The Journal of Bone and Joint Surgery (American). 2005;87:1129-1136.
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Current Concepts Review

Evidence-Based Review of the Role of Aprotinin in Blood Conservation During Orthopaedic Surgery

Agnieszka Kokoszka, MD1, Paul Kuflik, MD2, Fabien Bitan, MD2, Andrew Casden, MD2 and Michael Neuwirth, MD2

1 Department of Neurology, SVCMC'St. Vincent's Hospital Manhattan, 153 West 11th Street, Cronin 4, New York, NY 10011. E-mail address: agnieszka.kokoszka{at}mail.hsc.sunysb.edu
2 The Spine Institute, Beth Israel Medical Center, Phillips Ambulatory Care Center, 10 Union Square East, Suite 5P, New York, NY 10003

Investigation performed at the Spine Institute, Beth Israel Medical Center, New York, NY

The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Aprotinin is a serine protease inhibitor with antifibrinolytic properties that has been approved as a blood-conserving drug in cardiac surgery by the United States Food and Drug Administration.

On the basis of the current evidence from Level-I trials, we make a grade-A recommendation for use of the high-dose aprotinin regimen in hip and spine surgery.

Because of conflicting data, the low-dose aprotinin therapy as well as the use of aprotinin in patients with cancer cannot be recommended (grade-I recommendation).

High-quality randomized trials are necessary to determine the optimal (and minimal) therapeutic dose of aprotinin and the optimal time of aprotinin administration during surgery.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Aprotinin is a naturally occurring serine protease inhibitor that has been shown to reduce blood loss in cardiothoracic and liver surgery1-5. Aprotinin is nonspecific and inhibits several proteases, such as trypsin, chymotrypsin, cathepsin, elastase, kallikrein, plasmin, protein C, thrombin, and urokinase. Consequently, it has a variety of effects on several organ systems and the mechanism by which it reduces blood loss is not fully understood.

It has been postulated that aprotinin reduces bleeding through its effects on fibrinolytic pathways, coagulation pathways, the inflammatory response, and platelet function. It inhibits fibrinolysis, turnover of coagulation factors, and inflammatory cytokine release. In addition, by preserving the adhesive glycoproteins on the platelet membrane, it promotes platelet adhesion6-10. Taken together, these effects contribute to the pro-hemostatic function of aprotinin.

Orthopaedic surgery, which is associated with large amounts of blood loss that lead to increased morbidity and mortality, often requires blood transfusions. Transfusions increase the risk of transmission of infectious agents, such as human immunodeficiency virus, cytomegalovirus, hepatitis-C virus, hepatitis-B virus, and others, from the infected donor blood as well as the risk of postoperative infections through the suppression of the immune system11-13. Hemolytic reactions induced by transfusion may be fatal. Therefore, it is crucial to minimize both bleeding and the amount of transfused blood.

In 1993, the United States Food and Drug Administration approved the use of aprotinin in coronary artery bypass surgery, which provoked an interest in the potential use of this drug in other types of surgery. Several clinical trials are being carried out to investigate the role of aprotinin in orthopaedics. Evidence-based medicine, a relatively new discipline that provides tools for evaluating the medical literature to make decisions in clinical practice, is gaining popularity in orthopaedic surgery14-16. In this review, we utilized evidence-based-medicine principles to critically appraise the best studies demonstrating that aprotinin reduces blood loss as well as transfusion requirements during hip, knee, and spine surgery.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
To find all clinical trials addressing the role of aprotinin in orthopaedic surgery, we searched OVID/Medline, PubMed, EM-BASE, Web of Science, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from their earliest records until the time of the review (April 2004). To ensure that no relevant studies were missed, we first conducted an unrestricted search of the databases using combinations of keywords: aprotinin and orthopaedic surgery, aprotinin and spine surgery, aprotinin and pelvic surgery, aprotinin and knee surgery, and aprotinin and hip surgery. We then restricted our results to clinical trials and systematic reviews with the keywords clinical trial, randomized controlled trial, and review. Also, the references of pertinent articles in the literature as well as textbooks were manually screened for additional studies.

