Comparison of Blood-Conserving and Allogenic Transfusion-Sparing Effects of Antifibrinolytics in Scoliosis Correction Surgery.

BACKGROUND: Intraoperative antifibrinolytic drug administration is a safe and effective method of reducing blood loss and allogenic transfusions in patients undergoing spine deformity correction. AIM: This study aimed to compare the effectiveness of two antifibrinolytic drugs tranexamic acid (TXA) and epsilon amino caproic acid (EACA) in reducing peri-operative blood loss and transfusion requirements against a placebo control in patients with idiopathic scoliosis undergoing correction surgery. SETTING AND
DESIGN: This is a prospective, randomized, double-blinded, controlled comparative study.
METHODOLOGY: Patients in TXA group received 50 mg.kg-1 bolus and 10 mg.kg-1.h-1 infusion as against 100 mg.kg-1 and 10 mg.kg-1.h-1 infusion in EACA group. The placebo group had saline bolus and infusion. Parameters observed included baseline demographic and deformity data, duration of surgery, total peri-operative blood loss, and allogenic packed red cell transfusion requirements. STATISTICAL ANALYSIS: Mean and standard deviation were used to represent the quantitative continuous data, and percentage was used to represent categorical data. The Student's t-test and ANOVA were used to compare means between groups. Bonferroni's multiple comparison test was used to find out the association between categorical variables.
RESULTS: A total of 36 patients were enrolled with 12 patients in each group. Peri-operative blood loss was 50.1% lower in patients receiving TXA and 17.7% lower in patients receiving EACA compared with the placebo group. The volume of total packed red cell transfusion was 66.7% lower in patients receiving TXA and 45.6% lower in patients receiving EACA compared with placebo.
CONCLUSION: TXA was more effective in reducing total peri-operative blood loss and allogenic transfusion requirement in idiopathic scoliosis correction surgery compared to EACA. Copyright:

INTRODUCTION

Perioperative blood loss continues to be a major concern in idiopathic scoliosis correction surgeries. Blood loss in such surgeries may sometimes exceed the estimated total blood volume requiring massive blood transfusion. Excessive blood loss increases the operative time and is associated with the risk of transfusion-related disease transmission; postoperative infections; and end-organ damage leading to increased morbidity, mortality, and length of hospital stay.[1234] Among various factors, severe deformity, involvement of greater number of vertebrae, posterior approach for the surgery, neuromuscular involvement, intraoperative hypothermia, increased pressure in epidural venous plexuses, etc., have been found to be associated with increased blood loss during such surgeries. Consumptive and dilutional coagulopathy, factor deficiencies, clot dissolution, and increased fibrinolysis activation during massive blood loss are potential contributors to blood loss.[5678] When intraoperative blood loss exceeds more than 50% of the total blood volume, circulating levels of coagulation factors diminish, further contributing to ineffective hemostasis.[910]

Although recent improvements in donor screening with effective testing have resulted in a many-fold decrease in transfusion-related disease transmission, the risk of transfusion-related viral and prion disease transmission, alloimmunization, graft versus host disease, transfusion-related acute lung injury and immunomodulation are still matters of concern.[410111213]

As patients with scoliosis are subjected to multi-staged surgeries with exposure to many units of blood and blood components each time, efforts should be maximized to limit the transfusion units of blood products preventing alloimmunization to which a patient is exposed.[2410] Increased fibrinolysis is an important contributor for peri-operative blood loss in scoliosis surgery, which has led to the emergence of the role of antifibrinolytics in decreasing transfusion requirements during scoliosis, spine instrumentations and fusion surgeries.[45678141516]

The last two decades has witnessed an upsurge in the use of antifibrinolytics for various surgical procedures for blood conservation, as well as the downfall of aprotinin as an antifibrinolytic due to its various adverse effects.[41718192021]

In this study, we have evaluated and compared the efficacy of tranexamic acid (TXA) with that of epsilon amino caproic acid (EACA) using saline as a control, in reducing peri-operative blood loss and allogenic blood transfusion requirement in scoliosis surgery.

METHODOLOGY

This was a prospective, randomized, controlled, double-blind, comparative study conducted after institutional research ethics committee approval. Thirty-six patients of American Society of Anesthesiologists physical status I-III, of age group 7–18 years, belonging to either sex, with primary diagnosis of adolescent idiopathic scoliosis, were included in our study. Surgeries included were single-staged or multi-staged scoliosis correction by anterior or posterior approaches. Patients with bleeding diathesis, those with a history of thromboembolic episodes, those with preexisting renal disorders, those on chronic nonsteroidal anti-inflammatory drugs, and those with neuromuscular scoliosis were excluded from the study.

