Impact of the Evolution of the Fontan Operation on Early and Late Mortality: A Single-Center Experience of 405 Patients Over 3 Decades

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Impact of the Evolution of the Fontan Operation onEarly and Late Mortality: A Single-CenterExperience of 405 Patients Over 3 DecadesHideo Ohuchi, MD, PhD, Koji Kagisaki, MD, Aya Miyazaki, MD, Masataka Kitano, MD,Satoshi Yazaki, MD, Heima Sakaguchi, MD, PhD, Hajime Ichikawa, MD, PhD,Osamu Yamada, MD, and Toshikatsu Yagihara, MD, PhD
Departments of Pediatric Cardiology and Thoracic Surgery, National Cerebral and Cardiovascular Center, Osaka, Japan
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Background. Postoperative mortality has decreased inatients undergoing the Fontan operation, and the deter-inants of such mortality may also have changed

ignificantly.Methods. We conducted a study intended to focus on

larifying the determinants of mortality in 405 consecu-ive patients who had undergone a Fontan operation (62atients after an atriopulmonary connection, 105 after an

ntra-atrial rerouting, and 238 patients after an extracar-iac rerouting) between 1979 and 2010.Results. The overall 1-year, 5-year, 10-year, and 15-year

ates of survival were 87.1%, 84.6%, 83.4%, and 81.6%,espectively, and the type of procedure as well as hetero-axy syndrome, ventricular ejection fraction, and atrio-entricular valve repair at the time of the Fontan opera-ion were independent predictors of overall mortalityp < 0.05 for all). Heterotaxy syndrome and atrioventric-lar (AV) valve repair were independent predictors of
arly (less than 6 months postoperative) mortality and
jishiro-dai, Suita, Osaka 565-8565, Japan; e-mail: [email protected].

© 2011 by The Society of Thoracic SurgeonsPublished by Elsevier Inc

he type of procedure was an independent predictor ofate (6 or more months postoperative) mortality (p < 0.05o 0.01). In the era of intra-atrial rerouting, heterotaxyyndrome was the only independent predictor of total,arly, and late mortality (p < 0.05 for all), whereas a lowjection fraction, AV valve repair, and repair of a totalnomalous pulmonary vein connection, rather than het-rotaxy syndrome, were independent predictors of totalr early mortality or both (p < 0.05 for all) in the era ofxtracardiac rerouting.Conclusions. Even in the modern era of extracardiac

erouting in the Fontan operation, a low ventricularjection fraction, AV valve dysfunction, or a total anom-lous pulmonary vein connection remain significant riskactors for mortality in patients with a single-ventriclehysiology.

(Ann Thorac Surg 2011;92:1457–67)
© 2011 by The Society of Thoracic Surgeons
In 1992, Driscoll and colleagues reported the compre-hensive clinical profiles, including the early and late

mortality, of 352 patients who had undergone a Fontanoperation with an atriopulmonary connection (APC), anddemonstrated that only one third showed significantclinical improvement and that another one third diedwithin 5 years after having the operation. On the basis ofthose results, Driscoll and colleagues emphasized theimportance of the selection criteria for the operation [1].However, remarkable improvements in the Fontan pro-cedure have been introduced since the initial report of itsuse, such as the introduction of the total cavopulmonaryconnection through intra-atrial rerouting (IAR) in 1988 byde Leval and associates [2], a staged approach with aGlenn anastomosis in 1989 [3], and the version of extra-cardiac rerouting (ECR) introduced by Marcelletti and

Accepted for publication May 9, 2011.

Address correspondence to Dr Ohuchi, Department of Pediatric Car-diology, National Cerebral and Cardiovascular Center, 5-7-1, Fu-

coworkers in 1990 [4]. In addition to the baffle fenestra-tion introduced in the 1990s [5], postoperative manage-ment with nitric oxide has made a significant positivecontribution to the reduction in mortality among patientsundergoing the Fontan procedure [6]. The current trendtoward early surgical intervention with the goal of earlyvolume reduction of the systemic ventricle (SV), and theevolution in the decade after 2000 of pharmacotherapyfor the pulmonary circulation [7], may also have contrib-uted significantly to the recent low postoperative mortal-ity among patients undergoing the Fontan procedure. Asa result, the classic recommendations for the operationmade by Choussat and associates [8] may no longer besuitable for ECR in the current era of the Fontan proce-dure [9], and the clinically relevant determinants ofmortality after the procedure may and seemingly shouldhave changed over the course of time. Accordingly, weconducted a study to clarify changes in the clinicaldeterminants of total, early, and late mortality after theFontan operation on the basis of the type of Fontanprocedure used. Although we were also aware of theimportance of postoperative morbidity, such as arrhyth-
mias, in patients undergoing the procedure, we focused
0003-4975/$36.00doi:10.1016/j.athoracsur.2011.05.055

mailto:[email protected]

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1458 OHUCHI ET AL Ann Thorac SurgEVOLUTION OF THE FONTAN OPERATION 2011;92:1457–67

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on the mortality-related issues in the study partly be-cause of limitations in time and the scope of reporting.

