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Double-inlet ventricle presenting in infancy
J
THORAC CARDIOVASC SURG
1991;101:917-23
Double-inlet ventricle presenting in infancy II. Results ofpalliative operations The influence of palliation on survival was studied in 191 consecutive infants, presenting at under 1 year of age, with double-inlet ventricle (1973 to 1988, median follow-up 8.5 years), Palliative operatiOl~ were performed on 154 occasions in 121 patients (63% ~ Survival after a systemic-pulmonary arterial shunt (n = 57) and banding of the pulmonary trunk (n = 35) was comparable (84% and 77%
at 1 year, 62% and 45 % at 5 years), but those who underwent repair of aortic arch obstruction fared worse (n = 18, 44% and 22% at 1 and 5 years, p < O.OOI~ The remainder did not undergo an operation because of balanced physiology (n = 17, 9 % of entire group), complex anatomy (n = 32, 15%), or irreversible low output (n = 19, 12%). Palliative surgery, overall, had a deleterious effect on immediate survival «1 month relative risk 6.6, P < 0.001), but, in the survivors, medium-term outcome was improved (>6 months, 0.68, p < 0.05). This effect was most marked for those undergoing a systemic-pulmonary artery shunt «1 month, 2.52; >6 months, 0.43~ by contrast, after banding of the pulmonary trunk, with or without additional repair of the aortic arch repair, medium-term risk was not altered (>6 months, 1.13 and 0.91, respectively). These data will assist the clinician in making decisions concerning the management of infants with double-inlet ventricle and in the judicious use of palliative surgery. Rodney C: G. Franklin, MRcp,a David J. Spiegelhalter,PhD,b Robert H. Anderson, FRCPath,C Fergus J. Macartney, FRcp,a Raul I. Rossi Filho, MD,c Michael L. Rigby, MD, FRCP,c and John E. Deanfield, MRcp,a London and Cambridge, England
Ucertainty remainsas to the effectiveness of palliative operations at improving survival and the functionalstatus ofpatientswithcomplexcongenitalheart diseases suchas double-inlet ventricle. It is difficult to separate the effects of palliative operationsfrom those of the underlyingdisease becauseof the inabilityof predictingoutcome had a palliative procedure not been performed. This is further complicated by other factors, such as the age of the From the Thoracic Unit, The Hospital For Sick Children," Great Ormond Street, London, MRC BiostatisticsUnit,b Cambridge, and The Department of Paediatrics, National Heart and Lung Institute," London, England. R.HA is supported by the Joseph Levy and the British Heart Foundations. F.J.M. was supported by the Vandervell and British Heart Foundations. Received for publication July 18, 1988. Accepted for publication Dec. II, 1990. Address for reprints: Rodney C. G. Franklin, MRCP, Thoracic and Cardiac Surgical Unit, Harefield Hospital, Harefield, Middlesex UB9 6JH, England.
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patient and the type of palliative operation, which may also affect outcome. This secondstudy on patients with double-inlet ventricle investigates the effect of palliativeoperations on natural history, by comparing the outcome of patients undergoing palliative operationswith those not undergoing such operations(before definitive repair). It is recognized that the criticismsof the methods used for determining "natural history" without surgical intervention1 apply also to this paper. Patients and methods The details of the 191 consecutive patients with double-inlet ventricle, who presented in the first year of life between January 1973 and May 1985, have been given in the previous paper.' The actuarial survival and hazard rates after palliative operations were determined first, again censoring the patients as alive at the time of the definitive operation.' These were compared for the three main operative procedures: systemic-pulmonary artery shunt, isolated banding of the pulmonary trunk, and repair of the aortic arch together with banding of the pulmonary trunk. The multivariate analysis previously undertaken for deter-
917
The Journal of Thoracic and Cardiovascular Surgery
9 1 8 Franklin et al.
Table I. Types ofpalliative operation and median ages (months) Second operation
First operation
Third operation
Operation
n
Median age
n
Median age
n
Median age
Blalock SPA shunt + Atrial septectomy Central SPA shunt Banding of PT ± ligation PDA + Atrial septectomy + Coarctation repair + IAA repair Atrial septectomy TAPVC repair
49 I 7 33 2 17 I 8 3
4.6 8.2 2.0 5.3 4.3 0.9 4.6 2.5 6.6
19 I 4 4 I
37.6 29.5 66.6 4.8 7.6
2
44.7
Total
121
Total (N) 70 2 II 37 3
17 I 2
10
33.2
3 31
2
154
The median age and range for all the initial shunt operations was 13.9, range 0.1 to 314.3 weeks; for all initial isolated pulmonary trunk banding operations, 22, range 5.1 to 166.1 weeks; and for the operations of aortic arch repair with banding, 3.9, range 0.9 to 169.3 weeks. IAA, Interrupted aortic arch; PDA, patent ductus arteriosus; PT, pulmonary trunk; SPA, systemic-pulmonary arterial; TAPYC, total anomalous pulmonary venous connection.
Table II. Morphology and outcome ofpatiems with double-inlet ventricle and complex associated lesions Not palliated Right isomerism, CAVa, pulmonary atresia, TAPVC Coarctation, subaortic obstruction Right/left isomerism, DIRV/DIIV, CAVa, pulmonary atresia Left isomerism, CAVa, pulmonary atresia, TAPVC CAVa, pulmonary atresia, PA distortion CAVa regurgitation Right isomerism, CAVa, subaortic obstruction Aortic interruption, PA distortion Common arterial trunk, right A V valve regurgitation Established pulmonary vascular disease
Palliated
8
7
4 3
6 (1*) 3 (I *)
3 (It)
2
4
3
2 I
o
I
o o o 28 (2*)
22 (2*)
AY, Atrioventricular; CA YO, common atrioventricular orifice; OilY, double-inlet indeterminate ventricle; D1RY, double-inlet right ventricle; PA, pulmonary arterial; TAPYC, total anomalous pulmonary venous connection. • Alive when last seen. tLost to follow-up.
mining the risk factors for death was repeated, using the same variables I but also incorporating the relative risks of palliative surgery by introducing time-varying covariates? into the analysis (Appendix A). This was done for three time periods for each of the three palliative procedures, examining postoperative outcome in the immediate (up to 1 month), short (1 to 6 months), and medium term (more than 6 months). In addition, the additive index was recalculated including the risks associated with palliative operations, so as to investigate how robust the index was in the evaluation of all factors influencing mortality in the period before the definitive operation.
