Dhawale, Arjun A. MD*; Shah, Suken A. MD*; Sponseller, Paul D. MD†; Bastrom, Tracey MA‡; Neiss, Geraldine PhD*; Yorgova, Petya MS*; Newton, Peter O. MD‡; Yaszay, Burt MD‡; Abel, Mark F. MD§; Shufflebarger, Harry MD¶; Gabos, Peter G. MD*; Dabney, Kirk W. MD*; Miller, Freeman MD*
Spinal fusion surgery in children with neuromuscular scoliosis is associated with substantial intraoperative blood loss as compared with adolescent idiopathic scoliosis (AIS).1–3 The increased blood loss could result in hypotension, anemia, coagulopathy, and the need for transfusion of large volumes of blood products with the associated risks.4,5 Factors implicated in the major blood loss in patients with cerebral palsy (CP) include seizure medications, poor nutritional status, longer fusion levels, and depletion of clotting factors.3,6
Various strategies, including controlled hypotensive anesthesia, the use of the cell salvage system, and intraoperative use of fresh-frozen plasma and cryoprecipitate, to reduce the intraoperative blood loss during spine surgery have been attempted. There are various reports on the use of antifibrinolytic (AF) drugs, like epsilon-aminocaproic acid (EACA), aprotinin, and tranexamic acid (TXA), to reduce the blood loss and transfusion requirements in spine surgery.7 TXA is a lysine analog that blocks lysine-binding sites on plasminogen molecules and inhibits fibrinolysis. EACA is a lysine analog that inhibits fibrinolysis by binding to plasminogen and blocking binding of fibrin. Aprotinin is a serine protease inhibitor that inhibits kallikrein, plasmin, and platelet activation factors. There is evidence for the use of AFs in adult spine surgery and in children with AIS.7–10 It is important to understand the differences between the bleeding and coagulation changes during spinal fusion surgery in idiopathic and neuromuscular scoliosis. There is a greater depletion of clotting factors in patients with neuromuscular scoliosis as compared to AIS.1–3 Hence, the results of studies on the role of AFs in AIS surgery or other spine surgeries, however well designed, cannot be extrapolated to the CP scoliosis population.
There are only a few studies on the use of AF drugs in neuromuscular scoliosis surgery.11,12 Thompson et al11 reported the use of EACA in a retrospective series of 62 neuromuscular scoliosis patients with CP, muscular dystrophy, and other etiologies. They found that EACA was effective in reducing perioperative blood loss and blood transfusion requirements compared with that in a historical control group. Kasimian et al12 conducted a similarly designed retrospective study, using aprotinin in 14 patients with neuromuscular scoliosis, CP, and muscular dystrophy, and they found decreased intraoperative blood loss and transfusion requirements compared to a historical control group. The limitations of these studies are the heterogeneous diagnoses that constitute the neuromuscular scoliosis group, the small number of patients with CP, and the comparison with a historical control group. The role of TXA in reducing intraoperative blood loss and transfusions in Duchenne muscular dystrophy (DMD) scoliosis has been studied in a retrospective review13; however, we are not aware of any study on the role of TXA in pediatric CP scoliosis or studies comparing the efficacy of the commonly used AFs (TXA and EACA) in these patients.
In this multicenter study of patients with CP who had spinal deformity, we studied the efficacy of AF therapy in reducing the intraoperative blood loss, transfusion requirements, and length of stay for posterior spinal fusion (PSF) and instrumentation, and we compared the efficacy of EACA and TXA in reducing blood loss.
A retrospective review of a multicenter, prospectively collected database of children and adolescents (age < 18 years) with CP who underwent PSF and instrumentation as part of their spinal deformity correction for scoliosis/kyphosis was conducted. Ninety-one patients were enrolled during the period between January 2008 and December 2010. Of the 91 patients, 84 patients had sufficient intraoperative data (AF use, blood loss data) to include in the analysis. Patients with muscular dystrophy or other causes of neuromuscular scoliosis were excluded from the study. Demographic patient data, preoperative coronal and sagittal major curve Cobb angle, and curve flexibility were recorded.
