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Ann Thorac Surg 1999;68:278-286
© 1999 The Society of Thoracic Surgeons

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Collective Reviews

Aprotinin in deep hypothermic circulatory arrest

^a Columbia Presbyterian Medical Center, New York, New York, USA

Address reprint requests to Dr Smith, Columbia Presbyterian Medical Center, Milstein Hospital Building, Room 7-435, 177 Fort Washington Ave, New York, NY 10032
e-mail: crs2{at}columbia.edu

	Abstract

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 
Early experience with aprotinin in deep hypothermic circulatory arrest (DHCA) raised alarm about hazards associated with its use. Based on what little is known about possible mechanistic interactions between hypothermia, stasis, and aprotinin, there is no evidence that aprotinin becomes unusually hazardous in DHCA. Excessive mortality and complication rates have only been reported in clinical series in which the adequacy of heparinization is questionable. Benefits associated with use of aprotinin in DHCA have been inconsistently demonstrated. The only prospective, randomized series showed significant reduction in blood loss and transfusion requirements. Use of aprotinin in DHCA should be based on the same considerations applied in other cardiothoracic procedures.

	Introduction

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 
The complex mixture of procoagulant and anticoagulant forces unleashed by cardiopulmonary bypass (CPB) presents a challenging hemostatic paradox that complicates the management of anticoagulation. Minimizing the impact of anticoagulant forces has received the most attention, and a large number of randomized controlled clinical trials have clearly demonstrated that aprotinin reduces blood loss and transfusion requirements in many commonplace cardiac surgical procedures [1–3]. Although the precise mechanism has not been clearly defined, interference with contact activation of the intrinsic cascade, preservation of platelet function, and inhibition of fibrinolysis have all been cited as contributing to the beneficial effects of aprotinin in this setting (Fig 1) [4–6].

View larger version (32K): [in this window] [in a new window]   Fig 1. Aprotinin and CPB. Aprotinin interferes with the activation of coagulation during CPB at several steps, including inhibition of contact activation through blockade of kallekrein, blockade of platelet activation, and its direct antifibrinolytic effect. tPA = tissue plasminogen activator; C3a, C5a: complement fragments C3a and C5a.

This review addresses this controversy, beginning with clinical or experimental evidence on mechanistic interactions between aprotinin, stasis, and hypothermia. Next, all of the published clinical experience with aprotinin and DHCA is reviewed for evidence of benefit in terms of blood loss or transfusion requirements, based exclusively on series containing a control group. Finally, the incidence of complications possibly associated with aprotinin is considered, based on two categories of clinical material: (1) series containing a control group, and (2) series without a control group. A summary of complication rates associated with major aortic procedures is provided as a reference point, particularly for comparison with aprotinin/DHCA series lacking a control group. An explicit description of the literature search strategies used is contained in the Appendix.

	Stasis and hypothermia

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 
Hypothermia alone has several anticoagulant effects, most of which interfere with the coagulation pathways at the same steps as CPB (Fig 2). The simplest effect of hypothermia is kinetic, and slows coagulation reactions. Prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time display a negative exponential correlation with temperature, such that PT and APTT are prolonged 50%–60% at 29°C, independent of clotting factor levels [11]. Thrombin activation is 60% diminished at 25°C [12]. The kinetic effects are presumably the major factor responsible for prolongation in the activated clotting time (ACT) that occurs in cold blood independent of heparin concentration [13]. These effects of temperature are completely reversible with adequate rewarming, provided sufficient substrate remains, and are not affected by aprotinin.

View larger version (42K): [in this window] [in a new window]   Fig 2. Aprotinin and hypothermia. Aprotinin interferes with many of the procoagulant effects of hypothermia through its inhibitory effects on kallekrein and fibrinolysis and through its protective effects on platelets. tPA = tissue plasminogen activator; C3a, C5a: complement fragments C3a and C5a.

Similarly, CPB and hypothermia are both associated with many well-described platelet defects [16–21]. Hypothermia alone produces platelet dysfunction because of temperature-dependent morphologic alterations, including changes in platelet membranes and function [22]. Boldt and associates [6] demonstrated that hypothermic (< 28°C) CPB reduces platelet function and aggregation, and that recovery of function in the later bypass period occurs more slowly than in normothermic (> 34°C) patients. Aprotinin protects platelets by preserving GP1b receptor [4, 23], which may explain why Boldt and associates [6] also found that administration of aprotinin to a matched hypothermic group decreased the deficits in function and aggregation and minimized transfusion requirements. There are no clinical data available in the setting of profound hypothermia, but there is also no reason to assume that these effects of aprotinin would become less beneficial, or detrimental, at lower temperatures.

