Aprotinin improves outcome of single-ventricle palliation

Aprotinin Improves Outcome of Single-Ventricle Palliation James S. Tweddell, MD, Stuart Berger, MD, Peter C. Frommelt, MD, Andrew N. Pelech, MD, David A. Lewis, MD, Raymond T. Fedderly, MD, Michele A. Frommelt, MD, Terrence S. McManus, CCP, Kathleen A. Mussatto, RN, Maryanne W. Kessel, RN, and S. Bert Litwin, MD Medical College of Wisconsin, Children's Hospital of Wisconsin, Milwaukee, Wisconsin

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.

a r d i o p u l m o n a r y b y p a s s (CPB) can result in increased p u l m o n a r y vascular resistance (PVR) in the postoperative patient [11. Patients u n d e r g o i n g singleventricle palliation, either bidirectional c a v o p u l m o n a r y shunt (BDCPS) or the Fontan procedure, are exquisitely sensitive to acute elevation of PVR [21. Aprotinin is a serine protease inhibitor that inhibits the contact, neutrophil, a n d platelet activation system during CPB [3]. We speculated that aprotinin m a y ameliorate some of the adverse effects of CPB and i m p r o v e the early p o s t o p e r a tive course of patients u n d e r g o i n g single-ventricle palliation.

CPB on patients u n d e r g o i n g single-ventricle palliation, a n d therefore 1 patient, a g e d 29 years, u n d e r g o i n g a BDCPS with a thoracotomy without CPB was excluded. A second patient, aged 6 years, also u n d e r g o i n g BDCPS with a thoracotomy with an incomplete mixing lesion a n d significant a n t e g r a d e flow from the p u l m o n a r y artery was also excluded. All patients with single-ventricle a n a t o m y u n d e r w e n t staged palliation to completion Forttan. The r e m a i n i n g groups include 30 patients who u n d e r w e n t BDCPS a n d 16 patients who u n d e r w e n t the Fontan procedure. All p r o c e d u r e s used CPB a n d were p e r f o r m e d on patients with complete mixing lesions with the intent that all pulmonary, b l o o d flow w o u l d be delive r e d either t h r o u g h the BDCPS or Fontan connection. P u l m o n a r y artery closure was u s e d in cases of significant a n t e g r a d e p u l m o n a r y artery blood flow. A m o n g patients u n d e r g o i n g the Fontan p r o c e d u r e , trivial a n t e g r a d e blood flow persisted in 3 of 10 patients in the aprotinin group and 1 of 6 patients in the control group. A m o n g patients u n d e r g o i n g BDCPS, trivial antegrade b l o o d flow persisted in I of 8 patients in the aprotinin group and 7 of 22 patients in the control group. A p r o t i n i n was u s e d at the discretion of the surgeon, w h e n the patient was thought to be at increased risk for hemorrhage. Aprotinin was u s e d during operation in 8 of 30 patients u n d e r g o i n g BDCPS a n d in 10 of 16 patients u n d e r g o i n g the Fontan procedure. Patients were given a 1.4-mg test dose of aprotinin before receiving the full dose, which was 240

C

Material and M e t h o d s To d e t e r m i n e the effect of aprotinin on the outcome of single-ventricle palliation, we reviewed retrospectively all patients with single-ventricle a n a t o m y u n d e r g o i n g BDCPS a n d Fontan p r o c e d u r e s b e t w e e n January 1994 (when aprotinin first b e c a m e available at the C h i l d r e n ' s Hospital of Wisconsin) a n d D e c e m b e r 1995. All patients u n d e r g o i n g Fontan p r o c e d u r e s were included. The p u r p o s e of this r e t r o s p e c t i v e s t u d y was to d e t e r m i n e w h e t h e r aprotinin could ameliorate the adverse effects of 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. © 1996 by The Society of Thoracic Surgeons Published by Elsevier Science lnc

(Ann Thorac Surg 1996;62:1329-36)

0003-4975/961515.00 Pll S0003-4975(96)00670-4

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TWEDDELLET AL SINGLE-VENTRICLEPALLIATIONAND APROTININ

Table I. Preoperative Patient Characteristics BDCPS Characteristics

Aprotinin

Control

Fontan Aprotinin

Control

No. of patients 8 22 10 6 Age (mo) 10 - 1 12 ÷ 1 70 _+8 70 + 23 BSA (m 2) 0.36 z 0.01 0.38 ± 0.01 0.72 + 0.3 0.72 + 0.2 PVR (Wood 0.9 + 0.2 1.5 + 0.6 1.4 -- 0.2 1.8 + 0.3 units) PAP mean 17+5 15_+1 10_+1 12_+1 (ram Hg) EDP 11 ± 1 9- 1 10 + 1 7 +1 (ram Hg) S a O 2 (%) 78 + 3 77 + 1 86 ± 1 83 ± 3 Qp/Q~ 1.6 + 0.3 1.1 + 0.1 0.62 ± 0.07 0.59 + 0.05 BDCPS - bidirectional cavopulmonary shunt; BSA - body surface area; EDP end-diastolic pressure; PVR pulmonaryvascular resistance; Qp/Qs = ratio of pulmonary blood to systemic blood flow; SaO2 = arterial saturation.

