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Ann Thorac Surg 1996;62:1329-1335
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Aprotinin Improves Outcome of Single-Ventricle Palliation

Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Elevation of pulmonary vascular resistance as a consequence of cardiopulmonary bypass may lead to failure of single-ventricle palliation. We reviewed our experience with aprotinin, a nonspecific serine protease inhibitor, to determine whether it could ameliorate the inflammatory effects of cardiopulmonary bypass and improve outcome of single-ventricle palliation.

Methods. Forty-six consecutive patients undergoing single-ventricle palliation using cardiopulmonary bypass were reviewed retrospectively. Aprotinin was used in 8 of 30 bidirectional cavopulmonary shunt and 10 of 16 Fontan procedures.

Results. Aprotinin use was associated with a decrease in the early postoperative transpulmonary gradient among patients undergoing Fontan and bidirectional cavopulmonary shunt procedures. The bidirectional cavopulmonary shunt aprotinin group had a higher oxygen saturation and a decrease in quantity and duration of thoracic drainage. Among patients receiving aprotinin there were no episodes of mediastinitis, thrombus formation, or renal failure.

Conclusions. Aprotinin use in single-ventricle palliation was associated with decreased transpulmonary gradient and increased oxygen saturation consistent with decreased pulmonary vascular resistance. This retrospective study suggests that aprotinin has a favorable impact on the early postoperative course of single-ventricle palliation.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1335.

Cardiopulmonary bypass (CPB) can result in increased pulmonary vascular resistance (PVR) in the postoperative patient [1]. Patients undergoing single-ventricle palliation, either bidirectional cavopulmonary shunt (BDCPS) or the Fontan procedure, are exquisitely sensitive to acute elevation of PVR [2]. Aprotinin is a serine protease inhibitor that inhibits the contact, neutrophil, and platelet activation system during CPB [3]. We speculated that aprotinin may ameliorate some of the adverse effects of CPB and improve the early postoperative course of patients undergoing single-ventricle palliation.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
To determine the effect of aprotinin on the outcome of single-ventricle palliation, we reviewed retrospectively all patients with single-ventricle anatomy undergoing BDCPS and Fontan procedures between January 1994 (when aprotinin first became available at the Children's Hospital of Wisconsin) and December 1995. All patients undergoing Fontan procedures were included. The purpose of this retrospective study was to determine whether aprotinin could ameliorate the adverse effects of CPB on patients undergoing single-ventricle palliation, and therefore 1 patient, aged 29 years, undergoing a BDCPS with a thoracotomy without CPB was excluded. A second patient, aged 6 years, also undergoing BDCPS with a thoracotomy with an incomplete mixing lesion and significant antegrade flow from the pulmonary artery was also excluded. All patients with single-ventricle anatomy underwent staged palliation to completion Fontan. The remaining groups include 30 patients who underwent BDCPS and 16 patients who underwent the Fontan procedure. All procedures used CPB and were performed on patients with complete mixing lesions with the intent that all pulmonary blood flow would be delivered either through the BDCPS or Fontan connection. Pulmonary artery closure was used in cases of significant antegrade pulmonary artery blood flow. Among patients undergoing the Fontan procedure, trivial antegrade blood flow persisted in 3 of 10 patients in the aprotinin group and 1 of 6 patients in the control group. Among patients undergoing BDCPS, trivial antegrade blood flow persisted in 1 of 8 patients in the aprotinin group and 7 of 22 patients in the control group. Aprotinin was used at the discretion of the surgeon, when the patient was thought to be at increased risk for hemorrhage. Aprotinin was used during operation in 8 of 30 patients undergoing BDCPS and in 10 of 16 patients undergoing the Fontan procedure. Patients were given a 1.4-mg test dose of aprotinin before receiving the full dose, which was 240 mg/m² as a loading dose, followed by a continuous infusion of 56 mg • h^-1 • m^-2 with an additional 240 mg/m² added to the pump oxygenator.

