value <5, P-values were calculated by Monte Carlo calculations using 10,000 random tables. For cross-tabulation tables with >4 cells and a distribution achieving statistical significance, post hoc Fisher exact test was performed on reduced 2 × 2 tables of the variables of interest (present/absent) between the 2 groups. For all statistical tests, a P value of <0.05 was considered statistically significant. Statistical calculations were conducted with SPSS version 18.0.3 (IBM, Chicago, IL).
Seven hundred thirty-one surveys were returned (approximately 30%) yielding 129 possible adverse events after tonsillectomy; 1 was a duplicate when compared with the Closed Claims cases and was therefore deleted, and there were 36 additional cases that had insufficient data; thus 92 surveys met inclusion criteria with adequate data for analysis. Since some surveys were incomplete, it is possible that we actually underestimated the magnitude of the injuries. The ASA Closed Claims query yielded 45 additional cases, of which 23 did not meet inclusion criteria due to surgical procedure (e.g., adenoidectomy without tonsillectomy). Three claims were excluded due to inadequate data, leaving 19 that met inclusion criteria and had adequate data for analysis. Thus 111 surveys/reports meeting inclusion criteria and with adequate data for interpretation (Fig. 1) formed the final cohort for analysis. These cases occurred in 1990 to 2010, with more than half of the cases occurring in 2004 or later. More than half (57%) of the children met criteria for at risk for OSA. Table 1 presents demographics, indications for surgery, and comorbidities. Half of the children were 4 to 8 years of age and another 27% were younger, with no difference in age between children at risk for OSA and all others (Table 1). At-risk children were more likely to be obese than other children (P < 0.0001, Table 1). Ethnicity was associated with the categorization of patients being at risk for OSA (P < 0.0001). Higher ASA physical status was also associated with patients categorized as being at risk for OSA (P < 0.0001, Table 1).
Death (66%) was the most common outcome, followed by permanent neurologic injury (11%), and prolonged hospitalization (10%, Table 2). A larger proportion of at risk for OSA children had the event attributed to apnea (P = 0.016) whereas all others had a larger proportion attributed to hemorrhage (P = 0.006, Fig. 2). The adverse events took place in a variety of locations (e.g., operating room, PACU, ward, after discharge) with no difference between children categorized as at risk for OSA versus all others (Table 2). When events occurred after surgery, approximately half (58% of all 80 postoperative events, 77% of 61 postoperative events with specific timing known) occurred within 24 hours of the procedure. Of the total 63 events that occurred within 24 hours of the procedure, 30 (48%) occurred after discharge from the hospital. There was no difference between children at risk for OSA or all others in the timing of postoperative adverse events. Among the 80 total cases with postoperative events, 40 (50%) were reported to have received postoperative opioids including 14 (61%) of the 23 children with postoperative apnea events that occurred within 24 hours postoperatively. There were 4 children who were reported to have received postoperative opioids and had an apnea event >24 hours after the procedure. Cases with an event in the operating room either due to anesthesia or surgical issues are described in Table 3.
There were 13 children who suffered an event in the PACU. Several of these were attributed to opioid overdose, 6 attributed to apnea, 1 attributed to aspiration of a blood clot, and 1 attributed to cardiac arrest without details provided. Two deaths occurred in the PACU after monitors were removed from the child. One 5-year-old child in a first-stage PACU who received morphine and midazolam to treat emergence agitation was left in his father’s arms without monitors and the father thought his child was sleeping. The second death was a 3 year old in a second-stage PACU without monitoring. The mother was reclining in the same stretcher as her child, and this parent also thought her child was sleeping. One child with known OSA was admitted overnight and discharged the following morning, but was found dead approximately 48 hours after surgery. Table 4 presents sample surgical, anesthesia or combined adverse events.
Comorbidities played an important role in some of these adverse outcomes. Two children who had Williams syndrome (supravalvular aortic stenosis, abnormal coronary vessels, pulmonary stenosis) died during the induction or emergence from anesthesia; it is unclear whether these children had an established preoperative diagnosis.
Surgical complications included a variety of problems including kinking of the tracheal tube with a Dingman retractor, laceration of the carotid vessel, and hemorrhage either immediately during the case or a number of days postoperatively. Some of the children who experienced hemorrhage were able to be rescued, whereas others either died at home, in the emergency room, or were unable to be rescued in the operating room. Our data did not seem to provide any time-based relationship for these hemorrhages, i.e., they did not occur at the classic first 4 hours after surgery or on day 5 when the eschar separates. Further data are presented for all cases in Appendix 2 (see Supplemental Digital Content 2, https://links.lww.com/AA/A551).
