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CARDIOVASCULAR ANESTHESIA

Plasma Aprotinin Concentrations During Cardiac Surgery: Full- Versus Half-Dose Regimens

Susan M. Beath, MD^*, Gregory A. Nuttall, MD, David N. Fass, PhD, William C. Oliver, Jr., MD, Mark H. Ereth, MD, and Lance J. Oyen, Pharm D BCPS^§

Departments of *Cardiovascular Anesthesiology and Anesthesiology, Mayo Graduate School of Medicine; and Departments of Biochemistry and Molecular Biology, and §Hospital Pharmacy, Mayo Clinic, Rochester, Minnesota

Address correspondence and reprints 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 Appendix 1. Calculations References

 
Aprotinin is an effective but expensive drug used during cardiac surgery to reduce blood loss and transfusion requirements. Currently, aprotinin is administered to adults according to a fixed protocol regardless of the patient’s weight. The purpose of this study was to determine aprotinin levels in patients receiving full- and half-dose aprotinin regimens by a simple functional aprotinin assay and to design a more individualized aprotinin dosage regimen for cardiac surgical patients. The mean plasma aprotinin concentration peaked 5 min after the initiation of cardiopulmonary bypass (full 401 ± 92 KIU/mL, half 226 ± 56 KIU/mL). The mean plasma aprotinin concentration after 60 min on cardiopulmonary bypass was less (full 236 ± 81 KIU/mL, half 160 ± 63 KIU/mL). There was large variation in the aprotinin concentration among patients. A statistically significant correlation was found between aprotinin concentration and patient weight (r² = 0.67, P < 0.05).

Implications: The current dosing schedule for aprotinin results in a large variation in aprotinin plasma concentrations among patients and a large variation within each patient over time. We combined the information provided by our study with that of a previous pharmacokinetic study to develop a potentially improved, weight-based, dosing regime for aprotinin.

	Introduction

Top Abstract Introduction Methods Results Discussion Appendix 1. Calculations References

 
Aprotinin has antifibrinolytic, antiinflammatory, and platelet-sparing effects. Administered in large doses during cardiac surgery using cardiopulmonary bypass (CPB), it reduces bleeding and the need for transfusion (1–5). The reduced bleeding with aprotinin may be secondary to its antifibrinolytic effect (6), and/or its protective effect on platelet receptor glycoprotein Ib (7).

Currently, 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 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) (8). The half-dose regimen uses half of each of these doses. Although some studies have shown similar reductions in bleeding for cardiac surgery patients receiving small-dose aprotinin as large-dose (2,9–11), other studies have found no benefit in postoperative transfusion requirements (9) and questions of safety for the half-dose (12,13).

The result of the fixed dosing of aprotinin regardless of weight is that some patients may not be receiving an optimal dose and that others maybe overdosed, which may increase costs. Given the high cost of this drug, there have been rather few studies of its plasma concentrations during CPB over time on CPB (5,14–17). There is great intrapatient and interpatient variability in plasma levels for large-dose aprotinin regimen. The pharmacokinetics of aprotinin have been well determined only before CPB (18) and the elimination clearance has been determined only during and after CPB (19). In addition, there are even fewer studies of the plasma levels of aprotinin in patients receiving the half-dose aprotinin regimen (11,20). Alternative dosing regimens for aprotinin based on patient characteristics may reduce institutional costs and improve patient care.

There were three purposes of this study. The first was to test a simple functional aprotinin assay developed at our institution. The second was to measure plasma aprotinin levels in patients receiving full and half-dose aprotinin. The third was to design a more individualized aprotinin dosage regimen for cardiac surgical patients.

	Methods

Top Abstract Introduction Methods Results Discussion Appendix 1. Calculations References

 
After we received institutional review board approval and informed consent, we studied 30 adult cardiac surgical patients. The decision whether to use aprotinin and which dose the patient received were determined solely by the anesthesiologist caring for the patient. Our criteria for administering full-dose aprotinin were repeat complex cardiac surgical procedures and anticipated prolonged CPB. Patients undergoing repeat coronary artery grafting alone or single-valve replacement procedures receive half-dose aprotinin. We also tend to use half-dose aprotinin in smaller patients. Patients with renal impairment (serum creatinine >2.5 mg/dL) were excluded from the study, as were pregnant patients and patients with aprotinin allergy.

