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Ann Thorac Surg 1996;62:1659-1668
© 1996 The Society of Thoracic Surgeons
Good Samaritan Hospital, Portland, Oregon; Cardiothoracic and Vascular Surgeons, Austin, Texas; Heart and Lung Surgical Associates, Portland, Maine; Sentara Norfolk General Hospital, Norfolk, Virginia; The Carolinas Heart Institute, Charlotte, North Carolina; Southwestern Cardiovascular Surgical Associates, Lubbock, Texas; University of Texas Health Science Center, San Antonio, Texas; University of Arizona College of Medicine, Tucson, Arizona; Ochsner Clinic, New Orleans, Louisiana; Sharp Memorial Hospital, San Diego, California; University of Texas Southwestern Medical Center, Dallas, Texas; Baylor College of Medicine, Houston, Texas; and Brigham and Women's Hospital, Boston, Massachusetts
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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Methods. Seven hundred and four first-time coronary artery bypass grafting patients were randomized to receive one of three doses of aprotinin (high, low, and pump-prime–only) or placebo. The patients were stratified as to risk of excessive bleeding.
Results. All three aprotinin doses were highly effective in reducing bleeding and transfusion requirements. Consistent efficacy was not, however, demonstrated in the subgroup of patients at low risk for bleeding. There were no differences in mortality or the incidences of renal failure, strokes, or definite myocardial infarctions between the groups, although the pump-prime–only dose was associated with a small increase in definite, probable, or possible myocardial infarctions (p = 0.045).
Conclusions. Low-dose and pump-prime–only aprotinin regimens provide reductions in bleeding and transfusion requirements that are similar to those of high-dose regimens. Although safe, aprotinin is not routinely indicated for the first-time coronary artery bypass grafting patient who is at low risk for postoperative bleeding. The pump-prime–only dose is not currently recommended because of a possible association with more frequent myocardial infarctions.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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Aprotinin decreases postoperative bleeding and blood product transfusion requirements when administered to patients during coronary artery bypass grafting (CABG) [1–4]. Most reports describe use of the "high-dose" (or "full Hammersmith") regimen, in which the patient receives a loading dose of aprotinin (280 mg), a dose of aprotinin added to the cardiopulmonary bypass (CPB) circuit prime solution (280 mg), and a continuous infusion of aprotinin during the operation (70 mg/h).
For editorial comment, see 1575.
Because of the cost of aprotinin, there is interest in the use of doses smaller than the full dose, including a "low-dose" regimen that is one-half of the high-dose protocol and a "pump-prime–only" dose in which aprotinin (280 mg) is added to the CPB circuit prime fluid. The efficacy of these reduced doses has been reported [2–6], although the results of only one large multicenter trial comparing the effectiveness of these aprotinin doses with that of placebo have been published [7]. In addition to questions of dosage, the criteria for the selection of patients to be treated with this effective, but not inexpensive, drug are not clear-cut. Aprotinin use is currently indicated for patients at increased risk for postoperative bleeding (such as those undergoing repeat operations) and those who refuse blood transfusions for religious reasons; the utility of aprotinin administration to first-time CABG patients at low risk for bleeding is not certain.
The purpose of this multicenter, randomized, double-blind, placebo-controlled parallel study was to investigate the efficacy and safety of aprotinin in reducing bleeding and transfusion requirements when used in three different dosing regimens (high-dose, low-dose, and pump-prime–only) in patients undergoing first-time surgical myocardial revascularization. In addition, an effort was made to compare the effectiveness of aprotinin in patients judged to be at low risk for perioperative bleeding with its effectiveness in those at high risk.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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Before being randomized to receive one of the study drug regimens, each patient was stratified as to the investigator's assessment of the patient's risk for excessive perioperative bleeding. Patients judged to be at increased risk for excessive postoperative bleeding were assigned to group A. Reasons for assignment to group A (high risk of bleeding) were aspirin ingestion within the 5 days of operation, bleeding time longer than 10 minutes, a history of bleeding diathesis, preoperative coagulopathy, and a high likelihood of excessive perioperative bleeding in the opinion of the investigator. Patients not judged to be at increased risk for excessive perioperative bleeding were assigned to group B. The patients in each stratum were then randomly assigned to receive high-dose aprotinin, low-dose aprotinin, pump-prime–only aprotinin, or placebo. Efficacy variables were analyzed within each of the two strata (high or low risk for bleeding), but the two groups were combined for comparison of safety variables.