Numerous alterations in the fibrinolytic system in CPB have been documented, including elevated fibrin(ogen) degradation products [24], decreased plasminogen [25], and increased plasma fibrinolytic activity [26], all reasons for the original use of antifibrinolytic agents in this setting. Fibrinolytic activity is also altered by hypothermia alone. Yoshihara and associates [27] describe significant elevations in plasma fibrinolytic activity in mongrel dogs cooled to < 20°C. Maximal fibrinolytic activity occurred during early rewarming and trended to baseline after rewarming. This phenomenon was thought to represent primary fibrinolysis since hypercoagulability, hypofibrinogenemia, and decrease in antithrombin III were not observed. The antifibrinolytic action of aprotinin, therefore, should be salutary against the cumulative antifibrinolytic effects of CPB and hypothermia.

Stasis is one-third of Virchow’s triad, and is a powerful prothrombotic stimulus. In CPB, blood pooling in the pericardium and blood sequestered in the venous reservoir are examples of stasis that are routine and well tolerated in fully anticoagulated patients. DHCA procedures are certainly notable for a more profound period of stasis, but results in a large number of cases performed without aprotinin suggest that this is well tolerated [28–36]. The important question is whether circumstances are altered in the presence of aprotinin. There are simply no clinical or experimental data available to directly address this question. Studies are needed in which stasis and aprotinin are the only important variables, with DHCA and operative technical details as constants.

Protein C is one of the important natural anticoagulant mechanisms that might be exerting a protective effect in the setting of stasis, and one group of authors has suggested that the problems allegedly associated with the use of aprotinin in DHCA might be explained by the effect of aprotinin on Protein C [37]. Protein C is activated by thrombin through a calcium-dependent interaction with the endothelial cell receptor protein thrombomodulin (Fig 3) [38]. Activated Protein C inhibits clotting through the selective proteolytic destruction of factors Va and VIIIa, which prevents the formation of Factor Xa and thrombin. Activated Protein C induces fibrinolysis by releasing tissue plasminogen activator (t-PA) from the endothelial cell surface. Elevations in plasma Protein C levels have been documented in CPB [39, 40], where it is thought to play a role in the maintenance of blood fluidity and in the induction of fibrinolysis. Activated Protein C is a serine protease; therefore, there is a theoretical concern that its anticoagulant activity might be attenuated by the serine protease inhibitor aprotinin. This action of aprotinin is presumably taking place in non-DHCA procedures without obvious detriment, and there is no evidence to suggest that the net effect is altered at lower temperatures. Although aprotinin has been shown to markedly decrease Protein C activity in vitro [39], this effect was not found when Protein C was measured in CPB patients receiving aprotinin [40–43].

View larger version (33K): [in this window] [in a new window]   Fig 3. Anticoagulant effects of Protein C. Protein C is one of the important natural anticoagulants that promotes fibrinolysis through activation of tPA when activated in the presence if thrombin, and inhibits clotting through its inactivation of factors Va and VIIIa. tPA = tissue plasminogen activator.

	Benefits

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

Westaby and associates [37] reported results in a retrospective consecutive series of 80 patients operated between 1987 and 1992, during which time aprotinin use was introduced. Mean blood loss for 27 controls was 837 mL/24 h versus 1,929 mL/24 h in 53 aprotinin patients. A "significant" increase in blood loss was reported in DHCA patients who received aprotinin. Standard errors were calculated (± 90 mL/24 h in both groups), but tests for statistical significance were not applied.

The first positive results in adults were reported by Goldstein and associates [46], who compared 24 DHCA patients who received aprotinin with 24 matched historical controls, and found a significant (p < 0.01) reduction in requirements for postoperative homologous erythrocytes. Trends favoring the aprotinin group were seen in the number of patients not requiring any transfusion (16.7% vs 4.1%), and in the number of patients requiring 10 total units of exogenous blood products (45.8% vs 12.5%). Chest tube output in the first 12 hours did not differ (488 vs 495 mL).

Okita and associates [47] reported a series of 112 consecutive patients who underwent aortic surgery, 60 under DHCA, 39 of whom received aprotinin. The study began with a randomized design, but a selection bias favoring use of aprotinin in left thoracotomies entered at some unspecified point, based on the authors’ observation that "...aprotinin was effective for preventing...bleeding after lung manipulation." Blood loss after cardiopulmonary bypass, blood loss in the ICU, and fresh blood transfusion requirements were significantly less in the aprotinin group (p = 0.047, p = 0.039, and p = 0.009, respectively). The aprotinin dose used was much less than what has been used in most series, consisting of 2 x 10⁶ U in the pump prime only.

