A multicenter trial of 6-aminocaproic acid (Amicar) in the prevention of bleeding in infants on ECMO

A Multicenter Trial of 6-Aminocaproic Acid (Amicar) in the Prevention of Bleeding in Infants on ECMO By Jeffrey

R. Horwitz,

Houston,

Barry

R. Cofer,

Brad

W. Warner,

Texas; San Antonio,

Henry

W. Cheu,

Texas; and Cincinnati,

and

Kevin

I? Lally

Ohio

Be&ground/Purpose: Intracranial hemorrhage (ICH), is a major source of morbidity and the leading cause of death in neonates treated with extracorporeal membrane oxygenation (ECMO). Anecdotal reports have suggested that epsilonaminocaproic acid (EACA) can decrease the risk of ICH. The purpose of this study was to evaluate, in a multiinstitutional, prospective, randomized, blinded fashion, the effect of EACA on the incidence of hemorrhagic complications in neonates receiving ECMO.

Results: Twenty-nine neonates were enrolled (EACA, 13 and placebo, 16). Five (17.2%) patients had a significant (grade 3 or larger) ICH. There was no statistical difference in the incidence of significant ICH in patients who received EACA (23%) versus placebo (12.5%). Septic patients accounted for all of the ICH in the EACA group. Thrombotic complications (aortic thrombus and SVC syndrome) developed in two patients from the placebo group. There was no difference in thrombotic circuit complications between groups.

Methods: All neonates (except congenital diaphragmatic hernia) who met criteria for ECMO at three institutions were eligible for enrollment. EACA (100 mg/kg) or placebo was given at the time of cannulation followed by 25 mg/kg/h for 72 hours. Bleeding complications, transfusion requirements, and thrombotic complications were recorded. Post-ECMO imaging included head ultrasound scan computed tomography (CT) scan, and duplex ultrasound scan of the inferior vena cava and renal vessels.

Conclusions: Our results suggest that the use of EACA in neonates receiving ECMO is safe but may not decrease the overall incidence of hemorrhagic complications.

E

gestation.* Although many attempts have been made to limit the risk for bleeding, it remains a persistent problem. Excessive fibrinolysis is believed to play a role in bleeding complications of patients who undergo cardiopulmonary bypass.3 Recently, epsilon-aminocaproic acid EACA (Amicar) a fibrinolytic inhibitor, has been shown in uncontrolled trials to decrease the hemorrhagic complication rate of newborns on ECM0.4~5 Others, however, have not shown this to be true.6 The purpose of our study was to evaluate, in a multiinstitutional, prospective, randomized fashion, the effect of EACA on the incidence of hemorrhagic complications in infants receiving ECMO.

J Pediatr Surg 33:1610-7673. Saunders Company.

INDEX WORDS: Epsilon-aminocaproic membrane oxygenation, intracranial sis.

XTRACORPOREAL membrane oxygenation (ECMO) is standard therapy for the treatment of respiratory failure in the newborn that is unresponsive to conventional medical therapy. To successfully apply long-term bypass, patients must be maintained on systemic anticoagulation. The use of systemic anticoagulation accounts for bleeding during ECMO. The risk of bleeding may be diminished by maintaining normal platelet counts and fibrinogen levels and activated clotting time at less than 200 to 220 seconds. Despite these measures, hemorrhagic complications account for 21% of all medical complications in a review of over 3,500 neonatal ECMO cases.’ The most serious type of bleeding is intracranial hemorrhage (ICH), which is so prevalent in the premature infant that most ECMO centers will exclude from support infants of less than 34 weeks’ From the University of Texas-Houston Medical School and Hermann Children k Hospital, Houston, TX: Wiljord Hall USAF Medical Center; San Antonio, TX; and Childrens Hospital Medical Center; Cincinnati, OH. Presented at the 31st Annual Meeting of the Pacific Association of Pediatric Surgeons, Maui, Hawaiz, June 9-13, 1998. This study was supported by NIH Grant MO1 RR 02558, and in part by General Clinic Research Center Grant MO1 RR 00997. Address reprint requests to Kevin P Ially, MD, Division of Pediatric Surgery, 6431 Fannin, Suite 5.258, Houston, TX 77030. Copyright Q 1998 by KB. Saunders Company 0022-3468/98/3311-0006$03.00/O 1610

