Abstract
BACKGROUND:
As the life expectancy of patients with Down syndrome (DS) improves, the number of older DS patients requiring cardiac surgery for congenital heart disease will increase. Perioperative risk factors and outcomes in these patients are unknown.
METHODS:
In a multicenter retrospective study, teenage and adult DS patients undergoing cardiac surgery between 2008–2018 were matched by age and surgical procedure with non-DS patients. Demographic, medical, and surgical characteristics were compared. Outcome measures were length of stay (LOS), duration of mechanical ventilation, need for non-invasive positive pressure ventilation (NIPPV) and reintubation, additional cardiac interventions, postoperative infections, and early postoperative mortality. Risk factors for extended hospital LOS (>10 days) were explored using multivariable logistic regression.
RESULTS:
We compared 121 DS patients to 121 non-DS patients. DS patients had a longer median LOS (7 vs. 5 days, p<0.001), longer duration of mechanical ventilation (12.5 vs. 6.7 hours, p<0.001), greater need for NIPPV or reintubation (26% vs. 4%, p<0.001), and higher likelihood of postoperative infections (10% vs. 2%, p=0.035). There was no early mortality. Pre-operative risk factors for extended LOS for DS patients included pulmonary medication use (OR 4.0, p=0.046), history of immunodeficiency (OR 10.4, p=0.004), or ≥moderate tricuspid regurgitation (OR 12.7, p<0.001).
CONCLUSIONS:
Teenage and adult DS patients undergoing congenital cardiac surgery had a longer hospital LOS and more postoperative respiratory and infection complications compared to non-DS patients without increased mortality. Cardiac surgery can be performed safely in older DS patients. Management of pulmonary disease, immunodeficiency, and tricuspid regurgitation may mitigate risk.
Graphical Abstract
With the evolution of medical and surgical treatment of congenital heart disease (CHD), the number of patients surviving to adulthood has grown. The number of adults with congenital heart disease (ACHD) now accounts for approximately two-thirds of the CHD patient population, growing at a faster rate than the pediatric CHD population and resulting in increased healthcare utilization during adulthood.1,2
Congenital heart defects occur in approximately 50% of patients with Down syndrome, the most common chromosomal abnormality.3,4 Medical and surgical management of the comorbidities associated with DS has improved with many DS patients surviving past the age of 50.5,6 Although the most common cause of death in younger DS patients is CHD, older individuals with DS have a higher prevalence of non-cardiac diseases, such as neurologic, respiratory, and immune disorders, which have been shown to contribute to mortality.6–8
As the ACHD and DS populations continue to grow, the number of adult DS patients requiring cardiac surgery for CHD, including residual lesions after surgery in childhood, can be expected to increase, comprising a unique and medically complex patient cohort that will require specialized perioperative care.
Many studies have demonstrated that cardiac surgery can be performed safely on pediatric DS patients with similar mortality rates compared to the general population. However, there is a higher likelihood of postoperative complications and longer hospital length of stay (LOS).9,10 Many of the risk factors that have been identified in pediatric DS patients are known risk factors for adults undergoing cardiac surgery.11,12 However, little is known regarding whether those comorbidities increase the perioperative risk in the adult DS patient. The purpose of this study was to compare postoperative outcomes in teenage and adult DS patients undergoing cardiac surgery with a non-DS cohort to identify risk factors associated with greater morbidity and mortality.
PATIENTS AND METHODS
We performed a multicenter retrospective cohort study of teenagers and adults with DS who underwent cardiac surgery between 2009 and 2018. Inclusion criteria were age ≥13 years and a diagnosis of DS. Each DS patient was matched 1:1 to a non-DS patient at the same institution based on age within 1 year and surgical procedure. For the purposes of matching, procedures were organized by degree of complexity (Table 1). Patients who underwent multiple procedures were matched based on the highest complexity procedure, with attempts to match as many lower complexity surgical procedures as possible. Patients were excluded if they had additional genetic syndromes or other major birth defects.
Table 1.