Perioperative deaths associated with tonsillectomy are thankfully uncommon.11 The incidence of hemorrhage in our database (approximately 28%) is similar to the 3 reviews of otolaryngology-related malpractice cases.12–14 However, the seemingly larger percentage of severe adverse outcomes (death and neurologic injury) in our database related to apparent respiratory events (36%) compared with these otolaryngology reports (17%) could, in part, be related to observer bias with anesthesiologists more likely to report respiratory events and surgeons to report hemorrhagic events. Importantly, apnea was reported in 29 of 63 children categorized as at risk for OSA; these outcomes occurred in the PACU, on the ward, and at home.
Tonsillectomy-related malpractice settlements occur against anesthesiologists more commonly than against surgeons and settle for nearly 5-fold larger awards because of the devastating outcomes.12–14 Medication-related lawsuits reported inappropriate prescribing of opioids.12 One report described 11 postoperative deaths or neurologic injuries due to airway-related events, including a number of respiratory arrests of unclear etiology;13 these may have been related to opioid-induced apnea. Another review of adverse legal outcomes after tonsillectomy attributed approximately 17% of cases to postoperative medication issues.14 That article discussed abnormal cytochromes resulting in rapid metabolism of codeine to morphine as possibly contributory. Compression of an endotracheal tube by a mouth gag was also described, and this case was possibly 1 of the cases in our database. Anoxic intraoperative and postoperative events accounted for verdicts as large as $45 million.14 Negligent postoperative care, negligent anesthesia care, and overprescribing of opioids were among the common allegations.
A 32-question survey similar to ours was recently conducted by the Patient Safety and Quality Improvement Committee of the American Academic of Otolaryngology—Head and Neck Surgery.15 They reported 55 deaths or neurologic injury of which 40 were children. Six were attributed to bleeding, 9 to “med-narcotic,” and 16 were described as unexplained cause; of the latter group, 1 was in hospital and the remaining 15 occurred out of hospital.15 In the ear-nose-throat (ENT) survey, 8 pediatric deaths implicated opioid overdose including several that suggested the caregiver administering larger than prescribed doses or additional nonprescribed opioid medications. At least 2 cases in our study were also attributed to the administration of additional doses of medication than what was prescribed, thus these cases may be overlaps between the 2 surveys. Ten deaths reported in the ENT survey occurred in children with OSA. They found that “events unrelated to bleeding accounted for a preponderance of deaths and anoxic brain injury.” Since the timing of these surveys overlapped, there is no way of knowing how many of these cases were also reported to us by anesthesiologists; however, the message is clear from both surveys: unexpected deaths are occurring at home after discharge from medical supervision.
These cases collected from surgeons and anesthesiologists emphasize the need for better procedures for assessing perioperative risks after tonsillectomy. In particular, those with the potential for OSA need better evaluations to allow the surgical/anesthesia team to improve the safety net. At present, a formal sleep polysomnogram is the very expensive “gold standard”; perhaps further study of the minimal cost McGill overnight oximetry test is needed.16,17 This is a simple quantitation of desaturation nadir episodes based on a scale of 1 to 4 for events with hemoglobin saturations of <90%, <85%, and <80% during sleep.
Given that tonsillectomy is one of the most common outpatient surgical procedures performed in children (approximately 530,000 per year in children <15 years of age in the United States),10,18 it is important to accurately assess the safety of outpatient surgery. Despite great performance pressure to efficiently operate and discharge patients, some children are not appropriate candidates for outpatient tonsillectomy.9 The Subcommittee on Obstructive Sleep Apnea of the Section on Pediatric Pulmonology of the American Academy of Pediatrics19 and the Clinical Practice Guideline for Tonsillectomy from the American Academy of Otolaryngology—Head and Neck Surgery both suggest that children with OSA and other medical/social issues “should be treated in an inpatient setting.”10
Obesity, a history of OSA, and the need for postoperative opioid markedly increase the potential for adverse postoperative respiratory events. Children undergoing tonsillectomy may have a worsening of airway obstruction on the first night of surgery.16,20 Additionally, children with severe OSA, who exhibit desaturation during a sleep study, may have a heightened analgesic and respiratory sensitivity to opioids (average requirements approximately 50% less than for children undergoing tonsillectomy for recurrent tonsillitis).17,21,22 This opioid sensitivity may be related to hypoxia-induced opioid receptor regulation;23,24 animal models have confirmed this observation.25–27 Thus the standard dose of opioid may actually be an overdose in a child with OSA. Furthermore, there are increasing reports of children who are ultrarapid metabolizers of codeine (duplicated genes) which may accelerate its conversion to morphine and thus result in overdose.28–32 Conversely, children who lack the cytochrome to convert codeine to morphine may not obtain any opioid analgesia and achieve their analgesia simply from the coadministration of acetaminophen.33
Obesity is epidemic and frequently associated with OSA.1,3,5 Our data confirm this positive association and, unfortunately, also document preventable adverse outcomes. Some deaths were clearly related to less than ideal anesthetic management and/or poor surgical management. It is a major concern that 13 children experienced an event in the PACU either immediately on admission or within the first 3 hours; 10 children likely should have been rescued with more timely intervention. The subtleness and rapidity of the apnea in the 2 children who died in the PACU after monitors were removed emphasize the need for continuous monitoring. Of the 32 children labeled as obese, 28 died or suffered neurologic injury regardless of the described indications for surgery. The cause of the event in obese children was attributed to apnea in 19, hemorrhage in 6, and unknown in 3.