Copyright

MATERIALS

AND

o 1998 by W.B.

acid, extracorporeal hemorrhage, thrombo-

METHODS

This study encompassed a 29-month period from May 1994 to October 1996. Approval of the study protocol was obtained from the Committee for the Protection of Human Subjects at each of the three participating institutions (University of Texas Medical School at Houston and Hermann Children’s Hospital, Houston, TX; Children’s Hospital Medical Center, Cincinnati, OH; and Wilford Hall USAF Medical Center, San Antonio, TX). All infants who met criteria for ECMO were eligible for enrollment. Criteria for exclusion were any patient more than 30 days of age started on ECMO before random selection, congenital diaphragmatic hernia, and failure to obtain informed consent. Patients were selected randomly by each institution to control for interinstitutional variables. EACA (100 mg/kg) or similar placebo (saline) was administered as a loading dose at the time of cannulation followed by a continuous infusion of 25 mg/kg/h. The infusion was continued for 72 hours and then terminated. Patients were treated according to each study center’s

JournalofPadiatricSorgary.

Vol33,

No 11 (November),

1998: pp 1610-1613

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protocol for ECMO management with the following guidelines: activated clotting time range, 180 to 220 seconds; platelet count above lOO,OOO/dL; fibrinogen level above 100 mg/dL. Blood loss was calculated as milliliters per kilogram per day and transfusion needs were measured in milliliters per kilogram above replacement. All patients received a head ultrasound scan before initiating ECMO, and daily according to the protocol at each institution. Intracranial hemorrhage was graded according to the modified criteria of Papile et al.’ A duplex ultrasound of the renal vessels and inferior vena cava was performed at the completion of the ECMO run to look for evidence of thrombosis. A computed tomography (CT) scan of the head was performed within 2 weeks after completing ECMO to document potential hemorrhage not detected by ultrasound scan. Bleeding complications, transfusion requirements, and thrombotic complications (patient or circuit) were documented prospectively for each patient. Statistical analysis was performed using a x2 test and Fisher’s Exact test for qualitative data and a Student’s t test for continuous data. The data are presented as mean values ? SEM. A P value of .OS was considered significant.

RESULTS

A total of 29 infants were enrolled. Sixteen patients were selected randomly to receive EACA, and 13 were given a placebo. There was no difference in the mean gestational age (39.3 ? 2.0 weeks v 39 + 2.8 weeks) or birth weight (3.3 + 0.5 kg v 3.2 -+ 0.5 kg) between the two groups. The breakdown of the two groups by diagnosis is shown in Table 1. Septic patients made up 53% of the EACA group compared with 25% of the placebo group. One patient in the EACA group was preterm (<37 weeks’ gestation) compared with four in the placebo group. Four patients in the EACA group required cardiopulmonary resuscitation (CPR) before cannulation, and two were undergoing CPR during cannulation. No patients in the placebo group had preECMO CPR. There was no difference in the last arterial blood gas value before ECMO between the two groups (Table 2). Venoarterial ECMO was used in 61.5% of the study group compared with 68.7% of the placebo group. The length of the ECMO run was longer in the placebo group than in the study group (165 + 96 minutes v 104 -t- 56 minutes, P = .05). Overall, there were five significant (Zgrade 3) and four low-grade (grades 1 and 2) intracranial hemorrhages (ICH) that developed during the study. All but one ICH occurred within the first 5 days of ECMO. Three (23%) of the significant ICH occurred in the EACA group compared with two (12.5%) in the placebo group (P = .19).

Table 1. Patient

Diagnoses Amicar

Meconium Respiratory

aspiration distress

syndrome

Pneumonia/sepsis

Persistent Other Totals

pulmonary

hypertension

Placebo

6 0

4 2

7 0

4 5

0

1

13

16

Table 2. Last Arterial

Blood

Gas Value

Amicar

NOTE.