m g / m 2 as a loading dose, followed by a continuous infusion of 56 rng. h 1 - m 2 with an additional 240 m g / m 2 a d d e d to the p u m p oxygenator. Sources of data included preoperative cardiac catheterizations, echocardiograrns, and hospital records. We rev i e w e d patient characteristics including age at operation, anatomy, previous procedures, type of incision (thorac o t o m y or s t e r n o t o m y ) , a n d p r e o p e r a t i v e h e m o d y narnic data. We c o m p a r e d outcome b e t w e e n those patients wh o received aprotinin and those w h o did not. Failure of the p l a n n e d p r o c e d u r e was defined as death or t a k e d o w n to a BDCPS after the Fontan p r o c e d u r e or, for the BDCPS procedure, t a k e d o w n to a systemic-top u l m o n a r y artery shunt or the n e e d for addition of a s y s t e m i c - t o - p u l m o n a r y artery shunt to maintain adequate arterial oxygen saturation. Postoperative superior v e n a caval pressure, t r a n s p u l m o n a r y gradient, and oxygen saturations were obtained by reviewing intensive care unit records, and comparisons were m a d e 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 b e t w e e n the two groups were compared. As an indicator of renal function we r e v i e w e d s e r u m creatinine levels (BDCPS, days i to 3; Fontan, days I to 5) b e t w e e n the aprotinin and control groups. Statistical comparison b e t w e e n the two groups was p e r f o r m e d using S tu d e n t' s t test, M a n n - W h i t n e y rank sum, )(2, and Fisher's exact test. Analysis of variance on r e p e a t e d m e a s u r e s was used to compare the postoperative h e m o d y n a m i c and oxygen saturation data. A p value of less than 0.05 was d e e m e d to be statistically significant. All data are expressed as m e a n _+ the standard error of the mean.

Results Preoperative patient characteristics and h e m o d y n a m i c characteristics are s u m m a r i z e d in Table 1. There were no

Ann Thorac Surg 1996;62:1329-36

differences in the preoperative patient characteristics including age, h e m o d y n a m i c s , or oxygenation b e t w e e n either the BDCPS aprotinin and BDCPS control groups or the Fontan aprotinin and Fontan control groups. Singleventricle an at o m y is s u m m a r i z e d in Table 2. Twenty-five patients had single left ventricular anatomy, 10 had single right ventricular anatomy, and 11 h ad indeterminate single-ventricle morphology. Previous incisions are s u m m a r i z e d in Table 3. A m o n g patients u n d e r g o i n g BDCPS, there was a significantly greater proportion of previous m e d i a n sternotomies in the aprotinin group c o m p a r e d with the control group (p - 0.01, by Fisher's exact test). Previous p r o c e d u r e s are s u m m a r i z e d in Table 4. The BDCPSs were constructed as either bidirectional G l en n shunts or using the h e m i - F o n t a n technique. All Fontans w e r e constructed using a lateral tunnel technique, with a single small fenestration (1.5 to 5 mrn). In 5 of 6 control patients and in 8 of 10 patients receiving aprotinin, the fenestration was closed in the operating room using an extracardiac snare, after w e a n i n g from CPB. There were two deaths a m o n g the 16 patients u n d e r going the Fontan procedure. Both were in the control group. The first was a 12-month-old female baby with D o w n s y n d r o m e and tricuspid atresia in w h o m worsening cyanosis d e v e l o p e d d e s p i t e a w e l l - f u n c t i o n i n g BDCPS that had b e e n constructed at 6 months of age. She u n d e r w e n t the Fontan procedure, which was complicated by decreased arterial saturation and low output. Cardiac catheterization d e m o n s t r a t e d a t h r o m b u s in the lateral tunnel, and despite successful revision she eventually s u c c u m b e d to sepsis. The second death was in a 7-year-old boy with a single ventricle of right ventricular m o r p h o l o g y with systemic outflow obstruction w h o ha d u n d e r g o n e a coarctation repair and p u l m o n a r y artery b a n d i n g t h r o u g h a left thoracotomy in the n e w b o r n period. He s u b s e q u e n t l y u n d e r w e n t two sternotomies for relief of subaortic stenosis as well as a BDCPS. He then u n d e r w e n t a Fontan c o m b i n e d with a D a m u s - K a y e Stansel procedure. In the early postoperative period elevated superior vena caval pressure with low output developed, and he was placed on an extracorporeal m e m b r a n e oxygenator; he was s u b s e q u e n t l y w e a n e d

