Decreasing perioperative blood loss in idiopathic scoliosis is important to pediatric spine surgeons.1 Special operating tables/frames, controlled hypotensive anesthesia, infiltration of vasoconstrictive agents, intraoperative and posteroperative blood salvage systems, and preoperative autologous blood donation are used to decrease perioperative blood loss and the need for homologous blood transfusions.2–6 More recently, the use of pharmacologic agents, particularly Amicar7–9 and aprotinin,9–12 have been used to further reduce perioperative blood loss. These agents decrease the need for blood transfusion, particularly homologous transfusions. This decreases the risk for transmission of viral infections (HIV, hepatitis B, and hepatitis C) immunosuppression, and transfusion reactions. In 1998, we began using Amicar in all patients undergoing spinal surgery. This included patients with idiopathic scoliosis, neuromuscular scoliosis, and scoliosis secondary to other etiologies.
Amicar (epsilon aminocaproic acid) is an antifibrinolytic agent with documented efficacy in decreasing perioperative blood loss and fibrinolysis in pediatric cardiac surgery.13–16 It has a very low complication rate. It was thought that this would have efficacy in pediatric spine surgery. We have now completed four studies on patients with idiopathic scoliosis. These include a preliminary study,7 a prospective, randomized double-blind study,8 fibrinogen study, and most recently a study of patients undergoing same-day anterior (ASF) and posterior spinal fusion (PSF). We have yet to analyze the results of Amicar on our patients with neuromuscular or other types of scoliosis.
Materials and Methods
Between 1998 and 2000, we performed a prospective study on the efficacy of Amicar in decreasing perioperative blood loss in idiopathic scoliosis compared with a historical, retrospective control group. All patients had the following inclusion criteria: idiopathic scoliosis, age at surgery 11 to 18 years of age, PSF only, segmental spinal instrumentation (SSI), a standard surgical technique, and a standard postoperative care path. Patients with a same-day or staged anterior procedure were excluded. Our indications for transfusion were a hemoglobin less than 7 g/dL. We combined the estimated intraoperative blood loss and the measured postoperative Hemovac suction drainage to determine the perioperative blood loss.
There were two PSF patient groups: Group 1, 28 consecutive patients who received Amicar on a prospective basis; and Group 2, the 31 previous consecutive patients but without Amicar that had the same inclusion criteria and analyzed retrospectively. Factors analyzed include the age at surgery, gender, the corrected height (Bjure et al17) to allow determination of body surface area and estimated total body blood volume, Cobb angle of the major curve, the number of vertebra fused, length of procedure, intraoperative crystalloid total perioperative blood loss, autologous blood donation, and transfusion requirements (autologous and bank blood).
Amicar was administered intraoperatively, before skin incision, at 100 mg/kg over 15 minutes, not to exceed 5 g. Patients were then maintained at 10 mg/kg per hour until wound closure began. It was then discontinued. It has a half-life of approximately 2 hours. No Amicar was given after surgery.
Prospective, Randomized, Double-Blind Study.
Based on the results of the preliminary study, an Institutional Review Board approved prospective, randomized double-blind study was performed between 2000 and 2002. The patient inclusion criteria were identical to the preliminary study except that the patients who received Amicar were selected by random numbers by the pharmacy. Patients receiving Amicar were unknown to the anesthesiologist and surgeon until the completion of the study. Factors analyzed were identical with the preliminary study with the exception that fibrinogen levels were determined before surgery and on the first postoperative day. Amicar was administered in the same manner as the preliminary study. At the completion of the study period, 19 patients received Amicar and 17 patients did not.
Based on the increased fibrinogen levels on the first postoperative day in the Amicar patients in the prospective, randomized double-blind study, we analyzed fibrinogen levels on all postoperative days in the next 21 consecutive patients with idiopathic scoliosis undergoing a PSF. They had the exact same inclusion criteria and indications for transfusion as in the previous two studies. The same factors that were analyzed as in the previous two studies with the exception that fibrinogen levels were measured before surgery and all the postoperative days until discharge (4 or 5 days after surgery).
Same-Day Anterior and Posterior Spinal Fusion.
Most recently, we analyzed the perioperative blood loss in patients undergoing same-day ASF and PSF and SSI. This included an analysis of those patients between 1991 and 1998 when Amicar was not being used compared with those who received Amicar between 1998 and 2003. Again, the patient inclusion criteria and factors analyzed were identical, except the chest tube drainage was now included in the perioperative blood loss assessment. The indications for transfusion were also the same.
