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Anesth Analg 2002;94:283-289
© 2002 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

A Study of a Weight-Adjusted Aprotinin Dosing Schedule During Cardiac Surgery

Gregory A. Nuttall, MD*, David N. Fass, PhD{dagger}, Lance J. Oyen, PharmD, BCPS{ddagger}, William C. Oliver, Jr., MD*, and Mark H. Ereth, MD*

Departments of *Anesthesiology and {dagger}Biochemistry and Molecular Biology; and {ddagger}Hospital Pharmacy, Mayo Graduate School of Medicine, Rochester, Minnesota

Address correspondence and reprint requests to Gregory A. Nuttall, MD, Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905. Address e-mail to nuttall.gregory{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Aprotinin is effective during cardiac surgery for reducing blood loss and transfusion requirements, but it is expensive. Aprotinin is usually administered to adults according to a fixed protocol regardless of the patient’s weight. We previously developed a weight-based dosing protocol for aprotinin. The purpose of this prospective observational study was to determine aprotinin levels in four patient groups (n = 10 each) using the new weight-based aprotinin dosing schedule that should achieve concentrations over 100, 150, 200, and 250 kallikrein inhibitory units/mL compared with full-dose aprotinin regimen (n = 10) by a simple functional aprotinin assay. There was no difference in patient demographic or surgical variables among groups. There was less within patient variation in plasma aprotinin concentrations over time in the new weight-based aprotinin dosing schedule groups compared with the full-dose aprotinin regimen group (P < 0.02 for all comparisons). The mean plasma aprotinin concentration achieved with the new weight-based aprotinin dosing schedule was similar to the desired concentrations, but we were unable to reduce between-patient variability in aprotinin concentrations.

IMPLICATIONS: The current dosing schedule for aprotinin results in a large variation in aprotinin plasma concentrations between patients and a large variation within each patient over time. A new weight-based dosing schedule reduced variation of aprotinin concentration over time, but was unable to reduce between-patient variability in aprotinin concentration.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Excessive bleeding after cardiopulmonary bypass (CPB) is one of the most common complications of cardiac surgery (1). It results in transfusion of blood components, and has important health and economic consequences (2). Aprotinin is administered in large doses during cardiac surgery using CPB to reduce bleeding and the need for blood transfusions (3–6). Aprotinin is a costly drug administered to adults by a fixed dosage regardless of the patient’s weight, sex, and the presence of renal impairment or other disease states. A full dose is an initial loading dose of 2 x 106 kallikrein inhibitory units (KIU) (280 mg) followed by a maintenance infusion of 500 000 KIU/h (70 mg/h), with a CPB prime dose of 2 x 106 KIU (280 mg) (7). The half-dose regimen uses half of each of these doses.

The fixed dosing of aprotinin regardless of weight may result in some patients not receiving an optimal dose and others overdosed, which may reduce efficacy and increase costs. Despite the high cost of this drug, there have been few studies of aprotinin plasma concentrations measured over time during CPB (6,8–14). The plasma concentration of aprotinin in patients varies greatly between patients and over time within each patient for the large-dose aprotinin regimen. We previously developed a new weight-based aprotinin dosing schedule (9) designed to provide more consistent aprotinin plasma levels throughout CPB and reduce between-patient variability in aprotinin levels. The purpose of this prospective observational study was to determine aprotinin levels in four patient groups using the new weight-based aprotinin dosing schedule that should achieve concentrations over 100, 150, 200, and 250 KIU/mL and compare these to the full-dose aprotinin regimen by a simple functional aprotinin assay.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After IRB approval and informed consent, we studied 50 adult cardiac surgical patients undergoing CPB. The patients were assigned to 1 of 5 groups: 10 patients receiving the 100 KIU/mL aprotinin schedule, 10 patients receiving the 150 KIU/mL aprotinin schedule, 10 patients receiving the 200 KIU/mL aprotinin schedule, 10 patients receiving the 250 KIU/mL aprotinin schedule, and 10 patients receiving full-dose aprotinin. Only adult patients for whom the decision to use aprotinin therapy by clinical criteria were studied. Our criteria for administering aprotinin were repeat complex cardiac surgical procedures and anticipated prolonged CPB. A dedicated central venous catheter was used for aprotinin administration. Aprotinin was discontinued 2 h after arrival in the intensive care unit (ICU) in all patients.

