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Volume 14 No. 09
Earn CME
Accepted Papers





Scientific Investigations

Sleep-Disordered Breathing is Associated With Increased Mortality in Hospitalized Infants With Congenital Heart Disease

Daniel Combs, MD1,2,3; Grant Skrepnek, PhD, RPh4; Michael D. Seckeler, MD, MSc5; Brent J. Barber, MD5; Wayne J. Morgan, MD1; Sairam Parthasarathy, MD2,3
1Department of Pediatrics, Division of Pulmonary and Sleep Medicine, University of Arizona, Tucson, Arizona; ; 2Department of Medicine, University of Arizona, Tucson, Arizona; 3University of Arizona Health Sciences Center for Sleep and Circadian Sciences and Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Arizona, Tucson, Arizona; 4Department of Pharmacy: Clinical and Administrative Sciences, University of Oklahoma, Oklahoma City, Oklahoma; 5Department of Pediatrics, Division of Cardiology, University of Arizona, Tucson, Arizona

ABSTRACT

Study Objectives:

Sleep-disordered breathing (SDB) has adverse cardiovascular effects in children and adults. In adults with cardiac disease, SDB is highly prevalent and confers increased mortality risk. It is unknown if SDB confers a similar risk in infants with congenital heart disease (CHD). We evaluated clinical and economic outcomes associated with SDB among inpatient infants with CHD in the United States from 1997–2012.

Methods:

This retrospective, cross-sectional study used discharge data from the Kids' Inpatient Database. Inclusion criteria included diagnosed CHD and age younger than 1 year. Exclusion criteria included apnea of prematurity, cardiac surgery during admission, and invasive mechanical ventilation. Generalized linear models were used to assess outcomes of mortality, length of stay, and total charges after controlling for SDB, clinical characteristics, hospital characteristics, and economic factors.

Results:

Across 461,778 inpatient infant cases of CHD from 1997–2012, 4,839 involved SDB (14% obstructive, 4% central, 82% not specified). Multivariable analyses show that central sleep apnea was independently associated with increased risk of inpatient mortality (odds ratio 4.3), 92% longer inpatient stay, and 112% higher total charges when compared to infants with CHD without comorbid SDB (P < .05). Obstructive and unspecified SDB were associated with longer adjusted lengths of stay (56% and 18%, respectively) and higher charges (48% and 21%, respectively) relative to infants with CHD without comorbid SDB (P < .001).

Conclusions:

SDB, particularly central sleep apnea, was independently associated with worse outcomes in hospitalized infants with CHD. Further research on whether treatment of SDB in infants with CHD can abrogate adverse patient outcomes is needed.

Citation:

Combs D, Skrepnek G, Seckeler MD, Barber BJ, Morgan WJ, Parthasarathy S. Sleep-disordered breathing is associated with increased mortality in hospitalized infants with congenital heart disease. J Clin Sleep Med. 2018;14(9):1551–1558.


BRIEF SUMMARY

Current Knowledge/Study Rationale: Sleep-disordered breathing is known to have adverse cardiovascular effects in children and adults. It has been shown to be associated with increased risk of mortality in adults with cardiac disease, but there are no hospital outcomes data published for children.

Study Impact: Sleep-disordered breathing is associated with increased mortality, length of stay, and hospital charges in infants with congenital heart disease. Sleep-disordered breathing may represent a modifiable risk factor for mortality in this population.

INTRODUCTION

The prevalence of congenital heart disease (CHD) in the United States is estimated to be 8 in 1,000 live births,13 with 2 to 3 in 1,000 requiring surgical or catheter-based intervention.3,4 At least 40,000 infants are born each year with CHD in the United States, with 10,000 requiring intervention.3 Advances in the treatment of CHD have led to a survival rate of 90%,5 resulting in a greatly increasing population surviving into adulthood. In the United States, 1 in 150 adults have some form of CHD.6 As of 2012, there were an estimated 1.5 million adult survivors of CHD and this number is expected to continue to increase.7 As surgical and nonsurgical techniques continue to improve, there is a need to examine other modifiable factors that may influence hospital outcomes of infants with CHD.