There were three study groups: Group 1, 15 patients who did not receive Amicar (historical control); Group 2, 27 patients who received Amicar only during their PSF; and Group 3, 16 patients who received Amicar for both the ASF and PSF.
The clinical comparisons between the two groups were identical with the exception of the patients in Group 1 being slightly older than those in Group 2. The mean age at surgery in Group 1 was 14.5 ± 1.6 years compared with 13.3 ± 1.3 years in Group 2. Intraoperative blood loss was statistically less in Group 1 (988 ± 411 mL) compared with 1,405 ± 670 mL in Group 2 (P < 0.024). Postoperative Hemovac drainage was also statistically less in Group 1 (605 ± 253 mL) compared with 939 ± 455 mL in Group 2 (P < 0.003). Thus, the total perioperative blood loss was 1,604 ± 517 mL in Group 1 compared with 2,312 ± 994 mL in Group 2 (P < 0.003). The total estimated blood loss with respect to the percentage of estimated blood volume was 55% ± 21% in Group 1 and 74% ± 33% in Group 2 (P < 0.0.024). The amount of blood transfusion requirements were less in Group 1. They received only 1.1 ± 1.0 U of autologous blood intraoperative compared with 2.1 ± 1.1 U in Group 2 (P < 0.003). Only 1 patient in Group 1 received a single unit of bank blood transfusion compared with 4 patients and 4 U in the control group. There were no complications, such as neurologic injury, postoperative infection, deep venous thrombosis, thromboemboli, or other complications that could be attributed to the use of Amicar. These results were published in 2001.7
Based on this study, we concluded that Amicar was a safe, effective medication in idiopathic scoliosis. It decreased the total perioperative blood loss, perioperative transfusion rate, the need for autologous donation, and lowered the overall cost related to blood management. However, we thought a prospective, randomized double-blind study would be necessary to validate our results.
Prospective, Randomized, Double-Blind Study
The clinical characteristics between the 19 patients who received Amicar and 17 control patients including age, sex, Cobb angle, vertebrae fused, and intraoperative crystalloid were essentially identical. The intraoperative blood loss was 893 ± 166 mL in the Amicar group compared with 952 ± 303 mL in the control group. This was not statistically significant. However, the postoperative Hemovac drainage was significantly different. In the Amicar group, it was 498 ± 179 mL compared with 764 ± 284 mL in the control group (P < 0.05). Thus, the total perioperative blood loss was 1,391 ± 212 mL in the Amicar group compared with 1,716 ± 513 mL in the control group (P < 0.03). Blood utilization was again significantly less in the Amicar group. The autologous units transfused were 1.1 ± 1.0 in the Amicar group versus 2.1 ± 1.3 in the control group (P < 0.002). No patient received bank blood transfusion. Again, there were no complications. These results were published in 2004.8
The preoperative fibrinogen levels in the Amicar and control groups were essentially identical at 260.9 ± 51 and 260.1 ± 89 mg/dL, respectively. However, on the first postoperative day, the fibrinogen levels increased to 343.7 ± 141 mg/dL in the Amicar group; while in the control group, it remained essentially unchanged at 265.6 ± 94 mg/dL. The significance of this increase was uncertain.
We thought that these results confirmed that Amicar is a safe, effective medication in idiopathic scoliosis. It decreased perioperative blood loss, but predominantly in the postoperative Hemovac drainage, and perhaps was mediated by the increased fibrinogen secretion. This decreased perioperative transfusion, decreased need for autologous donation, and again lowered costs.
Based on the increased fibrinogen levels on this first postoperative day in the Amicar group in the previous study, we measured fibrinogen levels before surgery and on all postoperative days until discharge in the next 21 consecutive patients with idiopathic scoliosis undergoing a PSF and SSI. Perioperative blood loss in these patients was similar to the prospective, randomized double-blind study. Intraoperative blood loss was 670 ± 277 mL and the postoperative suction drainage was 502 ± 267 mL for a total perioperative blood loss of 1,172 ± 544 mL. Transfusion of autologous blood was 0.3 ± 0.4 U per patient. No patient received bank blood. There were no complications associated with Amicar.
We found that the fibrinogen levels steadily increased throughout all postoperative days (Table 1). Before surgery, the fibrinogen was 266 ± 63 mg/dL. On the first postoperative day, it increased to 282 ± 99 mg/dL; and on the fifth postoperative day, it was continuing to rise and was 699 ± 94 mg/dL. These results have not yet been published.