Only randomized clinical trials with the end points of aprotinin effects on blood loss and/or transfusion requirements were included in the review. Studies with other primary end points such as the effects of aprotinin on coagulation pathways, platelet function, lactate level, and prevalence of deep venous thrombosis, although interesting and often of high quality, were not included in the present review. Nonrandomized prospective studies, retrospective studies, case series, and case reports were also excluded. Studies in languages other than English were excluded as well because of a language barrier.

The levels of evidence were assigned according to The Journal of Bone and Joint Surgery guidelines for studies investigating the results of treatment (see Instructions to Authors).

Since we included only clinical randomized trials in our review, all of them were assigned either Level I or Level II. As a result of the lack of explicit criteria differentiating Level-I from Level-II studies (high versus poor-quality randomized trials), we used the "Users' Guides to the Medical Literature"17-19 to distinguish between the two levels. In almost all cases, we based this distinction on the study size because the trials were similar with regard to other aspects of their design (randomization, blinding, and inclusion of a properly matched control group). Consequently, large studies (arbitrarily defined as including more than twenty patients in both the experimental and the control groups) were assigned Level I, and smaller studies were assigned Level II. In one study20, the authors failed to specify whether the trial was blinded, so even though the study met the other criteria, it was assigned Level II.

Finally, a grade of recommendation on the use of aprotinin in orthopaedic surgery was determined according to the guidelines of the Oxford Centre for Evidence-Based Medicine (www.cebm.net) (Table I).


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  		TABLE I Grades of Recommendation from the Oxford Centre for Evidence-Based Medicine, with Modification

 


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
An exhaustive search of the databases identified twenty clinical trials20-39. (A few additional studies were found in references, but they were not in English and therefore were not included.) To our knowledge, no systematic reviews dealing specifically and exclusively with the use of aprotinin in orthopaedic surgery have been published to date. No Cochrane reviews, which are high-quality evidence-based reviews, were found except for one, by Henry et al.3, on the use of antifibrinolytics to minimize perioperative allogeneic blood transfusion. This review included only three studies on the use of aprotinin in orthopaedic surgery, among eighty-six studies on the effects of a variety of antifibrinolytics on several types of surgery (identified by electronic searches of Medline and EM-BASE to May 1998 and December 1997, respectively). The results of those three studies were not analyzed separately but instead were included in the combined analysis of noncardiac studies. Therefore, no conclusions about aprotinin use in orthopaedic surgery could be drawn from that Cochrane review.

Five of the twenty studies that we initially found were excluded because of their design35-37 (retrospective or partially retrospective) or because of irrelevant end points38,39. We categorized the fifteen remaining studies on the basis of the type of surgery and assigned every study a level of evidence as described in the Materials and Methods section. We identified four Level-I26,27,32,34 and one Level-II20 hip studies, two Level-II knee studies28,33, two Level-I22,30 and two Level-II23,29 spine studies, and one Level-I21 and three Level-II24,25,31 orthopaedic surgery studies that included different types of orthopaedic operations (Table II). Level-I studies from every category are discussed below, and the results of those studies are summarized in Table III.


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  		TABLE II Randomized Clinical Trials of Aprotinin Effects on Blood Loss and Transfusion Requirements in Orthopaedic Surgery

 

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  		TABLE III Results of Level-I Studies of Aprotinin in Orthopaedic Surgery

 

Four hip studies were graded as Level I. In the randomized, double-blind, clinical trial by Janssens et al.34, forty patients scheduled to have primary elective hip replacement were randomly allocated to receive either aprotinin (twenty patients), given as a bolus injection of two million kallikrein inhibitory units (KIU) over thirty minutes followed by an infusion of 0.5 million KIU/hr until the end of the surgery, or the same volume of normal saline solution according to the same protocol (twenty patients). The surgeon and the anesthesiologist did not know whether the patients were receiving aprotinin or the placebo. The methods of randomization and allocation concealment were not specified. Intraoperative blood loss was estimated by measuring the volume in the suction bottles and counting sponges. Postoperative blood loss was measured from the surgical drains. Intravenous infusion of lactated Ringer solution was started on induction of anesthesia, and gelatin solution was given intraoperatively and postoperatively to maintain normovolemia. Packed red blood cells were transfused to maintain a hematocrit of 30%. The two groups of patients were comparable with respect to age, weight, height, sex, operative time, and hemorrhagic risk. The average operative time was 169 ± 27 and 176 ± 32 minutes in the aprotinin and placebo groups, respectively. All patients who entered the study were included in the final analysis. The study showed that the average total blood loss (perioperative and postoperative) was reduced by 26% in the aprotinin group (p < 0.05). Blood transfusion requirements were also reduced, from 3.4 ± 1.3 units/patient in the placebo group to 1.8 ± 1.2 units/patient in the aprotinin group (an average difference of 1.6 units, p < 0.001). Deep venous thrombosis developed in four patients in the placebo group and in none in the aprotinin group (difference not significant). No other adverse effects were reported.

