Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol)

J

THoRAc CARDIOVASC SURG

1989;97:364-72

Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (Trasylol) The effect of high dose aprotinin (frasylol) was evaluated in three groups of patients undergoing cardiopulmonary bypass. In a prospective, placebo-controUed, double-blind study, 80 patients having primary aorta-coronary bypass grafting received aprotinin (700 mg approximately) or saline placebo from the beginning of the procedure until skin closure. Standardized anesthetic, perfusion, and surgical techniques were used. The total loss from the thoracic drains was significantly reduced in the aprotinin group as compared with the loss in the placebo group (309 ± 133 mI versus 573 ± 166 mI, p < 0.01; mean ± standard deviation). There was a threefold difference in the total hemoglobin loss into the chest drains (aprotinin 12.0 ± 12.6 gm versus placebo 37.7 ± 18.3 gm). Patients of the aprotinin group received remarkably less bank blood postoperatively: 13 units total compared with 75 units. Of the 40 patients in the aprotinin group, 32 received no bank blood compared with 2 of 37 patients in the placebo group. Venous hemoglobin levels preoperatively, on day 1, and on day 7 postoperatively did not differ between the groups. At day 7 the values were 13.1 ± 1.4 gmjdl versus 12.5 ± 1.2 gmjdl in the aprotinin group and the placebo group, respectively. Platelet counts determined at fixed times perioperatively did not differ between the two groups. In contrast, template bleeding time measured in 32 study patients was distinctly different between groups, with a postoperative rise of 6.2 ± 2.1 minutes in the placebo group opposed to only 1.5 ± 1.1 minutes in the aprotinin group. In a separate, randomized comparative trial, 11 of 22 patients having reoperations through a previous median sternotomy received the same dose of aprotinin. Blood loss was reduced from 1509 ± 388 mI to 286 ± 48 mI; p < 0.001 (mean ± standard error of the mean). Only four treated patients required transfusion (total of 5 units) whereas aU patients in the control group received transfusions (total of 41 units), Since then, a further 24 patients undergoing reoperation have aU been given aprotinin. Only four required transfusion (total of 5 units). A third group of 15 patients, aU requiring operation for the acute complications of infective endocarditis, received high dose aprotinin treatment The mean chest drainage was 388 mi. Only six patients received bank blood (total of 11 units). These results demonstrate that high dose aprotinin markedly reduces blood loss after cardiopulmonary bypass. It appears possible that aprotinin preserves platelet function without affecting platelet consumption under the conditions of extracorporeal circulation. Its use in cardiac operations offers a significant contribution toward blood conservation, especiaUy in patients at high risk of bleeding.

Benjamin P. Bidstrup, FRACS, FRCSEd" (by invitation), David Royston, FFARCSb (by invitation), Ralph N. Sapsford, ChM, FRCS" (by invitation), and Kenneth M. Taylor, MD, FRCS(E), FRCSb (by invitation), London, England Sponsored by Delos M. Cosgrove III, MD, Cleveland, Ohio

From The Humana Hospital Wellington,' St. John's Wood, and the Hammersmith Hospital," London, England. Supported by Bayer UK Ltd., Newbury, England. Read at the Sixty-eighth Annual Meeting of The American Association for Thoracic Surgery, Los Angeles, Calif., April 18-20, 1988. Address for reprints: B. P. Bidstrup, 66 Harley St., London WIN IAE, England.

364

Blood conservation has become a major area of concern for the cardiac surgeon. Many avenues have been explored to reduce the need for blood transfusion: normovolemic hemodilution,' intraoperative autotransfusion,' postoperative return of shed mediastinal blood,' predonation of autologous blood,' and pharmacologic manipulation with desmopressin-" and dipyridamole.'