Study Drug Administration
Enrolled patients were randomized to receive one of four study drug regimens: high-dose aprotinin, low-dose aprotinin, pump-prime–only aprotinin, or placebo (Table 1
). Aprotinin (Bayer Corporation, West Haven, CT) was supplied in a concentration of 1.4 mg/mL in 0.9% sodium chloride solution. Each 1.0 mg is equivalent to 7,143 kallikrein inactivator units (KIU). Identically appearing placebo (0.9% sodium chloride solution) was also supplied. Each patient received a loading dose, a continuous infusion dose, and a dose of study drug added to the prime solution of the CPB circuit, with identical volumes of study medication (aprotinin, placebo, or a combination of the two) being administered to all patients. Before administration of the loading dose, each patient received a test dose of 1.0 mL of the pump prime solution and was then observed for an allergic reaction for at least 10 minutes. Details of the four dose regimens are given in Table 1.
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For this study, the heparin loading dose administered before cannulation of the heart plus the quantity of heparin added to the prime volume of the CPB circuit was at least 350 USP units/kg of patient weight. During CPB, heparin was administered to maintain the blood heparin concentration at 2.7 U/mL or more using the heparin-protamine titration method with the Hepcon heparin-monitoring system (Medtronic HemoTec, Englewood, CO). During and after operation, the blood conservation techniques (such as intraoperative salvage and postoperative autotransfusion) employed followed the usual practices of the participating center (Table 2). Homologous red blood cells (RBCs) were transfused during CPB if the patient's hematocrit was less than 18% or at higher hematocrit values if the patient's condition warranted it. Postoperatively, RBCs were transfused if the hematocrit was less than 21% or if the clinical condition of the patient warranted it. Platelets, fresh frozen plasma, and cryoprecipitate were transfused as judged necessary by the investigator.
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Diagnosis of Myocardial Infarction
In this study, rigorous surveillance for perioperative myocardial infarctions (MIs) was conducted, including the investigators' assessment of the presence or absence of a CABG-related MI. Electrocardiograms were performed before operation; on postoperative days 3, 5, and 7; and just before discharge from the hospital. The serum creatine kinase total and the MB isozyme fraction (CK-MB) levels were measured upon the patient's arrival in the intensive care unit; at 6, 12, 18, and 24 hours after operation; and on postoperative days 3, 5, and 7. Serum glutamic-oxaloacetic transaminase (SGOT) and lactic dehydrogenase levels were measured upon the patient's arrival in the intensive care unit and on postoperative days 1, 3, and 5.
All electrocardiograms and creatine kinase, CK-MB, SGOT, and lactic dehydrogenase values were evaluated on a blinded basis by the Core ECG Laboratory at St. Louis University Medical Center, headed by Bernard R. Chaitman, MD. Myocardial infarction was defined by the appearance of diagnostic changes on the electrocardiogram, as defined by the Minnesota code for definite or probable MI [8], or by the occurrence of diagnostic elevations in CK-MB activity in the postoperative period [9], or by both findings. Specifically, patients were deemed to have suffered a definite perioperative MI if a new two-step Q-wave change in the Minnesota code was present as compared with the preoperative electrocardiogram or if the CK-MB level was 120 U/L or more at 6, 12, and 18 hours after operation. Quantification of the area under the CK-MB curve was performed when possible and was dependent on site compliance with enzyme determination requirements. The Core ECG Laboratory was provided with copies of the operative report and documentation of important clinical events that enhanced the MI classification (such as autopsy reports). Based on review of all submitted data, the Core ECG Laboratory (blinded to the nature of the study drug administered) answered the following questions for each patient (each question could be answered as "yes," "no," or "insufficient data"): (1) Did the patient have a definite MI as defined by a significant new Q wave? (2) Did the patient have a definite or probable MI, on the basis of any and all information, including but not limited to enzyme values? (3) Did the patient have a definite, probable, or possible MI on the basis of any and all information? and (4) Did the patient have no MI?
