Comparison of two aprotinin dosage regimens in pediatric patients having cardiac operations

Comparison of two aprotinin dosage regimens in pediatric patients having cardiac operations Influence on platelet function and blood loss Only a few studies have reported on the effects of aprotinin in pediatric cardiac surgery, and the correct dose is controversial. In a prospective, randomized study, three groups of children weighing less than 20 kg were investigated. In group 1 (n = 14): aprotinin 20,000 U/kg was given after induction of anesthesia, 20,000 U /kg was added to the prime, and another 20,000 U/kg was given every hour of cardiopulmonary bypass (low-dose regimen). In group 2 (n = 14) aprotinin 35,000 U /kg was given after induction followed by an infusion of 10,000 U/kg . min until the end of the operation and 35,000 U/kg was added to the prime (high-dose regimen). In group 3 (n = 14) no aprotinin was used (control). Platelet function was evaluated by aggregometry (maximum platelet aggregation, maximum gradient of platelet aggregation) by means of turbidometric technique (inductors: adenosine diphosphate, collagen, and epinephrine) before and after cardiopulmonary bypass until the first postoperative day. Platelet aggregation was significantly reduced during and after bypass, values ranging from -29 % to -54% (maximum aggregation) and -25% to -75% (maximum gradient of aggregation) with regard to baseline values. In the further postoperative course, platelet function recovered and mostly exceeded baseline values on the first postoperative day. Platelet aggregation variables were without any differences among aprotinin-treated and control patients. Blood loss was similar for all three groups and added up to approximately 28 ml/kg until the first postoperative day. The use of packed red cells was also comparable for the three groups, whereas the use of fresh frozen plasma was highest in group 1 (1680 ml until the first postoperative day). We conclude from this study that aprotinin did not improve platelet function and did nor reduce blood loss or the need for homologous blood transfusion in pediatric cardiac surgery, regardless of whether a low-dose or a high-dose regimen was used. (J THORAC CARDIOVASC SURG 1993;105:705-11)

J. Boldt, MD, C. Knothe, MD, B. Zickrnann, MD, N. Wege, F. Dapper, MD,a and G. Hempelmann, MD, Giessen, Germany

Intraoperative and postoperative bleeding continues to be a problem, particularly in infants and small children. Several attempts have been made to solve this problem in adult cardiac surgery, induding the use of various mechFrom the Department of Anesthesiology and Intensive Care Medicine (Head: Prof. Dr. G. Hempelmann), Department of Cardiovascular Surgery" (Head: Prof. Dr. F.W. Hehrlein), Justus-Liebig-University Giessen, 0-6300 Giessen, Germany. Received for publication March II, 1992. Accepted for publication July 13, 1992. Address for reprints: Joachim Boldt, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikstr. 29, Justus-Liebig-University Giessen, 0-6300 Giessen, Germany. Copyright

1993 by Mosby-Year Book, Inc.

0022-5223/93 $1.00 + .10

12/1/40975

anical devices and pharmacologic interventions. I, 2 The proteinase inhibitor aprotinin appears to be the most promising drug in this situation, and there are several studies reporting on the beneficial effects of aprotinin on blood loss and the need for homologous blood and blood products.I" Although the exact mechanisms of these beneficial properties are not yet fully elucidated, preservation of platelet function appears to be one of the major actions of aprotinin in this situation.r? Aprotinin was also occasionally used in pediatric cardiac surgery, and there are a few reports that demonstrated a reduction in blood loss and need for homologous blood. I0 However, most of these studies were done retrospectively, and study conditions were heterogeneous. Moreover, dosages of aprotinin in these studies varied 705

706

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Table I. Demographic data and data from CPB

Age (rno) Weight (kg) Cyanotic (n) Acyanotic (n) CPB (min) Ischemia (min) Total aprotinin (1000 U) PRC added to CPB (units a 250 ml) Minimal temperature (OC) Rectal Esophageal Blood Hypothermic cardiac arrest

