Survival and Probability of Cure Without and With Operation in Complete Atrioventricular Canal

Transcription

1 ORIGINAL ARTICLES Survival and Probability of Cure Without and With Operation in Coplete Atrioventricular Canal Thoas J. Berger, M.D., Eugene H. Blackstone, M.D., John W. Kirklin, M.D., L. M. Bargeron, Jr., M.D., Jane B. Hazelrig, Ph.D., and Malcol E. Turner, Jr., Ph.D. ABSTRACT Actuarial analysis based on postorte exaination of patients who had been treated nonsurgically for coplete atrioventricular (A-V) canal defect shows that only 54% survive to 6 onths of age, 35% to 12 onths, 15% to 24 onths, and 4% to 5 years of age. Our surgical experience since 1975 in 39 patients confirs the idea that priary repair is feasible in sall infants. The highest risk of hospital death is when the operation is done in the early onths of life; it falls to 17% by age 12 onths. Between 1967 and October, 1976, the fiveyear survival rate aong patients leaving the hospital alive after repair was 91%. The age-specific probability of surgical cure of patients operated upon for coplete A-V canal (alive five years later.with ean pulonary artery pressure less than 25 Hg) is axial at 73% when the operation is done at about 14 onths of age. Urgent earlier repair is frequently necessitated by the life history of the disease. A trend has recently developed toward earlier priary repair in patients with the copletc for of coon atrioventricular (A-V) canal defect [l, 2, 5, 11, 121. The risk of operation is soewhat higher in young infants than in older children [131. This raises questions concerning the long-ter results of this trend, and concerning the relative benefits of this patient anageent progra copared with others. Therefore, we have studied the age-specific survival without surgical treatent of indi- Fro the Departents of Surgery, Pediatrics and Bioatheatics, University of Alabaa School of Medicine and Medical Center, Biringha, AL. Supported in part by Progra Project Grant HLB 11,310 fro the National Heart, Lung and Blood Institute, Bethesda, MD. We are very appreciative of the skillful editorial and graphic work of Ms. Sandy O Brien in the preparation of this paper. Accepted for publication June 29, Address reprint requests to Dr. Kirklin, Departent of Surgery, University Station, Biringha, AL viduals born with the coplete for of coon A-V canal. We analyzed further the early and late results of priary repair. Fro a coparison of these data, we propose a progra of anageent for patients born with the coplete for of coon A-V canal defect. Material and Methods Life Expectancy Without Operation Life expectancy without surgical treatent of persons with the coplete for of coon A-V canal was investigated by detailed individual study of 39 subjects described in two review articles by Edwards and colleagues [16, 181. The cases of Rogers and Edwards [16], which include both partial and coplete fors of the alforation, were exained in their original publications to identify the 28 with the coplete for without other cardiac anoalies of ajor anatoical or functional iportance (their references 3,7,8,13,15,17,18,21-23,27, 29,34,35, 37,39,40,41,43). Siilar individual study was ade of 11 additional patients described by Wakai and Edwards [18]. Actual age at death was known in 32 of the 39 patients. In 7 patients, age at death was known only within a finite age interval. These data were analyzed by conventional nonparaetric actuarial ethods [9], with odification to take into account the patients whose age at death was known only within a finite age interval,* and also by the paraetric survival distribution ethod [171, using axiu likelihood estiation procedures [8]. The latter technique yielded a siple equation describing survival as a function of age. Fro this equation, the hazard function h(t), which is the instantaneous death rate, could be de- *Hazelrig JB, Turner ME Jr, Blackstone EH: Paraetric survival analysis by nuerical axiization of likelihood functions derived fro a generic faily of survival distributions. Subitted for publication by Thoas J. Berger