All patients were given a moderate-dose, opioid-based anesthetic supplemented with benzodiazepines, muscle relaxants, and inhaled anesthetics. A Univox membrane oxygenator (Bentley Inc., Irvine, CA) was used in a Sarns 9000 CPB machine (Sarns Inc., Ann Arbor, MI) at a flow of 2.4 L/min/m2. The CPB circuit was primed with 1.5 L of plasmalyte, 10 mEq of sodium bicarbonate (NaHCO3), and 12.5 g of mannitol. Porcine heparin was administered to patients as follows: an initial dose was given consisting of a bolus of 300 U/kg, and an oxygenator priming dose of 10,000 U. Additional heparin (5000 U) was administered when the kaolin activated clotting time (ACT) was <450 s, or the celite ACT was <750 s, or heparin concentration was <2.5 mg/kg for patients receiving aprotinin. After discontinuation of CPB, the initial protamine sulfate dose was 0.013 mg per unit of heparin administered. Heparin neutralization was regarded as adequate if the postprotamine ACT value was within 10% of the preheparin ACT value. Additional protamine (20–50 mg) was added at the discretion of the attending anesthesiologist if the ACT had not returned to this range. Intraoperative blood salvage and reinfusion of shed mediastinal blood was used in all cases. Ultrafiltration was not used for any of the patients.

Allogeneic red blood cells were transfused when the hemoglobin concentration became <8 g/dL after discontinuation of CPB and <7 g/dL during CPB. The transfusion of allogeneic fresh frozen plasma, platelets, or cryoprecipitate was based on clinical evidence of bleeding and supporting laboratory studies (Thrombelastograph® [Haemoscope Corp., Skokie, IL] maximum amplitude <48 mm, platelet count <102 K/mm3, prothrombin time >16.6 s, activated partial thromboplastin time >57 s, or fibrinogen level <144 mg/dL) (15).

Aprotinin Dosing Schedule
Our previously developed new weight-based aprotinin dosing schedule (9) was predicated on our results and those of Levy et al. (16). The origin of this weight-based dosing regimen is elaborated in our previous publication (9). Our proposed regimen was as follows: 100 KIU/mL: 1.75 mg/kg IV bolus dose, 35 mg pump prime load for 2-L CPB system (44 mg for 2.5-L CPB system), 2 mg · kg-1 · h-1 x 1 h, 0.5 mg · kg-1 · h-1 until risk period complete; 150 KIU/mL: 2.6 mg/kg IV bolus dose, 53 mg pump prime load for 2-L CPB system (66 mg for 2.5-L CPB system), 2.6 mg · kg-1 · h-1 x 1 h, 0.75 mg · kg-1 · h-1 until risk period complete; 200 KIU/mL: 3.5 mg/kg IV bolus dose, 70 mg pump prime load for 2-L CPB system (87.5 mg for 2.5-L CPB system), 3.5 mg · kg-1 · h-1 x 1 h, 1 mg · kg-1 · h-1 until risk period complete; 250 KIU/mL: 4.4 mg/kg IV bolus dose, 88 mg pump prime load for 2-L CPB system (109 mg for 2.5-L CPB system), 4.4 mg · kg-1 · h-1 x 1 h, 1.25 mg · kg-1 · h-1 until risk period complete.

The full dose of aprotinin ("Full-Dose" group) was an initial loading dose of 2 x 106 KIU (280 mg) followed by a maintenance infusion of 500,000 KIU/h (70 mg/h), with a CPB prime of 2 x 106 KIU (280 mg) (7).

Aprotinin Plasma Levels
Seven blood samples were drawn from each subject. The specific intervals chosen were: baseline before aprotinin; 5 min after aprotinin bolus; 5 min after initiation of CPB; 30 min after initiation of CPB; 1 h after initiation of CPB; at the discontinuation of the aprotinin infusion; and 1 h after discontinuation of aprotinin. Each 800-µL sample was drawn from an arterial catheter and placed in a tube with 100 µL of 3.8% sodium citrate. The samples were immediately placed on ice and centrifuged within 1 h. The platelet-poor plasma supernatant was transferred to a bullet tube that was stored at -70°C until analysis.