Low-dose

High-dose

aprotinin

aprotinin

Without aprotinin

13.3 ± 7.9 7.5 ± 3.8 8 6 126 ± 34 57 ± 26 475 ± 22 23

14.0 ± 7.9 9.8 ± 5.6 7 7 136 ± 44 69 ± 31 2560 ± 133 23

12.2 ± 6.9 7.2 ± 4.3 7 7 119 ± 35 61 ± 24

28.4 ± 4.1 26.7 ± 4.0 25.2 ± 4.0 2

28.0 ± 3.1 26.0 ± 3.3 25.3 ± 3.9 2

29.7 ± 2.9 27.1 ± 2.2 26.2 ± 3.1 2

25

Ischemia, Period of aortic crossclamping; Cyanotic, arterial oxygen tension/inspired oxygen fraction less than 100 mm Hg; Acyanotic, arterial oxygen tension/ inspired oxygen fraction greater than 100 mm Hg; PRe, packed red cells.

enormously. Thus this study was designed to randomly and prospectively investigate the influence of two dosage regimens of aprotinin on platelet function and blood loss in pediatric cardiac surgery. Methods Patients and grouping. The study was conducted in 42 children with congenital heart disease undergoing reparative or palliative operations with cardiopulmonary bypass (CPB). Inclusion criteria were a weight of less than 20 kg and no history of anticoagulant drugs use. No patients having reoperations were included in the study. Informed consent was obtained from the children's parents, and the study protocol was approved by the institutional ethics committee. Preoperatively, the children were randomly divided into three groups: Group 1 (n = 14). Aprotinin 20,000 U /kg was given after induction of anesthesia, 20,000 U /kg was added to the prime, and another 20,000 U /kg was given every hour during CPB (low-dose). Group 2 (n = 14). Aprotinin 35,000 U /kg was given after induction followed by a continuous infusion of 10,000 U /kg . min until the end oftheoperation, and 35,000 U /kg was added to the prime (high-dose). Group 3 (n = 14). No aprotinin was used (control). Anesthesia and CPB. Induction and maintenance of anesthesia were comparable for all groups and consisted of weightrelated doses of fentanyl, midazolam, and pancuronium bromide. Lungs of all patients were mechanically ventilated with regard to blood gas analyses. Five minutes before the start of CPB, bovine heparin 300 IE/kg was administered to achieve anticoagulation, followed by one half of the initial dose after 60 minutes of CPB. The activated clotting time was kept beyond 400 seconds within the entire bypass period. A COBE VPCMLplus membrane oxygenator (Cobe Laboratories, Lakewood, Colo.) and a flow rate of 2.4 L/min . m 2 were used for CPB. During hypothermia (rectal temperature <24 0 C), perfusion flow was reduced to half of the initial flow. The extracorporeal circuit was primed with 500 ml of Ringer's solution, 250 ml of

5% human albumin and weight-related doses of electrolytes. Packed red cells were added to the prime with regard to the children's weight and preoperative hemoglobin value. When necessary, Ringer's solution was added to keep the circuit full. When hemoglobin value fell below 7 gm/dl, packed red cells were given. After termination of bypass, the blood remaining in the extracorporeal oxygenation equipment was prepared by a centrifugation device (Cell Saver III, Hemonetics, Munich, Germany), and this autologous blood was retransfused in the postbypass period. Heparin was neutralized by protamine chloride in a ratio of I: I to the initial dose of heparin. All children were operated on by the same surgeon, who was blinded to the grouping. Measured parameters. Platelet function was assessed from arterial blood samples by aggregometry (turbidometric technique]! by means of a double-channel APACT-aggregometer (Fa. LAbor, Ahrensburg, Germany). Agents used to induce platelet aggregation were adenosine diphosphate (2.0 ,umol/L), collagen (4 ,ug/ml), epinephrine (25 ,umol/L), and sodium chloride (control). Maximum platelet aggregation was defined as the maximum change in light transmission of platelet-rich plasma after addition of the aggregating agent, and maximum gradient ofplatelet aggregation was defined as the maximum increase per minute. All measurements were performed in duplicate. Hemoglobin value, hematocrit value, platelet count, blood gas variables, electrolytes, activated clotting time, and thrombelastogram (at the end of the operation) were also monitored. Rectal, esophageal, and blood (in the oxygenator) temperatures were also measured. Fluid balances (input and output), blood loss from (postbypass) suction and from postoperative drainage, and use of fresh frozen plasma, platelets, and packed red cells were documented. Postoperatively, packed red cells were given when the hemoglobin level was less than 9.0 grn/dl, fresh frozen plasma was indicated when bleeding exceeded 5 ml/kg per hour and platelet count was greater than 50.000/ml (activated clotting time <200 seconds), and platelet concentrates were administered when bleeding exceeded 5 nil/kg per hour and platelet count was less than 50,ODO/ml (activated clotting time <200 seconds). All volume therapy and blood transfusions were indicated by anesthesiologists and pediatric intensive care staff

