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J Thorac Cardiovasc Surg 1998;115:220-224
© 1998 Mosby, Inc.
CARDIOPULMONARY SUPPORT AND PHYSIOLOGY |
From the Department of Cardio-Thoracic Surgerya and Nephrology,b University of Vienna, Vienna, Austria.
Received for publication April 22, 1997; revisions requested July14, 1997; revisions received Sept. 11, 1997; accepted for publication Sept.11, 1997. Address for reprints: Marek Ehrlich, MD, Department of Cardio-ThoracicSurgery, Mount Sinai Medical Center, One Gustave Levy Place, Box 1028, NewYork, NY 10029.
Abstract
Introduction: The safety of aprotinin,especially when used with profound hypothermic circulatory arrest, is stilla matter of intense debate despite its presumed salutary effects on bloodloss. Many investigators have reported toxic renal effects of high-dose aprotininin such patients, but no prospective, randomized study has been conducted.To assess the potential detrimental effect of aprotinin on renal functionand its putative reduction of blood loss, 50 patients undergoing thoracicaortic operations with the use of profound hypothermic circulatory arrestwere randomly assigned to receive either low-dose aprotinin (1 x10
6 kallikrein activationunits) or placebo.
Methods: The specificrenal tubular markers ß-2-microglobulin and ß-N-acetyl-d-glucosaminidase,as well as serum creatinine and blood urea nitrogen, creatinine clearance,sodium excretion, and potassium excretion, were measured to evaluate renalfunction preoperatively, immediately after the procedure, and 24 hours and48 hours later.
Results: No statisticallysignificant difference was found in any measured renal parameter between thetwo groups (analysis of variance). Renal dysfunction, defined as an elevationof serum creatinine early postoperatively (
1.5 times the preoperativevalue), occurred in two patients who received aprotinin and in one patientin the control group. Temporary dialysis (hemodialysis or continuous venovenoushemofiltration) was needed in two patients in the aprotinin group versus onein the control group. Furthermore, patients treated with aprotinin had significantlyless total postoperative blood loss (718 ± 340 ml vs 920 ±387 ml, p = 0.04). The aprotinin recipientsalso had a significantly lower transfusion requirement (p <0.05).
Conclusion: Thiscontrolled trial of low-dose aprotinin in patients undergoing thoracic aorticoperations using profound hypothermic circulatory arrest demonstrated no detectabledeleterious effects on renal function; moreover, the use of aprotinin wasassociated with significantly lower need for transfusion. (J Thorac CardiovascSurg 1998;115:220–5)
Aprotinin (Trasylol), a serine protease inhibitor, has been widely advocatedfor preservation of hemostatic function in cardiopulmonary bypass surgery.Several mechanisms appear to exert a hemostatic effect, including reductionof fibrinolysis, 1 inhibitionof neutrophil activation, 2and preservation of platelet function. 3,4 Furthermore, its molecular weightis low (6500 D) and it is rapidly eliminated (t
= 2 hr) from the circulationby glomerular filtration with a temporary partial storage of the administereddose (80% to 90%) by the proximal tubular cells.
Aprotinin is now routinely used in many centers for all cardiac operations,and in this setting few complications or side effects attributed to its usehave been reported. Aprotinin may be of particular benefit in high-risk cardiacprocedures such as redo cardiopulmonary bypass (CPB) operations and especiallyin patients undergoing complex aortic procedures in which profound hypothermiccirculatory arrest is used and coagulopathies such as platelet dysfunctionmay be expected.
Some recent clinical studies have shown an increased risk of myocardialinfarction, multiorgan platelet thrombi, and especially renal dysfunctionand failure in patients receiving high-dose aprotinin (2 x 106 kallikrein inactivation units [KIU] aprotinin as a loading dose, 2 x106 KIU added to the CPB circuit, and a continuous infusion of250,000 KIU/hr until conclusion of the operation) during hypothermic circulatoryarrest. 5,6
Therefore the primary objective of this study was to evaluate the efficacyand safety of low-dose aprotinin on renal function in patients undergoingoperations on the thoracic aorta under conditions of profound hypothermiaand circulatory arrest compared with a placebo-controlled group. We also rigorouslyevaluated postoperative blood loss and transfusion requirements in both groupsof patients.
