- Email: [email protected]
Outcomes of multistage palliation of infants with functional single ventricle and heterotaxy syndrome
Accepted Manuscript Outcomes Of Multistage Palliation Of Infants With Functional Single Ventricle And Heterotaxy Syndrome Bahaaldin Alsoufi, MD, Courtney McCracken, PhD, Brian Schlosser, BS, RDCS, Ritu Sachdeva, MBBS, Andrew Well, PhD, Brian Kogon, MD, William Border, MBChB, MPH, Kirk Kanter, MD PII:
S0022-5223(16)00303-2
DOI:
10.1016/j.jtcvs.2016.01.054
Reference:
YMTC 10362
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 9 September 2015 Revised Date:
22 December 2015
Accepted Date: 23 January 2016
Please cite this article as: Alsoufi B, McCracken C, Schlosser B, Sachdeva R, Well A, Kogon B, Border W, Kanter K, Outcomes Of Multistage Palliation Of Infants With Functional Single Ventricle And Heterotaxy Syndrome, The Journal of Thoracic and Cardiovascular Surgery (2016), doi: 10.1016/ j.jtcvs.2016.01.054. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Outcomes Of Multistage Palliation Of Infants With Functional Single Ventricle And Heterotaxy
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Syndrome
3 Bahaaldin Alsoufi1, MD, Courtney McCracken2, PhD, Brian Schlosser2, BS, RDCS, Ritu Sachdeva2,
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MBBS, Andrew Well1, PhD, Brian Kogon1, MD, William Border2, MBChB, MPH, Kirk Kanter1, MD.
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Medicine, Atlanta, GA, USA.
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Division of Cardiology, Children’s Healthcare of Atlanta, Emory University School of Medicine,
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Division of Cardiothoracic Surgery, Children’s Healthcare of Atlanta, Emory University School of
Atlanta, GA, USA.
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Presented at the 41st Annual Meeting of the Western Thoracic Surgical Association in Whistler, BC,
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Canada, June 2015
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Total Word count: 3829
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Potential conflict of interest: None of the authors have any potential conflict of interest to disclose.
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Source of funding: Institutional. No external source of funding for this project.
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Bahaaldin Alsoufi, MD Division of Cardiothoracic Surgery Emory University School of Medicine Children’s Healthcare of Atlanta 1405 Clifton Road, NE Atlanta, GA 30322 Phone: 1 404 785-6330 Fax: 1 404 785-6266 Email: [email protected]
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Abbreviations:
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TAPVC: total anomalous pulmonary venous connection
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ECMO: extra-corporeal membrane oxygenation
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HR: hazard ratio
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OR: odds ratio
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IQR: interquartile range
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RAI: right atrial isomerism
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LAI: left atrial isomerism
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BTS: modified Blalock-Taussig shunt
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PAB: pulmonary artery band
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Central image legend:
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Competing events following palliation for heterotaxy vs. non-heterotaxy single ventricle.
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Single ventricle palliation for heterotaxy is associated with higher morbidity and mortality than other single
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ventricle anomalies.
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38 Perspective:
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First-stage palliation of infants with heterotaxy syndrome and functional single ventricle anomalies is
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associated with high operative mortality and increased resource utilization due to surgical morbidity.
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Nonetheless, outcomes beyond hospital discharge are comparable to infants with other non-heterotaxy
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single ventricle anomalies.
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Abstract:
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Background: Management of infants with heterotaxy syndrome and functional single ventricle is
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complicated due to associated cardiac and extra-cardiac anomalies. We report current-era palliation
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results.
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Methods: From 2002-2012, 67 infants with heterotaxy syndrome underwent multistage palliation.
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Competing risks analyses modeled events after surgery (death vs. Glenn) and examined factors associated
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with survival. Additionally, early and late outcomes following first stage palliation surgery were
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compared with a matched contemporaneous control group of non-heterotaxy single ventricle patients.
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Results: Fifty-eight patients (87%) required neonatal palliation including modified Blalock-Taussig shunt
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(n=34, 51%), Norwood (n=12, 18%) or pulmonary artery band (n=12, 18%), whereas 9 patients (13%)
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received primary Glenn. Competing risks analysis showed that at 1 year following first stage palliation
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surgery, 29% of patients had died or received transplantation and 63% had undergone Glenn. By 5 years
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following Glenn, 64% of patients had undergone Fontan. Overall 8-year survival was 66%. On
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multivariable analysis, factors associated with mortality were unplanned reoperation (HR: 2.9 (1.1-7.3),
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p=0.005) and TAPVC repair (HR: 2.3 (1.0-5.6), p=0.056). Comparison with the contemporaneous
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matched single ventricle patients showed that first-stage palliation in heterotaxy patients was associated
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with higher hospital death (27% vs.10%, p=0.022), and significantly longer ventilation hours and
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intensive care unit stay duration. Nonetheless, interstage mortality, survival after Glenn and progression
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to Fontan were comparable.
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Conclusions: The management of heterotaxy infants with functional single ventricle remains challenging.
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First-stage palliation is associated with high operative mortality and increased resource utilization due to
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surgical morbidity. Nonetheless, outcomes beyond hospital discharge are comparable to other single
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ventricle patients. Efforts to improve survival in those patients should focus on perioperative care.
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Introduction:
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Visceral heterotaxy syndrome is defined as an abnormality where the internal thoraco-abdominal organs
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demonstrate abnormal arrangement across the left-right axis of the body. [1] Children born with the
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heterotaxy syndrome often have complex congenital cardiac anomalies that require surgical intervention.
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While some of those children have cardiac anomalies that are amenable to biventricular repair; many
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others have functional single ventricle that requires multistage palliation with the initial surgery dictated
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by the anatomy and the degree of systemic or pulmonary outflow obstruction. [1-8]
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Surgical management of children with heterotaxy syndrome and functional single ventricle is challenging
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due to the presence of complex morphologic features such as total anomalous pulmonary venous
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connection (TAPVC), atrioventricular valve dysfunction, pulmonary atresia, arrhythmias and heart block
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that are all established risk factors for increased morbidity and mortality following single ventricle
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palliation. [2-13] Additional extra-cardiac anomalies that are associated with the heterotaxy syndrome
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such as ciliary dysfunction, intestinal malrotation and asplenia can all contribute to increased early
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operative morbidity and complexity of post-discharge management, further adversely affecting late
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outcomes in those challenging patients. [7,11,12,14-17]
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We hypothesized that results of multistage palliation of neonates born with the heterotaxy syndrome and
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functional single ventricle have improved in the current era owing to advances in perioperative care and
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outpatient management, and that palliation outcomes are comparable to those in those born with other
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non-heterotaxy single ventricle anomalies. To test this hypothesis, we examined early and late results
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following single ventricle palliation in infants with heterotaxy syndrome and compared them to those of a
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matched group of contemporaneous infants with non-heterotaxy single ventricle anomalies at our
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institution.
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Patients and Methods:
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Inclusion criteria:
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Between 2002 and 2012, 67 consecutive infants with heterotaxy syndrome underwent their first palliative
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surgery at Children’s Healthcare of Atlanta, Emory University. Patients were identified using our
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institutional surgical database. Demographic, morphologic, clinical, operative, and hospital details were
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abstracted from the medical records for analysis. Approval of this study was obtained from our hospital’s
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Institutional Review Board and requirement for individual consent was waived for this observational
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study.
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Echocardiographic data collection and classification:
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All preoperative echocardiograms were retrospectively reviewed by a single echocardiographer (BS). Our
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morphologic inclusion criteria were based on the most recent nomenclature review and classification by
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Jacobs et al in 2007. [1] In that report, heterotaxy is defined as an abnormality where the internal thoraco-
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abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. By
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convention, heterotaxy does not include patients with either the expected usual or normal arrangement of
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the internal organs along the left-right axis, also known as `situs solitus', or patients with complete mirror-
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imaged arrangement of the internal organs along the left-right axis also known as `situs inversus'. [1] Left
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atrial isomerism (LAI) is defined as a subset of heterotaxy where some paired structures on opposite sides
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of the left-right axis of the body are symmetrical mirror images of each other, and have the morphology
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of the normal left-sided structures. This is commonly associated with polysplenia. Right atrial isomerism
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(RAI) is defined as a subset of heterotaxy where some paired structures on opposite sides of the left-right
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axis of the body are symmetrical mirror images of each other, and have the morphology of the normal
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right-sided structures. This is commonly associated with asplenia. [1] All patients were considered to
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have functional single ventricle although some of them had two well-formed ventricles however they
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were not thought to be amenable to septation due to the presence of non-committed ventricular septal
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defect, multiple ventricular septal defects or straddling of the atrioventricular valves.
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Follow up:
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Time-related outcomes were determined from recent office visits documented in the electronic chart of
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Children’s Healthcare of Atlanta system or from direct correspondence with pediatric cardiologists
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outside the system. Mean follow up duration was 5.5 ± 4.2 years and was 94% complete.
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Statistical analysis:
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Data are presented as means with standard deviation, medians with interquartile ranges (IQR) or
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frequencies and percentages, as appropriate. Time-dependent outcomes after first stage palliation surgery
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and after Glenn were parametrically modeled. Parametric probability estimates for time-dependent
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outcomes uses models based on multiple overlapping phases of risk using PROC HAZARD (available for
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use with the SAS system at http://www.clevelandclinic.org/heartcenter/hazard). The HAZARD procedure
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uses maximum likelihood estimates to resolve risk distribution of time to event in up to 3 phases of risk
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(early decreasing or peaking hazard, constant hazard, and late increasing hazard). Maximum likelihood
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estimates are iteratively calculated using nonlinear optimization based algorithms. Smoothed survival
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curves were generated using the HAZPRED procedure in SAS. PROC HAZPRED computes predictions
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for the survivorship and hazard functions along with their confidence limits.
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Competing risks analysis was performed to model the probability over time of each of the two mutually
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exclusive endpoints after first stage palliation surgery: death/transplantation and survival to Glenn. After
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the Glenn, competing risks models were not performed due to the small number of death/transplantation
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events following Glenn.
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For the outcome hospital death following first stage palliation, logistic regression was used to determine
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risk factors associated with hospital death. Variables that were tested included the following: gender, age,
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weight, prematurity, extra-cardiac anomalies, heterotaxy type (RAI vs. LAI), dominant ventricle
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morphology (left, right or both), morphology of the atrioventricular valve (common atrioventricular
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valve, tricuspid, mitral or both) , antegrade pulmonary blood flow (absent, restricted, unrestricted),
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TAPVC (absent, present unobstructed, present obstructed), type of initial palliation surgery (Norwood,
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modified Blalock-Taussig shunt (BTS), pulmonary artery band (PAB), primary Glenn), concomitant
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TAPVC repair, post-operative extracorporeal membrane oxygenation (ECMO) support use, and
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unplanned cardiac reoperation. To identify risk factors associated with death/transplant following first
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stage palliation surgery, parametric survival models were constructed using one risk factor at a time. The
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same variables listed above were tested. Given the limited sample size available for analysis,
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multivariable models were created using forward entry of variables significant at the 0.2 significance
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level in univariate analysis. Effects of covariates on the probability of outcomes in survival models are
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given as hazard ratio (HR) with 95% confidence interval.
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Neonates with heterotaxy and single ventricle anomalies who underwent first stage palliation were
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compared to a propensity matched contemporary cohort of neonates with single ventricle anomalies other
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than heterotaxy who also underwent first stage palliation. Propensity score matching was performed to
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balance the two groups on baseline characteristics at a 1:1 ratio. Briefly, multivariable logistic regression
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was used to predict patients with heterotaxy. Patient demographic and anatomical features were
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considered in the logistic model and included: gender, age at initial surgery, prematurity, weight, first
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stage palliation surgery, dominant ventricle and the use of cardiopulmonary bypass during first stage
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palliation surgery. The deviance test was used to measure goodness of fit of the proposed logistic model.