Patients were assigned to the treatment arm on the basis of what the operative surgeon reported in the database in terms of AF utilization during the surgery. Patients either received AF therapy (AF group) or did not receive AF therapy (NAF group) on the basis of surgeon preference. There were no predefined criteria for patient selection in each of the treatment arms. The operating surgeon decided to use or not to use AF, depending on their normal practice. The patients who received AF therapy were divided into 2 groups, depending on the drug administered: EACA or TXA. The dosage for EACA consisted of a loading dose of 100 mg/kg given during 20 to 30 minutes followed by a 10 mg/kg infusion until closure of the incision began. The dosage for TXA consisted of a loading dose of 100 mg/kg given for 20 to 30 minutes followed by a 10 mg/kg infusion until closure of the incision began. In cases of longer surgeries, the infusion for both drugs was limited to 8 hours. The intraoperative blood loss during PSF was determined by the anesthesiologist, who estimated the cumulative blood loss from the sponges, the suction canister, the cell salvage, and the surgical drapes. Estimated blood loss (EBL) was expressed as a percentage of blood volume (EBL/BV) and then normalized for weight (mL/kg). Postoperative blood loss was not measured because most of the surgeons did not use a wound drain.
Eight centers and 14 surgeons were involved in this multicenter study. Except for the occasional complex case, there was 1 primary surgeon. All surgeons involved in the study were pediatric orthopedic or spine fellowship trained with considerable experience in treating spinal deformity. All surgeons involved in the study used a standard posterior fusion technique involving exposure of the spine, posterior release/osteotomies as indicated, decortication, and fusion with instrumentation. Some patients underwent Ponte osteotomies. Instrumentation included a unit rod or surgeon-contoured rods and segmental fixation with only sublaminar wires, only pedicle screws, or hybrid constructs with sublaminar wires and pedicle screws. The fusion segment levels and operating time for PSF were recorded (skin to skin). For patients who underwent a staged anterior procedure, the blood loss of the anterior and posterior procedures was recorded separately, and, for the purpose of this study, the blood loss during PSF was used for the analysis. Total perioperative transfusion of allogenic products, individual components, and cell salvage was recorded. Any adverse effects related to AF drug use were recorded.
We used descriptive and comparative statistics with P < 0.05 for significance for the analyses.
Comparison of AF and NAF Groups
Our null hypothesis was that there is no significant difference between the AF and NAF groups in intraoperative blood loss during PSF for CP scoliosis. Our alternative hypothesis was that there is a significant difference in intraoperative blood loss between the AF and NAF groups. We used the independent-samples t test to test this hypothesis.
Our null hypothesis was that there is no significant difference between the AF and NAF group in total transfusion requirements during PSF for CP scoliosis. Our alternative hypothesis was that there is a significant difference in transfusion requirements between the AF and NAF groups.
We compared the AF and NAF groups for age, preoperative major coronal and sagittal Cobb angles, curve flexibility, the number of levels fused, and operating time to determine whether the groups were similarly matched. We compared EBL, EBL/level fused (mL), EBL normalized for weight (mL/kg), and blood volume. We also compared total blood products transfused in the groups along with individual components and cell salvage. Length of hospital and intensive care unit stay were compared as well.
Comparison of NAF, EACA, and TXA Groups
A secondary outcome was to determine whether there was a difference in the efficacy of the drugs in the AF groups (EACA and TXA) with respect to EBL and transfusion requirements. For this we compared the 3 groups with the 1-way analysis of variance with post hoc Bonferroni analysis. We used SPSS version 17.0 (IBM SPSS Data Collection, Chicago, IL) to perform the analyses.