The patients enrolled in the study were randomly assigned to one of the three groups as follows:

Group I: TXA group. Received TXA bolus dose of 50 mg.kg−1 immediate postinduction followed by 10 mg.kg−1/h infusion until wound closure

Group II: EACA group. Received EACA bolus 100 mg.kg−1 immediate postinduction followed by 10 mg.kg−1.h−1 infusion until wound closure

Group III: Placebo group. Received bolus of 10 mL.kg−1 saline immediate postinduction followed by 1 mL.kg−1.h−1 infusion.

Randomization and group allocation of patients were done by a computer-generated table and concealment by opaque sealed envelope, respectively. The bolus solution was prepared in a 100-mL 0.9% normal saline bottle followed by an infusion in a 50-mL syringe using a syringe pump. The rate of infusion was based on prefixed dose calculation handed over to the anesthesia technician, and the subsequent re-filling was done by the same technician who did not participate in any other phase of the study. Masking was ensured by using apparently identical saline bottles and syringes in all the three groups.

Anesthesia technique and performance

Written informed parental consent and patient's consent/assent for the surgery were taken. They were also explained about the intraoperative wake-up test. Intraoperative monitoring included 5-lead electrocardiography, invasive and noninvasive blood pressure, pulse-oximetry, end-tidal carbon dioxide, minimum alveolar concentration (MAC), nasopharyngeal temperature, urine output, central venous pressure (CVP), neuromuscular monitoring, and somatosensory-evoked potential (done by an electrophysiological assistant). After securing a large-bore intravenous (i.v.) cannula, anesthesia induction was done using i.v. glycopyrrolate 0.02 mg−1.kg−1, fentanyl 2 μg/kg, titrated dose of propofol up to 2 mg−1.kg−1, and atracurium 0.5 mg−1.kg−1. i.v. lignocaine 1.5 mg−1.kg−1 was given 45 s prior to intubation to attenuate laryngoscopy and intubation response. Oxygen and nitrous oxide combination was administered in low-flow, 50:50 ratio with sevoflurane not exceeding 1 MAC to facilitate neurological monitoring. Serial arterial blood gas (ABG) analysis was also done. Patients were positioned in prone or lateral position as per the requirement of the procedure, with adequate precautionary positioning measures such as eye-care and abdominal compression prevention. For patients undergoing scoliosis correction by anterior approach, a double-lumen tube was introduced by direct laryngoscopy or assisted by fiberoptic bronchoscope in order to facilitate lung isolation. Periodic intermittent continuous positive airway pressure application in nondependent lung and positive end-expiratory pressure in dependent lung were used to prevent atelectasis. Minute ventilation was targeted to achieve normocarbia. Normothermia was maintained by using convective hot air blankets with forced air warmer, prewarmed i.v. fluids, online fluid warmer for intraoperative infusion, and passive and active humidifiers.

Bolus dose of antifibrinolytic drugs or placebo was given well ahead of skin incision over 15 min. Infusion of the drugs or saline was continued till the end of the procedure. Nitroglycerine infusion was utilized, if needed to maintain mean arterial pressure (MAP) in the range of 55–65 mmHg intraoperatively. Surgical interventions included decortication of lamina, facet joints, and transverse process at each level and insertion of stabilizing rods with a de-rotation maneuver. Somatosensory-evoked potentials were monitored at each step, and the surgeons were informed in case of any discrepancy. Wake-up test was also done to confirm the adequacy of de-rotation maneuvers and to rule out any neurological deficits. An epidural catheter was introduced by the surgeon under direct vision, which was threaded out from the skin and attached to a filter ready for drug administration. An intercostal drain was left in situ at the site of pleural opening/tear. At the end of the procedure, the patients were turned supine and antifibrinolytic or saline infusion was stopped before shifting to the intensive care unit for elective ventilation.

Intraoperatively, i.v. fluids were administered as per the attending anesthesiologist's preference guided by MAP, CVP (target of 6–10 mmHg), urine output, and lactate levels. Blood transfusion was initiated upon blood loss exceeding 20%–30% of blood volume or if hematocrit <21% was recorded. Blood products such as fresh frozen plasma and platelet concentrates were transfused as per institutional policy or if >50% of blood volume was lost. Postoperatively, packed red cells were transfused if laboratory hemoglobin was below 7 g/dL. The exception to this rule was the presence of an active bleeding, hemodynamic instability, or any evidence of organ ischemia.