Results Patient outcome. Palliative operations were performed on 154 occasions in 121 (63%) of the patients (Table I). Survival rates for the 57 patients after an initial shunt procedure and the 35 patients after isolated bandingof the pulmonarytrunk werecomparable(84% and 77%at 1 year,62%and 45%at 5 years, 51%and 45% at 10years), but the 18patientswhounderwent repair of aorticarch obstruction inadditionto bandingfared worse (44%and 22%at 1 and 5 years;p < 0.001, logrank test; Fig.1).The hazard rate beforethe definitive operation for these patients was twofold to fourfold higher.for those whounderwent repair of the aortic arch (Fig.2, TableAI). An initial isolated Blalock-Hanlon atrial septectomy wasperformed in eight patients (medianage 10.4weeks, range6.0to 240.6weeks). Twopatientsdiedat operation, five wereknown to bealiveat over4 years,and onepatient waslostto follow-up. Repair of extracardiactotal anomalous pulmonary venous connection was undertaken in three infants with right atrial isomerism and a common atrioventricular orifice (aged 14,28, and 50 weeks), but none survived infancy. Just over one third of the patients (70, 37%) did not undergo a palliative operation. Nineteen were neonates with irreversible low cardiac output at presentation (pH < 7.20 for >6 hours), who were neverjudged to be sufficiently fit to withstandan operation (17 presented in the pre-prostaglandin era). All died soonafter presentation. In 32 infants,with extremely complex combinations oflesions, surgerywasnot believed to offerany long-term chanceof definitive repair.This decision was madeon an arbitrary and individual basis in conjunction with the parents. Table II compares the outcome of 28 of these patientswiththat of22 infantswithsimilarcomplex heart
Volume 101
Double-inlet ventricle, II
Number 5 May 1991
9I9
100
~80
---oco > >
'::J
... - - ...
60
----
Shunt
--------. -
en
-
-
- a
Band
CO 40 CO
'-
::J
«o
Coarct
20
O+---~-.......,r---~----r---~---.---~----.--------.
o
2
Age (years) 6 33 25 18 13 4
8
10
40 Shunt 57 20 11 25 8 Band 35 3 6 4 1 1 Coarct 18 o - - - - - Overall actuarial survival ____ - - - Survival, with censoring (withdrawn) at the time of definitive surgery Fig. 1. Actuarial survival curves for the patients who underwent palliative intervention by systemic-pulmonary arterial shunt (56 patients-Shunt), by banding of the pulmonary trunk (35 patients-Band), and by repair of aortic coarctation or interruption with banding of the pulmonary trunk (18 patients-Coarct). The dashed curves refer to the survival of the patients before definitive surgery (i.e., "censored" as alive at the time of definitive surgery; see Patients and methods section). Patients who underwent repair of systemic arch obstruction had a significantly worse outcome (p < 0.00 I). The vertical bars are the actuarial 70% confidence limits and· the numbers are the remaining patients for each group still being followed at that time, with reference to the time scale on the x-axis.
lesions but who did undergo a palliative operation. The two groups fared equally badly with only three of all 50 patients known to be alive. In contrast, 17 children (9% of the whole group) with balanced physiology remained well with no palliative operation throughout the period of study. Finally, two patients died before surgical intervention as neonates: one patient at catheterization and one during separation of conjoined twins. Palliative surgery and analysis of risk factors. When the effects of palliative operations were incorporated into the multivariate analysis, there was little change in the relative risks from the previous analysis (Appendix Table A-II). Only three minor changes resulted when the additive index was recalculated (Table III). Overall, there was a 6.S-fold higher relative risk of death immediately postoperatively than for similar patients who did not undergo surgical palliation (Table IV). This risk had practically "normalized" by I month postoperatively and, after 6 months, a significant benefit was perceived, amounting to a one third less relative risk of death in the surviving patients, compared with patients
Table III. Simple additive index for patients with double-inlet ventricle, calculated from the multivariate-derived relative risks, with the inclusion of the risks ofpalliative operations Rounded off Cox coefficient Pulmonary valvular or subvalvular stenosis Presentation at age greater than 2 months Presentation at age 2 weeks to 2 months Balanced pulmonary blood flow Double-inlet right ventricle Left atrial isomerism Mirror-image arrangement (situs inversus) Right atrial isomerism Concordant ventriculoarterial connection Pulmonary atresia Systemic outflow obstruction at any level Presentation before 1980 Low pulmonary blood flow Double-outlet dominant ventricle Anomalous pulmonary venous connection Aortic atresia or common arterial trunk Presentation with severe low output and acidosis
- 2 - 2 -I -I -I -I -I +I +1 +1
+J +I +I +2 +2 +3 +5
The Journal of
9 20
Franklin et al.
Thoracic and Cardiovascular Surgery
0.8
-
J::
~
c
....0 _
0.6
.:.::'0
Shunts Banding PT Coarct Repair
o
l/l'"
ii: ~ 0.4
--
• 8
>.J:
J::
c::
~
0.2
0.0
0-1
1-3 3-6 6-12 12-24 24-60 60-120 Time after palliation (months)
Fig. 2. Histogram of the instantaneous monthly risk of death (hazard function) before definitive surgery for the patients who underwent palliative intervention by systemic-pulmonary arterial shunt (56 patients~Shunt), by banding of the pulmonary trunk (35 patients~Banding PD, and by repair of aortic coarctation or interruption with banding of the pulmonary trunk (18 patients-c-Coercr repair). There was a significantly higher risk for those undergoing repair of the aortic arch compared with that of the other groups during the first month, although subsequent hazards were not significantly different. Risks are numerated in Table A-I.
Table IV. Relative risks ofpalliative operations during different postoperative time brackets after adjusting for variables in Table I (95% confidence limits are in parentheses) Period
Overall In = /2/)
Shunt In = 57)
Up to I month
6.56 (3.60, 11.90) 1.84 (0.84, 4.0 I) 0.68 (0.28, 1.69)
2.52 ( 1.05, 6.00) 1.03 (0.36, 2.93) 0.43 (0.15, 1.24)
1-6 months Over 6 months
Banding PT In = 35)
20.00 (5.05, 79.20) 5.49 (1.41. 21.28) 1.13 (0.29, 4.44)
Coarct In = /8)
16.92 (5.87,48.90) 1.25 (0.14,11.10) 0.91 (0.19.4.27)
Coarct. Repair or aortic coarctation or intcrruption together with banding or the pulmonary trunk: PT. pulmonary trunk: Shunt. systemic-pulmonary arterial shunt.