Our simple functional aprotinin assay is based on the ability of aprotinin to inhibit plasmin as the target enzyme. Our assay’s ability to measure aprotinin during CPB and its correlation with the enzyme-linked immunosorbent assay for aprotinin have been previously published (9). Plasmin inhibition is thought to be a likely factor for the prophylactic effectiveness of aprotinin (17). The plasma samples were diluted 50-fold with 0.3 M TRIS-HCL, 0.15 M NaCl, pH 7.3. Dilute plasma samples were incubated with 10 µL of 1 U/µL added porcine plasmin (Sigma P-8644; Sigma-Aldrich, St. Louis, MO) for 30 min. Twenty microliters of 1 mM benzoyl-phe-val-arg-p-nitroanlide (Sigma B-7632) was added to the sample as a plasmin substrate, and the spectrophotometric absorbance at 405–490 nm was read over 10 min at 30-s intervals as an index of plasmin activity. We calculated the amount of aprotinin in the sample from a standard inhibition curve developed by adding known concentrations of aprotinin to pooled citrated normal human plasma (n = 30, all male). Because the concentration of aprotinin added to the normal plasma in our standard inhibition curve was measured in kallikrein inhibitory units, we reported aprotinin concentration in kallikrein inhibitory units/milliliter. To measure aprotinin in the patient samples, we defined the preoperative sample in the assay set as having 100% (uninhibited) plasmin activity and all other time points as having a fraction of the zero time activity. Because the baseline sample contained 0 KIU/mL aprotinin, the calculated aprotinin concentration value of this sample was adjusted to zero and an identical adjustment was made to all subsequent sample values of that patient.

Each patient’s cumulative blood loss (volume of chest tube drainage, at 4, 12, and 24 h postoperatively) was recorded. Cell salvage and allogenic blood transfusions were recorded.

Baseline characteristics were compared across the five groups by using one-way analysis of variance for continuous variables and an exact test for categorical variables. For each group (100, 150, 200, and 250 KIU/mL), the one-sample t-test was used to compare the mean aprotinin concentrations achieved versus the targeted concentration. For each patient, the variability in aprotinin concentration over time was quantified by using the standard deviation of the given subject’s measurements obtained after aprotinin bolus, 5 min after commencement of CPB, 30 min after commencement of CPB, 60 min after commencement of CPB, and at discontinuation of aprotinin infusion. For each of these endpoints, the ranked sum test was used to compare each dosing group versus the Full-Dose group. To assess whether the between-patient variability was reduced compared with the Full-Dose group, a test for common variance was performed (18,19). In all cases, P values <= 0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
There were no statistically significant differences among the patient groups for demographic, surgical, or preoperative laboratory variables (Table 1). There also were no differences among groups for transfusion and blood loss variables (Table 2). There were no differences in postoperative ICU entry laboratory variables, except for a prolongation of the postoperative ICU activated partial thromboplastin time in the 250 KIU/mL group. Because the cost of aprotinin is related to the volume administered, the amount of aprotinin administered to each group is shown in Table 3. There were large differences in the volumes of aprotinin administered among groups, and no difference in the duration of time that the maintenance infusion was administered.


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  		Table 1. Demographic, Surgical, and Laboratory Values for Each Group
 

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  		Table 2. Transfusions and Blood Loss in Each Group
 

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  		Table 3. Amount of Aprotinin Administered
 
The plasma aprotinin concentrations for each individual patient in each group for the seven time points are shown in Figure 1. There was less within-patient variation in plasma aprotinin concentrations over time in the new weight-based aprotinin dosing schedule groups compared with the full-dose group (P < 0.02 for all comparisons). Between-patient variability was reduced using the 250 KIU/mL group compared with the full-dosing schedule at time points 3 and 7 (P = 0.024, P = 0.049). In all other comparisons, there was no evidence to suggest that between-patient variability was reduced using the 100, 150, 200, or the 250 KIU/mL doses compared with the full-dosing schedule (P > 0.113 for all cases).



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  		Figure 1. Individual patient plasma aprotinin concentrations at each of the 7 time points for the new weight-based aprotinin dosing schedule designed to achieve concentrations over 100, 150, 200, and 250 kallikrein inhibitory units (KIU/mL) compared with a full-dose aprotinin regimen. 1 = baseline before aprotinin, 2 = 5-min aprotinin bolus, 3 = 5 min after initiation of cardiopulmonary bypass (CPB), 4 = 30 min after initiation of CPB, 5 = 1 h after initiation of CPB, 6 = at the discontinuation of the aprotinin infusion, and 7 = 1 h after discontinuation of aprotinin. The shaded area is the time of CPB.