Patients and Methods

SubjectsWe retrospectively reviewed a total of 405 consecutivepatients (245 males and 160 females) with congenitalheart disease who had undergone a Fontan operationbetween October 1979 and May 2010 (Table 1), and forwhom the last follow-up visit took place at the end ofDecember 2010. The morphology of the patients’ SVs wascategorized into three groups based on the dominantventricle, as previously described [10]. A left ventricular(LV) type SV was present in 159 patients, a biventriculartype SV in 72, and a right ventricular (RV) type SV in 174.The major cardiac diagnoses were a univentricular heartin 109 patients, followed by tricuspid atresia, double

Table 1. Patient Characteristics

Total

—(1979–2009)

n 405Age at Fontan operation (years) 4.9 � 5.2SV type (LV/BV/RV) 159/72/174Diagnosis

Heterotaxy 136UVH 109TA 85DORV 67MA 39CAVC 38PA 28HLHS 14Others 25

Type of repairAPC 62IAR 105ECR 238

Previous or additional procedures attime of Fontan operation

APS 225PAB 97Glenn 201AVVP 71DKS 41TAPVC repair 21Coil embolization for collaterals 146Fenestration 37

Values are mean � SD.

APC � atriopulmonary connection; APS � aortopulmonary shunt;common atrioventricular canal; DORV � double-outlet right ventricle

LHS � hypolastic left heart syndrome; IAR � intra-atrial rerouting
valve atresia; PAB � pulmonary artery banding; RV � right ventricle;otal anomalous pulmonary vein connection; UVH � univentricular heart.
outlet right ventricle, mitral atresia, atrioventricular (AV)septal defect, pulmonary valve atresia, hypoplastic leftheart, and other, less frequent diagnoses. Among all 405patients in the study, heterotaxy syndrome (HS) and acommon AV valve were seen in 136 (33.6%) and 119patients (29.4%), respectively.

We observed a significant transition in the type ofFontan operation, from an APC- to an ECR- through anIAR-type operation, in the patients enrolled in our studyaccording to the time at which the procedure was done,and our current procedure is an ECR-type Fontan oper-ation. Of the patients with an ECR-type procedure, 126(52.9%) underwent the ECR in an off-pump fashion. Thenumber of surgical procedures per patient, includingpalliative ones, ranged from 1 to 7, and a primary Fontanoperation was performed in 62 patients. Among thepatients’ palliative pre-Fontan procedures, the majorprocedure was the creation of an aortopulmonary shunt,

Era of First FontanOperation

1980s 1990s 2000s(1979–1989) (1990–1999) (2000–2010)

67 164 1746.9 � 5.0 5.1 � 5.3 3.8 � 5.137/8/22 56/24/84 66/40/68

20 (30%) 69 (42%) 47 (27%)17 60 3227 28 305 31 314 18 177 11 204 5 190 4 103 7 15

52 10 015 86 40 68 170

44 87 942 36 596 52 1434 30 370 12 292 11 87 43 960 19 18

VP � atrioventricular valvuloplasty; BV � biventricle; CAVC �KS � Damus-Kay-Stansel procedure; ECR � extracardiac rerouting;

LV � left ventricle; MA � mitral valve atresia; PA � pulmonary

AV; D;

SV � single ventricle; TA � tricuspid valve atresia; TAPVC �

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1459Ann Thorac Surg OHUCHI ET AL2011;92:1457–67 EVOLUTION OF THE FONTAN OPERATION

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such as a Blalock-Taussig (BT) shunt, in 55.6% of thepatients, followed by a Glenn anastomosis in 49.6%, coilembolization for minimizing aortopulmonary collateralflow in 36.0%, pulmonary artery banding, and atrioven-tricular valve repair (AVVR), including the use of amechanical AV valve replacement, in the remainingpatients. This study protocol was approved by the EthicsCommittee of the National Cerebral and CardiovascularCenter.

Definition of Early and Late Postoperative MortalityBecause the postoperative mortality was high at 6 monthsafter the operation [1, 11], and it might not have beenvery difficult to prolong patients’ lives with currentlyused advanced intensive care procedures through a de-vice system that might have obscured early mortality, wedefined early mortality as death at less than 6 monthspostoperatively and late mortality as death beyond 6months postoperatively.

Clinical VariablesThe clinical variables included the era in which thepatient’s Fontan operation was done (1980s, 1990s, and2000s), as well as the type of Fontan operation (APC, IAR,and ECR), age of the patient at the time of the first Fontanoperation, SV morphology (LV, biventricular, and RV),HS, preoperative SV function, mean pulmonary arterypressure, fenestration at the time of the Fontan operation,Glenn anastomosis done before the Fontan operation(staged strategy), AVVR at the time of the Fontan oper-ation, and repair of a total anomalous pulmonary veinconnection (TAPVC) before or at the time of the Fontanoperation.

Systemic Ventricular Function and HemodynamicsCardiac catheterization in patients under 12 years of agehad been performed 0.4 � 0.5 years before the operation

nder light sedation with pethidine and promethazineydrochlorides. Patients 12 years of age or older wereedated with oral pentobarbital calcium. With regard toV morphology, the groups categorized as having aorphology of the LV or non-LV type were used to

etermine the major factors associated with the cardiacjection fraction (EF). The measures of SV function usedn the study included the EF, end-diastolic volume di-ided by the body surface area (EVDI), and end-diastolicressure (EDP). The SV volumes were estimated withimpson’s rule on the basis of cine ventriculography, ase previously described [10]. We excluded the size of theulmonary artery as a variable because the currenttrategy for the staged Glenn anastomosis made it diffi-ult to accurately measure the diameter of the anasto-osed pulmonary artery. It was also difficult to accu-

ately estimate the resistance of the pulmonary arteryecause of the absence of a ventricle that mixes theystemic venous return as well as the possible existencef venovenous collateral vessels [12].Our traditional policy of treating AV valvular regurgi-

ation was based on the grade of regurgitation. If the
atient had moderate or greater AV valvular regurgita-
ion, repair was performed at the time of the Fontanperation. The severity of AV valvular regurgitation wasstimated by Doppler color flow mapping and wasraded as none to mild, moderate, and severe. A grade ofild implied that the AV valvular regurgitation jet

rossed less than two-thirds of the systemic atrium; arade of moderate implied that it reached beyond two-hirds of the systemic atrium; and a grade of severemplied that the jet reached the posterior wall of thetrium at a significant width.