Murkin et al.32 performed a study of fifty-three patients who underwent revision total hip arthroplasty (fifty patients) or bilateral total hip arthroplasty (three patients). Patients were randomly assigned (with a computer-generated random code) to receive either aprotinin (twenty-nine patients) or a placebo (twenty-four patients). In the aprotinin group, patients who weighed between 60 and 80 kg were given a loading dose of 2 million KIU over fifteen minutes followed by an infusion of 0.5 million KIU for the duration of the surgery and for one hour postoperatively. Patients who weighed <60 kg or >80 kg received a loading dose of 2.8 mL/kg and an infusion of 0.7 mL/kg/hr. Patients in the placebo group received an equivalent volume of 0.9% saline solution. The study was double-blind, with the aprotinin or saline solution administered from uniformly blinded bottles. Intraoperative blood loss was estimated from the volume in the suction bottles and the weight of the sponges by a blinded observer, and postoperative blood loss was determined from volumetric wound drains. Lactated Ringer solution was administered intravenously for intraoperative volume replacement. Transfusion of packed red blood cells was permitted to achieve an intraoperative blood volume exceeding 15% of the preoperative blood volume or a postoperative hemoglobin level of <8 g/dL (<80 g/L). The two groups were similar regarding age, gender, and duration of the operation (average duration, 180 ± 7.5 minutes in the aprotinin group and 194 ± 11.0 minutes in the placebo group), and all patients were included in the final analysis of the results. The study demonstrated that the average total blood loss was decreased to 1498 ± 110 mL in the aprotinin group compared with 2096 ± 223 mL in the placebo group (p < 0.022). Transfusion requirements were reduced as well, with the patients in the aprotinin group receiving an average of 2.0 ± 0.2 units and those in the placebo group receiving an average of 2.9 ± 0.4 units (average difference, 0.9 unit; 95% confidence interval = -1.69 to -0.07). Deep venous thrombosis developed in three of the placebo-treated patients and in none of the aprotinin-treated patients. No other complications were observed.

In their second clinical trial, Murkin et al.27 took the study a step further and compared different concentrations of aprotinin. In this multicenter, randomized, double-blind trial, patients were assigned to four groups. Seventy-six patients received a low dose of aprotinin (a 0.5-million-KIU bolus), seventy-five patients received a medium dose of aprotinin (a 1-million-KIU bolus followed by an infusion of 0.25 million KIU/hr), seventy-seven patients received a high dose of aprotinin (a 2-million-KIU bolus followed by an infusion of 0.5 million KIU/hr), and seventy-three patients received normal saline solution. Intraoperative blood loss was monitored by the anesthesiologist. Postoperative blood loss was estimated from the surgical drains. Patients were given a blood transfusion when the hematocrit was ≤18% (or if "clinically necessary"). The patients were comparable with respect to race, age, height, weight, and operative approach. Despite randomization, the high-dose-aprotinin group had more men (p = 0.08) and the medium-dose-aprotinin group had a lower mean baseline hemoglobin level (p = 0.005) than the placebo group. The mean operating time was 1.7 hours in the low-dose group, 1.7 hours in the medium-dose group, 1.8 hours in the high-dose group, and 1.9 hours in the placebo group. Transfusion requirements, which were expressed as the percentage of patients in each group who received blood, were reduced from 47% in the placebo group to 28% in the low-dose-aprotinin group (p = 0.02) and 27% in the high-dose-aprotinin group (p = 0.08). Forty percent of the patients who received the medium dose of aprotinin received a transfusion; however, the 7% difference between this group and the placebo group did not reach significance. Blood loss was reduced from 698 mL in the placebo group to 558 mL (p = 0.02), 573 mL (p = 0.04), and 603 mL (p = 0.1) in the low, medium, and high-dose-aprotinin groups, respectively. Deep venous thrombosis developed in a few patients, but there was no significant difference among the groups.