Table 2. Single Ventricle Anatomy BDCPS Anatomy TA L-TGA Single LV HLHS PA[WS Heterotaxy Other

Fontan

Aprotinin

Control

Aprotinin

Control

3 1 3 0 0 1

6 5 3 2 4 2

2 4 0 1 1 2

3 1 1 0 0 1

BDCPS - bidirectional cavopulmonary shunt; HLHS - hypoplastic left heart syndrome; L-TGA ~ c-malpositioned great vessels with L-looped ventricles; LV - left ventricle; PAJlVS - pulmonary atresia with intact ventricular septum; TA - tricuspid atresia.

Ann Thorac Surg 1996;62:1329-36

TWEDDELL ET AL SINGLE-VENTRICLE PALLIATION AND APROTININ

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Table 3. Previous Incisions BDCPS

Fontan

Aprotinin No. of Previous Operations

Control

Aprotinin

Control

No.

Type of Incision

No.

Type of Incision

No.

None One

0 4

2 16

.,.

0

0

...

0

3

Three

1

... MS - 3 T-13 MS+T=3 MS + MS 1 ...

0

Two

... MS - 3 T-1 MS+T-1 MS + MS 2 MS + T + T

BDCPS = bidirectional cavopulmonary shunt;

4 0

MS = median sternotomy;

from extracorporeal membrane oxygenator support with t h e h e l p of i n h a l e d n i t r i c oxide. H e w a s h e m o d y n a m i cally s t a b l e , w i t h m e c h a n i c a l v e n t i l a t o r y s u p p o r t , a n d s u c c u m b e d to f u n g a l m e d i a s t i n i t i s . There were three failures (no deaths) among the pat i e n t s u n d e r g o i n g B D C P S ; all w e r e a m o n g p a t i e n t s w h o d i d n o t r e c e i v e a p r o t i n i n . T h e first p a t i e n t h a d a p r o g r e s sive i n c r e a s e i n s u p e r i o r v e n a c a v a l p r e s s u r e a n d d e c r e a s e d o x y g e n s a t u r a t i o n in t h e first 24 h o u r s p o s t o p e r a t i v e l y a n d r e q u i r e d t a k e d o w n to a c e n t r a l s y s t e m i c - t o pulmonary artery shunt. Two patients required a 4-mm polytetrafluoroethylene systemic-to-pulmonary artery s h u n t i n a d d i t i o n to t h e B D C P S to a c h i e v e a d e q u a t e a r t e r i a l s a t u r a t i o n to w e a n f r o m CPB. T h e r e w e r e n o 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 w e r e c o m p a r e d i m m e d i a t e l y o n a r r i v a l to t h e p o s t o p e r a t i v e i n t e n s i v e c a r e u n i t a n d 6, 12, 18, a n d 24 h o u r s p o s t o p e r a t i v e l y . T h e r e w a s n o s i g n i f i c a n t d i f f e r e n c e in the superior vena caval pressure between the aprotinin a n d c o n t r o l g r o u p s a m o n g e i t h e r B D C P S or F o n t a n

Type of Incision

4

MS+T-4

6

MS+T+T-4 MS + MS ~ T

No.

Type of Incision

4

MS+T 3 MS + MS = 1 MS+MS+T=1 MS+T+T-1

2 2

T = thoracotomy.

patients. However, superior vena caval pressure measurements were consistently lower in the Fontan aprotin i n g r o u p c o m p a r e d w i t h t h e F o n t a n c o n t r o l g r o u p (Fig 1). T h e t r a n s p u l m o n a r y g r a d i e n t w a s s i g n i f i c a n t l y i m proved in the aprotinin-treated groups, both among

BDCPS Postoperative Superior Vena Cava Pressure 20 19 18 17

~16 E

15

1211109

• Control o

P=NS 6

6

1'2

1'8

Aprotinin 2'4

Fontan Postoperative Superior Vena Cava Pressure 20 19 18 17

~16 e 15 E v¢.)1 4 ~ 13 12 11 10 ,1-

Table 4. Previous Procedures Fontan (in addition to BDCPS)

BDCPS Procedure SPAS Norwood PAB PAB + coarctation repair DKS Other

Aprotinin

Control

Aprotinin

Control

5 3 2 0

11 4 3 2

9 0 1 1

5 1 0 1

1 2

0 4

1 4

0 1

BDCPS = bidirectional cavopulmonary shunt; Stansel; PAB = pulmonary artery band; pulmonary artery shunt.