Statistical AnalysisThe study data are expressed as mean � standard devi-ation. We used a univariate Cox proportional hazardsmodel to predict the associations of the clinical factorswith mortality (ie, the era in which the Fontan operationwas performed), the patient’s age at the time of the firstFontan operation, the type of Fontan operation per-formed (APC, IAR, ECR), fenestration, HS, type of SVmorphology (RV, biventricular, LV), cardiac function andhemodynamics (EF, EDVI, EDP, and pulmonary arterypressure), and previous or additional procedures or both(AVVR, TAPVC repair, or Glenn procedure before theFontan operation). In the patients with an ECR-typeoperation, an off-pump procedure was also included inthe clinical factors in the proportional hazards model.The variables that proved to be significant predictors ofoutcome in the univariate analysis (p � 0.05) wereincluded in the multivariate analysis done with the Coxregression model to determine any independent pre-dictors of overall and late mortality with a hazard ratio(HR) and 95% confidence interval (CI). A multivariatelogistic regression model was used to identify theindependent predictors of early mortality with an ORand 95% CI. The status of a variable as being indepen-dent of the overall and late mortality was estimatedwith the Kaplan-Meier method, and the differences inthe study groups’ event-free status were assessed withlog-rank tests. A value of p � 0.05 was consideredstatistically significant (Stat-View 5.0; Abacus Con-cepts, Berkeley, CA).

Results

The clinical profiles based on the era in which the Fontanoperation was done are summarized in Table 1.

Era and Fontan OperationThe age of patients at the time of the Fontan operationdecreased steadily despite a lack of change in the com-plexity of their disease, such as in the percentage ofpatients with a univentricular heart, HS, or both.

Type of Fontan Operation and Additional ProceduresAs in many other institutions, our current strategy for theFontan operation consists of performing the final ECRafter a staged Glenn anastomosis followed by a coilembolization to diminish any aortopulmonary collateralflow. Some patients required a Damus-Kay-Stansel pro-
cedure for preventing future subaortic stenosis. Although

Table 2. Univariate and Multivariate Predictors of Overall, Early, and Late Mortality in all Patients After the Fontan Operation

All(n � 405)

All(n � 405)

All(n � 360)

Total MortalityEarly Mortality

(�30 days)Early Mortality

(�6 months)Late Mortality(�6 months)

Variables HR 95% CI p Value OR 95% CI p Value OR 95% CI p Value HR 95% CI p Value

Univariate analysisEra of Fontan

operation vs2000s

1980s 7.11 3.61–14.01 �0.0001 0.02 0.00–0.15 0.0002 11.66 4.69–29.04 �0.0001 3.43 1.07–11.06 0.03891990s 2.32 1.18–4.58 0.0149 0.13 0.02–1.07 0.0573 4.52 2.19–9.34 �0.0001 1.85 0.63–5.40 0.2606

Type of repair vs ECRAPC 6.03 3.33–10.91 �0.0001 0.05 0.01–0.18 �0.0001 8.32 3.77–18.39 �0.0001 4.14 1.46–11.75 0.0077IAR 2.75 1.50–5.03 0.0010 0.20 0.33–1.27 0.0884 1.82 0.49–6.82 0.3727 2.53 0.94–6.77 0.0657

Age at time of firstFontan operation

1.03 0.99–1.07 0.0552 0.95 0.90–1.01 0.1200 1.06 1.01–1.11 0.0179 1.00 0.92–1.08 0.9122

Fenestration 0.79 0.32–1.97 0.6149 0.94 0.21–4.20 0.9399 0.97 0.33–2.87 0.9514 0.46 0.06–3.44 0.4523Heterotaxy syndrome 2.44 1.54–3.88 0.0002 2.74 1.17–6.42 0.0205 3.11 1.65–5.86 0.0004 1.87 0.87–3.99 0.1081Type of SV vs LV

BV 1.22 0.61–2.45 0.5789 0.62 0.19–2.02 0.4239 1.12 0.43–2.89 0.8224 1.40 0.47–4.17 0.5436RV 1.55 0.92–2.60 0.0964 0.68 0.26–1.81 0.4415 1.66 0.83–3.33 0.1558 1.44 0.62–3.34 0.3914

EF 0.97 0.95–0.99 0.0085 1.04 1.00–1.10 0.0812 0.96 0.93–0.99 0.0222 0.98 0.94–1.01 0.1747EDVI 1.01 1.00–1.02 0.0006 0.99 0.98–1.00 0.0049 1.01 1.00–1.02 0.0049 1.01 1.00–1.02 0.0872EDP 0.94 0.87–1.02 0.1399 1.22 1.03–1.43 0.0183 0.90 0.80–1.01 0.0644 1.00 0.89–1.12 0.9639PAP 1.01 0.96–1.07 0.6830 1.02 0.92–1.14 0.7100 1.03 0.96–1.11 0.3801 1.00 1.00–1.00 0.3521AVVR at time of