Before

ECMO Placebo

PH

7.44 2 0.2

7.47 I 0.2

PO2 Pco,

76.7 2 60.8 37.9 2 17.0

52.1 t 26.0 38.5 f 11.5

Sao,

77.8 5 19.5

71.9 + 23.8

Data are expressed

as ? SEM.

Six patients were taken off ECMO because of the intracranial hemorrhage, and three of these died. Septic patients accounted for all of the grade 3 ICH in the EACA group and one of the two in the placebo group. Nine patients in the placebo group and six in the EACA group received a post-ECMO CT of the brain, and there was no missed ICH. No patient in this series required wound reexploration for bleeding, nor were any other major bleeding complications noted. In addition, transfusion requirements were similar between the two groups. Patients in the EACA group required a mean of 25.9 i 29 mL/kg/d of packed red blood cells compared with 17.2 ? 12.9 ml/kg/d in the placebo group (P = .28). Significant thrombotic complications developed in two patients from the placebo group. One infant had multiple thromboses throughout the thoracic and abdominal aorta and subsequently died. Another had clinical evidence of a superior vena cava occlusion. No thrombotic complications occurred in the EACA group. Eight patients in the placebo group and six in the EACA group had a post-ECMO duplex ultrasound scan of the inferior vena cava and renal vessels and all were normal. There was no difference in thrombotic circuit complications between the two groups. One entire circuit required replacement in the EACA group compared with three in the placebo group. Only one membrane lung needed replacement during the study, and this occurred in a placebo patient. DISCUSSION

Hemorrhage from multiple sites, but primarily ICH, is the principle source of morbidity and the leading cause of death in infants who receive ECMO.* Besides the obvious consequences of systemic heparinization, long-term cardiopulmonary bypass also has been shown to stimulate the fibrinolytic cascade, which may increase the risk for hemorrhagic complications9 EACA, an inhibitor of fibrinolysis, has been used widely in patients with abnormal bleeding for several decades.lO-l2 However, there are only three reports of its use in newborns on ECM0.4-6 Ackerman et al4 first reported the use of EACA in patients on ECMO. Nine patients with congenital diaphragmatic hernia on ECMO initially were given EACA at cannulation (100 mgkg loading dose) and a continuous infusion of 20 to 30 mg/kg/h was continued through decannulation. Patients treated with EACA had a

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reduction in bleeding from 4.2 mL/h to 2.0 r&/h compared with historical controls. Wilson et al5 administered EACA in a similar fashion to all of their ECMO patients believed to be at “high risk” for an intracranial hemorrhage.5 They reported that patients who received EACA had significantly less bleeding while on ECMO and required fewer blood transfusions than patients not receiving EACA. In addition, their incidence of intracranial hemorrhage was reduced from 20% to 0% in high-risk group. This was most striking in the congenital diaphragmatic hernia and cardiac subgroups. In agreement with the results of our study, however, there did not appear to be any reduction in bleeding or transfusion requirements in their patients with a diagnosis of primary pulmonary hypertension or meconium aspiration syndrome. Tuggle et aL6 reported on their experience with EACA during a single year’s experience of neonatal ECMO. They found no difference in the incidence of significant intracranial hemorrhage compared with their historical controls. The results of our study suggest that the incidence of significant intracranial hemorrhage and overall transfusion requirements was not reduced by the addition of EACA to newborns (excluding congenital diaphragmatic hernia patients) on ECMO. We limited EACA prophylaxis to 72 hours because the majority of significant bleeding complications occur within the first 3 days of an ECMO runI We also chose to exclude patients with congenital diaphragmatic hernia because some centers routinely give EACA during the surgical repair. With the tendency toward more delayed repair of diaphragmatic hernia, which could occur beyond the 72-hour infusion period, including these patients may have confused our data analysis. EACA acts by competitive inhibition of the activator that converts plasminogen into plasmin, the proteolytic enzyme that is primarily responsible for thrombus degradation.14 By means of this clot-stabilizing effect, EACA promotes clot maturation and decreases the likelihood of further hemorrhage. There is limited information on the fibrinolytic mechanism in the normal newborn patient and even less in the severely stressed newborn. Normal newborns are characterized by a physiological hypofibrinolytic state.15 They have reduced plasminogen levels and activity (PA) but have similar levels and activity of plasminogen activator inhibitor (PAI) compared with normal adults.15 Normal newborns also have a slower plasmin generation in response to exogenous plasminogen activators.15 This is corroborated by evidence that newborns require significantly higher dosages of fibrinolytics (urokinase and tissue plasminogen activator) to achieve the minimal plasminogen activation rate of an adult.16 Taken together, this would suggest that newborns