Patients, materials, and methods
Between July 1995 and July 1996, 50 patients, with informed consent,underwent resection of different parts of the aorta at the University Hospitalof Vienna. All patients were randomly assigned to receive either low-doseaprotinin or placebo. Each group contained 25 patients who had given informedconsent. Patients randomized to be in the aprotinin group received 1 x106 KIU of aprotinin (140 mg) (Trasylol; Bayer AG, Leverkusen,Germany) before onset of CPB with the heart-lung machine. The patients inthe control group received an equal volume of 0.9% saline solution as a placebo.
The preparation for randomization of the study was as follows: Eachbottle of aprotinin provided by the Bayer Company contained 500,000 KIU. Therefore,50 bottles were obtained to provide 1 x 106 KIU of aprotinin foreach of 25 patients. These 50 bottles were placed in a box with 50 bottlesof normal saline solution. These bottles were indistinguishable from one another.One assistant, who was only involved in randomization of the medications,arranged these 100 bottles into 50 pairs. Each pair consisted of two bottlesof aprotinin or two bottles of saline solution. Each of these pairs was randomlyassigned a number from 1 to 50. Only the aforementioned assistant was privyto the assignments. Each patient was randomly assigned a number and then giventhe corresponding bottles. After the study was completed, the randomizationcode was broken and the data were statistically analyzed. Patients with apreoperative serum creatinine level exceeding 2 mg/dl were excluded from thisstudy. Table I summarizes important demographic and clinical characteristicsof both groups. The incidences of hypertension, smokinghistory, and coronary artery disease were comparable in both groups, whereasthe control group had a higher frequency of diabetes.
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Systemic anticoagulation for CPB was obtained according to standardprotocol by the administration of 3 mg/kg of intravenous heparin. Activatedclotting time (ACT) was measured during CPB and at onset of circulatory arrestwith a kaolin assay. The amount of heparin administered and the ACTs achievedare shown in Table II. Urine and blood samples were takenat the following times: (1) before the operations, (2) immediately after theoperations, (3) on the first postoperative day, and (4) the second day postoperatively.The urine samples were taken from a urinary catheter. All samples were collectedand stored at –20° C before further processing. Homologous packedred cells were administered postoperatively only when the hematocrit valuefell to less than 25%. The mediastinal and thoracic blood was collected, andthe amount was measured for the first 24 hours postoperatively.
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7 A p value less than 0.05 was considered significant.
Surgical technique.
The surgical technique and the application of profound hypothermic circulatoryarrest throughout the study period were standard. The method of deep hypothermiaand circulatory arrest has been previously described in detail. 8 In brief, it consists of core cooling during CPB toproduce deep hypothermia to a rectal temperature of 18° C. Operationson the ascending aorta and proximal arch were performed through median sternotomy,whereas access for operations on the descending aorta was through a posterolateralincision in the fourth intercostal space. Depending on the extension of thepathologic involvement, either the aortic arch or the ascending or descendingaorta was resected and replaced by a tubular graft (Vascutek, Inchinnan, Scotland).In cases of arch involvement the period of circulatory arrest was used forinspection and reconstruction of the arch.
Results
Intraoperative parameters.
As depicted in Table III, no differences were found in aortic crossclamp,extracorporeal circulation, and circulatory arrest times.
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Transfusion requirements and blood loss.
The number of units of red blood cells that were transfused postoperativelyin the two groups are shown in Table VII. Aprotininrecipients required fewer postoperative transfusions than the control group(p = 0.04). The mean chest tube drainage in both groups for the first24 hours postoperatively is also shown in .Reoperation for bleeding was not required in either group.
