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© 2001 International Anesthesia Research Society
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Abstract |
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Pediatric patients who undergo posterior spinal fusion surgery to correct scoliosis often require multiple blood transfusions. Tranexamic acid is a synthetic antifibrinolytic drug that reduces transfusion requirements in cardiac surgery and total knee arthroplasty. We evaluated the efficacy of prophylactic tranexamic acid to reduce perioperative blood transfusion requirements in a prospective, double-blinded, placebo control study. Forty patients, 9–18 yr of age, were randomized to either tranexamic acid (initial dose of 10 mg/kg and infusion of 1 mg · kg-1 · h-1) or placebo (isotonic saline). Perioperative management was standardized. A uniform transfusion threshold for noncell saved red blood cells was 7.0 g/dL. The total amount of blood transfused in the perioperative period was significantly reduced in the Tranexamic group (P = 0.045). No thrombotic complications were detected in either group. The administration of prophylactic tranexamic acid in patients with scoliosis undergoing posterior spinal fusion surgery has the potential to reduce perioperative blood transfusion requirements.
Implications: The administration of prophylactic tranexamic acid in patients with scoliosiswho are undergoing posterior spinal fusion surgery has the potential to reduceperioperative blood transfusion requirements.
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Introduction |
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Pediatric patients undergoing surgery to correct scoliosis usually require multiple blood transfusions because they routinely lose one or more blood volumes during the procedure (1,2). The etiology of the blood loss is multifactorial, but coagulation factor deficiencies and increased fibrinolysis are potential contributing components to the blood loss (2,3).1
Tranexamic acid (TXA) is a synthetic antifibrinolytic drug that competitively blocks the lysine-binding sites of plasminogen, plasmin, and tissue plasminogen activator, thereby retarding fibrinolysis and blood clot degradation (4). Prophylactic TXA reduces blood loss and transfusion requirements after cardiac surgery (5,6). Hiippala et al. (7) have demonstrated similar benefits with TXA use in patients undergoing total knee arthroplasty. Enhanced fibrinolysis secondary to the use of a tourniquet in knee surgery has been implicated as a potential cause of increased blood loss (8). The use of TXA to counter the increased fibrinolysis reduced blood transfusion requirements by >1 U (7). Because increased fibrinolysis is also a problem in scoliosis surgery, we hypothesized that TXA administration would decrease transfusion requirements for pediatric patients undergoing posterior spinal fusion for scoliosis.
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Methods |
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After IRB approval, informed parental consent was obtained for each patient. Patients with a history of a bleeding disorder, a low platelet count (<150), abnormal partial thromboplastin time or international ratio test, body mass index >30 kg/m2, previous thromboembolic event, or a family history of thromboembolism were excluded. A patient was considered for inclusion into the study only if the planned procedure was a posterior spinal fusion.
All patients received standard monitoring, including an arterial catheter in a radial artery and a central venous catheter in the right internal jugular vein. The Relton-Hall frame was used for patient positioning. The induction of anesthesia was achieved with sufentanil (0.3 µg/kg) and sodium thiopental (5 mg/kg). A muscle relaxant was used at the discretion of the attending anesthesiologist. Maintenance of anesthesia was accomplished with a sufentanil infusion at 0.2 µg · kg-1 · h-1, nitrous oxide 66%, oxygen 33%, and isoflurane. Minute ventilation was titrated to maintain normocarbia. Deliberate hypotension was generated by increasing the inspired concentration of isoflurane. The mean arterial blood pressure was decreased to 55 ± 5 mm Hg after final patient positioning and was continued until spinal manipulation (i.e., straightening), at which time the mean arterial pressure was returned to within 20% of the baseline pressure. Maintenance fluid requirements and third-space losses were replaced at the discretion of the attending anesthesiologist with balanced crystalloid solutions and pentastarch to maintain a central venous pressure between 4 and 8 mm Hg. The choice and dosing of muscle relaxant was left to the preference of the attending anesthesiologist. A cell saver (Dideco STATTM; Sorin Biomedica Canada, Richmond Hill, Canada) was used for all patients.
The design of the study was such that the patient, surgeon, anesthesiologist, and the investigator collecting the experimental data were all blinded as to which solution was administered. A minibag and two syringes containing the study drug or placebo were labeled with the patient’s name and study number only. The minibag that contained an initial dose of 10 mg/kg TXA (Cyclokapron® 100 mg/mL; Pharmacia, Mississauga, Canada) or placebo was administered over 15 min after final patient positioning. A maintenance infusion of 1 mg · kg-1 · h-1 of TXA or placebo was initiated upon completion of the initial dose and was continued until skin closure.