Volume 97 Number 3 March 1989

Recently, we" performed a controlled study in which half the patients were given aprotinin, a serine proteinase inhibitor with inhibitory effects on human plasmin, trypsin, plasma, and tissue kaliikrein.t'? The other half received no aprotinin. We made a striking clinical observation, namely that intraoperative and postoperative bleeding was exceptionally low in most of the patients treated with aprotinin. Despite the small number of patients (11 aprotinin, 11 control), there was a highly significant difference between the two groups in the loss from the mediastinal drains (p < 0.Ql). This was also reflected in a significant reduction in the amount of transfused homologous blood required by the patients of the aprotinin group. I I We therefore undertook a further clinical study to test the hypothesis that high dosage aprotinin would reduce the blood loss and the need for homologous blood transfusion after cardiac procedures. The results of this new prospective, randomized, double-blind study are reported here, together with the findings from a separate prospectivecomparative study in patients having cardiac reoperations, who are at much higher risk of bleeding," and our retrospectively compared data about the use of aprotinin in patients with sepsis at the time of operation." Methods Study design Part I. A prospective, placebo-controlled clinical trial was set up in patients scheduled to have an elective aorta-coronary bypass operation with anticipated bridging of two or more vessels. Patients older than 70 years, having reoperations, or being grosslyoverweight were excluded as were patients with a history of ingestion of platelet-active drugs within 2 weeks of operation. Patients with a known or suspected previous exposure to aprotinin (e.g., with a history of acute pancreatitis) were not eligible for inclusion. Although the study was performed in a double-blind manner, strict rules were defined in advance about when homologousblood or red cells should be given to the patients of this study. Blood or blood components were administered only when the packed cell volume fell below 30% in the postoperative course. Not affected by this rule was the retransfusion of I unit of autologous blood at the end of the operation. This blood was taken from the patients when possible and appropriate at the commencement of the operation. By this transfusion policy, we expected to minimize under the prevailing conditions of routine coronary bypass operation the use of donor blood independent of any effect of the trial drug. Many reports on blood conservation techniques contain no information that such a precaution was taken. Part II. A prospective, randomized study was set up in patients having elective cardiac reoperations via a previous median sternotomy. All adult patients were eligible, the only exclusion criterion being previous exposure to aprotinin. Patients were randomized to receive aprotinin or no aprotinin with a series of sealed envelopes. Administration of blood products and colloid solutions was as already described. All

Aprotinin in cardiac surgery

36 5

patients whose packed cell volume was above 30% before operation had I unit of blood drawn after induction and stored for retransfusion at the end of bypass. Part III. All patients requiring operation for the acute complications of infective endocarditis (increasing cardiac failure, uncontrolled sepsis, evidence of destruction of the cardiac skeleton, or systemic embolism) were eligible for inclusion in the third part of our study. All were given aprotinin. Autologous blood was taken as in the reoperation group and similar transfusion rules applied. Informed consent was obtained from all patients and the protocols were approved by the ethical committees of our institutions. Aprotinin dosage and administration. The trial drug was provided by the manufacturer (Bayer AG, Leverkusen, Federal Republic of Germany) in identical case packs, each of 12 bottles identifiable only by the random number. One bottle of the active drug contained 70 mg of aprotinin (500,000 kallikrein inactivator units) in 50 rnl 0.9% saline solution without further additives or preservative substances. The respective placebo bottles contained only saline. Dosage and administration of aprotinin was as follows: after induction of anesthesia, a loading dose of 280 mg was given intravenously through a central venous cannula over 20 minutes. Immediately afterward, a continuous infusion of 70 mg/hour was begun and maintained until the patient left the operating theater. In addition to the intravenous infusion, another 280 mg of aprotinin was added to the priming volume of the heart-lung machine by replacement of an aliquot of the priming volume. Thus a patient whose operation lasted for about 2 hours would receive a total dose of 700 mg (5 million kallikrein inactivator units) or the corresponding volume of saline placebo. Control patients in the reoperation study did not receive placebo. Patients in the third arm of the study (that is, those having valve replacement for infective endocarditis) received 420 mg of aprotinin via the oxygenator prime, and the continuous infusion was maintained until 3 to 5 hours postoperatively. Operative management. All patients were premedicated with papaveretum (Ornnopon, IS to 20 fig) and scopolamine (0.2 to 0.4 mg). After induction of anesthesia, intermittent positive pressure ventilation was supplemented with a narcotic analgesic, a muscle relaxant, and halothane as necessary. Bovine lung heparin (300 IV/kg) was injected into a central line before cannulation of the heart. Tests for activated clotting times were performed at regular intervals and further heparin administered if times fell below 400 seconds. A Harvey H 1700 (Bard Limited, Sunderland, England) bubble oxygenator was primed with 2000 rnl of Hartmann's solution. Flows of 2.4 L/min/m2 were obtained with a minimally occlusive roller pump (Sarns Inc., Ann Arbor, Mich.), Systemic hypothermia to 28° to 29° C was maintained while the aorta was occluded. Myocardial preservation during aortic clamping was maintained with St. Thomas' Hospital cardioplegic solution injected into the aortic root. Mean arterial blood pressure during bypass was kept between 50 and 80 mm Hg with nitroglycerin supplemented with pentolinium as necessary. After rewarming to 37° C at the completion of the operation and discontinuation of bypass, the effects of residual heparin were reversed with protamine sulfate (1 mg/loo IV heparin). After transfer to the intensive care ward, intermittent positive pressure ventilation was continued until the patient was warm peripherally, was not bleeding, and was otherwise in