2 105 Berger et al: Coplete Atrioventricular Canal scribed: h(t) = S (t)/s(t), where S (t) is the slope (first derivative) of the survival function S(t) [6]. Operative Results The early risk of priary repair in the coplete for of coon A-V canal is described fro our experience with 39 patients operated upon between January 1, 1975, and January, Sixteen of those less than 24 onths of age and operated upon between January, 1975, and October, 1976, have been previously reported [2]. A probability-of-event analysis was ade of the relationship between hospital death and age at operation using nonlinear logistic regression [4, 191. In a previous study we presented the late results in patients less than 2 years old [2]. For the present study we obtained follow-up inforation for the 23 patients of all ages leaving the hospital alive after operation in the years 1967 to This was obtained fro a systeatic review of each patient s postoperative visit records, correspondence with each patient s personal physician, and telephone conversations with the patient s faily. The date of inquiry was March 1, None of the patients have been lost to follow-up. We perfored an actuarial analysis [91 of the event of death for this group of patients to yield an estiate of the probability of five-year survival. The probability of patients having no ajor pulonary hypertension five or ore years after repair, as a function of age at operation, was assued to be the sae as that for patients operated upon for repair of large ventricular septal defects [41. Deterination of Age-Related Probability of Surgical Cure The optial age for repair of the coplete for of coon A-V canal was deterined by anipulation of the siple equations, each representing a probability function, generated by the ethods described. The probability of late survival without pulonary hypertension after surgical repair was calculated as the agespecific probability of leaving the hospital alive after operation, ultiplied by the probability of long-ter survival, ultiplied by the agespecific probability of having no pulonary hypertension five or ore years postoperatively. We have labeled this age-specific probability surgical cure. Results Life Expectancy Without Operation By actuarial analysis (Fig 1A) of the age at death of nonsurgically treated patients with the coplete for of coon A-V canal who were exained postorte, we found only 54% of individuals born with this alforation to be alive at 6 onths of age, 35% at 12 onths, 15% at 24 onths, and 4% at 5 years of age. Paraetric analysis of these data, with 70% confidence liits (CL),+ is shown in Figure 1B. The hazard function, reflecting the instantaneous rate of dying (see Methods), is highest in the first few onths of life and gradually falls after that, nearly to plateau at about 36 onths of age (Fig 1C). Life Expectancy With Operation We have considered life expectancy to be the cobined result of the risk of operation, the risk of late death after operation, and the late result in ters of pulonary vascular resistance. The present age-related risk of priary repair for the coplete for of A-V canal can be inferred in part fro our experience (Table). A paraetric analysis is shown in Figure 2. Of the 23 patients undergoing priary coplete repair and leaving the hospital alive between 1967 and October, 1976, 2 died late postoperatively, 1 at 2.8 onths and 1 at 2.9 onths postoperatively. No deaths have occurred later than this interval. Fro this experience, we have actuarially deterined the late survival to be 91% (CL, 81 to 97%), and assued this to be pertinent five years postoperatively. Age-Related Probability of Surgical Cure These data on hospital ortality and late survival were cobined with the age-specific probability of patients who have had repair of large ventricular septal defects having ean pulonary artery pressure less than 25 Hg five *Throughout this paper, CL refers to the 70% confidence liits.

3 106 The Annals of Thoracic Surgery Vol 27 No 2 February 1979 y 1.0 U t v) E 0.6 '1 0.s - > 5 0.L) LL 3 z L k n 0 g J 0 I0-2 2 nl nl J OD J J In 8 A AGE (MONTHS) g 0. 0 ~ ~ ~ ~ " ~ ~ ~ " " ~ ~ " " " " " " " " " " ~ " " " " " " ~ ~ ' ~ ~ ' " " ' " KL 0 w ' u _. N f M 0 M W N f f IIl f 0 W 2 7 B AGE (MONTHS) Fig 1. Life expectancy without operation for the coplete for of atrioventricular canal. (A) Nonparaetric actuarial analysis of the data fro the two review reports [16, 181. (B) Paraetric analysis. Plus signs represent the nonparaetric estiates; the solid line, enclosed within its 70% confidence liits (dotted lines), represents the paraetric survival distribution described by the equation: Q(t) = [I + (pt)-"]-"" where Q(t) = probability of dying and S(t) = 1 - QCt) = probability of surviving beyond age t; p = eso where Po = f and e = the base of the natural logariths, and u = 1.36 k Significance level of coefficients: P(&) < and P(u) < ; correlation between coefficients: r = (0 Hazard function.

4 ~ ~~ 107 Berger et al: Coplete Atrioventricular Canal C Fig 1 (continued) AGE (MONTHS) years postoperatively (Fig 3). We found overall surgical cure to be axial at about 73% (CL, 62 to 82%) when the operation was done at 14 onths of age (CL, 3 to 31 onths) (Fig 4). When the operation was done at 2 onths of age, about 55% (CL, 38 to 72%) of patients have a surgical cure, at 3 onths 61% (CL, 47 to 73%), and at 6 onths 68% (CL, 58 to 78%). This contrasts with the very high probability of preature death (96% probability of death by age 5 years) without operation. Coent Prospective deterination of the natural history of alforations such as the coplete A-V canal defect is no longer possible because of the availability of effective surgical treatent. Yet knowledge of natural history is iportant to the forulation of optial patient anageent progras. We took the only ethod available for estiation of life expectancy without operation: age at death in a sizeable and presuably representative group of patients exained postorte following nonsurgical treatent of their defect. The results of a siilar analysis for tetralogy of Fallot were not significantly different fro an estiation ade by census techniques of life expectancy for persons with this alforation [3]. Therefore, we believe it likely that the life expectancy without operation por- Priary Repair of Coplete For of Coon Atrioventricular Canal (University of Alabaa, ) < 3 3< 6 6 < < 24 2< 5yr 5 < 10 yr S 10 yr Total Hospital Deaths No. of Patients NO. (%) 70% CL CL = confidence liits % 10-55% 246% 0-17 '/o 3-63% 3-53% 0-85'/ '/o trayed in Figure 1 and in the Table is a reasonably accurate estiate of the truth. This belief is supported by the siilarity in age distribution between patients who underwent surgical treatent in our recent experience and patients who survived without such treatent (Fig 5). This is presued to be deterined by the proportion of persons at various ages who develop serious syptos which, if untreated, would soon lead to death. We have assued that individuals with the coplete for of coon A-V canal are surgically cured if they are alive five years later and

