The Open Anesthesia Journal


Formerly: The Open Anesthesiology Journal

ISSN: 2589-6458 ― Volume 13, 2019
RESEARCH ARTICLE

Increased Nociception Following Administration of Different Doses of Tranexamic Acid in Adolescent Idiopathic Scoliosis Surgery



Ashraf Nabil Saleh, Raham Hasan Mostafa*
Faculty of Medicine, Ain Shams University, El-hay El-Sabee, Nasr City, Cairo, Egypt

Abstract

Background:

The inhibitory effect of Tranexamic Acid (TXA) on γ-aminobutyric acid and glycine receptors of spinal dorsal horn neurons which leads to pain arousal, has been highlighted recently in animal studies. Such findings would elicit concerns about adverse effects of TXA as a routine agent used to reduce perioperative blood loss.

Objectives:

This study aimed to evaluate the effect of different doses of TXA on analgesic requirements in adolescent patients undergoing elective single-stage posterior spine fusion surgery for idiopathic scoliosis.

Patients and Methods:

This prospective, randomized, double-blinded study comprised 75 patients who were randomly allocated to one of three groups. Each group comprised 25 patients. In group C (Control), patients received normal saline. While in group HD (High Dose), patients received TXA with a loading dose of 50 mg/kg and maintenance dose of 20 mg/kg/h and patients in group LD (Low Dose) received TXA with a loading dose of 10 mg/kg and maintenance dose of 1 mg/kg/h. The total intraoperative fentanyl dose was calculated for each patient which we used as a measure of the patients’ nociception level.

Results:

Group HD patients’ required the highest dose of fentanyl compared to those in LD group (mean of 60µg versus 27µg). Patients in group C received no extra intraoperative narcotic doses and experienced the longest duration of surgical procedure. These results showed high statistically significant difference (p < 0.001).

Conclusion:

Intraoperative administration of TXA increases the analgesic requirement during elective single stage posterior spine fusion surgery which likely reflects an increase in patients’ intraoperative nociception.

Keywords: Adverse effects, Bleeding, Fentanyl, Idiopathic Scoliosis, Nociception, Tranexamic Acid.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 61
Last Page: 68
Publisher Id: TOATJ-12-61
DOI: 10.2174/2589645801812010061

Article History:

Received Date: 28/5/2018
Revision Received Date: 5/9/2018
Acceptance Date: 10/9/2018
Electronic publication date: 28/09/2018
Collection year: 2018

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© 2018 Saleh et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Faculty of Medicine, Ain Shams University, El-hay El-Sabee, Nasr City, Cairo, Egypt; Tel: 002/01222530020; E-mail: rahamhasan@yahoo.com