Estimation of blood loss was done by weighing sponges and quantifying suction bottles' volume after deduction of saline used and hemoglobin values in serial ABGs. In our study, large mops, medium sponges, and small gauzes were used, each with a dry weight of 25 g, 10 g, and 3 g, respectively. Blood loss on nonabsorbable surgical drapes and gown was not considered as it was difficult to quantify. Postoperatively, the total volume of blood collected in the surgical drain for 48 h was added in total blood loss.

Statistical methodology

The study sample size was determined to be 12 patients in each of the three groups, which provided 80% power for detecting a significant difference in total blood loss between the groups by at least 200 mL based on previous studies. Sample size calculations were done using nQuery Advisor® Version 7.0 (Statistical solution Ltd., Boston, MA, USA). Descriptive statistical tools such as mean and standard deviation were used to represent the quantitative continuous data, and percentage was used to represent categorical data. The Student's t-test was used both to assess homogeneity and to compare the main results and also to find difference between the groups for continuous variables. ANOVA was used to compare means between the three groups. Bonferroni's multiple comparison test was used to find out the association between categorical variables and post hoc analysis. For data which were not normally distributed and for evaluation at different time intervals, Kruskal–Wallis test was used and for skewed data Mann–Whitney test was used to determine interquartile range. Qualitative categorical data were analyzed using Chi-square test. In all cases, the level of statistical significance (P value) was 0.05. Data were analyzed using SPSS for Windows (version 23, SPSS, Chicago, IL, USA).

RESULTS

Out of 36 patients included in this study, there were 30 girls and 6 boys, suggesting a predominance of adolescent idiopathic scoliosis among the female population [Figure 1]. There was no statistically significant difference in patients of the three groups with regard to demographics, preoperative laboratory parameters, ASA status, operative indications, and distribution of scoliosis severity [Tables 1 and 2].

Figure 1

Consort diagram

Table 1

Comparison of quantitative variables (mean±standard deviation) (ANOVA)

	Group			P
	EACA (n=12)	TXA (n=12)	Placebo (n=12)
Age	14.67±1.723	12.83±3.689	13.5±1.883	0.229
Weight	45.75±29.366	30.25±10.306	37.67±5.742	0.131
Height	148.92±11.0	138.5±14.994	146.33±9.884	0.107
Preoperative hemoglobin (g/dL)	12.78±1.102	13.14±1.177	13.18±1.523	0.7
Preoperative platelets (cells/mm3)	307.33±50.748	319.25±110.299	294±128.067	0.832
Preoperative INR (s)	1.18±0.199	1.14±0.152	1.12±0.152	0.723

INR=International normalized ratio, TXA=Tranexamic acid, EACA=Epsilon amino caproic acid

Table 2

Comparison of qualitative measures (Chi-square)

	Group			Total (n=36)	P
	EACA (n=12)	TXA (n=12)	Placebo (n=12)
Sex
Female	11	8	11	30	0.165
Male	1	4	1	6
ASA grade
I	11	11	12	34	0.589
II	1	1	0	2

ASA=American Society of Anesthesiologists, TXA=Tranexamic acid, EACA=Epsilon amino caproic acid

The mean numbers of vertebrae fused, Cobb's angle, duration of surgery, surgical approach (25 posterior approach vs. 11 anterior approach), baseline parameters, and intraoperative hemodynamic variables in the form of MAP, CVP, urine output, core body temperature, and partial pressure of carbon-dioxide were also comparable among the groups [Table 3 and Figures 2 and 3].

Table 3

Factors influencing blood loss in our study as subgroup analysis (Kruskal-Wallis)

Median	Total blood loss	P
Age (years)
≤14	1577.5	0.138
>14	1215.91
Cobb’s angle (degrees)
≤56.5	1462.28	0.377
>56.5	1250.28
Number of vertebral level fused
≤10.5	1017.5	0.003
>10.5	1695.56
Duration of surgery (h)
≤5	1147.38	0.034
>5	1649.33

Figure 2

Comparison of intraoperative mean arterial pressure among the groups

Figure 3

Comparison of intraoperative central venous pressures

Use of both TXA and EACA resulted in significant reduction in perioperative blood loss compared to placebo group [Table 3]. Total perioperative blood loss was 874 ± 274 mL in the TXA group compared to 1442 ± 394 mL in the EACA group against that 1752 mL ± 335 mL in the saline group. Perioperative blood loss was 50.1% lower in patients receiving TXA compared with placebo, whereas it was 17.7% lower in patients receiving EACA compared to placebo [Figures 3 and 4] The total peri-operative blood loss was the summation of intraoperative blood loss and postoperative blood loss. The intraoperative blood loss was 46.5% lower in patients in the TXA group (592 mL) and 10.48% lower in the EACA group (991 mL) compared with the placebo group (1107 mL). The postoperative blood loss was 56.4% lower in patients in the TXA group (281 mL) compared with the placebo group (645 mL), whereas it was 30.08% lower in patients receiving EACA (451 mL) with respect to the placebo group [Figure 4].

