EFFECTIVENESS OF PROPHYLACTIC TRANEXAMIC ACID FOR REDUCING BLOOD LOSS IN CHILDREN UNDERGOING WILMS TUMOUR SURGERY: A RANDOMIZED CONTROL STUDY

INTRODUCTION

Wilms tumor (WT) incidence of around is 1:10000 in children. Its surgery is often associated with significant blood loss and subsequent need of blood transfusion. Excessive blood can lead to major perioperative morbidity and mortality.  Complications related to perioperative bleeding include severe hypotension, metabolic acidosis, cardiac arrest, transfusion reactions, venous air embolism, coagulopathies, infections, acute lung injury, postoperative ventilation, and death.  Decreasing blood loss and trans-fusion requirements should improve patient safety, expedite postoperative recovery, and decrease hospital costs.²

Tranexamic acid (TXA, trans-4-aminomethyl cyclohexane carboxylic acid) is a synthetic amino acid lysine analogue that forms a reversible complex with both plasminogen and plasmin by binding at lysine-binding sites.⁵ This binding competitively blocks the conversion of plasminogen to plasmin. It inhibits the proteolytic action of plasmin on fibrin clot and platelet receptors and inhibits fibrinolysis at the surgical wound. TXA binds poorly to plasma proteins and is excreted primarily by the kidneys unchanged.  TXA has been used clinically for decades and has Food and Drug Administration approval for the indications of prophylaxis and treatment of bleeding during surgery. Randomized trials of TXA use in pediatric cardiac and major noncardiac surgery have found that TXA demonstrates efficacy in reducing perioperative blood loss and the amount of blood transfused without apparent morbidity or mortality.

Research Hypothesis: In this study hypothesis is that intraoperative tranexamic acid infusion will significantly reduce intraoperative bleeding than control group.

AIMS AND OBJECTIVE

AIM:

•      Aim of this study is to know effectiveness of prophylactic tranexamic acid for reducing blood loss in children undergoing Wilms tumour surgery

•      Primary Objective:

–     Blood loss quantity in each group

•      Secondary objectives:

–     Blood transfusion quantity required in each group

–     Postoperative Hb level after surgery

–     Intraoperative haemodynamic parameters- Heart rate and SBP

–     Need of vasopressor infusion

–     Surgical field quality

–     Any adverse event

MATERIAL AND METHODS

Study settings:

The study will be conducted in Department of Anaesthesiology, King George’s Medical University, Lucknow

Study duration:

One year

Study design:

Prospective Randomized control study

Sample Size:

On the basis of previous study, the mean difference in Blood loss (ml) in between tranexamic acid group (224.3) and control group (362) was 137.7 and the average variance (σ2) was 145.25 (Goobie SM et al., 2011). The sample size was calculated by formula (n) = 2 (Zα/₂ + Z _[1-β])² × σ²/( μ1−μ2)², assuming 0.05 level significance (Z_α/2 =1.96), and 80% power (Z _[1-β])=0.84) was 27.75.

n=29≈ 30 in each group

In this study we will enroll 30 patients in each group of the study.

•      Inclusion Criteria:

–     Age less than 10 year

–     Planned elective Wilms tumour surgery

–     Both with or without chemoradiotherapy

•      Exclusion criteria:

–     Refusal of patient’s attendant

–     Age more than 10 years

–     Presence of haematological, coagulation, hepatic, renal, or vascular disorders

–     Platelet count less than 1.5 lakh/ml

–     INR value more than 1.5

–     Ingestion of nonsteroidal anti-inflammatory agents within 14 days

–     Allergy to study drugs

 Methodology:

The study will be conducted after getting approval from ethics committee of King George’s Medical University, Lucknow. All cases divided in to two groups:

Randomization, concealment, and blinding:

Patients will be randomly assigned using a simple randomization procedure to receive either intravenous Tranexamic acid (TXA group) or 0.9% saline (NS group). A 1:1 allocation ratio computer-generated, random number table will be used for this, and the results of randomization will be kept in sealed envelopes to ensure proper concealment. Both patient and attending anaesthesiologist will be kept blinded to type of study group. Drug infusion syringe will be unlabelled to make sure that attending anaesthesiologist doesn’t recognise it.

Group Allocated in this study:

1.     Group TXA: Patient allocated in this this group will be given inj Tranexamic acid in a loading dose of 50 mg/kg followed by an infusion of 5 mg/kg/h.

2.     Group NS: Patient allocated in this this group will be given inj Normal Saline with same volume but without any drug in it.