This study documented that fibrinogen levels rise substantially in patients receiving Amicar undergoing a posterior spinal fusion and segmental spinal instrumentation. The mechanism of action of Amicar is uncertain, but since the total perioperative blood loss was again substantially decreased, we think that Amicar is a possible explanation for the increased fibrinogen levels.
Same-Day Anterior and Posterior Spinal Fusion
The results of this study demonstrated that there was no statistical difference when Amicar administration was started before or after the anterior procedure (Table 2). In Group 1 (no Amicar), the estimated intraoperative blood loss for the ASF was 239 ± 148 mL. This was compared with 171 ± 201 mL and 180 ± 102 mL in Group 2 (Amicar for PSF only) and Group 3 (both ASF and PSF), respectively.
The estimated intraoperative blood loss with the PSF was significantly less in Group 2 and Group 3: 2,175 ± 1081 mL in Group 1 compared with 751 ± 298 mL in Group 2, and 664 ± 599 mL in Group 3. Chest tube drainage was also less in Group 2 and Group 3: 890 ± 327 mL in Group 1 compared with 654 ± 377 mL, and 481 ± 215 mL in Group 2 and Group 3. Interestingly, the postoperative Hemovac drainage was very similar in all three groups: 503 ± 218 mL, 503 ± 212 mL, and 496 ± 128 mL, for all three groups, respectively. Thus, the total perioperative blood loss in patients undergoing a same-day anterior and posterior spinal fusion was 3,807 ± 1,058 mL in Group 1, 2,080 ± 659 mL in Group 2, and 2,183 ± 852 mL in Group 3. Blood utilization was also dramatically less in Group 2 and Group 3. In Group 1, the total number of units transfused was 3.1 ± 1.5 U, while in Group 2 and Group 3, it was 1.9 ± 0.9 and 1.0 ± 0.8, respectively. Again, there were no complications associated with the use of Amicar. These results have not yet been published.
We concluded that Amicar is effective in decreasing perioperative blood loss in same-day ASF and PSF with segmental spinal instrumentation. There was no difference if it was given before or after the anterior procedure. Amicar significantly decreases the need for intraoperative and postoperative transfusion.
Amicar (ε-aminocaproic acid) is a 6-aminohexanoic acid belonging to the lysine class of antifibrinolytic agents. These agents bind the lysine site on plasminogen and plasmin preventing plasmin from binding to fibrin.12 The exact mechanism of action of Amicar is unknown. Although most commonly used in spine surgery, Amicar, aprotinin, and other pharmacologic agents are now being used for other orthopedic procedures.18–21
The results of our four studies have confirmed that Amicar is an effective, safe medication in decreasing perioperative blood loss in patients with idiopathic scoliosis undergoing spinal surgery. There was a significant reduction in perioperative blood loss in the preliminary study in the patients receiving Amicar. However, the use of a historical control group was thought to be unsatisfactory. In the prospective, randomized double-blind study, Amicar did not decrease the estimated intraoperative blood loss but did significantly decrease the postoperative suction drainage. This resulted in a statistically significant decrease in the total perioperative blood loss and percent loss of estimated blood volume. The total perioperative autologous blood transfusion between the groups was almost statistically significant (P = 0.061). These differences between the preliminary and prospective, randomized double-blind studies appear to result from the use of a historical control group in the preliminary study. When the preliminary study and the prospective, randomized double-blind study are compared, the Amicar groups are essentially identical (Table 3). The results in the control groups, however, were significantly different. In the preliminary study, the historical control group had a mean total perioperative blood loss of 2,312 ± 994 mL; whereas in the prospective, randomized double-blind study, it was only 1,716 ± 513 mL. This indicates the potential problem of using historical control group. Four surgeons participated in the preliminary and prospective, randomized double-blind study, but the majority of these were by the senior author. We analyzed the results by surgeon and found no differences.