DKS = Damus-KayeSPAS = systemic~to-

• Control o Aprotinin

6

(~

1'2 1'8 Time (hours)

2'4

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.

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TWEDDELLET AL SINGLE-VENTRICLEPALLIATION AND APROTININ

Ann Thorac Surg 1996;62:1329-36

BDCPS Postoperative Arterial Saturation

BDCPS Postoperative Transpulmonary Gradient 12-

100-

1110" 9"

9080-

~' 7E

¢~ 70-

t= 65-

60-

4-

3! 2~ 1

• Control OAprotinin

*P<0.05

6

1'2

1'8

2'4

12 11109-

100

6

1'2

1'8

2'4

-~ 8-

8O

90

~ 7E

6

Fontan Postoperative Arterial Saturation

Fontan Postoperative Transpulmonary Gradient

~s

*P<0.05

504C

6

• Control O Aprotinin

70

a¢=

60

3 21-

ol

• Control o Aprotinin

• Control *P<0,05

°Apr°tinin

50 ¸

40 6

(~

1'2 1'8 Time (hours)

2'4

6

6

1'2 1'8 Time (hours)

2'4

Fig 2. Postoperative transpulmonaw 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).

Fig 3. Postoperative arterial saturation (SaO 2) in patients undergoing bidirectional cavopulmonary shunt (BDCPS) (top) and Fontan (bottom) procedures. Bidirectional cavopulmonary shunt patients receiving aprotinin had a signifi'cantly higher arterial saturation in the postoperative period (p <0.05 by analysis of variance on repeat measures).

p a t i e n t s u n d e r g o i n g B D C P S a n d the F o n t a n p r o c e d u r e s (Fig 2). T h e F o n t a n a p r o t i n i n g r o u p d e m o n s t r a t e d the g r e a t e s t i m p r o v e m e n t , w i t h a significant difference in t r a n s p u l m o n a r y g r a d i e n t at 12 a n d 18 h o u r s p o s t o p e r a tively c o m p a r e d w i t h the F o n t a n control group. The B D C P S a p r o t i n i n g r o u p d e m o n s t r a t e d an i m p r o v e m e n t at 6 h o u r s p o s t o p e r a t i v e l y c o m p a r e d w i t h B D C P S control g r o u p . A r t e r i a l o x y g e n s a t u r a t i o n s also s h o w e d i m p r o v e m e n t in the B D C P S a p r o t i n i n g r o u p c o m p a r e d w i t h the B D C P S control g r o u p (Fig 3). S a t u r a t i o n s w e r e significantly g r e a t e r in the B D C P S a p r o t i n i n g r o u p at 12 a n d 18 h o u r s p o s t o p e r a t i v e l y . A l t h o u g h arterial saturations w e r e c o n s i s t e n t l y g r e a t e r in t h e F o n t a n a p r o t i n i n g r o u p c o m p a r e d w i t h the F o n t a n control group, this difference did not r e a c h statistical significance. T h o r a c i c d r a i n a g e (all m e d i a s t i n a l a n d p l e u r a l drainage i n c l u d e d ) d u r i n g the first 24 h o u r s a n d the d u r a t i o n of thoracic d r a i n a g e w e r e significantly r e d u c e d in the B D C P S a p r o t i n i n g r o u p (Table 5). T h e r e was no signific a n t difference in t h e thoracic d r a i n a g e d u r i n g t h e first 24 h o u r s or in the d u r a t i o n of thoracic d r a i n a g e in t h e F o n t a n g r o u p s (Table 5). T h e r e w e r e no significant dif-

f e r e n c e s in t r a n s f u s i o n s b e t w e e n t h e a p r o t i n i n a n d control groups, a m o n g p a t i e n t s u n d e r g o i n g B D C P S or the F o n t a n p r o c e d u r e (Table 5).

Table 5. Transfusions and Thoracic Drainage BDCPS

Fontan

Variables

Aprotinin Control Aprotinin

RBCs (donors/24 h) Platelets and FFP (donors/24 h) Total donors (donors/24 h) Thoracic drainage first 24 hours (mL' m ~. 24h 1) Duration of thoracic drainage (days)

1.6 + 0.2 0.6 ± 0.3

1.1+-0.2 1.9-+0.4 1.6 + 0.4 2.9 + 0.7

2.2 +1.2 5.7 + 3.0

2.3 ± 0.5

2.7÷ 0.4 4.7 ÷0.9

7.8±4.1

380 + 33 a 639 +64

947-+ 130 859-+200

3.0 - 0.23 5.4-+0.9 11.4±1.4

a p < 0.05 compared with BDCPS control group. BDCPS = bidirectional cavopulmona D, shunt; plasma; RBC = red blood cell.