Sources of data included preoperative cardiac catheterizations, echocardiograms, and hospital records. We reviewed patient characteristics including age at operation, anatomy, previous procedures, type of incision (thoracotomy or sternotomy), and preoperative hemodynamic data. We compared outcome between those patients who received aprotinin and those who did not. Failure of the planned procedure was defined as death or takedown to a BDCPS after the Fontan procedure or, for the BDCPS procedure, takedown to a systemic-to-pulmonary artery shunt or the need for addition of a systemic-to-pulmonary artery shunt to maintain adequate arterial oxygen saturation. Postoperative superior vena caval pressure, transpulmonary gradient, and oxygen saturations were obtained by reviewing intensive care unit records, and comparisons were made at 0, 6, 12, 18, and 24 hours. Thoracic drainage during the first 24 hours and duration of thoracic drainage were compared. Transfusions received after cessation of CPB between the two groups were compared. As an indicator of renal function we reviewed serum creatinine levels (BDCPS, days 1 to 3; Fontan, days 1 to 5) between the aprotinin and control groups.

Statistical comparison between the two groups was performed using Student's t test, Mann-Whitney rank sum, ², and Fisher's exact test. Analysis of variance on repeated measures was used to compare the postoperative hemodynamic and oxygen saturation data. A p value of less than 0.05 was deemed to be statistically significant. All data are expressed as mean ± the standard error of the mean.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Preoperative patient characteristics and hemodynamic characteristics are summarized in Table 1. There were no differences in the preoperative patient characteristics including age, hemodynamics, or oxygenation between either the BDCPS aprotinin and BDCPS control groups or the Fontan aprotinin and Fontan control groups. Single-ventricle anatomy is summarized in Table 2. Twenty-five patients had single left ventricular anatomy, 10 had single right ventricular anatomy, and 11 had indeterminate single-ventricle morphology. Previous incisions are summarized in Table 3. Among patients undergoing BDCPS, there was a significantly greater proportion of previous median sternotomies in the aprotinin group compared with the control group (p = 0.01, by Fisher's exact test). Previous procedures are summarized in Table 4.

There were two deaths among the 16 patients undergoing the Fontan procedure. Both were in the control group. The first was a 12-month-old female baby with Down syndrome and tricuspid atresia in whom worsening cyanosis developed despite a well-functioning BDCPS that had been constructed at 6 months of age. She underwent the Fontan procedure, which was complicated by decreased arterial saturation and low output. Cardiac catheterization demonstrated a thrombus in the lateral tunnel, and despite successful revision she eventually succumbed to sepsis. The second death was in a 7-year-old boy with a single ventricle of right ventricular morphology with systemic outflow obstruction who had undergone a coarctation repair and pulmonary artery banding through a left thoracotomy in the newborn period. He subsequently underwent two sternotomies for relief of subaortic stenosis as well as a BDCPS. He then underwent a Fontan combined with a Damus-Kaye-Stansel procedure. In the early postoperative period elevated superior vena caval pressure with low output developed, and he was placed on an extracorporeal membrane oxygenator; he was subsequently weaned from extracorporeal membrane oxygenator support with the help of inhaled nitric oxide. He was hemodynamically stable, with mechanical ventilatory support, and succumbed to fungal mediastinitis.

There were three failures (no deaths) among the patients undergoing BDCPS; all were among patients who did not receive aprotinin. The first patient had a progressive increase in superior vena caval pressure and decreased oxygen saturation in the first 24 hours postoperatively and required takedown to a central systemic-to-pulmonary artery shunt. Two patients required a 4-mm polytetrafluoroethylene systemic-to-pulmonary artery shunt in addition to the BDCPS to achieve adequate arterial saturation to wean from CPB. There were no failures among the patients undergoing single-ventricle palliation who received aprotinin. These differences in failure rates between the aprotinin and control groups were not significant.

Hemodynamic parameters, superior vena caval pressure, and transpulmonary gradient were compared between the aprotinin and control groups. Measurements were compared immediately on arrival to the postoperative intensive care unit and 6, 12, 18, and 24 hours postoperatively. There was no significant difference in the superior vena caval pressure between the aprotinin and control groups among either BDCPS or Fontan patients. However, superior vena caval pressure measurements were consistently lower in the Fontan aprotinin group compared with the Fontan control group (Fig 1). The transpulmonary gradient was significantly improved in the aprotinin-treated groups, both among patients undergoing BDCPS and the Fontan procedures (Fig 2). The Fontan aprotinin group demonstrated the greatest improvement, with a significant difference in transpulmonary gradient at 12 and 18 hours postoperatively compared with the Fontan control group. The BDCPS aprotinin group demonstrated an improvement at 6 hours postoperatively compared with BDCPS control group. Arterial oxygen saturations also showed improvement in the BDCPS aprotinin group compared with the BDCPS control group (Fig 3). Saturations were significantly greater in the BDCPS aprotinin group at 12 and 18 hours postoperatively. Although arterial saturations were consistently greater in the Fontan aprotinin group compared with the Fontan control group, this difference did not reach statistical significance.