Surgical procedure prioritization in descending order for DS and non-DS matching
| Surgical procedure |
|---|
| 1. Mitral valve repair/replacement |
| 2. Aortic valve repair/replacement |
| 3. Aortic root revision/replacement |
| 4. Sub-aortic membrane or left ventricular outflow tract revision |
| 5. Pulmonary valve repair or replacement or right ventricle to pulmonary artery (RV-PA) conduit revision |
| 6. Tricuspid valve repair/replacement |
| 7. VSD closure or VSD patch revision |
| 8. ASD closure |
| 9. Branch pulmonary arterioplasty |
| 10. Double chamber right ventricle resection |
| 11. Pacemaker lead/generator insertion or surgical ablation |
VSD, ventricular septal defect; ASD, atrial septal defect.
For both cohorts, we collected patient demographics, cardiac diagnosis and cardiac surgical history, non-cardiac comorbidities and medications, and surgical characteristics. Preoperative valvar and ventricular function was obtained from echocardiograms performed within 1 year before the surgery.
The primary outcome variable was hospital LOS (days), explored as both a continuous and binary outcome measurement. Secondary outcome variables included ICU LOS (days), duration of mechanical ventilation (hours), need for non-invasive positive pressure ventilation or reintubation after surgery, postoperative infection, additional cardiac surgical or catheter-based interventions, and mortality within 30 days of surgery.
Categorical patient characteristics and outcomes were expressed as proportions and compared for the DS and non-DS cohorts using McNemar’s test; continuous data were described using median values and interquartile ranges and compared with the Wilcoxon signed-rank test. Within the DS cohort, multivariable logistic regression was used to explore associations between patient risk factors and short LOS (≤10 days) vs. long LOS (>10 days, 75th percentile). Purposeful selection was used for risk factors significant at the 0.20 level in univariate analysis; p < 0.05 by the likelihood ratio test was required for retention in the final model. The model also adjusted for primary indication for surgery. The same variables identified as risk factors for prolonged LOS were then included in a generalized linear model with log link for LOS as a continuous outcome measure. Statistical analysis was performed using SAS 9.4 (SAS Institute Inc., Cary, NC). This study was considered exempt by the institutional review board of each participating center.
RESULTS
121 teenagers and adults with DS underwent cardiac surgery were matched to a non-DS cohort of 121 patients. Patients were identified from 6 different pediatric hospital centers, including Boston Children’s Hospital (n=47), C.S. Mott Children’s Hospital (n=16), Cincinnati Children’s Hospital Medical Center (n=16), Morgan Stanley Children’s Hospital (n=19), the Medical University of South Carolina (n=6), and Texas Children’s Hospital (n=17).
Patient characteristics
Characteristics of the cohorts are described in Table 2. DS patients were more likely to carry a diagnosis of atrioventricular septal defect (AVSD) (50% vs. 12%, p<0.001) or tetralogy of Fallot (TOF) with AVSD (12% vs. 0%, p<0.001) and were less likely to have isolated mitral valve (4% vs. 19%, p<0.001) or isolated aortic valve disease (2% vs. 12%, p=0.002) compared to the non-DS cohort. Patients with DS were more likely to be prescribed a thyroid medication (45% vs. 0%, p<0.001) and/or a neuropsychiatric medication (19% vs. 8%, p=0.024) at the time of surgery compared to non-DS patients. There was no significant difference in the number of DS and non-DS patients receiving pulmonary medications or pulmonary arterial hypertension medications.
Table 2.