1. INTRODUCTION

The surgical management of scoliosis is generally indicated to improve patient’s posture through correct of spinal curvatures and more importantly to prevent the occurrence of long-term pulmonary complications. Such surgical interventions can result in a large amount of blood loss due to rich venous plexus and a large raw area of decorticated bony tissue [1Entwistle MA, Patel D. Scoliosis surgery in children. Contin Educ Anaesth Crit Care Pain 2006; 6: 13-6.[http://dx.doi.org/10.1093/bjaceaccp/mki063] ]. Measures to reduce blood loss in such surgeries have included the application of improved surgical techniques, proper patient positioning in addition to controlled hypotension and aggressive management of hypothermia and coagulopathies [2Thakrar SV, Clevenger B, Mallett S. Patient blood management and perioperative anaemia. BJA Educ 2017; 17: 28-34.[http://dx.doi.org/10.1093/bjaed/mkw061] , 3Kuklo TR, Owens BD, Polly DW Jr. Perioperative blood and blood product management for spinal deformity surgery. Spine J 2003; 3(5): 388-93.[http://dx.doi.org/10.1016/S1529-9430(02)00554-5] [PMID: 14588951] ]. The use of powerful antifibrinolytic agents such as Tranexamic Acid (TXA) has gained wider acceptance in major cardiovascular and orthopedic surgeries in which huge blood loss is anticipated [4Verma K, Kohan E, Ames CP, et al. A comparison of two different dosing protocols for tranexamic acid in posterior spinal fusion for spinal deformity: A prospective, randomized trial. Int J Spine Surg 2015; 9: 65.[http://dx.doi.org/10.14444/2065] [PMID: 26767157] ]. TXA is a synthetic lysine analogue that acts by inhibition of plasminogen activation [5Pabinger I, Fries D, Schöchl H, Streif W, Toller W. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr 2017; 129(9-10): 303-16.[http://dx.doi.org/10.1007/s00508-017-1194-y] [PMID: 28432428] ]. The utilization of TXA for adolescents and adults experiencing spinal corrective surgeries for spinal disfigurement has turned into the standard of care in several organizations [6Eroglu A, Solak M, Ozen I, Aynaci O. Stress hormones during the wake-up test in scoliosis surgery. J Clin Anesth 2003; 15(1): 15-8.[http://dx.doi.org/10.1016/S0952-8180(02)00474-9] [PMID: 12657405] ]. Notwithstanding, there remains a scarcity of uniform information as regards to the optimum dose and timing of TXA without developing adverse effects. A recent animal study highlighted that this inhibitory effect on such receptors in the spinal dorsal horn neurons can lead to pain arousal [7Ohashi N, Sasaki M, Ohashi M, Kamiya Y, Baba H, Kohno T. Tranexamic acid evokes pain by modulating neuronal excitability in the spinal dorsal horn. Sci Rep 2015; 5: 13458.[http://dx.doi.org/10.1038/srep13458] [PMID: 26293582] ]. Accordingly, intraoperative TXA usage might increase the amounts of analgesics needed during surgeries [8Ohashi N, Ohashi M, Endo N, Kohno T. Administration of tranexamic acid to patients undergoing surgery for adolescent idiopathic scoliosis evokes pain and increases the infusion rate of remifentanil during the surgery. PLoS One 2017; 12(3): e0173622.[http://dx.doi.org/10.1371/journal.pone.0173622] [PMID: 28282425] ].

Therefore, this study aimed at evaluating the effect of different doses of TXA on analgesic requirements in adolescent Egyptian patients undergoing elective single stage posterior spine fusion surgery for Adolescent Idiopathic Scoliosis (AIS).

2. PATIENTS AND METHODS

2.1. Study Design and Setting

This was a prospective, randomized, double-blinded study that was conducted in Ain Shams University Hospital (ASUH) through the period from April 2017 to November 2017.

2.2. Study Population

The study comprised 75 patients who participated in the study after informed consents have been obtained from their parents or their legal guardians. The work was approved by the Ethics committee of ASUHs and in accordance with the ethical guidelines of the Declaration of Helsinki, 1975. Eligibility criteria for this study included patients 12-18 years of age, American Society of Anesthesiologists Physical Status (ASA PS) class I and II, who were scheduled for elective single stage posterior spine fusion surgery for idiopathic scoliosis under general anesthesia. Patients with known renal or hepatic disorders, bleeding diathesis, thromboembolic event one year prior to surgery, preoperative anemia (hemoglobin < 10 gm%), thrombocytopenia, International Normalized Ratio > 1.4, or those with severe pulmonary disease, neuromuscular diseases, congenital or syndromic scoliosis or intra-spinal malformations were not eligible for this study. Additionally, patients who suffered from intraoperative surgical complications that led to unexpected blood loss or those who had the surgical performed via either combined anterior and posterior spinal fusions or the anterior procedure were also exempted from the study. It is to be noted that all surgeries were done by the same surgeons and anesthesiologists working at ASUH- Assembled Theater – Orthopedics operating rooms.

2.3. Data Collection

Demographic characteristics and relevant clinical data were collected for each patient by the aid of a standardized data collection form.

2.4. Preoperative Preparation

All patients were admitted to ASUH one day before the operation. A preoperative visit was directed to explain the manoeuvre, obtain history and check relevant investigations which included complete blood count, liver and renal function tests, coagulation profile, random blood sugar and serum electrolytes. In addition to baseline Electrocardiogram (ECG), chest X ray, pulmonary function test and echocardiogram were obtained. Patients’ Heart Rate (HR) and Blood Pressure (BP) were recorded.

In the pre-anesthetic room, a peripheral intravenous line was inserted and midazolam 0.01 mg/kg was administrated.

2.5. Patients’ Randomization, Intraoperative Interventions and Management

Patients were randomly allocated in one of three groups by a computer-generated random numbers list and the use of opaque sealed envelopes. Each group comprised 25 patients.