Sleep-disordered breathing (SDB) is a common comorbid condition with congestive heart failure in adults, with an estimated prevalence up to 84%.8 There is strong evidence showing an increased risk of mortality associated with SDB in adults with heart failure.9 In adults, treatment of SDB—specifically of obstructive sleep apnea—has been shown to improve cardiac function, reduce sympathetic activity, and improve quality of life in a randomized study.10 Moreover, prospective observational research has shown that treatment of obstructive sleep apnea reduces the risk of mortality and hospitalizations in adults with heart failure and comorbid obstructive sleep apnea.11 Given that infants with CHD are at risk for heart failure,12 similar to adults, SDB may be an important treatable comorbidity that is associated with poor clinical outcomes in infants with CHD. In general, SDB is a prevalent condition in children, with obstructive sleep apnea seen in 1.2% to 5.7% of children in a community setting.13 Although there are no large-scale studies of prevalence of SDB in infants with CHD, in a small prospective study, 79% of infants with CHD being evaluated for cardiac surgery were found to have comorbid SDB.14 This high prevalence of obstructive sleep apnea in infants with CHD may be related to craniofacial abnormalities, the most common noncardiac malformation among children with CHD.15 This phenotype may also be related to underlying neural crest cell migration defects that contribute to both CHD and airway abnormalities.16

Given the reported high prevalence of SDB in infants with CHD, and known association of SDB with poor outcomes in adults with heart failure, we hypothesized that SDB would be associated with worse health outcomes in hospitalized infants with CHD. To test this hypothesis, we examined clinical and economic outcomes associated with SDB among hospitalized infants with CHD in the United States from 1997–2012 using nationally representative inpatient discharge records.

METHODS

We performed a cross-sectional, retrospective cohort study utilizing inpatient discharge data from the Agency for Healthcare Research and Quality (AHRQ) Healthcare Utilization Project (HCUP).17 Nationally representative cases from the 1997–2012 Kid's Inpatient Database (KID) were used, which includes pediatric discharges from more than 4,100 United States community hospitals in 44 states.17 Given that data within the KID are collected every 3 years, a total of 6 independent years were analyzed across the study's 16-year time frame. As these data are fully de-identified and anonymized without protected health information, the study was considered exempt by the University of Arizona Institutional Review Board.

Cases were included if age was younger than 1 year and an International Classification of Diseases, 9th Edition, Clinical Modification (ICD-9) diagnosis of CHD was included in the discharge diagnosis list (Table 1). Cases were excluded if a diagnosis of apnea of prematurity was present, if cardiac surgery was conducted during the inpatient stay, or if invasive mechanical ventilation was used. These exclusion criteria were selected to minimize prematurity and immediate postoperative effects of cardiac surgery as potential causes for a diagnosis of apnea. SDB was classified as obstructive, central, or unspecified based on the listed ICD-9 diagnosis (Table 1). We performed sensitivity analysis excluding the diagnosis “apnea” (ICD-9 786.03), as it is may represent either SDB or apnea due to another cause.

Diagnostic codes for SDB and CHD.

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Table 1

Diagnostic codes for SDB and CHD.

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To assess for potential bias related to CHD severity, we used the Risk Adjustment for Congenital Heart Surgery (RACHS) score as a measure of CHD severity.18 Increased RACHS score has previously been shown to be predictive of higher risk of mortality, longer length of stay, and higher hospital charges.19 RACHS scores were assigned based on the typical surgery for a given ICD-9 diagnosis by a board-certified pediatric cardiologist. We excluded ICD-9 diagnoses that were not specific enough to determine the most common surgery, as well as diagnoses for which repair is performed using more than one common surgical technique. A total of 316,574 cases were included in the analysis.

Outcomes analyzed included inpatient mortality, length of stay, and hospital charges (using inflation-adjusted charges using the medical service component of the consumer price index).20 Independent predictor variables included patient demographics (sex, regional income level, primary payer), hospital characteristics (children's hospital designation, urban/ rural location and teaching status, geographic region, and number of beds), specific clinical covariates (presence of other congenital disorders, premature birth, and sepsis), overall case-mix risk adjustor (Deyo-Charlson comorbidity index), and the use of noninvasive respiratory support.17,21 Other congenital disorders were identified as those extending beyond CHD, particularly those involving other circulatory, digestive, genitourinary, nervous system, and other anomalies defined, in part, via AHRQ's validated clinical classification software algorithms.17 Down syndrome, which is commonly associated with both CHD and SDB, was included in the category of other congenital disorders.