All patients received a moderate-dose opioid-based anesthetic technique, 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^-1 · m^-2. The CPB circuit was primed with 1.5 L of plasmalyte, 10 mEq of sodium bicarbonate (NaHCO₃), and 12.5 gm 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 units. Additional heparin (5,000 units) was administered when the kaolin activated coagulation time (ACT) was less than 450 s, when the celite ACT was less than 750 s, or when the heparin concentration was less than 2.5 mg/mL 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.

Allogeneic red blood cells were transfused when the hemoglobin concentration was <8 g/dL after discontinuation of CPB or <7 g/dL during CPB. Transfusion of allogeneic fresh-frozen plasma, platelets, or cryoprecipitate was based on clinical evidence of bleeding and supporting laboratory studies (thromboelastography, platelet count, prothrombin time, activated partial thromboplastin time, or fibrinogen level).

Ten patients received the full dose of aprotinin (Full-Dose group), an initial 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) (8). Ten patients received the half dose of aprotinin (Half-Dose group), an initial dose of 1 x 106 KIU (140 mg) followed by a maintenance infusion of 250,000 KIU/h (35 mg/h), with a CPB prime of 1 x 106 KIU (140 mg). A dedicated central venous catheter was used for aprotinin administration. Aprotinin was discontinued 2 h after arrival in the intensive care unit. Ten patients did not receive aprotinin (Control group).

Nine blood samples were drawn from each patient. The specific intervals chosen were baseline before aprotinin or heparin (control patients); 5 min after heparinisation (control patients) or aprotinin bolus (aprotinin patients); 5 min after the initiation of CPB; 30 min after the initiation of CPB; 1 h after the initiation of CPB; at the discontinuation of the aprotinin infusion (on leaving the operating room for controls); 1 h after the discontinuation of aprotinin; 4 h after the termination of CPB; and 24 h after the termination of CPB. Each 800-µL sample was drawn from an arterial catheter and placed in a tube with 100 µL 3.8% sodium citrate. The samples were immediately placed on ice and were centrifuged within 1 h. The platelet-poor plasma supernatant was transferred to a bullet tube that was stored at -20°C until analysis.

We based our simple functional aprotinin assay on the ability of aprotinin to inhibit plasmin as the target enzyme, which is a modification of a previous assay that used kallikrein (21). Plasmin inhibition is a likely candidate for the prophylactic effectiveness of aprotinin in the operating room (22). 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) for 30 min. Twenty microliters 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 for 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 KIU, we reported aprotinin concentration in KIU/mL. 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 the sample values of that patient assayed on that day. Nine samples of plasma from all three groups were sent to the Institute of Clinical Pharmacology (Wuppertal, Germany) for competitive enzyme-linked immunosorbent assay (ELISA).

Each patient’s cumulative blood loss and volume of chest tube drainage were recorded at 4, 12, and 24 postoperatively. Cell-saver and allogenic blood transfusions were recorded.

Single-factor analysis of variance was used for comparisons among multiple groups, followed by Student’s t-tests for paired group comparisons. Correlation analysis was conducted by using Pearson’s product momentum. Statistical significance was defined as P 0.05.

	Results

Top Abstract Introduction Methods Results Discussion Appendix 1. Calculations References

 
There were no statistically significant differences among the patient groups for age, weight, or height (Table 1). The control group consisted of patients having their first sternotomy. The aprotinin-treated groups were undergoing their second or subsequent sternotomies (with the exception of one patient in the half-dose aprotinin group, a Jehovah’s Witness who refused blood transfusion). The duration of CPB was significantly longer in the full-dose group (p < 0.0005) but cross-clamp time was not significantly different (Table 2). One full-dose and one half-dose patient were excluded from analysis as a result of a clerical error. None of the patients had ultrafiltration.