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Table II. Classification of operative procedure in the three groups

AV canal repair Kawasaki syndrome Fallot IV repair ASD + VSD repair AP shunt TGA Replacement of aortic arch Truncus arteriosus PST + ASD repair Mitral valve replacement

max.

aqqr egat 1 on

-

ADP 2. 0 JLmol /1

70

Low-dose aprotinin

High-dose aprotinin

Without aprotinin

60

2

3

I 1

50

2

I

3

3

3 4

40

2 2

4

1 3

30

I

I I

•

•

• • •

20

•

_low-dOSE' apr o t i ru n .·-··~hlgh-dose

stenosis.

ap~otlnln

O' D control

A V, Atrioventricular; ASD, atrial septal defect; VSD, ventricular septal defect; AP, aortopulmonary; TCA, transposition of great arteries; PST, pulmonary artery

110 100

Table III. Cumulative post bypass blood loss in the three groups Low-dose aprotinin Five hours postop. (nil/kg) Postop. day I (rnl/kg)

(/j

70 7

X t SO

90

• p

80

f

70

Without aprotinin

60

(mlfkg)

High-dose aprotinin (ml/kg)

(mlfkg)

50

8.3 ± 6.0 28.0 ± 10.1

6.9 ± 4.9 27.2 ± 9.6

6.9 ± 3.8 28.2 ± 6.5

30

40

after i

whowere not involved in the study and who were blinded to the grouping. Measurements were performed after induction of anesthesia (baseline values), 20 minutes after the onset of CPB, after weaning from CPB (before infusion of protamine), at the end of the operation,S hours after the end of the operation, and on the first postoperative day. Statistics. Before the investigation was started, a power analysiswasdone to evaluate the number of patients that would be necessary to protect the study from type II errors in statistical interpretation. Results are expressed as mean values ± standard deviation. Percentage changes of maximum platelet aggregation from baseline values were also calculated (expressedas changesin relativepercent). Statistical interpretation was performed by multivariate (repeated measures) analysisof variance (including multiple range tests [Scheffe's test]). The Kruskal-Wallis test was also used to assess differencesamong the groups at baselineand during or after CPB. The Xl test was usedto analyzedifferencesfor homologous blooduse.A p value of less than 0.05 was considered statistically significant. Results Biometric data and data from CPB are listed in Table I. There were no differences among the groups with regard to bypass period, lowest temperatures during bypass, and the need for homologous blood added to the prime. The numbers of cyanotic and acyanotic patients with congenital heart failure were also without differ-

< 0.05

nduc t r cn

CPS

after CP8

end of

5 h after'"

oper at I on oper at 1on

l s t p.o. day

Fig. 1. Changes in maximum platelet aggregation induced by adenosinetriphosphate (ADP 2.0 ,umoI/L). *p < 0.05 different from baseline values. SD, Standard deviation. ences among the groups (Table II). Classification of operative procedure was comparable for all groups (Table 11). In all groups, maximum platelet aggregation and maximum gradient of platelet aggregation deteriorated during CPB, with no differences among groups (Figs. I to 3). Reduction in maximum platelet aggregation was most pronounced at the end of the operation and ranged from - 29 to -54 relative percent. In the later postoperative period, maximum platelet aggregation recovered and mostly exceeded baseline values on the first postoperative day. In collagen-induced aggregation (Fig. 3), however, maximum aggregation completely recovered only in the group treated with high-dose aprotinin (+22 relative percent with regard to baseline values). Maximum gradient of platelet aggregation was even more extensively altered than maximum aggregation variables. Reduction in maximum gradient of aggregation from baseline values ranged from - 25 to - 77 relative percent. Also, maximum gradient recovered in the postoperative