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For each patient, the multivariable logistic model was used to obtain their predicted probability, or
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propensity, of having heterotaxy. A 1:1 greedy matching algorithm was utilized to match SV patients with
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and without heterotaxy based on their propensity scores. After matching, the matched cohort was then
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assessed to ensure balanced distribution of covariates between groups using similar methods as described
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above in addition to presenting standardized mean differences (SMD). Statistical significance was
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assessed at the 0.05 level. All statistical analyses were performed using SAS v9.3 (The SAS Institute,
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Cary, NC).
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Results:
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Patients’ characteristics, morphologic and operative details:
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Sixty-seven infants with heterotaxy underwent their initial palliation surgery. There were 37 males (55%).
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Median age at surgery was 11 days (IQR 5-50) and median weight was 3.1 kg (IQR 2.6-3.8) with 14
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patients (21%) ≤ 2.5 kg. There were 17 patients (25%) who were born prematurely ≤ 36 weeks gestation.
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Complete morphologic Echocardiographic examination was available in 66 patients and showed that 42
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(64%) had RAI while 24 (36%) had LAI. Dominant ventricle morphology was dominant right (n=32,
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48%), dominant left (n=17, 26%) or two equally formed ventricles (n=17, 26%). Fifty-eight patients
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(88%) had double outlet right ventricle and 53 (80%) had common atrioventricular valve. Overall, 33
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patients (50%) had TAPVC. The TAPVC type was supra-cardiac (n=14, 43%), cardiac (n=9, 27%), infra-
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cardiac (n=6, 18%) or mixed (n=4, 12%); with 9 (27%) having obstructed drainage at time of initial
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presentation. Antegrade pulmonary blood flow was absent in 16 (24%), restricted in 27 (40%) and
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unrestricted in 24 (36%). Aortic arch obstruction was present in 13 patients (19%) while aortic annulus
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hypoplasia was present in 12 patients (18%). Twenty-three patients (34%) had interrupted drainage of the
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inferior vena cava and 43 (64%) had bilateral superior vena cava. Table 1
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Fifty-eight patients (87%) required neonatal palliation including BTS (n=34, 51%), Norwood operation
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(n=12, 18%) and PAB (n=12, 18%). In the remaining 9 patients (13%), primary Glenn bidirectional
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cavopulmonary shunt was the initial palliative surgery. In neonates who underwent Norwood, the source
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of pulmonary blood flow was BTS (n=3) or Sano shunt (n=9). Concomitant surgery at time of palliation
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was performed in 34 patients (51%) and that included TAPVC repair (n=20, 30%), atrioventricular valve
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repair (n=4, 6%), pulmonary artery augmentation (n=10, 15%), arch repair (n=1, 2%) and pacemaker
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implantation (n=1, 2%).
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Early hospital outcomes:
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Following surgery, 8 patients (12%) required ECMO support. Among those, 5/8 were following TAPVC
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repair and BTS, 1/8 was following BTS and unifocalization of interrupted branch pulmonary arteries plus
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pulmonary artery augmentation, and 2/8 following Norwood operation with BTS as source of pulmonary
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blood flow. Hospital survival for patients who required ECMO support was 1/8 (13%).
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Nine patients (13%) required early unplanned reoperations during the same hospital admission. Among
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those, 4/9 were following BTS and TAPVC repair (2 for tying of the main pulmonary artery due to
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overcirculation, 1 for shunt revision and 1 for removal of left atrial clots), 2/9 were following BTS (1 for
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shunt revision and 1 for pulmonary artery augmentation), 2/9 following PAB (both for addition of BTS),
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and 1/9 following Norwood (for replacement of the atrioventricular valve). Hospital survival for patients
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who underwent unplanned reoperation was 4/9 (44%).
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Overall, hospital mortality occurred in 15 patients (22%) including 9/15 following BTS, 3/15 following
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PAB and 3/15 following Norwood. Among those, 9/15 (60%) had concomitant TAPVC repair and 3/15
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(20%) had concomitant atrioventricular valve repair. Risk factors for hospital death were examined are
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present in Table 2. On multivariable analysis, concomitant TAPVC repair was associated with hospital
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mortality (OR: 4.8 (1.1-21.0), p=0.036).
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Competing risks analysis following first stage palliation surgery:
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Following the 58 neonatal first stage surgeries, hospital mortality occurred in 15 (26%) and 43 (74%)
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were discharged alive. There were 2 additional interstage mortalities (3%) prior to Glenn while 1 patient
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(2%) received heart transplantation. The remaining 40 patients (69%) progressed to receive the Glenn
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shunt.
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Competing risks models showed that the proportion of patients who underwent Glenn started to rise
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around 3 months and peaked around 7 months following first stage palliation. The hazard function for
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death prior to Glenn was characterized by the presence of an early risk phase during the initial 6 months
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that decreased gradually until it disappeared around 1 year of age. Competing risks analysis showed that
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at 6 months following first stage palliation surgery, 29% of patients had died or received transplantation,
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44% had undergone Glenn and 27% were alive awaiting Glenn. At 1 year, 29% of patients had died or
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received transplantation, 63% had undergone Glenn, and 8% were alive awaiting Glenn. [Figure-1]
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Outcomes following Glenn:
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Overall, 49 patients received the Glenn shunt; 40 following first stage palliation surgery and 9 primary
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Glenn. Among those, 16/49 (33%) had unilateral while 33/49 (67%) had bilateral Glenn shunts. Of note,
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19/49 (39%) had interrupted inferior vena cava and hence they received the Kawashima procedure at time
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of Glenn. Additional surgeries at time of Glenn were required in 20 patients and included pulmonary
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artery augmentation (n=9), atrioventricular valve repair (n=6), TAPVC repair (n=5), pacemaker
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implantation (n=3), atrial septectomy (n=2), and Damus-Kaye-Stansel anastomosis (n=2).
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Following Glenn in those 49 patients, 23 patients (47%) underwent Fontan, 3 (6%) died before Fontan
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and 23 (47%) were alive and considered proper Fontan candidates (including 12 patients who had
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Kawashima). Concomitant surgery at time of Fontan included pulmonary artery augmentation (n=3),
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pulmonary venous stenosis repair (n=2), atrial septectomy (n=1), atrioventricular valve repair (n=1) and
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pacemaker implantation (n=1).
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Competing risks models could not be performed following Glenn due to the very low death incidence.
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The proportion of patients who underwent Fontan started to rise around 1.2 years and peaked around 1.9
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years following Glenn. At 5 years following Glenn, 64% of patients had undergone the Fontan operation.
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[Figure-E1]
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Overall survival and risk factors:
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Parametric survival estimates for the entire cohort following surgery were 87% (79% - 93%), 71% (60% -
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81%), and 66% (54% - 77%) at 1 month, 1 year and 8 years. The hazard function for death after surgery
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was characterized by the presence of an early risk phase during the initial 1 year following surgery and a
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low late risk phase that continued following surgery with low attrition with time. [Figure-E2]
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Risk factors affecting overall survival were examined and are presented in Table E1. On multivariable
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analysis, risk factors for overall mortality were ECMO use (HR: 7.9 (3.2-19.4), p<0.001) and unplanned
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reoperation (HR: 3.6 (1.5-8.9), p=0.005). Given that concomitant TAPVC repair and ECMO use were
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strongly correlated, concomitant TAPVC repair became a risk factor for overall mortality (HR: 2.3 (1.0-
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5.6), p=0.056) if ECMO use was removed from the multivariable model. [Figure-2]
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Although survival following primary Glenn in our series was 100%, survival following first stage
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palliation was not associated with initial surgery type on univariate analysis. The effect of anatomic
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factors on survival was assessed; there was a trend for improved survival in patients with LAI that did not
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reach statistical significance. Interestingly, dominant right ventricle was associated with statistically
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higher survival that did not reach statistical significance, suggesting that surgery type and coexisting
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anomalies played a more important role in survival than dominant ventricle morphology. Although the
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presence of obstructed TAPVC affected survival, the degree of pulmonary valve obstruction did not.
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Comparison with matched group of non-heterotaxy single ventricle patients:
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Given that mortality risk in heterotaxy patients was mainly following first stage palliation surery and that
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the hazard of death decreased significantly following the Glenn shunt; comparison was made between
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neonates with heterotaxy and a matched control contemporaneous group of neonates with other forms of
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single ventricle anomalies who underwent first stage palliation surgery. Table E1 The two groups were
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matched for age, gender, weight, prematurity, dominant ventricle, cardiopulmonary bypass use and type
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of first stage palliation as shown in Table 3. Comparison between those two matched groups showed that
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the incidence of unplanned reoperation was comparable (14% heterotaxy vs. 10% control, p=0.54) while
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there was a trend for higher need of ECMO use in the heterotaxy group (15% heterotaxy vs. 6% control,
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p=0.11). Hospital mortality was significantly higher for the heterotaxy group (27% heterotaxy vs. 10%
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control, p=0.022). Additionally, patients with heterotaxy had significantly longer ventilation hours and
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intensive care unit stay duration. Table 3
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Comparison of the hazard of death prior to Glenn shunt between the two groups of patients showed that
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the early hazard of death for heterotaxy patients following first stage palliation was higher and more
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prolonged than that of the control group. Nonetheless, the risk of interstage mortality and the rate
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progression to the subsequent Glenn shunt for hospital survivors were comparable between the two
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groups. [Figure-3] As noted, competing risks analysis of events following first stage palliation in the
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heterotaxy group showed that at 1 month following first stage palliation surgery, 19% were dead or
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received transplantation as compared to 7% for the control group. However, at 6 months following first
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stage palliation surgery, 30% were dead or received transplantation in the heterotaxy group (additional
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11%) as compared to 21% in the control group (additional 14%) suggesting comparable interstage
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mortality between the two groups. Additionally, at 1 year following first stage palliation surgery, the
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number of patients alive and awaiting Glenn was comparable between the two groups (8% heterotaxy vs.
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1% control) suggesting similar progression to subsequent Glenn shunt in hospital survivors between the
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two groups (especially taking into account the higher incidence of interrupted inferior vena cava in the
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heterotaxy group necessitating a delay in Glenn / Kawashima operation). The hazard of death and the
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overall survival between the two groups of patients is shown in Figure-4. While the disparity in outcomes
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was noted in early phase survival, the survival for the two groups of patients was parallel subsequent to
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that phase. Parametric survival at 8 years following first stage palliation surgery was 62% (48-74%) for
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the heterotaxy group as compared to 75% (61-85%) for the control group (p=0.171).
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Discussion:
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Our current study demonstrates that, despite current advances in the perioperative care of single ventricle
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patients, the management of infants with heterotaxy syndrome and functional single ventricle continues to
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be challenging and associated with high operative mortality and morbidity. This finding is parallel to
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other reports that showed increased mortality risk in patients with heterotaxy syndrome following various
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palliative procedures including modified BTS, Norwood operation or PAB. [1,18-21] Similarly, a recent
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Society of Thoracic Surgeons study examining hospital survival of 1505 patients with heterotaxy who
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underwent surgery demonstrated that discharge mortality was higher in patients with heterotaxy compared
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with patients without heterotaxy for every procedure mortality risk category and for different subgroups
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of patients such as those who underwent BTS or Fontan operation. [1] Although there are few small
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studies that showed some encouraging results in heterotaxy patients that seemed to be superior to older
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reports, [22,23] this improvement has not been consistent and a recent large series from Australia
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examining outcomes of 182 heterotaxy patients showed that no improvement in survival could be noticed
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with time. [8]
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In our series, we examined outcomes of neonates who underwent first stage palliation and compared early
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and late results between those who had heterotaxy syndrome and those who had other non-heterotaxy
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single ventricle anomalies. Given that there are several established risk factors such as low weight,
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prematurity and genetic syndromes that are associated with poor outcomes following single ventricle
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palliation, [21,24-27] we aimed to compare outcomes with a control group of non-heterotaxy patients that
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was matched for those additional risk factors. In our matched comparison, heterotaxy patients continued
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to have higher resource utilization (ventilation and intensive care unit stay), higher operative mortality
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and lower overall survival. Those findings suggest that heterotaxy syndrome is an independent factor
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associated with increased morbidity and mortality following single ventricle palliation. Our findings are
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similar to those from a recent series from Washington DC that compared outcomes of 84 heterotaxy
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patients with 634 non-heterotaxy patients with congenital heart disease and comparable Risk Adjustment
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in Congenital Heart Surgery-1 scores who underwent surgery at their institution. [12] They found that
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heterotaxy patients had increased postsurgical mortality, increased postsurgical respiratory complications
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and more complicated postsurgical course. [12] The same group from Washington DC identified that
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increased respiratory complications might be related to airway ciliary dysfunction similar to that of
309
primary ciliary dyskinesia. They suggested that future studies are warranted to examine gene mutations
310
associated with ciliary dyskinesia and to assess the potential role of prophylactic treatment of heterotaxy
311
patients with therapies that improve mucous clearance that might reduce respiratory complications and
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improve outcomes in those challenging patients. [14,15] In addition to ciliary dyskinesia, heterotaxy
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patients often have other extra-cardiac malformations such as intestinal malrotation that might require
314
surgery with the subsequent risk of abdominal complications and asplenia with the subsequent risk of
315
sepsis. [1,7,11,16,17] In our series, none of the early and late mortalities were related to those additional
316
extra-cardiac manifestations suggesting that they might contribute to morbidity or longer hospitalization
317
but not necessarily to increased operative mortality, likely owing to improved awareness and management
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of those existing malformations.
