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J Thorac Cardiovasc Surg 1994;108:517-521
© 1994 Mosby, Inc.

SURGERY FOR CONGENITAL HEART DISEASE

Aprotinin in children undergoing correction of congenital heart defectsA double-blind pilot study

Porto Alegre, Brazil

From the Department of Cardiac Surgery, Instituto de Cardiologia do Rio Grande do Sul, Porto Alegre, Brazil.

Received for publication April 9, 1993. Accepted for publication Jan. 28, 1994. Address for reprints: F. Herynkopf, MD, Department of Cardiac Surgery, Instituto de Cardiologia do Rio Grande do Sul, Av. Princesa Isabel, 395, Porto Alegre, RS, Brasil - 90.620-001.

Abstract

Thirty children undergoing surgical repair for congenital heart defects were randomly selected for a double-blind study on the antihemorrhagic and blood-saving properties of aprotinin. The treatment group comprised 14 patients who received aprotinin 7 mg/kg of body weight until the end of perfusion. The placebo group (n = 16) received an infusion of the corresponding volumes of saline. Patients treated with aprotinin bled less during the operation (12.6 ml/kg versus 18.1 ml/kg, p = 0.25) and in the first 24 postoperative hours (chest drainage 12.1 ml/kg versus 17.7 ml/kg, p = 0.07). Hemoglobin loss into chest drainage was reduced in the treated group by half (0.66 versus 1.21 gm in 24 hours, p = 0.07). Fewer blood donors were needed during hospitalization by patients receiving aprotinin (1.07 versus 2.75 donors per patient, p = 0.04). Postoperative transfusion was unnecessary in 64.2% of patients receiving aprotinin compared with only 25% of the placebo group (p = 0.03). Aprotinin increased diuresis significantly during perfusion (4.3 ml/kg versus 1.0 ml/kg, p = 0.005). Other parameters are evaluated, and considerations are made regarding adequacy of the dosage regimen. The drug seems to be safe and easy to handle in children. (J THORAC CARDIOVASCSURG 1994;108:517-21)

By April 1991, when this protocol was developed, several articles had been published that demonstrated the advantages of using aprotinin as an antihemorrhagic drug in adult patients subjected to cardiopulmonary bypass. ^1-16 However, at that time only two studies using aprotinin to reduce bleeding in pediatric cardiac surgery were available, ^17,18 and even those were of limited value because of the nature of the reports. ¹⁹ Besides the risks of bleeding in a small patient and the impact on blood resources, we were deeply concerned with the large number of blood donors to which a pediatric patient used to be exposed. As a matter of fact, children received platelet concentrates, cryoprecipitates, and plasma units for treating hemorrhage more frequently than adults. Moreover, blood and packed cells needed to transfuse a child during a working day frequently came from different adult donors, increasing the risk of blood-transmitted diseases. As a result, pediatric patients often were exposed to a greater number of blood donors than adult patients. This major concern prompted us to undertake the present pilot study.

PATIENTS AND METHODS

Patients.
Thirty consecutive patients, from June 1991 to July 1992, were selected among children referred to the Instituto de Cardiologia do Rio Grande do Sul for surgical repair of congenital heart defects. Inclusion criteria were as follows: no use of aspirin, dipyridamol, or ticlopidine in the previous 7 days; no prior use of aprotinin; and normal blood urea, creatinine, and blood clotting tests. A minimum cardiopulmonary bypass time of 45 minutes was requested and patients were accepted only if their cardiopathy was not associated with a high surgical mortality rate. The childrens' ages ranged between 8 months and 11 years and body weight ranged from 6.1 to 36 kg. Children were randomly assigned to an aprotinin-treated group (n = 14) or to a placebo group (n = 16) for this prospective double-blind pilot study. Written informed consent was obtained from parents and the study protocol was approved by the ethics committee of this hospital.

Surgical procedure.
After induction of anesthesia with sodium thiopental (4 mg/kg), halothane or isoflurane was administered for maintenance. Pancuronium (0.1 mg/kg) and fentanyl (10 µg/kg) were also used as needed.

A median sternotomy was performed and heparin (3 mg/kg) was administered. Cardiopulmonary bypass was instituted with a bubble oxygenator with flows of 2.4 L/min per square meter. Body temperature was lowered during bypass to 28° C. Myocardial preservation during aortic crossclamping was maintained with St. Thomas' Hospital cardioplegic solution. After discontinuation of bypass, heparin was reversed with protamine sulfate in a 1:1 ratio.

In the intensive care unit intermittent positive-pressure ventilation was continued until a stable condition was achieved.