Control

10.0m2.2

FFP = fresh frozen

A n n Thorac S u r g 1996;62:1329-36

TWEDDELL ET AL SINGLE-VENTRICLE PALLIATION AND APROTININ

BDCPS Creatinine 1.0'1

0.9" 0.8"

• Control o Aprotinin

0.7" ==

="T= O

0.6" 0.5"

0.40.30.20.10.0

P=NS Pre:Op

i

2

Postoperative Days

Fontan Creatinine 1.0. 0.9'

0.8. 0.7,

0.6, .m ¢=

o

0.5

0.4 0.3

• Contr01

0.2 0.1 0.C

o Aprotinin

P=NS Pre'Op Postoperative Days

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.

Serum creatinine level was measured in all patients preoperatively and on postoperative days 1 to 3 for BDCPS patients and postoperative days 1 to 5 for Fontan patients. There was no significant change in creatinine level in either the aprotinin-treated or control groups a m o n g patients undergoing the BDCPS or the Fontan procedure (Fig 4). Comment Despite being good candidates for single-ventricle palliation, some patients fail BDCPS or Fontan procedures [2, 4, 5]. Cardiopulmonary bypass can lead to an elevation of PVR attributable to the production of vasoactive substances or as a consequence of atelectasis, which can be worsened by increased capillary permeability and the resultant increase in extravascular lung water [1, 6, 7]. Failure of single-ventricle palliation in good-risk candidates may be due, in part, to acute elevation of PVR as a consequence of CPB. We hypothesized that aprotinin could improve the outcome of patients undergoing single-ventricle palliation by decreasing the inflammatory

1333

response to CPB. Aprotinin is a nonspecific serine protease inhibitor and diminishes the inflammatory response of CPB at the contact, neutrophil, and platelet activation systems [8]. Early studies with high-dose aprotinin infusion during cardiac operations were initiated with the intent to decrease postperfusion syndrome and improve lung function after CPB by inhibiting the kallikrein and complete systems and neutralizing neutrophil elastase [9]. However, the impact on perioperative blood loss was the predominant finding and has become the primary indication for the use of aprotinin during cardiac operations. Patients undergoing single-ventricle palliation are in a unique situation in which the antiinflammatory effects of aprotinin rather than solely the hemostatic effects may become more obvious. 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 a m o n g Fontan patients receiving aprotinin and increased arterial saturation a m o n g 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 n u m b e r of vasoactive substances [10]. The two agents most likely to be responsible for the acute elevation of PVR after CPB are thromboxane A 2 and endothelin-1 [11-14]. The primary source of thromboxane A 2 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 n u m b e r of circulating leukocytes or to prevent leukocyte activation are thought to be successful in decreasing PVR after CPB by decreas-

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ing release of endothelin-1 [17, 18]. By preventing activation of leukocytes a n d platelets, aprotinin m a y decrease release of endothelin-1. Further study will be n e e d e d to identify the exact m e c h a n i s m s by which aprotinin lowers PVR. A p r o t i n i n has b e e n shown to decrease transfusion r e q u i r e m e n t s after pediatric and adult cardiac procedures [19-21]. In our study, patients u n d e r g o i n g BDCPS who received aprotinin were in a higher risk group for bleeding; 7 of 8 patients h a d u n d e r g o n e previous m e d i a n sternotomies c o m p a r e d with 7 of 22 control patients. Despite the increased risk for b l e e d i n g there was no difference in n u m b e r of transfusions b e t w e e n the BDCPS aprotinin a n d BDCPS control groups. Thoracic drainage was r e d u c e d in the BDCPS aprotinin group c o m p a r e d with the BDCPS control group. Duration of thoracic d r a i n a g e was also decreased in the BDCPS aprotinin group c o m p a r e d with the BDCPS control group. All patients u n d e r g o i n g the Fontan p r o c e d u r e h a d u n d e r gone at least two previous operations including at least one m e d i a n sternotomy. More patients in the Fontan aprotinin group h a d u n d e r g o n e three previous procedures (60%, 6 of 10 patients) c o m p a r e d with the Fontan control group (33%, 2 of 6 patients), b u t this difference was not significant. There was no significant difference in red cell transfusions, clotting factor transfusions, or total transfusions b e t w e e n the Fontan aprotinin group a n d the Fontan control group, although in all categories the Fontan aprotinin group a v e r a g e d fewer transfusions. Likewise, thoracic drainage was not d i m i n i s h e d either in the first 24 hours or in total duration. These data suggest reduction in thoracic drainage a n d transfusion r e q u i r e m e n t s in BDCPS patients who received aprotinin, b u t this reduction was not seen in the Fontan patients. The lack of difference in transfusions and thoracic drainage a m o n g Fontan patients m a y be attributable to the more extensive nature of the Fontan p r o c e d u r e in patients who h a d u n d e r g o n e (all cases) at least two previous operations. In addition, in the Fontan patient, thoracic drainage is a function of elevated venous p r e s s u r e rather than solely a function of hemostasis [22, 23]. N o a t t e m p t was m a d e to alter transfusion strategy in this study. Transfusion of red cells and clotting factors was directed by the subjective interpretation of b l e e d i n g b y the surgeon a n d anesthesiologist rather than by specific factor deficiency. Therefore, to a degree, transfusions were given b a s e d on previous institutional experience a n d this m a y account for the lack of larger differences b e t w e e n the aprotinin a n d control groups. Aprotinin has b e e n implicated in an increased incidence of t h r o m b u s formation, renal failure, a n d m e d i a s tinitis after cardiac operations [21, 24-26]. In our study, no adverse affects of aprotinin were identified. The only failed p r o c e d u r e s occurred in the control group. A single e p i s o d e of t h r o m b u s formation occurred in the lateral tunnel of a Fontan control patient. O n e episode of m e d i astinitis also occurred in a control Fontan patient. Renal failure was not seen in any patient a n d there was no difference in s e r u m creatinine b e t w e e n the aprotinin a n d control groups. Profound h y p o t h e r m i c circulatory arrest