Statistical Methods
All statistical tests for treatment effect were two-tailed and performed at the 0.05 level of significance. The primary efficacy variable was the number of donor units of RBC transfusions through postoperative day 12. The primary comparison was that of high-dose aprotinin to placebo. The study was designed to have 90% power to detect a one-unit treatment difference for the primary efficacy variable under the null hypothesis of no treatment difference. Categoric variables (excluding incidence rates of adverse events and abnormal results of laboratory tests) were analyzed using a Mantel-Haenszel test adjusting for center. Chi-square tests were used to analyze laboratory test result abnormalities. For adverse events, Fisher's exact tests were employed if at least one fourth of the cells had expected values of less than 5; otherwise 
2 tests were used. In the adverse event analyses, p values were mainly used as flags to indicate possible safety issues; adjustments for the multiplicity of tests were not made. Because of gross departures from normality, all variables accounting for units of donor blood product required were analyzed nonparametrically. These variables were ranked over all centers, with ties receiving the average rank. Ranked variables, as well as other continuous variables, were then analyzed by a standard two-way analysis of variance model. The model included the effects of drug and center. For continuous variables that were analyzed nonparametrically, the arithmetic by drug-group means and standard errors on the nonranked data are presented in the tables for descriptive purposes. For all other continuous variables, the means and standard errors tabulated are the least-squares means with their associated standard errors.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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). The high-dose aprotinin group had a shorter mean CPB time; otherwise, there were no differences among the groups in the surgical variables, such as in the incidence of the use of membrane or bubble oxygenators, the type of cardioplegia, the number of bypass grafts per patient, the incidence of internal mammary artery graft use, the total intraoperative heparin dose, the frequency of use of adjunctive blood conservation techniques (cell salvage and intraoperative blood sequestration), and preoperative hemoglobin levels (see Table 2
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Effectiveness of Aprotinin Administration (Three Dose Regimens)
Blood product transfusion rates and thoracic tube drainage volumes for each aprotinin dose group are compared in Table 4. This study demonstrates a highly significant efficacy of the high-dose, low-dose, and pump-prime–only dose of aprotinin over placebo. The mean number of RBC units transfused per patient was reduced by approximately 50% in all three aprotinin-treated groups, and the mean number of blood product exposures per patient was approximately 2
times greater in the placebo group than in any of the three aprotinin-treated groups. Considerable reductions in the percentage of aprotinin-treated patients requiring transfusion of any blood product and in the mean number of platelet, fresh frozen plasma, and cryoprecipitate units required per patient were demonstrated. There was, however, no difference in the mean hemoglobin decrease from preoperation to discharge, indicating that the differences in transfusion rates were not the result of unevenly applied transfusion practices.
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-aminocaproic acid) for prophylactic purposes, the investigators could administer such agents to patients after CABG if they were thought to be indicated. In this regard, significantly more placebo patients (15%) than high-dose (3%), low-dose (3%), or pump-prime–only dose (6%) patients were treated with aminocaproic acid. No patients in this study received tranexamic acid. There were no differences in the three aprotinin-treated groups compared with the placebo group with regard to the number of postoperative days spent by patients in the intensive care unit or in the hospital. Follow-up patient interviews at 4 to 6 weeks after operation found no differences among the groups in the incidence of recurrence of angina.
Analysis of Patients on Basis of Risk of Bleeding
Approximately 75% (539/704) of all patients enrolled were judged by the investigators to be at high risk for postoperative bleeding (group A). The vast majority of these patients (524/539; 97%) were so assigned because of preoperative aspirin ingestion. None of the group B patients had received aspirin within 5 days of operation. The group A patients who received aprotinin (at any of the three doses) had smaller chest tube drainage volumes and lower incidences of the need for transfusion of any blood product, and required fewer transfusions of RBCs, platelets, plasma, and cryoprecipitate as compared with the placebo group (Table 5). For the group B patients, judged preoperatively to be at low risk for bleeding, aprotinin treatment was not associated with a consistent reduction in transfusion requirements, although the mean 6-hour chest tube drainage volumes were lower in those who received aprotinin. Although fewer group B high-dose aprotinin patients required transfusions of any blood product and fewer RBC units were transfused in the group B low-dose group, no other significant differences from the transfusion requirements in the placebo group were demonstrated. The mean total number of blood product exposures for the aprotinin-treated group B patients (at any dose) was not significantly different from that of placebo-treated patients.