Dose regimen.
Aprotinin 7 mg/kg body weight (50,000 Kallikrein inactivator units, KIU/kg) was given to patients in the treatment group as follows: 40% of the calculated dose was infused over a 15- to 20-minute period at the start of anesthesia. Thereafter, a continuous infusion containing 20% of the dose was started and maintained until the end of bypass. Another 40% of the dose was added to the prime volume of the oxygenator. Aprotinin (Trasylol) was supplied by Bayer AG, Leverkusen, Germany) in bottles containing 50 ml of saline solution without any additives or preservatives, each milliliter containing 10,000 KIU. The placebo group received saline volumes calculated and administrated in the same manner as the treated group.

Samples and hematologic evaluation.
Blood samples were collected at the start of anesthesia and 5 minutes after protamine sulfate administration for measurement of hematocrit value, hemoglobin concentration, platelet count, thrombin time, partial thromboplastin time, prothrombin time, reptilase time, fibrinogen, activated clotting time, and euglobulin lysis time. Bleeding time was obtained as well. Another sample was taken 90 minutes after the end of bypass and 7 days after the operation for hemoglobin, hematocrit, and platelet count. Bleeding time was measured again 90 minutes after the end of bypass.

Chest drainage was measured hourly during the first 24 hours after the operation and the material was preserved for determination of hemoglobin concentration by the cyanmethemoglobin technique.

Diuresis was measured during bypass and recorded as mentioned in other studies ^3,6; hematologic evaluation was performed by standard routine methods currently used in the laboratory of hemostasis of this hospital, ²⁰ and bleeding time was determined by the Ivy method.

Aprotinin efficacy.
Antihemorrhagic and blood-saving efficacy of the drug was evaluated by the following parameters, most of which have already been used by other authors: chest closure time ^2,19,21; bleeding during the surgical procedure, ^6,8,14,21 measured in milliliters per kilogram of body weight; whole blood and packed cells transfused in the operating room ^8,10,21; chest drainage in the first 24 hours measured both in milliliters per kilogram of body weight and in grams of hemoglobin lost ^1,2,6,21; whole blood, packed cells, and plasma needed in the first 24 postoperative hours, measured in milliliters per kilogram of body weight ^1,2,8; platelet concentrates and cryoprecipitates needed in the first 24 postoperative hours, measured in units per patient; number of blood donors per patient used during the entire hospitalization ^12,19; and percentage of patients not receiving a transfusion during the postoperative period. ^2,6,11,14,21 Additionally, patients were observed while the chest was being opened to empirically evaluate bleeding. ^1,2,21

Transfusion policy.
Blood was used in each patient's prime to compensate for dilution caused by the relatively large oxygenators used (to keep a hematocrit value of 25%). Each patient in the treated group used an average of 655.7 ml of blood, and those in the placebo group received 589.1 ml individually. These volumes were not considered when transfusion needs data were being computed. In the postoperative period, transfusion was indicated when cyanotic patients had a hemoglobin concentration less than 14.0 gm/dl or when acyanotic patients had a hematocrit value less than 30%. These criteria were not too rigid and some flexibility was allowed to the attending intensive care physician. Frozen plasma, cryoprecipitate, and platelet concentrates were administered according to individual needs.

Statistical analysis.
Statistical analysis was performed with the EPI-INFO 501 A software by covariance analysis and by the ² test. A p value of less than 0.05 was considered significant.

RESULTS

Comparability of groups.
The two groups were similar when preoperative data were compared, as shown in Tables I and II. Patients did not differ with regard to postoperative coagulation tests measured 10 minutes after protamine sulfate administration (Table III) or duration of surgical interventions (Table IV). Hemoglobin concentration in blood samples taken before the operation averaged 12.4 gm/dl in the treated group and 13.2 gm/dl in the placebo group, whereas in samples collected 7 days after the operation hemoglobin concentration was 12.3 gm/dl for the treated group and 13.1 gm/dl for the placebo group. These figures demonstrate that the transfusion policy was applied similarly to both groups.

Chest closure time and total surgical time were similar for the two groups (Table IV), in contrast to other results. ^1,2,21

Fibrinolytic activity measured by the euglobulin lysis time, 5 minutes after protamine sulfate administration, showed no reduction in the treated group, in contrast to the literature. ^1,13,14,22 In fact, their results were even shorter than those of the placebo group (Table III).

Confirming previous studies, ^3,6 diuresis was significantly higher in the treated group than in the placebo group (4.38 ml/kg versus 1.00 ml/kg, p = 0.005) during bypass.

Postoperative results.
Patients who received aprotinin bled considerably less through their chest tubes in the first 24 hours than those who received placebo (Table V). Bleeding from sites other than chest tubes was negligible during the postoperative period.