There were 84 patients with CP who had scoliosis (80) and kyphosis (4). The average age at the time of surgery was 14.4 ± 2.6 years.
Comparison of AF and NAF Groups
There were 44 patients (52%) in the AF group and 40 patients (48%) in the NAF group. The 2 groups were similar with respect to the age at the time of surgery, weight, preoperative major Cobb angle, major curve flexibility, kyphosis (T5–T12), preoperative hematocrit, operating time, and levels of fusion (Table 1). The groups were similarly matched for sex: 16 females and 24 males in the NAF group and 17 females and 27 males in the AF group (chi-square P = 0.89). Twenty-seven patients (67.5%) in the NAF group and 35 patients (79.5%) in the AF groups were receiving seizure medications (Pearson χ2 value 1.5, P = 0.21). Details of preoperative feeding status, divided into 4 categories, were recorded; that is; oral, G-tube, GJ-tube and combined oral, and G-tube feeding, and we found no differences between the NAF group and the AF group (Pearson χ2 value 7.74, P = 0.25).
In the AF group (n = 44), EACA was used in 14 patients and TXA was used in 30 patients.
Of the 84 patients, 5 patients (6%) had fusion to the lumbar spine (L4, L5) and 79 patients (94%) had fusion extending to the sacrum/pelvis. Twenty-four patients received unit rod constructs and 60 patients received pedicle screw/hybrid constructs. In the NAF group, there were 22 patients who received unit rods and 18 patients who received pedicle screw/hybrid constructs. In the AF group, there were 2 patients who received unit rod constructs and 42 patients who received pedicle screw/hybrid constructs. There was a statistically significant difference between the AF and NAF groups with respect to the instrumentation used (Pearson χ2 26.1, P < 0.001). This was also observed on comparison of the 3 groups, NAF, EACA, and TXA (Pearson χ2 27.09, P < 0.001).
Three patients underwent vertebral resection (2 in the AF group, 1 each in the TXA and EACA groups, and 1 in the NAF group). Forty-three patients underwent Ponte osteotomies (30 in the AF group, which is 68%, and 13 in the NAF group, which is 32.5%). Eight patients had staged anterior release surgery (4 in the AF group and 4 in the NAF group). Allograft or synthetic bone substitutes were used for the fusion in all except 1 case. Iliac-crest autograft was harvested in 2 cases, and bone-marrow aspiration to supplement fusion was done in 5 cases.
Blood Loss and Transfusion Requirements
There was a significant difference in the EBL, EBL/level fused, and EBL normalized for body weight and blood volume between the AF and NAF groups (Table 2). In the 3 cases that underwent vertebral resection, the blood loss was 3260 mL (NAF group), 1200 mL (AF group, EACA), and 800 mL (AF group, TXA). We could not demonstrate a significant difference in the transfusion requirements between the AF and NAF groups except for the amount of cell salvage transfused, which was greater in the NAF group (Table 3). There was a trend for a decreased hospital stay in the AF group, but not for the intensive care unit stay or duration of intubation (Table 3).
Comparison of NAF, EACA, and TXA Groups
The 3 groups were similarly matched with respect to preoperative major Cobb angle, kyphosis, operating time, and levels fused (Table 4). There was a significant difference between the TXA group and the other groups (EACA and NAF) with respect to the EBL, EBL/level fused, and cell salvage transfusion. The total transfusion requirements in the TXA group were less than those in the other groups, although this was not statistically significant (Table 5). Bonferroni post hoc analysis showed a significant difference between the TXA group and the NAF group (P < 0.05) and between the TXA group and the EACA group (P < 0.05) for EBL, EBL/level fused, and cell salvage requirements. No significant difference was observed between the EACA group and the NAF group.