708

The Journal of Thoracic and Cardiovascular Surgery

Boldt et al.

April 1993

max.

max. aggregatIon <%) - epInephrIne 70

• •

60

aqqr egat I on
call agen

-

50

•

~o

50

•

•

30

~o

20

30

10

20

••

•

10

•

o

_______ low-dose apr at 1 ru n .,......, hi qh do s e apr ot i rn n

.......... l ou-r do s e apr 011 ru n .,......, hi gh-dosE' apr ot I ru n

r

O' -0 control

O· -0 control

max.

max. gradIent <%/mIn) - epInephrIne

•

~o

35

x±

•

SO

gr adi ent <%/mi ri)

x

~o

30 25

-

call agen

..

50

/1

± SO

30

20

•

15 10

20 10

5

•

o at t er Induct Ion

CPB

after CPB

errd of

•

o 5 h after

oper at ron ccer er ico

ls1 pv o.

after

ddLJ

Induct Ion

CPB

after CPB

• end of

5 h after

OpE'''' at I on cper at 1on

l s t p.o. dau

Fig. 2. Changesin maximum plateletaggregation induced by epinephrine. *p < 0.05 different from baseline values. **p < 0.05 different from the other groups.

Fig. 3. Changesin maximum plateletaggregation induced by collagen. *p < 0.05 different from baseline values. **p < 0.05 different from the other groups.

period. The only group differences were seen in collageninduced aggregation (highest increase in group 2: +30 relative percent) and epinephrine-induced maximum gradient of aggregation (highest increase in group 3: +34 relative percent). Postbypass blood loss was comparable for the three groups (Table III). Hemoglobin values did not differ among the groups (Fig. 4). Platelet count decreased significantly during CPB in all groups and did not recover in the postoperative period until the first postoperative day (Fig. 4). The use of homologous blood and blood products is illustrated in Fig. 5: In the postbypass period, a similar amount of packed red cells and platelets were given until the first postoperative day. Significantly more fresh frozen plasma was infused in the patients treated with lowdose aprotinin (group 1) than in the control patients. None of the patients needed reoperation because of excessive and enhanced postoperative bleeding.

Discussion CPB induces several derangements in vascular, platelet, coagulation, and fibrinolytic components of the hemostatic system.l- Bleeding after pediatric cardiac operations is reported to be due to primary fibrinolysis, reduction of coagulation factors, disseminated intravascular coagulation, thrombocytopenia, and acquired defects in platelet function.!" 13. 14 The contact between blood and synthetic surfaces of the extracorporeal oxygenation equipment and direct blood trauma caused by sheer stress of the roller pumps and suction produce adverse platelet alterations that seem to be the most important reason for enhanced bleeding after cardiac operations.P: 16 Platelet dysfunction can be expressed as a decreased adhesion and a diminished sensibility to triggering agonists such as adenosine diphosphate- and epinephrine-induced aggregation. In adult surgery, various pharmacologic attempts have been made to limit CPB-induced coagulation abnormal-

The Journal of Thoracic and Cardiovascular Surgery Volume 105, Number 4

Boldt et al.

blood and blood derivates Cml)

hgb (WdD

16

709

1200

15

1000

14

13

800

12

600

11

400

10

200

9

o

8

PRe

iIJII lie

x

)(

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lie

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,

)(

101

,

J(

"

)(

FFP

7

. . ~.:1

2000

6 ______ lou-dose apr ot 1 ru n

1600

•.....~ hi gh-dose apr ot 1 ru n

1200

O' -0 control

x

x

platelet count (lOOO/ml)