In Group C (control), patients received normal saline. While in the other two groups; group HD (High Dose) and group LD (Low Dose); patients received Intravenous (IV) TXA with different loading and maintenance doses. Loading doses of either 50 mg/kg or 10 mg/kg were administered to patients in group HD and group LD, respectively, over a period of 30 -minutes before skin incision. Continuous infusion at a rate of either 20 mg/kg/h or 1 mg/kg/h was administered to patients in group HD and group LD, respectively, after skin incision through the end of the procedure and skin closure. This dosing regimen followed current literature and guidelines [9Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. In: Henry DA, Ed. Cochrane Database Syst Rev 2011; CD001886.[http://dx.doi.org/10.1002/14651858.CD001886.pub3] -11Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006; 105(5): 1034-46.[http://dx.doi.org/10.1097/00000542-200611000-00026] [PMID: 17065899] ].

An anesthesiology technician prepared the IV solution to be administered, based on the patient’s assigned group, handed it to the investigating anesthesiologist and had no role in patient’s assessment. The patients, their parents, the investigating anesthesiologist, the surgeon, and the Post Anesthesia Care Unit (PACU) nurse remained blinded to the groups.

General anesthesia induction and maintenance were achieved by means of standard agents. Namely, propofol was first administered at a dose of 2 mg/kg followed by fentanyl at a dose of 1 μg/kg and endotracheal intubation was facilitated with atracurium 0.5 mg/kg as a neuromuscular blocker. After tracheal intubation the patient was positioned prone, ensuring that the eyes, nose and abdomen were free of pressure and there was no undue compression to the vessels or hindrance to respiration. Anesthesia was maintained with isoflurane 1-2 MAC and atacurium 0.1 mg/kg given every 20 minutes. End tidal CO2 was kept between 35-40 mmHg. Intraoperative monitoring included noninvasive BP, HR, ECG, pulse oximetry, capnography and urine output. To fulfill the primary objective of this study, patients’ vital signs such as HR, Systolic BP (SBP), and Diastolic BP (DBP) values were recorded preoperatively and at different timings for 120 minutes following induction of anesthesia.

Fentanyl infusion at a constant rate of 0.5 μg/kg/h was being used in order to control intraoperative nociception which was interpreted by elevation of BP & HR. Bolus doses of 25 μg were being introduced if required so as to keep HR and BP maintained within 20% of their baseline values (which were previously determined at the onset of operation and on the day of hospital admission). In addition, ephedrine was used whenever systolic BP dropped below 80 mmHg. The total dose of intraoperative fentanyl was calculated for each patient.

After a wake-up test was successfully completed, a single bolus dose of 5 mg morphine (IV) was given with subsequent cessation of the fentanyl infusion 30 minutes after morphine’s administration. The following clinical parameters were also recorded:

  • Patients body weight, and ASA PS classification.
  • Duration of surgery (time from skin incision till removal of surgical drapes).
  • The total amount of intraoperative blood loss. This was calculated by summing the volume of blood collected in suction bottles and the weight of gauze.

Patients were extubated at the end of surgery and observed in the PACU. Any cardiac, pulmonary, renal vascular or neurological complications that occurred during the 1st postoperative day were documented. Also, postoperative analgesic consumption during 1st postoperative day was measured and documented. Postoperative analgesic plan was: fixed dose of paracetamol 10 mg/kg/6 hours (IV) in addition to 0.5 mg/kg intravenous pethidine on demand (Not to exceed 100 mg pethidine/day, and at least 4 hours should pass after each dose of pethidine).

2.6. Sample Size Determination

A sample size of 75 cases (25 cases per group) was found satisfactory to detect an effect size of 0.4 (a medium effect size) using omnibus Analysis of Variance (ANOVA) test with level of significance of 0.05 and power of 0.80.

2.7. Statistical Analysis

Data were analyzed using SPSS 21.0 for Windows (SPSS, Chicago, IL, USA). Qualitative data were presented as number and percentages while quantitative data were presented as mean, standard deviations and ranges. ANOVA was used to compare the three groups for quantitative parametric data with post-hoc Tukey’s test performed if there was a significant difference among the groups. Comparison between two groups with qualitative data was done using Chi-square. p-value was considered as the following: p > 0.05: non-significant, p < 0.05: significant and p < 0.01: highly significant.