Limitations of our study include the large number of questionnaires that were not completed, provided partial information, or had reporting bias. There is also the potential that some cases were reported more than once from any 1 institution. However, by cross-checking age, ethnicity, year of the event, and descriptive text, we were only able to identify 1 duplicate. Furthermore, the survey did not define apnea or hemorrhage when eliciting the cause of the event, so there is a possibility of inconsistency in attribution. It is highly likely that the questionnaire survey performed by the ENT surgeons and our survey greatly underestimated the number of children with these adverse outcomes. In addition, the ASA Closed Claims cases had extracted data not specifically addressing the issue of OSA; these records had significant deficits in the information we were seeking. Our study does not shed light on the overall safety or risk of performing tonsillectomy on an outpatient basis as we lack a denominator for risk calculation.
Identification of children at risk for OSA is essential for all children undergoing anesthesia. Perianesthetic risk is likely increased if the surgery involves a major body cavity or the airway and if there will be need for postoperative opioids. Conversely, risk is likely quite minimal if it is a peripheral procedure and there is no need for opioids. Because tonsillectomy involves the airway and also the need for postoperative opioids, this procedure when combined with the diagnosis of OSA places children at increased risk for adverse perioperative events. Our analysis and results suggest that the identification scoring system for assessing perianesthetic risk developed by the ASA which includes predisposing physical characteristics, historical questions regarding airway obstruction, and daytime somnolence due to interrupted sleep patterns appears to have merit.9 Unfortunately that guideline was meant to be applicable to adults and children. Table 5 presents a list of pediatric-specific signs and symptoms of OSA that may further help identify children at risk.
Our data also suggest that ethnicity may be another important variant since 20 of 26 African American, 11 of 14 Hispanic, and 3 of 3 Asian children were described in this cohort as having a history consistent with being at risk for OSA. The incidence of OSA may be 4 or more times greater in African American children,4 and they also exhibit more profound desaturation with obstructive events compared with Caucasian children.34–37 In addition, our data suggest that higher ASA physical status was associated with patients who were at risk for OSA. The OSA identification scoring system for assessing perianesthetic risk developed by the ASA appears to have merit; modification of the guideline with more pediatric-specific language would need to be validated.
In conclusion, it is imperative that the surgeon and anesthesiologist identify children at risk for OSA.39 Children who are obese (gender-specific weight or body mass index ≥95th percentile) and who have other clinical indicators of OSA (Table 5) even in the absence of a sleep polysomnogram may be at risk.40,41 Despite the need for cost containment, we must recommend a more considered management of at-risk children since 10 deaths or neurologic injury occurred at home, 2 in the PACU, and 3 on the ward within 24 hours of surgery. These children could have been rescued had proper monitoring been continued throughout first- and second-stage recovery, as well as on the ward during the first postoperative night.22 In addition, practitioners must be aware of the marked opioid sensitivity of these children and therefore reduce the usual opioid dose by approximately 50%.8,17 Further consideration should be given to the possibility of rapid codeine metabolizers that would place them at additional risk.29,31 It may be safer to avoid the use of codeine altogether and use alternate opioid analgesics.33 The Food and Drug Administration has recently issued a “black box” warning regarding the use of codeine in children undergoing tonsillectomy.a Death after tonsillectomy related to hemorrhage may not be preventable, but death due to apnea is preventable. It is for these at-risk children that we need to develop an improved safety net. The ASA OSA guideline was an important first step in this direction, but further multi-institution prospective study of a pediatric-specific risk identification and assessment scoring system is needed.
Name: Charles J. Coté, MD.
Contribution: This author contributed to study design, conduct of the study, data collection, data analysis, and manuscript preparation.