All patients will receive standard monitoring, including continuous ECG, pulse-oximetry, NIBP, temperature, urine-output and intermittent arterial blood gas analysis. Thoracic epidural will also be inserted for perioperative analgesia. Through epidural we will give bupivacaine in strength of 0.125% and fentanyl in strength of 1.0 mcg/ml. An arterial catheter in a radial artery will also be inserted after induction for accuracy in measurement of blood pressure. The induction of anesthesia will be achieved by fentanyl 2.0 mcg/kg and propofol in dose of 1-2mg/kg. Atracurium will be given at the dose of 0.5 mg/kg to facilitate intubation. Maintenance of anesthesia was accomplished with a sevoflurane inhalation near 1 mac value and fentanyl boluses in dose of 1.0 mcg/kg at every hour. Epidural anesthesia will be repeated every 90 minutes in dose of 0.3 ml/kg of 0.125% bupivacaine. Minute ventilation will be titrated to maintain normocarbia.

TXA will be given in a loading dose of 50 mg/kg followed by an infusion of 5 mg/kg/h during surgery in interventional arm of study. Same amount of normal saline without containing any drug will be given in control group. Fluid therapy and blood loss will be managed by the administration of crystalloid solution and blood products.  Decisions regarding replacement and maintenance of intravascular volume will be at the discretion of the individual anesthesiologist and guided by monitoring arterial blood pressure, urinary output (1ml/kg/h), haemoglobin, and arterial blood gas measurements performed every 30 min. Packed erythrocytes (PRBC) were transfused if the haemoglobin value approaches towards 7 gm/dl.

All patients will be examined postoperatively for clinical evidence of adverse events related to TXA, including clinically evident thromboembolic (including deep vein thrombosis) or neurologic events.

Data to be recorded: Age, weight, gender, ASA, tumour size, duration of surgery, preoperative Hb, platelets, INR, serum creatinine, intraoperative haemodynamic (HR, SBP every 15 min), total blood loss, total PRBC transfused, urine output, lactic acid (ABG).

Statistical analysis

All data will be collected and processed using SPSS software (ver. 20.0; SPSS Inc., USA). All results will be expressed as mean (SD) and ranges (as numbers or percentages). Categorical data will be compared using a chi-square test. Non-parametric data will be compared using the Mann-Whitney U test. Numerical data will be compared using the independent samples Student’s t test. P < 0.05 will be considered significant.

Follow-Up

Analysed  (n=  )

Analysis

Analysed  (n=  )

Lost to follow-up (give reasons) (n=  )

Lost to follow-up (give reasons) (n=  )

Enrollment

Allocated to   Tranexamic acid (TXA) group (n=  )

Allocation

Allocated to Control normal saline (NS) group (n=  )

Randomized (n=  )

Excluded  (n=   ) ¨   Not meeting inclusion criteria (n=  ) ¨   Declined to participate (n=  ) ¨   Other reasons (n=  )

Assessment for eligibility (n=  )

 PATIENT FLOWCHART

REVIEW OF LITERATURE

Goobie et al (2011) conducted a study that total 43 children, ages 2 months to 6 yr, received either placebo or TXA in a loading dose of 50 mg·kg(-1), followed by an infusion of 5 mg·kg·h(-1) during surgery. TXA plasma concentrations were measured. The TXA group had significantly lower perioperative mean blood loss (65 vs. 119 ml·kg(-1), P < 0.001) and lower perioperative mean blood transfusion (33 vs. 56 ml· kg(-1), P = 0.006) compared to the placebo group. The mean difference between the TXA and placebo groups for total blood loss was 54 ml·kg(-1) (95% CI for the difference, 23-84 ml·kg(-1)) and for packed erythrocytes transfused was 23 ml·kg(-1) (95% CI for the difference, 7-39 ml·kg(-1)). TXA administration also significantly diminished (by two thirds) the perioperative exposure of patients to transfused blood (median, 1 unit vs. 3 units; P < 0.001). TXA plasma concentrations were maintained above the in vitro thresholds reported for inhibition of fibrinolysis (10 μg·ml(-1)) and plasmin-induced platelet activation (16 μg·ml(-1)) throughout the infusion. TXA is effective in reducing perioperative blood loss and transfusion requirement in children undergoing craniosynostosis reconstruction surgery.