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In this first prospective, double-blind randomized study, we examinedthe influence of a low-dose aprotinin regimen on kidney function and postoperativeblood loss in operations performed under profound hypothermic circulatoryarrest.
Clinical use of aprotinin, a serine protease inhibitor with a broadspectrum of activity, has shown a substantial effect in reducing the needfor blood transfusion. 9–11 Its mechanism remains to a certain degreeunclear, but it appears that aprotinin inhibits activation of the kallikrein-kininsystem 12 and plasmin fibrinolysissystem, preserves platelet function, 13 and partially inhibits neutrophil activation during CPB. 2 Aprotinin is now routinely administered prophylactically,mostly in the conventional "Hammersmith" full-dose regimen withconsiderable success, especially in high-risk cardiac procedures, such asredo operations, at a number of European heart centers. It would seem logicalto use aprotinin in highly complex operation on the thoracic aorta in whichdeep hypothermia and circulatory arrest are advocated and coagulopathies maybe expected.
The efficacy and safety of aprotinin during profound hypothermia andcirculatory arrest are still matters of intense debate. Clinical evidenceis gaining that under deep hypothermic perfusion aprotinin is ineffectiveand even potentially harmful. 5,6 Because approximately 90% of anadministered dose is known to collect in the brush border of the convolutedtubules, 14 speculation hasbeen raised that high-dose aprotinin might adversely affect the kidneys.
Therefore the goal of this study was to investigate whether the useof low-dose aprotinin (1 million KIU) would also lead to a higher rate ofrenal complications. We explored the question of whether the reduction inpostoperative bleeding could still be achieved with a reduced dose of aprotinin.
Our study demonstrated that no increase in renal dysfunction was foundin the first 48 hours postoperatively. With regard to renal parameters, especiallythe very specific markers ß-NAG and ß-2-microglobulinthat clearly reflect damage to the proximal tubule cells of the kidney, nosignificant difference was seen among the study and the control groups. Similarly,there was no difference in blood urea nitrogen, creatinine, creatinine clearance,and excretion fractions of potassium and sodium. None of the surviving patientsrequired permanent hemodialysis.
Conversely, Sundt and colleagues 5 administered aprotinin to 20 patients undergoing operations on thethoracic aorta under conditions of profound hypothermic circulatory arrestand compared the results with a well-matched control group. Renal dysfunction,defined as an elevation of the serum creatinine level in the first postoperativeweek to a level 1.5 times higher than preoperatively, occurred in 65% of theirpatients who received aprotinin and only one patient who did not receive thedrug. Twenty-five percent of their patients who received aprotinin had undergonerenal dialysis. Postmortem findings on these patients showed major evidenceof platelet-fibrin thrombi formation in the kidneys. However, Goldstein andcolleagues 15 recently performeda retrospective study comparing 24 patients who received high-dose aprotininand placebo, and they did not observe any statistical difference in termsof renal dysfunction or failure comparing both groups. The findings by Sundtand colleagues might be because their study was performed at a time when thedistorting effect of aprotinin ACT after filtration with Celite diatomaceousearth (Celite Corporation, Quincy, Wash.) was not clearly recognized. 16,17 So far, it is known that aprotinin neutralizes the anticoagulatingeffect of heparin to some extent, and ACT times should be maintained at >greaterthan 700 seconds. 17 It mustbe emphasized that in our study ACT was measured in all 50 patients usinga kaolin assay, which is essentially unaffected by aprotinin. 18,19
Blauhut and associates 20 investigated renal function in 26 patients undergoing coronary arterybypass grafting with hypothermia to 28° C; half of their patients receivedhigh-dose aprotinin. No difference in postoperative creatinine clearance wasfound between the groups; the osmolar clearance and potassium and sodium excretionwere slightly higher in the aprotinin-treated patients postoperatively. Wecould not find any significant differences between both groups in our studyconcerning sodium and potassium excretion, although both parameters increasedin the first 48 hours compared with baseline values.
