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Ann Thorac Surg 1998;66:1521-1526
© 1998 The Society of Thoracic Surgeons

Surgical management of total anomalous pulmonary venous drainage: impact of coexisting cardiac anomalies

^a Division of Cardiovascular Surgery, The Hospital for Sick Children, University of Toronto and University of Toronto Faculty of Medicine, Toronto, Ontario, Canada

Address reprint requests to Dr Caldarone, Division of Cardiovascular Surgery, The Children’s Hospital of Iowa at the University of Iowa Hospitals and Clinics, 200 Hawkins Dr, 1616A JCP, Iowa City, IA 52242-1083
e-mail: (Chris-Caldarone{at}UIowa.edu)

Accepted for publication August 6, 1998.

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
Background. Recent reports have cited improving results for surgical management of isolated total anomalous pulmonary venous drainage. Complex cases (with other cardiac anomalies) are less frequently reported and are associated with higher mortality.

Methods. Retrospective review identified 170 consecutive patients treated for total anomalous pulmonary venous drainage from 1982 to 1996: 44 cases were "complex" (with significant associated cardiac lesions) and 126 cases were "simple."

Results. Operative mortality for simple cases decreased from 26% to 8%, and mortality for complex cases remained constant at 52%. Age, size, and the presence of atrial isomerism were univariate predictors of mortality. Multivariable analysis identified only univentricular hearts and associated cardiac lesions as predictors of operative mortality. Pulmonary artery (n = 16) and arteriopulmonary (n = 7) shunting strategies for complex cases resulted in less than 30% long-term survival.

Conclusions. Despite improvement in survival for simple cases, management of total anomalous pulmonary venous drainage with single-ventricle hearts or other associated cardiac lesions remains problematic.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Total anomalous pulmonary venous drainage is a rare cardiac anomaly, often associated with other complex cardiac malformations. In the absence of other anomalies, multiple centers have cited decreasing mortality rates in the current era. Recent studies have attributed the mortality rate of 2% to 18% [1, 2] to improvements in management before, during, and after operation [3, 4].

Most studies, however, include only patients with isolated total anomalous pulmonary venous drainage and exclude patients with other cardiac lesions [4–6]. Improvement in the mortality associated with repair of complex total anomalous pulmonary venous drainage with associated cardiac anomalies has been less well documented.

In this report, the experience with total anomalous pulmonary venous drainage at the Hospital for Sick Children of Toronto is reviewed. Patients with and without associated complex anomalies are included in the review. The goal of the analysis is to define the results of operative management of this lesion and assess the impact of associated cardiac anomalies.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Review of the cardiovascular surgical database at the Hospital for Sick Children of Toronto between July 1982 and July 1996 identified 170 patients undergoing surgical repair of total anomalous pulmonary venous drainage. Patients with associated complex anatomic lesions are included in this cohort.

In general, the approach to the neonate with total anomalous pulmonary venous drainage at the Hospital for Sick Children has included aggressive preoperative stabilization and correction of metabolic abnormalities concurrent with diagnostic studies. In the early portion of the series, preoperative catheterization was commonly performed. In the latter portion of the series (after 1984), however, the use of diagnostic echocardiography has supplanted catheterization in routine cases. In cases of obstructed anomalous venous drainage, a strategy of preoperative intubation, aggressive correction of blood gas abnormalities and acidosis, and early operative repair was followed.

Operative techniques varied over the duration of the series. In general, during the early portion of the series, cardiopulmonary bypass with total hypothermic circulatory arrest was used, whereas in the latter portion of the series, more emphasis was placed on use of low-flow bypass. A right-sided approach to the pulmonary venous confluence through the right atrium and atrial septum was used (similar to the type I approach described by Wilson and colleagues [7]. In the early portion of the series, intracardiac pulmonary venous drainage was treated with simple unroofing of the coronary sinus and patch closure of the atrial septum, and for the latter portion of the series, dissection down to the transverse venous confluence and direct anastomosis of the confluence to the left atrium was emphasized (rather than simple unroofing of the venous confluence). Supracardiac cases are exposed using an extracardiac approach between the aorta and superior vena cava [8, 9]. Infracardiac cases are exposed by lifting the apex of the heart with direct anastomosis of the vertical confluence to the left atrium through a left-sided approach.

"Simple" cases were defined as patients with cardiac anomalies limited to total anomalous pulmonary venous drainage. Coexisting patent foramen ovale, patent ductus arteriosus, and atrial septal defect were also included in the simple group. "Complex" cases included patients with total anomalous pulmonary venous drainage and any other intracardiac lesion including univentricular hearts and atrial isomerism. For the purposes of the multivariable analysis, the group of complex cases was subdivided into patients having single-ventricle hearts, atrial isomerism, or associated complex lesions. The term associated complex lesions, therefore, refers to any cardiac anomaly other than simple patent ductus arteriosus, atrial septal defect, single ventricle, or isomerism. Operative deaths were defined as mortality occurring at less than 30 days after operative repair. Late deaths were defined as mortality occurring at greater than 30 days after operative repair.