who had not been so treated. This trend was similar when the three main palliative procedures were considered separately (Table IV), with those receiving a shunt having the most benefit from palliation in the medium term. Those who required banding of the pulmonary trunk with or without additional repair of the aortic arch had a much higher risk in the first postoperative month and did not show any apparent longer term benefit from palliation, although the risk had normalized by 6 months. Discussion Currently, despite the fact that the long-term results after definitive repair are unknown, the accepted aim of palliative intervention at most centers is to establish, and maintain, suitable hemodynamics and anatomy so that the patient is fit for an eventual modified Fontan procedure or ventricular septation.': 4
Critique of methods and results Statistical analysis. Assessment of the effects of palliative operations on outcome presents analytic problems, inasmuch as there is no control group and the operations are undertaken at differing times and for unspecified reasons. In particular, there is a danger that death soon after an operation might be ascribed to the intervention itself, when it could primarily be due to the underlying clinical condition and morphologic feature that prompted the operation. Furthermore, the extent to which statistical analyses can reconstruct the "natural history" of patients with congenital heart disease (survival without palliative or definitive surgery), to act as a control, remains arguable. The reasons for this are generally the same as those which make analyses of randomized trials by "treatment received" (rather than by "intention to treat") subject to considerable bias.' Patients who receive palliative opera-
Volume 101 Number 5 May 1991
tionsmay,in someway, be differentfrom those withsimilarmorphology whodid not.Simplydeletingthem byany physical or statistical maneuverintroducesthe chance of considerable error. In addition,selection of patients, and the clinical status of the child before the operation, add other potential and unquantifiable biases. Finally, the analysis makes the strong assumption that the relative riskafter an operationis independent of the morphologic factors either existing at presentation or at the time of operation. Nevertheless, while understanding these drawbacks, we attempted the analysis using the technique of timevarying covariates? to express the relativerisksof the palliative procedurein comparison with the basic risk of a morphologically similargroup (obtained by stratification of the actuarial survival of this "control" group by means of the appropriate Cox coefficients). We weredisappointed that currentlyavailablestatistical techniques were unable to reach a point that predictionsand comparisons specific for each patient could be madeforoutcomewith and withoutpalliative operations. We are currently investigating this possibility. Operative mortality. The risks of surgery are known to be higherin infants than in older children/'- 7 Survival after palliative operations in our series was similar to results from other series involving infants'r!' and worse than results in older children.v 12 Stefanelli and associates' reported an 85%actuarial survival rate at 10 years for those receiving systemic-pulmonary arterial shuntscompared with 56%at 8 years in our study. Less than 10% of the 121 patientsundergoing palliation in our group,however, wereolder than the median age at operation of 22 months in their series. The useofpalliative surgery. Although most patients who required an operation received it, there remains a dilemma as to how best to manage the infant with double-inlet ventricle and hemodynamically severe associated lesions. Throughout this study, the decision as to whetheror not to undertake an operationwas arbitrary. It couldbeargued that surgeryshouldhavebeenattempted in more of these, often criticallysick, patients. When an operation was performed, however, the outcome proved no better than in those who did not undergo surgery. Thus, although neonatal surgical innovations may improve the outlookin the future.f 13 the roleof palliative surgery in this difficult group remains controversial. Assessing the benefits of palliative surgery. This analysis showed that, despitea relatively high early mortality rate «1 month) after palliative operations, the infantswhosurvived benefited in the medium term when compared with those still alive but not undergoing an operation. In contrast, Moodie and associates'? have
Double-inlet ventricle. II 9 2 1
shown that, in older patients (already selected by their survival), palliative operations do not significantly enhance long-termsurvival. This suggests that palliative operations enablepatients to reach an age whendefmitive procedures are currently undertaken, but are not, in themselves, a meansof ensuringlong-termsurvival. Care must be taken, however, in drawing such conclusions, becauseneitherstudy wasrandomizedand the suitability for definitive operations was not addressedin these analyses. We l4 haveexaminedthis questionof suitabilityin a separate study. It wasnotablethat patientswhounderwentbandingof the pulmonarytrunk, with and without repair of an aortic arch lesion, did not appear to showa benefitfrom palliation, even in the medium term. This was due to the subsequent early, and usually fatal, development of subaortic stenosis in many of these patients, particularly those who required surgery to the aortic arch. 14. 15 This emphasizes that the analysis must be interpreted with care, becauseit takes into account only factors detected at presentation and assumesthat theseremain ofconstant importancethroughout follow-up. Thus the analysisdid not consider newadverseeventsthat developed after palliation, but that were nevertheless related to the underlying disease. We l 5 have thus argued that this form of palliation is inappropriate for many of these patients. We thank Dr. C. Bull, Mr. M. E. Elliot, Mr. M. R. de Leval, Dr. P. G. Rees, Mr. J. Stark, and Dr. J. F. N. Taylor of the Hospital for Sick Children, Great Ormond Street, and Mr. J. C. R. Lincoln and Dr. E. A. Shinebourne of The Royal Brompton Hospital for allowing us to.study patients under their care.
1.
2. 3.
4.
5.
6.
REFERENCES Franklin RCG, Spiegelhalter DJ, Anderson RH, et al. Double-inlet ventricle presenting in infancy. I. Survival without definitive repair. J THORAC CARDIOVASC SURG 1991;101:767-76. Cox DR, Oakes D. Analysis of survival data. London: Chapman and Hall, 1985. Stefanelli G, Kirklin JW, Naftel DC, et al. Early and intermediate-term (lO-year) results of surgery for univentricular atrioventricular connection ("single ventricle"). Am J CardioI1984;54:811-21. Anderson R, Macartney FJ, Shinebourne EA, Tynan M. Paediatric cardiology. Vol 2. London: Churchill Livingstone, 1987:643-73. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Part II. Analysis and samples. Br J Cancer 1977;35:1-39. CastanedaAR,Mayer JE,JonasRA,LockJE, WesseIDL, Hickey PRoThe neonate with critical congenital heart dis-
The Journal of Thoracic and Cardiovascular Surgery
9 2 2 Franklin et al.
7.
8.
9.
10.
II.
12.
13.
14.