Parolari and associates [48] compared 18 DHCA patients who underwent thoracic aortic procedures between 1990 and 1994 and received aprotinin with 21 patients treated from 1987 through 1989 who did not receive aprotinin. Thirteen parameters of blood loss and transfusion requirements were highly similar in the two groups. Some caution may be appropriate before accepting conclusions based on an experience of 3.6 procedures per year during the aprotinin era.

The obvious need for a randomized prospective trial was finally met by Ehrlich and associates [49], who reported experience in 50 DHCA patients undergoing thoracic aortic operations, randomized to receive low-dose aprotinin or placebo. A highly significant reduction in blood loss and transfusion parameters was noted in the aprotinin group (Table 2).

	Complications

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

	Complications of major aortic surgery

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 
DHCA is typically employed in major aortic procedures that lie towards the complex and hazardous end of the spectrum of cardiac procedures. It is reasonable to expect this fact to be reflected in the incidence of complications, with or without aprotinin. Mortality was 13% in 2,975 patients undergoing major aortic surgery without the use of aprotinin in the 11 clinical series summarized in Table 3. The largest recent series [29] reported a 12% in-hospital mortality and a 7% incidence of cerebrovascular events in 656 patients who underwent aortic surgery with DHCA from 1979 to 1991. At the opposite end of the spectrum, Gott and associates [28] reported a 4.8% mortality in 270 patients, but results are undoubtedly skewed by a unique predominance of operations for annuloaortic ectasia in patients with Marfan’s syndrome, accounting for 69% of the series, in whom mortality was 2.5%. Only 10% of the patients in Gott’s series were subjected to DHCA, and only 23% had ascending aortic dissection.

	Heparinization

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

Whenever aprotinin is implicated as a possible cause of complications in a clinical series, the methods must be scrutinized carefully for evidence of adequate heparinization, particularly in reports appearing before 1995. A number of protocols to achieve adequate heparinization are now available. The protocol used at Columbia Presbyterian Medical Center since 1994 is summarized in Table 6.

	Clinical series with control data

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

In the randomized prospective trial reported by Dietrich and associates [45], in which high-dose aprotinin was associated with reduced blood loss, little attention was paid to reporting complications. All patients survived, and "No side effects attributable to aprotinin were observed." At a later date (1995), the same authors reported a 5-year experience with DHCA and aprotinin in "about 500" children, observing "none of the harmful consequences described by Sundt and co-workers" [57].

After the three reports discussed above, there have been four clinical series reported containing control group data that were carried out under heparinization protocols likely to guarantee adequate anticoagulation, beginning with Goldstein and associates [46]. In one series [48], the authors reported a trend (p < 0.1) towards a higher rate of permanent neurologic deficits and a "complicated postoperative course" in the 18 patients who received aprotinin. Otherwise, no significant differences were seen in any of these series between the aprotinin and control groups in mortality, or with respect to neurologic, renal, or other complications. The most recent series in this group was prospective and randomized [49].

	Clinical series without control data

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 
Results from five series containing DHCA patients who received aprotinin, but without control group data, are summarized in Table 8. Since aprotinin was not necessarily the primary focus of each series, DHCA/aprotinin patients cannot be accurately counted in two reports [50, 58]. The maximum possible number of aprotinin/DHCA patients in these two series is 168, although the actual number is undoubtedly less. One hundred forty patients in the other three series certainly qualify [59–61]. Only two of the series [46, 60] describe the heparinization protocol used, and in both instances, the protocol takes into account the effects of aprotinin on ACT. Two of the other three series were carried out before 1995, and the third overlapped (1991 to 1996).

	Conclusions

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 
To summarize the mechanistic interactions between stasis, hypothermia, and aprotinin, the hemostatic perturbations attributable to hypothermia are anticoagulant, and are very similar to those encountered in routine CPB, where aprotinin would be expected to exert a beneficial effect by blunting coagulopathy. The role of stasis, which is the major prothrombotic stimulus associated with DHCA, is not well defined clinically or experimentally. The theoretical prothrombotic link between aprotinin and inhibition of activated Protein C is unsubstantiated. There is no evidence to support a belief that aprotinin becomes uniquely prothrombotic in DHCA.