5 108 The Annals of Thoracic Surgery Vol 27 No 2 February 1979 AGE AT REPAIR (MONTHS) Fig 2. Relationship of age at operation and the probability of hospital death in the University of Alabaa expcrience, 1975 to January, Logistic equation (solid line) enclosed by 70% confidence liits is: P(death) = 1 /(I + exp[ k f * ln(age)l) where exp is e, the base of the natural logariths (In), and age at operation is given in onths. Significance level of coefficients: P(intercept) = 1.O, P(age) = 0.07; correlation between coefficients: r = L, 0. I 0 ' ' ' ' 6 I AGE (MONTHS) AT REPAIR OF VSD Fig 3. Probability of ean pulonary arterial blood pressure (Pd being less than 25 Hg in patients surviving five years after operation for repair of large ventricular septa1 defect. The dotted lines enclose the 70% confidence liits. Logistic equation for this re- ~41.) lationship: Pr = 1/(2 + exp[-9.4 f k In(age)l) where the definitions are as in Figure 2. Significance level of coefficients: Rintercept) = , P(age) = ; correlation between coefficients: r = (Data and analysis are fro Blackstone and colleagues

6 109 Berger et al: Coplete Atrioventricular Canal 1.o =w 0.9 U 2 0.8,,...~~-~~-~-.. a 0.1 A 1 I 1 I 1 0.o I N t ID 2 2 AGE (YEARS) AT OPERATION 1.o = 0.9 W U _ _ > 0.1) ; k !.. B ~ ~. " ' ~ ~ " l ~. ' ' " ' ~ " " ' ' ~ ' ~ ' ' ' l '..... ~. l ~.. ~. I. l l... l... I s- W 2 - N 1c) 0 ID 1c) N f AGE (MONTHS) AT OPERATION f f I n W o Fig 4. Age-specific probability of "surgical cure" of patients with the coplete for of coon A-V canal (solid line), enclosed by its 70% confidence liits (dotted lines). Maxiu surgical cure occurs when operation is perfored between 3 and 31 onths (peak at about 14 onths) of age. (A) Plotted to age 22 years; (B) plotted to age 60 onths.

7 110 The Annals of Thoracic Surgery Vol 27 No 2 February 1979 AGE (MONTHS) Fig 5. Relation of age to proportion of patients coing to operation at the University of Alabaa between October, 1976, and January, 1978 (N = 20; 1 patient aged 63 onths at repair, I aged 65 onths, and I aged 21 years are off scale to the right of the graph), expressed as 1.O inus the cuulative proportion coing to operation by the stated age. For coparison, the paraetric analysis of survival without operation is shown. have a ean pulonary artery pressure lower than 25 Hg because no patient has developed late coplete heart block or notable A-V valve incopetence. These coplications have also been rare in the experience of others [5, 7, 10, 131. The assuption of a 91% five-year survival rate based on our data could be challenged. This figure is, however, copatible with follow-up reported by the Mayo Clinic [13] on older children after repair. The high proportion of deaths in surgically untreated infants with the coplete for of the coon A-V canal defect, as shown in Figures 1 and 2, is consistent with the experiences of any pediatric cardiologists [14]. Most of the deaths in infancy are fro severe congestive heart failure caused by the large left-to-right shunt and whatever A-V valve incopetence ay be present. Deaths after about 5 years of age are probably fro pulonary vascular disease in ost instances. Severe pulonary vascular disease tends to develop earlier in persons with co- plete A-V canal than in those with large ventricular septa1 defects [15], and it ay be present in any patients by 18 onths of age. Down's syndroe, present in 30% of our surgically treated patients [2], probably also affects the natural history of persons with this alforation because of its tendency to produce upper airway obstruction and frequent episodes of pulonary congestion. The present risk of priary repair of coplete A-V canal in infants is probably reasonably well represented by the data in Figure 2, since they are siilar to the results reported by Mair and McGoon [lll and by Culpepper and colleagues [5]. Pulonary artery banding and later repair ight iprove the results in patients requiring operation when younger than 3 onths of age, but a previous review of the hospital ortality after banding for this alforation does not support this idea [21. Further, we expect the ortality in patients younger than 3 onths of age to be reduced soewhat ore now that understanding of the alforation and the techniques for anaging it have iproved. However, the relatively high proportion of infants with very severe fors of the alforation, including arked left or right ventricular hypoplasia, who are in serious trouble in the first onth or so of life ay keep surgical ortality high in this age group. Ideally, no patient with coplete A-V canal should die without diagnosis and surgical