Selected DS and non-DS cohort characteristics
| Patient Characteristic | DS (% or IQR) n=121 | Non-DS n=121 | P value |
|---|---|---|---|
| Age at surgery (years)a | 17.9 [14.9,24.5] | 16.9 [14.4,23.5] | - |
| Sex (female) | 65 (54%) | 52 (43%) | 0.14 |
| BMI (kg/m2) | 25.9 [22.0,33.1] | 22.1 [19.9,26.1] | <0.001 |
| Surgery prior to index surgery | 94 (78%) | 82 (68%) | 0.04 |
| Cardiac diagnosis | |||
| Atrioventricular septal defect (AVSD) | 61 (50%) | 14 (12%) | <0.001 |
| Mitral valve disease | 5 (4%) | 23 (19%) | <0.001 |
| Aortic valve disease | 3 (2%) | 15 (12%) | 0.002 |
| Tetralogy of Fallot (TOF) | 22 (18%) | 28 (23%) | 0.26 |
| TOF with AVSD | 15 (12%) | 0 (0%) | <0.001 |
| Other | 14 (12%) | 46 (38%) | <0.001 |
| Medications | |||
| Diabetes medication | 7 (6%) | 1 (1%) | 0.07 |
| Thyroid medication | 54 (45%) | 0 (0%) | <0.001 |
| Pulmonary medicationb | 14 (12%) | 7 (6%) | 0.17 |
| Pulmonary arterial hypertension medication | 3 (2%) | 2 (2%) | 1.0 |
| Neuropsychiatric medication | 23 (19%) | 10 (8%) | 0.02 |
| Past medical history | |||
| Pulmonary arterial hypertension | 28 (23%) | 25 (21%) | 0.74 |
| Pulmonary disease | 26 (21%) | 16 (13%) | 0.12 |
| Obstructive sleep apnea | 30 (25%) | 4 (3%) | <0.001 |
| Immunodeficiency or infections | 11 (9%) | 5 (4%) | 0.21 |
| Endocrine disease | 63 (52%) | 4 (3%) | <0.001 |
| Echocardiogram findings | |||
| Degree of aortic stenosis | 0.36 | ||
| Normal/mild | 101 (83%) | 107 (88%) | |
| Moderate or greater | 20 (17%) | 14 (12%) | |
| Degree of mitral regurgitation | 0.005 | ||
| None/mild | 77 (64%) | 94 (78%) | |
| Moderate or greater | 44 (36%) | 27 (22%) | |
| Degree of tricuspid regurgitation | 0.36 | ||
| None/mild | 99 (82%) | 104 (86%) | |
| Moderate or greater | 22 (18%) | 17 (14%) | |
| Primary indication for surgery | 0.78 | ||
| Mitral valve stenosis or regurgitation | 42 (35%) | 43 (36%) | |
| Aortic valve stenosis or regurgitation | 9 (7%) | 15 (12%) | |
| Left ventricular outflow tract obstruction | 9 (7%) | 6 (5%) | |
| Pulmonary valve/RV-PA conduit stenosis or regurgitation | 29 (24%) | 31 (26%) | |
| Tricuspid valve stenosis or regurgitation | 5 (4%) | 5 (4%) | |
| Number of cardiopulmonary bypass runs | 0.65 | ||
| 0 | 9 (7%) | 8 (7%) | |
| 1 | 104 (86%) | 103 (85%) | |
| ≥2 | 8 (7%) | 10 (8%) | |
| Total cardiopulmonary bypass time (min) | 106 [79,152] | 102 [69,149] | 0.55 |
BMI, body mass index.
Patients were matched by age and surgical procedure so these variables were not significantly different between the 2 cohorts.
Pulmonary medications included inhaled beta agonists, inhaled corticosteroids and oral medications for the management of reactive airway disease.
DS patients were more likely to have obstructive sleep apnea (25% vs. 3%, p<0.001) and endocrine disease (52% vs. 3%, p<0.001) than the non-DS cohort. The number of patients with pulmonary disease, pulmonary arterial hypertension, and immunodeficiency were not significantly different between the 2 cohorts. Moderate or greater mitral regurgitation was more common in DS patients (36% vs. 22%, p=0.005) but there was no significant difference in other valve dysfunction or the degree of left or right ventricular systolic dysfunction between the 2 cohorts. There was no significant difference in the duration of cardiopulmonary bypass.
Postoperative outcomes
Postoperative outcomes of both cohorts are described in Table 3. The median hospital LOS was 2 days longer in the DS cohort compared to the non-DS cohort (7 days vs. 5 days, p<0.001). In 25% of matched pairs, the difference in hospital LOS was greater than or equal to 5 days (Figure 1). DS patients were more likely to have an ICU admission lasting longer than 2 days compared to non-DS patients (49% vs. 22%, p<0.001). DS patients remained on mechanical ventilation for longer (12.5 hours vs. 6.7 hours, p<0.001) and more often required non-invasive positive pressure ventilation or re-intubation (26% vs. 4%, p<0.001) after surgery. Postoperative infections were more common in DS patients (10% vs. 2%, p=0.035). There was no significant difference in the number of additional cardiac interventions between groups. There was no early mortality in either cohort.
Table 3.