The patients were grouped anatomically according to the site of anomalous pulmonary venous drainage. Supracardiac drainage was defined as pulmonary venous drainage exclusively to a right superior vena cava through a direct connection or through a left vertical vein and innominate vein. Intracardiac drainage refers to pulmonary venous drainage exclusively to the coronary sinus or the right atrium. Infracardiac drainage refers to exclusive pulmonary venous drainage to a site draining to the inferior vena cava. Mixed drainage refers to any case in which there is a combination of pulmonary venous drainage sites.

Follow-up was obtained by reviewing medical records for recent visits or by direct telephone contact. Statistical analysis was performed with Statistica statistical software (StatSoft, Tulsa, OK). Actuarial analysis of survival was performed using the Kaplan-Meier method. Univariate analysis was performed using Gehan’s generalized Mann-Whitney U test with a p value of 0.05 considered statistically significant. Multivariable analyses were performed using a forward and reverse stepwise proportional hazards Cox regression model.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Of the 170 patients in the study population, the ratio of males to females is 1.7 to 1. The median age at operative repair is 20.5 days (range, 1 day to 14.1 years), and the median patient weight is 3.5 kg (range, 1.9 to 30.1 kg).

The anatomic subtypes of the anomalous pulmonary venous connection are summarized in Table 1. Forty-four (26%) patients are considered to have complex anatomy. Twenty-two (50%) of the 44 complex patients had univentricular hearts and an additional 22 patients had complex anatomy because of other associated cardiovascular lesions.

View larger version (19K): [in this window] [in a new window]   Fig 1. The percentage incidence of each anatomic subtype is plotted as a function of age at repair. In the neonatal period (<1 month), the majority of cases are intracardiac. As age at repair increases, the percentage of supracardiac lesions increases. (Least squares multiple regression used to smooth data).

View larger version (13K): [in this window] [in a new window]   Fig 2. Actuarial survival for total anomalous pulmonary venous drainage.

View larger version (16K): [in this window] [in a new window]   Fig 3. Actuarial survival for the entire group stratified by the presence of simple versus complex anatomy (p < 0.001).

View larger version (18K): [in this window] [in a new window]   Fig 4. Survival stratified by age at first operation. Early deaths are the major determinant of age-based differences in survival (p < 0.01).

The cumulative operative mortality over the 14-year study period was analyzed to define changes in efficacy of perioperative management strategies. Overall operative mortality limited to patients with simple anatomy was 15% (19 operative deaths of 126 patient). In Fig 5, the cumulative operative mortality for cases with simple anatomy is plotted against the number of consecutive cases. The cumulative operative mortality is not well represented by a single linear regression and has an inflection point after approximately 50 cases (corresponding to an operative date in September 1987). Operative mortality before this juncture (first 50 cases) is 26%, and after this point (most recent 76 cases) is 7.9% (p < 0.02, ²). In contrast, the cumulative mortality for the complex cases remains relatively constant with a operative mortality rate of 52% (23 operative deaths of 44 cases, Fig 6).

View larger version (73K): [in this window] [in a new window]   Fig 5. Cumulative operative mortality for 125 consecutive cases with simple anatomy. A least squares regression line is included with a marker at the 50th case in the series, corresponding to an operative date of September 5, 1987. Operative mortality for the first 50 cases was 26.0% and for the following 76 cases was 7.9%.

View larger version (36K): [in this window] [in a new window]   Fig 6. Cumulative operative mortality for 44 consecutive cases with complex anatomy. A linear regression is plotted to demonstrate the lack of change in operative mortality.

View larger version (16K): [in this window] [in a new window]   Fig 7. Comparison of survival for univentricular and biventricular hearts (p < 0.001).

Seven patients underwent pulmonary artery banding to control excessive pulmonary blood flow. Of these patients nearly all had univentricular hearts. Five of the patients (71%) were operative mortalities. (Two patients had transposition of the great arteries and atrial isomerism, 1 had aortic coarctation with ventricular septal defect, and 2 had univentricular hearts associated with total anomalous pulmonary venous drainage). The other 2 were late survivors with univentricular hearts. Both patients underwent subsequent Fontan procedures and are alive at 6.6 and 11.8 years after initial palliation (double-outlet right ventricle with isomerism and atrioventricular septal defect with isomerism). Long-term survival was 29%.