The primary outcome was the total amount of blood transfused in the perioperative period, which mandated the use of a uniform transfusion policy. The transfusion threshold for all types of red blood cells (allogeneic, autologous, and directed donation blood units) was a hemoglobin level of 7.0 g/dL or less. The threshold was not applied to cell-saved blood; it was deemed unethical to withhold this product because of the limited time frame for which it can be safely stored. Patients could receive a unit of blood if the attending anesthesiologist or surgeon deemed it clinically unsafe to withhold transfusion, but the reason for transfusion was to be documented. The transfusion threshold was applied to the intraoperative period and the first 24 h after surgery. The use of plasma, platelets, and other blood products was, however, left to the discretion of the attending physicians. A list of the Canadian Medical Association’s recommendations (9) for the use of all forms of blood products was, however, included with each data collection sheet and was present in the operating room to guide physicians.
All fluids, including all blood products, were administered via a volumetric infusion pump, and the infusion volumes were documented. The volume of packed red blood cells was the summation of the volumes of all allogeneic, autologous, and directed blood units transfused. The total amount of blood transfused was the sum of the cell-saved blood volume and the total volume of packed red blood cells. Intraoperative blood loss was measured by weighing sponges, suction drainage (cell saver and noncell saver), and an estimate of loss on the surgical drapes and gowns by the attending anesthesiologist. Postoperative blood loss was the amount of blood recovered in the surgical drains if intraoperative drains were placed. Patients were assessed daily for any clinical evidence of deep venous thrombosis by visual inspection and palpation of extremities. No special investigations for thrombotic complications, such as duplex Dopplers or venography, were clinically indicated. Arterial blood samples were used to determine intraoperative hemoglobin values. A complete blood count, prothrombin time, partial thromboplastin time, international ratio, and fibrinogen concentration were measured at the completion of the operation and on the first postoperative day.
The attending surgeon was asked to complete a short questionnaire at the completion of the operative procedure. The surgeon rated the level of surgical difficulty on a visual analog scale with anchors of 0 (no difficulty) and 10 (extremely difficult). The surgeon also rated the operative conditions in regard to bleeding on a visual analog scale score with anchors of 0 (negligible bleeding) and 10 (massive bleeding).
The sample size allowed the detection of a 25% absolute change in the amount of blood transfused with a significance level of 0.05, an 80% power, and a 5% dropout rate. By using a computer-generated table, patients were randomly assigned into the TXA group (n = 22) or Control group (n = 18). Statistical analyses were performed with Minitab Release 12.21 (Minitab, Inc., State College, PA), unless noted otherwise. All analyses were performed on an intention-to-treat basis. A two-sample Student’s t-test was used for the analysis of continuous variables. Ordinal data were assessed with the Kruskal-Wallis test. Statistical significance was determined at P < 0.05.
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Results |
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Forty patients aged 9 to 18 yr with either primary or secondary scoliosis who were undergoing posterior spinal fusion were recruited. The two groups had similar demographic data (Table 1). The TXA group had a nonsignificantly larger proportion of patients with secondary scoliosis (P = 0.62). Patients with secondary scoliosis had a significantly smaller body mass compared with patients with primary scoliosis (38.1 kg versus 58.4 kg; P < 0.001).
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The operative conditions for the two groups were comparable for levels fused, surgical duration, degree of difficulty, and operative field conditions (Table 2). The hemoglobin levels measured at the end of surgery and on the first postoperative day were similar.
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The TXA group had smaller blood requirements in the perioperative period (Table 3). The total amount of blood transfused to the TXA group (1253 ± 884 mL), as compared with the Control group (1784 ± 733 mL) was significantly less (P = 0.045). The TXA group received a smaller volume of packed red blood cells as compared with the Control group, but the difference was not significant (P = 0.08). An analysis of covariance by use of a four-variable model was conducted to adjust for potential confounders, including weight, scoliosis form, and treatment group, to determine their impact on total blood transfusion. Weight was not significant (P = 0.11), but treatment group (P = 0.028) and scoliosis form (P = 0.001) were significant predictors for total blood transfused.