Postoperative outcomes
| Outcome measure | DS (% or IQR) n=121 | Non-DS n=121 | P value |
|---|---|---|---|
| Hospital LOS (days, median) | 7 [5,10] | 5 [4, 7] | <0.001 |
| ICU LOS > 2 days | 58 (49%) | 26 (22%) | <0.001 |
| Additional cardiac interventionsa | 16 (13%) | 10 (8%) | 0.29 |
| Non-invasive positive pressure ventilation and/or reintubation | 31 (26%) | 5 (4%) | <0.001 |
| Postoperative infectionb | 12 (10%) | 3 (2%) | 0.04 |
Cardiac interventions included additional cardiac surgeries, catheterizations, or electrophysiology studies.
Postoperative infections included mediastinitis, cellulitis, bacteremia/sepsis, pneumonia and tracheitis.
Figure 1.
The difference in hospital LOS between the DS and non-DS patient cohorts was statistically significant (7 vs. 5 days, p <0.001), with 25% of DS patients requiring a hospital stay longer than 10 days.
Risk factors for extended length of stay
The characteristics of the short and long-LOS DS patients are described in Table 4. Within the long-LOS DS cohort (hospital LOS >10 days), patients were more likely to have pulmonary arterial hypertension (39% vs. 20%, p=0.044), immunodeficiency (55% vs. 22%, p=0.005), and ≥moderate tricuspid regurgitation (TR) (50% vs. 19%, p=0.005) before surgery. Long-LOS patients were more likely to require non-invasive positive pressure ventilation or reintubation (45% vs. 18%, p=0.004) or an additional cardiac intervention during their hospitalization (56% vs. 20%, p=0.004). Long-LOS patients also had more infections compared to the short-LOS DS cohort (58% vs. 21%, p=0.010).
Table 4.
Selected characteristics of short vs. long-stay DS patients (total n=121).
| Characteristic | Total number of patients | Number with LOS >10 days (%) | P value |
|---|---|---|---|
| Age at surgery (years) | 0.41 | ||
| <19 | 72 | 16 (22%) | |
| 19–23 | 16 | 6 (38%) | |
| ≥24 | 33 | 8 (24%) | |
| BMI (kg/m2) | 0.51 | ||
| <25 | 53 | 15 (28%) | |
| 25–29.9 | 30 | 5 (17%) | |
| ≥30 | 38 | 10 (26%) | |
| Any surgery prior to index surgery | 0.46 | ||
| Yes | 94 | 25 (27%) | |
| No | 27 | 5 (19%) | |
| History of pulmonary arterial hypertension | 0.044 | ||
| Yes | 28 | 11 (39%) | |
| No | 92 | 18 (20%) | |
| History of pulmonary disease | 0.21 | ||
| Yes | 26 | 9 (35%) | |
| No | 95 | 21 (22%) | |
| History of obstructive sleep apnea | 0.23 | ||
| Yes | 30 | 10 (33%) | |
| No | 91 | 20 (22%) | |
| History of airway anomalies | 0.64 | ||
| Yes | 6 | 2 (33%) | |
| No | 115 | 28 (24%) | |
| History of immunodeficiency | 0.027 | ||
| Yes | 11 | 6 (55%) | |
| No | 110 | 24 (22%) | |
| History of left ventricular dysfunction | 0.15 | ||
| Normal | 96 | 26 (27%) | |
| Mild | 20 | 2 (10%) | |
| Moderate or severe | 5 | 2 (40%) | |
| Degree of tricuspid regurgitation | 0.005 | ||
| Normal/mild | 99 | 19 (19%) | |
| Moderate or severe | 22 | 11 (50%) | |
| Primary indication for surgery | 0.15 | ||
| Mitral valve stenosis or regurgitation | 42 | 15 (36%) | |
| Pulmonary valve or RV-PA conduit stenosis or regurgitation | 29 | 5 (17%) | |
| Other | 50 | 10 (20%) |
In a multivariable logistic regression model adjusted for primary indication for surgery, DS patients receiving any pulmonary medication (OR 4.23), with a history of immunodeficiency (OR 11.1), and having preoperative ≥moderate TR (OR 11.2) were all more likely to have a long-LOS (Table 5). Additionally, DS patients whose primary indication for surgery was mitral valve stenosis or regurgitation had a higher odds of long LOS (OR 3.56), although this did not reach statistical significance (p=0.064). The model did not change significantly when adjusted for surgical center.