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On the other hand, the majority of hospital mortalities in our series were cardiac related, highlighting the
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ongoing challenges in those patients related to the complexity of the intra-cardiac anatomy and
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association with multiple anomalies that increase mortality risk such as the presence of TAPVC,
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atrioventricular valve dysfunction, pulmonary atresia, arrhythmia and heart block.
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Atrioventricular valve regurgitation is common in patients with heterotaxy syndrome, especially in those
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with common atrioventricular valve. [1,5,7,8,23] Atrioventricular valve regurgitation is a known risk
325
factor for early and late mortality following single ventricle palliation. [1,5,7,8,23,28] In our series,
326
atrioventricular valve regurgitation or repair was not associate with increased mortality however this is
327
likely due to the statistically small cohort size. Although there are reports of improved results of
328
atrioventricular valve repair in heterotaxy patients, [29] this issue remains a challenge that is associated
329
with increased morbidity, need for unplanned reoperation and decreased late survival. [23,28] Similarly,
330
there was a trend for worse survival in infants with pulmonary atresia that did not reach statistical
331
significance in our series, likely due to small cohort size. In larger studies examining outcomes of
332
palliation with BTS in single ventricle patients, pulmonary atresia has been found to be associated with
333
increased mortality risk. [18]
334
On the other hand, concomitant TAPVC repair was significantly associated with increased operative
335
mortality in our series, especially when performed for obstructed TAPVC during neonatal palliation.
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TAPVC repair in heterotaxy patients is especially challenging and has been repeatedly shown to be
337
associated with significantly worse early and late outcomes than those following simple TAPVC repair.
338
[9,10,30-32] Part of the challenge is due to the inability to accurately predict the amount of native
339
pulmonary outflow obstruction except for patients with pulmonary atresia, and the existence of varying
340
degrees of lung pathology, and elevated pulmonary vascular resistance in patients with obstructed
341
TAPVC that complicate recovery following BTS and compromise the ability to perform adequate PAB.
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In addition to high operative mortality following first stage palliation surgery, late outcomes in heterotaxy
343
patients have been shown to be inferior due to the emergence of problems related to arrhythmias,
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atrioventricular valve regurgitation and pulmonary arteriovenous malformation in patients with
345
interrupted inferior vena cava. [5,7,8,33-36] Several studies have shown inferior outcomes in children
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with heterotaxy following Glenn or Fontan operations. [33-36] In our series, outcomes in heterotaxy
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patients seem to be comparable to those in non-heterotaxy single ventricle patients beyond hospital
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discharge although our findings are limited by the small series and the intermediate nature of our follow
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up.
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Summary:
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Despite recent advances in the management of neonates undergoing multistage palliation of single
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ventricle anomalies, the management of heterotaxy patients with functional single ventricle remains
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challenging. Compared to non-heterotaxy patients, heterotaxy patients are associated with higher
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operative mortality and increased resource utilization due to surgical morbidity following their first stage
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palliation. Nonetheless, outcomes beyond hospital discharge are comparable to other single ventricle
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patients suggesting that efforts to improve survival in those difficult patients should focus on
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perioperative care.
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References: 1- Jacobs JP, Pasquali SK, Morales DL, Jacobs ML, Mavroudis C, Chai PJ et al. Heterotaxy: lessons
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learned about patterns of practice and outcomes from the congenital heart surgery database of the
361
Society of Thoracic Surgeons. World J Pediatr Congenit Heart Surg 2011;2:278–86.
RI PT
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2- Hashmi A, Abu-Sulaiman R, McCrindle BW, Smallhorn JF, Williams WG, Freedom RM.
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Management and outcomes of right atrial isomerism: a 26-year experience. J Am Coll Cardiol.
364
1998;31:1120-6.
SC
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3- Yun T-J, Al-Radi OO, Adatia I, Caldarone CA, Coles JG, Williams WG et al. Contemporary
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management of right atrial isomerism: effect of evolving therapeutic strategies. J Thorac
367
Cardiovasc Surg. 2006;131:1108-13.
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4- Lim JSL, McCrindle BW, Smallhorn JF, Golding F, Caldarone CA, Taketazu M et al. Clinical
369
features, management, and outcome of children with fetal and postnatal diagnoses of isomerism
370
syndromes. Circulation. 2005;112:2454-61.
372
5- Jonas RA. Surgical management of the neonate with heterotaxy and long-term outcomes of
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heterotaxy. World J Pediatr Congenit Heart Surg. 2011;2:264-74. 6- Takeuchi K, McGowan FX Jr, Bacha EA, Mayer JE Jr, Zurakowski D, Otaki M et al. Analysis of
374
surgical outcome in complex double-outlet right ventricle with heterotaxy syndrome or complete
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atrioventricular canal defect. Ann Thorac Surg. 2006;82:146-52..
377
7- Jacobs ML, Mavroudis C. Challenges of univentricular physiology in heterotaxy. World J Pediatr
AC C
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EP
373
Congenit Heart Surg. 2011;2:258-63.
378
8- Bhaskar J, Galati JC, Brooks P, Oppido G, Konstantinov IE, Brizard CP et al. Survival into
379
adulthood of patients with atrial isomerism undergoing cardiac surgery. J Thorac Cardiovasc
380
Surg. 2015 Jun;149:1509-13.
381
9- Khan MS, Bryant R 3rd, Kim SH, Hill KD, Jacobs JP, Jacobs ML et al. Contemporary Outcomes
382
of Surgical Repair of Total Anomalous Pulmonary Venous Connection in Patients With
383
Heterotaxy Syndrome. Ann Thorac Surg. 2015;99:2134-9.
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10- Morales DLS, Braud BE, Booth JH, Graves DE, Heinle JS, McKenzie ED et al. Heterotaxy
385
patients with total anomalous pulmonary venous return: improving surgical results. Ann Thorac
386
Surg. 2006;82:1621-7. 11- Song J, Kang IS, Huh J, Lee OJ, Kim G, Jun TG et al. Interstage mortality for functional single
388
ventricle with heterotaxy syndrome: a retrospective study of the clinical experience of a single
389
tertiary center. J Cardiothorac Surg. 2013;8:93.
RI PT
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12- Swisher M, Jonas R, Tian X, Lee ES, Lo CW, Leatherbury L. Increased postoperative and
391
respiratory complications in patients with congenital heart disease associated with heterotaxy. J
392
Thorac Cardiovasc Surg. 2011;141:637-44.
M AN U
SC
390
393
13- Sinzobahamvya N, Arenz C, Reckers J, Photiadis J, Murin P, Schindler E et al. Poor outcome for
394
patients with totally anomalous pulmonary venous connection and functionally single ventricle.
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Cardiol Young. 2009;19:594-600.
14- Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, et al. High prevalence of
397
respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation.
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2012;125:2232-42.
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15- Harden B, Tian X, Giese R, Nakhleh N, Kureshi S, Francis R et al. Increased postoperative
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respiratory complications in heterotaxy congenital heart disease patients with respiratory ciliary
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dysfunction. J Thorac Cardiovasc Surg. 2014;147:1291-1298.
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16- Chiu SN, Shao PL, Wang JK, Chen HC, Lin MT, Chang LY et al. Severe bacterial infection in
AC C
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399
patients with heterotaxy syndrome. J Pediatr. 2014;164(1):99-104.
404
17- Sen S, Duchon J, Lampl B, Aspelund G, Bacha E, Krishnamurthy G. Heterotaxy syndrome
405
infants are at risk for early shunt failure after Ladd procedure. Ann Thorac Surg. 2015;99(3):918-
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25.
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18- Alsoufi B, Gillespie S, Kogon B, Schlosser B, Sachdeva R, Kim D et al. Results of Palliation
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With an Initial Modified Blalock-Taussig Shunt in Neonates With Single Ventricle Anomalies
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Associated With Restrictive Pulmonary Blood Flow. Ann Thorac Surg. 2015;99(5):1639-46.
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19- Alsoufi B, Manlhiot C, Ehrlich A, Oster M, Kogon B, Mahle WT et al. Results of palliation with
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an initial pulmonary artery band in patients with single ventricle associated with unrestricted
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pulmonary blood flow. J Thorac Cardiovasc Surg. 2015;149:213-20. 20- Jacobs JP, O'Brien SM, Chai PJ, Morell VO, Lindberg HL, Quintessenza JA. Management of 239
414
patients with hypoplastic left heart syndrome and related malformations from 1993 to 2007. Ann
415
Thorac Surg. 2008;85(5):1691-6.
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21- Alsoufi B, McCracken C, Ehrlich A, Mahle WT, Kogon B, Border W et al. Single ventricle
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palliation in low weight patients is associated with worse early and midterm outcomes. Ann
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Thorac Surg. 2015;99:668-76.
420
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419
SC
416
22- Ota N, Fujimoto Y, Murata M, Tosaka Y, Ide Y, Tachi M et al. Improving outcomes of the surgical management of right atrial isomerism. Ann Thorac Surg. 2012;93:832-8. 23- Anagnostopoulos PV, Pearl JM, Octave C, Cohen M, Gruessner A,Wintering E et al. Improved
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current era outcomes in patients with heterotaxy syndromes. Eur J Cardiothorac Surg.
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2009;35:871-7; discussion 877-8.
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24- Alsoufi B, Manlhiot C, Mahle WT, Kogon B, Border WL, Cuadrado A et al. Low-weight infants
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are at increased mortality risk after palliative or corrective cardiac surgery. J Thorac Cardiovasc
426
Surg. 2014;148:2508-14.
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25- Curzon CL, Milford-Beland S, Li JS, O'Brien SM, Jacobs JP, Jacobs ML et al. Cardiac surgery in
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infants with low birth weight is associated with increased mortality: analysis of the Society of
429
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Thoracic Surgeons Congenital Heart database. J Thoracic Cardiovasc Surg 2008;135:546-51.
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26- Kalfa D, Krishnamurthy G, Duchon J, Najjar M, Levasseur S, Chai P et al. Outcomes of cardiac
431
surgery in patients weighing <2.5 kg: affect of patient-dependent and -independent variables. J
432
Thorac Cardiovasc Surg. 2014;148:2499-506.
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27- Alsoufi B, Gillespie S, Mahle W, Deshpande S, Kogon B, Maher K et al. The impact of non-
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cardiac and genetic abnormalities on outcomes following neonatal congenital heart surgery. J
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Thorac Cardiovasc Surg. 2015 (revision under review).
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28- Honjo O, Atlin CR, Mertens L, Al-Radi OO, Redington AN, Caldarone CA et al. Atrioventricular
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valve repair in patients with functional single-ventricle physiology: impact of ventricular and
438
valve function and morphology on survival and reintervention. J Thorac Cardiovasc Surg.
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2011;142:326-35.