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A post hoc analysis was conducted to determine the percentage of patients who did not receive any allogeneic blood products (yes or no phenomenon). Because there was heterogeneity in the number of autologous units available to each patient, allogeneic exposure rate was performed by comparing only patients who had donated the same number of autologous units (e.g., 2 U versus 2 U, etc.). An exact conditional test from StatXact-4® (Cytel Software Corporation, Cambridge, MA) did not show a difference in allogeneic exposure between groups (P = 0.40). A sample size calculation was performed with an
value of 0.05, a power of 80%, and the proportions obtained from our study (0.39 for placebo and 0.31 for treatment). The estimated total sample size required to demonstrate a difference would be more than 1500 patients. The intraoperative blood loss in the TXA group (2453 ± 1526 mL) was not significantly different (P = 0.58) than in the Control group (2703 ± 1292 mL). Operative drains were not placed in all patients, and therefore, perioperative blood loss was not compared between the groups.
Six patients in each group received at least 1 U of blood at a hemoglobin value above threshold. The absolute number of units of red blood cells transfused at a hemoglobin value more than the transfusion trigger was 7 U in both groups. The most common reason was acute blood loss necessitating treatment before the results of the hemoglobin levels became available. Other reasons included persistent tachycardia (2 U for a TXA patient) and the desire to use up autologous blood (one in each group). A post hoc analysis was performed after the volume of these 14 blood units was subtracted from the total blood transfused values. The TXA group received significantly less total blood compared with the Control group (P = 0.04).
TXA was well tolerated by all subjects in the Treatment group. There were no cases of hemodynamic instability, clinically overt thrombotic complications, or other adverse effects associated with its use. The duration of mechanical ventilation in the intensive care unit for the TXA group (5.4 ± 9.2 h) and the Control group (7.3 ± 12.0 h) was similar (P = 0.57). The total time spent in the intensive care unit for the TXA group (28.8 ± 13.7 h) and the Control group (32.2 ± 22.1 h) was similar (P = 0.58).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study, pediatric patients undergoing posterior spinal fusion for scoliosis received 28% less blood when given prophylactic TXA as compared with placebo. A reduced volume of packed red blood cells transfused in the Treatment group resulted in the smaller perioperative blood requirements, because the amount of cell-saved blood transfused was similar in both groups.
The study groups had similar estimates of operative blood loss. The lack of difference in blood loss should not lessen the significance of the study. Although blood loss has been used as a surrogate outcome for transfusion requirements, the use of surrogate end points is not recommended (10,11). Estimating blood loss by weighing sponges and measuring operative suction volumes has also been demonstrated to be highly imprecise (12). This study was designed to avoid the use of a surrogate end point, so it used the more clinically relevant outcome of blood transfusion.
The baseline demographics of the two groups were not identical. Generally, these slight differences put the TXA group at increased risk for perioperative blood transfusions. Most notably, the TXA group had a larger proportion of patients with secondary scoliosis (68%) compared with the Control group (56%). Previous studies have demonstrated that patients with secondary scoliosis lose more blood and have larger transfusion requirements than patients with primary scoliosis (1,13). The larger proportion of patients with secondary scoliosis in the TXA group accounts for the lower body mass and the greater Cobb’s angle. Despite these differences, the TXA group still required fewer transfusions than the Control group. A multivariate analysis on total blood transfused was performed to adjust for scoliosis form and weight. The treatment benefit of TXA administration persisted (P = 0.028), but weight was not a significant predictor. The Control group had a larger proportion of female patients, which likely reflects the increased incidence of primary scoliosis in females (14). The impact of sex on blood requirements for scoliosis surgery has not been reported, but it is not likely responsible for the transfusion differences.
The use of transfusion requirements as the primary outcome in the study mandated that a uniform transfusion policy be used. The hemoglobin levels were very similar at the end of surgery and on the first postoperative day in both groups, which demonstrates that the implementation of the transfusion policy was similar in both groups. Thus, a transfusion bias could not account for the transfusion differences between the two groups.
This study has several potential limitations. The unrestricted use of cell-saved blood could have potentially biased the results. The amount of cell-saved blood was, however, similar in both groups and thus does not likely account for the transfusion differences between the groups. The transfusion of blood at a hemoglobin value above the threshold could potentially have biased the results. The allowance for this practice was deemed to be a necessary safety feature for the study. The total number of transfused units was the same in both groups, with a slightly larger proportion occurring in the TXA group (12%) compared with the Control group (11%). Treatment benefit from TXA persisted when the volume of these units was removed from the totals (P = 0.04).