Why did Amicar decrease postoperative suction drainage? The role of increased fibrinogen levels after surgery in the Amicar group is possibly a major factor. This may have enhanced clotting after surgery and, thereby, decreased bleeding. This increase in fibrinogen levels after surgery and the associated decrease in postoperative suction drainage may explain why other authors who measured only the estimated intraoperative blood loss found that Amicar was not as effective as aprotinin.9,10
The results of the fibrinogen study are interesting but difficult to interpret. Are the increased fibrinogen levels due to the effects of surgery itself or the use of Amicar? These elevated levels have been discussed with hematologists at our institution and elsewhere and are thought to be higher than would have been expected from surgery alone. However, without a control group, this explanation is speculative. Brenn et al22 in a recent study found no increase in fibrinogen levels between the preoperative levels and at a 15% estimated intraoperative blood volume loss in a group of 17 patients with cerebral palsy and 17 patients with idiopathic scoliosis undergoing a PSF. In the idiopathic scoliosis group, the preoperative fibrinogen was 288 ± 81 mg/dL and at 15% estimated blood volume loss was 197 ± 33 (P = 0.19). Unfortunately, their study did not analyze fibrinogen and other clotting factors with greater intraoperative blood loss or during the postoperative period. Similar decline in fibrinogen was reported by Krohn et al in 10 adolescents and young adults, age 11 to 28 years, undergoing surgery for thoracic scoliosis.23 Before surgery, the fibrinogen was 217 ± 35 mg/dL, but after a 40% blood volume loss was 123 ± 42 mg/dL. They thought that this indicated a strong fibrinolysis from the surgical wound. Tuman et al described a mild hypercoagulable state persisted at 50% to 80% blood volume loss in adults.24 This may indicate elevated levels of fibrinogen that potentially could persist through the postoperative period for an unknown number of days. Since the total perioperative blood loss and the need for autologous blood transfusion were so slow, we think that the use of Amicar is a possible explanation. Wei et al analyzed the coagulation on 65 patients undergoing orthopedic surgery.25 Platelet count, prothrombin time, partial thromboplastin time, and fibrinogen were measured before surgery and on postoperative days 1, 3, and 7. Fibrinogen was not significantly altered on the first postoperative day, was elevated on the third postoperative day, and was normal on the seventh postoperative day. Our results are distinctly different, as the fibrinogen levels increased steadily and excessively through the fifth postoperative day. When they returned to normal is uncertain. Greilich et al26 in 2004 found that Amicar was as effective as aprotinin in decreasing perioperative blood loss in patients undergoing cardiopulmonary bypass surgery. Both decreased monocyte-platelet adhesion. In controls, this is increased because of excessive plasmin activity. How increased fibrinogen levels may interact with the decreased leukocyte and platelet adhesion is unknown.
The same-day anterior and posterior spinal fusion in idiopathic scoliosis demonstrated the apparent significant effect of Amicar on perioperative blood loss. However, it suffers from the same problems as the preliminary study as it used a historical control group. However, we anticipate the results will be verified if repeated in a prospective, double-blind, randomized study. It appears that giving Amicar during the anterior procedure offers no significant advantages, as the estimated intraoperative blood loss in all three study groups was similar. However, the postoperative chest tube drainage was less in the two Amicar groups, which indicates its effect when given during the posterior procedure. The estimated intraoperative blood loss during the posterior procedure was markedly less in the two groups who received Amicar. One interesting observation was that, although the chest tube drainage was less in Groups 2 and 3, the postoperative Hemovac drainage was essentially the same in all three groups. The exact reason for this similarity is uncertain. Nevertheless, the overall decrease in blood loss with Amicar and decreased need for intraoperative and postoperative transfusion was statistically significant.
Amicar is also used successfully in other orthopedic surgery procedures including total hip arthroplasty, osteotomies, and adult spine surgery.9,17,27,28 In 2002, Harley et al demonstrated a 27% reduction in perioperative blood loss, including postoperative suction drainage, in patients undergoing primary total hip arthroplasty who received Amicar.18 This, too, was a randomized, double-blind study with 26 patients receiving Amicar and 29 patients a saline placebo. There were no postoperative complications, such as deep venous thrombosis. They concluded that Amicar was effective in reducing blood loss and consequently transfusions and transfusion-related risk in patients requiring primary total hip replacement. In 2001, Urban et al compared the efficacy of both Amicar and aprotinin in reducing blood loss during complex adult reconstructive spine surgery.9 Fifty-five patients underwent a same-day anterior and posterior thoracolumbar spinal fusion. Their diagnoses were not listed. Seventeen patients received Amicar, 20 patients received aprotinin, and 18 patients served as controls. Postoperative blood loss was estimated from drainage from the surgical wounds and chest tube. The total estimated perioperative blood loss in the control group of 5,181 mL, compared with Amicar 4,056 mL, and aprotinin 3,628 mL. Thus, the best results were obtained with aprotinin. The results with Amicar were not thought to be statistically significant. There was no increased incidence of deep venous thrombosis or other thromboemboli abnormalities after surgery in the two treated groups. It was thought that the aprotinin group has less postoperative respiratory complications due to its anti-inflammatory affect.