The Journal of Thoracic and Cardiovascular Surgery

3 6 6 Bidstrup et al.

ml (± SD) 800

all patients (n = 74) 573

autologous blood retransfused (n = 27)

Table I. Demographic data for the two groups* (mean ± standard deviation)

513

Aprotinin (n = 40)

600 288

400 200 0--'---

p<0.01 •

placebo

~

aprotinin

1-

Fig. 1. Chest drainage in milliliters ± standard deviation (SD) after return to ICU for all primary patients having bypass grafting and for the subgroup of patients who had autologous blood retransfused. Losses were significantly reduced in the patients receiving aprotinin. stable condition. Hypertension (mean arterial pressure> 100 mm Hg) was treated with infusions of nitroglycerin and nitroprusside. Low cardiac output was treated with combinations of dopamine and adrenaline. Nonhemic colloid solutions (hydroxyethylated starch or gelatin) were infused to maintain adequate filling pressures. Blood was given only as previously defined. A crystalloid intake of 80 to 100 ml/hour was infused. Measurements. In the double-blind study, blood samples were taken preoperatively, after induction of anesthesia, after sternotomy, after 10 minutes of bypass, before rewarming commenced, 2 minutes after release of the cross-clamp, at the end of bypass, 10 minutes after protamine infusion, immediately before transfer to the intensive care unit (ICU), 24 hours after operation, and at 7 days after operation. Platelet counts were done within 2 hours of the time samples were taken into trisodium citrate on ice with a Coulter Counter (Coulter Ltd., Harpenden, England). Packed cell volume was determined with a standard microhematocrit method and hemoglobin concentrations by the cyanmethemoglobin technique. Plasma aprotinin levels were determined according to the method of Muller-Esterl." Bleeding times were determined preoperatively and 90 minutes after the end of the procedure by the template method (Simplate, General Diagnostics, Morris Plains, N.J.). All crystalloids, colloids, and blood products infused and urine output were recorded. Blood loss during the operation into the swabs and suction apparatus was recorded before and after bypass. Losses into the chest drains were measured hourly until their removal 18 to 24 hours later. Because individual drainage volumes can vary in hemoglobin content, the total hemoglobin loss into the drains was measured. Similar but less frequent measurements were made in the other two sections of the overall study. Statistical methods. Considering the mean blood loss in our pilot study," we calculated that a study size of 40 plus 40 patients would have 80% power not to miss a differenceof 30% between the two groups, a difference that would be significant below the 5% limit of probability of error (a = 2.5%, fJ = 20%). The study size of 80 patients was also found

Sex (m/f) Age (yr) Bypass time (min) Total time of operation (min) Average number of grafts IMA grafts Patients with autologous blood retransfused

Placebo = 37)

(n

37/3 58.1 (8.6) 63 (II) 134 (20)

32/5 57.7 (8.3) 68 (IS) 138 (22)

3.88 (0.5)

3.86 (0.8)

7

8 II

17

Figures in parentheses are the standard deviation. IMA, Internal mammary artery. 'There were no significant differences between the two groups.

powerful enough to detect any preservation of platelet numbers compared with the expected drop of about 25% as seen, for example, in the placebo group of an earlier aprotinin study." The statistical analysis for the double-blind study was based on both descriptive and inferential methods. For comparison of aprotinin and placebo treatment, the total postoperative chest drainage volume and the platelet counts were chosen as target variables. A t test for independent samples was performed to test the difference in drainage volumes (one-sided hypothesis). Covariance analysis for repeated measurements after normal rank transformation of the data was applied to test the differencesin platelet counts before transfer to the ICU and 24 hours after bypass, with the baseline values before induction of anesthesia taken as covariates. A t test for independent samples was used for explorative testing of differences in drainage volumes in the first 8 hours postoperatively, the bleeding times, the urine output, and the loss into the swabs after bypass. The frequency of autologous blood transfusion in both groups was tested with Fisher's exact test. Other parameters were assessed by standard descriptive methods. All results are expressed as arithmetic mean and standard deviation if not otherwise indicated.