HORWllZ

ET AL

are at a greater risk of thrombotic as opposed to hemorrhagic complications. When subjected to stressful situations, newborns are able to activate their fibrinolytic cascade. Corrigan and Jeter17 reported that stressed newborns increase plasminogen activity up to seven times the level of plasminogen activator inhibitor activity, which would suggest an increased risk for bleeding complications in this subset of patients. In that study, however, 50% of the patients who died had significant thrombotic disease noted during autopsy. Their conclusion was that although stressed newborns can increase PA, it is not adequate to inhibit thrombotic complications. ECMO has been shown to decrease both PA and PA1 activity in a study of 16 newborns.‘* PA1 activity decreased to a greater degree than PA, which would suggest an imbalance toward hemorrhagic complications. However, given the fact that the majority of patients on ECMO do not suffer significant hemorrhagic complications, the clinical significance of this finding is unclear. The overall incidence of significant intracranial hemorrhage during our study was slightly higher than reported from over 7,000 neonatal ECMO cases compiled from the Extracorporeal Life Support Organization.lg Patients with a primary diagnosis of sepsis accounted for 38% of our entire study population and four of the five significant intracranial hemorrhages that occurred during the study. The EACA group contained over twice the percentage of septic patients as did the control group, and this affected our results. Septic newborns treated with ECMO are known to be at a significantly increased risk for intracranial hemorrhage.20 In the report from Wilson, et al, septic patients were not analyzed independently.5 In our study, if the septic infants were eliminated, there would have been only one significant intracranial hemorrhage during the entire study. There were only two significant thrombotic complications during the study, and both occurred in the placebo group. We looked specifically for post-ECMO thrombosis in the renal vessels and inferior vena cava. EACA has been associated with thrombotic complications including myocardial infarction, pulmonary embolism, and cerebral sinus and renal glomerular thrombosis.21-24 In the report of Wilson et al5 there were slight increases in both patient and circuit thrombotic complications. None, however, were statistically significant. Our EACA infusion only lasted for 72 hours compared with the entire ECMO run in that study, which may account for this difference. Hemorrhage during ECMO is unquestionably related to a number of factors including primary diagnosis, anticoagulation, platelet dysfunction, and fibrinolysis. Our results suggest that the addition of EACA to newborns (noncongenital diaphragmatic hernia) with cardiorespiratory failure on ECMO does not decrease the

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incidence of hemorrhagic complications nor does it decrease transfusion requirements. EACA did, however, appear to be safe and not associated with any significant thrombotic complications when limited to a brief duration. We recognize fully the fact that our study size was

relatively small and that we may not have been able to distinguish statistically significant differences between the two groups. Continued clinical investigation will be necessary before final conclusions can be made concerning the efficacy of EACA in this patient population.

REFERENCES 1. Stolar CJ, Snedecor SM, Bartlett RI-I: Extracorporeal membrane oxygenation and neonatal respiratory failure: Experience from the extracorporeal life support organization. J Pediatr Surg 26563-571, 1991 2. Bartlett RH, Gazzaniga AB, Toomasian J, et al: Extracorporeal membrane oxygenation (ECMO) in neonatal respiratory failure-100 cases. Ann Surg 204:236-245, 1986 3. Gram J, Janetzko T, Jespersen J, et al: Enhanced effective fibrinolysis following the neutralization of heparin in open heart surgery increases the risk of post-surgical bleeding. Thromb Haemost 63:241-