Multivariable regression analyses using a generalized linear model framework were conducted to assess the association between outcomes and predictor (independent) variables using the following distributions with logarithmic links: (1) binomial/logistic for inpatient mortality (reporting odds ratios [OR]); (2) negative binomial for length of stay (reporting incidence ratios [IR]); and (3) gamma for charges (reporting exponentiated coefficients [exp(b)]).22,23 Maximum likelihood estimation was used and Taylor series linearization was conducted for covariance matrix and standard error calculations to allow for nationally representative estimates based upon the complex sampling approach used within HCUP.17,2325 All analyses were performed using SAS 9.3 (Cary, North Carolina, United States) or Stata MP 14.2 and 15.1 (College Station, Texas, United States) with an a priori alpha of .05 for statistical significance.

RESULTS

Overall, 461,778 CHD cases met inclusion criteria from 1997– 2012. SDB was noted in 4,968 cases (1.0%) and classified accordingly: obstructive (14%, n = 679); central (4%, n = 193); and unspecified (82%, n = 4,096). All cases of obstructive SDB were obstructive sleep apnea. For central SDB, 23% of cases were primary central sleep apnea, whereas 59% of cases were central sleep apnea in conditions classified elsewhere. Other central SDB codes (Table 1) made up the remaining 18% of cases (due to KID database user agreement and risk of identifying individual patients; we are unable to report specific information for diagnoses with n ≤ 10). For unspecified SDB, 94% of cases were apnea, and 6% of cases were unspecified sleep apnea. SDB cases predominantly involved Medicaid as a primary payer (62.3%), were seen in large bed (62.9%) and urban teaching facilities (79.8%), and often presented with other congenital disorders (38.7%). Relative to CHD cases, bivariate analyses suggested that SDB cases involved higher proportions of male sex, Medicaid, and presence of other congenital disorders (P < .05). Medical inflation-adjusted charges (as calculated in United States dollars in 2017) averaged $66,894 ± $149,007 per visit (median $25,684, IQR $12,364, $63,202) for CHD cases with SDB versus $51,482 ± $129,192 (median $14,439, IQR $5,871, $46,436) without SDB (P < .001). The most common comorbid diagnoses listed for children with CHD and SDB included esophageal reflux (82.5%), anomalies of the larynx, trachea, and bronchus (41.5%), Down syndrome (33.7%), feeding difficulties and mismanagement (29.8%), hypoxemia (22.7%), gastrostomy (22.3%), failure to thrive (22.1%), and anomalies of skull and face bones (19.0%). Full demographics are presented in Table 2.

Descriptive statistics associated with hospitalized infant CHD cases and SDB in the United States, 1997–2012.*

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Table 2

Descriptive statistics associated with hospitalized infant CHD cases and SDB in the United States, 1997–2012.*

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The multivariable analyses that controlled for numerous demographic, hospital, and clinical factors including CHD severity, other congenital disorders, premature birth, sepsis, and requirement of noninvasive ventilation (Table 3) indicated that central SDB was independently associated with higher odds of inpatient mortality (OR 4.25), 92% longer inpatient stay (IR 1.92), and 112% higher total charges (exp(b) 2.04, P < .05 for all) (Figure 1). Obstructive SDB was associated with 56% longer lengths of stay (IR 1.56) and 48% higher charges (exp(b) 1.58, P < .001 for both). Unspecified SDB was associated with 18% (IR 1.18) longer lengths of stay, and 21% higher charges (exp(b) 1.21, P < .001). Over time, mortality decreased 5.5%, whereas length of stay and charges increased 0.8% and 4.1%, respectively (P < .001).

Multivariable regression analyses of inpatient death, length of stay, and charges among hospitalized infant CHD cases in the United States, 1997–2012.*

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Table 3

Multivariable regression analyses of inpatient death, length of stay, and charges among hospitalized infant CHD cases in the United States, 1997–2012.*

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Effect of clinical characteristics on hospital outcomes in children with congenital heart disease.