A n n Thorac S u r g 1996;62:1329-36

was u s e d in I patient receiving aprotinin without adverse renal or neurologic events. This was a retrospective study involving a limited n u m b e r of patients with single-ventricle anatomy. Given the paucity of data concerning the use of aprotinin in this group of patients w h e r e r e o p e r a t i o n is frequent a n d i m p r o v e d hemostasis as well as d e c r e a s e d PVR are of significant benefit, the data in this report m a y be useful. A d d i t i o n a l p r o s p e c t i v e studies will be n e c e s s a r y to confirm t h e s e findings a n d i d e n t i f y the m e c h a n i s m b y w h i c h a p r o t i n i n i m p r o v e d the o u t c o m e of s i n g l e ventricle palliation. In conclusion, in a retrospective study of patients u n d e r g o i n g single-ventricle palliation, aprotinin was associated with d e c r e a s e d thoracic drainage and evidence of lowered PVR. Aprotinin use was not associated with an increased failure rate a n d no complications could be related to aprotinin use. There was no incidence of t h r o m b u s formation, renal failure, or neurologic events in the aprotinin group. W e conclude that aprotinin is safe in patients u n d e r g o i n g single-ventricle palliation a n d a p p e a r s to i m p r o v e the early postoperative outcome. 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.

References 1. Utley JR. Pathophysiology of cardiopulmonary bypass: current issues. J Cardiac Surg 1990;5:177-89. 2. Bridges ND, Jonas RA, Mayer JE, Flanagan MF, Keane JF, Castaneda AR. Bidirectional cavopulmonary anastomosis as interim palliation for high-risk Fontan candidates. Circulation 1990;82(Suppl 4):170-6. 3. Westaby S. Aprotinin in perspective. Ann Thorac Surg 1993; 55:1033-41. 4. Hopkins RA, Armstrong BE, Serwer GA, Peterson RJ, Oldham HN Jr. Physiological rationale for a bidirectional cavopulmonary shunt. J Thorac Cardiovasc Surg 1985;90:391-8. 5. Mayer JE Jr, Helgason H, Jonas RA, et al. Extending the limits for modified Fontan procedure. J Thorac Cardiovasc Surg 1986;92:1021-8. 6. Sladen RN, Berkowitz RN. Cardiopulmonary bypass and the lung. In: Gravlee GP, Davis RE, Utley JR, eds. Cardiopulmonary bypass. Baltimore: Williams and Wilkins, 1993, 468-87. 7. Allison RC, Kyle J, Adkins WK, Prasad VR, McCord JM, Taylor AE. Effect of ischemia reperfusion or hypoxia reoxygenation on lung vascular permeability and resistance. J Appl Physiol 1990; 69:597-603. 8. Wachtfogel YT, Kucick U, Hack CE, et al. Aprotinin inhibits the contact, neutrophil and platelet activation systems during simulated extracorporeal perfusion. J Thorac Cardiovasc Surg 1993;106:1-10. 9. Royston D, Bidstrup B, Taylor K, et al. Effect of aprotinin on the need for blood transfusion after repeat open heart surgery. Lancet 1987;2:1989-91. 10. Downing SW, Edmunds HL Jr. Release of vasoactive substances during cardiopulmonary bypass. Ann Thorac Surg 1992;54:1236-43. 11. Komai H, Adatia IT, Elliott MJ, de Leval MR, Haworth SG. Increased plasma levels of endothelin-1 after cardiopulmonary bypass in patients with pulmonary hypertension and congenital heart disease. J Thorac Cardiovasc Surg 1993;106: 473- 8. 12. Cave AG, Manche A, Derias NW, Hearse DJ. Thromboxane

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13.