12. Midell AI, Hallman GL, Bloodwell RD, et al: Epsilonaminocaproic acid for bleeding after cardiopulmonary bypass. Ann Thorac Surg 11:577-582, 1971 13. Khan AM, Shabarek FM, Zwischenberger JB, et al: Utility of daily head ultrasound in infants on ECMO. J Pediatr Surg 33:1229-

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N, Lyon J, Ratner I, et al: A proposal for a multicenter trial of 6-amino-hexanoic actd (Am&r) for the prevention of bleeding of infants on ECMO. Presented at the 2nd Annual Extracorporeal Life Support Organization Meeting, Ann Arbor, MI, November 1990 5. Wilson JM, Bower LK, Fackler JC, et al: Aminocaproic acid decreases the incidence of intracranial hemorrhage and other hemorrhagic complications of ECMO. J Pediatr Surg 28:536-541, 1993 6. Tuggle DW, Wehling L, Megison S: Failure of Aminocaproic acid to prevent intracranial hemorrhage during neonatal ECMO. Presented at the 9th Annual Childrens National Medical Center ECMO Symposium, Keystone, CO, March 1993 7. Papile LA, Burstein J, Burstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birthweights less than 1,500 grams. J Pediatr 92:529-534, 1978 8. Cilley RB, Zwischenberger JB, Andrew AF, et al: Intracranial hemorrhage during extracorporeal membrane oxygenation in neonates. Pediatrics 78:699-704, 1986 9. Bick RL: Hemostasis defects associated with cardiac surgery, prosthetic devices, and other extracorporeal circuits. Semin Thromb Hemost 11:249-280, 1985 10. Kang Y, Lewis JH, Navalgund A, et al: Epsilon-aminocaproic acid for treatment of fibrinolysis during liver transplantation. Anesthesiology 66:766-773, 1987 11. Garewal HS, Dude GM: Anti-fibrinolytic therapy with aminocaproic acid for the control of bleeding in thrombocytopenic patients. Stand J Haemoatol35:497-500, 1985

1232,1998 14. Hardy JF, Desroches J: Natural and synthetic antifibrinolytics in cardiac surgery. Can J Anesth 39:353-365.1992 15. Corrigan JJ Jr, Sleethe JJ, Jeter M, et al: Newborn’s fibrinolytic mechanism: Components and plasmin generation. Am J Hematol 16. Andrew M, Brooker L, Leaker M, et al: Fibrin clot lysis by thrombolytic agents is impaired in newborns due to a low plasminogen concentration. Thromb Haemost 68:325-330, 1992 17. Corrigan JJ Jr, Jeter MA: Tissue-type plasminogen activator, plasminogen activator inhibitor and histidine-rich glycoproteins in stressed human newborns. Pediatr 89:43-46,1992 18. McVeen RV, Larch V, Carroll RC, et al: Changes in fibrinolytic factors in newborns during extracorporeal membrane oxygenation (ECMO). Am J Hematol38:254-255, 1991 (letter) 19. Zwischenberger JB, Nguyen ‘IT, Upp JR. et al: Complications of neonatal extracorporeal membrane oxygenation: Collective experience from the Extracotporeal Life Support Organization. J Thorac Cardiovast Surg 107:838-848, 1994 20. Horwitz JR, Elerian LF, Sparks JW, et al: Use of extracorporeal membrane oxygenation in the septic neonate. J Pediatr Surg 30:813815.1995 21. Agrawal BL, Zelkowitz L, Hletko P: Acute myocardial infarction in a young hemophiliac patient during therapy with factor IX concentrate and epsilon aminocaproic acid. J Pediatr 98:931-933, 1981 22. Jotkowitz S: Ipsilon aminocaproic acid and possible pulmonary emboli. N Engl J Med 290:861, 1974 (letter) 23. Achiron A, Gomish M, Melamed E: Cerebral sinus thrombosis as a potential hazard of antifibrinolytic treatment in menorrhagia. Stroke 21:817-819, 1990 24. Gralnick HR, Greipp P: Thrombosis with epsilon aminocaproic acid therapy. Am J Clin Path01 56:151-154, 1971