Aprotinin is also being used successfully in elective orthopaedic reconstructive procedures to decrease perioperative blood loss.9,11,19,20,27–31 Aprotinin is a proteinase inhibitor with antifibrinolytic properties. However, Amar et al29 in 2003 found that neither Amicar nor aprotinin was useful in cancer patients undergoing major orthopedic procedures. Perhaps their compromised health from their cancer chemotherapy and other treatments interfere with their ability to increase fibrinogen production.
Complications associated with the use of Amicar appear to be extremely low. Laupacis and Fergusson performed a meta-analysis of all published randomized trails using Amicar, aprotinin, desmopressin, and tranexamic acid in patients undergoing cardiac surgery.32 There were no reported thromboemboli or other complications related to the use of Amicar. In another meta-analysis of Amicar and aprotinin in cardiac surgery, Munoz et al33 reported a decreased risk of reexploration and no effect on postoperative myocardial infraction or overall mortality. We have had no clinical complications, such as venous thrombosis or thromboemboli, in any of our studies. Similar findings have been reported by others, including both pediatric and adult spine surgery and total hip arthroplasty.7–10,18 The reasons are unclear but may be due to lower postoperative hematocrits and hemoglobins. However, contraindications to the use of Amicar include active intravascular clotting disorders, such as disseminated intravascular coagulation, bradycardia, elevated creatine phosphokinase, muscle weakness, pulmonary embolism, and thrombosis.34
Based on current results, we think that Amicar is helpful in decreasing blood loss in patients undergoing spinal fusion and will decrease the number of autologous units needed to maintain safe perioperative hemoglobin levels, thereby improving safety and lowering costs associated with scoliosis surgery. It is also quite inexpensive compared with aprotinin.7,35 The cost of Amicar is $0.56 to $1.12 per patient compared with the cost of aprotinin, which is approximately $1,200 per patient. Nevertheless, we have not compared the efficacy of these two pharmacologic agents.
Based on the results of these four studies, we think that there are many more questions to be answered. At this point, we are planning to proceed with a triple-blind, Institutional Review Board -approved study, which will include a control, Amicar group, and aprotinin group. We will also have the assistance of a pediatric hematologist and a transfusion medicine physician to determine if other clotting factors should be analyzed before surgery and after surgery. We will also try to determine whether the fibrinogen levels, which were increased in the third study, are truly the results of Amicar and not the effect of surgery itself.
- Amicar is effective in decreasing perioperative blood loss and the need for transfusion in patients with idiopathic scoliosis undergoing posterior spinal fusion.
- Its main effect is primarily decreased postoperative suction drainage.
- Fibrinogen levels are markedly elevated in the postoperative period in patients receiving Amicar.
- Because blood loss associated with an anterior spinal fusion is low, administration of Amicar is recommended only during the posterior spinal fusion in patients undergoing a same-day anterior and posterior spinal fusion.
1.Guay J, Haig M, Lortie L, et al. Predicting blood loss in surgery for idiopathic scoliosis. Can J Anaesth
2.McNeill TW, DeWald RL, Kuo KN, et al. Controlled hypotensive anesthesia in scoliosis surgery. J Bone Joint Surg Am
3.Patel NJ, Patel BS, Paskin S, et al. Induced moderate hypotensive anesthesia or spinal fusion and Harrington rod instrumentation. J Bone Joint Surg Am
4.Phillips WA, Hensinger RN. Control of blood loss during scoliosis surgery. Clin Orthop
5.Relton JES, Hall JE. An operation frame for spinal fusion: a new apparatus designed to reduce haemorrhage during operation. J Bone Joint Surg Br
6.Cowell MR, Swickard JW. Autotransfusion in children' orthopaedics. J Bone Joint Surg Br
7.Florentino-Pineda I, Blakemore LC, Thompson GH, et al. The effect of epsilon aminocaproic acid on perioperative blood loss in patients with idiopathic scoliosis undergoing posterior spinal fusion: a preliminary prospective study. Spine
8.Florentino-Pineda I, Thompson GH, Poe-Kochert C, et al. The effect of Amicar on perioperative blood loss in idiopathic scoliosis: the results of a prospective, randomized double-blind study. Spine
9.Urban MK, Beckman J, Gordon M, et al. The efficacy of antifibrinolytics in the reduction of blood loss during complex adult reconstructive spine surgery. Spine
10.Cole JW, Murrary DJ, Snider RJ, et al. Aprotinin reduces blood loss during spinal surgery in children. Spine
11.Koshhal K, Clark P, Jarvis J, et al. The efficacy of aprotinin in reducing blood loss in spinal fusion for idiopathic scoliosis. Presented at Pediatric Orthopaedic Society of North America Annual Meeting, Cancun, Mexico, May 1–5, 2001.