Table 5.
Risk factors for prolonged hospital LOS in DS cohort using multivariable logistic regression and generalized linear model with log link.
| Risk factor | Multivariable logistic regression | Generalized linear model with log link | ||||
|---|---|---|---|---|---|---|
| Odds ratio | 95% CI | P value | Estimated coefficient | 95% CI | P value | |
| Any pulmonary medication | 4.23 | (1.11,16.2) | 0.04 | 0.75 | (0.07, 1.44) | 0.03 |
| History of immunodeficiency | 11.1 | (2.44,50.2) | 0.002 | 0.32 | (−0.08, 0.73) | 0.12 |
| Moderate or greater tricuspid regurgitation | 11.2 | (3.32,37.6) | <0.001 | 1.12 | (0.37, 1.88) | 0.004 |
| Primary indication for surgery | ||||||
| Mitral valve stenosis or regurgitation | 3.56 | (0.93,13.7) | 0.06 | 0.48 | (0.04, 0.92) | 0.03 |
| Other | 0.69 | (0.17, 2.73) | 0.59 | 0.08 | (−0.41, 0.57) | 0.75 |
Risk factors for longer LOS in the DS cohort were similar in a generalized linear model evaluating LOS as a continuous measure. DS patients receiving any pulmonary medication (p=0.031) or having ≥moderate TR (p=0.004) prior to surgery were more likely to have a longer hospital LOS. DS patients undergoing surgery primarily for mitral valve stenosis or regurgitation were also more likely to remain in the hospital for longer (p=0.031). A history of immunodeficiency was not significantly associated with longer LOS in the generalized linear model.
COMMENT
In this study, we examined whether teenage and adult patients with DS have different outcomes after cardiac surgery than age- and procedure-matched non-DS patients. Amongst those with DS, we further explored which risk factors contributed to prolonged LOS after cardiac surgery. In comparing the DS and non-DS cohorts, we found that DS patients were more likely to have the congenital heart defects known to be associated with DS and were more likely to have undergone surgery in the past. DS patients were also more likely to have ≥moderate MR on presentation, consistent with the known long-term residual disease after AVSD repair. Many of the characteristics and comorbidities associated with DS, including elevated BMI, endocrine or neuropsychiatric disease, and obstructive sleep apnea, were more likely to occur in the DS cohort. DS patients were not more likely to carry a diagnosis of pulmonary arterial hypertension or receive pulmonary arterial hypertension medication compared to non-DS patients. This could be due to practice variation and increased risk stratification of those DS patients with pulmonary arterial hypertension, resulting in fewer being referred for surgery.
In general, DS patients did well in the postoperative period with no early mortality. Many studies have demonstrated similar low mortality rates in pediatric DS patients compared to the general pediatric population.9,13,14 DS patients did have a longer hospital LOS by 2 days (median 7 days vs. 5 days, p<0.001) and were more likely to stay in the ICU longer compared to the non-DS cohort. This has been demonstrated in the pediatric DS population as well, resulting in higher healthcare resource utilization and cost.9
In addition to perceived higher risk in the postoperative period which could result in more conservative care with slower clinical progression, there are other factors that could contribute to longer LOS in the DS cohort. Our patients were more likely to have undergone cardiac surgery in the past which could result in greater surgical complexity. Although bypass times were not different in this study, increased surgical complexity could lead to longer anesthesia exposure and a higher risk of postoperative bleeding requiring blood product resuscitation.15 Pediatric DS patients have been found to require more blood transfusions than non-DS patients, as well as higher doses of inotropic drugs in the postoperative period.9 Difficulty with dissection could result in lung injury or a larger systemic inflammatory response, increasing the need for vasoactive infusions or mechanical ventilation, contributing to longer LOS.
Furthermore, the developmental delay associated with DS may result in communication barriers, leading to over- or under-treatment of postoperative pain and anxiety. This may result in prolonged mechanical ventilation, hypoventilation and pulmonary decruitment, limited mobilization, and delirium, all of which may prolong hospital LOS.