350

x )(

l(

)(

X

l(

III

l(

)(

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)(

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lie l(

l(

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8 400 0 0 l l l J I T L I l X

lie

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l(

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l(

l(

)(

lie

)(

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III

II

l(

)(

l(

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l(

X

300

250

1000

200

800

platelets

600

150

l(

)(

)( X

X

x

lie

X X

)(

x )( X

)( )(

X

X X

)(

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400LUlLI 200

100

lie

o

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lie

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lie

)(

)( x

)(

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x

)(

X

)(

l(

~ lou-dose aprotlnln at t er Induct i ori

CPS

after CPS

end of, 5 h after oper at I on oper at Ion

1st p.o. day

Fig. 4. Plateletcount and hemoglobin (hgb; gjdl) in the three groups. CPR, Cardiopulmonary bypass.

ities.17- 19 These interventions were less effective in pediatric cardiac surgery: Desmopressin, for example, failed to reduce blood loss significantly in this situation.j? The widespread use of aprotinin in adult cardiac surgery has been advocated owing to a reduction in blood loss and a reduced need for homologous blood in aprotinintreated patients.i! In addition to the effects on the kallekrein/kinin system, it is postulated that aprotinin also has significant platelet-protective effects." However, these direct beneficial effects on platelets have been doubted by others, who assumed that aprotinin acts only by its antifibrinolytic properties.F The optimal dose of aprotinin in adult cardiac surgery is controversial; it is still interesting to speculate on the best dose" In an early report from 1984, in which an aprotonin dose of only 5000 U /kg was used after induction of anesthesia and 10,000 U /kg was added to the prime, a significant reduction in postoperative blood loss was demonstrated.P Doses of aprotinin used in the few studies dealing with pediatric cardiac surgery vary widely. Divided doses of

~ high-dose aprotlnln

B

control

Fig. 5. Use of homologous blood and blood derivatives until firstpostoperative day. PRC, Packed red cells(withoutaddition tothe prime,which wascomparablefor the twopairsof groups). FFP, Fresh frozen plasma.

aprotinin over the period of the operation adding up to a total of 45,000 U /kg decreased blood loss approximately 60% and even reduced mortality in comparison with an untreated control group." In a study by Popov-Cenic, Urban, and Noe, 10 a single bolus of aprotinin was used in children submitted to a cardiac operation. Doses ranged from 50,000 U in children who weighed less than 5 kg to 100,000 U in children weighing 5 to 10 kg to 200,000 U in children weighing 10 to 20 kg. Many children received aprotinin 24 and 48 hours before the operation. In another group of patients, aprotinin was administered only in the postbypass period. Blood loss was similar in cyanotic and acyanotic patients (2.6 ml/kg per hour within the first hours). However, in acyanotic patients receiving aprotinin in the postbypass period, blood loss (6.4 ml/kg per hour) was higher than in comparable patients in whom aprotinin was given before the operation (2.6 ml/kg per hour). There was no randomized control group, the number of