The treated group received more whole blood transfusions than the placebo group, whereas the reverse was true for packed cells, frozen plasma, platelet concentrates, and cryoprecipitate (Table VI). Considering those figures, it is clear that the placebo group received more transfusions than the treated group, although other authors have shown larger differences. ^2,6,11,14,21

Also significant was the difference in the number of patients not receiving a transfusion in the postoperative period: 64.2% of patients in the aprotinin group versus only 25% of patients in the placebo group (p = 0.03). These figures compare properly with the literature. ^2,6,9,21,22

DISCUSSION

Aprotinin regimen and safety.
At the time we designed this protocol, sufficient experience had not been obtained with the use of aprotinin in children to define an optimum dose. For this reason we derived our dose regimen from the adult standard regimen. Assuming an average of 2 hours of surgery for a population weighing from 60 to 100 kg, an adult patient would receive from 7.0 to 11.66 mg of aprotinin per kilogram of body weight during the procedure. We chose the minimum adult dose of 7.0 mg/kg (50,000 KIU/kg) as the safest because this dose is similar to the dose safely used by Popov-Cenic, ¹⁷ Murday, ¹⁸ and their associates in children (45,000 KIU/ kg).

Used in that manner, the drug proved to be safe because no reaction or illness attributable to its use was detected during the study. All 30 patients left the hospital within a 2-week period and no reoperations for bleeding were necessary.

Aprotinin efficacy.
Although the small size of samples rendered several parameters insignificant, the benefits of using aprotinin are apparent when the two groups are compared.

Intraoperative bleeding was reduced in the aprotinin group by 30.4%, a figure that corresponds with those of other investigators who found 38.7%, ⁶ 28.7%, ¹⁴ and 35.1% ²¹ reductions in adults. Intraoperative transfusions of whole blood were more frequent in our patients who received aprotinin (plus 15.9%), whereas packed cell transfusions were 37.3% lower in the aprotinin group. Approximately 60% of all intraoperative transfusions were packed cells, which resulted in a net blood-saving pattern similar to that reported in the literature (7% ²¹ to 58% ⁸).

Postoperative chest drainage measured in milliliters per kilogram was reduced by 31.6% in patients treated with aprotinin, and the reduction in grams of lost hemoglobin was 44.8%. In adult patients Bidstrup, Royston, and Taylor ⁶ obtained a 45.5% reduction in chest volumes and a 68.4% fall in hemoglobin losses. In a multicenter study in Europe mentioned by Royston ¹⁹ in his excellent review article, the chest drainage volumes were reduced by 40% to 50%. Again, in the postoperative period patients in the aprotinin group received more whole blood transfusions than those in the placebo group (8% plus). However, a 22.8% savings in packed cells was observed in the same period. Packed cells corresponded to approximately 65% of all postoperative transfusions. These blood savings are less impressive than expected from the literature, perhaps, at least in part, because of the more flexible transfusion policy we used.

The use of hemostatic transfusion in patients receiving aprotinin was clearly reduced because 37% less frozen plasma was used and no platelet concentrates or cryoprecipitates were necessary. If we remember also that the treated group received 1.07 blood donations during hospitalization as compared with 2.75 donations for the placebo group (p = 0.047) and that 64.2% of the aprotinin group did not receive a transfusion in the postoperative period as compared with only 25% of the placebo group (p = 0.03), it is easy to conclude, beyond any doubt, that aprotinin was effective in preventing bleeding and reducing the need for transfusion. However, some findings in our study call for further attention. First, we observed no reduction in fibrinolytic activity in the treated group during perfusion, at least as measured by euglobulin lysis time. Other articles showed direct or indirect evidence of lower fibrinolytic activity related to the use of aprotinin during the perioperative period. ^1,13,14,22 Second, no clear-cut incision dryness or reduced chest closure time could be observed in patients receiving treatment, in contrast to the observation of others. ^1,2,19,21 Third, blood savings in the postoperative period were much less impressive than expected, even considering the more flexible transfusion policy we used.

These observations raise the possibility that suboptimal aprotinin doses had been used in the present study. In fact, the currently recommended dose for children ¹⁹ averages 75,000 KIU/kg, which is 50% higher than the dose we used. According to this hypothesis, we should soon start a new study group in which 75,000 KIU/kg doses are used.

Acknowledgments

We are indebted to Dr. Dora Veronesi Palombini for selecting patients for this study and for helping in the collection of patient data; to Cesar Roberto Coelho Pintos for randomizing the patients and preparing the doses; and to Dr. José Roberto Goldin for performing the statistical analysis.

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): Ivo Abrahão Nesralla Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Herynkopf, F. Articles by Nesralla, I. A. Search for Related Content PubMed PubMed Citation Articles by Herynkopf, F. Articles by Nesralla, I. A.