12.Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs
13.Rao BH, Saxena N, Chauhan S, et al. Epsilon aminocaproic acid in paediatric cardiac surgery to reduce postoperative blood loss. Indian J Med Res
14.Vander Salm TJ, Kaur S, Lancey RA, et al. Reduction of bleeding after heart operations through the prophylactic use of epsilon-aminocaproic acid. J Thorac Cardiovasc Surg
15.Williams GD, Bratton SL, Riley EC, et al. Efficacy of epsilon-aminocaproic acid in children undergoing cardiac surgery. J Cardiothorac Vasc Anesth
16.Chauhan S, Das SN, Bisoi A, et al. Comparison of epsilon aminocaproic acid and tranexamic acid in pediatric cardiac surgery. J Cardiothorac Vasc Anesth
17.Bjure J, Grimby G, Nachemson A. Correction of body height in predicting spirometric values in scoliotic patients. Scand J Clin Lab Invest
18.Harley BJ, Beaupre LD, Jones A, et al. The effect of epsilon aminocaproic acid on blood loss in patients who undergo primary total hip replacement: a pilot study. Can J Surg
19.Lentchener C, Cottin P, Bouaziz H, et al. Reduction of blood loss and transfusion requirement by aprotinin in posterior lumbar spine fusion. Anesth Analg
20.Murkin JM, Shannon NA, Bourne RB, et al. Aprotinin decreases blood loss in patients undergoing revision in bilateral total hip arthroplasty. Anesth Analg
21.Alanay A, Acaroglu E, Özdemir O, et al. Effects of deamino-8-d-arginin vasopressin on blood loss and coagulation factors in scoliosis surgery. a double-blind randomized clinical trial. Spine
22.Brenn BR, Theroux MC, Dabney KW, et al. Clotting parameters and thromboelastography in children with neuromuscular and idiopathic scoliosis undergoing posterior spinal fusion. Spine
23.Krohn CD, Reikeras O, Bjornsen S, et al. Fibrinogen, fibrin and its degradation products in drained blood after major orthopaedic surgery. Blood Coagul Fibrinolysis
24.Tuman KJ, Spiess RD, McCarthy RJ, et al. Effects of progressive blood loss on coagulation as measured by thromboelastography. Anesth Analg
25.Wei KL, Lin CJ, Lai KA. Changes in coagulation profile after orthopedic surgery. J Formos Med Assoc
26.Greilich DE, Brouse CF, Rinder CS, et al. Effects of epsilon-aminocaproic acid and aprotinin in leukocyte-platelet adhesion in patients undergoing cardiac surgery. Anesthesiology
27.Tobias JD. Strategies for minimizing blood loss in orthopedic surgery. Semin Hematol
28.Booth D, Kothmann E, Tidmarsh M. A strategy for reducing blood-transfusion requirements in elective orthopaedic surgery. J Bone Joint Surg Br
29.Amar D, Grant FM, Zhang H, et al. Antifibrinolytic therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery. Anesthesiology
30.Samama CM, Langeron O, Rosencher N, et al. Aprotinin versus placebo in major orthopedic surgery: a randomized, double-blinded, dose-ranging study. Anesth Analg
31.Samama CM. A direct antifibrinolytic agent in major orthopaedic surgery. Orthopedics
32.Laupacis A, Fergusson D. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood loss as the outcome. Anesth Analg
33.Munoz JJ, Birkmeyer NJ, Birkmeyer JD, et al. Is epsilon-aminocaproic acid as effective as Aprotinin in reducing bleeding with cardiac surgery? A meta-analysis. Circulation
34.Slaughter TF, Greenberg CS. Antifibrinolytic drugs and perioperative hemostasis. Am J Hematol
35.Ray MJ, O'Brien MF. Comparison of epsilon aminocaproic acid and low-dose aprotinin in cardiopulmonary bypass: efficiency, safety, and cost. Ann Thorac Surg