Fontan operation2.38 1.38–4.10 0.0018 3.28 1.28–8.40 0.0135 2.91 1.39–6.09 0.0046 1.92 0.73–5.09 0.1873

TAPVC repair 2.67 1.28–5.57 0.0089 3.03 0.83–11.16 0.0950 2.69 0.94–7.73 0.0666 3.16 0.95–10.52 0.0606Staged Glenn

procedure0.35 0.20–0.59 0.0001 0.14 0.04–0.48 0.0017 0.25 0.12–0.53 0.0002 0.53 0.23–1.24 0.1433

Multivariate analysis (n � 388) (n � 388) (n � 389) (n � 360)Type of repair vs ECR

APC 3.89 1.24–12.20 0.0196 0.05 0.00–1.31 0.0724 — — — 3.95 0.75–20.75 0.1047IAR 1.25 0.54–2.92 0.6072 — — —

Heterotaxy syndrome 2.27 1.14–4.51 0.0192 — — — 3.06 1.18–7.96 0.0218 — — —EF 0.97 0.94–0.99 0.0155 — — — 0.97 0.93–1.01 0.0857 — — —AVVR at Fontan

operation2.74 1.39–5.40 0.0035 9.74 2.43–39.12 0.0013 4.48 1.76–11.42 0.0017 — — —

APC � atriopulmonary connection; AVVR � atrioventricular valve repair; BV � bivalvular; CI � confidence interval; ECR � extracardiac rerouting; EDP � end-diastolic pressure;EDVI � end-diastolic volume index; EF � ejection fraction; HR � hazard ratio; IAR � intra-atrial rerouting; LV � left ventricle; OR � odds ratio; PAP � mean pulmonary arterypressure; RV � right ventricle; SV � single ventricle; TAPVC � total anomalous pulmonary vein connection.

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the prevalence of a TAPVC repair has remained constant,that of AVVR has slightly increased.

Mortality and Mode of DeathDuring a mean follow up of 9.9 � 7.0 years (median,9.1years, range, 0 to 31.3 years), 74 patients (18.3%) died. Ofthese, 45 patients died at less than 6 months after theFontan operation, and 23 of these 45 early deaths occurredat less than 30 days after the operation. Twenty-nine pa-tients died at 6 months or more after the operation. Thereasons for the deaths in both groups were a postoperativelow cardiac output syndrome in 30 patients, heart failure in18 patients, arrhythmias in 10 patients, hematologic eventssuch as bleeding in 6 patients, infection and sudden deathin 3 patients each, a protein-losing enteropathy in 2 pa-tients, and an unknown cause in 2 patients. The reasons forthe 29 late deaths were heart failure in 14 patients,arrhythmias in 5 patients, hematologic events and sud-den death in 3 patients each, infection in 2 patients, anda protein-losing enteropathy and unknown cause ofdeath in 1 patient each.

Predictors of Overall Mortality in All Fontan GroupsTable 2 summarizes the predictors of overall, early, and latemortality in all of the patients who had Fontan procedures.

Fig 1. (a) The Kaplan-Meier survival-rate curves for all types of Foning [IAR], and extracardiac rerouting [ECR]. (b) Curves for patients wquired atrioventricular valve repair (AVVR) at the time of the Fontanoperation) in patients with atriopulmonary connection, intra-atrial re
fidence intervals.
In the case of overall mortality, the era of the operation, typeof procedure (Fig 1a), HS (Fig 1b), SV function, and addi-tional surgical procedures, such as AVVR (Fig 1c), wereassociated with mortality. Of these factors, the type ofprocedure, HS, EF, and AVVR were independent predictorsof mortality. Pulmonary artery pressure was not a predictorof mortality. In the case of early mortality, the univariatelogistic regression model revealed that the era and patient’sage at the time of the first Fontan operation, type ofprocedure, HS, SV function, AVVR, and staged Glennanastomosis were associated with mortality. According tothe multivariate logistic regression model, HS and AVVRwere independent predictors of mortality. In the case of latemortality, the era and type of Fontan operation (Fig 1d)predicted mortality, and none of these variables were theindependent predictors of mortality. Tables 3, 4, and 5summarize the predictors of overall, early, and late mortal-ity in the patients who had APC-type, IAR-type, and ECR-type Fontan operations, respectively.

Predictors of Overall Mortality in Patients With APCOperationsIn patients who had an APC-type Fontan operation, HS,EDVI, and AVVR were the predictors of overall mortality.

erations (ie, atriopulmonary connection [APC], intra-atrial rerout-nd without heterotaxy syndrome. (c) Curves for patients who re-ation. (d) Curves for late survivors (6 or more months after Fontang, and extracardiac rerouting. The vertical bars represent 95% con-

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Of these, EDVI and AVVR were independent predictorsof mortality.

Heterotaxy syndrome and EDVI were the only predic-tors of early and late mortality, respectively.

Predictors of Overall Mortality in IAR PatientsIn patients who had an IAR-type Fontan operation, HS,AVVR, and TAPVC repair were the predictors of overallmortality. Of these, HS was an independent predictor ofmortality, and was the only independent predictor ofboth early and late mortality.