View larger version (17K): [in this window] [in a new window]   Figure 1. The mean and standard error of the mean for seven standard inhibition curves developed by adding known concentrations of aprotinin to citrated normal human plasma. For each assay, the standards data were plotted as rate of substrate hydrolysis versus added aprotinin concentration and a least squares equation derived. The different standard curves were normalized by taking the zero concentration of added aprotinin as a plasmin activity of 1.0 and expressing the inhibited samples’ rate as fractional activities. To calibrate each standard curve, the Y intercept (% plasmin activity with zero aprotinin) of the least squares equation was adjusted to 1.0 arithmetically. For seven standard curves, the mean calculated plasmin activity at 0 KIU aprotinin was 1.017, so these corrections are small. The slopes of the standard curves were very consistent with the standard error of the mean being 2.2%. There was a inhibition of 10% ± 0.06% of the input plasmin activity for each 64.7 KIU/mL aprotinin in the sample.

View larger version (39K): [in this window] [in a new window]   Figure 2. Plasma aprotinin concentrations achieved over time in each of the patients receiving full, half, and no (control) aprotinin. Sample 1: baseline, Sample 2: after aprotinin bolus, Sample 3: 5 min after the commencement of cardiopulmonary bypass (CPB), Sample 4: 30 min after the commencement of CPB, Sample 5: 60 min after the commencement of CPB, Sample 6: at the discontinuation of the aprotinin infusion, Sample 7: 1 h after the discontinuation of aprotinin, Sample 8: 4 h after CPB, Sample 9: 24 h after CPB.

View larger version (20K): [in this window] [in a new window]   Figure 3. Correlation of patient weight and plasma aprotinin concentration after the initial dose in patients receiving the full dose of aprotinin. One patient was withdrawn from this group because of a clerical error.

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1. Calculations References

 
We have developed a functional assay to measure aprotinin concentrations which, with this assay, were very similar to those previously reported by using the full-dose protocol during cardiac surgery (5,14–17). There was a large variation in aprotinin concentration within each patient over time and among patients. There was a significant negative correlation between aprotinin concentration and patient weight for the Full-Dose group. A previous review (8) noted a lack of relationship between aprotinin level and patient size–a surprising finding for a drug that is administered to most patients as a fixed-dose regimen. Aprotinin has three-compartment pharmacokinetics (18). Insufficient filling of the first compartment with the half-dose load may explain the lack of correlation of aprotinin concentration with weight in the half-dose group. This may also explain the lack of a large peak in aprotinin concentration five minutes after the onset of CPB and the effects of the prime dose. Royston (8) has suggested that the aprotinin level at the end of CPB–the nadir concentration–is the most relevant to postoperative blood loss. We did not measure the end-CPB level, but demonstrated a continuous degradation in aprotinin concentration with time on CPB. A dosing scheme for aprotinin that does not allow a degradation in aprotinin concentration over time may be more clinically effective.

The three groups of patients in this study are not directly comparable. This was not a randomized study, and the decision whether to use aprotinin was a clinical one. The control group consisted of patients having their first sternotomy. The control group in this study was a control for the functional assay only. The Full-Dose group of patients had a significantly longer duration of CPB than either the control or Half-Dose groups (Table 2). Duration of CPB may alter the pharmacokinetics of aprotinin. Therefore, this Full-Dose group may be different from this Half-Dose group in more ways than just the dose of aprotinin administered. None of the patients had ultrafiltration, which may effect aprotinin distribution and metabolism. Finally, other inhibitors of plasmin may have been present and measured as aprotinin activity. This is unlikely, because none of our control patients during or after CPB exhibited antiplasmin activity beyond the variability of the assay. Our assay variability is similar to that of the kallikrein-based assay (23).

Functional aprotinin assays described previously have used inhibition of added trypsin (21) or kallikrein (17,23) enzyme activity as the measure of the aprotinin level in a plasma sample. ELISA determinations of aprotinin levels (18) measure the actual concentration of aprotinin present rather than the effective concentration. Aprotinin inhibits kallikrein and plasmin by the formation of a reversible enzyme-inhibitor complex (24). The binding of aprotinin to plasmin is markedly stronger than that to kallikrein (25), so a larger concentration is necessary to inhibit the activity of kallikrein. As the affinity of aprotinin for plasmin is much higher than for kallikrein and as plasmin inhibition may be more important for the clinical effect of aprotinin (9), we developed an assay using plasmin as the indicator enzyme.