RI PT
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29- Sano S, Fujii Y, Arai S, Kasahara S, Tateishi A. Atrioventricular valve repair for patient with
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heterotaxy syndrome and a functional single ventricle. Semin Thorac Cardiovasc Surg Pediatr
442
Card Surg Annu. 2012;15:88-95.
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30- Hancock Friesen CL, Zurakowski D, Thiagarajan RR, Forbess JM, del Nido PJ, Mayer JE et al.
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Total anomalous pulmonary venous connection: an analysis of current management strategies in a
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single institution. Ann Thorac Surg 2005;79:596–606.
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31- Lodge AJ, Rychik J, Nicolson SC, Ittenbach RF, Spray TL, Gaynor JW. Improving outcomes in
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functional single ventricle and total anomalous pulmonary venous connection. Ann Thorac Surg
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2004;78:1688–95.
32- Caldarone CA, Najm HK, Kadletz M, Smallhorn JF, Freedom RM, Williams WG et al. Surgical
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management of total anomalous pulmonary venous drainage: impact of coexisting cardiac
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anomalies. Ann Thorac Surg 1998;66:1521–6.
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33- Kim SJ, Kim WH, Lim HG, Lee JY. Outcome of 200 patients after an extracardiac Fontan procedure. J Thorac Cardiovasc Surg. 2008;136:108-16. 34- Alsoufi B, Manlhiot C, Awan A, Alfadley F, Al-Ahmadi M, Al-Wadei A et al. Current outcomes
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of the Glenn bidirectional cavopulmonary connection for single ventricle palliation. Eur J Cardiothorac Surg. 2012;42:42-8.
35- Lee TM, Aiyagari R, Hirsch JC, Ohye RG, Bove EL, Devaney EJ. Risk factor analysis for second-stage palliation of single ventricle anatomy. Ann Thorac Surg. 2012;93:614-8. 36- Koudieh M, McKenzie ED, Fraser CD Jr. Outcome of Glenn anastomosis for heterotaxy syndrome with single ventricle. Asian Cardiovasc Thorac Ann. 2006;14:235-8.
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Table 1: Differences in patients’ characteristics, cardiac morphology and post-operative details between
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patients with left atrial isomerism and patients with right atrial isomerism.
p-value
22 (52%) 3.0 (2.6 – 3.6) 9 (21%) 11 (26%) 10 (5 – 50)
14 (58%) 3.4 (2.8 – 3.9) 4 (17%) 5 (21%) 14 (5 – 49)
0.640 0.009 0.755 0.625 0.695
SC
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Left atrial isomerism (N = 24)
14 (33%) 16 (38%) 12 (29%) 37 (88%) 40 (95%) 32 (76%) 9 (21%) 2 (5%) 3 (7%)
3 (13%) 16 (67%) 5 (21%) 16 (67%) 18 (75%) 1 (4%) 0 (0%) 10 (42%) 10 (42%)
7 (17%) 21 (50%) 14 (33%) 0 (0%) 25 (60%)
15 (67%) 6 (25%) 2 (8%) 23 (96%) 17 (71%)
28 (67%) 2 (5%) 5 (12%) 7 (17%) 19 (45%) 29 (69%) 7 (17%) 6 (14%) 11 (26%)
6 (25%) 10 (42%) 6 (25%) 2 (8%) 0 (0%) 15 (63%) 1 (4%) 2 (8%) 4 (17%)
464 465
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Patients’ characteristics Male gender, N (%) Weight (kg), median (25th – 75th) Weight ≤ 2.5 kg, N (%) Prematurity, N (%) Age (days), median (25th – 75th) Morphology Dominant ventricle morphology, N (%) Left ventricle Right ventricle Both ventricles Atrioventricular septal defect, N (%) Double outlet right ventricle, N (%) Anomalous pulmonary venous drainage, N (%) Obstructed pulmonary venous drainage, N (%) Aortic annulus hypoplasia, N (%) Aortic arch obstruction, N (%) Pulmonary valve, N (%) Unobstructed Pulmonary stenosis Pulmonary atresia Interrupted inferior vena cava, N (%) Bilateral superior vena cava, N (%) Operative and post-operative details First palliative surgery type, N (%) Modified Blalock-Taussig shunt Norwood Pulmonary artery band Primary Glenn bidirectional shunt Concomitant TAPVC repair, N (%) Cardiopulmonary bypass use, N (%) Unplanned reoperation, N (%) ECMO requirement, N (%) Hospital death, N (%)
Right atrial isomerism (N = 42)
0.064 0.053 0.023 < 0.001 < 0.001 < 0.001 0.001
< 0.001 < 0.001 0.358
< 0.001 <0.001 0.587 0.134 0.700 0.377
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Table 2: Univariable analysis of hospital death following first stage single ventricle palliation in neonates
467
with heterotaxy. Odds Ratio
95% CI
Prematurity
0.68
(0.17 – 2.77)
0.589
Weight ≤ 2.5 kg Right atrial isomerism Dominant ventricle Left vs. right
0.93 1.77
(0.22 – 3.89) (0.50 – 6.34)
0.922 0.378
3.06
(0.77 – 12.10)
0.112
Both vs. right
1.72
(0.40 – 7.50)
0.468
TAPVC Obstructed TAPVC
2.52 3.76
(0.76 – 8.41) (0.85 – 16.54)
0.133 0.080
Pulmonary valve Stenosis vs. unobstructed Atresia vs. unobstructed Concomitant TAPVC First palliative surgery type Band vs. shunt ECMO Use
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Unplanned reoperation
SC
4.31
(0.51 – 36.23)
0.179
0.68
(0.17 – 2.61)
0.576
1.0
(0.23 – 4.31)
1.00
6.15
(1.77 – 21.31)
0.004
0.93
(0.20 – 4.20)
0.921
0.93
(0.20 – 4.20)
0.921
44.6
(4.8 – 412.7)
<0.001
4.88
(1.10 – 21.57)
0.037
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Norwood vs. shunt
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Table E1: Univariable model of overall survival following initial palliation in children with heterotaxy. Hazard Ratio
95% CI
P-value (early)
Prematurity
1.1
(0.4 – 2.8)
0.176
Weight ≤ 2.5 kg Right atrial isomerism Dominant ventricle Right vs. not Right
1.1 2.1
(0.4 – 3.0) (0.8 – 5.9)
0.202 0.146
0.70
(0.25 – 1.97)
0.501
1.20
(0.40 – 3.56)
0.746
2.2 5.6
(0.9 – 5.1) (0.8 – 41.5)
0.084 0.094
(0.7 – 6.41)
0.193
TAPVC Common atrioventricular valve Obstructed TAPVC Pulmonary valve Unobstructed vs. stenosis Unobstructed vs. atresia Concomitant TAPVC First palliative surgery type Shunt vs. Norwood ECMO Use
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Unplanned reoperation
471 472
1.1
(0.4 – 2.7)
0.914
1.0
(0.3 – 3.2)
0.949
2.9
(1.3 – 6.7)
0.013
1.4
(0.4 – 4.1)
0.608
1.3
(0.4 – 3.8)
0.679
9.9
(4.0 – 24.2)
< 0.001
3.7
(1.5 – 9.2)
0.004
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2.1
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Left vs. not left
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Risk Factor
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Table E2: Differences in patients’ characteristics, cardiac morphology and post-operative details between
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neonates with heterotaxy and single ventricle and contemporaneous neonates with other forms of single
475
ventricle anomalies who underwent first stage palliation surgery. p-value
249 (60%) 3.2 (2.8 – 3.5) 54 (13%) 52 (13%) 5 (4 – 9) 51 (12.4%)
0.46 0.07 0.025 0.007 0.002 0.045
14 (24%) 29 (50%) 15 (26%)
130 (32%) 271 (66%) 12 (3%)
< 0.001
34 (59%) 12 (21%) 12 (21%) 17 (30%) 35 (60%) 9 (16%) 8 (14%)
81 (20%) 271 (66%) 61 (15%) 4 (0.1%) 286 (70%) 45 (11%) 43 (10%)
SC
32 (55%) 3.0 (2.6 – 3.4) 14 (24%) 15 (26%) 8 (5 – 21) 2 (3.5%)
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Patients’ characteristics Male gender, N (%) Weight (kg), median (25th – 75th) Weight ≤ 2.5 kg, N (%) Prematurity, N (%) Age (days), median (25th – 75th) Chromosomal or Extra-Cardiac Anomaly Dominant ventricle morphology, N (%) (n = 478) Left ventricle Right ventricle Both ventricles Operative and post-operative details First palliative surgery type, N (%) Modified Blalock-Taussig shunt Norwood Pulmonary artery band Concomitant TAPVC repair, N (%) Cardiopulmonary bypass use, N (%) Unplanned reoperation, N (%) ECMO requirement, N (%)
Non-heterotaxy (N = 413)
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Heterotaxy (N = 58)
<0.001 < 0.001 0.17 0.30 0.44
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Table 3: Comparison between neonates with heterotaxy and single ventricle and a matched
479
contemporaneous control group of neonates with other forms of single ventricle anomalies who
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underwent first stage palliation surgery. Group Non-heterotaxy (N = 52)
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22 (42%) 21 (41%) 9 (17%)
Heterotaxy (N = 52)
SMD1
P –value
30 (42%) 8 (5 – 19) 3.0 (2.6 – 3.4) 10 (19%) 11 (21%)
-0.12 0.12 -0.06 0.00 -0.05
0.55 0.55 0.78 1.00 0.81
28 (54%) 12 (23%) 12 (23%)
0.38
0.17
0.19
0.33
0.15
0.43
0.46 0.48 0.58 0.19 0.12 0.32
0.022 0.018 0.007 0.028 0.54 0.11
SC
33 (64%) 7 (4 – 15) 3.2 (2.7 – 3.5) 10 (19%) 12 (23%)
21 (40%) 31 (60%) 26 (50%)
26 (50%) 26 (50%) 30 (58%)
5 (10%) 16 (12 – 24) 154 (98 – 286) 102 (54 – 243) 5 (10%) 3 (6%)
14 (27%) 24 (14 – 41) 269 (158 – 636) 185 (74 – 475) 7 (14%) 8 (15%)
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Matched Variables Gender- Male Age (Days), median (25th – 75th) Weight (kg), median (25th – 75th) Weight ≤ 2.5 (kg), N (%) Premature (< 36 weeks), N (%) First Palliation Type, N (%) Modified Blalock-Taussig shunt Norwood Pulmonary artery band Dominant Ventricle Right Left or both Cardiopulmonary bypass use, N (%) Outcomes Hospital Death, N (%) Length of Stay (days), median (25th – 75th) ICU Length of Stay (hours), median (25th – 75th) Ventilator Duration (hours), median (25th – 75th) Reoperation, N (%) ECMO Use, N (%)
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Figures Legends:
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Figure-1:
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Competing risks analysis of outcomes after first stage palliation surgery in 58 neonates with heterotaxy.
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The solid lines represent parametric point estimates and the dashed lines enclose the 95% confidence
487
interval.
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a- Competing hazard functions for each outcome.
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b- Proportion of neonates in each of the categories at any given time after first stage surgery.
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Proportion of patients without the Fontan operation over time following Glenn in 49 infants with
493
heterotaxy (a) and the hazard for the Fontan operation (b). The solid lines represent parametric point
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estimates and the dashed lines enclose the 95% confidence interval. Circles represent non-parametric
495
estimates.
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Figure-E2:
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Time-dependent survival (a) and risk hazard of death (b) over time following initial palliation surgery in
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67 infants with heterotaxy. The solid lines in the parametric model represent parametric point estimates
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and the dashed lines enclose the 95% confidence interval. Circles represent non-parametric estimates.
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Figure-2:
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Parametric model for survival following initial palliation surgery in 67 infants with heterotaxy stratified
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by the need for concomitant TAPVC repair.
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Figure-3:
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Competing risks depiction of events following first stage palliation in neonates with heterotaxy and a
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matched control group of neonates without heterotaxy with other forms of single ventricle anomalies.
509 Figure-4:
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Time-dependent survival (a) and risk hazard of death (b) over time following first stage palliation in
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neonates with heterotaxy and a matched control group of neonates without heterotaxy with other forms of
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single ventricle anomalies.