Central sleep apnea is associated with increased hospital charges, longer length of stay, and increased risk of mortality while obstructive sleep apnea is associated with increased hospital charges and longer length of stay.

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Figure 1

Effect of clinical characteristics on hospital outcomes in children with congenital heart disease.

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All other clinical factors investigated were associated with higher odds of inpatient death, longer lengths of stay, and higher charges (P < .001). Increased risk of mortality was independently associated with the presence of other congenital disorders (OR 4.40), premature birth (OR 2.56), sepsis (OR 1.96), and required use of noninvasive respiratory support (OR 3.04) (P < .001 for all). Consistent with prior report,19 increased RACHS score was independently associated with a 73% increased risk of mortality (OR 1.7, P < .001, 95% confidence interval [CI] 1.6, 1.9), 8% longer length of stay (IR 1.08, P < .001, 95% CI 1.07, 1.09), and 20% higher charges (exp(b) 1.2, P < .001, 95% CI 1.18, 1.21).

Because of the risk of potential miscoding, sensitivity analysis excluding “apnea” (ICD-9 code 786.03) was performed, but did not change outcome results. For mortality, central SDB was associated with a multivariable adjusted OR of 3.8 (95% CI 1.3–11.4, P = .016), the OR for obstructive SDB was 0.7 (95% CI 0.3–1.8, P = .430) and the OR for unspecified SDB was 1.3 (95% CI 0.8–2.2, P = .289).

Additionally, to assess for potential selection bias related to CHD severity, we examined the relationship between RACHS score and odds of SDB diagnosis. Increased severity of CHD according to RACHS score was associated with a small unadjusted increase in odds for any SDB diagnosis (OR 1.12, P < .001, 95% CI 1.07–1.16). This slight increase in odds was similar for all types of SDB: obstructive SDB (OR 1.17, P < .001, 95% CI 1.08–1.28), central SDB (OR 1.24, P < .001, 95% CI 1.11–1.39), and unspecified SDB (OR 1.10, P < .001, 95% CI 1.05–1.15).

Given the known association between heart failure and central SDB in adults, we also examined the association between heart failure and central SDB in children with CHD. There was no significant association present in our sample (P = 1.000).

DISCUSSION

Our results in this nationally representative sample from 1997–2012 suggest that SDB is associated with significantly worse hospital outcomes in infants with CHD. After controlling for numerous patient demographic, clinical, and hospital characteristics, infants with CHD and SDB had significantly longer lengths of stay and charges compared to infants with CHD without SDB (P < .01). Central sleep apnea, in particular, was independently associated with a fourfold increased risk of mortality (OR 4.3) and approximately twofold longer lengths of stay (IR 1.9) and charges (exp(b) = 2.1) (P < .05).

The worse hospital outcomes seen in infants with CHD and comorbid SDB may be related to the underlying adverse effects of SDB on the cardiovascular system. SDB in children is associated with adverse cardiovascular effects including dysregulation of blood pressure26,27 and cardiac dysfunction.28,29 Elevated systolic26 and diastolic27 systemic blood pressures have been shown in children with SDB. Additionally, children with SDB have been found to have significantly elevated pulmonary arterial pressure.29 There is also evidence for left ventricular dysfunction28 as well as right ventricular dysfunction and hypertrophy in children with SDB.29 The underlying pathophysiologic effects of SDB that may cause these deleterious effects include endothelial dysfunction,30 autonomic dysfunction,31 and chronic inflammation.32 Importantly, these adverse cardiovascular effects appear to be reversible with treatment, considering that the treatment of SDB in children without CHD has been shown to mitigate the cardiovascular effects of SDB.29 A single study has examined central sleep apnea in relation to the cardiovascular system, specifically in children with cardiomyopathy. In this study, the authors found that the severity of cardiac dysfunction correlated with central apnea-hypopnea index.33 To our knowledge, no studies have reported cardiovascular outcomes of either obstructive or central SDB in children with CHD.