In vitro inhibition of plasmin occurs at a plasma aprotinin concentration of 125 KIU/mL, whereas "strong" kallikrein inhibition occurs at 250 to 500 KIU/mL (21). The quoted "target" concentration of aprotinin is 200 KIU/mL (5,8,17). However, there are difficulties with using this in vitro concentration as an in vivo target. Royston (8) has stated in his review article that, "such concentrations may be inadequate to inhibit the enzyme in question in vitro, or conversely, that in combination with naturally occurring inhibitors of these various serine proteases, these concentrations of aprotinin may be in excess of that required to fully inhibit these target enzymes in vivo. These complications confound the issue of defining a specific inhibitory concentration of aprotinin for a specific target protease in any patient." If 200 KIU/mL is to be taken as a target aprotinin concentration, then the use of the half-dose regimen needs to be reviewed, as rarely do patients receiving this dose maintain the target concentration. They do, however, transiently achieve a sufficient level for plasmin inhibition (9).

Levy et al. (18) developed a potentially improved dosing regimen for aprotinin. They describe the pharmacokinetics of aprotinin with a three-compartment model and suggest a sequence of three infusions to maintain aprotinin levels of at least 250 KIU/mL in their normal preoperative patient population. Although Levy et al.’s (18) findings are well supported, their dosing schedule is impractical, remains untested in the bypass patient population, and may be more costly than the full-dosing currently used.

We propose a weight-based dosing schedule based on pharmacokinetic variables determined by Levy et al. (18) and our plasma concentration results (Appendix 1, see Calculations). To adjust Levy et al.’s (18) rates with our results, we used the following equations:

Extrapolating our findings on initial doses and resultant levels, we calculated an initial dose based on weight individualized to meet patient variables as 0.0175 mg/kg x KIU_d (where KIU_d = the desired plasma concentration in KIU/mL) (Figure 3, . Clearly, the pump prime dose in the full-dosing regimen (Figure 2) yields an additional systemic "load" because of the larger than necessary load required for the average bypass circuit. The prime dose necessary to achieve stable levels need only be 0.35 mg x KIU_d for a 2-L CPB circuit volume (Equation 3). In addition, the full-dose regimen provides inadequate rates of infusion during early therapy because of high initial distribution phase clearance of the first 60 minutes of infusion 0.0175 mg/kg x KIU_d. Thereafter, the maintenance infusion of 0.005 mg · kg^-1 · h^-1 x KIU_d is appropriate because aprotinin is then in the elimination phase of clearance.

By using the evidence from our data, as well as the comprehensive pharmacokinetics of Levy et al. (18), our proposed regimen to maintain 200 KIU/mL plasma concentration is as follows:

• 3.5-mg/kg IV bolus dose,

• 70-mg pump prime load for a 2-L CPB system (87.5 mg for a 2.5-L system),

• 3.5 mg · kg^-1 · h^-1 for one hour, and

• 1 mg · kg^-1 · h^-1 until aprotinin is no longer clinically indicated.

If our dosing regimen achieves stable drug plasma concentrations as designed, we will then be able to evaluate specific target aprotinin plasma concentrations and relate these concentrations to clinical blood loss.

Many limitations of pharmacokinetic calculations are inherent. For example, Levy et al. (18) analyzed preoperative cardiac bypass candidates as its population and thus did not elicit many variables associated with surgery, such as fluid status, CPB, and altered organ elimination associated with operative care. We may have underestimated our CPB prime load because of potential tubing and filter adsorption. The difficulty and impracticality of pure pharmacokinetic investigation to assess the actual intraoperative scenario (multiple loads, abnormal organ excretion variables, fluid shifts, etc.) may preclude a more exhaustive analysis. Therefore, it is reasonable to use the above scheme and assess drug levels and clinical measures of efficacy (bleeding, platelet aggregation, and enzyme inhibition) as a next step. Finally, none of our patients had renal insufficiency, which affects aprotinin clearance (19).

Our functional assay has produced results very similar to those in the literature. Advantages of this plasmin-based functional assay are that it is fast and easy to perform. We have developed a potentially improved dosing regimen for aprotinin therapy in cardiac surgery patients. Reduced initial-dose, reduced pump-prime dose, and weight-specific dosing and infusion will likely allow for improved cost effectiveness. Prospective studies will need to be performed to determine if this proposed new dosing regimen results in stable consistent plasma aprotinin levels during CPB and to determine what level of aprotinin is needed to prevent bleeding after CPB.