Results Part I. Of the 80 patients admitted to the doubleblind study, three from the placebo group were excluded from subsequent analysis. Two patients required reexploration for excessive bleeding of surgical origin; one patient died of low cardiac output 24 hours postoperatively. The two groups of patients did not differ in regard to age, sex, bypass time, total operation time, number of grafts, or the use of internal mammary artery grafts (Table I). The use of autologous blood was not significantly different. All patients had normal coagulation parameters, platelet counts, and bleeding times before operation.

Volume 97 Number 3

Table n. Bank blood transfusions

g(± SD) 80

In

= 37)

autologous blood retransfused (n ~ 27)

%

No.

%

8

20

35

95

32.0 40 12.0

75

13 18

11/11

37.7

60

No.

3/17

all patients (n ~ 74)

Placebo

Aprotinin In = 40)

No. of patients having transfusion Total transfusion (units) Patients in autologous blood group having transfusion *

36 7

Aprotinin in cardiac surgery

March 1989

20

100

'Number of patients receiving bank blood in relation to those who received autologous blood.

Postoperative blood loss. Total postoperative loss into the chest drains was reduced by 50% in the group treated with aprotinin. From the statistical analysis it follows that the reduction of the total average drainage volume was greater than 30% as compared with that in patients treated with placebo; this difference was statistically significant at the 1% level (p < 0.01). If the subgroup of patients who received autologous blood retransfusion is analyzed separately, the effect of aprotinin remains unchanged (Fig. 1). The intraoperative loss into swabs after bypass was significantly less in the aprotinin group (30 ± 11 ml versus 49 ± 39 ml, P < 0.05) as was the loss in the first 8 hours after return to the leu (165 ± 102 ml versus 326 ± 113 ml, p < 0.05). The loss of hemoglobin into the chest drainage fluid was reduced threefold in the aprotinin group. Again the use of autologous blood did not alter the difference (Fig. 2). Blood transfusions. There was a marked reduction in the amounts of bank blood used postoperatively in the patients treated with aprotinin (Table II). The use of autologous blood did not confer any benefit with respect to blood loss or use. No patient required the transfusion of platelets or fresh frozen plasma. Hemoglobin levels. The preoperative hemoglobin levels were similar in both groups. At 24 hours postoperatively, the levels in both groups fell by a similar amount. On postoperative day 7, levels had risen in both groups and were slightly higher in the patients treated with aprotinin. This difference was not significant (Fig. 3). Platelet counts. Platelet numbers fell in both groups after the institution of bypass (Fig. 4, a). This was paralleled by a fall in packed cell volume, seen after mixing of the patient's blood volume with the crystalloid prime (Fig. 4, b). There was a further fall in platelet num-

~

0

•

placebo

~

apratinin

~-

Fig. 2. Total hemoglobin loss in grams ± standard deviation (SD) into chest drains for primary patients having bypass grafting. Use of autologous blood did not alter the differences.

g/dl( ± SD) 15.0

14.0

13.0

I

1'\\\ I ~I

aprotinin

\'\1·~r- - - - - l

12.0

placebo

11.0

pre-op.

24 h post-op,

I

7 days post-op.

Fig. 3. Venous hemoglobin levels preoperatively, 24 hours postoperatively, and on day 7. There were no significant differences between the two groups. SD, Standard deviation.

bers after the administration of protamine, which could not be attributed to a change in packed cell volume. Thereafter in both groups the counts rose. There was no significant difference between the two groups. Bleeding times. Template bleeding times tested preoperatively did not differ between the two groups. There were no excessively prolonged times in either group. The postoperative measurements were strikingly different. There was a significant prolongation from baseline values in the placebo group (6.5 minutes) as opposed to a nonsignificant increase in the aprotinin group (1.5 minutes) (Fig. 5). Urine output. Patients receiving aprotinin had a higher urine output during the operation (995 ± 423 ml

The Journal of Thoracic and Cardiovascular Surgery

3 6 8 Bidstrup et al.

Vol.%(± SO)

x 10'/1 (± SO) 420

48

tJ

350

42

I I\I\\ II I~I~I .