14.

15. 16.

17. 18. 19.

A 2 mediates pulmonary hypertension after cardiopulmonary bypass in the rabbit. J Thorac Cardiovasc Surg 1993;106: 959-67. Friedman M, Wang SY, Sellke FW, Franklin A, Weintraub RM, Johnson RG. Pulmonary injury after total or partial cardiopulmonary bypass with thromboxane synthesis inhibition. Ann Thorac Surg 1995;59:598-603. Kirshbom PM, Tsui SS, DiBernardo LR, et al. Blockage of endothelin-converting enzyme reduces pulmonary hypertension after cardiopulmonary bypass a n d circulatory arrest. Surg 1995;118:2:440-4. H u a n g H, Ding W, Su Z, Zhang W. Mechanism of the preserving effect of aprotinin on platelet function and its use in cardiac surgery. J Thorac Cardiovasc Surg 1993;106:11-8. Rinder CS, Gaal D, Student LA, Smith BR. Platelet-leukocyte activation and modulation of adhesion receptors in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1994;107:280-8. Bando KO, Pillai R, Cameron DE, et al. Leukocyte depletion ameliorate free radical-mediated lung injury after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1990;99:873-7. Gillinov AM, Redmond JM, Zehr KJ, et al. Inhibition of neutrophil adhesion during cardiopulmonary bypass. Ann Thorac Surg 1994;57:126-33. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass

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20. 21. 22.

23. 24. 25.

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with high-dose aprotinin. J Thorac Cardiovasc Surg 1989;97: 364-72. Hazan E, Pasaoglu I, Demircin M, Bozer AY. The effect of aprotinin (Trasylol) on postoperative bleeding in cyanotic congenital heart disease. Turkish J Pediatr 1991;33:99-110. Penkoske PA, Entwistle LM, Marchak BE, Seal RF, Gibb W. Aprotinin in children undergoing repair of congenital heart defects. Ann Thorac Surg 1995;60:$529-32. Zellers TM, Driscoll DJ, Humes RA, Feldt RH, Puga FJ, Danielson GK. Glenn shunt: effect on pleural drainage after modified Fontan operation. Thorac Cardiovasc Surg 1989;98: 725-9. Bridges ND, Lock JE, Castaneda AR. Baffle fenestration with subsequent transcatheter closure. Circulation 1990; 82:1681-9. Cosgrove DM III, Heric B, Lytle BW, et al. Aprotinin therapy for reoperative myocardial revascularization: a placebocontrolled study. A n n Thorac Surg 1992;54:1031-8. Saffitz JE, Stahl DJ, Sundt TM, Wareing TH, Kouchoukos NT. Disseminated intravascular coagulation after administration of aprotinin in combination with deep hypothermic circulatory arrest. Am J Cardiol 1993;72:1080-2. Sundt TM III, Kouchoukos NT, Saffitz JE, Murphy SF, Wareing TH, Stahl DJ. Renal dysfunction a n d intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418-24.

DISCUSSION DR MEHMET C. OZ (New York, NY): There is an adult equivalent to this operation, and it is called a left ventricular assist device placement. We have done a similar analysis. We used aprotinin in 31 of 116 left ventricular assist device patients, and again many of them had true Fontan physiology with either arrhythmias or very poor right ventricular function. The anaphylaxis rate was low as you showed also, but the right ventricular assist device incidence was also lower in the aprotinin group than in the control group. Interestingly, the t h r o m b o e m bolic incidence was higher in the control group, I think because flows were often so low in these patients because they were bleeding. This translated to a significant 7-day mortality in the control group compared with the aprotinin group. Aprotinin inhibits the detrimental inflammation effects of cardiopulmonary bypass and bleeding. I think it is not just the effects of cardiopulmonary bypass with neutrophil degranulation and thromboxane A 2 release that result in elevated pulmonary vascular resistance, but also the bleeding and resuscitation and resulting elevated circulating cytokines. So my question for you is: Is there a patient in whom you would not use aprotinin? And do you have experience with redosing of aprotinin, and what do you do in that situation? DR TWEDDELL: Thank you. None of the patients who underwent bidirectional cavopulmonary shunts or Fontan procedures in this study had previously received aprotinin. All patients receive a 1.4-mg test dose of aprotinin before receiving the full dose. In patients being redosed with aprotinin, I believe the test dose is particularly important to avoid a hypersensitivity reaction. I agree with you that the mechanism of action by which aprotinin improves postoperative pulmonary function may be to prevent increased capillary permeability, which leads to increased pulmonary vascular resistance. Alternatively, the mechanism of action may be to decrease the release of vasoactive substances normally elevated by cardiopulmonary bypass including thromboxane A 2 and endothelin-1. At this point, we can only speculate as to the mechanism of action. Future efforts by