Post hoc power analysis was performed. To show a difference between the groups for length of hospital stay, using mean values of 14.3NAF and 10.1AF, SD of 13.9NAF and 6.5AF, effect size of 0.18 and P = 0.093, the number needed for achieving adequate power of 80% would be 125 patients in each group. To show a difference in transfusion requirements between the groups for transfused products, using mean values of 2637.2NAF and 2566.6AF, SD of 1490NAF and 2796AF, effect size of 0.02 and P = 0.88, the number needed for achieving adequate power of 80% would be an infinite number of patients because of the low effect size.
Children with neuromuscular scoliosis have greater blood loss and transfusion requirements as compared to AIS and have more potential of developing bleeding complications.1–3 Meert et al1 have shown that neuromuscular scoliosis, lower body weight, and higher number of vertebral levels fused are predictive independently of a greater number of allogenic red-cell transfusions. Kannan et al2 found that depletion of clotting factors (factor 7) during spine fusion surgery occurred to a greater extent in patients with neuromuscular scoliosis. Brenn et al3 observed prolongation of clotting parameters (PT, PTT), decrease in coagulation factor levels, and narrowing of thromboelastography amplitudes suggestive of a functional abnormality in platelet aggregation in patients with CP undergoing spinal fusion; this occurred after only a 15% blood-volume loss. Poor nutritional status and seizure medications also increase intraoperative blood loss in CP patients.3,6
Blood conservation methods include patient positioning to avoid abdominal compression, controlled hypotension, and infiltration of tissues with epinephrine.1 Cell salvage has been shown to decrease the allogenic transfusion requirements,14 although, some studies have found otherwise.4 Desmopressin was not found to decrease blood loss and transfusion requirements during surgery.15 The use of the AF drugs, such as TXA, EACA, and aprotinin, has been found beneficial in decreasing blood loss and transfusion requirements in adult spine surgery4,7 and in children undergoing AIS surgery.8–10,16,17. Gill et al7 and Elgafy et al4 have shown that the side-effect profile of aprotinin is more significant than those of the other 2 drugs. In a systematic review, Elgafy et al4 found that both EACA and TXA were safe for use, but they expressed concerns related to aprotinin on the basis of safety data in cardiac literature and recommended that it should not be used. In 2007, the U.S. Food and Drug Administration announced that the production of aprotinin had been halted because the results of a clinical trial showed that patients receiving aprotinin had a higher mortality rate after cardiac surgery.4,7
Thompson et al11 studied the role of EACA in neuromuscular scoliosis and found that it reduced blood loss and transfusion requirements. Kasimian et al12 reported similar results with the use of aprotinin in 14 patients. Shapiro et al13 showed the efficacy of TXA in reducing intraoperative blood loss and transfusions in patients with DMD scoliosis. All of these studies were retrospective with a historical control.11–13 To our knowledge, there are no studies on the role of TXA in children undergoing surgery for CP scoliosis. Thompson et al11 studied a heterogeneous group of patients with DMD, CP, and other diagnosis. They had twice as many patients with DMD in the historical control group as in the treatment group. Patients with DMD have greater blood loss during spinal surgery, and, although the authors did attempt to analyze the groups separately, the resultant sample sizes were significantly smaller.11
In this retrospective review of a multicenter, prospectively collected database of 84 children with CP, the AFs used were TXA and EACA. The groups were well matched with respect to preoperative and intraoperative variables. There was a significant reduction in the blood loss in the group that received AFs. This is important because CP spinal fusion surgery is associated with major blood loss. Any method to decrease the blood loss could potentially reduce transfusion-related complications, although we did not encounter any significant transfusion-related complications in our series. The use of AFs decreased EBL but could not circumvent the transfusion requirements in the AF group except for the cell salvage. In this aspect, our findings differ from previous neuromuscular studies that have shown a decrease in transfusion requirements with the use of AF agents. One of the reasons that the transfusion rates were not different despite the differences in blood loss could be the use of cell salvage systems. Another reason could be that there were variations in transfusion criteria at 8 different centers, and this may be a confounding factor in the assessment of transfusion differences. Broadly defined criteria for blood transfusion were percent volume of blood loss of greater than 20%, intraoperative hypotension, hemoglobin less than 8 g/dL, and hematocrit less than 25%.