15.
ease: repair-a surgical challenge. J THORAC CARDIOVASC SURa 1989;98:869-75. StarkJ,deLevaIM, Macartney F, Taylor JFN.Openheart surgery in the first year of life: current state and future trends. In: Vogel JHK, ed. Advances in cardiology Basel: S Karger, 1980;27:243-53. Chen S-C, Pennington G, Nouri S, SivakoffM, Fagan LF. Management of infants with univentricular heart. Am Heart J 1984;107:1252-6. Sapire DW, Ho SY, Anderson RH, Rigby ML. Diagnosis and significance of atrial isomerism. Am J Cardiol 1986; 58:342-6. Villani M, Crupi G, Locatelli G, Tiraboshi R, Vanini V, Parenzan L. Experience in palliative treatment of univentricular heart including tricuspid atresia. Herz 1979;4:25661. Crupi G, Pignatelli R, Carminati M, et al. In: Anderson RH, Crupi G, Parenzan L, eds. Double inlet ventricle. Tunbridge Wells, England: Castle House Publications Ltd, 1987:165-73. Moodie DS, Ritter DG, Tajik AH, McGoon DC, Danielson GK, O'Fallon WM. Long-term follow-up after palliative operation for univentricular heart. Am J Cardiol 1984;53:1648-51. Rothman A, Lang P, Lock JE, Jonas RA, Mayer JE, Castaneda AR. Surgical management of subaortic obstruction in single left ventricle and tricuspid atresia. J Am Coli CardioI1987;10:421-6. Franklin RCG, Spiegelhalter DJ, Rossi Filho R, et al. Double-inlet ventricle presenting in infancy. III. Outcome and potential for definitive repair. J THORAC CARDIOVASC SURa 1991:101:924-34. Franklin RCG, Sullivan ID, Anderson RH, Shinebourne EA, Deanfield JE. Is banding of the pulmonary trunk obsolete for infants with tricuspid atresia and double inlet ventricle with a discordant ventriculo-arterial connection? Role of aortic arch obstruction and subaortic stenosis.J Am Coli Cardiol 1990;16:1455-64.
Appendix A Palliative surgery. The postoperative hazard rates (instantaneous monthly risk of death) before the definitiveoperation for the three main palliative procedures are given in Table A-I and correspond to Fig. 2. The effects of this operation were assessed by means of a proportional hazards analysis with added time-
Table A-I. Postoperative hazard rates (instantaneous
monthly risks of death) before the definitive operation for 110 patients with double-inlet ventricle who underwent various palliativeprocedures Months
Shunt (n = 57)
Banding PT (n = 35)
Coarct repair (n = 18)
Up to 1 1-3 3-6 6-12 12-24 24-60 60-120
0.152 0.032 O.oJ5 0.004 0.002 0.006 0.002
0.123 0.035 0.Q25 0.000 0.007 0.005 0.000
0.667 0.063 0.000 0.000 0.Q28 0.009 0.000
Coarct, Repair of aortic coarctation or interruption together with banding of the pulmonary trunk; PT, pulmonary trunk; shunt, systemic-pulmonary arterial shunt.
varying covariates indicating time periods after palliative operations overall and after the three main procedures. These additional risk factors were "turned on" and "turned off" again within particular time periods. Thus the immediate postoperative risk was assessed by introducing a variable that turned on at the time of operation and turned off again after 1 month. Severity of the lesion was assessed by taking into account the variables listed previouslyI and considered in the multivariate analysis, but the coefficients were newly estimated simultaneously with the effects of the operations. By this technique patients of a similar age and with a similar morphologic characteristics (i.e., a similar underlying total relative risk), but who had not received the corresponding operation, acted as simultaneous "controls". Consider a patient with baseline features with labels in I, who had a palliative operation at time d. Then, the relative risk at time t before definitivesurgery, RR(t) (relative to a patient with all the baseline categories, who has had no palliative or definitive surgery), is given by the following equation: RR(t) = product {r;: i in I} . rp(t) . rsft) . rm(t) where: rp(t) = rp if d < t < d + 1 month = 1 otherwise; (immediate relative risk) rsft) = 's if d + I month < t < d + 6 months 1 otherwise; = (short-term relative risk) rm(t)rm if d + 6 months < t = 1 otherwise. = (medium-term relative risk)
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Double-inlet ventricle, II
May 1991
923
Table A-II. Multivariate risk factor analysis for the 191 patients, using factors as found at presentation: Without and with the incorporation ofpalliative operations
Without relative risk Variable/category
n
Atrial arrangement (situs) Usual (solitus)* 137 Mirror-image (inversus) 6 34 Right isomerism Left isomerism 14 Dominant ventricular morphology Left* 136 Right 34 Indeterminate 21 Mode of A V connection Two A V valves* 110 Common A V orifice 81 VA connection Discordant* 85 Concordant 17 Pulmonaryatresiat 38 4 Aortic atresia/truncus Double outlet'[ 47 Pulmonary valvular and/or subvalvular obstruction Absent* 115 Present 76 Systemic outflow obstruction Absent* 157 Present 34 Pulmonary venous connection Normal* 163 APVC 28 Pulmonary blood flow (at presentation) High* 86 Low 87 Balanced 18 Severe acidosis at presentation No acidosis* 168 Acidosis present 23 Age at presentation <2 weeks* 129 2 weeks-2 months 36 After 2 months 26 Era of presentation After 1979* 77 Before 1980 114
(%)
(95%
With relative risk
cu
(95%
cu
(72) (3) (18) (7)
0.47 1.45 0.38
P = 0.02 (0.14, 1.60) (0.71, 2.95) (0.14, 1.01)
0.50 1.56 0.41
(0.14, 1.76) (0.74, 3.27) (0.15, 1.10)
(71) (18) (II)
0.54 0.81
P = 0.13 (0.29,0.99) (0.38, 1.71)
0.49 0.84
(0.27,0.90) (0.39, 1.79)
(58) (42)
1.35
P = 0.30 (0.77, 2.37)
1.34
(0.74,2.41 )
(44) (9) (20) (2) (25)
1.85 1.93 4.73 3.40
P = 0.01 (0.89, 3.87) (0.57,6.51) (1.16,19.28) (1.64,7.06)
1.75 2.32 6.23 3.17
(0.81,3.76) (0.65, 8.28) (1.35, 28.75) (1.53, 6.52)
(60) (40)
0.35
P = 0.03 (0.13, 0.92)
0.50
(0.17, 1.43)
(82) (18)
2.33
P = 0.01 (1.25, 4.32)
2.47
(1.03, 6.00)
(85) (15)
4.83
P < 0.0001 (2.41,9.72)
5.17
(2.55, 10.44)
(45) (46) (9)
1.28 0.51
p = 0.23 (0.46, 3.56) (0.15, 1.65)
1.99 0.59
(0.66, 5.97) (0.17, 1.98)
(88) (12)
16.56
p < 0.0001 (7.36, 37.32)
28.21
(11.23, 70.89)
(67) (19) (14)
0.54 0.23
p < 0.003 (0.29, 1.00) (0.09,0.60)
0.46 0.22
(0.25,0.94) (0.08, 0.58)
(40) (60)
2.16
P = 0.001 (1.36, 3.42)
2.30
(1.43, 3.67)
To calculate the iotal relative risk of a patient with a particular variant of double-inlet ventricle at presentation. all the relative risks for that patient are multiplied together, as previously described.' AV, Atrioventricular; VA, ventriculoarterial. 'Baseline category. tVentriculoarterial outlet from either dominant or rudimentary ventricle.