our group are aimed at identifying the mechanism by which aprotinin improves postoperative pulmonary function. DR EDWARD L. BOVE (Ann Arbor, MI): Doctor TweddeU, were any of your patients operated on using circulatory arrest? DR TWEDDELL: Yes, we have used aprotinin in 2 patients undergoing procedures using profound hyperthermic circulatory arrest. Both of these patients had previously undergone the Norwood procedure and u n d e r w e n t repair of recurrent coarctation using profound hyperthermic circulatory arrest. In 1 patient this procedure was combined with a bidirectional cavopulmonary shunt and he is included in this study. The second patient underwent revision of his Blalock-Taussig shunt and repair of branch pulmonary artery stenosis at the same procedure. Subsequently, he went on to a bidirectional cavopulmonary shunt but did not receive aprotinin during that procedure. We identified no complications or adverse sequelae in either of these patients. D R BOVE: Would you have any hesitation using aprotinin in a

patient who is going to have a planned circulatory arrest? D R TWEDDELL: I have some hesitation in using aprotinin in

the setting of profound hyperthermic circulatory arrest. I am not certain that the action of aprotinin in the local microvascular environment in the setting of stasis is completely understood. In these 2 patients in whom we have used aprotinin in the setting of profound hyperthermic circulatory arrest, the circulatory arrest time was between 15 and 20 minutes. I felt comfortable using it for this relatively short period of time, but I would be concerned about using it for longer periods. ! must admit, however, that I have no data to support that conclusion. D R BOVE: We have used it in our patients undergoing Fontan

procedures, even those with circulatory arrest, and have had no adverse sequelae from it and feel fairly comfortable with that.

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I have one other question. As you may know, in the coronary bypass literature there is some evidence to suggest that it may actually be effective even after cardiopulmonary bypass to reduce bleeding and not for reasons you have discussed. Have you had any experience using it in patients after bypass? DR TWEDDELL: We have not used aprotinin to attempt to decrease bleeding after cardiopulmonary bypass. None of the patients in this study required reoperation for bleeding. We have used aprotinin in an attempt to control bleeding in 1 patient on postcardiotomy extracorporeal membrane oxygenation support. Although this patient did not have any complications attributable to the use of aprotinin (in particular, there was no thrombus formation or renal failure), i do not believe we had an impact on the bleeding situation either. DR DONALD C. WATSON, JR (Memphis, TN): There is a difference in oxygen saturation between your two groups. One explanation may be a difference in baffle fenestration rate. Did you fenestrate the baffles, or were they all complete Fontans? DR TWEDDELL: That is an excellent question. All the Fontans were constructed using a lateral tunnel technique. All of them were initially fenestrated. In 8 of the 10 aprotinin patients and 5 of 6 control patients the fenestration was closed before leaving the operating room. All the procedures were performed with the use of transesophageal echocardiography, and we were able to demonstrate that the fenestrations were, in fact, closed. Therefore, there were essentially equal rates of fenestrations in the

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aprotinin and control groups, and I do not think this had an impact on our findings or conclusions. DR CARLO MARCELLETTI (Rome, Italy): Have you used nitrous oxide in any of your patients when you were concerned that pulmonary vascular resistance might be high postoperatively? DR TWEDDELL: Yes, we have used nitric oxide to reduce pulmonary vascular resistance in a postoperative Fontan patient. This patient was a 6-year-old boy who underwent a combined Damus-Kaye-Stansel and Fontan procedure. He went on to be supported with extracorporeal membrane oxygenation and was successfully weaned from extracorporeal m e m b r a n e oxygenation with the help of nitric oxide. At that point, he was hemodynamically stable on mechanical ventilation until eventually he succumbed to sepsis. This suggests to me that the patient was probably a good hemodynamic candidate for a Fontan procedure. It suggests further that the extensive nature of his operative procedure was responsible for his initial inability to function initially as a Fontan. We have used inhaled nitric oxide in a number of other patients undergoing operation for congenital heart disease who had an elevated pulmonary vascular resistance with generally very positive results. Nitric oxide may also be useful as an agent to test the effectiveness of aprotinin in reducing postoperative pulmonary vascular resistance. Inhaled nitric oxide could be administered in the postoperative period to determine how much further the pulmonary vascular resistance can be reduced by aprotinin or other agents one might wish to study.

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