Attestation: Charles Coté attests to the integrity of the original data and the analysis reported in this manuscript, and has approved the final manuscript.
Name: Karen L. Posner, PhD.
Contribution: This author helped with data collection, data analysis, and manuscript preparation.
Attestation: Karen Posner attests to the integrity of the original data and the analysis reported in this manuscript, and has approved the final manuscript. Karen Posner is the archival author.
Name: Karen B. Domino, MD, MPH.
Contribution: This author helped with data collection and manuscript preparation.
Attestation: Karen Domino attests to having approved the final manuscript.
This manuscript was handled by: Peter J. Davis, MD.
We would like to thank the leadership of the Society for Pediatric Anesthesia for facilitating the survey. We also thank Lynn Akerlund for her excellent assistance in manuscript preparation.
a U.S. Food and Drug Administration. Codeine Use in Certain Children After Tonsillectomy and/or Adenoidectomy: Drug Safety Communication—Risk of Rare, But Life-Threatening Adverse Events or Death. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm315627.htm. Accessed February 22, 2013.
1. Costa DJ, Mitchell R. Adenotonsillectomy for obstructive sleep apnea in obese children: a meta-analysis. Otolaryngol Head Neck Surg. 2009;140:455–60
2. Friedman M, Wilson M, Lin HC, Chang HW. Updated systematic review of tonsillectomy and adenoidectomy for treatment of pediatric obstructive sleep apnea/hypopnea syndrome. Otolaryngol Head Neck Surg. 2009;140:800–8
3. Mitchell RB, Boss EF. Pediatric obstructive sleep apnea in obese and normal-weight children: impact of adenotonsillectomy on quality-of-life and behavior. Dev Neuropsychol. 2009;34:650–61
4. Lumeng JC, Chervin RD. Epidemiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc. 2008;5:242–52
5. Arens R, Muzumdar H. Childhood obesity and obstructive sleep apnea syndrome. J Appl Physiol. 2010;108:436–44
6. Bhattacharjee R, Kim J, Kheirandish-Gozal L, Gozal D. Obesity and obstructive sleep apnea syndrome in children: a tale of inflammatory cascades. Pediatr Pulmonol. 2011;46:313–23
7. Carter R 3rd, Watenpaugh DE. Obesity and obstructive sleep apnea: or is it OSA and obesity? Pathophysiology. 2008;15:71–7
8. Brown KA, Laferrière A, Lakheeram I, Moss IR. Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates. Anesthesiology. 2006;105:665–9
9. Gross JB, Bachenberg KL, Benumof JL, Caplan RA, Connis RT, Coté CJ, Nickinovich DG, Prachand V, Ward DS, Weaver EM, Ydens L, Yu SAmerican Society of Anesthesiologists Task Force on Perioperative Management. . Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology. 2006;104:1081–93
10. Baugh RF, Archer SM, Mitchell RB, Rosenfeld RM, Amin R, Burns JJ, Darrow DH, Giordano T, Litman RS, Li KK, Mannix ME, Schwartz RH, Setzen G, Wald ER, Wall E, Sandberg G, Patel MMAmerican Academy of Otolaryngology-Head and Neck Surgery Foundation. . Clinical practice guideline: tonsillectomy in children. Otolaryngol Head Neck Surg. 2011;144:S1–30
11. Bhattacharyya N. Ambulatory pediatric otolaryngologic procedures in the United States: characteristics and perioperative safety. Laryngoscope. 2010;120:821–5
12. Simonsen AR, Duncavage JA, Becker SS. A review of malpractice cases after tonsillectomy and adenoidectomy. Int J Pediatr Otorhinolaryngol. 2010;74:977–9
13. Morris LG, Lieberman SM, Reitzen SD, Edelstein DR, Ziff DJ, Katz A, Komisar A. Characteristics and outcomes of malpractice claims after tonsillectomy. Otolaryngol Head Neck Surg. 2008;138:315–20
14. Stevenson AN, Myer CM 3rd, Shuler MD, Singer PS. Complications and legal outcomes of tonsillectomy malpractice claims. Laryngoscope. 2012;122:71–4
15. Goldman JL, Baugh RF, Davies L, Skinner ML, Stachler RJ, Brereton J, Eisenberg LD, Roberson DW, Brenner MJ. Mortality and major morbidity after tonsillectomy: etiologic factors and strategies for prevention. Laryngoscope.