Langdown et al.26 investigated the effects of low-dose aprotinin on blood loss in sixty patients with primary osteoarthritis requiring total hip arthroplasty. The patients were randomly assigned to receive either a 1.5-million-KIU bolus of aprotinin (thirty patients) or an equal volume of normal saline solution (thirty patients). In this study, the patients did not receive a maintenance dose of aprotinin. The study was double-blind, with the patient, anesthesiologist, and surgeon unaware of which solution was given. Intraoperative blood loss was estimated by weighing the swabs and measuring suction losses, and postoperative blood loss was estimated from the drains. There was no significant difference between the two groups with regard to total blood loss, which averaged 414 ± 213 mL in the placebo group and 417 ± 203 mL in the aprotinin group. The transfusion requirements were not quantified, and the transfusion threshold was not specified. However, the authors did include a comment that postoperative hemoglobin and transfusion requirements were similar between the two groups. The average operative time was 100 minutes in both groups. There was no report of any side effects associated with aprotinin use.

In these studies, a high-dose aprotinin regimen decreased blood loss by 14% to 29% and transfusion requirements by 0.9 to 1.6 units. As these were all high-quality studies with no major methodological flaws, we make a grade-A recommendation for the use of high-dose aprotinin in hip surgery. Another equally important conclusion that can be derived from the above studies26,27,32,34 is that there is conflicting evidence for the benefit of the low-dose aprotinin regimen in hip surgery; thus, we cannot recommend its use in hip surgery (grade-I recommendation).

We found no Level-I knee studies.

Both of the Level-I spine studies demonstrated a clinically relevant effect of aprotinin on blood loss and transfusion requirements. Lentschener et al.30 randomly assigned seventy-two patients scheduled to undergo elective posterior lumbar fusion for degenerative spine disease to receive high-dose aprotinin therapy or a placebo. The assignments were made in a double-blind fashion with use of a computer-generated random code. Patients in the aprotinin group received an initial dose of 2 million KIU over twenty minutes followed by a continuous infusion of 0.5 million KIU/hr until skin closure. An additional bolus of 0.5 million KIU of aprotinin was infused for every three transfusions of packed red blood cells. Patients in the placebo group received an equivalent volume of 0.9% saline solution. Intraoperative blood loss was measured by adding the volume of the blood in suction bottles to the weight of sponges and deducting the volume of fluids added to the surgical field. Blood harvested up to six hours after surgery was systematically reinfused. Drainage that occurred after six hours postoperatively was quantified and included in the final assessment of blood loss. The target hematocrit was 26%. The average duration of surgery was 195 ± 53 minutes in the aprotinin group and 175 ± 44 minutes in the placebo group. The study demonstrated that aprotinin reduced blood loss from 2839 ± 993 mL in the placebo group to 1935 ± 873 mL in the experimental group (a 32% difference, p < 0.007). The drug also reduced the total amount of transfused blood from 95 units in the placebo group to 42 units in the aprotinin group (p < 0.001). No adverse drug effects were detected.

Cole et al.22 studied the effects of aprotinin administration during long-segment spinal fusions in children. Forty-four children were randomized to either a placebo or an aprotinin group by drawing an odd or even number from an envelope. Aprotinin was administered as a 240-mg/m2 load over thirty minutes followed by a continuous infusion of 56 mg/m2/hr until four hours after surgery (equivalent to the high-dose aprotinin regimen). Neither the surgeon nor the anesthesiologist knew whether the patient had received the drug or the placebo. Blood loss was estimated by weighing surgical sponges, measuring blood collected in drainage and suction canisters, and subtracting the volume of all irrigation fluids added to the surgical field. Transfusion was performed to maintain a hematocrit of >27%. The average duration of the surgery was 371 ± 128 and 340 ± 94.7 minutes in the aprotinin and placebo groups, respectively. The estimated blood loss in the aprotinin group (545 ± 312 mL) was significantly less than that in the placebo group (930 ± 772 mL) (p < 0.039), and this reduction in blood loss translated into decreased transfusion requirements: from 2.2 units/patient in the placebo group to 1.1 units/patient in the aprotinin group (p < 0.016). The investigators reported a 13% prevalence of deep venous thrombosis in the control group and no evidence of deep venous thrombosis in the aprotinin group (difference not significant).