THORAC CARDIOVASC SURG
1991;101:917-23
Double-inlet ventricle presenting in infancy II. Results ofpalliative operations The influence of palliation on survival was studied in 191 consecutive infants, presenting at under 1 year of age, with double-inlet ventricle (1973 to 1988, median follow-up 8.5 years), Palliative operatiOl~ were performed on 154 occasions in 121 patients (63% ~ Survival after a systemic-pulmonary arterial shunt (n = 57) and banding of the pulmonary trunk (n = 35) was comparable (84% and 77%
at 1 year, 62% and 45 % at 5 years), but those who underwent repair of aortic arch obstruction fared worse (n = 18, 44% and 22% at 1 and 5 years, p < O.OOI~ The remainder did not undergo an operation because of balanced physiology (n = 17, 9 % of entire group), complex anatomy (n = 32, 15%), or irreversible low output (n = 19, 12%). Palliative surgery, overall, had a deleterious effect on immediate survival «1 month relative risk 6.6, P < 0.001), but, in the survivors, medium-term outcome was improved (>6 months, 0.68, p < 0.05). This effect was most marked for those undergoing a systemic-pulmonary artery shunt «1 month, 2.52; >6 months, 0.43~ by contrast, after banding of the pulmonary trunk, with or without additional repair of the aortic arch repair, medium-term risk was not altered (>6 months, 1.13 and 0.91, respectively). These data will assist the clinician in making decisions concerning the management of infants with double-inlet ventricle and in the judicious use of palliative surgery. Rodney C: G. Franklin, MRcp,a David J. Spiegelhalter,PhD,b Robert H. Anderson, FRCPath,C Fergus J. Macartney, FRcp,a Raul I. Rossi Filho, MD,c Michael L. Rigby, MD, FRCP,c and John E. Deanfield, MRcp,a London and Cambridge, England
Ucertainty remainsas to the effectiveness of palliative operations at improving survival and the functionalstatus ofpatientswithcomplexcongenitalheart diseases suchas double-inlet ventricle. It is difficult to separate the effects of palliative operationsfrom those of the underlyingdisease becauseof the inabilityof predictingoutcome had a palliative procedure not been performed. This is further complicated by other factors, such as the age of the From the Thoracic Unit, The Hospital For Sick Children," Great Ormond Street, London, MRC BiostatisticsUnit,b Cambridge, and The Department of Paediatrics, National Heart and Lung Institute," London, England. R.HA is supported by the Joseph Levy and the British Heart Foundations. F.J.M. was supported by the Vandervell and British Heart Foundations. Received for publication July 18, 1988. Accepted for publication Dec. II, 1990. Address for reprints: Rodney C. G. Franklin, MRCP, Thoracic and Cardiac Surgical Unit, Harefield Hospital, Harefield, Middlesex UB9 6JH, England.
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patient and the type of palliative operation, which may also affect outcome. This secondstudy on patients with double-inlet ventricle investigates the effect of palliativeoperations on natural history, by comparing the outcome of patients undergoing palliative operationswith those not undergoing such operations(before definitive repair). It is recognized that the criticismsof the methods used for determining "natural history" without surgical intervention1 apply also to this paper. Patients and methods The details of the 191 consecutive patients with double-inlet ventricle, who presented in the first year of life between January 1973 and May 1985, have been given in the previous paper.' The actuarial survival and hazard rates after palliative operations were determined first, again censoring the patients as alive at the time of the definitive operation.' These were compared for the three main operative procedures: systemic-pulmonary artery shunt, isolated banding of the pulmonary trunk, and repair of the aortic arch together with banding of the pulmonary trunk. The multivariate analysis previously undertaken for deter-
917
The Journal of Thoracic and Cardiovascular Surgery
9 1 8 Franklin et al.
Table I. Types ofpalliative operation and median ages (months) Second operation
First operation
Third operation
Operation
n
Median age
n
Median age
n
Median age
Blalock SPA shunt + Atrial septectomy Central SPA shunt Banding of PT ± ligation PDA + Atrial septectomy + Coarctation repair + IAA repair Atrial septectomy TAPVC repair
49 I 7 33 2 17 I 8 3
4.6 8.2 2.0 5.3 4.3 0.9 4.6 2.5 6.6
19 I 4 4 I
37.6 29.5 66.6 4.8 7.6
2
44.7
Total
121
Total (N) 70 2 II 37 3
17 I 2
10
33.2
3 31
2
154
The median age and range for all the initial shunt operations was 13.9, range 0.1 to 314.3 weeks; for all initial isolated pulmonary trunk banding operations, 22, range 5.1 to 166.1 weeks; and for the operations of aortic arch repair with banding, 3.9, range 0.9 to 169.3 weeks. IAA, Interrupted aortic arch; PDA, patent ductus arteriosus; PT, pulmonary trunk; SPA, systemic-pulmonary arterial; TAPYC, total anomalous pulmonary venous connection.
Table II. Morphology and outcome ofpatiems with double-inlet ventricle and complex associated lesions Not palliated Right isomerism, CAVa, pulmonary atresia, TAPVC Coarctation, subaortic obstruction Right/left isomerism, DIRV/DIIV, CAVa, pulmonary atresia Left isomerism, CAVa, pulmonary atresia, TAPVC CAVa, pulmonary atresia, PA distortion CAVa regurgitation Right isomerism, CAVa, subaortic obstruction Aortic interruption, PA distortion Common arterial trunk, right A V valve regurgitation Established pulmonary vascular disease
Palliated
8
7
4 3
6 (1*) 3 (I *)
3 (It)
2
4
3
2 I
o
I
o o o 28 (2*)
22 (2*)
AY, Atrioventricular; CA YO, common atrioventricular orifice; OilY, double-inlet indeterminate ventricle; D1RY, double-inlet right ventricle; PA, pulmonary arterial; TAPYC, total anomalous pulmonary venous connection. • Alive when last seen. tLost to follow-up.
mining the risk factors for death was repeated, using the same variables I but also incorporating the relative risks of palliative surgery by introducing time-varying covariates? into the analysis (Appendix A). This was done for three time periods for each of the three palliative procedures, examining postoperative outcome in the immediate (up to 1 month), short (1 to 6 months), and medium term (more than 6 months). In addition, the additive index was recalculated including the risks associated with palliative operations, so as to investigate how robust the index was in the evaluation of all factors influencing mortality in the period before the definitive operation.