16. Brown KA, Morin I, Hickey C, Manoukian JJ, Nixon GM, Brouillette RT. Urgent adenotonsillectomy: an analysis of risk factors associated with postoperative respiratory morbidity. Anesthesiology. 2003;99:586–95
17. Brown KA, Laferrière A, Moss IR. Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia. Anesthesiology. 2004;100:806–10
18. Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report. 2009:1–25
19. Marcus CL, Brooks LJ, Draper KA, Gozal D, Halbower AC, Jones J, Schechter MS, Sheldon SH, Spruyt K, Ward SD, Lehmann C, Shiffman RNAmerican Academy of Pediatrics. . Diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2012;130:576–84
20. Nixon GM, Kermack AS, McGregor CD, Davis GM, Manoukian JJ, Brown KA, Brouillette RT. Sleep and breathing on the first night after adenotonsillectomy for obstructive sleep apnea. Pediatr Pulmonol. 2005;39:332–8
21. Waters KA, McBrien F, Stewart P, Hinder M, Wharton S. Effects of OSA, inhalational anesthesia, and fentanyl on the airway and ventilation of children. J Appl Physiol. 2002;92:1987–94
22. Raghavendran S, Bagry H, Detheux G, Zhang X, Brouillette RT, Brown KA. An anesthetic management protocol to decrease respiratory complications after adenotonsillectomy in children with severe sleep apnea. Anesth Analg. 2010;110:1093–101
23. Hambrecht VS, Vlisides PE, Row BW, Gozal D, Baghdoyan HA, Lydic R. G proteins in rat prefrontal cortex (PFC) are differentially activated as a function of oxygen status and PFC region. J Chem Neuroanat. 2009;37:112–7
24. Peng PH, Huang HS, Lee YJ, Chen YS, Ma MC. Novel role for the delta-opioid receptor in hypoxic preconditioning in rat retinas. J Neurochem. 2009;108:741–54
25. Laferrière A, Liu JK, Moss IR. Neurokinin-1 versus mu-opioid receptor binding in rat nucleus tractus solitarius after single and recurrent intermittent hypoxia. Brain Res Bull. 2003;59:307–13
26. Lalley PM. Mu-opioid receptor agonist effects on medullary respiratory neurons in the cat: evidence for involvement in certain types of ventilatory disturbances. Am J Physiol Regul Integr Comp Physiol. 2003;285:R1287–304
27. Moss IR, Laferrière A. Central neuropeptide systems and respiratory control during development. Respir Physiol Neurobiol. 2002;131:15–27
28. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Br J Clin Pharmacol. 1991;31:381–90
29. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351:2827–31
30. Kirchheiner J, Schmidt H, Tzvetkov M, Keulen JT, Lötsch J, Roots I, Brockmöller J. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7:257–65
31. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant—an ultra-rapid metabolizer. Paediatr Anaesth. 2007;17:684–7
32. Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, Carleton B, Hayden MR, Madadi P, Koren G. More codeine fatalities after tonsillectomy in North American children. Pediatrics. 2012;129:e1343–7
33. Pickering AE, Bridge HS, Nolan J, Stoddart PA. Double-blind, placebo-controlled analgesic study of ibuprofen or rofecoxib in combination with paracetamol for tonsillectomy in children. Br J Anaesth. 2002;88:72–7
34. Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems. Am J Respir Crit Care Med. 1999;159:1527–32
35. Redline S, Tishler PV, Hans MG, Tosteson TD, Strohl KP, Spry K. Racial differences in sleep-disordered breathing in African-Americans and Caucasians. Am J Respir Crit Care Med. 1997;155:186–92
36. Stepanski E, Zayyad A, Nigro C, Lopata M, Basner R. Sleep-disordered breathing in a predominantly African-American pediatric population. J Sleep Res. 1999;8:65–70
37. Boss EF, Smith DF, Ishman SL. Racial/ethnic and socioeconomic disparities in the diagnosis and treatment of sleep-disordered breathing in children. Int J Pediatr Otorhinolaryngol. 2011;75:299–307
38. Su MS, Li AM, So HK, Au CT, Ho C, Wing YK. Nocturnal enuresis in children: prevalence, correlates, and relationship with obstructive sleep apnea. J Pediatr. 2011;159:238–42.e1
39. Coté CJ, Sheldon SH. Obstructive sleep apnea and tonsillectomy: do we have a new indication for extended postoperative observation? Can J Anaesth. 2004;51:6–12
40. Wilson K, Lakheeram I, Morielli A, Brouillette R, Brown K. Can assessment for obstructive sleep apnea help predict postadenotonsillectomy respiratory complications? Anesthesiology. 2002;96:313–22
41. Nixon GM, Kermack AS, Davis GM, Manoukian JJ, Brown KA, Brouillette RT. Planning adenotonsillectomy in children with obstructive sleep apnea: the role of overnight oximetry. Pediatrics. 2004;113:e19–25