	Appendix 1. Calculations

Top Abstract Introduction Methods Results Discussion Appendix 1. Calculations References

 
Our dosing scheme for aprotinin was based on the clearance kinetics of aprotinin reported by Levy et al. (18) combined with the volume of distribution data derived in our study (refer to correlation figure of aprotinin with weight in full-dose).

Levy et al. (18) proposed a dosing scheme for aprotinin based on the volume of distribution of aprotinin in normal non-CPB patients. To target 250 KIU/mL by the Levy et al. scheme:

• 52,000 KIU/min x 30 min

• 26,000 KIU/min x 60 min

• 10,400 KIU/min x final duration (risk period)

• Note: Lack of prime dose in normal population. Without the effect of this bolus on loading the systemic circulation, no kinetic estimation can be made to the effect on CPB influence in pharmacokinetics in actual patients.

Determining the Volume of Distribution (Vd)
By using the average weight of the patient population of Levy et al. (18) incorrectly labeled as height on their demographics table), their Vd for their central compartment (V1) is

Based on from the text, our Vd for a given weight can be calculated as follows (from Fig 2); for a 70-kg person):

(concentration for 70 kg person) = 8000 ml = 8 L

Nominal to weight:

Rounding up because of potential errors in interpreting the data points places our approximate Vd at 0.120 L/Kg or 120 ml/kg.

Difference in volume of distribution for aprotinin between Levy et al.’s (18) patient population and ours can be explained by the usual intraoperative administration of fluids, CPB, and altered organ elimination associated with operative care. Additionally, the exact phase of distribution or elimination cannot be ascertained by using the kinetic data we measured. To do so would require a nonreal-life scenario of no multiple initial doses and much more frequent drug levels as performed by Levy et al. (18) Further, it may be unethical or impractical to give aprotinin therapy without a pump prime, this being the period of highest theoretical risk of inducing bleeding.

We approached a dosing solution by integrating our estimation of the Vd (in presence of operating room situations and CPB) from our data with the elimination data of Levy et al. (18) to determine a best approximation of an initial and drug rate scheme in actual CPB patients.

Our calculations for determining the initial dose (LD) and rates to attain a plasma level of 200 KIU/mL (Vd = 120 mL/kg from our data, see above derivation) are as follows:

1. Loading dose = Concentration_desired x Vd. LD = 200 KIU/mL x 120 mL/kg = 24000 KIU/kg = 3.36 mg/kg (where 1 mg = 7143 KIU).

2. LD_{pump prime} = 200 KIU/mL x 2500 ml (for 2.5-L circuit) = 500,000 KIU = 70 mg.

Because of the unknown effect of tubing binding (allowing for greater Vd) and unforeseeable losses (allowing for greater elimination rate) of drug in the CPB device, we will target a level of 250 [as Levy et al. (18) did] during the highest risk period to assure therapeutic level. Then the final dose for pump prime would be 70 mg for the 2-L circuit and 84 mg for the 2.5-L circuit.

We adjusted rates to achieve our goal of deriving the aprotinin infusion rate for first infusion as follows Example: Levy et al. (18) (second infusion rate = 26,000 KIU/min x 30 min):

(This direct relation comes from in the text.)

Because the infusion will likely overlap with the distribution phase, which coincides with the period of highest risk (during CPB initiation and low flow states), as well as the much higher volume of distribution seen in Levy et al.’s (18) study during distribution, a conservative rounding to 3.5 mg · kg^-1 · h^-1 was made to ensure therapeutic levels.

We adjusted rates to achieve our goal of deriving the aprotinin infusion rate for the second infusion as follows (Example: Levy et al.’s (18) final infusion rate = 10,400 KIU/min):

(This direct relation comes from in the text.)

For ease of use and the higher volume of distribution probably seen secondary to operating room factors compared with Levy et al.’s study, a conservative rounding to 1.0 mg · kg^-1 · h^-1 was made to ensure therapeutic levels.

Comparative Doses

	Acknowledgments

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

We would like to thank Dr. Michael Zuehlsdorf from the Institute of Clinical Pharmacology (Wuppertal, Germany) for performing the aprotinin concentration determinations by using competitive enzyme-linked immunosorbent assay (ELISA).

	References

Top Abstract Introduction Methods Results Discussion Appendix 1. Calculations References

 

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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