Clinical reports describing aprotinin use in patients undergoing heartsurgery have also raised the possibility that the drug is associated withan increased risk of thrombotic complications and a higher incidence of perioperativemyocardial infarction. In a study performed on 80 patients undergoing surgeryfor acute type A aortic dissections with and without the perioperative administrationof aprotinin, Westaby and colleagues 6 described an increased incidence of postoperative bleeding complicationsand thrombosis-related deaths among aprotinin recipients. Sundt and colleagues 5 reported a 20% high incidence ofperioperative myocardial infarction in 20 patients who underwent aortic operationswith profound hypothermic circulatory arrest.
We did not note any statistically significant difference in the incidenceof transient or permanent neurologic deficits, nor did we see an increaseof myocardial infarction in the aprotinin-treated group. This might be explainedprimarily by the low-dose regimen that we administered in our study and againby the fact that ACT was measured with the kaolin method.
In summary, it can be said that low-dose aprotinin can safely and effectivelybe used in patients undergoing aortic procedures under conditions of profoundhypothermic circulatory arrest. Our results have shown that the administrationof low-dose aprotinin has no deleterious effect on renal function and doesnot increase the risk of myocardial infarction. Most important, low-dose aprotinineffectively reduces blood loss and red blood cell transfusion requirements.
References
This article has been cited by other articles:
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  L. H. Edmunds Jr Managing Fibrinolysis Without Aprotinin. Ann. Thorac. Surg., January 1, 2010; 89(1): 324 - 331. [Abstract] [Full Text] [PDF]
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 J. H Shuhaiber Evaluating the Quality of Trials of Hypothermic Circulatory Arrest Aortic Surgery Asian Cardiovasc Thorac Ann, October 1, 2007; 15(5): 449 - 452. [Abstract] [Full Text] [PDF]
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 A. Sedrakyan, A. Wu, G. Sedrakyan, M. Diener-West, M. Tranquilli, and J. Elefteriades Aprotinin use in thoracic aortic surgery: Safety and outcomes J. Thorac. Cardiovasc. Surg., October 1, 2006; 132(4): 909 - 917. [Abstract] [Full Text] [PDF]
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 D. Spielvogel, M. N. Mathur, and R. B. Griepp Aneurysms of the Aortic Arch Card. Surg. Adult, January 1, 2003; 2(2003): 1149 - 1168. [Full Text]
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V. Casati, L. Sandrelli, G. Speziali, G. Calori, M. A. Grasso, and S. Spagnolo Hemostatic effects of tranexamic acid in elective thoracic aortic surgery: A prospective, randomized, double-blind, placebo-controlled study J. Thorac. Cardiovasc. Surg., June 1, 2002; 123(6): 1084 - 1091. [Abstract] [Full Text] [PDF]
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 C. T. Mora Mangano, M. J. Neville, P. H. Hsu, I. Mignea, J. King, and D. C. Miller Aprotinin, Blood Loss, and Renal Dysfunction in Deep Hypothermic Circulatory Arrest Circulation, September 18, 2001; 104 (2009): I-276 - I-281. [Abstract] [Full Text] [PDF]
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 H. A. Hennein Inflammation After Cardiopulmonary Bypass: Therapy for the Postpump Syndrome Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 236 - 255. [Abstract] [PDF]
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C. R. Smith and T. B. Spanier Aprotinin in deep hypothermic circulatory arrest Ann. Thorac. Surg., July 1, 1999; 68(1): 278 - 286. [Abstract] [Full Text] [PDF]
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S. Westaby Anti-fibrinolytic therapy in thoracic aortic surgery Ann. Thorac. Surg., June 1, 1999; 67(6): 1983 - 1985. [Abstract] [Full Text] [PDF]
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J. B. Rich The efficacy and safety of aprotinin use in cardiac surgery Ann. Thorac. Surg., November 1, 1998; 66(90050): S6 - 11. [Abstract] [Full Text] [PDF]
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M. Ehrlich Aprotinin J. Thorac. Cardiovasc. Surg., August 1, 1998; 116(2): 374 - 374. [Full Text]
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