The body of clinical experience with aprotinin and DHCA has several frustrating features. Only seven series [8, 37, 44–46, 48, 49] contain any kind of control group data, and treatment groups are very small in number. Only two trials were prospective and randomized [45, 49]. One of these [45] was carried out in infants, before a time when the importance of aprotinin effects on ACT were recognized, and the analysis of results failed to separate the results for DHCA infants from the minority (38%) treated with CPB alone. A third [47] began with a randomized design but aborted the protocol in the face of what the authors felt were compelling benefits favoring aprotinin. Significant variation exists between series in the criteria used to assess efficacy, and in the attention devoted to the analysis of complications other than mortality.

Five clinical series [47, 50, 58–60] contain larger numbers but have no control group data, making comparisons possible only to benchmark outcomes derived from experience with similar procedures. Among the uncontrolled series, only two provide a description of the heparinization protocol followed [47, 61]. In two series [50, 59], the data presented do not allow separation of the results for those patients who had DHCA with aprotinin from the results for the entire group.

Certain conclusions are still defensible. First and foremost, the alarming incidence of complications emerging from the first reported series [44] almost certainly resulted from inadequate heparinization. Nothing approaching the same level of complications has been seen in the other 6 controlled and 5 uncontrolled clinical series comprising the world’s literature on the subject. Importantly, excessive complications were not observed in the only prospective randomized trial that exists. From the standpoint of safety, the data support use of aprotinin in DHCA, provided that adequate heparinization is achieved by following a protocol that accounts for the effects of aprotinin on ACT.

Comparisons with similar procedures without aprotinin are useful with respect to outcomes such as mortality and complications. Where efficacy is concerned, the extreme diversity in methods used to report blood loss and transfusion requirements renders such comparisons meaningless, and makes the 5 series without control data useless. Left with the 7 controlled series summarized in Table 1, the evidence for a reduction in blood loss and transfusion requirements attributable to the use of aprotinin in DHCA is not overwhelming. Among 202 aprotinin patients and 152 controls in seven series, reduction in blood loss was observed in three series [45, 47, 49], and reduction in transfusion requirements was observed in three [46, 47, 49]. Nonetheless, it should be emphasized that the only two trials that were prospective and randomized [45, 49] both found significant reductions in blood loss. Reduction in transfusion requirements was observed in the prospective randomized trial in adults [49], but not in the trial carried out in children [45]. It could be argued that transfusion requirements in infants are less relevant, since all infants require transfusion on CPB, and differences might be more difficult to demonstrate. Conclusions from that trial are also compromised by inability to isolate results for DHCA infants.

In summary, there is no reason to believe that DHCA increases the risk associated with the use of aprotinin. Benefits in terms of blood loss and transfusion requirements have not been uniformly demonstrated, and may depend on other clinical factors not easily isolated[55].

	Acknowledgments

 
We wish to acknowledge the invaluable assistance of Xzabia Caliste, for her help in the preparation of this manuscript, and Dr Alan Weinberg for his thorough analysis of statistical issues.

	Appendix

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 
A MEDLINE search was carried out from 1960 through 1998, without language restriction. The clinical literature search was designed to identify all published reports of aprotinin use in the setting of hypothermia and circulatory arrest, hypothermia alone, or circulatory arrest alone. Key words used in the clinical search were aprotinin/circulatory arrest/hypothermia/neurologic complications/mortality/cardiopulmonary bypass/cardiac surgery. Any report containing information on one or more patients who received aprotinin during operations performed under hypothermia or circulatory arrest was included in the review. The bibliographies of all publications reviewed were manually searched for evidence of relevant references that might have been missed. The subject was discussed with several colleagues at other institutions known to have interest in the problem in an attempt to locate unpublished data, to assure that no important published data was missed, or to clarify published findings included in the review.

The search for data related to mechanisms of action was designed to focus on clinical or experimental data on interactions between aprotinin and hypothermia or circulatory arrest. Key words were aprotinin/anticoagulation/hypothermia/coagulation/stasis/clotting/protein C/heparin/cardiopulmonary bypass/circulatory arrest/cardiac surgery. This search was necessarily more selective. Because data describing specific interactions were rare, publications thought to provide useful information on hypothermia alone, stasis alone, or aprotinin alone were included if they provided a basis for reasonable inference regarding possible interactions.

	References

Top Abstract Introduction Stasis and hypothermia Benefits Complications Complications of major aortic... Heparinization Clinical series with control... Clinical series without control... Conclusions Appendix References

 

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