Predictors of Overall Mortality in ECR PatientsIn patients who had an ECR-type Fontan operation, asfor the total mortality, EF and TAPVC repair wereindependent predictors of overall mortality, and HS wasnot associated with mortality. Both EF and AVVR wereindependent predictors of early mortality. However, novariables, including off-pump procedures, were associ-ated with late mortality in this group. Impacts of theTAPVC repair, AVVR at the time of Fontan operation,and low EF (�0.58) on the total mortality are shown inFigures 2a–c.

Impact of HS on Type of Fontan OperationAn adverse effect of HS on each type of Fontan procedureis shown in Figures 3a–c, and this effect decreased

Table 3. Univariate and Multivariate Predictors of the Overal

Total Mortality

ariables HR 95% CI p Value

nivariate AnalysisAge at time of first Fontan

operation1.02 0.96–1.10 0.4999

Heterotaxy syndrome 6.02 2.43–14.88 0.0001Type of SV vs LV

BV 2.23 0.81–6.14 0.1202RV 1.51 0.64–3.54 0.3439

EF 0.95 0.90–1.00 0.0678EDVI 1.01 1.00–1.02 0.0107EDP 0.92 0.80–1.06 0.2341PAP 1.02 0.95–1.09 0.5988AVVR at Fontan operation 6.23 1.71–22.74 0.0056Staged Glenn procedure 1.12 0.34–3.73 0.8566ultivariate analysisHeterotaxy syndrome — — —EDVI 1.01 1.00–1.02 0.0052AVVR before/at time of

Fontan operation30.61 4.10–228.8 0.0009

APC � atriopulmonary connection; AVVR � atrioventricular valve repressure; EDVI � end-diastolic volume index; EF � ejection fractionean pulmonary artery pressure; RV � right ventricle; SV � sing

ramatically over the successive eras of the operation.

Determinants of EF Before ECRWe attempted to clarify the factors determining thepreoperative EF because this variable was relevant to theoverall and early mortality in the group that had ECR-type Fontan operations. We found that EF was inverselycorrelated with age at the time of the first Fontan oper-ation (r � –0.213, p � 0.001). Also associated with a low EFwere HS (HS: EF � 54 � 11%, non-HS: EF � 0.59 � 9,p � 0.0001), a non-LV SV morphology (LV: EF � 0.62 � 8,non-LV: EF � 55 � 10%, p � 0.0001), and a fenestration(fenestration: EF � 54 � 11%, non-fenestration: EF � 0.58 �0, p � 0.0179). Of these, the multivariate regression model

reviealed that a late Fontan operation (p � 0.001), HS (p �0.013) and a non-LV SV morphology (p � 0.0001) wereindependently associated with a low EF.

Comment

The present study clearly confirmed that the latestmodification of the Fontan operation, the ECR-typeFontan procedure, reduced overall, early, and latepostoperative mortality in patients who had undergonethe operation, and that the survival of patients with HShad improved considerably from the era of the firstFontan procedure, with HS ceasing to be an indepen-dent risk factor for mortality in the era of the ECR-typeFontan procedure. Instead, impaired SV function as

rly, and Late Mortality After APC-Type Fontan Operation

APC (n � 62)

Early Mortality(�6 months)

Late Mortality(�6 months)

95% CI p Value HR 95% CI p Value

7 0.96–1.19 0.2517 0.98 0.84–1.14 0.7488

5 3.44–270.89 0.0021 — — —

0 0.47–13.31 0.2828 2.47 0.50–12.23 0.26919 0.75–8.93 0.1312 0.49 0.06–4.04 0.51084 0.86–1.03 0.2124 0.94 0.87–1.03 0.17181 0.99–1.03 0.1949 1.02 1.00–1.03 0.01700 0.64–1.01 0.0608 1.03 0.84–1.28 0.75682 0.93–1.13 0.6443 1.02 0.92–1.14 0.6847

— — — — —4 0.6–5.20 0.5951 2.01 0.41–9.77 0.3895

5 3.44–270.89 0.0021 — — —— — 1.02 1.00–1.03 0.0170— — — — —

BV � bivalvular; CI � confidence interval; EDP � end-diastolicHR � hazard ratio; LV � left ventricle; OR � odds ratio; PAP �ntricle.

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important risk factors for mortality in patients under-going the operation, and that more effort is requiredtoward reducing their effect and producing a betteroutcome in patients with an SV physiology who havethese risk factors. With further regard to the determi-nants of SV function, a non-LV type SV morphologyand the presence of HS may be becoming more signif-icant risk factors in the era of the ECR-type Fontanprocedure with a strategy of early SV volume loadreduction, although in our study these variables werenot independent risk factors for mortality.

Reducing Early and Late MortalityEvery leading institute has reported recently improvedsurvival after the Fontan operation (13–15). In the era ofthe APC-type Fontan procedure, the 1-year, 5-year, 10-year, and 15-year survival rates were 66%, 62%, 58%, and56%, respectively, which much lower than the rates in theinitial report of the “ideal” patients for the Fontan pro-cedure [9], indicating inappropriate selection of the op-

ration, inadequate experience with it, or both. However,s with many other institutions, we found that modifica-ions of the Fontan procedure with IAR and ECR dramat-cally improved patient survival (Fig 1A). With these

modifications, the 1-year, 5-year, 10-year, and 15-yearsurvival rates rose to 94%, 92%, 92%, and 92%, respec-tively, which were equivalent to of the rates reported byGiannico and colleagues and Kim and associates [16, 17].