280 210

'. =

~I'"

I

140

36

I

30

----·1""-;-1 I~ ~I

e-,

18

70 I

Base

A

24

A-

0---

I

I

I

I

I

I

i

I


r

I

Stern 10' EC Rewarm End X End EC Protam End OP 24 h

Base

B

.0---'

I

r

I

I

I

I

I

Stern 10' EC Rewarm End X End EC Protam End OP 24 h ~aprotinin

~

placebo

(n~40)

(n~36)

Fig. 4. A. Platelet counts (mean ± standard deviation [SD]). Counts during CPB are not corrected for hemodilution. There was no significant difference betwen the two groups. B, Hematocrit values (%) during and after operation. Base, Baseline; Stern, after sternotomy; 10' Ee. 10 minutes of bypass; Rewarm, rewarming commenced; End X, release of aortic cross-clamp; End Ee. end of bypass; Protam, 10 minutes after protamine administration; End OP, immediately before transfer to ICU; 24 h, 24 hours after operation.

min(±SD) 14

Placebo (n=16)

Aprotinin (n=16)

12 10

8 6 4

~

p<0.05

2

pre-op.

post-op. pre-op.

post-op.

Fig. 5. Bleeding time (minutes) preoperatively and 90 minutes after operation. Preoperative values and increase in aprotinin group not significant.

versus 670 ± 528 ml) and in the first 6-hour period in the ICU (1756 ± 937 versus 1333 ± 713 ml,p < 0.05). Thereafter, urine output was similar between the groups. Aprotinin levels. Aprotinin levels were determined in 17 patients. Ten minutes after the onset of bypass, the median value achieved was 5.5 J,LmoljL, range 3.6 to 8.5 J,LmoljL. At the end of bypass, the levels had fallen to 3.9 J,Lmol/L. The values ranged from 1.3 to 5.8 J,LmoljL. Part ll: Reoperations. Twenty-two patients undergoing reoperation were randomized to the study group or the control group. There were no deaths. Both groups were of similar composition with respect to age and type of previous operation. The 11 patients receiving

aprotinin lost significantly less blood into the chest drains. Transfusion needs were significantly reduced (p < 0.001) (Table III). Hemoglobin levels on postoperative day 7 did not differ significantly between the two groups (aprotinin 11.9 ± 0.6 gm/dl, control 12.1 ± 0.5 gm/dl, mean ± standard error of the mean). Since then, this drug has been used in a further 24 reoperations. The bank blood use for these patients is also shown in Table III. Part Ill: Infective endocarditis. Fifteen patients were admitted to this section and all were given aprotinin. These patients were somewhat younger than those in the other groups. Twelve patients had undergone previous valve replacement, two were having dialysis for renal failure caused by the sepsis, and five had laboratory evidence of intravascular coagulation with reduced platelet counts and increased partial thromboplastin and prothrombin times. Blood and hemoglobin losses were comparable with those of the other treated patients. Transfusions are shown in Table III. However, three patients required blood primes because of preexisting anemia (5 units). Because of the difficulties in setting up prospective controls, a historical control group was established for these patients. The transfusion requirements in 15 consecutive patients operated on in the previous 12-month period for the same condition were more than eight times greater (9.3 units/patient).

Discussion These clinical investigations have demonstrated that high dose aprotinin reduces postoperative blood loss

Volume 97 Number 3 March 1989

Table

Aprotinin in cardiac surgery

m. Results in patients having reoperation and in patients

with infective endocarditis

Reoperation Aprotinin (n

Age (yr) Operation MVR AVR DVR ACBG Blood loss (ml) Hemoglobin loss (gm) No. of patients receiving transfusion Blood used (units)

= /I)

53 3 4 1 3 286 (48) 8.3 (2.4) 4 5

369

Control (n = /I) 57 5 5 0 1 1509 (388) 78 (23) 11 41

Infective endocarditis Additional (n = 24) 52 6 8 1 9 245 (16) 4.3 (0.6) 4 5

Aprotinin (n = 15) 46 (4.1) 5 9 1 388 (67) 6.6 (1.5) 6 11

Patients in aprotinin and control groups are from our randomized study." The additional group comprises patients having reoperations, all of whom were given aprotinin. Patients with infective endocarditis are the third arm of the study. Values expressed as mean ± standard error of the mean (in parentheses). MVR, Mitral valve replacement; AVR, aortic valve replacement; DVR, double valve replacement; ACBG, aorta-coronary bypass grafting.