The transfusion data distribution was skewed by one TXA patient in whom the perioperative transfusion requirement was 3171 milliliters. The patient’s surgery was complicated because of the presence of abnormally soft vertebral bone. The surgeon had to repeatedly replace the wires used to secure the Luque rods, and this resulted in a prolonged and complicated procedure. The inclusion of this patient skewed the data, but the patient was included in all analyses on an intention-to-treat basis.
The use of antifibrinolytics to reduce blood transfusion has been used successfully in cardiac surgery (5,6) and total knee arthroplasty (7). Increased fibrinolysis has been demonstrated during both of these operations, thereby accounting for the potential benefit of TXA. Increased fibrinolysis has been demonstrated in patients undergoing scoliosis surgery.1 The use of TXA for scoliosis surgery was reported in an abstract by Dell et al. (15). The TXA dosing regiment in the Dell et al. study was the same as that used in this study, but the degree of deliberate hypotension was less aggressive, and the transfusion threshold was higher, at 8 mg/dL. The preliminary results did not report any differences in intraoperative blood loss or intraoperative transfusion (15). There are several possible reasons why the results of the Dell et al. (15) study differed from this study. The most important reason may be the differences in the patient populations. Dell et al. involved only patients with primary scoliosis, who tend to bleed less and require fewer blood transfusions. Also, Dell et al. (15) had less power because of greater observed SD and smaller sample size (n = 20).
No patient in this study experienced a complication from the use of TXA, although no investigations beyond physical examination and history taking were indicated. The primary concern when administering an antifibrinolytic drug is the potential increased incidence of thromboembolic events. The use of TXA in patients undergoing total knee arthroplasty did not increase the incidence of deep venous thrombosis (7,16). A common misconception is that synthetic antifibrinolytic drugs increase blood clotting. The drugs do not alter blood clotting, but rather slow dissolution of blood clots. Benoni et al. (16) suggested that TXA was not associated with thromboembolic events because the effects of TXA are more pronounced in operative wounds than in the peripheral venous blood. Although this study suggests that TXA can be safely used in patients undergoing posterior spinal fusion, a constant vigilance for deep venous thrombosis is recommended.
Although prevention of allogeneic blood products was not an outcome of this study, a post hoc analysis was performed to determine the potential benefit conferred by TXA. The number of patients who remained free from allogeneic blood was not significantly different between the groups (P = 0.40). The estimated sample size required to assess this variable was more than 1500 patients. Although this study does not demonstrate a complete prevention of exposure to allogeneic blood products, it did demonstrate a decrease in blood transfusion by more than 500 milliliters, or approximately one unit of blood. The cost of TXA was $CAN 29, which is considerably less than the cost of one allogeneic unit ($CAN 210) or autologous unit ($CAN 338) (17). Reduced alloimmunization to foreign antigens is important in pediatric patients and especially so in female patients (18). Potential decreases in blood-borne pathogens and decreased adverse immunomodulatory effects are other benefits from reduced blood transfusion (19). Thus, the potential advantages of TXA for pediatric patients undergoing posterior spinal fusion are considerable, even though a complete prevention of allogeneic exposure did not occur.
We conclude that TXA has the potential to reduce the perioperative transfusion requirements in pediatric patients undergoing posterior spinal fusion for scoliosis. Although the safety of TXA in this patient population has not been thoroughly established, no thrombotic complications or other adverse events were detected in this clinical trial.
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Acknowledgments |
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This study was funded by an unrestricted grant from Pharmacia Pharmaceuticals.
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Footnotes |
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1Lin R, Baker A, Rose K, et al. Bleeding and coagulopathy associated with major spinal surgery [abstract]. Can J Anaesth 1996;43:A46.
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Guay J, Reinberg C, Poitras B, et al. A trial of desmopressin to reduce blood loss in patients undergoing spinal fusion for idiopathic scoliosis. Anesth Analg 1992; 75: 405–10.
[Abstract/Free Full Text] - Murray DJ, Pennell BJ, Weinstein SL, Olson JD. Packed red cells in acute blood loss: dilutional coagulopathy as a cause of surgical bleeding. Anesth Analg 1995; 80: 336–42.[Abstract]
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[Abstract/Free Full Text] - Kobrinsky NL, Letts RM, Patel LR, et al. 1-Desamino-8-D-arginine (desmopressin) decreases operative blood loss in patients having Harrington rod spinal fusion surgery. Ann Intern Med 1987; 107: 446–50.
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