3. RESULTS

The study participants were 32 females (42.7%) and 43 males (57.3%). Relevant demographic and clinical data are shown in Table 1. There was no statistically significant difference between the 3 study groups as regards any of the patients’ recorded characteristics.

Table 1
Demographic and clinical data of all study participants (n = 75).


Similarly, no significant differences had been observed between the 3 groups of patients as regards the hemodynamic parameters recorded before anesthesia induction and at various times up to 120 minutes (Figs. 1, 2 and 3). However, there were high statistical significant differences between the groups as regards the duration of surgical procedure, the total intraoperative blood loss and fentanyl consumption. The HD group showed shortest surgical duration (mean of 128.3 min; p < 0.001) and least blood loss (mean of 181.25 ml; p < 0.001) when compared to the LD group and control group. Also, the LD group when compared with the control group showed significant shorter duration (mean of 188 min versus 208.3 min) and lesser blood loss (mean of 229 ml versus 266.7 ml) (Table 2).

Regarding, the total consumption of fentanyl, it was found that patients in the HD group required the highest dose of fentanyl compared to those in the LD group (mean of 60 µg versus 27 µg). Patients in the control group received no extra intraoperative narcotic doses (Table 2). This result showed high statistical significant difference (p < 0.001). On the other hand, total postoperative analgesic consumption during 1st postoperative day was statistically insignificant between the 3 groups (Table 3). We didn’t record any intra or postoperative complications among patients who participated in the study that could be associated with the use of TXA and so no patients were excluded from the study.

Fig. (1)
Systolic Blood Pressure (SBP) variations throughout the operation Group C = Control Group, Group LD = Low dose tranexamic acid, Group HD = High dose tranexamic acid.


Fig. (2)
Diastolic Blood Pressure (DBP) variations throughout the operation Group C = Control Group, Group LD = Low dose tranexamic acid, Group HD = High Dose tranexamic acid.


Fig. (3)
Heart Rate (HR) variations throughout the operation Group C = Control Group, Group LD = Low dose tranexamic acid, Group HD = High dose tranexamic acid.


Table 2
Comparison between the 3 study groups as regards the duration of surgery, intraoperative blood loss and intraoperative fentanyl consumption.


Table 3
Comparison between the 3 study groups as regards postoperative analgesic consumption during 1st 24 hours.


4. DISCUSSION

The current study demonstrated that TXA increased intraoperative analgesic requirements in a dose dependent manner in adolescent Egyptian patients undergoing elective single-stage posterior spine fusion surgery for idiopathic scoliosis but on the other hand, had decreased intraoperative blood loss and surgical operative time.

The results of the study didn’t show significant differences between the three groups of patients as regards any of the recorded hemodynamic parameters at any of the observed time points. Similar results were obtained by Elwatidy et al. [12Elwatidy S, Jamjoom Z, Elgamal E, Zakaria A, Turkistani A, El-Dawlatly A. Efficacy and safety of prophylactic large dose of tranexamic acid in spine surgery: A prospective, randomized, double-blind, placebo-controlled study. Spine 2008; 33(24): 2577-80.[http://dx.doi.org/10.1097/BRS.0b013e318188b9c5] [PMID: 19011538] ] who demonstrated hemodynamic stability between two groups of patients undergoing spinal surgery where one group received TXA to reduce perioperative blood loss and the other received placebo.

The current study findings verify the hypothesis that TXA might affect the analgesic requirement which was elucidated by the increased fentanyl consumption in the HD group (60.5 ± 12.5 μg) compared to the LD group (27± 17.6 μg) with a p value < 0.001, while the control group didn’t receive any added narcotics. Our results are in agreement with a recently published study by Ohashi and colleagues [8Ohashi N, Ohashi M, Endo N, Kohno T. Administration of tranexamic acid to patients undergoing surgery for adolescent idiopathic scoliosis evokes pain and increases the infusion rate of remifentanil during the surgery. PLoS One 2017; 12(3): e0173622.[http://dx.doi.org/10.1371/journal.pone.0173622] [PMID: 28282425] ] in which patients who received TXA during the idiopathic scoliosis surgery required a higher infusion rate of analgesics. Though in their study, they included only two groups of patients, the first received remifentanil as an analgesic agent and the other did not. Also, Ohashi et al. [7Ohashi N, Sasaki M, Ohashi M, Kamiya Y, Baba H, Kohno T. Tranexamic acid evokes pain by modulating neuronal excitability in the spinal dorsal horn. Sci Rep 2015; 5: 13458.[http://dx.doi.org/10.1038/srep13458] [PMID: 26293582] ] previously reported that TXA evoked behaviors indicative of spontaneous pain and mechanical allodynia in a concentration-dependent manner in rats. Their results indicated that TXA directly inhibited GABA and glycine receptors located at postsynaptic sites in spinal dorsal horn neurons, which increased neuronal excitability.