Although the groups were similarly matched with respect to most of the preoperative variables, there were some differences with respect to the type of instrumentation used and Ponte osteotomies performed. The reasons for the higher proportion of Ponte osteotomies in the AF group could be 2-fold. First, the mean Cobb angle magnitudes were slightly higher in the AF group than in the NAF group (although not statistically significant). Second, there are some variations in practice between the different surgeons involved in the study with respect to indications for performing Ponte osteotomies and preference for the use of AF agents. Some surgeons do these releases routinely, and they were recorded as part of the prospective surgical data. It is known that there would be increased blood loss due to the Ponte osteotomies and pedicle screws due to the increased opportunity for bone bleeding. Despite this, the AF group had less bleeding.
In facilities where a cell salvage system is not available, the use of AFs may decrease the transfusion requirements. A decrease in cell salvage transfusion is a benefit. There are isolated reports on complications related to the use of cell salvage.18,19 Keverline and Sanders18 have reported hematuria associated with low-volume cell salvage in 4 children undergoing orthopedic surgery. Vorweg et al19 have expressed concerns about reinfusion of heparinized blood with altered hemostasis with the older cell salvage systems. Although there was a decreased hospital stay in the treated group, it was not statistically significant, and we cannot conclude that it was due to the AF treatment. We have not performed a cost analysis because this is a multicenter trial with variations in costs between the participating institutions, which are situated in different states and provinces.
We found that TXA is more efficacious than EACA in decreasing the blood loss in CP scoliosis. We did not find a significant difference between the NAF and EACA groups; however, the TXA group was larger than the EACA group. There was an inequality in the distribution of the groups as we included all the patients with complete data in the analysis to avoid any selection bias. Our findings differ from those of Gill et al,7 who conducted a systematic review and found that EACA had a greater effect on blood loss and transfusions as the complexity of surgery increased. Their meta-analysis included a heterogeneous population of patients undergoing spine surgery. We did not find any adverse effects related to the use of TXA and EACA.
The limitations of this study are the multicenter design with some expected variation in blood-loss measurement and transfusion criteria followed at the different centers. Postoperative blood loss was not measured as most surgeons did not use a drain. In this retrospective review of a prospectively collected database of 91 patients with CP, blood loss and transfusion data were not available in 7 patients so these patients were excluded. The treatment was not randomized. The patients either received or did not receive AF treatment on the basis of surgeon preference. Although the AF and NAF groups were almost equal, the TXA group had more patients than the EACA group. Some patients underwent a staged anterior procedure, and, although blood loss was recorded separately, this could have a confounding effect on the transfusion requirements. Transfusion criteria were not discussed between centers at the outset of the study. The advantages of this study are the relatively large number of patients who had CP with similarly matched groups, and multicenter results, which are more universally representative and account for expected variations in techniques.
In conclusion, the use of AFs was efficacious in decreasing the intraoperative blood loss and cell salvage transfusions during PSF for CP scoliosis in children and has no adverse effects. TXA was found to be more efficacious than EACA in decreasing the intraoperative blood loss and cell salvage transfusions. The AFs did not decrease the transfusion requirements in these patients.
AFs are effective in decreasing intraoperative blood loss during PSF and instrumentation in CP scoliosis.
Except for a difference in cell salvage transfusion, no differences in total transfusion could be demonstrated.
TXA was found to be more efficacious than EACA in decreasing the blood loss.
There was a trend of decreased hospital stay in the patients who received AFs.
There were no adverse effects related to the use of AFs.
This study was supported by a research grant from DePuy Spine to the Harms Study Group Foundation, whose contributions we gratefully acknowledge.
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scoliosis; cerebral palsy; blood loss; antifibrinolytics; EACA; TXA
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