 
When compared with the full-dose schedule, the new weight-based aprotinin dosing schedules resulted in mean plasma aprotinin concentrations that were more consistent over time and in general closer to the goal level of plasma aprotinin concentrations (Fig. 2). A negative value was produced when the mean aprotinin concentration achieved was less than that desired by the aprotinin dosing schedule. If a goal of achieving a stable mean plasma aprotinin concentration of 200 KIU/mL is assumed for the full-dose schedule, then this was not achieved with this schedule.



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  		Figure 2. The mean difference in plasma aprotinin concentrations at each of the 7 time points from the goal concentration for the new weight-based aprotinin dosing schedule designed to achieve concentrations over 100, 150, 200, and 250 kallikrein inhibitory units (KIU)/mL compared with a full-dose aprotinin regimen. A goal concentration of 200 KIU/mL was assumed for the full-dose regimen. 1 = baseline before aprotinin, 2 = 5-min aprotinin bolus, 3 = 5 min after initiation of cardiopulmonary bypass (CPB), 4 = 30 min after initiation of CPB, 5 = 1 h after initiation of CPB, 6 = at the discontinuation of the aprotinin infusion, and 7 = 1 h after discontinuation of aprotinin. The asterisks denote instances in which the mean plasma aprotinin concentration differed significantly (P <= 0.05; one-sample t-test) from the goal. The shaded area is the time of CPB.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This prospective observational study has demonstrated that the new weight-based aprotinin dosing schedule results in more stable plasma aprotinin concentrations throughout the duration of CPB with the mean plasma aprotinin concentrations near the targeted level. Our study confirms the large variability of aprotinin concentrations over time associated with the full-dose regimen (6,8–14). There were no statistically significant differences in our study among groups in blood loss or transfusion requirements, but our study was not powered to detect differences in these secondary outcome variables.

Royston et al. (8) recently reported the only other study in which a weight-based dosing schedule was compared with the full-dose regimen. In their study, a weight-based initial loading dose and pump prime dose without infusion were compared with a full-dose regimen. They also were unable to reduce variation in aprotinin concentrations between patients with the weight-based dosing. They also had large variation in aprotinin concentration over time in their weight-based regimen because there was no aprotinin infusion.

The plasma concentration of aprotinin required to prevent the bleeding associated with cardiac surgery and CPB is not known. It also is not known whether there is any relationship between plasma aprotinin concentration and safety or clinical efficacy. Royston (7) has suggested that the aprotinin level at the end of CPB, the nadir concentration, is the most relevant to postoperative blood loss. However, in a later publication, Royston et al. (8) noted that there is no predictive or significant relationship between aprotinin concentration at peak or end of CPB or surgery and the postoperative chest tube drainage. There is a relationship between the total dose of aprotinin and the drugs’ efficacy in preventing transfusion of allogeneic blood products (20,21). Aprotinin is a naturally occurring polypeptide inhibitor of plasmin, kallikrein, thrombin, trypsin, and chymotrypsin (22,23). The aprotinin-plasmin binding is approximately 30 times stronger than that of kallikrein (24,25), therefore a larger blood level is necessary to inhibit the activity of kallikrein. The reduction in bleeding by aprotinin is believed to be directly related to its antifibrinolytic activity (26,27) and protective effect on platelet receptor glycoprotein Ib, platelet-sparing effects (27). Although decreased bleeding has been demonstrated in patients having cardiac surgery with CPB and small-dose aprotinin (4,28,29), larger doses are usually required to reliably inhibit both plasmin and kallikrein. Also, other studies have found no benefit in postoperative transfusion requirements (30) and there are questions of safety for the half-dose regimen (30,31). Aprotinin concentration is measured in kallikrein inhibitory units. One kallikrein inhibitory unit is defined as the amount of aprotinin that decreases the activity of two biological kallikrein units by 50% (22). Plasmin is inhibited (50% effective dose) in vitroat a plasma aprotinin concentration of 125 KIU/mL, whereas in vitrokallikrein inhibition (50% effective dose) occurs at 200–250 KIU/mL (22). There also are no data on the relationship between plasma aprotinin concentration and tissue or organ injury. If aprotinin can prevent tissue or organ injury, this is thought to be secondary to its ability to inhibit Kallikrein. A relative unknown is the potential effect of unnecessarily high levels of aprotinin on coagulation and other systems.