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S0022-5223(16)00303-2
DOI:
10.1016/j.jtcvs.2016.01.054
Reference:
YMTC 10362
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 9 September 2015 Revised Date:
22 December 2015
Accepted Date: 23 January 2016
Please cite this article as: Alsoufi B, McCracken C, Schlosser B, Sachdeva R, Well A, Kogon B, Border W, Kanter K, Outcomes Of Multistage Palliation Of Infants With Functional Single Ventricle And Heterotaxy Syndrome, The Journal of Thoracic and Cardiovascular Surgery (2016), doi: 10.1016/ j.jtcvs.2016.01.054. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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1
Outcomes Of Multistage Palliation Of Infants With Functional Single Ventricle And Heterotaxy
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Syndrome
3 Bahaaldin Alsoufi1, MD, Courtney McCracken2, PhD, Brian Schlosser2, BS, RDCS, Ritu Sachdeva2,
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MBBS, Andrew Well1, PhD, Brian Kogon1, MD, William Border2, MBChB, MPH, Kirk Kanter1, MD.
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Medicine, Atlanta, GA, USA.
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Division of Cardiology, Children’s Healthcare of Atlanta, Emory University School of Medicine,
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Division of Cardiothoracic Surgery, Children’s Healthcare of Atlanta, Emory University School of
Atlanta, GA, USA.
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Presented at the 41st Annual Meeting of the Western Thoracic Surgical Association in Whistler, BC,
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Canada, June 2015
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Total Word count: 3829
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Potential conflict of interest: None of the authors have any potential conflict of interest to disclose.
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Source of funding: Institutional. No external source of funding for this project.
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Bahaaldin Alsoufi, MD Division of Cardiothoracic Surgery Emory University School of Medicine Children’s Healthcare of Atlanta 1405 Clifton Road, NE Atlanta, GA 30322 Phone: 1 404 785-6330 Fax: 1 404 785-6266 Email: [email protected]
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Abbreviations:
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TAPVC: total anomalous pulmonary venous connection
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ECMO: extra-corporeal membrane oxygenation
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HR: hazard ratio
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OR: odds ratio
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IQR: interquartile range
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RAI: right atrial isomerism
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LAI: left atrial isomerism
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BTS: modified Blalock-Taussig shunt
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PAB: pulmonary artery band
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Central image legend:
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Competing events following palliation for heterotaxy vs. non-heterotaxy single ventricle.
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34 Central Message:
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Single ventricle palliation for heterotaxy is associated with higher morbidity and mortality than other single
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ventricle anomalies.
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38 Perspective:
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First-stage palliation of infants with heterotaxy syndrome and functional single ventricle anomalies is
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associated with high operative mortality and increased resource utilization due to surgical morbidity.
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Nonetheless, outcomes beyond hospital discharge are comparable to infants with other non-heterotaxy
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single ventricle anomalies.
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Abstract:
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Background: Management of infants with heterotaxy syndrome and functional single ventricle is
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complicated due to associated cardiac and extra-cardiac anomalies. We report current-era palliation
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results.
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Methods: From 2002-2012, 67 infants with heterotaxy syndrome underwent multistage palliation.
50
Competing risks analyses modeled events after surgery (death vs. Glenn) and examined factors associated
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with survival. Additionally, early and late outcomes following first stage palliation surgery were
52
compared with a matched contemporaneous control group of non-heterotaxy single ventricle patients.
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Results: Fifty-eight patients (87%) required neonatal palliation including modified Blalock-Taussig shunt
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(n=34, 51%), Norwood (n=12, 18%) or pulmonary artery band (n=12, 18%), whereas 9 patients (13%)
55
received primary Glenn. Competing risks analysis showed that at 1 year following first stage palliation
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surgery, 29% of patients had died or received transplantation and 63% had undergone Glenn. By 5 years
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following Glenn, 64% of patients had undergone Fontan. Overall 8-year survival was 66%. On
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multivariable analysis, factors associated with mortality were unplanned reoperation (HR: 2.9 (1.1-7.3),
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p=0.005) and TAPVC repair (HR: 2.3 (1.0-5.6), p=0.056). Comparison with the contemporaneous
60
matched single ventricle patients showed that first-stage palliation in heterotaxy patients was associated
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with higher hospital death (27% vs.10%, p=0.022), and significantly longer ventilation hours and
62
intensive care unit stay duration. Nonetheless, interstage mortality, survival after Glenn and progression
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to Fontan were comparable.
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Conclusions: The management of heterotaxy infants with functional single ventricle remains challenging.
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First-stage palliation is associated with high operative mortality and increased resource utilization due to
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surgical morbidity. Nonetheless, outcomes beyond hospital discharge are comparable to other single
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ventricle patients. Efforts to improve survival in those patients should focus on perioperative care.
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Introduction:
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Visceral heterotaxy syndrome is defined as an abnormality where the internal thoraco-abdominal organs
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demonstrate abnormal arrangement across the left-right axis of the body. [1] Children born with the
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heterotaxy syndrome often have complex congenital cardiac anomalies that require surgical intervention.
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While some of those children have cardiac anomalies that are amenable to biventricular repair; many
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others have functional single ventricle that requires multistage palliation with the initial surgery dictated
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by the anatomy and the degree of systemic or pulmonary outflow obstruction. [1-8]
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Surgical management of children with heterotaxy syndrome and functional single ventricle is challenging
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due to the presence of complex morphologic features such as total anomalous pulmonary venous
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connection (TAPVC), atrioventricular valve dysfunction, pulmonary atresia, arrhythmias and heart block
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that are all established risk factors for increased morbidity and mortality following single ventricle
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palliation. [2-13] Additional extra-cardiac anomalies that are associated with the heterotaxy syndrome
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such as ciliary dysfunction, intestinal malrotation and asplenia can all contribute to increased early
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operative morbidity and complexity of post-discharge management, further adversely affecting late
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outcomes in those challenging patients. [7,11,12,14-17]
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We hypothesized that results of multistage palliation of neonates born with the heterotaxy syndrome and
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functional single ventricle have improved in the current era owing to advances in perioperative care and
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outpatient management, and that palliation outcomes are comparable to those in those born with other
90
non-heterotaxy single ventricle anomalies. To test this hypothesis, we examined early and late results
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following single ventricle palliation in infants with heterotaxy syndrome and compared them to those of a
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matched group of contemporaneous infants with non-heterotaxy single ventricle anomalies at our
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institution.
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Patients and Methods:
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Inclusion criteria:
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Between 2002 and 2012, 67 consecutive infants with heterotaxy syndrome underwent their first palliative
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surgery at Children’s Healthcare of Atlanta, Emory University. Patients were identified using our
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institutional surgical database. Demographic, morphologic, clinical, operative, and hospital details were
99
abstracted from the medical records for analysis. Approval of this study was obtained from our hospital’s
100
Institutional Review Board and requirement for individual consent was waived for this observational
101
study.
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Echocardiographic data collection and classification:
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All preoperative echocardiograms were retrospectively reviewed by a single echocardiographer (BS). Our
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morphologic inclusion criteria were based on the most recent nomenclature review and classification by
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Jacobs et al in 2007. [1] In that report, heterotaxy is defined as an abnormality where the internal thoraco-
106
abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. By
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convention, heterotaxy does not include patients with either the expected usual or normal arrangement of
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the internal organs along the left-right axis, also known as `situs solitus', or patients with complete mirror-
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imaged arrangement of the internal organs along the left-right axis also known as `situs inversus'. [1] Left
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atrial isomerism (LAI) is defined as a subset of heterotaxy where some paired structures on opposite sides
111
of the left-right axis of the body are symmetrical mirror images of each other, and have the morphology
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of the normal left-sided structures. This is commonly associated with polysplenia. Right atrial isomerism
113
(RAI) is defined as a subset of heterotaxy where some paired structures on opposite sides of the left-right
114
axis of the body are symmetrical mirror images of each other, and have the morphology of the normal
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right-sided structures. This is commonly associated with asplenia. [1] All patients were considered to
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have functional single ventricle although some of them had two well-formed ventricles however they
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were not thought to be amenable to septation due to the presence of non-committed ventricular septal
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defect, multiple ventricular septal defects or straddling of the atrioventricular valves.
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Follow up:
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Time-related outcomes were determined from recent office visits documented in the electronic chart of
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Children’s Healthcare of Atlanta system or from direct correspondence with pediatric cardiologists
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outside the system. Mean follow up duration was 5.5 ± 4.2 years and was 94% complete.
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Statistical analysis:
124
Data are presented as means with standard deviation, medians with interquartile ranges (IQR) or
125
frequencies and percentages, as appropriate. Time-dependent outcomes after first stage palliation surgery
126
and after Glenn were parametrically modeled. Parametric probability estimates for time-dependent
127
outcomes uses models based on multiple overlapping phases of risk using PROC HAZARD (available for
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use with the SAS system at http://www.clevelandclinic.org/heartcenter/hazard). The HAZARD procedure
129
uses maximum likelihood estimates to resolve risk distribution of time to event in up to 3 phases of risk
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(early decreasing or peaking hazard, constant hazard, and late increasing hazard). Maximum likelihood
131
estimates are iteratively calculated using nonlinear optimization based algorithms. Smoothed survival
132
curves were generated using the HAZPRED procedure in SAS. PROC HAZPRED computes predictions
133
for the survivorship and hazard functions along with their confidence limits.
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Competing risks analysis was performed to model the probability over time of each of the two mutually
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exclusive endpoints after first stage palliation surgery: death/transplantation and survival to Glenn. After
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the Glenn, competing risks models were not performed due to the small number of death/transplantation
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events following Glenn.
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For the outcome hospital death following first stage palliation, logistic regression was used to determine
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risk factors associated with hospital death. Variables that were tested included the following: gender, age,
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weight, prematurity, extra-cardiac anomalies, heterotaxy type (RAI vs. LAI), dominant ventricle
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morphology (left, right or both), morphology of the atrioventricular valve (common atrioventricular
142
valve, tricuspid, mitral or both) , antegrade pulmonary blood flow (absent, restricted, unrestricted),
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TAPVC (absent, present unobstructed, present obstructed), type of initial palliation surgery (Norwood,
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modified Blalock-Taussig shunt (BTS), pulmonary artery band (PAB), primary Glenn), concomitant
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TAPVC repair, post-operative extracorporeal membrane oxygenation (ECMO) support use, and
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unplanned cardiac reoperation. To identify risk factors associated with death/transplant following first
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stage palliation surgery, parametric survival models were constructed using one risk factor at a time. The
148
same variables listed above were tested. Given the limited sample size available for analysis,
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multivariable models were created using forward entry of variables significant at the 0.2 significance
150
level in univariate analysis. Effects of covariates on the probability of outcomes in survival models are
151
given as hazard ratio (HR) with 95% confidence interval.
152
Neonates with heterotaxy and single ventricle anomalies who underwent first stage palliation were
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compared to a propensity matched contemporary cohort of neonates with single ventricle anomalies other
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than heterotaxy who also underwent first stage palliation. Propensity score matching was performed to
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balance the two groups on baseline characteristics at a 1:1 ratio. Briefly, multivariable logistic regression
156
was used to predict patients with heterotaxy. Patient demographic and anatomical features were
157
considered in the logistic model and included: gender, age at initial surgery, prematurity, weight, first
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stage palliation surgery, dominant ventricle and the use of cardiopulmonary bypass during first stage
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palliation surgery. The deviance test was used to measure goodness of fit of the proposed logistic model.
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For each patient, the multivariable logistic model was used to obtain their predicted probability, or
161
propensity, of having heterotaxy. A 1:1 greedy matching algorithm was utilized to match SV patients with
162
and without heterotaxy based on their propensity scores. After matching, the matched cohort was then
163
assessed to ensure balanced distribution of covariates between groups using similar methods as described
164
above in addition to presenting standardized mean differences (SMD). Statistical significance was
165
assessed at the 0.05 level. All statistical analyses were performed using SAS v9.3 (The SAS Institute,
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Cary, NC).