Figure 4

Comparison of mean perioperative blood loss among the groups

Total packed red cell transfusion was 66.7% lower in patients receiving TXA (250 ± 152 mL) and 45.6% lower in patients receiving EACA (408 ± 207 mL) compared with the placebo group (750 ± 224 mL) [Figure 5]. We did not find any significant difference in the amount of fresh frozen plasma, crystalloids, colloid, and platelets transfused.

Figure 5

Intergroup comparison of total perioperative blood loss

Intergroup comparison revealed that use of TXA caused a statistically significant reduction in total perioperative blood loss compared to the placebo group (P = 0.005). Reduction in total perioperative blood loss in EACA group was not statistically significant (P = 0.098). Similarly, transfusion requirement was significantly reduced in the TXA group when compared with the placebo group (P = 0.006) but not in the EACA group (0.883). Although use of EACA reduced perioperative blood loss and transfusion requirement when compared with placebo, it did not achieve statistical significance [Table 4 and Figures 4 and 5]. On further analysis of factors, we found that surgery on >10.5 vertebral levels (P = 0.003) and surgery duration more than 5 h (P = 0.034) were associated with greater blood loss [Figure 6]. We did not find any significant association between blood loss and Cobb's angle [Figure 7].

Table 4

Intergroup comparison for blood loss and transfusion (ANOVA and Bonferroni)

Group	Comparator	P
Intergroup comparison for total blood loss
EACA	Placebo	0.702
TXA	Placebo	0.005
EACA	TXA	0.098
Intergroup comparison for transfusion requirement
EACA	Placebo	0.084
TXA	Placebo	0.006
EACA	TXA	0.883

ASA=American Society of Anesthesiologists, TXA=Tranexamic acid, EACA=Epsilon amino caproic acid

Figure 6

Comparison of total transfusion requirements among the groups (mL)

Figure 7

Major surgical determinants of blood loss

DISCUSSION

Scoliosis correction surgeries are associated with major blood loss for which various strategies such as preoperative autologous donation, hematinics and erythropoietin administration, acute normovolemic hemodilution, intraoperative cell salvage, and use of antifibrinolytics are practiced. Need for blood conservation and reduction in allogenic blood transfusion becomes paramount in scoliosis surgeries as most of these patients are subjected to multiple staged procedures.[4]

TXA is a lysine analog that reversibly binds lysine receptor sites on plasminogen or plasmin to inactivate them, thus preventing fibrinolysis and protecting the clot and encouraging stasis.[522] TXA has proven efficacy in reducing blood loss as well as transfusion requirements in spine surgeries for adolescent idiopathic scoliosis.[42324] Horrow et al. found that 10 mg.kg−1 was the minimum dose needed to obtain anti-hemorrhagic effect for TXA as per the pharmacologic dose–response trials.[25] The suggested TXA dosing regimen for scoliosis surgery by Dell et al.[26] and Neilipovitz et al.[5] was 10 mg.kg−1 bolus followed by 1 mg.kg−1.h−1 infusion, but the optimal dose has not yet been established. Both high- and low-dose TXA dosing regimens have been used in pediatric patients undergoing spinal fusion for correction of idiopathic scoliosis and it varies from 10 mg.kg−1 bolus to 150 mg.kg−1.[42324] A 20 mg.kg−1 minimum dose of TXA has been recommended by a recent meta-analysis to decrease the total blood loss and intraoperative blood loss during scoliosis surgery.[2728] Johnson et al. reported that high-dose TXA (50 mg.kg−1) was more effective than low dose (10 mg.kg−1) in reducing blood loss and transfusion requirements in pediatric idiopathic scoliosis patients undergoing surgery.[29] Similar dose has been used in other studies too.[293031] Dose–response trials on adults undergoing cardiac surgery have suggested that 70 mg.kg−1 TXA is more effective than 10 mg.kg−1 in one trial and a dose of 100 mg.kg− 1 was found to be more effective than 50 mg.kg−1 but equally effective to 150 mg.kg−1 in a second trial.[32] Reid et al. used higher initial doses of TXA 100 mg.kg−1 followed by 10 mg.kg−1.h−1, which showed reduction in total blood loss by 24% and total transfusion volume by 38% in children undergoing repeat cardiac surgery.[2] Sethna et al. also used the same 100 mg.kg−1 bolus followed by 10 mg.kg−1.h−1 in their study on pediatric patients undergoing scoliosis surgery and showed significant reduction in surgical blood loss during posterior spinal instrumentation by 41% compared with placebo.[33] Sui et al. in their retrospective analysis stated that large-dose TXA (100 mg.kg−1 and 10 mg.kg−1.h−1 infusion) was effective and safe in reducing allogenic blood transfusion and blood loss in adolescent idiopathic scoliosis surgery.[23]