View larger version (54K): [in this window] [in a new window]   Fig 1. . Postoperative superior vena caval pressure in patients undergoing bidirectional cavopulmonary shunt (BDCPS) (top) and Fontan (bottom) procedures. There was no significant difference in the postoperative superior vena caval pressure (SVC) in patients undergoing bidirectional cavopulmonary shunt during the first 24 hours. There did appear to be a trend toward a higher superior vena caval pressure in the Fontan control group. The largest difference was at 18 hours when the p value reached 0.07.

View larger version (51K): [in this window] [in a new window]   Fig 2. . Postoperative transpulmonary gradient ( TPG) measured in patients undergoing bidirectional cavopulmonary shunt ( BDCPS) (top) and Fontan (bottom) procedures. Transpulmonary gradient was significantly decreased among bidirectional cavopulmonary shunt and Fontan patients who received aprotinin ( p <0.05 by analysis of variance on repeat measures).

View larger version (44K): [in this window] [in a new window]   Fig 3. . Postoperative arterial saturation (SaO2) in patients undergoing bidirectional cavopulmonary shunt (BDCPS) (top) and Fontan (bottom) procedures. Bidirectional cavopulmonary shunt patients receiving aprotinin had a significantly higher arterial saturation in the postoperative period (p <0.05 by analysis of variance on repeat measures).

View larger version (40K): [in this window] [in a new window]   Fig 4. . Postoperative creatinine level among patients undergoing bidirectional cavopulmonary shunt (BDCPS) (top) and Fontan (bottom) procedures. There was no difference in postoperative creatinine between the control and aprotinin groups among patients undergoing either bidirectional cavopulmonary shunt or Fontan procedures.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Aprotinin-treated patients demonstrated evidence of decreased postoperative PVR. The transpulmonary gradient was significantly lower in the Fontan aprotinin group compared with the Fontan control group. This decrease in transpulmonary gradient was also seen in the BDCPS patients, but it was less sustained. Arterial saturation was significantly improved in the BDCPS aprotinin group. These findings are consistent with the effect lower PVR would have on BDCPS and Fontan physiology. Assuming normal lung function and minimal fenestration, all blood entering the systemic ventricle after the Fontan procedure will be nearly fully saturated. A small reduction in saturation may be seen as the results of coronary sinus return to the systemic circulation. As long as cardiac output can be maintained, the transpulmonary gradient will increase as the PVR increases. In the BDCPS patient, arterial saturation depends on the ratio of pulmonary to systemic blood flow or Qp/Qs. Indeed, one of the benefits of staging single-ventricle palliation with a BDCPS is that acute elevation of PVR is tolerated as systemic cardiac output is maintained, albeit with some degree of systemic desaturation [2]. With increasing PVR the BDCPS patient will have a decrease in the Qp/Qs and a decrease in arterial saturation. The findings of a lower transpulmonary gradient among Fontan patients receiving aprotinin and increased arterial saturation among BDCPS patients receiving aprotinin are both consistent with a lower PVR in these two anatomic arrangements.

The initiation of CPB is associated with the production of a number of vasoactive substances [10]. The two agents most likely to be responsible for the acute elevation of PVR after CPB are thromboxane A₂ and endothelin-1 [11–14]. The primary source of thromboxane A₂ is the platelets [10]. Aprotinin prevents platelet activation by preserving platelet glycoprotein Ib [15]. Glycoprotein Ib is expressed in decreased quantity on the surface of platelets in children with cyanotic heart disease; therefore, they may be more susceptible to platelet activation on CPB and more likely to benefit from aprotinin [16]. Endothelin-1 is produced by endothelial cells [10]. Association of activated platelets or leukocytes with endothelial cells is thought to be necessary for release of endothelin-1. Strategies to decrease the number of circulating leukocytes or to prevent leukocyte activation are thought to be successful in decreasing PVR after CPB by decreasing release of endothelin-1 [17, 18]. By preventing activation of leukocytes and platelets, aprotinin may decrease release of endothelin-1. Further study will be needed to identify the exact mechanisms by which aprotinin lowers PVR.