In the current study, the amount of blood loss decreased by TXA administration with the least amount in the HD group (181.25 ± 18.7 ml). The LD and the control groups showed more blood loss (229 ± 22.44 ml) and (266.7 ± 42.4 ml) respectively. Similar results were reported in earlier studies conducted on patients undergoing spinal surgeries [12Elwatidy S, Jamjoom Z, Elgamal E, Zakaria A, Turkistani A, El-Dawlatly A. Efficacy and safety of prophylactic large dose of tranexamic acid in spine surgery: A prospective, randomized, double-blind, placebo-controlled study. Spine 2008; 33(24): 2577-80.[http://dx.doi.org/10.1097/BRS.0b013e318188b9c5] [PMID: 19011538] -15Ng BKW, Chau WW, Hung ALH, Hui ACN, Lam TP, Cheng JCY. Use of Tranexamic Acid (TXA) on reducing blood loss during scoliosis surgery in Chinese adolescents. Scoliosis 2015; 10: 28.[http://dx.doi.org/10.1186/s13013-015-0052-9] [PMID: 26442124] ].

Our results showed shorter surgical duration in the HD group (mean of 128 min) compared to the LD and the control group (mean of 188 min versus 208 min respectively; p < 0.001). Ohashi and colleagues [8Ohashi N, Ohashi M, Endo N, Kohno T. Administration of tranexamic acid to patients undergoing surgery for adolescent idiopathic scoliosis evokes pain and increases the infusion rate of remifentanil during the surgery. PLoS One 2017; 12(3): e0173622.[http://dx.doi.org/10.1371/journal.pone.0173622] [PMID: 28282425] ] also showed similar data; Their TXA group had significant shorter surgical duration (mean of 267 minutes) when compared to their control group (mean of 320 minutes).

Patients in this study suffered none of the common intra or postoperative complications that could be attributed to TXA administration. Absence of deep venous thrombosis detection may be attributed to the short monitoring period in the study which extended up to 24 hours after the operation only. Yet, this was in accordance with previously published reports which didn’t document any significant association between TXA use and increased risk of vascular complications whether TXA used was in a low dose [12Elwatidy S, Jamjoom Z, Elgamal E, Zakaria A, Turkistani A, El-Dawlatly A. Efficacy and safety of prophylactic large dose of tranexamic acid in spine surgery: A prospective, randomized, double-blind, placebo-controlled study. Spine 2008; 33(24): 2577-80.[http://dx.doi.org/10.1097/BRS.0b013e318188b9c5] [PMID: 19011538] , 14Kushioka J, Yamashita T, Okuda S, et al. High-dose tranexamic acid reduces intraoperative and postoperative blood loss in posterior lumbar interbody fusion. J Neurosurg Spine 2017; 26(3): 363-7.[http://dx.doi.org/10.3171/2016.8.SPINE16528] [PMID: 27885960] ] or in a high dose [16Sethna NF, Zurakowski D, Brustowicz RM, Bacsik J, Sullivan LJ, Shapiro F. Tranexamic acid reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery 2005., 17Shapiro F, Zurakowski D, Sethna NF. Tranexamic acid diminishes intraoperative blood loss and transfusion in spinal fusions for duchenne muscular dystrophy scoliosis. Spine 2007; 32(20): 2278-83.]. Another theory why TXA did not increase the risk of thromboembolism is that TXA reduces blood loss by deactivating the fibrinolytic system, not by activating the coagulation cascade [14Kushioka J, Yamashita T, Okuda S, et al. High-dose tranexamic acid reduces intraoperative and postoperative blood loss in posterior lumbar interbody fusion. J Neurosurg Spine 2017; 26(3): 363-7.[http://dx.doi.org/10.3171/2016.8.SPINE16528] [PMID: 27885960] ]. On the contrary, there were three thromboembolic complications, including one Pulmonary Embolism (PE) and two Deep Vein Thrombosis (DVTs) in Lin's and his colleagues [13Lin JD, Lenke LG, Shillingford JN, et al. Safety of a high-dose tranexamic acid protocol in complex adult spinal deformity: Analysis of 100 consecutive cases. Spine Deform 2018; 6(2): 189-94.[http://dx.doi.org/10.1016/j.jspd.2017.08.007] [PMID: 29413743] ] study which were all treated successfully with anticoagulation. There were no other complications as cases of myocardial infarction, seizure, stroke, or acute renal failure. A recent systematic review of 11 RCTs involving TXA in spinal surgery found only 1 case of myocardial infarction and no DVT or PEs [18Cheriyan T, Maier SP 2nd, Bianco K, et al. Efficacy of tranexamic acid on surgical bleeding in spine surgery: A meta-analysis. Spine J 2015. 15:752e61. doi: 10.1016/j.spinee.2015.01.013]. Since the publication of that meta-analysis, Peters et al. reported 1 case complicated by PE in the TXA group of their RCT [19Peters A, Verma K, Slobodyanyuk K, et al. Antifibrinolytics reduce blood loss in adult spinal deformity surgery: A prospective, randomized controlled trial. Spine (Phila Pa 1976) 2015;40:E443e9. doi: 10.1097/BRS.0000000000000799.].