Gupta K,  et al (2012) conducted a study that total 60 ASA class I and II adult consented female patients, scheduled for elective radical surgery and met the inclusion criterion, were blindly randomized into two groups to receive either intravenous 1 g tranexamic acid 20 min before skin incision or an equivalent volume of normal saline as placebo (P). All patient’s total blood loss was measured and recorded perioperatively at the 12^thh postoperatively. The preoperative and postoperative hemoglobin, hematocrit values, serum creatinine, activated thromboplastin time, prothombin time, thrombocyte count, fibrinogen, D-dimer, and symptoms of pulmonary embolism were comparatively evaluated. The tranexamic acid significantly reduced the quantity of total blood loss, 576 ± 53 mL in study group as compared to 823 ± 74 mL in the control group (P<0.01). Postoperatively hematocrit values were higher in the tranexamic acid group. The coagulation profile did not differ between the groups, but D-dimer concentrations were increased in the control group. No complications or adverse effects were reported in the either group. The prophylactic administration of tranexamic acid has effectively reduced theblood loss and transfusion needs during radical surgery without any adverse effects or complication of thrombosis.

Wang Y  et al (2019)  studied that the 21 randomized controlled trials with a total of 3852 patients were included. Only one research reported thromboembolic events. Compared with control groups, the intra-operative blood loss (mean difference [MD] -155.23 mL, 95% confidence interval [CI] -195.64 - 114.81; P<0.01), postoperative blood loss (MD -26.67 mL, 95% CI -32.98 to -20.36; P<0.01), total blood loss (MD -184.88 mL, 95% CI -218.83 to -150.94; P<0.01), transfusion requirements (relative risk [RR] 0.29, 95% CI 0.18-0.49, P<0.01), massive hemorrhage (RR 0.39, 95% CI 0.30 to 0.51; P<0.01) and additional uterotonic agents use (RR 0.40, 95% CI 0.30-0.55, P<0.01) were markedly reduced in TXA-treated patients. Besides, TXA yielded a significant reduction in hemoglobin drop (MD -0.80 g/dL, 95% CI -1.07 to -0.53; P<0.01) and hematocrit drop (MD -2.05, 95% CI -3.09 to -1.01; P<0.01) compared with control groups.  Prophylactic application of TXA can decrease perioperative blood loss and transfusion requirements in patients undergoing CS. More high-quality researches are needed to determine optimal dose of the drug.

Wei Y  et al (2021) studied that the efficacy of TXA in pediatric surgeries. Two reviewers choosed studies, evaluated quality, extracted data, and assessed the risk of bias independently. Mean difference (MD) was calculated as the summary statistic for continuous data. We used a random-effects model to measure mean effects. Data were generated from the corresponding 95% confidence interval (CI) using RevMan 5.3 software. Primary outcomes included intraoperative and postoperative blood loss, red blood cell (RBC) transfusion as well as fresh frozen plasma (FFP) transfusion.  Fifteen studies enrolling 1,332 patients were included in this study. The pooled outcomes demonstrated that TXA was associated with a decreased intraoperative (MD = −1.57 mL/kg, 95% CI, −2.54 to −0.60, P = 0.002) and postoperative (MD = −7.85 mL/kg, 95% CI, −10.52 to −5.19, P < 0.001) blood loss, a decreased intraoperative (MD = −7.08 mL/kg, 95% CI, −8.01 to −6.16, P < 0.001) and postoperative (MD = −5.30 mL/kg, 95% CI, −6.89 to −3.70, P < 0.001) RBC transfusion, as well as a decreased intraoperative (MD = −2.74 mL/kg, 95% CI, −4.54 to −0.94, P = 0.003) and postoperative (MD = −6.09 mL/kg, 95% CI, −8.26 to −3.91, P < 0.001) FFP transfusion in pediatric surgeries. However, no significant difference was noted between two groups in duration of surgery (MD = −12.51 min, 95% CI −36.65 to 11.63, P = 0.31). Outcomes of intraoperative and postoperative blood loss and the duration of surgery in included studies were not pooled due to the high heterogeneity.  This meta-analysis demonstrated that TXA was beneficial for bleeding in pediatric surgeries.