On the basis of the results of these two high-quality studies22,30, we make a grade-A recommendation for use of aprotinin in spine surgery.

We identified one Level-I study of aprotinin use in "major orthopaedic surgery." In this double-blind study by Amar et al.21, sixty-nine patients with a malignant tumor who were scheduled to have pelvic, extremity, or spine surgery were randomized to three groups by the staff of the biostatistics department and the pharmacy, who used sealed treatment-code envelopes. Twenty-three patients received aprotinin (a bolus of 2 million KIU followed by infusion of 0.5 million KIU/hr), twenty-two patients received epsilon-aminocaproic acid (a bolus of 150 mg/kg followed by a 15-mg/kg/hr infusion), and twenty-four patients received a placebo. All patients and clinical study personnel were blinded to the group assignments. Blood loss was estimated on the basis of suction losses and weighed sponges during surgery and wound drainage losses for forty-eight hours after the surgery. Packed red blood cells were transfused when the hematocrit was <24%. The operative time averaged 291 ± 160 minutes in the aprotinin group, 368 ± 203 minutes in the group treated with epsilon-aminocaproic acid, and 284 ± 148 minutes in the placebo group. Bronchospasm attributed to the aprotinin developed in one patient, so administration of the drug was discontinued for that patient. All other patients completed the study and were included in the analysis of the final results. Other complications included deep venous thrombosis (in three patients treated with epsilon-aminocaproic acid and in three in the placebo group) and pulmonary embolism (in two patients in the aprotinin group and in one in the placebo group). The prevalence of complications did not differ significantly among the groups (p = 0.72), and the investigators also found no significant difference in blood loss or transfusion requirements among the groups. However, these results do not apply to all patients because this study dealt only with patients with cancer. For the same reason, the results do not contradict the findings of other studies presented in this review.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It is well documented that aprotinin is effective as a blood-conserving agent in a variety of very different types of operative procedures. Consequently, it was postulated that aprotinin might reduce blood loss and transfusion requirements independently of the type of operative procedure being performed. Some authors6,22 proposed that the clinical benefit of aprotinin seems to be affected by variables such as the duration of surgery and amount of blood loss—that is, the longer the surgery and the greater the blood loss, the greater the effects of aprotinin. Interestingly, the study that demonstrated the greatest blood-loss reduction (41% in the study by Cole et al.22) in our review was also the one with the longest duration of surgery (average, 340 ± 94.7 minutes). The study that showed the second greatest effect on blood loss (a 32% reduction in the study by Lentschener et al.30) had the greatest amount of bleeding (2839 ± 993 mL in the placebo group). On the basis of this observation, it is worth investigating whether aprotinin is effective in different surgical procedures as long as they meet the criteria regarding operative time and amount of blood loss.

The results presented in our review suggest that the effects of aprotinin are dose-dependent. This conclusion is in concert with an observation that aprotinin binds to different proteases with different affinities40. Generally, clinically relevant effects are seen at high doses, but the optimal (and minimal) therapeutic dose or concentration is yet to be determined. In a study of weight-adjusted doses of aprotinin in cardiac surgery, Royston et al.41 showed that peak plasma concentrations of aprotinin were less variable when a weight-related dose schedule had been used. The authors suggested that this observation may have implications for determining the optimal aprotinin regimen.

An important question is whether there is an optimal time during or before surgery when aprotinin should be administered. The answer probably depends on the pharmacokinetics of this drug that determine the amount of time that it takes aprotinin to reach its therapeutic concentration.

One of the most challenging aspects of determining the optimal therapeutic dose of aprotinin and its mechanism of action in blood conservation is the nonspecificity of the drug. In fact, many of aprotinin's effects counteract one another (e.g., aprotinin inhibits plasmin, a substance that inhibits fibrinolysis, and it also inhibits thrombin and thus prevents thrombus formation). Beckmann et al.42 offered a solution to this problem. They described the synthesis of chemically mutated homologues of aprotinin and showed that substituting one amino acid residue of aprotinin with other amino acids modifies the affinity of aprotinin for its substrates. The substitution of valine enhances inhibition of human leukocyte elastase. This mutant aprotinin shows no detectable affinity to pancreatic trypsin. This elegant idea could be used to enhance the specificity of aprotinin for the antifibrinolytic pathway and to diminish its anticoagulant (as well as other irrelevant) properties at the same time.