Certain limitations should be noted for this investigation. It is possible that SDB was underdiagnosed, given that SDB screening rates in children are poor.34 If this is the case, our results may underestimate the effects of SDB on patient outcomes. Although discharge data were used, strict diagnoses without supplemental subjective or objective data may not always appropriately reflect a true clinical assessment of the patient. Detailed information on specific treatment interventions involving current procedural terminology codes or pharmacotherapy is not present within these discharge data. Additionally, data on SDB severity and how the diagnosis of SDB was established are not available (ie, was polysomnography performed?). In an effort to mitigate this, we performed sensitivity analysis excluding the diagnosis “apnea” as this is more commonly diagnosed based on clinical observation, whereas central sleep apnea and obstructive sleep apnea are more commonly diagnosed based on polysomnography. Additionally, a prior validation study of the use of SDB ICD diagnostic codes in an administrative database found that a hospital discharge diagnosis of SDB was associated with 98% specificity and 9% sensitivity.35 Given this excellent specificity, it is likely that cases with a discharge diagnosis of SDB did in fact have SDB. The reported poor sensitivity of an SDB hospital discharge diagnosis likely resulted in an underestimation of the effects of SDB on patient outcomes. It is also possible that sicker patients were more likely to be evaluated for SDB and subsequently SDB is diagnosed. To mitigate this possible selection bias, we included RACHS score as a measure of CHD severity. We also included the Deyo-Charlson comorbidity index as a covariate in our model to account for overall patient morbidity/complexity from all conditions. Similarly, we included prematurity, sepsis, and other congenital disorders as covariates. Prevalence may not be accurately estimated from the KID database. Data were taken from each hospital discharge event, without being able to distinguish one patient from another so children with multiple admissions may be counted more than once in the analysis. Given that the study's sampling frame involves only acute inpatient settings, no assessment of out-patient care could be undertaken. Finally, this cross-sectional study demonstrates a strong association between SDB and increased risk of mortality, longer hospital stays, and higher hospital charges, but cannot determine causality.

CONCLUSIONS

SDB was independently associated with significantly worse hospital outcomes in infants with CHD. Future research needs to explore the effects of treatment of SDB in children with CHD on such tangible patient outcomes.

DISCLOSURE STATEMENT

All authors have seen and approved this manuscript. This work was supported by the National Institutes of Health Grants (HL138377 to S.P.); Patient-Centered Outcomes Research Institute contract (IHS-1306-2505; EAIN 3394-UOA; and PPRND-1507-31666 to S.P); and the American Sleep Medicine Foundation (ASMF 150-JF-16 to D.C.). The statements in this manuscript are solely the responsibility of the author and do not necessarily represent the views of PCORI, its Board of Governors or Methodology Committee.

Conflicts of Interest: Dr. Parthasarathy reports grants from ASMF (169-SR-17), NIH/ NHLBI (HL13877), grants from Patient Centered Outcomes Research Institute (IHS-1306-2505, EAIN #3394-UoA, PPRND-1507-31666), grants from US Department of Defense, grants from NIH/NCI (1R21CA184920), grants from Johrei Institute, personal fees from American Academy of Sleep Medicine, personal fees from UpToDate Inc., grants from Younes Sleep Technologies, Ltd., grants from Niveus Medical Inc., personal fees from Vapotherm, Inc., personal fees from Merck, Inc., grants from Philips Respironics, Inc., personal fees from Philips Respironics, Inc., personal fees from Bayer, Inc. outside the submitted work; In addition, Dr. Parthasarathy has a patent UA 14-018 U.S.S.N. 61/884,654; PTAS 502570970 (Home breathing device) issued. Dr. Morgan has received consultant fees from Genentech and the Cystic Fibrosis Foundation. The above-mentioned conflicts including the patent are unrelated to the topic of this paper. Drs. Combs, Skrepnek, Barber, and Seckeler report no conflicts of interest.

ABBREVIATIONS

AHRQ

Agency for Healthcare Research and Quality

CHD

congenital heart disease

HCUP

Healthcare Utilization Project

ICD

International Classification of Disease

KID

Kid's Inpatient Database

RACHS

Risk Adjustment for Congenital Heart Surgery

SDB

sleep-disordered breathing

ACKNOWLEDGMENTS

The KID database is provided through the Healthcare Cost and Utilization Project, with partners (https://www.hcup-us.ahrq.gov/db/hcupdatapartners.jsp) contributing data.

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