We chose 50 mg.kg− 1 bolus followed by 10 mg.kg−1.h−1 TXA infusion as lower dose regimens are not as effective in reducing blood loss and transfusion requirements. Higher dose regimen of 50 mg.kg−1 was chosen instead of 100 mg.kg−1 because it offers no additional advantage in pharmacological dose response and limited reports of use of such dose in pediatric noncardiac surgery subsets.[293031]

Our study demonstrated that use of TXA led to 50% reduction in total blood loss compared to placebo (P = 0.005). Many previous studies have shown similar results. Sethna et al.[33] documented a blood loss reduction by 41%, whereas Susan et al.[31] demonstrated 27% reduction.

In our study, the total transfusion requirement was reduced by 500 mL in TXA group (250 mL vs. 750 mL in placebo), which was nearly 66% transfusion reduction (P = 0.006). Neilipovitz et al. showed 28% reduction in perioperative blood transfusions in TXA group in children undergoing scoliosis surgery, probably because of the lower dose regimen adopted (10 mg.kg−1 boluses +1 mg.kg−1.h−1).[5] Similarly, 23% reduction in transfusion rate was demonstrable in the study by Bosch et al.,[7] whereas Alajmi et al. demonstrated 72.27% blood transfusion reduction by TXA in their study.[34]

EACA has a very similar mechanism of action to reduce bleeding as that of TXA. The dosage of EACA chosen for our study was 100 mg.kg−1 bolus followed by 10 mg.kg−1.h−1 infusion, which was similar to the dose used by Florentino-Pineda et al.[1415] for scoliosis surgery and by Camarasa et al.[35] for total knee replacement surgeries.

In our study, EACA use resulted in 17.7% reduction in total blood loss compared to placebo, which is clinically significant, but was not found to be statistically significant (P = 0.702). This result is comparable to the study by Florentino-Pineda et al., who used the same dosage on patients with idiopathic scoliosis and demonstrated total peri-operative blood loss reduction by 19%.[15]

We did not observe any drug-related adverse events in our study. The incidence of hypercoagulation status has not been reported with either of the drugs in the dosages studied. Although intravascular thrombosis has been described in isolated nonsurgical case reports of patients receiving TXA for bleeding control, the actual incidence of vascular thrombosis has been reported to be very low in prospective controlled trials in children and adults.[252130363738]

Currently, there is no clinical evidence that the use of TXA increases the risk of thromboembolic events, namely myocardial infarction, stroke, deep-vein thrombosis, or pulmonary embolism as per many clinical trials as well as meta-analyses, and its safety has been well established.[431394041]

A common misconception is that synthetic antifibrinolytics increase blood clotting. The drugs do not alter blood clotting but rather slow down the dissolution of blood clots. Hence, TXA and EACA can be safely used in patients undergoing scoliosis correction with a constant vigilance for deep-vein thrombosis.[41921]

Limitations of our study could be that a uniform stringent transfusion policy could not be strictly employed in our study. Need for transfusion was determined by the attending anesthesiologist depending on intraoperative hemodynamics and transfusion trigger of 7 g/dL. Second, TXA being 6–10 times more potent than EACA,[28] dose equivalence could not be ensured in our study. Based on our study, we can make the following suggestions: (1) Continuation of antifibrinolytic infusion into postoperative period: Bleeding persists at a lower rate till 48 h after surgery, for which the antifibrinolytic infusion would be beneficial if extended postoperatively. (2) Each medical center must design its own blood salvage strategy taking into account the existing resources and specific circumstances and device individual practices to avoid allogenic transfusion risk using multimodality approach.

CONCLUSION

TXA is effective in reducing peri-operative blood loss and allogenic blood transfusions in idiopathic scoliosis corrective surgeries without significant side effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.