167
Results:
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Patients’ characteristics, morphologic and operative details:
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Sixty-seven infants with heterotaxy underwent their initial palliation surgery. There were 37 males (55%).
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Median age at surgery was 11 days (IQR 5-50) and median weight was 3.1 kg (IQR 2.6-3.8) with 14
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patients (21%) ≤ 2.5 kg. There were 17 patients (25%) who were born prematurely ≤ 36 weeks gestation.
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Complete morphologic Echocardiographic examination was available in 66 patients and showed that 42
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(64%) had RAI while 24 (36%) had LAI. Dominant ventricle morphology was dominant right (n=32,
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48%), dominant left (n=17, 26%) or two equally formed ventricles (n=17, 26%). Fifty-eight patients
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(88%) had double outlet right ventricle and 53 (80%) had common atrioventricular valve. Overall, 33
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patients (50%) had TAPVC. The TAPVC type was supra-cardiac (n=14, 43%), cardiac (n=9, 27%), infra-
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cardiac (n=6, 18%) or mixed (n=4, 12%); with 9 (27%) having obstructed drainage at time of initial
178
presentation. Antegrade pulmonary blood flow was absent in 16 (24%), restricted in 27 (40%) and
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unrestricted in 24 (36%). Aortic arch obstruction was present in 13 patients (19%) while aortic annulus
180
hypoplasia was present in 12 patients (18%). Twenty-three patients (34%) had interrupted drainage of the
181
inferior vena cava and 43 (64%) had bilateral superior vena cava. Table 1
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Fifty-eight patients (87%) required neonatal palliation including BTS (n=34, 51%), Norwood operation
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(n=12, 18%) and PAB (n=12, 18%). In the remaining 9 patients (13%), primary Glenn bidirectional
184
cavopulmonary shunt was the initial palliative surgery. In neonates who underwent Norwood, the source
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of pulmonary blood flow was BTS (n=3) or Sano shunt (n=9). Concomitant surgery at time of palliation
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was performed in 34 patients (51%) and that included TAPVC repair (n=20, 30%), atrioventricular valve
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repair (n=4, 6%), pulmonary artery augmentation (n=10, 15%), arch repair (n=1, 2%) and pacemaker
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implantation (n=1, 2%).
189
Early hospital outcomes:
190
Following surgery, 8 patients (12%) required ECMO support. Among those, 5/8 were following TAPVC
191
repair and BTS, 1/8 was following BTS and unifocalization of interrupted branch pulmonary arteries plus
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pulmonary artery augmentation, and 2/8 following Norwood operation with BTS as source of pulmonary
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blood flow. Hospital survival for patients who required ECMO support was 1/8 (13%).
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Nine patients (13%) required early unplanned reoperations during the same hospital admission. Among
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those, 4/9 were following BTS and TAPVC repair (2 for tying of the main pulmonary artery due to
196
overcirculation, 1 for shunt revision and 1 for removal of left atrial clots), 2/9 were following BTS (1 for
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shunt revision and 1 for pulmonary artery augmentation), 2/9 following PAB (both for addition of BTS),
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and 1/9 following Norwood (for replacement of the atrioventricular valve). Hospital survival for patients
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who underwent unplanned reoperation was 4/9 (44%).
200
Overall, hospital mortality occurred in 15 patients (22%) including 9/15 following BTS, 3/15 following
201
PAB and 3/15 following Norwood. Among those, 9/15 (60%) had concomitant TAPVC repair and 3/15
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(20%) had concomitant atrioventricular valve repair. Risk factors for hospital death were examined are
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present in Table 2. On multivariable analysis, concomitant TAPVC repair was associated with hospital
204
mortality (OR: 4.8 (1.1-21.0), p=0.036).
205
Competing risks analysis following first stage palliation surgery:
206
Following the 58 neonatal first stage surgeries, hospital mortality occurred in 15 (26%) and 43 (74%)
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were discharged alive. There were 2 additional interstage mortalities (3%) prior to Glenn while 1 patient
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(2%) received heart transplantation. The remaining 40 patients (69%) progressed to receive the Glenn
209
shunt.
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Competing risks models showed that the proportion of patients who underwent Glenn started to rise
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around 3 months and peaked around 7 months following first stage palliation. The hazard function for
212
death prior to Glenn was characterized by the presence of an early risk phase during the initial 6 months
213
that decreased gradually until it disappeared around 1 year of age. Competing risks analysis showed that
214
at 6 months following first stage palliation surgery, 29% of patients had died or received transplantation,
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44% had undergone Glenn and 27% were alive awaiting Glenn. At 1 year, 29% of patients had died or
216
received transplantation, 63% had undergone Glenn, and 8% were alive awaiting Glenn. [Figure-1]
217
Outcomes following Glenn:
218
Overall, 49 patients received the Glenn shunt; 40 following first stage palliation surgery and 9 primary
219
Glenn. Among those, 16/49 (33%) had unilateral while 33/49 (67%) had bilateral Glenn shunts. Of note,
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19/49 (39%) had interrupted inferior vena cava and hence they received the Kawashima procedure at time
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of Glenn. Additional surgeries at time of Glenn were required in 20 patients and included pulmonary
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artery augmentation (n=9), atrioventricular valve repair (n=6), TAPVC repair (n=5), pacemaker
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implantation (n=3), atrial septectomy (n=2), and Damus-Kaye-Stansel anastomosis (n=2).
224
Following Glenn in those 49 patients, 23 patients (47%) underwent Fontan, 3 (6%) died before Fontan
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and 23 (47%) were alive and considered proper Fontan candidates (including 12 patients who had
226
Kawashima). Concomitant surgery at time of Fontan included pulmonary artery augmentation (n=3),
227
pulmonary venous stenosis repair (n=2), atrial septectomy (n=1), atrioventricular valve repair (n=1) and
228
pacemaker implantation (n=1).
229
Competing risks models could not be performed following Glenn due to the very low death incidence.
230
The proportion of patients who underwent Fontan started to rise around 1.2 years and peaked around 1.9
231
years following Glenn. At 5 years following Glenn, 64% of patients had undergone the Fontan operation.
232
[Figure-E1]
233
Overall survival and risk factors:
234
Parametric survival estimates for the entire cohort following surgery were 87% (79% - 93%), 71% (60% -
235
81%), and 66% (54% - 77%) at 1 month, 1 year and 8 years. The hazard function for death after surgery
236
was characterized by the presence of an early risk phase during the initial 1 year following surgery and a
237
low late risk phase that continued following surgery with low attrition with time. [Figure-E2]
238
Risk factors affecting overall survival were examined and are presented in Table E1. On multivariable
239
analysis, risk factors for overall mortality were ECMO use (HR: 7.9 (3.2-19.4), p<0.001) and unplanned
240
reoperation (HR: 3.6 (1.5-8.9), p=0.005). Given that concomitant TAPVC repair and ECMO use were
241
strongly correlated, concomitant TAPVC repair became a risk factor for overall mortality (HR: 2.3 (1.0-
242
5.6), p=0.056) if ECMO use was removed from the multivariable model. [Figure-2]
243
Although survival following primary Glenn in our series was 100%, survival following first stage
244
palliation was not associated with initial surgery type on univariate analysis. The effect of anatomic
245
factors on survival was assessed; there was a trend for improved survival in patients with LAI that did not
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reach statistical significance. Interestingly, dominant right ventricle was associated with statistically
247
higher survival that did not reach statistical significance, suggesting that surgery type and coexisting
248
anomalies played a more important role in survival than dominant ventricle morphology. Although the
249
presence of obstructed TAPVC affected survival, the degree of pulmonary valve obstruction did not.
250
Comparison with matched group of non-heterotaxy single ventricle patients:
251
Given that mortality risk in heterotaxy patients was mainly following first stage palliation surery and that
252
the hazard of death decreased significantly following the Glenn shunt; comparison was made between
253
neonates with heterotaxy and a matched control contemporaneous group of neonates with other forms of
254
single ventricle anomalies who underwent first stage palliation surgery. Table E1 The two groups were
255
matched for age, gender, weight, prematurity, dominant ventricle, cardiopulmonary bypass use and type
256
of first stage palliation as shown in Table 3. Comparison between those two matched groups showed that
257
the incidence of unplanned reoperation was comparable (14% heterotaxy vs. 10% control, p=0.54) while
258
there was a trend for higher need of ECMO use in the heterotaxy group (15% heterotaxy vs. 6% control,
259
p=0.11). Hospital mortality was significantly higher for the heterotaxy group (27% heterotaxy vs. 10%
260
control, p=0.022). Additionally, patients with heterotaxy had significantly longer ventilation hours and
261
intensive care unit stay duration. Table 3
262
Comparison of the hazard of death prior to Glenn shunt between the two groups of patients showed that
263
the early hazard of death for heterotaxy patients following first stage palliation was higher and more
264
prolonged than that of the control group. Nonetheless, the risk of interstage mortality and the rate
265
progression to the subsequent Glenn shunt for hospital survivors were comparable between the two
266
groups. [Figure-3] As noted, competing risks analysis of events following first stage palliation in the
267
heterotaxy group showed that at 1 month following first stage palliation surgery, 19% were dead or
268
received transplantation as compared to 7% for the control group. However, at 6 months following first
269
stage palliation surgery, 30% were dead or received transplantation in the heterotaxy group (additional
270
11%) as compared to 21% in the control group (additional 14%) suggesting comparable interstage
271
mortality between the two groups. Additionally, at 1 year following first stage palliation surgery, the
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number of patients alive and awaiting Glenn was comparable between the two groups (8% heterotaxy vs.
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1% control) suggesting similar progression to subsequent Glenn shunt in hospital survivors between the
274
two groups (especially taking into account the higher incidence of interrupted inferior vena cava in the
275
heterotaxy group necessitating a delay in Glenn / Kawashima operation). The hazard of death and the
276
overall survival between the two groups of patients is shown in Figure-4. While the disparity in outcomes
277
was noted in early phase survival, the survival for the two groups of patients was parallel subsequent to
278
that phase. Parametric survival at 8 years following first stage palliation surgery was 62% (48-74%) for
279
the heterotaxy group as compared to 75% (61-85%) for the control group (p=0.171).
280
Discussion:
281
Our current study demonstrates that, despite current advances in the perioperative care of single ventricle
282
patients, the management of infants with heterotaxy syndrome and functional single ventricle continues to
283
be challenging and associated with high operative mortality and morbidity. This finding is parallel to
284
other reports that showed increased mortality risk in patients with heterotaxy syndrome following various
285
palliative procedures including modified BTS, Norwood operation or PAB. [1,18-21] Similarly, a recent
286
Society of Thoracic Surgeons study examining hospital survival of 1505 patients with heterotaxy who
287
underwent surgery demonstrated that discharge mortality was higher in patients with heterotaxy compared
288
with patients without heterotaxy for every procedure mortality risk category and for different subgroups
289
of patients such as those who underwent BTS or Fontan operation. [1] Although there are few small
290
studies that showed some encouraging results in heterotaxy patients that seemed to be superior to older
291
reports, [22,23] this improvement has not been consistent and a recent large series from Australia
292
examining outcomes of 182 heterotaxy patients showed that no improvement in survival could be noticed
293
with time. [8]
294
In our series, we examined outcomes of neonates who underwent first stage palliation and compared early
295
and late results between those who had heterotaxy syndrome and those who had other non-heterotaxy
296
single ventricle anomalies. Given that there are several established risk factors such as low weight,
297
prematurity and genetic syndromes that are associated with poor outcomes following single ventricle
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palliation, [21,24-27] we aimed to compare outcomes with a control group of non-heterotaxy patients that
299
was matched for those additional risk factors. In our matched comparison, heterotaxy patients continued
300
to have higher resource utilization (ventilation and intensive care unit stay), higher operative mortality
301
and lower overall survival. Those findings suggest that heterotaxy syndrome is an independent factor
302
associated with increased morbidity and mortality following single ventricle palliation. Our findings are
303
similar to those from a recent series from Washington DC that compared outcomes of 84 heterotaxy
304
patients with 634 non-heterotaxy patients with congenital heart disease and comparable Risk Adjustment
305
in Congenital Heart Surgery-1 scores who underwent surgery at their institution. [12] They found that
306
heterotaxy patients had increased postsurgical mortality, increased postsurgical respiratory complications
307
and more complicated postsurgical course. [12] The same group from Washington DC identified that
308
increased respiratory complications might be related to airway ciliary dysfunction similar to that of
309
primary ciliary dyskinesia. They suggested that future studies are warranted to examine gene mutations
310
associated with ciliary dyskinesia and to assess the potential role of prophylactic treatment of heterotaxy
311
patients with therapies that improve mucous clearance that might reduce respiratory complications and
312
improve outcomes in those challenging patients. [14,15] In addition to ciliary dyskinesia, heterotaxy
313
patients often have other extra-cardiac malformations such as intestinal malrotation that might require
314
surgery with the subsequent risk of abdominal complications and asplenia with the subsequent risk of
315
sepsis. [1,7,11,16,17] In our series, none of the early and late mortalities were related to those additional
316
extra-cardiac manifestations suggesting that they might contribute to morbidity or longer hospitalization
317
but not necessarily to increased operative mortality, likely owing to improved awareness and management
318
of those existing malformations.