significantly. The need for bank blood transfusion was greatly reduced in those patients receiving aprotinin. Despite this, postoperative anemia was avoided. The bleeding time was kept within the normal range by aprotinin although platelet numbers were not preserved. In patients at higher risk of bleeding postoperatively (those undergoing reoperation and those needing valve replacement in the acute phase of endocarditis) the benefit of aprotinin treatment was greater. The majority of patients so treated did not require blood transfusions. Our studies were not designed to elucidate the mechanism of action of aprotinin. A detailed analysis of alterations in platelet function and plasma protein cascade activation was considered outside the scope of these investigations in which the principal aim was to show efficacy. The use of aprotinin to reduce postoperative bleeding is not new. In 1963, Tice and associates" treated patients with Trasylol for bleeding due to hyperfibrinolysis. Subsequently, he and others continued to use it albeit as a treatment and not prophylactically.":" Care must be taken in extrapolating the results of those early investigations, inasmuch as hyperfibrinolysis was often seen with earlier types of cardiopulmonary (CPB) bypass apparatus. Later it was realized that aprotinin was not effective when given after bypass." Philipp" suggested that if the levels of aprotinin were adequate, inhibition of plasmin and plasma kallikrein could be achieved. When it became possible to measure plasma aprotinin easily, regimes to achieve known concentrations were possible." The dosage schedule used in this study was able to achieve plasma concentrations of more than 4 f,LmoljL for the majority of the time spent on bypass, which are sufficient to inhibit plasmin and plasma kallikrein."

The hemostatic defect associated with cardiopulmonary bypass is complex."?' What seems to be certain is that a transient and occasionally severe defect in platelet function occurs.>" Alterations in platelet surface membrance receptors during extracorporeal circulation have been described that may contribute to this defect, 29-3I The initial phase of platelet adhesion requires glycoprotein Ib surface membrane receptor and von Willebrand factor. The finding in our study of a near normal bleeding time early after bypass suggests that there is preservation of the normal platelet response to vessel injury. Recently, preliminary observations have shown that the glycoprotein Ib receptor is preserved during early cardiopulmonary bypass with aprotinin." Harker" believed that fibrinolysis after CPB is probably not a major contributing factor. Examination of the changes in platelet numbers do not appear to throw much light onto the problem. As has been seen before, there is wide variation in the counts, and often little correlation with subsequent blood loss and transfusion needs. Thus aprotinin has preserved platelet function without reducing platelet consumption. Recent studies have evaluated the effects of other drugs on blood loss after CPB. Desmopressin" and dipyridamole? showed significant reductions in blood loss and transfusions but neither was able to eliminate the need for bank blood entirely. Prostacyclin was also reinvestigated and its routine use was not recommended." The synthetic antifibrinolytic drug s-aminocaproic acid reduced blood loss slightly but no difference in blood use was reported. 34 None of these studies has addressed the problem of the patient at much greater risk of needing blood replacement, for example, those with endocarditis. Our

370

The Journal of Thoracic and Cardiovascular Surgery

Bidstrup et al.

data show that the effect of aprotinin on blood loss is even more pronounced in these patients. Acceptance of normovolemic anemia has been widely practiced as an adjunct to blood conservation. More than mild anemia has been questioned, and it is our belief that a packed cell volume of less than 30% is undesirable." Predonation of autologous blood in the weeks before operation for reinfusion postoperatively did not prevent this anemia.' Storing 1 or 2 units of blood taken after induction of anesthesia is often practiced for patients of the Jehovah's Witness faith." In the present study, such a technique conferred no advantage in either blood loss or blood requirements. At the same time, no significant anemia (hemoglobin value less than 10.0 gm/dl) was seen. Homologous blood is a limited and possibly dangerous resource. The stimulus to blood conservation has been brought about by reduced donations both commercial and voluntary and by the increasing fears of the medical profession and the public having major operations about the risks of transfusion. Human immunodeficiency virus transmission is estimated to be of low probability at present.F-" but not so that of non-A and non-B hepatitis. There is a 6% to 10% incidence of this illness after transfusion and it is the greatest cause of hepatitis after cardiac operations.P:" Other transfusionrelated morbidity has been reviewed elsewhere.' This study has shown that high dose aprotinin significantly reduces bleeding and the need for postoperative blood component therapy. Transfusion is obviated in the majority of patients with safety. Patients who are likely to benefit most are those at high risk of postoperative bleeding (those having reoperations and those with infective endocarditis) and patients who for religious or other reasons cannot or will not have blood transfusions. Its use in cardiac operations offers a major contribution to blood conservation. We would like to thank Dr. F. Schumann of Bayer AG for his constant advice and encouragement. This study could not have been done without the cooperation of the staff of the ICU at Hurnana Hospital, Wellington, and the Hammersmith Hospital, our anesthetic colleagues, and our perfusionists. Aprotinin levels were measured by Dr. M. Jochum, Department of Clinical Biochemistry, University of Munich, Federal Republic of Germany, to whom we are also indebted. Statistical evaluation was done by Dr. W. Haase, Institut fur Numerische Statistik, Koln, Federal Republic of Germany, whose valuable contribution we wish to acknowledge. REFERENCES 1. Cosgrove DM, Loop FD, Lytle BW, et al. Determinants of blood utilization during myocardial revascularization. Ann Thorac Surg 1985;40:380-4. 2. Mayer ED, Welsch M, Tanzeem A, et al. Reduction of