Two patients underwent concurrent repair of aortic coarctation, with 1 late death (6 months) and 1 long-term survivor (4.8 years). A single neonate underwent closure of an atrial septal defect with aortic valvotomy for severe aortic stenosis and was an operative mortality. Finally, a single infant required closure of an isolated ventricular septal defect and was successfully discharged. The patient has been lost to follow-up at 4 months.

Four patients required perioperative extracorporeal membrane oxygenation support. Two patients who did not improve with extracorporeal membrane oxygenation died at 8 and 64 days postoperatively. The other 2 patients who needed extracorporeal membrane oxygenation were successfully discharged and are alive at 2.9 and 5.1 years follow-up. All 4 patients who were placed on extracorporeal membrane oxygenation had simple cardiac anatomy. The 2 survivors had intracardiac and supracardiac anomalous pulmonary venous connections. Long-term survival was 50% in this subset.

Three patients had evidence of restricted pulmonary arterial flow caused by pulmonary valvar or pulmonary artery stenosis. Two of these 3 patients had pulmonary arterioplasties at the time of palliative arteriopulmonary shunting for pulmonary atresia associated with atrial isomerism. Both were operative deaths. A single patient with restricted pulmonary arterial flow caused by pulmonary valve stenosis associated with a univentricular heart underwent pulmonary valvuloplasty and was an operative death. Operative mortality in this subset was 100%.

A final 3 patients underwent repair of tetralogy of Fallot, double-outlet right ventricle, and atrioventricular septal defect with mortalities at 69, 2, and 3 days, respectively.

For the entire series, the median follow-up was 4.7 years, and the duration of follow-up was greater than 1 year in 83% of the survivors.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

 
In the absence of associated cardiac anomalies, surgical management of total anomalous pulmonary venous drainage is associated with recent improvement in perioperative mortality [2–4]. This improvement has been ascribed to a constellation of factors including preoperative echocardiographic diagnosis [10, 11], improved preoperative stabilization and control of postoperative pulmonary hypertension [4], improved operative techniques [7], and early operative intervention [4, 5, 8]. In the present study, improvement in the operative mortality for patients without associated anomalies is also noted. The operative mortality rate of 7.9% in the current era compares favorably with other reports [2, 4, 7]. The factors responsible for this improvement, however, cannot be identified with the data presented. We speculate that the combination of the adoption of echocardiographic diagnosis rather than catheterization, more reliance on a left-sided approach to the pulmonary venous confluence, and better postoperative management of the critically ill neonate has resulted in this improved mortality.

It is difficult to reconcile the improved results in the simple group with the lack of improvement in the complex group. There was no evidence of improvement in the operative mortality for this group during the era studied. Because the preoperative management variables cited above would be nearly identical for the simple and complex groups (eg, use of the same diagnostic techniques, intensive care unit staff, institutional management policies), the lack of improvement may be because of a failure of intraoperative management strategies.

In the complex group, two distinct management strategies were used, based on the underlying anatomic problems encountered. In the first group, pulmonary flow was augmented with an arteriopulmonary shunt. Despite improvements in anesthetic and postoperative management, operative mortality was 50% with this approach, with no evidence of improvement over time. The overriding difficulty in operative management is to match an appropriate amount of systemic to pulmonary venous flow in a setting of a critically ill neonate with abnormalities in the pulmonary arterial and venous vasculature beyond that found in the normal postoperative neonate. Yamaki and coworkers [12] have described increased thickness in the media of the pulmonary arterial and venous vessels as well as fibrous thickening of the pulmonary venous intima in infants with total anomalous pulmonary venous connection. In cases of pulmonary hypertension, these changes were accentuated. The interplay of a systemic shunt with congenitally abnormal pulmonary vasculature may contribute to the difficulty in maintaining stable postoperative pulmonary to systemic flow ratios. The importance of the pulmonary vasculature as a determinant of survival is underscored in the report of Jenkins and associates [13], in which individual pulmonary vein size was identified as an important predictor of survival in patients with simple and complex total anomalous pulmonary venous drainage.

Heinemann and colleagues [14] reported an operative mortality rate of 25% (4 of 16 newborns) with visceral heterotaxy who underwent arteriopulmonary shunting with or without simultaneous repair of total anomalous pulmonary venous drainage. In the present study, long-term survival for this group was 27%. Differences between the two studies may be related to the slightly different populations. Patients in the study by Heinemann and associates were limited to newborns with heterotaxy. The degree to which other anomalies are present is not clear and, therefore, may preclude direct comparison with the present study.

Sadiq and coworkers [15], however, reported a 38% long-term survival in patients with right atrial isomerism and total anomalous pulmonary venous drainage requiring palliation with arteriopulmonary shunting. When this group is further limited to patients requiring operation within the first month of life, long-term survival decreased to 13%. A recent report from this institution by Hashmi and colleagues [16] has also noted higher mortality rates for patients with right atrial isomerism and total anomalous pulmonary venous drainage requiring operation within the first month of life.