The Journal of Thoracic and Cardiovascular Surgery April 1993

7 I a Boldt et al.

patients varied widely among the groups, and the study conditions were also inhomogeneous (temperatures varied and ages ranged from a few days to 13 years). In a retrospective study with children who had congenital heart disease, children with (after 1980) and without pretreatment with aprotinin (before 1980) were compared.i" Most of them were operated on with the aid of deep hypothermic circulatory arrest (18° C). Aprotinin was given I or 2 days before the operation. Another bolus was given three times before start of CPB (15,000 U jkg each bolus), and 300,000 to 500,000 U was added to the prime. Blood loss was significantly reduced by this aprotinin regimen (51.8 mljkg per 24 hours in the control group and 22.4 mljkg per 24 hours in the aprotinin group). The need for homologous blood (fresh whole blood) was also less in the aprotinin-treated patients. In a case report of severe hemodynamic instability after aprotinin, an aprotinin dose of more than 50,000 U jkg was given within 5 minutes after induction of anesthesia. 25 In the present study, we used both the single-bolus method (after induction of anesthesia, addition to the prime, complementary dose 60 minutes after the start of CPB) and the bolus technique plus continuous infusion until the end of the operation. The later method is the most popular technique in adult cardiac surgery. Projected to the adult weighing 80 kg, the high-dose aprotinin regimen in the present study largely exceeded amounts usually given to adults.': 4 However, in adult cardiac surgery, the dosage of aprotinin is not related to the patient's body weight. Because of different pharmacokinetics, it is problematic to transfer the dose regimen of pharmacologic interventions from the adult to children or infants. Thus one objection to the results of the present study may be that the doses of aprotinin, even though exceeding adult dosages, were not high enough. However, aprotinin may be associated with severe side effects.r'' It is a nonhuman agent and may cause adverse reactions, which may become more likely with repeated use. Some of the children in the present study may have a second operation after they have grown older. Beneficial effects of aprotinin appear to be more pronounced in patients having reoperations." but administration of the substance to children already pretreated with aprotinin may increase the risk of adverse reactions. The present study mostly focused on aprotinin and its influence on platelet function. As already described by others,28.29 platelet aggregation was significantly reduced by CPB, without differences among the three groups. The loss of platelet aggregability seems to be the most important consequence of CPB with regard to postbypass bleeding in this situation. 14. 29. 30 Platelet function re-

turned to normal over the first postoperative hours and even exceeded baseline values. Platelet population is heterogeneous, normally consisting of old (hypoaggregating), normal, and young (hyperaggregating) platelets. It is not certain whether improvement in platelet aggregation results from improved platelet function (i.e., restoration of platelet membrane receptors) or from arrival of new, young (hyperaggregating) platelets. Platelet function (and thus postbypass bleeding) is affected by multiple factors: age, degree of hypothermia, priming of CPB, type of oxygenator, amount of heparin and protamine, various drugs (anesthetics, antibiotics), transfusion regimen, and others. The wide variability in the effects on hemostasis may result from these differences in equipment, CPB technique, and interstudy differences. Last, the surgeon markedly contributes to the postoperative bleeding tendency. We conclude that qualitative platelet defects are of great importance in cardiac surgery. Both dosages of aprotinin used in the present study failed to prevent deterioration in platelet function assessed by aggregometry. Blood loss and the need for homologous blood or blood products were also not reduced by either low-dose or high-dose infusion of aprotinin. Because of the potential side effects and uncertain mechanism of action.l' aprotinin cannot be clearly recommended for pediatric surgery. Much work remains to be done to fully elucidate the role of aprotinin in pediatric cardiac surgery. REFERENCES 1. Mayer ED, Welsch M, Tanzeem A, et al. Reduction of postoperative donor blood requirements by use of the cell separator. Scand J Thorac Cardiovasc Surg 1985;19:16571. 2. Boldt J, Kling D, Ziige M, Hempelmann G. Blood conservation in cardiac surgery: cell saving versus hemofiltration. J THORAC CARDIOVASC SURG 1989;97:832-40. 3. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin (Trasylol). J THORAC CARDIOVASC SURG 1989;97:364-72. 4. Dietrich W, Spannagel M, Jochum M, et al. Influence of high-dose aprotinin treatment on blood loss and coagulation patterns in patients undergoing myocardial revascularization. Anesthesiology 1990;73: 1119-26. 5. Angelini GD, Cooper GJ, Lamarra M, Bryan AJ. Unorthodox use of aprotinin to control life-threatening bleeding after cardiopulmonary bypass. Lancet 1990;335:799-800. 6. Fraedrich G, Weber C, Bernard C, Hettner A, Schlosser V. Reduction of blood transfusion requirements in open heart surgery by administration of high doses of aprotinin: preliminary results. Thorac Cardiovasc Surg 1989;37:89-91. 7. van Oeveren W, Harder MP, Roozendaal KJ, Eijsman L, Wildevuur CR. Aprotinin protects platelets against the ini-

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