The inability of the new weight-based aprotinin dosing schedule to reduce variability of plasma aprotinin concentrations among patients in the same aprotinin dosing schedule group is not surprising. Weight-based dosing of other drugs results in wide variation in plasma concentrations of the drugs (32,33). The pharmacokinetics of aprotinin has only been well determined before CPB (16) and only the elimination clearance determined during and after CPB (10). Further, CPB influences the achievement of steady-state pharmacokinetics of aprotinin elimination. Aprotinin is predominantly lost from the plasma by binding to the endothelium (8). Aprotinin has an affinity for the renal microvasculature, yet only a small amount of bound aprotinin is excreted into the urine (34). Metabolism and redistribution are considered important for the elimination of aprotinin (8). Further, the variables influencing free drug concentrations for drugs that are largely distributed to the extracellular fluids (such as aprotinin) include: acid-base status, volume status of patients, weight used to calculate the dose (actual versus lean), or factors influencing normal binding sites for the drug (i.e., concomitant drugs using the same tissue binding sites, protein status). Acid base changes may change either conformation or electrostatic charging influencing relative binding status of proteins to drugs. Drugs circulating in the extracellular fluid normally have less dependence on adipose distribution; therefore, they would "hemoconcentrate" to the plasma volume relatively in obese patients. If the same dose of aprotinin based on actual body weight is given to a relatively lean patient, it would be more evenly dispersed throughout their fluids (less adipocyte fluid as percent of total body weight), which would result in a small aprotinin serum concentration. Thus, the greater the variation in body mass index or relative obesity of the study population may have contributed to greater variation in peak concentrations when weight-based dosing is based on actual body weight (as we did). Basing the dosing on a lean (or adjusted, calculated) weight may result in less variability.

As noted by Royston et al. (8), the complexity of aprotinin’s binding and pharmacokinetics are similar to those of heparin. Aprotinin shares many molecular similarities with heparins, especially the low-molecular-weight heparin (LMWH) congeners (35). Unfortunately, the molecular structure of heparin makes it extremely difficult to assay directly (as can be done with aprotinin) and perfect comparisons cannot be made based on pharmacokinetics. Some striking comparisons include the dependence of renal metabolism, similar molecular weight, and similar distribution. The overwhelming evidence with heparin and LMWHs suggests patient weight as the most important factor influencing distribution, with the dependency on "lean" weight versus actual weight still controversial (36). Likewise, many of the same factors affecting aprotinin (plasma volume status, renal function) noted above can influence variability of kinetic dosing of unfractionated heparin or LMWHs (35). Perhaps the only method to assess the variables associated with greater or lesser variation from group to group would be multivariate analysis of a large data set including the effects of weight (actual and/or patient’s lean weight), renal function, pH, or volume status (10).

We have devised a feasible and testable approach to both decreasing the required load, as well as pump prime dose, combined with increasing initial rates of infusion to enable a more individualized approach to targeting aprotinin levels. Although the calculations are simple relative to the complex pharmacokinetics of aprotinin, they provide sound rationale for individualized dosing to a wider patient population. Because of the reduced initial loading dosing, reduced pump prime dosing and weight-specific dosing, the potential for improved cost effectiveness was the desired outcome. Aprotinin is an expensive drug ($750–$1500 per patient for a half- or full-dose schedule). The cost of aprotinin is a function of the total amount administered. As shown in Table 3, the total amount of aprotinin administered in the two lower weight-based aprotinin dose schedules was less than the full-dose schedule but the higher two weight-based aprotinin dose schedules resulted in larger amounts of total aprotinin being given. An improved dosing schedule could result in improved patient care and may or may not reduce institutional costs. Additionally, side effects potentially could be reduced with minimizing the plasma concentration to the smallest dose necessary.

We were able to achieve and maintain our target levels of aprotinin plasma concentrations throughout the duration of CPB in this study. A large prospective study would be required to determine the efficacy of these different levels for preventing bleeding in cardiac surgery patients and to determine what plasma level of aprotinin is needed to prevent bleeding.


   Acknowledgments
 
Supported by a Grant and the Mayo Foundation for Medical Education and Research.


   Footnotes
 
To be presented as a poster at the 2001 Annual Meeting of the American Society of Anesthesiologists, New Orleans, LA.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication October 8, 2001.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press