Results Patient outcome. Palliative operations were performed on 154 occasions in 121 (63%) of the patients (Table I). Survival rates for the 57 patients after an initial shunt procedure and the 35 patients after isolated bandingof the pulmonarytrunk werecomparable(84% and 77%at 1 year,62%and 45%at 5 years, 51%and 45% at 10years), but the 18patientswhounderwent repair of aorticarch obstruction inadditionto bandingfared worse (44%and 22%at 1 and 5 years;p < 0.001, logrank test; Fig.1).The hazard rate beforethe definitive operation for these patients was twofold to fourfold higher.for those whounderwent repair of the aortic arch (Fig.2, TableAI). An initial isolated Blalock-Hanlon atrial septectomy wasperformed in eight patients (medianage 10.4weeks, range6.0to 240.6weeks). Twopatientsdiedat operation, five wereknown to bealiveat over4 years,and onepatient waslostto follow-up. Repair of extracardiactotal anomalous pulmonary venous connection was undertaken in three infants with right atrial isomerism and a common atrioventricular orifice (aged 14,28, and 50 weeks), but none survived infancy. Just over one third of the patients (70, 37%) did not undergo a palliative operation. Nineteen were neonates with irreversible low cardiac output at presentation (pH < 7.20 for >6 hours), who were neverjudged to be sufficiently fit to withstandan operation (17 presented in the pre-prostaglandin era). All died soonafter presentation. In 32 infants,with extremely complex combinations oflesions, surgerywasnot believed to offerany long-term chanceof definitive repair.This decision was madeon an arbitrary and individual basis in conjunction with the parents. Table II compares the outcome of 28 of these patientswiththat of22 infantswithsimilarcomplex heart
Volume 101
Double-inlet ventricle, II
Number 5 May 1991
9I9
100
~80
---oco > >
'::J
... - - ...
60
----
Shunt
--------. -
en
-
-
- a
Band
CO 40 CO
'-
::J
«o
Coarct
20
O+---~-.......,r---~----r---~---.---~----.--------.
o
2
Age (years) 6 33 25 18 13 4
8
10
40 Shunt 57 20 11 25 8 Band 35 3 6 4 1 1 Coarct 18 o - - - - - Overall actuarial survival ____ - - - Survival, with censoring (withdrawn) at the time of definitive surgery Fig. 1. Actuarial survival curves for the patients who underwent palliative intervention by systemic-pulmonary arterial shunt (56 patients-Shunt), by banding of the pulmonary trunk (35 patients-Band), and by repair of aortic coarctation or interruption with banding of the pulmonary trunk (18 patients-Coarct). The dashed curves refer to the survival of the patients before definitive surgery (i.e., "censored" as alive at the time of definitive surgery; see Patients and methods section). Patients who underwent repair of systemic arch obstruction had a significantly worse outcome (p < 0.00 I). The vertical bars are the actuarial 70% confidence limits and· the numbers are the remaining patients for each group still being followed at that time, with reference to the time scale on the x-axis.
lesions but who did undergo a palliative operation. The two groups fared equally badly with only three of all 50 patients known to be alive. In contrast, 17 children (9% of the whole group) with balanced physiology remained well with no palliative operation throughout the period of study. Finally, two patients died before surgical intervention as neonates: one patient at catheterization and one during separation of conjoined twins. Palliative surgery and analysis of risk factors. When the effects of palliative operations were incorporated into the multivariate analysis, there was little change in the relative risks from the previous analysis (Appendix Table A-II). Only three minor changes resulted when the additive index was recalculated (Table III). Overall, there was a 6.S-fold higher relative risk of death immediately postoperatively than for similar patients who did not undergo surgical palliation (Table IV). This risk had practically "normalized" by I month postoperatively and, after 6 months, a significant benefit was perceived, amounting to a one third less relative risk of death in the surviving patients, compared with patients
Table III. Simple additive index for patients with double-inlet ventricle, calculated from the multivariate-derived relative risks, with the inclusion of the risks ofpalliative operations Rounded off Cox coefficient Pulmonary valvular or subvalvular stenosis Presentation at age greater than 2 months Presentation at age 2 weeks to 2 months Balanced pulmonary blood flow Double-inlet right ventricle Left atrial isomerism Mirror-image arrangement (situs inversus) Right atrial isomerism Concordant ventriculoarterial connection Pulmonary atresia Systemic outflow obstruction at any level Presentation before 1980 Low pulmonary blood flow Double-outlet dominant ventricle Anomalous pulmonary venous connection Aortic atresia or common arterial trunk Presentation with severe low output and acidosis
- 2 - 2 -I -I -I -I -I +I +1 +1
+J +I +I +2 +2 +3 +5
The Journal of
9 20
Franklin et al.
Thoracic and Cardiovascular Surgery
0.8
-
J::
~
c
....0 _
0.6
.:.::'0
Shunts Banding PT Coarct Repair
o
l/l'"
ii: ~ 0.4
--
• 8
>.J:
J::
c::
~
0.2
0.0
0-1
1-3 3-6 6-12 12-24 24-60 60-120 Time after palliation (months)
Fig. 2. Histogram of the instantaneous monthly risk of death (hazard function) before definitive surgery for the patients who underwent palliative intervention by systemic-pulmonary arterial shunt (56 patients~Shunt), by banding of the pulmonary trunk (35 patients~Banding PD, and by repair of aortic coarctation or interruption with banding of the pulmonary trunk (18 patients-c-Coercr repair). There was a significantly higher risk for those undergoing repair of the aortic arch compared with that of the other groups during the first month, although subsequent hazards were not significantly different. Risks are numerated in Table A-I.
Table IV. Relative risks ofpalliative operations during different postoperative time brackets after adjusting for variables in Table I (95% confidence limits are in parentheses) Period
Overall In = /2/)
Shunt In = 57)
Up to I month
6.56 (3.60, 11.90) 1.84 (0.84, 4.0 I) 0.68 (0.28, 1.69)
2.52 ( 1.05, 6.00) 1.03 (0.36, 2.93) 0.43 (0.15, 1.24)
1-6 months Over 6 months
Banding PT In = 35)
20.00 (5.05, 79.20) 5.49 (1.41. 21.28) 1.13 (0.29, 4.44)
Coarct In = /8)
16.92 (5.87,48.90) 1.25 (0.14,11.10) 0.91 (0.19.4.27)
Coarct. Repair or aortic coarctation or intcrruption together with banding or the pulmonary trunk: PT. pulmonary trunk: Shunt. systemic-pulmonary arterial shunt.