Table 4. Univariate and Multivariate Predictors of Overall, E

Total Mortality


nivariate analysisAge at time of first Fontan

operation1.00 0.91–1.10 0.9608

Fenestration 2.97 0.69–12.75 0.1430Heterotaxy syndrome 4.95 1.70–14.46 0.0034Type of SV vs LV

BV 1.37 0.31–6.13 0.6795RV 2.33 0.79–6.90 0.1264

EF 0.99 0.95–1.03 0.4714EDVI 1.00 0.99–1.01 0.6714EDP 0.98 0.87–1.10 0.7157PAP 1.02 0.92–1.14 0.6523AVVR at time of Fontan

operation2.84 1.25–6.43 0.0126

TAPVC repair 3.30 1.23–8.84 0.0175Staged Glenn procedure 0.41 0.12–1.38 0.1501ultivariate analysisHeterotaxy syndrome 3.94 1.28–12.13 0.0169

AVVR � atrioventricular valve repair; BV � bivalvular; CI � convolume index; EF � ejection fraction; HR � hazard radio; IARmean pulmonary artery pressure; RV � right ventricle; SV � sing

urprisingly, no deaths were reported among patients

undergoing the ECR-type procedure in d’Udekem’s se-ries, although the number of patients was relatively small[15]. The recent evolution of modifications of the Fontanprocedure has definitely improved the postoperativesurvival of patients with an SV physiology. However, theevidence for an excellent outcome with the IAR-typemodification implies that other important risk factors formortality exist among patients undergoing the Fontanoperation[18].

Risk Factors for Early Mortality Other Than Type ofRepairThe presence of HS has been widely recognized as animportant postoperative risk factor in patients undergo-ing the Fontan operation [1, 14, 19, 20]. Among the mainreasons for the high mortality rate in patients with HSmay be the complexity of the combined cardiac structuralanomalies in such patients, such as an RV-type SVmorphology, a common AV valve, TAPVC, and an intrin-sic susceptibility to arrhythmias [21], all of which havebeen considered as risk factors doe mortality. In our 136patients with HS, a non-LV type SV morphology, com-mon AV valve, and TAPVC were present in 119 patients(87.5%), 104 patients (76.5%), and 26 patients (19.1%),respectively, and these prevalence rates were signifi-cantly greater than those in patients without HS, inwhom the corresponding percentages were 52.8%, 5.6%,and 0%, respectively. However, HS itself was not a

and Late Mortality After IAR-Type Fontan Operation

IAR (n � 105)




2 0.89–1.18 0.7630 0.98 0.83–1.16 0.8186

9 0.74–32.31 0.0995 — — —2 1.19–26.53 0.0293 4.96 1.07–23.02 0.0407

0 0.47–13.31 0.2828 1.95 0.12–31.27 0.63629 0.75–8.93 0.1312 5.21 0.66–41.23 0.11750 0.94–1.06 0.9680 0.97 0.92–1.03 0.34811 0.99–1.02 0.3133 1.00 0.98–1.01 0.69683 0.78–1.12 0.4691 1.02 0.87–1.20 0.79887 0.93–1.22 0.3445 0.95 0.81–1.13 0.57612 0.83–9.59 0.0979 3.22 0.94–11.05 0.0625

7 0.74–14.54 0.1192 3.40 0.73–15.88 0.12032 0.03–1.73 0.1485 0.67 0.15–3.11 0.6099

2 1.19–26.53 0.0293 4.96 1.07–23.02 0.0407

ce interval; EDP � end-diastolic pressure; EDVI � end-diastolicra-atrial rerouting; LV � left ventricle; OR � odds ratio; PAP �ntricle; TAPVC � total anomalous pulmonary vein connection.

arly,

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sions, such as an AVVR or TAPVC repair, emerged asimportant risk factors from within the ambiguous patho-physiology of HS. Interestingly, a history of AVVR beforethe Fontan operation had no significant adverse effect on

Fig 2. Effect of (a) repair of a total anomalous pulmonary vein conneof the Fontan operation, and (c) of a low ejection fraction (EF) of thewith a Fontan operation done with extracardiac rerouting (ECR) (c) w

Table 5. Univariate and Multivariate Predictors of Overall, E

Total Mortality


nivariate AnalysisAge at time of first Fontan

operation1.03 0.97–1.09 0.3063

Off-pump 0.50 0.20–1.26 0.1389Fenestration 1.19 0.35–4.07 0.7857Heterotaxy 2.30 0.94–5.67 0.0693Type of SV vs LV

BV 1.88 0.47–7.53 0.3709RV 2.71 0.86–8.51 0.0878

EF 0.96 0.93–1.00 0.0312EDVI 1.01 0.99–1.02 0.3073EDP 1.05 0.90–1.22 0.5749PAP 1.01 0.90–1.13 0.8260AVVR repair at Fontan 2.74 0.99–7.60 0.0533TAPVC repair 4.18 1.22–14.36 0.0231Staged Glenn procedure 0.67 0.26–1.70 0.3958ultivariate AnalysisEF 0.96 0.92–1.00 0.0305AVVR at time of Fontan

operation— — —

TAPVC repair 4.27 1.24–14.72 0.0214

AVVR � atrioventricular valve repair; BV � bivalvular; CI � copressure; EDVI � end-diastolic volume index; EF � ejection fractionmean pulmonary artery pressure; RV � right ventricle; SV � single

ejection fraction. The vertical bars represent 95% confidence intervals.