A second management strategy, dictated by the preoperative anatomy, was to limit excessive pulmonary blood flow with pulmonary artery banding. Similarily, operative mortality was high (71%) and the long-term survival in this group was 21%. Although the surgical objective (limitation of pulmonary blood flow) was different from that for the shunting group (augmentation of pulmonary blood flow), the end result was similar. A common aspect of both strategies, however, was the placement of fixed resistors within the pulmonary arterial inflow in an attempt to regulate pulmonary blood flow. The static matching of this resistance to the cardiac output in the face of abnormal pulmonary vasculature may not allow appropriate regulation of the pulmonary blood flow during the dynamic changes associated with the early postoperative period.

In conclusion, multivariable analysis identifies the presence of complex associated cardiac lesions and univentricular hearts as risk factors for death after repair of total anomalous pulmonary venous drainage. There is a marked improvement in the operative mortality in the latter era for simple cases, with no evidence of improvement in the complex cases. Nondynamic regulation of pulmonary blood flow may contribute to hemodynamic instability in patients with complex lesions and single-ventricle physiology.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

1. Sano S., Brawn W.J., Mee R.B. Total anomalous pulmonary venous drainage. J Thorac Cardiovasc Surg 1989;97:886-892.[Abstract]
2. Lamb R.K., Qureshi S.A., Wilkinson J.L., Arnold R., West C.R., Hamilton D.I. Total anomalous pulmonary venous drainage: seventeen-year surgical experience. J Thorac Cardiovasc Surg 1988;96:368-375.[Abstract]
3. Cobanoglu A., Menashe V.D. Total anomalous pulmonary venous connection in neonates and young infants: repair in the current era. Ann Thorac Surg 1993;55:43-49.[Abstract]
4. Bando K., Turrentine M.W., Ensing G.J., et al. Surgical management of total anomalous venous connection: thirty year trends. Circulation 1996;94(Suppl 2):II-12-II-16.
5. Raisher B.D., Grant J.W., Martin T.C., Strauss A.W., Spray T.L. Complete repair of total anomalous pulmonary venous connection in infancy. J Thorac Cardiovasc Surg 1992;104:443-448.[Abstract]
6. Serraf A., Bruniaux J., Lacour-Gayet F., et al. Obstructed total anomalous pulmonary venous return: toward neutralization of a major risk factor. J Thorac Cardiovasc Surg 1991;101:601-606.[Abstract]
7. Wilson W.R., Ilbawi M.N., DeLeon S.Y., et al. Technical modifications for improved results in total anomalous pulmonary venous return. J Thorac Cardiovasc Surg 1992;103:861-871.[Abstract]
8. Lupinetti F.M., Kulik T.J., Beekman R.H., Crowley D.C., Bove E.L. Correction of total anomalous pulmonary venous return in infancy. J Thorac Cardiovasc Surg 1993;106:880-885.[Abstract]
9. Tucker B.L., Lindesmith G.G., Stiles Q.R., Meyer B.W. The superior approach for correction of the supracardiac type of total anomalous pulmonary venous return. Ann Thorac Surg 1976;22:374-377.[Abstract]
10. Smallhorn J.F., Freedom R.M. Pulsed Doppler echocardiography in the preoperative evaluation of total anomalous pulmonary venous return. J Am Coll Cardiol 1986;8:1413-1420.[Abstract]
11. Van der Velde M.E., Parness I.A., Colan S.D., et al. Two-dimensional echocardiography in the pre- and postoperative management of total anomalous pulmonary venous return. J Am Coll Cardiol 1991;18:1746-1751.[Abstract]
12. Yamaki S., Tsunemoto M., Shimada M. Quantitative analysis of pulmonary vascular disease in total anomalous pulmonary venous connection in sixty infants. J Thorac Cardiovasc Surg 1992;104:728-735.[Abstract]
13. Jenkins K.J., Sanders S.P., Orav J. Individual pulmonary vein size and survival in infants with totally anomalous pulmonary venous connection. J Am Cardiol 1993;22:201-206.
14. Heinemann M.K., Hanley F.L., Van Praagh S., et al. Total anomalous pulmonary venous drainage in newborns with visceral heterotaxy. Ann Thorac Surg 1994;57:88-91.[Abstract]
15. Sadiq M., Stumper O., De Giovanni J.V., et al. Management and outcome of infants and children with right atrial isomerism. Heart 1996;75:314-319.[Abstract/Free Full Text]
16. Hashmi A., Abu-Sulaiman, McCrindle B.W., Smallhorn J.F., Williams W.G., Freedom R.F. Management and outcomes of right atrial isomerism: a 26-year experience. J Am Coll Cardiol 1998;31:1120-1126.[Abstract/Free Full Text]

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