Naeiji et al (2021) conducted a study that the efficacy and safety of tranexamic acid in decreasing the bleeding in women undergoing elective cesarean section. 200 term singleton pregnant women who were scheduled for elective cesarean section were randomized to 2 groups and received a bolus of 1 gm tranexamic acid if body weight was <90 kg and 1.5 g if body weight was >90 kg diluted in 15 ml of 5% dextrose intravenously, or 5 ml of distilled water in 15 ml of 5% dextrose as placebo (before skin incision). Intra-operative and post-operative blood loss and hemoglobin levels were compared. Tranexamic acid decreased the mean blood loss by 25.3 % in our studied women. Mean volume of intra-operative blood loss was 391.1 (±67.4) ml in tranexamic acid group and 523.8 (±153.4) ml in control group which was statistically significant lesser with a 132.7 ml difference. Rate of >1000 ml and >500 ml bleeding and need to blood transfusion were also statistically significant lower in tranexamic acid group., mean hemoglobin level was statistically significant lower in placebo group than tranexamic acid group (11.77 ± 0.50 versus 11.31 ± 0.56) 6 h after cesarean section. No adverse reaction was documented. Prophylactic use of intravenous tranexamic acid decreases the blood loss safely in women undergoing elective cesarean section.

REFERENCES:

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2.     Adam MP, Fechner PY, Ramsdell LA, Badaru A, Grady RE, Pagon RA, et al. Ambiguous genitalia: what prenatal genetic testing is practical? Am J Med Genet A. 2012;158:1337–43

3.     Reiner D: Intracranial pressure in craniosynostosis: Pre- and postoperative recordings— correlation with functional results, Scientific Foundations and Surgical Treatment of Craniosynostosis. Edited by Persing JA, Edgerton MT, Jane JA. Baltimore, Williams & Wilkins, 1989, pp 263–9

4.     White N, Marcus R, Dover S, Solanki G, Nishikawa H, Millar C, Carver ED: Predictors of blood loss in fronto-orbital advancement and remodeling. J Craniofac Surg 2009; 20:378–81

5.     Vamvakas EC: Long-term survival rate of pediatric patients after blood transfusion. Transfusion 2008; 48:2478 – 80

6.     Czerwinski M, Hopper RA, Gruss J, Fearon JA: Major morbidity and mortality rates in craniofacial surgery: An analysis of 8101 major procedures. Plast Reconstr Surg 2010; 126:181– 6

7.     Stricker PA, Shaw TL, Desouza DG, Hernandez SV, Bartlett SP, Friedman DF, Sesok-Pizzini DA, Jobes DR: Blood loss, replacement, and associated morbidity in infants and children undergoing craniofacial surgery. Paediatr Anaesth 2010; 20:150 –9

8.     Goobie SM, Meier PM, Pereira LM, McGowan FX, Prescilla RP, Scharp LA, Rogers GF, Proctor MR, Meara JG, Soriano SG, Zurakowski D, Sethna NF. Efficacy of tranexamic acid in pediatric craniosynostosis surgery: a double-blind, placebo-controlled trial. Anesthesiology. 2011 Apr;114(4):862-71. doi: 10.1097/ALN.0b013e318210fd8f. PMID: 21364458.

9.     Gupta K, Rastogi B, Krishan A, Gupta A, Singh VP, Agarwal S. The prophylactic role of tranexamic acid to reduce blood loss during radical surgery: A prospective study. Anesth Essays Res. 2012 Jan-Jun;6(1):70-3. doi: 10.4103/0259-1162.103378. PMID: 25885506; PMCID: PMC4173437.

10. Wang Y, Liu S, He L. Prophylactic use of tranexamic acid reduces blood loss and transfusion requirements in patients undergoing cesarean section: A meta-analysis. J Obstet Gynaecol Res. 2019 Aug;45(8):1562-1575. doi: 10.1111/jog.14013. Epub 2019 Jun 25. PMID: 31237747.

11. Wei Y, Zhang Y, Jin T, Wang H, Li J, Zhang D. Effects of Tranexamic Acid on Bleeding in Pediatric Surgeries: A Systematic Review and Meta-Analysis. Front Surg. 2021 Oct 13;8:759937. doi: 10.3389/fsurg.2021.759937. PMID: 34722626; PMCID: PMC8548606.

DATA RECORD SHEET

 UHID No.:

Name:                                                Age/Sex:              

Mob. No.:

Address:                                            Height/ Weight:                        BMI:

ASA Grade I/II/III:

Tumor Size:

Duration of surgery:

Preoperative hemoglobin:

Platelet count:                                    INR:                     S. Creatinine:

TXA infusion:

Intraoperative Hemodynamic:

Total blood loss:   …..ml

Total PRBC transfused: …..ml

Urine output:  …ml/kg/hr

S. Lactate :   ….

Vasopressor requirement:  Yes/No

Surgical field quality: …..