mortality, implying the importance of better control ofthe AV valvular regurgitation before the Fontan opera-tion in controlling the mortality associated with it. Incontrast, patients with an SV physiology who required a

(TAPVC) and (b) atrioventricular valve repair (AVVR) at the timemic ventricle inpatients with a Fontan operation with. The patientsivided into two groups according to the median value (0.57) of their

and Late Mortality After ECR-Type Fontan Operation

ECR (n � 238)




5 0.98–1,12 0.1581 0.98 0.82–1.16 0.7687

4 0.13–1.51 0.1923 0.61 0.14–2.74 0.52061 0.27–6.26 0.7378 1.05 0.13–8.69 0.96725 0.82–8.51 0.1028 1.99 0.45–8.90 0.3670

2 0.26–14.03 0.5226 1.87 0.26–13.29 0.53085 0.84–19.58 0.0824 1.50 0.25–9.00 0.65484 0.89–0.99 0.0135 1.00 0.93–1.07 0.91161 0.99–1.02 0.3841 1.00 0.98–1.03 0.72299 0.89–1.32 0.4021 0.99 0.81–1.20 0.89363 0.89–1.19 0.7063 0.99 0.81–1.20 0.89362 1.13–14.32 0.0318 1.32 0.16–10.93 0.79982 0.92–25.32 0.0629 4.36 0.52–36.20 0.17317 0.23–2.66 0.6828 0.53 0.12–2.36 0.4023

4 0.89–0.99 0.0174 — — —1 1.01–13.61 0.0482 — — —

— — — — —

ce interval; ECR � extracardiac rerouting; EDP � end-diastolicR � hazard radio; LV � left ventricle; OR � odds ratio; PAP �

icle; TAPVC � total anomalous pulmonary vein connection.

ctionsysteere d

arly,

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1.0

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1.94.00.91.01.01.04.04.80.7

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TAPVC repair remained as challenges in completing theFontan circulation even in the era of ECR [22].

In the present study, pulmonary artery pressure wasnot a risk factor for mortality, which may contradict theresults of previous reports [13, 17, 20]. However, asO’Brien and colleagues mentioned, our recent exclusionfrom Fontan surgery of patients with a high pulmonaryartery pressure may be partly responsible for our results[23]. In addition, the possible influence on pulmonaryartery pressure of developed venovenous collateral vesselsafter the staged Glenn strategy [12], as well as of aortopul-monary collaterals, may obscure an association betweenpulmonary artery pressure and mortality. Recent advancesin pharmacologic agents for the pulmonary circulation [6]

ay also be responsible for the lack of an associationetween pulmonary artery pressure and mortality.Impaired SV function, as estimated by a low EF,

merged as an important risk factor for overall and earlyortality in the era of the ECR-type Fontan procedure, as

t had been in past versions of the procedure [6]. Someeports have also specified a high EDP as one of the riskactors for mortality in the Fontan operation [1, 14]. TheDP is easily influenced by hemodynamic conditions,uch as in the case of its elevation by a high preload onhe SV in the situation of left-to-right shunting in com-lex congenital heart disease. The data from the Mayolinic study may support the concept of a greater cardio-

horacic ratio with a high EDP (greater preload on the SVefore the Fontan operation) adversely affecting the out-ome of the operation [14]. Our independent predictorsf EDVI may be consistent with the results in the era ofhe APC-type operation without a staged strategy. Inontrast, the assessment of SV function with less volumeverloading may be crucial to predicting mortality aftern ECR-type Fontan operation given that the state of SVoading also influences the EF. In this respect, the fact

Fig 3. Effect of heterotaxy syndrome on the overall survival rate in pa(b) intra-atrial rerouting (IAR), and (c) extracardiac rerouting (ECR).

hat a low EF, a non-LV type SV, and HS all indepen-

ently predicted a low EF implies an intrinsic SV func-ional abnormality in patients with HS, as well as themportance of SV morphology even in the era of theCR-type Fontan operation.Our study has several limitations. First, it was of a

etrospective nature, preventing us from demonstraing aause-effect relationship between the factors we investi-ated and the risk of mortality in patients having theontan operation. Second, the relatively small number ofatients with APC- and IAR-type Fontan procedures waslimitation in detecting independent predictors of mor-

ality. Third, the estimation of SV function with cineentriculography had certain methodologic disadvan-ages relative to more recently developed imaging mo-alities such as magnetic resonance imaging. However,

hese newer techniques were not available in the earlyistory of the Fontan procedure. A future study with new

maging modalities will be needed, and analyses of earlynd late complications, such as arrhythmias, are alsoeeded, to assess the long-term quality of life in patientsndergoing the Fontan operation.

ConclusionsMortality after the Fontan operation, and especially earlypostoperative mortality, has decreased dramatically fromwhat it had been in earlier eras of the operation, and inaccord with this the risk factors for mortality havechanged over the past three decades with the modifica-tions that have been made in the Fontan procedure.However, even in the modern era of the ECR-type Fontanprocedure, a low EF, AV valvular dysfunction, andTAPVC repair remain as significant risk factors for mor-tality. Therefore, meticulous strategies directed at pre-serving the function of the SV and AV valve may becrucial to further improving the outcome of patientsundergoing the Fontan operation in the modern era of

s with Fontan operations with (a) atriopulmonary connection (APC),ertical bars represent 95% confidence intervals.

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References

1. Driscoll DJ, Offord KP, Feldt RH, Schaff HV, Puga FJ,Danielson GK. Five- to fifteen-year follow-up after Fontanoperation. Circulation 1992;85:469–96.