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Investigator-reported postoperative renal failure occurred in only 2 patients: 1 patient in the pump-prime–only dose group and 1 patient in the placebo group. Postoperative serum creatinine level increases of more than 0.5 mg/dL over preoperative levels occurred in 18 of the 173 (10%) high-dose patients, 12 of the 180 (7%) low-dose patients, 14 of the 173 (8%) pump-prime–only dose patients, and 15 of the 178 (8%) placebo-treated patients, with no significant differences between the aprotinin-treated patients and the placebo-treated patients (overall p = 0.652). Perioperative cerebral infarctions were diagnosed in only 4 of the 704 patients who were enrolled in this study, with one occurring in a patient in each of the four study drug groups.
Myocardial infarction was reported by the investigators to occur in 8 of the 173 (5%) high-dose patients, 5 of the 180 (3%) low-dose patients, 9 of the 173 (5%) pump-prime–only dose patients, and 4 of the 178 (2%) placebo-treated patients (overall p = 0.392). Table 6 shows the results of the blinded analysis of the perioperative MI surveillance data of the 670 patients (95% of the total) for whom sufficient data were obtained. There were no significant differences in the incidence of definite or of definite or probable MI between the three aprotinin-treated groups and the placebo group. For the definite, probable, or possible MI category, however, 16% of the pump-prime–only dose patients were assigned to this group as compared with 9% of the placebo-treated patients, a difference that reached statistical significance (p = 0.045).
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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The transfusion-reducing efficacy of high-dose aprotinin is well documented and further substantiated by the results of our study [1–7]. Our study also affirms the effectiveness of the low-dose aprotinin regimen, as previously demonstrated in two randomized, placebo-controlled studies involving repeat CABG patients [2, 7]. Likewise, Liu and associates [6] demonstrated the efficacy of the low (half)-dose aprotinin regimen in primary CABG patients and found the low dose to be associated with the inhibition of fibrinolysis and with plasma levels sufficient to both inhibit kallikrein and prevent plasmin-induced platelet dysfunction.
The reported effectiveness of the pump-prime–only dose (280 mg of aprotinin to the pump prime solution without loading or maintenance doses) has been less consistent. Van Oeveren and associates [10] reported on a comparison of high-dose and the pump-prime–only aprotinin doses. Both doses reduced blood loss and transfusion requirements, were associated with the inhibition of plasmin activity, and preserved platelet adhesive capacity (lb glycoprotein receptors). Schönberger and colleagues [5] reported that the pump-prime–only aprotinin dose in primary CABG patients was associated with a reduction in blood product transfusions, although no difference from controls was observed in the perioperative blood loss. In a multicenter study similar to ours, Levy and associates [7] tested the high, low, and pump-prime–only doses versus placebo in 287 patients undergoing repeat CABG. In that study, the high- and low-dose aprotinin regimens clearly reduced bleeding and transfusion requirements, but the pump-prime–only dose was less effective. Although this dose was associated with fewer mean total blood product exposures, reductions in thoracic tube drainage, the units of RBCs transfused, and the percentage of patients requiring donor blood products were not demonstrated. Thus, our study and the Levy report are in agreement regarding the effectiveness of the high and low aprotinin doses but disagree on the usefulness of the pump-prime–only dose. One difference between the studies is the nature of the patient populations. The patient population in the trial reported on by Levy and associates involved only repeat CABG patients and ours involved only first-time CABG patients. However, because repeat CABG patients have a higher transfusion requirement than primary CABG patients, this difference in patient populations would be expected to magnify, rather than minimize, any blood-conserving effect of the pump-prime–only dose. In any event, although our study indicates a transfusion-reducing effectiveness of the pump-prime–only dose, this result is not consistent with that reported by some other groups.