8 111 Berger et al: Coplete Atrioventricular Canal treatent. However, soe infants are born with variants such as severe left or right ventricular hypoplasia and extree overriding of the coon A-V orifice over one ventricle. (Soe are born with severe associated cardiac alforations, but these are not considered here.) These infants ay die so early in life as to preclude surgical repair. Otherwise, under ideal circustances, the hospital ortality at the various ages should be no ore than the total early ortality fro the alforation. Conclusions Infants with the coplete for of coon A-V canal should have priary repair whenever notable syptos occur. Our analysis indicates that this is often in the early onths of life. Infants with the coplete for of coon A-V canal who have no ajor heart failure and whose pulonary vascular resistance is noral or nearly so should be deferred for operation until about 14 onths of age. This is predicted to give the highest probability of obtaining a surgical cure in patients who can be operated upon electively. The broad 70% CL of the idea1 age for operation (3 to 31 onths) indicate the reasonableness of doing the procedure a few onths earlier in infants who are not thriving or who have elevated pulonary vascular resistance, and a few onths later in those who are doing well clinically and have low pulo- nary vascular resistance. When operation is done any onths earlier, salvage is liited at present by the higher hospital ortality. When done uch later than this age, the probability of surgical cure is liited by pulonary vascular disease. Further, with the passage of tie, an increasing nuber of patients becoe inoperable after 1 year of age because of pulonary vascular disease. References Barratt-Boyes BG: Correction of atrioventricular canal defects in infancy using profound hypotheria, in Heart Disease in Infancy: Diagnosis and Surgical Treatent. Edited by BG Barratt-Boyes, Jh4 Neutze, EA Harris. Edinburgh and London, ChurchilllLivingstone, 1973, p 110 Berger TJ, Kirklin JW, Blackstone EH, et al: Priary repair of coplete atrioventricular canal in patients less than 2 years old. A J Cardiol 41:906, Bertranou EG, Blackstone EH, Hazelrig JB, et al: Life expectancy without surgery in the tetralogy of Fallot. A J Cardiol 42:458, 1978 Blackstone EH, Kirklin JW, Bradley EL, et al: Optial age and results in repair of large ventricular septa1 defects. J Thorac Cardiovasc Surg 72:661, 1976 Culpepper W, Kolff J, Replogle R, et al: Correction of coplete atrioventricular canal defect during infancy (abstract). A J Cardiol 39:293, 1977 Gross AJ, Clark VA: Survival Distributions: Reliability Applications in the Bioedical Sciences. New York, Wiley, 1975, pp 1-22 Hardesty RL, Zuberbuhler JR, Bahnson HT: Surgical treatent of atrioventricular canal defect. Arch Surg 110:1391, 1975 Hazelrig JB, Turner ME Jr, Ackeran E: A function iniization coputer package (MFIT) for nonlinear paraeter estiation providing readily accessible axiu likelihood estiates. Coput Bioed Res 11:51, 1978 Kaplan EL, Meier P: Non-paraetric estiation fro incoplete observations. J A Stat Assn 53:487, 1958 Lillehei CW, Anderson RC, Ferlic RM, et al: Persistent coon atrioventricular canal: recatheterization results in 37 patients following intracardiac repair. J Thorac Cardiovasc Surg 57333, 1969 Mair DD, McGoon DC: Surgical correction of atrioventricular canal during the first year of life (abstract). A J Cardiol 39:293, 1977 McGoon DC, McMullan MH, Mair DD, et al: Correction of coplete atrioventricular canal in infants. Mayo Clin Proc 48:769, 1973 McMullan MH, Wallace RB, Weidan WH, et al: Surgical treatent of coplete atrioventricular canal. Surgery 72:905, 1972 Nadas AS, Fyler DC: Pediatric Cardiology. Philadelphia, Saunders, 1972 Newfeld EA, Sher M, Paul MH, et al: Pulonary vascular disease in coplete atrioventricular canal defect. A J Cardiol39:721, 1977 Rogers HM, Edwards JE: Incoplete division of the atrioventricular canal with patent interatrial foraen priu (persistent, coon atrioventricular ostiu): report of five cases and review of the literature. A Heart J 36:28, 1948 Turner ME Jr, Pruitt KM: A coon basis for survival, growth, and autocatalysis. Math Biosci 39:113, 1978 Wakai CS, Edwards JE: Developental and pathologic considerations in persistent coon atrioventricular canal. Mayo Clin Proc 31 :487, 1956 Walker SH, Duncan DB: Estiation of the probability of an event as a function of several independent variables. Bioetrika 54:167, 1967