As noted above, we found no Level-I studies of aprotinin use in knee surgery. Level-II studies28,33 offered conflicting evidence, perhaps because knee procedures are too short for aprotinin effects to become apparent. Possibly, the drug has to be administered hours prior to knee surgery to have the desired effect. Level-I studies on the use of aprotinin in knee surgery would be helpful to prove or disprove this hypothesis.

The use of aprotinin when orthopaedic surgery is performed in patients with cancer is a complex issue. The Level-I study21 discussed in this review showed no reduction in blood loss or transfusion requirements by aprotinin in patients with malignant disease. On the other hand, several studies have shown that aprotinin decreases transfusion requirements in patients undergoing surgery for malignant tumors such as femoral osteosarcoma, metastatic adenocarcinoma, meningioma, and hepatic tumors31,43,44. Malignant disease is associated with a coagulopathy45. It is known that the degree of coagulation and activation of the fibrinolytic pathway depends on the tumor type40. For example, some tumors generate thrombin, and others do not. Consequently, the effects of aprotinin on blood conservation in patients with malignant disease may also depend on the tumor type.

The use of aprotinin is associated with minimal risk. Anaphylactic reactions are very rare, can be avoided by giving a small test dose, and are a risk only in patients who have already been sensitized to aprotinin by a prior exposure or exposures to the drug. Given its antithrombolytic properties, it is logical to ask if aprotinin use increases the prevalence of deep venous thromboses and pulmonary emboli. We found no evidence of such an association in the studies presented in this review. Furthermore, Haas38 found no association between the use of aprotinin and the prevalence of deep venous thrombosis.

Aprotinin should not be used in pregnant patients as it is a pregnancy class-B drug (i.e., it was found to be safe in animal studies, but there are no data from clinical trials in humans).

Aprotinin is expensive. Even though there have been encouraging cost analysis studies35,36, it would be interesting to know how this antifibrinolytic drug compares with other, less extensively studied and less expensive drugs such as tranexamic acid and epsilon-aminocaproic acid.

How does the effect of aprotinin on patients undergoing orthopaedic surgery compare with that on patients undergoing cardiac surgery, a procedure for which the FDA has already approved the use of aprotinin? According to the Cochrane review, by Henry et al.3, of fifty-five trials of aprotinin use in cardiac surgery, aprotinin reduced the need for allogeneic blood transfusion by 31% (relative risk = 0.69; 95% confidence interval = 0.63 to 0.76). Thus, the effects of aprotinin in cardiac surgery are comparable with those in orthopaedic surgery.

Overall, we propose a grade-A recommendation for the use of high-dose aprotinin in long orthopaedic procedures that are associated with large blood losses, such as spine or hip surgery. The drug has been successfully used in both pediatric22 and adult populations. On the basis of current evidence and until proven otherwise, aprotinin should be first given as a bolus of 2 million KIU and then as a maintenance dose of 0.5 million KIU/hr throughout the surgery. The data on the use of low-dose aprotinin are inconsistent and therefore this regimen cannot be recommended (grade-I recommendation).

Our conclusions are also supported by Level-II studies that were not included in this review for methodological reasons. Three studies of orthopaedic surgery24,25,31 and two studies of spine surgery23,29 showed a benefit of aprotinin in terms of decreasing blood loss and transfusion requirements. One Level-II hip trial20 showed no benefit of aprotinin given as a single bolus without a maintenance dose.

More high-quality Level-I trials are needed to investigate the optimal dose and mode of administration of aprotinin. Basic-science studies expanding our knowledge of this drug are needed as well, as it is important that the clinical trials be designed with a better understanding of the molecular context of aprotinin's mode of action.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Postoperative Renal Failure After Aprotinin Infusion and Spine Operations
Anesth. Analg., October 1, 2006; 103(4): 1062 - 1063.
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