319
On the other hand, the majority of hospital mortalities in our series were cardiac related, highlighting the
320
ongoing challenges in those patients related to the complexity of the intra-cardiac anatomy and
321
association with multiple anomalies that increase mortality risk such as the presence of TAPVC,
322
atrioventricular valve dysfunction, pulmonary atresia, arrhythmia and heart block.
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Atrioventricular valve regurgitation is common in patients with heterotaxy syndrome, especially in those
324
with common atrioventricular valve. [1,5,7,8,23] Atrioventricular valve regurgitation is a known risk
325
factor for early and late mortality following single ventricle palliation. [1,5,7,8,23,28] In our series,
326
atrioventricular valve regurgitation or repair was not associate with increased mortality however this is
327
likely due to the statistically small cohort size. Although there are reports of improved results of
328
atrioventricular valve repair in heterotaxy patients, [29] this issue remains a challenge that is associated
329
with increased morbidity, need for unplanned reoperation and decreased late survival. [23,28] Similarly,
330
there was a trend for worse survival in infants with pulmonary atresia that did not reach statistical
331
significance in our series, likely due to small cohort size. In larger studies examining outcomes of
332
palliation with BTS in single ventricle patients, pulmonary atresia has been found to be associated with
333
increased mortality risk. [18]
334
On the other hand, concomitant TAPVC repair was significantly associated with increased operative
335
mortality in our series, especially when performed for obstructed TAPVC during neonatal palliation.
336
TAPVC repair in heterotaxy patients is especially challenging and has been repeatedly shown to be
337
associated with significantly worse early and late outcomes than those following simple TAPVC repair.
338
[9,10,30-32] Part of the challenge is due to the inability to accurately predict the amount of native
339
pulmonary outflow obstruction except for patients with pulmonary atresia, and the existence of varying
340
degrees of lung pathology, and elevated pulmonary vascular resistance in patients with obstructed
341
TAPVC that complicate recovery following BTS and compromise the ability to perform adequate PAB.
342
In addition to high operative mortality following first stage palliation surgery, late outcomes in heterotaxy
343
patients have been shown to be inferior due to the emergence of problems related to arrhythmias,
344
atrioventricular valve regurgitation and pulmonary arteriovenous malformation in patients with
345
interrupted inferior vena cava. [5,7,8,33-36] Several studies have shown inferior outcomes in children
346
with heterotaxy following Glenn or Fontan operations. [33-36] In our series, outcomes in heterotaxy
347
patients seem to be comparable to those in non-heterotaxy single ventricle patients beyond hospital
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discharge although our findings are limited by the small series and the intermediate nature of our follow
349
up.
350
Summary:
351
Despite recent advances in the management of neonates undergoing multistage palliation of single
352
ventricle anomalies, the management of heterotaxy patients with functional single ventricle remains
353
challenging. Compared to non-heterotaxy patients, heterotaxy patients are associated with higher
354
operative mortality and increased resource utilization due to surgical morbidity following their first stage
355
palliation. Nonetheless, outcomes beyond hospital discharge are comparable to other single ventricle
356
patients suggesting that efforts to improve survival in those difficult patients should focus on
357
perioperative care.
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References: 1- Jacobs JP, Pasquali SK, Morales DL, Jacobs ML, Mavroudis C, Chai PJ et al. Heterotaxy: lessons
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learned about patterns of practice and outcomes from the congenital heart surgery database of the
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Society of Thoracic Surgeons. World J Pediatr Congenit Heart Surg 2011;2:278–86.
RI PT
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2- Hashmi A, Abu-Sulaiman R, McCrindle BW, Smallhorn JF, Williams WG, Freedom RM.
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Management and outcomes of right atrial isomerism: a 26-year experience. J Am Coll Cardiol.
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1998;31:1120-6.
SC
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3- Yun T-J, Al-Radi OO, Adatia I, Caldarone CA, Coles JG, Williams WG et al. Contemporary
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management of right atrial isomerism: effect of evolving therapeutic strategies. J Thorac
367
Cardiovasc Surg. 2006;131:1108-13.
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4- Lim JSL, McCrindle BW, Smallhorn JF, Golding F, Caldarone CA, Taketazu M et al. Clinical
369
features, management, and outcome of children with fetal and postnatal diagnoses of isomerism
370
syndromes. Circulation. 2005;112:2454-61.
372
5- Jonas RA. Surgical management of the neonate with heterotaxy and long-term outcomes of
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heterotaxy. World J Pediatr Congenit Heart Surg. 2011;2:264-74. 6- Takeuchi K, McGowan FX Jr, Bacha EA, Mayer JE Jr, Zurakowski D, Otaki M et al. Analysis of
374
surgical outcome in complex double-outlet right ventricle with heterotaxy syndrome or complete
375
atrioventricular canal defect. Ann Thorac Surg. 2006;82:146-52..
377
7- Jacobs ML, Mavroudis C. Challenges of univentricular physiology in heterotaxy. World J Pediatr
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373
Congenit Heart Surg. 2011;2:258-63.
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8- Bhaskar J, Galati JC, Brooks P, Oppido G, Konstantinov IE, Brizard CP et al. Survival into
379
adulthood of patients with atrial isomerism undergoing cardiac surgery. J Thorac Cardiovasc
380
Surg. 2015 Jun;149:1509-13.
381
9- Khan MS, Bryant R 3rd, Kim SH, Hill KD, Jacobs JP, Jacobs ML et al. Contemporary Outcomes
382
of Surgical Repair of Total Anomalous Pulmonary Venous Connection in Patients With
383
Heterotaxy Syndrome. Ann Thorac Surg. 2015;99:2134-9.
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10- Morales DLS, Braud BE, Booth JH, Graves DE, Heinle JS, McKenzie ED et al. Heterotaxy
385
patients with total anomalous pulmonary venous return: improving surgical results. Ann Thorac
386
Surg. 2006;82:1621-7. 11- Song J, Kang IS, Huh J, Lee OJ, Kim G, Jun TG et al. Interstage mortality for functional single
388
ventricle with heterotaxy syndrome: a retrospective study of the clinical experience of a single
389
tertiary center. J Cardiothorac Surg. 2013;8:93.
RI PT
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12- Swisher M, Jonas R, Tian X, Lee ES, Lo CW, Leatherbury L. Increased postoperative and
391
respiratory complications in patients with congenital heart disease associated with heterotaxy. J
392
Thorac Cardiovasc Surg. 2011;141:637-44.
M AN U
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13- Sinzobahamvya N, Arenz C, Reckers J, Photiadis J, Murin P, Schindler E et al. Poor outcome for
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patients with totally anomalous pulmonary venous connection and functionally single ventricle.
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Cardiol Young. 2009;19:594-600.
14- Nakhleh N, Francis R, Giese RA, Tian X, Li Y, Zariwala MA, et al. High prevalence of
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respiratory ciliary dysfunction in congenital heart disease patients with heterotaxy. Circulation.
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2012;125:2232-42.
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15- Harden B, Tian X, Giese R, Nakhleh N, Kureshi S, Francis R et al. Increased postoperative
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respiratory complications in heterotaxy congenital heart disease patients with respiratory ciliary
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dysfunction. J Thorac Cardiovasc Surg. 2014;147:1291-1298.
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16- Chiu SN, Shao PL, Wang JK, Chen HC, Lin MT, Chang LY et al. Severe bacterial infection in
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patients with heterotaxy syndrome. J Pediatr. 2014;164(1):99-104.
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17- Sen S, Duchon J, Lampl B, Aspelund G, Bacha E, Krishnamurthy G. Heterotaxy syndrome
405
infants are at risk for early shunt failure after Ladd procedure. Ann Thorac Surg. 2015;99(3):918-
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25.
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18- Alsoufi B, Gillespie S, Kogon B, Schlosser B, Sachdeva R, Kim D et al. Results of Palliation
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With an Initial Modified Blalock-Taussig Shunt in Neonates With Single Ventricle Anomalies
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Associated With Restrictive Pulmonary Blood Flow. Ann Thorac Surg. 2015;99(5):1639-46.
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19- Alsoufi B, Manlhiot C, Ehrlich A, Oster M, Kogon B, Mahle WT et al. Results of palliation with
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an initial pulmonary artery band in patients with single ventricle associated with unrestricted
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pulmonary blood flow. J Thorac Cardiovasc Surg. 2015;149:213-20. 20- Jacobs JP, O'Brien SM, Chai PJ, Morell VO, Lindberg HL, Quintessenza JA. Management of 239
414
patients with hypoplastic left heart syndrome and related malformations from 1993 to 2007. Ann
415
Thorac Surg. 2008;85(5):1691-6.
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21- Alsoufi B, McCracken C, Ehrlich A, Mahle WT, Kogon B, Border W et al. Single ventricle
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palliation in low weight patients is associated with worse early and midterm outcomes. Ann
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Thorac Surg. 2015;99:668-76.
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22- Ota N, Fujimoto Y, Murata M, Tosaka Y, Ide Y, Tachi M et al. Improving outcomes of the surgical management of right atrial isomerism. Ann Thorac Surg. 2012;93:832-8. 23- Anagnostopoulos PV, Pearl JM, Octave C, Cohen M, Gruessner A,Wintering E et al. Improved
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current era outcomes in patients with heterotaxy syndromes. Eur J Cardiothorac Surg.
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2009;35:871-7; discussion 877-8.
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24- Alsoufi B, Manlhiot C, Mahle WT, Kogon B, Border WL, Cuadrado A et al. Low-weight infants
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are at increased mortality risk after palliative or corrective cardiac surgery. J Thorac Cardiovasc
426
Surg. 2014;148:2508-14.
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25- Curzon CL, Milford-Beland S, Li JS, O'Brien SM, Jacobs JP, Jacobs ML et al. Cardiac surgery in
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infants with low birth weight is associated with increased mortality: analysis of the Society of
429
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Thoracic Surgeons Congenital Heart database. J Thoracic Cardiovasc Surg 2008;135:546-51.
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26- Kalfa D, Krishnamurthy G, Duchon J, Najjar M, Levasseur S, Chai P et al. Outcomes of cardiac
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surgery in patients weighing <2.5 kg: affect of patient-dependent and -independent variables. J
432
Thorac Cardiovasc Surg. 2014;148:2499-506.
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27- Alsoufi B, Gillespie S, Mahle W, Deshpande S, Kogon B, Maher K et al. The impact of non-
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cardiac and genetic abnormalities on outcomes following neonatal congenital heart surgery. J
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Thorac Cardiovasc Surg. 2015 (revision under review).
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28- Honjo O, Atlin CR, Mertens L, Al-Radi OO, Redington AN, Caldarone CA et al. Atrioventricular
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valve repair in patients with functional single-ventricle physiology: impact of ventricular and
438
valve function and morphology on survival and reintervention. J Thorac Cardiovasc Surg.
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2011;142:326-35.