While most DS patients in our study did well in the postoperative period with only a slightly longer hospital LOS, the upper quartile of DS patients had a much longer LOS compared to the non-DS cohort. We anticipated that a regression analysis comparing hospital LOS in the DS and non-DS cohorts would identify many of the known comorbidities of DS as risk factors. By better characterizing the upper quartile of DS patients with long LOS, we could describe those patients at greatest risk for a prolonged LOS compared to both non-DS patients and most of the DS patients. This led us to perform a regression analysis within the DS cohort which identified several risk factors for prolonged LOS, including pulmonary disease requiring pulmonary medications, immunodeficiency, significant TR, and mitral valve disease as the primary indication for surgery.
In this study, DS patients receiving pulmonary medications had a 4-fold increased odds of a prolonged hospital LOS compared to other DS patients. While a diagnosis of pulmonary disease alone did not confer an increased odds of prolonged LOS, it is possible that those patients receiving preoperative pulmonary medications represent a subset of patients with more severe pulmonary disease. These patients may also progress more slowly in the postoperative period due to perceived or actual risk of requiring reintubation or non-invasive positive pressure ventilation. Previous studies have demonstrated that pediatric DS patients are more likely to require prolonged mechanical ventilation and fail extubation in the postoperative period due to an increased incidence of pulmonary disease and airway abnormalities such as obstructive sleep apnea, subglottic stenosis, and airway malacia, as well as an increased incidence of postoperative pneumonia, atelectasis and pneumothoraces.16–18 In non-DS adult patients undergoing cardiac surgery, pulmonary disease, including obstructive sleep apnea and chronic obstructive pulmonary disease, is also known risk factor for prolonged LOS.11,12
DS patients with immunodeficiency had 11-fold increased odds of prolonged LOS. Immunologic dysfunction in DS is known to increase the risk of upper respiratory tract infections and ventilator associated pneumonias, prolonging the duration of mechanical ventilation.18,19 However, the actual number of patients with immunodeficiency and postoperative infections in our study was too small to further characterize.
DS patients whose primary indication for surgery was mitral valve stenosis or regurgitation trended toward longer LOS irrespective of their degree of mitral valve disease, although this did not reach statistical significance. This may reflect a higher degree of surgical complexity or prolongation of the hospital course due to titration of anticoagulation to therapeutic effect, particularly in those receiving a mitral valve replacement.
DS patients with tricuspid valve regurgitation were also more likely to have a prolonged LOS. In these patients, TR could be a marker of baseline right ventricular hypertension, dilation, or dysfunction.20 However, we did not find that our long LOS DS patients were more likely to have preoperative right ventricular hypertension or systolic dysfunction. TR could indicate more complex atrioventricular valve anatomy and disease, resulting in greater surgical complexity or longer surgery duration.
TR could also result in greater postoperative illness due arrhythmias, adverse ventricular-ventricular interactions due to RV dilation and/or dysfunction, or subclinical hepatic or renal dysfunction due to chronic central venous hypertension.21–23 We did not find that any of our patients in either non-DS or DS cohorts had significant rates of chronic kidney disease preoperatively but this does not exclude subclinical disease or a predisposition to renal dysfunction after surgery. All of these possible mechanisms could be further exacerbated by the persistence of TR in the postoperative period.
Limitations
This study was limited by its retrospective design with a small patient population. We included teenagers and found that there were no significant differences in outcomes in the teenage, young adult, and older adult groups (Table 4). The median age in our DS cohort was 17.9 years so these patients may not have developed some of the comorbidities found in older DS patients. Future studies may better capture the comorbidities associated with this aging population and their impact on postoperative outcomes. Our study could underestimate the risk for DS patients with greater medical complexity due to surgical referral selection bias for a healthier DS cohort. Lastly, the effects of variable institutional patient volume and practices were addressed by including multiple tertiary institutions, matching on procedure within each institution to minimize surgeon or center effect. We found no difference in risk factors after adjusting for surgical center in our multivariable model.
Conclusions
Teenage and young adult DS patients may undergo cardiac surgery safely, but those with pulmonary disease, immunodeficiency, or significant atrioventricular valve disease should be counseled on possible prolonged hospital LOS. Efforts to optimize preoperative pulmonary disease and immunodeficiency may mitigate associated postoperative risk.
FUNDING:
Funding for this study was provided by the Pediatric Heart Network of the National Heart, Lung, and Blood Institute.
Footnotes
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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