3.

4.

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14.

15.

16.

17.

postoperative donor blood requirement by use of the cell separator. Scand J Thorac Cardiovasc Surg 1985;19:16571. Cosgrove DM, Amiot DM, Meserko 11. An improved technique for autotransfusion of shed mediastinal blood. Ann Thorac Surg 1985;40:519-20. Love TR, Hendren WG, O'Keefe DD, Daggett WM. Transfusion of predonated autologous blood in elective cardiac surgery. Ann Thorac Surg 1987;43:508-12. Czer LS, Bateman TM, Gray RJ, et al. Treatment of severe platelet dysfunction and hemorrhage after cardiopulmonary bypass: reduction in blood product usage with desmopressin. J Am Coli Cardiol 1987;9:1139-47. Salzman EW, Weinstein MJ, Weintraub RM, et al. Treatment with desmopressin acetate to reduce blood loss after cardiac surgery. N Engl J Med 1986;314:1402-6. Teoh KH, Christakis GT, Weisel RD, et al. Blood conservation with membrane oxygenators and dipyridamole. Ann Thorac Surg 1987;44:40-7. Fritz H. The target enzymes of aprotinin in vitro and in vivo. In: Dudziak R, Reuter HD, Kirchhoff PG, Schumann F, eds. Proteolyse und Proteinaseninhibition in der Herz- und Gefa/:khirurgie. Stuttgart: Schattauer, 1985: 143-54. Fritz H, Wunderer G. Biochemistry and applications of aprotinin, the kallikrein inhibitor from bovine organs. Arzneimittel-Forschung 1983;33:479-94. Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985;29:236-61. van Oeveren W, Jansen NJG, Bidstrup BP, et al. Effects of aprotinin on hemostatic mechanisms during cardiopulmonary bypass. Ann Thorac Surg 1987;44:640-5. Royston D, Bidstrup BP, Taylor KM, Sapsford RN. The effect of aprotinin on need for blood transfusion after repeat open heart surgery. Lancet 1987;2:1289-91. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Effect of aprotinin on need for blood transfusion in patients with septic endocarditis having open heart surgery. Lancet 1988;1:366-7. Miiller-Esterl W. Aprotinin, pancreatic basic trypsin inhibitor: enzyme linked immunosorbent assay. In: Bergmeyer HU, Bergmeyer J, Gram M, eds. Methods of enzymatic analysis: vol 12. 3rd ed. Weinheim: VCH Verlagsgesellschaft mbH, 1986:246-56. Popov-Cenic S, Murday H, Kirchhoff PG, Hack G, Fenyes J. Anlage und zusammenfassendes Ergebnis einer klinischen Doppelblindstudie bei aorto-koronaren Bypass Operationen. In: Dudziak R, Kirchhoff PG, Reuter HD, Schumann F, eds. Proteolyse und Proteinaseninhibition in der Herz- und Gefal3chirurgie. Stuttgart: Schattauer, 1985:171-86. Tice DA, Reed GE, Clauss RH, Worth MH. Hemorrhage due to fibrinolysis occuring with open heart operations. J THoRAc CARDIOVASC SURG 1963;46:673-9. Gans H, Castaneda AR, Subramanian V, John S, Lillehei CWo Problems in hemostasis during open heart surgery. IX. Changes observed in the plasminogen-plasmin system

Volume 97 Number 3 March 1989

18.

19.

20.

21.

22.

23.

24.