This study is not without its limitations. To begin with, the number of studied patients may not reveal all the complications owing to the relatively small sample size. Additionally, larger studies that include patients undergoing other surgical procedures will be needed to determine the incidence of untoward events associated with TXA use. Second, it’s a single center study that included only Egyptian patients. Third, the anesthetic depth between patients was not compared owing to the lack of required equipment. Finally, subjective judgement (by the anesthesiologist) was used to guide the administration of intra operative fentanyl, which may have influenced our results.

CONCLUSION

This study demonstrates that intraoperative administration of TXA increases the analgesic requirement during elective single stage posterior spine fusion surgery for idiopathic scoliosis which in turn reflects an increase in patients’ intraoperative nociception.

SOURCE OF FUNDING

Declared none.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The work was approved by the Ethics committee of ASUHs.

HUMAN AND ANIMAL RIGHTS

All experiment were carried out in accordance with the ethical guidelines of the Declaration of Helsinki, 1975 (https://www.wma.net/policies-post/wma-declaration- of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/).

CONSENT FOR PUBLICATION

The study comprised 75 patients who participated in the study after informed consents have been obtained from their parents or their legal guardians.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

This study was done in the Surgical Department of Ain Shams University Educational Hospital, Cairo, Egypt.

REFERENCES

[1] Entwistle MA, Patel D. Scoliosis surgery in children. Contin Educ Anaesth Crit Care Pain 2006; 6: 13-6.[http://dx.doi.org/10.1093/bjaceaccp/mki063]
[2] Thakrar SV, Clevenger B, Mallett S. Patient blood management and perioperative anaemia. BJA Educ 2017; 17: 28-34.[http://dx.doi.org/10.1093/bjaed/mkw061]
[3] Kuklo TR, Owens BD, Polly DW Jr. Perioperative blood and blood product management for spinal deformity surgery. Spine J 2003; 3(5): 388-93.[http://dx.doi.org/10.1016/S1529-9430(02)00554-5] [PMID: 14588951]
[4] Verma K, Kohan E, Ames CP, et al. A comparison of two different dosing protocols for tranexamic acid in posterior spinal fusion for spinal deformity: A prospective, randomized trial. Int J Spine Surg 2015; 9: 65.[http://dx.doi.org/10.14444/2065] [PMID: 26767157]
[5] Pabinger I, Fries D, Schöchl H, Streif W, Toller W. Tranexamic acid for treatment and prophylaxis of bleeding and hyperfibrinolysis. Wien Klin Wochenschr 2017; 129(9-10): 303-16.[http://dx.doi.org/10.1007/s00508-017-1194-y] [PMID: 28432428]
[6] Eroglu A, Solak M, Ozen I, Aynaci O. Stress hormones during the wake-up test in scoliosis surgery. J Clin Anesth 2003; 15(1): 15-8.[http://dx.doi.org/10.1016/S0952-8180(02)00474-9] [PMID: 12657405]
[7] Ohashi N, Sasaki M, Ohashi M, Kamiya Y, Baba H, Kohno T. Tranexamic acid evokes pain by modulating neuronal excitability in the spinal dorsal horn. Sci Rep 2015; 5: 13458.[http://dx.doi.org/10.1038/srep13458] [PMID: 26293582]