2. de Leval MR, Kilner P, Gewillig M, Bull C. Total cavopul-monary connection: a logical alternative to atriopulmonaryconnection for complex Fontan operations. Experimentalstudies and early clinical experience. J Thorac CardiovascSurg 1988;96:682–95.

3. Mazzera E, Corno A, Picardo S, et al. Bidirectional cavopul-monary shunts: clinical applications as staged or definitivepalliation. Ann Thorac Surg 1989;47:415–20.

4. Marcelletti C, Corno A, Giannico S, Marino B. Inferiorvena cava-pulmonary artery extracardiac conduit. A newform of right heart bypass. J Thorac Cardiovasc Surg1990;100:228 –32.

5. Bridges ND, Mayer JE Jr, Lock JE, et al. Effect of bafflefenestration on outcome of the modified Fontan operation.Circulation 1992;86:1762–9.

6. Yahagi N, Kumon K, Tanigami H, et al. Inhaled nitric oxidefor the postoperative management of Fontan-type opera-tions. Ann Thorac Surg 1994;57:1371–3.

7. Uhm JY, Jhang WK, Park JJ, Seo DM, Yun SC, Yun TJ.Postoperative use of oral sildenafil in pediatric patients withcongenital heart disease. Pediatr Cardiol 2010;31:515–20.

8. Choussat A, Fontan F, Cesse P, Vallot F, Chauve A, BricaudH. Selection criteria for Fontan’s procedure. In: AndersonRH, Shinebourne EA, eds. Paediatric cardiology. Edinburgh:Churchill Livingstone, 1978:559–566.

9. Hosein RB, Clarke AJ, McGuirk SP, et al. Factors influencingearly and late outcome following the Fontan procedure inthe current era. The ‘Two Commandments’? Eur J Cardio-thorac Surg. 2007;31:344–52.

10. Ohuchi H, Yasuda K, Hasegawa S, et al. Influence ofventricular morphology on aerobic exercise capacity inpatients after the Fontan operation. J Am Coll Cardiol2001;37:1967–74.

11. Fontan F, Kirklin JW, Fernandez G, et al. Outcome after a“perfect” Fontan operation. Circulation 1990;81:1520–36.

12. Magee AG, McCrindle BW, Mawson J, Benson LN, WilliamsWG, Freedom RM. Systemic venous collateral development

ith an increased risk of mortality. These results, cou-

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after the bidirectional cavopulmonary anastomosis.Prevalence and predictors. J Am Coll Cardiol 1998;32:502–8.

13. Cetta F, Feldt RH, O’Leary PW, et al. Improved earlymorbidity and mortality after Fontan operation: the MayoClinic experience, 1987 to 1992. J Am Coll Cardiol 1996;28:480–6.

14. Bartz PJ, Driscoll DJ, Dearani JA, et al. Early and late resultsof the modified fontan operation for heterotaxy syndrome 30years of experience in 142 patients. J Am Coll Cardiol2006;48:2301–5.

15. d’Udekem Y, Iyengar AJ, Cochrane AD, et al. The Fontanprocedure: contemporary techniques have improved long-term outcomes. Circulation 2007;116(Suppl):I157–64.

16. Giannico S, Hammad F, Amodeo A, et al. Clinical outcome of193 extracardiac Fontan patients: the first 15 years. J Am CollCardiol 2006;47:2065–73.

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INVITED COMMENTARY

The ultimate paradigm for single-ventricle palliationeludes our field, yet significant strides in understandingphysiology and outcomes related to our interventions areevident. The panacea for those with single-ventriclephysiology will encompass stratifying patients to a par-ticular surgical strategy at each stage based on anatomicheterogeneity, physiologic anomalies, comorbid condi-tions, among other factors. This approach will be para-mount to obtain the best outcomes from a quality of life,neurologic, and physiologic standpoint.

Ohuchi and colleagues [1] present a 3-decade experi-nce and evolution of the Fontan operation. The investi-ators evaluated risk factors associated with early and

ate mortality in light of the type of Fontan operationatriopulmonary, intracardiac rerouting, and extracardiacerouting). The authors noted improved outcomes withime; however despite advances in surgical techniquend perioperative care, low single-ventricle ejection frac-ion, atrioventricular valve dysfunction, and total anom-lous pulmonary venous connection repair are associated

led with the many reports in the literature over the pastecade, continue to fuel the debate over the approach toingle-ventricle palliation. Piecing together the puzzle ishallenging; to ultimately understand the outcomes ofhe Fontan operation, the literature must be reviewed tooints well before the Fontan operation is even accom-lished. One must note the variability in surgical inter-ention, perioperative care, preparation of stages, includ-ng the approach to aortopulmonary collaterals, let alonehe heterogeneity in the anatomic substrate itself.

Despite 40 years of attempting to understand theontan operation and the approach to single-ventriclehysiology, many questions remain. The ever-increasingopulation of patients surviving single-ventricle pallia-

ion into adulthood begets further consternation. Studiesuch as these are vital pieces to the puzzle. In order tottempt to account for all variables leading to a successfulutcome after the Fontan operation, queries must startith the perinatal period, although obviously this is notractical for most studies. With this type of global think-

ng, failure of the Fontan operation might have been

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Documents

Impact of the Evolution of the Fontan Operation on Early and Late Mortality: A Single-Center Experience of 405 Patients Over 3 Decades