who had not been so treated. This trend was similar when the three main palliative procedures were considered separately (Table IV), with those receiving a shunt having the most benefit from palliation in the medium term. Those who required banding of the pulmonary trunk with or without additional repair of the aortic arch had a much higher risk in the first postoperative month and did not show any apparent longer term benefit from palliation, although the risk had normalized by 6 months. Discussion Currently, despite the fact that the long-term results after definitive repair are unknown, the accepted aim of palliative intervention at most centers is to establish, and maintain, suitable hemodynamics and anatomy so that the patient is fit for an eventual modified Fontan procedure or ventricular septation.': 4
Critique of methods and results Statistical analysis. Assessment of the effects of palliative operations on outcome presents analytic problems, inasmuch as there is no control group and the operations are undertaken at differing times and for unspecified reasons. In particular, there is a danger that death soon after an operation might be ascribed to the intervention itself, when it could primarily be due to the underlying clinical condition and morphologic feature that prompted the operation. Furthermore, the extent to which statistical analyses can reconstruct the "natural history" of patients with congenital heart disease (survival without palliative or definitive surgery), to act as a control, remains arguable. The reasons for this are generally the same as those which make analyses of randomized trials by "treatment received" (rather than by "intention to treat") subject to considerable bias.' Patients who receive palliative opera-
Volume 101 Number 5 May 1991
tionsmay,in someway, be differentfrom those withsimilarmorphology whodid not.Simplydeletingthem byany physical or statistical maneuverintroducesthe chance of considerable error. In addition,selection of patients, and the clinical status of the child before the operation, add other potential and unquantifiable biases. Finally, the analysis makes the strong assumption that the relative riskafter an operationis independent of the morphologic factors either existing at presentation or at the time of operation. Nevertheless, while understanding these drawbacks, we attempted the analysis using the technique of timevarying covariates? to express the relativerisksof the palliative procedurein comparison with the basic risk of a morphologically similargroup (obtained by stratification of the actuarial survival of this "control" group by means of the appropriate Cox coefficients). We weredisappointed that currentlyavailablestatistical techniques were unable to reach a point that predictionsand comparisons specific for each patient could be madeforoutcomewith and withoutpalliative operations. We are currently investigating this possibility. Operative mortality. The risks of surgery are known to be higherin infants than in older children/'- 7 Survival after palliative operations in our series was similar to results from other series involving infants'r!' and worse than results in older children.v 12 Stefanelli and associates' reported an 85%actuarial survival rate at 10 years for those receiving systemic-pulmonary arterial shuntscompared with 56%at 8 years in our study. Less than 10% of the 121 patientsundergoing palliation in our group,however, wereolder than the median age at operation of 22 months in their series. The useofpalliative surgery. Although most patients who required an operation received it, there remains a dilemma as to how best to manage the infant with double-inlet ventricle and hemodynamically severe associated lesions. Throughout this study, the decision as to whetheror not to undertake an operationwas arbitrary. It couldbeargued that surgeryshouldhavebeenattempted in more of these, often criticallysick, patients. When an operation was performed, however, the outcome proved no better than in those who did not undergo surgery. Thus, although neonatal surgical innovations may improve the outlookin the future.f 13 the roleof palliative surgery in this difficult group remains controversial. Assessing the benefits of palliative surgery. This analysis showed that, despitea relatively high early mortality rate «1 month) after palliative operations, the infantswhosurvived benefited in the medium term when compared with those still alive but not undergoing an operation. In contrast, Moodie and associates'? have
Double-inlet ventricle. II 9 2 1
shown that, in older patients (already selected by their survival), palliative operations do not significantly enhance long-termsurvival. This suggests that palliative operations enablepatients to reach an age whendefmitive procedures are currently undertaken, but are not, in themselves, a meansof ensuringlong-termsurvival. Care must be taken, however, in drawing such conclusions, becauseneitherstudy wasrandomizedand the suitability for definitive operations was not addressedin these analyses. We l4 haveexaminedthis questionof suitabilityin a separate study. It wasnotablethat patientswhounderwentbandingof the pulmonarytrunk, with and without repair of an aortic arch lesion, did not appear to showa benefitfrom palliation, even in the medium term. This was due to the subsequent early, and usually fatal, development of subaortic stenosis in many of these patients, particularly those who required surgery to the aortic arch. 14. 15 This emphasizes that the analysis must be interpreted with care, becauseit takes into account only factors detected at presentation and assumesthat theseremain ofconstant importancethroughout follow-up. Thus the analysisdid not consider newadverseeventsthat developed after palliation, but that were nevertheless related to the underlying disease. We l 5 have thus argued that this form of palliation is inappropriate for many of these patients. We thank Dr. C. Bull, Mr. M. E. Elliot, Mr. M. R. de Leval, Dr. P. G. Rees, Mr. J. Stark, and Dr. J. F. N. Taylor of the Hospital for Sick Children, Great Ormond Street, and Mr. J. C. R. Lincoln and Dr. E. A. Shinebourne of The Royal Brompton Hospital for allowing us to.study patients under their care.
1.
2. 3.
4.
5.
6.
REFERENCES Franklin RCG, Spiegelhalter DJ, Anderson RH, et al. Double-inlet ventricle presenting in infancy. I. Survival without definitive repair. J THORAC CARDIOVASC SURG 1991;101:767-76. Cox DR, Oakes D. Analysis of survival data. London: Chapman and Hall, 1985. Stefanelli G, Kirklin JW, Naftel DC, et al. Early and intermediate-term (lO-year) results of surgery for univentricular atrioventricular connection ("single ventricle"). Am J CardioI1984;54:811-21. Anderson R, Macartney FJ, Shinebourne EA, Tynan M. Paediatric cardiology. Vol 2. London: Churchill Livingstone, 1987:643-73. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Part II. Analysis and samples. Br J Cancer 1977;35:1-39. CastanedaAR,Mayer JE,JonasRA,LockJE, WesseIDL, Hickey PRoThe neonate with critical congenital heart dis-
The Journal of Thoracic and Cardiovascular Surgery
9 2 2 Franklin et al.
7.
8.
9.
10.
II.
12.
13.
14.