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29- Sano S, Fujii Y, Arai S, Kasahara S, Tateishi A. Atrioventricular valve repair for patient with
441
heterotaxy syndrome and a functional single ventricle. Semin Thorac Cardiovasc Surg Pediatr
442
Card Surg Annu. 2012;15:88-95.
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30- Hancock Friesen CL, Zurakowski D, Thiagarajan RR, Forbess JM, del Nido PJ, Mayer JE et al.
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Total anomalous pulmonary venous connection: an analysis of current management strategies in a
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single institution. Ann Thorac Surg 2005;79:596–606.
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31- Lodge AJ, Rychik J, Nicolson SC, Ittenbach RF, Spray TL, Gaynor JW. Improving outcomes in
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functional single ventricle and total anomalous pulmonary venous connection. Ann Thorac Surg
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2004;78:1688–95.
32- Caldarone CA, Najm HK, Kadletz M, Smallhorn JF, Freedom RM, Williams WG et al. Surgical
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management of total anomalous pulmonary venous drainage: impact of coexisting cardiac
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anomalies. Ann Thorac Surg 1998;66:1521–6.
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33- Kim SJ, Kim WH, Lim HG, Lee JY. Outcome of 200 patients after an extracardiac Fontan procedure. J Thorac Cardiovasc Surg. 2008;136:108-16. 34- Alsoufi B, Manlhiot C, Awan A, Alfadley F, Al-Ahmadi M, Al-Wadei A et al. Current outcomes
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of the Glenn bidirectional cavopulmonary connection for single ventricle palliation. Eur J Cardiothorac Surg. 2012;42:42-8.
35- Lee TM, Aiyagari R, Hirsch JC, Ohye RG, Bove EL, Devaney EJ. Risk factor analysis for second-stage palliation of single ventricle anatomy. Ann Thorac Surg. 2012;93:614-8. 36- Koudieh M, McKenzie ED, Fraser CD Jr. Outcome of Glenn anastomosis for heterotaxy syndrome with single ventricle. Asian Cardiovasc Thorac Ann. 2006;14:235-8.
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Table 1: Differences in patients’ characteristics, cardiac morphology and post-operative details between
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patients with left atrial isomerism and patients with right atrial isomerism.
p-value
22 (52%) 3.0 (2.6 – 3.6) 9 (21%) 11 (26%) 10 (5 – 50)
14 (58%) 3.4 (2.8 – 3.9) 4 (17%) 5 (21%) 14 (5 – 49)
0.640 0.009 0.755 0.625 0.695
SC
RI PT
Left atrial isomerism (N = 24)
14 (33%) 16 (38%) 12 (29%) 37 (88%) 40 (95%) 32 (76%) 9 (21%) 2 (5%) 3 (7%)
3 (13%) 16 (67%) 5 (21%) 16 (67%) 18 (75%) 1 (4%) 0 (0%) 10 (42%) 10 (42%)
7 (17%) 21 (50%) 14 (33%) 0 (0%) 25 (60%)
15 (67%) 6 (25%) 2 (8%) 23 (96%) 17 (71%)
28 (67%) 2 (5%) 5 (12%) 7 (17%) 19 (45%) 29 (69%) 7 (17%) 6 (14%) 11 (26%)
6 (25%) 10 (42%) 6 (25%) 2 (8%) 0 (0%) 15 (63%) 1 (4%) 2 (8%) 4 (17%)
464 465
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Patients’ characteristics Male gender, N (%) Weight (kg), median (25th – 75th) Weight ≤ 2.5 kg, N (%) Prematurity, N (%) Age (days), median (25th – 75th) Morphology Dominant ventricle morphology, N (%) Left ventricle Right ventricle Both ventricles Atrioventricular septal defect, N (%) Double outlet right ventricle, N (%) Anomalous pulmonary venous drainage, N (%) Obstructed pulmonary venous drainage, N (%) Aortic annulus hypoplasia, N (%) Aortic arch obstruction, N (%) Pulmonary valve, N (%) Unobstructed Pulmonary stenosis Pulmonary atresia Interrupted inferior vena cava, N (%) Bilateral superior vena cava, N (%) Operative and post-operative details First palliative surgery type, N (%) Modified Blalock-Taussig shunt Norwood Pulmonary artery band Primary Glenn bidirectional shunt Concomitant TAPVC repair, N (%) Cardiopulmonary bypass use, N (%) Unplanned reoperation, N (%) ECMO requirement, N (%) Hospital death, N (%)
Right atrial isomerism (N = 42)
0.064 0.053 0.023 < 0.001 < 0.001 < 0.001 0.001
< 0.001 < 0.001 0.358
< 0.001 <0.001 0.587 0.134 0.700 0.377
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Table 2: Univariable analysis of hospital death following first stage single ventricle palliation in neonates
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with heterotaxy. Odds Ratio
95% CI
Prematurity
0.68
(0.17 – 2.77)
0.589
Weight ≤ 2.5 kg Right atrial isomerism Dominant ventricle Left vs. right
0.93 1.77
(0.22 – 3.89) (0.50 – 6.34)
0.922 0.378
3.06
(0.77 – 12.10)
0.112
Both vs. right
1.72
(0.40 – 7.50)
0.468
TAPVC Obstructed TAPVC
2.52 3.76
(0.76 – 8.41) (0.85 – 16.54)
0.133 0.080
Pulmonary valve Stenosis vs. unobstructed Atresia vs. unobstructed Concomitant TAPVC First palliative surgery type Band vs. shunt ECMO Use
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Unplanned reoperation
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4.31
(0.51 – 36.23)
0.179
0.68
(0.17 – 2.61)
0.576
1.0
(0.23 – 4.31)
1.00
6.15
(1.77 – 21.31)
0.004
0.93
(0.20 – 4.20)
0.921
0.93
(0.20 – 4.20)
0.921
44.6
(4.8 – 412.7)
<0.001
4.88
(1.10 – 21.57)
0.037
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P-value
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Table E1: Univariable model of overall survival following initial palliation in children with heterotaxy. Hazard Ratio
95% CI
P-value (early)
Prematurity
1.1
(0.4 – 2.8)
0.176
Weight ≤ 2.5 kg Right atrial isomerism Dominant ventricle Right vs. not Right
1.1 2.1
(0.4 – 3.0) (0.8 – 5.9)
0.202 0.146
0.70
(0.25 – 1.97)
0.501
1.20
(0.40 – 3.56)
0.746
2.2 5.6
(0.9 – 5.1) (0.8 – 41.5)
0.084 0.094
(0.7 – 6.41)
0.193
TAPVC Common atrioventricular valve Obstructed TAPVC Pulmonary valve Unobstructed vs. stenosis Unobstructed vs. atresia Concomitant TAPVC First palliative surgery type Shunt vs. Norwood ECMO Use
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Unplanned reoperation
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1.1
(0.4 – 2.7)
0.914
1.0
(0.3 – 3.2)
0.949
2.9
(1.3 – 6.7)
0.013
1.4
(0.4 – 4.1)
0.608
1.3
(0.4 – 3.8)
0.679
9.9
(4.0 – 24.2)
< 0.001
3.7
(1.5 – 9.2)
0.004
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Left vs. not left
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Risk Factor
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Table E2: Differences in patients’ characteristics, cardiac morphology and post-operative details between
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neonates with heterotaxy and single ventricle and contemporaneous neonates with other forms of single
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ventricle anomalies who underwent first stage palliation surgery. p-value
249 (60%) 3.2 (2.8 – 3.5) 54 (13%) 52 (13%) 5 (4 – 9) 51 (12.4%)
0.46 0.07 0.025 0.007 0.002 0.045
14 (24%) 29 (50%) 15 (26%)
130 (32%) 271 (66%) 12 (3%)
< 0.001
34 (59%) 12 (21%) 12 (21%) 17 (30%) 35 (60%) 9 (16%) 8 (14%)
81 (20%) 271 (66%) 61 (15%) 4 (0.1%) 286 (70%) 45 (11%) 43 (10%)
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32 (55%) 3.0 (2.6 – 3.4) 14 (24%) 15 (26%) 8 (5 – 21) 2 (3.5%)
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Patients’ characteristics Male gender, N (%) Weight (kg), median (25th – 75th) Weight ≤ 2.5 kg, N (%) Prematurity, N (%) Age (days), median (25th – 75th) Chromosomal or Extra-Cardiac Anomaly Dominant ventricle morphology, N (%) (n = 478) Left ventricle Right ventricle Both ventricles Operative and post-operative details First palliative surgery type, N (%) Modified Blalock-Taussig shunt Norwood Pulmonary artery band Concomitant TAPVC repair, N (%) Cardiopulmonary bypass use, N (%) Unplanned reoperation, N (%) ECMO requirement, N (%)
Non-heterotaxy (N = 413)
RI PT
Heterotaxy (N = 58)
<0.001 < 0.001 0.17 0.30 0.44
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Table 3: Comparison between neonates with heterotaxy and single ventricle and a matched
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contemporaneous control group of neonates with other forms of single ventricle anomalies who
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underwent first stage palliation surgery. Group Non-heterotaxy (N = 52)
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22 (42%) 21 (41%) 9 (17%)
Heterotaxy (N = 52)
SMD1
P –value
30 (42%) 8 (5 – 19) 3.0 (2.6 – 3.4) 10 (19%) 11 (21%)
-0.12 0.12 -0.06 0.00 -0.05
0.55 0.55 0.78 1.00 0.81
28 (54%) 12 (23%) 12 (23%)
0.38
0.17
0.19
0.33
0.15
0.43
0.46 0.48 0.58 0.19 0.12 0.32
0.022 0.018 0.007 0.028 0.54 0.11
SC
33 (64%) 7 (4 – 15) 3.2 (2.7 – 3.5) 10 (19%) 12 (23%)
21 (40%) 31 (60%) 26 (50%)
26 (50%) 26 (50%) 30 (58%)
5 (10%) 16 (12 – 24) 154 (98 – 286) 102 (54 – 243) 5 (10%) 3 (6%)
14 (27%) 24 (14 – 41) 269 (158 – 636) 185 (74 – 475) 7 (14%) 8 (15%)
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Matched Variables Gender- Male Age (Days), median (25th – 75th) Weight (kg), median (25th – 75th) Weight ≤ 2.5 (kg), N (%) Premature (< 36 weeks), N (%) First Palliation Type, N (%) Modified Blalock-Taussig shunt Norwood Pulmonary artery band Dominant Ventricle Right Left or both Cardiopulmonary bypass use, N (%) Outcomes Hospital Death, N (%) Length of Stay (days), median (25th – 75th) ICU Length of Stay (hours), median (25th – 75th) Ventilator Duration (hours), median (25th – 75th) Reoperation, N (%) ECMO Use, N (%)
RI PT
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Figures Legends:
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Figure-1:
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Competing risks analysis of outcomes after first stage palliation surgery in 58 neonates with heterotaxy.
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The solid lines represent parametric point estimates and the dashed lines enclose the 95% confidence
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interval.
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a- Competing hazard functions for each outcome.
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b- Proportion of neonates in each of the categories at any given time after first stage surgery.
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Proportion of patients without the Fontan operation over time following Glenn in 49 infants with
493
heterotaxy (a) and the hazard for the Fontan operation (b). The solid lines represent parametric point
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estimates and the dashed lines enclose the 95% confidence interval. Circles represent non-parametric
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estimates.
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Figure-E2:
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Time-dependent survival (a) and risk hazard of death (b) over time following initial palliation surgery in
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67 infants with heterotaxy. The solid lines in the parametric model represent parametric point estimates
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and the dashed lines enclose the 95% confidence interval. Circles represent non-parametric estimates.
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Figure-2:
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Parametric model for survival following initial palliation surgery in 67 infants with heterotaxy stratified
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by the need for concomitant TAPVC repair.
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Figure-3:
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Competing risks depiction of events following first stage palliation in neonates with heterotaxy and a
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matched control group of neonates without heterotaxy with other forms of single ventricle anomalies.
509 Figure-4:
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Time-dependent survival (a) and risk hazard of death (b) over time following first stage palliation in
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neonates with heterotaxy and a matched control group of neonates without heterotaxy with other forms of
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single ventricle anomalies.
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