Aprotinin Effectiveness Based on the Risk for Bleeding
Each patient in this study was stratified before randomization to a study drug regimen as to the investigator's estimate of the patient's risk for excessive bleeding. Although there were multiple reasons for a patient to be assigned to the group at increased risk for bleeding (group A), in actuality 97% of the 539 group A patients were assigned to this group because they were receiving aspirin therapy preoperatively. Thus, comparison of group A to group B is, in effect, a comparison of patients who were being treated with aspirin preoperatively with patients who were not being treated with aspirin preoperatively and who had no other known risk factors for excessive postoperative bleeding. Aprotinin at all three doses tested was clearly effective in reducing bleeding and the transfusion requirements in the group A patients. In the group B patients, all three doses were associated with reduced postoperative thoracic tube drainage as compared with the placebo group, but consistent efficacy in reducing the transfusion parameters was not demonstrated at any dose. As shown in Table 5, the numbers of units of blood products and the proportion of patients who received transfusions in group B are very similar to those in group A. The major difference is that the group B placebo-treated patients required fewer transfusions than the group A placebo-treated patients (2.8 versus 4.6 units per patient, respectively). This difference in transfusion rates between the placebo groups affirms the validity of the patient assignments to the two strata.
Our results indicate a limited clinical benefit is conferred by aprotinin in patients at low risk for bleeding who undergo primary CABG. Most trials of aprotinin use have enrolled patients who are at increased risk for postoperative bleeding (such as repeat operation patients, patients on aspirin, and patients with endocarditis), and its effectiveness in these patients has been well demonstrated [2–4, 7, 11, 12]. Reports of aprotinin use in patients at low risk for postoperative bleeding are less numerous. Lass and associates [13] compared high-dose aprotinin with placebo in aspirin-free elective primary CABG patients and found this dose to reduce bleeding and transfusion requirements. In a similar trial, Harder and associates [14] found a decrease in the number of postoperative RBC transfusions in the aprotinin-treated patients but no difference in the number of intraoperative RBC units required. Because the latter accounted for more than two thirds of the total units transfused in the patients in this study, the overall clinical benefit of aprotinin administration to this group of patients at low risk for bleeding was limited.
The lack of effectiveness of aprotinin in primary CABG patients not receiving aspirin should be interpreted with caution because of the risk of a type II statistical error. The primary purpose of this study was to investigate the effectiveness and safety of three aprotinin dosage regimens, and sample size calculations were made on that basis. Patients were first enrolled and then stratified as to the risk of bleeding. Because approximately 75% of the patients enrolled in the study fulfilled criteria for assignment to group A, the number of group B patients in each of the four study drug groups was relatively small. Although statistical significance was not consistently present, there was a trend toward less bleeding and fewer transfusions in those group B patients who received aprotinin than in the group B placebo-treated patients (see Table 5). If this trend continued in a trial involving many more patients in each group, statistical significance might be demonstrated, although the clinical significance might be less certain.
Aprotinin Safety
Aprotinin use, at the three doses tested, was not associated with an increased incidence of operative mortality, stroke, or renal failure, a safety profile that is in agreement with the reported results of multiple other clinical trials [3, 4, 7, 15, 16]. In this study, an experienced independent laboratory conducted a rigorous surveillance for perioperative MIs with blinded analysis of the data. The diagnosis of MI, as assessed by the investigators, was not different among the treatment groups. Similarly, as determined by the independent blinded analysis of the available data, there was no difference between the aprotinin-treated groups and the placebo group in the number of patients assigned to the definite and definite or probable MI categories. These results are consistent with those from other studies that have found no increase in the rates of perioperative MI or bypass graft closure in patients who received high- or low-dose aprotinin in conjunction with CABG [3, 7, 14, 17], although they do differ from the study reported on by Cosgrove and associates [2] in which both high- and low-dose aprotinin therapy was associated with a non–statistically significant trend toward more frequent MIs.
In our study, the pump-prime–only dose patients were more likely than the placebo-treated patients to be assigned to the definite, probable, or possible MI category (p = 0.045). Patients receiving the two larger aprotinin doses, however, were not more frequently assigned to this less specific but more sensitive category.