15.
ease: repair-a surgical challenge. J THORAC CARDIOVASC SURa 1989;98:869-75. StarkJ,deLevaIM, Macartney F, Taylor JFN.Openheart surgery in the first year of life: current state and future trends. In: Vogel JHK, ed. Advances in cardiology Basel: S Karger, 1980;27:243-53. Chen S-C, Pennington G, Nouri S, SivakoffM, Fagan LF. Management of infants with univentricular heart. Am Heart J 1984;107:1252-6. Sapire DW, Ho SY, Anderson RH, Rigby ML. Diagnosis and significance of atrial isomerism. Am J Cardiol 1986; 58:342-6. Villani M, Crupi G, Locatelli G, Tiraboshi R, Vanini V, Parenzan L. Experience in palliative treatment of univentricular heart including tricuspid atresia. Herz 1979;4:25661. Crupi G, Pignatelli R, Carminati M, et al. In: Anderson RH, Crupi G, Parenzan L, eds. Double inlet ventricle. Tunbridge Wells, England: Castle House Publications Ltd, 1987:165-73. Moodie DS, Ritter DG, Tajik AH, McGoon DC, Danielson GK, O'Fallon WM. Long-term follow-up after palliative operation for univentricular heart. Am J Cardiol 1984;53:1648-51. Rothman A, Lang P, Lock JE, Jonas RA, Mayer JE, Castaneda AR. Surgical management of subaortic obstruction in single left ventricle and tricuspid atresia. J Am Coli CardioI1987;10:421-6. Franklin RCG, Spiegelhalter DJ, Rossi Filho R, et al. Double-inlet ventricle presenting in infancy. III. Outcome and potential for definitive repair. J THORAC CARDIOVASC SURa 1991:101:924-34. Franklin RCG, Sullivan ID, Anderson RH, Shinebourne EA, Deanfield JE. Is banding of the pulmonary trunk obsolete for infants with tricuspid atresia and double inlet ventricle with a discordant ventriculo-arterial connection? Role of aortic arch obstruction and subaortic stenosis.J Am Coli Cardiol 1990;16:1455-64.
Appendix A Palliative surgery. The postoperative hazard rates (instantaneous monthly risk of death) before the definitiveoperation for the three main palliative procedures are given in Table A-I and correspond to Fig. 2. The effects of this operation were assessed by means of a proportional hazards analysis with added time-
Table A-I. Postoperative hazard rates (instantaneous
monthly risks of death) before the definitive operation for 110 patients with double-inlet ventricle who underwent various palliativeprocedures Months
Shunt (n = 57)
Banding PT (n = 35)
Coarct repair (n = 18)
Up to 1 1-3 3-6 6-12 12-24 24-60 60-120
0.152 0.032 O.oJ5 0.004 0.002 0.006 0.002
0.123 0.035 0.Q25 0.000 0.007 0.005 0.000
0.667 0.063 0.000 0.000 0.Q28 0.009 0.000
Coarct, Repair of aortic coarctation or interruption together with banding of the pulmonary trunk; PT, pulmonary trunk; shunt, systemic-pulmonary arterial shunt.
varying covariates indicating time periods after palliative operations overall and after the three main procedures. These additional risk factors were "turned on" and "turned off" again within particular time periods. Thus the immediate postoperative risk was assessed by introducing a variable that turned on at the time of operation and turned off again after 1 month. Severity of the lesion was assessed by taking into account the variables listed previouslyI and considered in the multivariate analysis, but the coefficients were newly estimated simultaneously with the effects of the operations. By this technique patients of a similar age and with a similar morphologic characteristics (i.e., a similar underlying total relative risk), but who had not received the corresponding operation, acted as simultaneous "controls". Consider a patient with baseline features with labels in I, who had a palliative operation at time d. Then, the relative risk at time t before definitivesurgery, RR(t) (relative to a patient with all the baseline categories, who has had no palliative or definitive surgery), is given by the following equation: RR(t) = product {r;: i in I} . rp(t) . rsft) . rm(t) where: rp(t) = rp if d < t < d + 1 month = 1 otherwise; (immediate relative risk) rsft) = 's if d + I month < t < d + 6 months 1 otherwise; = (short-term relative risk) rm(t)rm if d + 6 months < t = 1 otherwise. = (medium-term relative risk)
Volume 101 Number 5
Double-inlet ventricle, II
May 1991
923
Table A-II. Multivariate risk factor analysis for the 191 patients, using factors as found at presentation: Without and with the incorporation ofpalliative operations
Without relative risk Variable/category
n
Atrial arrangement (situs) Usual (solitus)* 137 Mirror-image (inversus) 6 34 Right isomerism Left isomerism 14 Dominant ventricular morphology Left* 136 Right 34 Indeterminate 21 Mode of A V connection Two A V valves* 110 Common A V orifice 81 VA connection Discordant* 85 Concordant 17 Pulmonaryatresiat 38 4 Aortic atresia/truncus Double outlet'[ 47 Pulmonary valvular and/or subvalvular obstruction Absent* 115 Present 76 Systemic outflow obstruction Absent* 157 Present 34 Pulmonary venous connection Normal* 163 APVC 28 Pulmonary blood flow (at presentation) High* 86 Low 87 Balanced 18 Severe acidosis at presentation No acidosis* 168 Acidosis present 23 Age at presentation <2 weeks* 129 2 weeks-2 months 36 After 2 months 26 Era of presentation After 1979* 77 Before 1980 114
(%)
(95%
With relative risk
cu
(95%
cu
(72) (3) (18) (7)
0.47 1.45 0.38
P = 0.02 (0.14, 1.60) (0.71, 2.95) (0.14, 1.01)
0.50 1.56 0.41
(0.14, 1.76) (0.74, 3.27) (0.15, 1.10)
(71) (18) (II)
0.54 0.81
P = 0.13 (0.29,0.99) (0.38, 1.71)
0.49 0.84
(0.27,0.90) (0.39, 1.79)
(58) (42)
1.35
P = 0.30 (0.77, 2.37)
1.34
(0.74,2.41 )
(44) (9) (20) (2) (25)
1.85 1.93 4.73 3.40
P = 0.01 (0.89, 3.87) (0.57,6.51) (1.16,19.28) (1.64,7.06)
1.75 2.32 6.23 3.17
(0.81,3.76) (0.65, 8.28) (1.35, 28.75) (1.53, 6.52)
(60) (40)
0.35
P = 0.03 (0.13, 0.92)
0.50
(0.17, 1.43)
(82) (18)
2.33
P = 0.01 (1.25, 4.32)
2.47
(1.03, 6.00)
(85) (15)
4.83
P < 0.0001 (2.41,9.72)
5.17
(2.55, 10.44)
(45) (46) (9)
1.28 0.51
p = 0.23 (0.46, 3.56) (0.15, 1.65)
1.99 0.59
(0.66, 5.97) (0.17, 1.98)
(88) (12)
16.56
p < 0.0001 (7.36, 37.32)
28.21
(11.23, 70.89)
(67) (19) (14)
0.54 0.23
p < 0.003 (0.29, 1.00) (0.09,0.60)
0.46 0.22
(0.25,0.94) (0.08, 0.58)
(40) (60)
2.16
P = 0.001 (1.36, 3.42)
2.30
(1.43, 3.67)
To calculate the iotal relative risk of a patient with a particular variant of double-inlet ventricle at presentation. all the relative risks for that patient are multiplied together, as previously described.' AV, Atrioventricular; VA, ventriculoarterial. 'Baseline category. tVentriculoarterial outlet from either dominant or rudimentary ventricle.