25. 26.

27.

28.

29.

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32. van Oeveren W, Eijsman L, Roozendaal KJ, Wildevuur CRH. On the mechanism of platelet preservation during cardiopulmonary bypass by aprotinin. Lancet 1988; 1:644. 33. Fish KJ, Sarnquist FH, van Steennis C, et al. A prospective, randomized study of the effects of prostacyclin on platelets and blood loss during coronary bypass operations. J THoRAc CARDIOVASC SURG 1986;91:436-42. 34. Vander Salm 'I'J, Ansell lE, Okike ON, et al. The role of epsilon-aminocaproic acid in reducing bleeding after cardiac operation: a double blind randomized study. J THoRAc CARDIOVASC SURG 1988;95:538-40. 35. Weisel RD, Charlesworth DC, Mickleborough LL, et al. Limitations of blood conservation. J THORAC CARDIOVASC SURG 1984;88:26-38. 36. Henderson AM, Maryniak JK, Simpson JC. Cardiac surgery in Jehovah's Witnesses: a review of 36 cases. Anaesthesia. 1986;41:748-53. 37. Ward JW, Holmberg SD, Allen JR, et al. Transmission of human immunodeficiency virus (HIV) by blood transfusions screened as negative for HIV antibody. N Engl 1 Med 1988;318:473-8. 38. Zuck TF. Transfusion-transmitted AIDS reassessed. N Engl J Med 1988;318:511-2. 39. Iwarson SA. Non-A, non-B hepatitis: dead ends or new horizons? Br Med J 1987;295:946-8. 40. Collins JD, Bassendine MF, Codd AA, Collins A, Ferner RE, James OFW. Prospective study of post-transfusion hepatitis after cardiac surgery in a British centre. Br Med J 1983;287:1422-4. 41. Ayrnard JP, Janot C, Gayet S, et al. Post-transfusion non-A, non-B hepatitis after cardiac surgery: prospective analysis of donor blood anti-Hbc antibody as a predictive indicator of the occurrence of non-A, non-B hepatitis in recipients. Vox Sang 1986;51:236-8.

Discussion Dr. Richard D. Weisel (Toronto, Ontario, Canada). I would like to congratulate the authors on an excellent prospective randomized double-blind clinical trial. Carefully performed clinical trials are desperately needed to assess alternative interventions intended to reduce postoperative bleeding. I wonder if you could speculate about the mechanism for the beneficial effect of aprotinin on blood loss and blood usage? If aprotinin improved platelet function postoperatively, then I would have expected to see an increase in the postoperative platelet counts. However, there was a substantial decrease in platelet counts in both groups. Therefore the effects of aprotinin were likely independent of any effects on platelets. The results in the experimental group are excellent. However, it is impossible to compare these results with those obtained in other reports. Small differences in protocol may have markedly influenced postoperative bleeding and the number of units of red cells transfused. Therefore, I cannot compare your results with those obtained in our studies. We must ask you to continue your clinical investigations to assess alternative interventions. I believe that pretreatment will be required for all patients undergoing bypass operations to reduce postoperative blood loss and blood product utilization.

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Carefully conducted controlled clinical trials are required to determine which drugs we should use and in what doses. Dr. L. Henry Edmunds (Philadelphia, Pa.). I think this is an important clinical research study and I congratulate the authors. These are the first data of which I am aware that suggest that platelets may be activated by the contact activation pathway in extracorporeal bypass systems. If this proves true or if it proves to be the mechanism of platelet activation, it raises the possibility that activation of platelets, white cells, and the coagulation cascade could be inhibited by a single inhibitor of factor XII or Hageman factor. The prize for finding this inhibitor is quite enormous, inasmuch as it would

The Journal of Thoracic and Cardiovascular Surgery

control bleeding after bypass, thrombosis during bypass, and thromboembolism from prosthetic heart valves and would open the door to artificial organs including liver and lung, as well as heart. There are a number of possible candidates for this inhibitor of the contact pathway, and I will mention three: com trypsin inhibitor, arginine-IS aprotinin, which is a derivative of aprotinin, and alpha-l antitrypsin-Pittsburgh. I find these data most interesting and exciting. Dr. Bidstrup (Closing). I would like to thank Dr. Weisel and Dr. Edmunds for their kind comments about our paper. We hope that these studies will stimulate further research into the hemostatic defect of cardiopulmonary bypass and the important area of blood conservation.

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