On initial analysis, this is a curious result, in that the lowest dose of aprotinin tested appears to be associated with more frequent possible perioperative MIs. Royston [18] has offered an explanation for why a very low aprotinin dose may cause a greater incidence of thrombotic complications than larger doses of the agent. Cardiopulmonary bypass causes the activation of both the intrinsic pathway of coagulation and fibrinolytic processes, and both of these enzymatic systems are mediated by serine proteases. As a nonspecific inhibitor of serine proteases, aprotinin has multiple different effects that are concentration dependent. When administered in high doses to patients undergoing open heart operations, aprotinin acts to inhibit both coagulation (resulting in reduced thrombin formation) and fibrinolysis (resulting in less D-dimer formation) [4, 19]. At lower doses, however, the anticoagulation property (mediated through kallikrein inhibition) of aprotinin is less important. The plasma concentration generally recognized as sufficient to inhibit kallikrein is 200 KIU/mL or greater, while the plasmin inhibition level is 50 KIU/mL [20, 21]. Thus, at high plasma concentrations (achieved with the high-dose regimen), the anticoagulant and antifibrinolytic effects of aprotinin (in addition to platelet function preservation) may combine to enhance hemostasis but not promote thrombosis. At very low plasma concentrations, however, fibrinolysis inhibition without concomitant inhibition of the intrinsic clotting cascade may result in a state with the potential for thrombotic complications.
The fact that aprotinin has inhibitory effects on multiple enzymatic processes and that the relative magnitude of these effects differs at different aprotinin concentrations serves as the basis for this interesting but unproven theory as to how a lower dose of the drug may actually be less safe than a higher one. It has been noted that in instances in which thrombosed bypass grafts have occurred in association with aprotinin use, the aprotinin dose implicated was smaller than that used in the high-dose regimen [2, 22].
In our study, the association between an increased number of possible MIs and use of the pump-prime–only aprotinin dose regimen is not strong and is noted only for the most sensitive, but least specific, of the MI diagnostic categories. The p value of 0.045 indicates that this may be a trend that only becomes apparent when relatively large numbers of patients are involved. Furthermore, our findings of a trend toward more frequent definite, probable, or possible MIs in the aprotinin pump-prime–only group differs from the findings of Levy and associates [7], who also performed a rigorous blinded analysis for MIs in repeat CABG patients who received aprotinin at the same doses as those in our study. In that report, there was a trend toward fewer definite, probable, or possible MIs in the pump-prime–only dose group, with the incidence being 24% as compared with an incidence of 31% in the placebo group (p = 0.329). Our finding is also contradicted by the findings in the investigation conducted by Kalangos and colleagues [23]. In that placebo-controlled study of 55 patients, the pump-prime–only regimen was associated with less bleeding and fewer transfusions and there was no difference in bypass graft patency (determined by graft arteriography done 8 days after operation) or in the postoperative CK-MB levels. It may be that our study, which involved considerably more patients in each treatment group, reveals a weak adverse effect of the pump-prime–only regimen that is not apparent in smaller trials.
Aprotinin substantially reduces postoperative bleeding and homologous blood product exposures in patients undergoing first-time CABG operations. The cost-effectiveness of aprotinin use should be enhanced by the administration of a smaller, but effective and safe, dose to those patient groups for which consistent efficacy has been demonstrated. In the United States, aprotinin use is currently indicated for patients undergoing repeat CABG or primary CABG, patients receiving aspirin or with known impaired hemostasis, and patients who refuse blood product transfusions for religious reasons. Based on the results of our study, we recommend the use of the low (half)–dose aprotinin regimen for patients with such indications, as this will result in fewer transfusions at a drug cost that is less than that of the high-dose regimen. We do not, however, recommend extending the indications for aprotinin use to include routine first-time CABG patients who are at low risk for postoperative bleeding. At this time, the pump-prime–only dose is not recommended because of its possible association with more frequent perioperative MIs.
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Appendix 1. Participating Centers (Investigators) |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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Supported by Bayer Corporation, West Haven, CT.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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Address reprint requests to Dr Lemmer, Northwest Surgical Associates, 2226 NW Pettygrove, Portland, OR 97210.
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1. Participating...AcknowledgmentsReferences |
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