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J Thorac Cardiovasc Surg 1998;115:723-724
© 1998 Mosby, Inc.

BRIEF COMMUNICATIONS

Fatal intraoperative pulmonary thrombosis after graft replacement ofan aneurysm of the arch and descending aorta in association with deephypothermic circulatory arrest and aprotinin therapy

Melbourne, Australia

From the Departments of Cardiothoracic Surgery^aand Anaesthesia,^b Monash Medical Centre, Clayton, Melbourne, and theVictorian Institute of Forensic Medicine,^c Monash University,Melbourne, Australia.

Received for publication August 15, 1997. Accepted for publication Sept. 30, 1997. Address for reprints: J. M. Alvarez, FRACS, Department ofCardiothoracic Surgery, Monash Medical Centre, Clayton, 3168 Melbourne,Australia.

A 69-year-old woman had graft replacement of the distal aortic arch andproximal descending thoracic aorta for a 13 cm atherosclerotic aneurysm. Leftventricular function and coronary artery anatomy were normal, as were results ofall preoperative hematologic and coagulation assays.

Heparin administration was 300 units/kg plus 5000 units in the pumpprime. Kaolin-based activated clotting time (ACT) was kept above 500 secondsduring cardiopulmonary bypass (CPB) and above 750 seconds before circulatoryarrest. Protamine was reversed on a 1 mg/100 units heparin ratio (Table I).Aprotinin (Trasylol) was given for a total dose of 6 x 10⁶kallikrein inactivation units (KIU; 2 x 10⁶ KIUintravenously after anesthetic induction, 2 x 10⁶ KIU inthe pump prime, and 0.5 x 10⁶ KIU/hr).

The patient was weaned from CPB unaided, with normal hemodynamic indexes,effective myocardial contractility, and a dry operative field. Ten minuteslater, unheralded right ventricular failure with a normal electrocardiogramoccurred. Protamine was discontinued and heparin was readministered to thepatient. Despite inotropic support and intraaortic balloon counterpulsation,cardiac function was inadequate. CPB was recommenced, and right ventricularfailure frustrated attempts to discontinue CPB. Transesophageal echocardiographyrevealed no valvular abnormality, with effective biventricular contraction inthe decompressed heart. The pulmonary artery was opened, yet no evidence ofpulmonary embolism was demonstrable. Right ventricular assistance was commenced.Unexplained intermittent inadequate venous return and raised pulmonary pressureshampered effective right ventricular assistance action, and the patient died 70minutes later.

Postmortem examination revealed extensive deposits of skeinlike,fibrinous material loosely adherent to the walls of the main and segmentalpulmonary arteries, right ventricle, and within the venous cannulas. Histologicexamination revealed extensive thrombosis within the small pulmonary arterybranches. No evidence of thrombosis was detected in other organs.

Aprotinin is highly effective in reducing blood loss after cardiacoperations. However, safety concerns, initially raised by the Cleveland Clinicgroup, ¹ remain unanswered. Thesafety of aprotinin in the setting of aortic reconstruction with deephypothermic circulatory arrest is currently unclear.

Sundt and associates ²from St. Louis and Westaby's group from Oxford ³ have reported a detrimental effectof aprotinin in this setting of complex aortic operations with deep hypothermiccirculatory arrest. The St. Louis group found a higher operative mortality rate,perioperative myocardial infarction rate, and renal failure rate in theaprotinin group than in a historical case-matched control group (15% vs 0%,20% vs 0%, and 65% vs 5%, respectively). ² The Oxford group reported a greaterincidence of bleeding and thrombosis-related deaths associated with aprotinin. ³

These reports represent large series by experienced operators.Inadvertent underheparinization in these two groups has been proposed as apossible explanation by Smith and associates, ⁴ because the diatomaceous earth(Celite)–based ACT used in these two series is spuriously raised in thepresence of aprotinin. Westaby and coworkers ³point out that this vital information was not available when aprotinin(Trasylol) was released into the marketplace.

Goldstein and colleagues ⁵recently reported their experience with aprotinin use in this specific group ofpatients; they found no differences from a historical case-matched control groupin operative mortality and perioperative myocardial infarction rates. Renaldysfunction was more common in the aprotinin group (29.2% vs 8.3%),but not significantly so (no p value was given). In the series of Goldstein andcolleagues, ⁵ kaolin-based ACT(aprotinin does not affect this measurement) was kept above 500 seconds andCelite-based ACT was maintained above 750 seconds. Their conclusions are totallyat odds with those of Sundt and coworkers ²and Westaby and colleagues. ³

In our case, kaolin-based ACT was used and kept within acceptedguidelines. It is noteworthy that the St. Louis group encountered a similar caseof acute right ventricular failure from pulmonary thrombosis or embolism. Thiscase is the only other such complication ever reported with this type ofoperation. In this case, no evidence of preoperative venous thrombosis waspresent at autopsy. We firmly believe that this patient was notunderheparinized.

Is aprotinin safe? We concur with Westaby and coworkers ³ in saying that we do not know. Onlya prospective randomized trial will yield the answer. Does it actually produce abenefit? In the series of Goldstein and colleagues, ⁵ there was no benefit in terms oftotal transfusion requirements. Unless aprotinin results in significantly fewerpatients needing blood transfusions and fewer transfusions per patient,differences in volume of drainage and number or type of blood products used arerelatively unimportant.

This case strongly implicates aprotinin use in intravascular thrombosis;acute pulmonary thrombosis in this setting is extremely rare. This patient wasnot underheparinized, nor had she any known coagulation diathesis. Is this sosurprising? Put simply, we do not know what aprotinin's physiologic role is, howit works, or how much to give—or even when the best time to give it is.What we do know is that it sure does work; is it surprising when it works toowell? To quote Voltaire, "We use drugs about which we know very little inpatients in whom we know even less."

References

1. Cosgrove DM 3rd, Heric B, Lytle B, et al.Aprotinin therapy for reoperative myocardial revascularization: a placebocontrolled study. Ann Thorac Surg 1992;54:1031-8.[Abstract]
   
2. Sundt TM, Kouchoukos NT, Saffitz JE, MurphySF, Wareing TH, Stahl DJ. Renal dysfunction and intravascular coagulation withaprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418-24.[Abstract]
   
3. Westaby S, Forni A, Dunning J, et al.Aprotinin and bleeding in profoundly hypothermic perfusion. Eur J CardiothoracSurg 1994;8:82-6.[Abstract]
   
4. Smith CR, Mongero LB, DeRosa CM, Michler RE,Oz MC. Safety of aprotinin ion profound hypothermia and circulatory arrest. AnnThorac Surg 1994;58:603-8.
   
5. Goldstein DJ, DeRosa CM, Mongero LB, et al.Safety and efficacy of aprotinin under conditions of deep hypothermia andcirculatory arrest. J Thorac Cardiovasc Surg 1995;110:1615-22.[Abstract/Free Full Text]
   

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