Aprotinin has been shown to decrease transfusion requirements after pediatric and adult cardiac procedures [19–21]. In our study, patients undergoing BDCPS who received aprotinin were in a higher risk group for bleeding; 7 of 8 patients had undergone previous median sternotomies compared with 7 of 22 control patients. Despite the increased risk for bleeding there was no difference in number of transfusions between the BDCPS aprotinin and BDCPS control groups. Thoracic drainage was reduced in the BDCPS aprotinin group compared with the BDCPS control group. Duration of thoracic drainage was also decreased in the BDCPS aprotinin group compared with the BDCPS control group. All patients undergoing the Fontan procedure had undergone at least two previous operations including at least one median sternotomy. More patients in the Fontan aprotinin group had undergone three previous procedures (60%, 6 of 10 patients) compared with the Fontan control group (33%, 2 of 6 patients), but this difference was not significant. There was no significant difference in red cell transfusions, clotting factor transfusions, or total transfusions between the Fontan aprotinin group and the Fontan control group, although in all categories the Fontan aprotinin group averaged fewer transfusions. Likewise, thoracic drainage was not diminished either in the first 24 hours or in total duration.

These data suggest reduction in thoracic drainage and transfusion requirements in BDCPS patients who received aprotinin, but this reduction was not seen in the Fontan patients. The lack of difference in transfusions and thoracic drainage among Fontan patients may be attributable to the more extensive nature of the Fontan procedure in patients who had undergone (all cases) at least two previous operations. In addition, in the Fontan patient, thoracic drainage is a function of elevated venous pressure rather than solely a function of hemostasis [22, 23]. No attempt was made to alter transfusion strategy in this study. Transfusion of red cells and clotting factors was directed by the subjective interpretation of bleeding by the surgeon and anesthesiologist rather than by specific factor deficiency. Therefore, to a degree, transfusions were given based on previous institutional experience and this may account for the lack of larger differences between the aprotinin and control groups.

Aprotinin has been implicated in an increased incidence of thrombus formation, renal failure, and mediastinitis after cardiac operations [21, 24–26]. In our study, no adverse affects of aprotinin were identified. The only failed procedures occurred in the control group. A single episode of thrombus formation occurred in the lateral tunnel of a Fontan control patient. One episode of mediastinitis also occurred in a control Fontan patient. Renal failure was not seen in any patient and there was no difference in serum creatinine between the aprotinin and control groups. Profound hypothermic circulatory arrest was used in 1 patient receiving aprotinin without adverse renal or neurologic events.

This was a retrospective study involving a limited number of patients with single-ventricle anatomy. Given the paucity of data concerning the use of aprotinin in this group of patients where reoperation is frequent and improved hemostasis as well as decreased PVR are of significant benefit, the data in this report may be useful. Additional prospective studies will be necessary to confirm these findings and identify the mechanism by which aprotinin improved the outcome of single-ventricle palliation.

In conclusion, in a retrospective study of patients undergoing single-ventricle palliation, aprotinin was associated with decreased thoracic drainage and evidence of lowered PVR. Aprotinin use was not associated with an increased failure rate and no complications could be related to aprotinin use. There was no incidence of thrombus formation, renal failure, or neurologic events in the aprotinin group. We conclude that aprotinin is safe in patients undergoing single-ventricle palliation and appears to improve the early postoperative outcome.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We acknowledge the contribution of Drs David Z. Friedberg and John B. Thomas to the outcome of this study. We are indebted to the expert secretarial support of Karen Reinhold.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.

Address reprints requests to Dr Tweddell, Department of Cardiovascular Surgery, MS# 715, Children's Hospital of Wisconsin, 9000 W Wisconsin Ave, PO Box 1997, Milwaukee, WI 53201.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): James S. Tweddell Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tweddell, J. S. Articles by Litwin, S. B. Search for Related Content PubMed PubMed Citation Articles by Tweddell, J. S. Articles by Litwin, S. B. Related Collections Related Article