[8] Ohashi N, Ohashi M, Endo N, Kohno T. Administration of tranexamic acid to patients undergoing surgery for adolescent idiopathic scoliosis evokes pain and increases the infusion rate of remifentanil during the surgery. PLoS One 2017; 12(3): e0173622.[http://dx.doi.org/10.1371/journal.pone.0173622] [PMID: 28282425]
[9] Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. In: Henry DA, Ed. Cochrane Database Syst Rev 2011; CD001886.[http://dx.doi.org/10.1002/14651858.CD001886.pub3]
[10] Florentino-Pineda I, Thompson GH, Poe-Kochert C, Huang RP, Haber LL, Blakemore LC. The effect of amicar on perioperative blood loss in idiopathic scoliosis: The results of a prospective, randomized double-blind study. Spine 2004; 29(3): 233-8.[http://dx.doi.org/10.1097/01.BRS.0000109883.18015.B9] [PMID: 14752343]
[11] Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery? Anesthesiology 2006; 105(5): 1034-46.[http://dx.doi.org/10.1097/00000542-200611000-00026] [PMID: 17065899]
[12] Elwatidy S, Jamjoom Z, Elgamal E, Zakaria A, Turkistani A, El-Dawlatly A. Efficacy and safety of prophylactic large dose of tranexamic acid in spine surgery: A prospective, randomized, double-blind, placebo-controlled study. Spine 2008; 33(24): 2577-80.[http://dx.doi.org/10.1097/BRS.0b013e318188b9c5] [PMID: 19011538]
[13] Lin JD, Lenke LG, Shillingford JN, et al. Safety of a high-dose tranexamic acid protocol in complex adult spinal deformity: Analysis of 100 consecutive cases. Spine Deform 2018; 6(2): 189-94.[http://dx.doi.org/10.1016/j.jspd.2017.08.007] [PMID: 29413743]
[14] Kushioka J, Yamashita T, Okuda S, et al. High-dose tranexamic acid reduces intraoperative and postoperative blood loss in posterior lumbar interbody fusion. J Neurosurg Spine 2017; 26(3): 363-7.[http://dx.doi.org/10.3171/2016.8.SPINE16528] [PMID: 27885960]
[15] Ng BKW, Chau WW, Hung ALH, Hui ACN, Lam TP, Cheng JCY. Use of Tranexamic Acid (TXA) on reducing blood loss during scoliosis surgery in Chinese adolescents. Scoliosis 2015; 10: 28.[http://dx.doi.org/10.1186/s13013-015-0052-9] [PMID: 26442124]
[16] Sethna NF, Zurakowski D, Brustowicz RM, Bacsik J, Sullivan LJ, Shapiro F. Tranexamic acid reduces intraoperative blood loss in pediatric patients undergoing scoliosis surgery 2005.
[17] Shapiro F, Zurakowski D, Sethna NF. Tranexamic acid diminishes intraoperative blood loss and transfusion in spinal fusions for duchenne muscular dystrophy scoliosis. Spine 2007; 32(20): 2278-83.
[18] Cheriyan T, Maier SP 2nd, Bianco K, et al. Efficacy of tranexamic acid on surgical bleeding in spine surgery: A meta-analysis. Spine J 2015. 15:752e61. doi: 10.1016/j.spinee.2015.01.013
[19] Peters A, Verma K, Slobodyanyuk K, et al. Antifibrinolytics reduce blood loss in adult spinal deformity surgery: A prospective, randomized controlled trial. Spine (Phila Pa 1976) 2015;40:E443e9. doi: 10.1097/BRS.0000000000000799.

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(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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