European Journal of Cardiovascular Medicine

Paediatric cardiac surgery patients are at high risk for bleeding, in part because of the cardiopulmonary bypass (CPB) circuits that activate coagulation, inflammatory and fibrinolytic systems.[1] Bleeding is more common in Paediatric than in adults, exposing children to all the risks associated with allogenic transfusions.[2]

The use of antifibrinolytic drugs is one of the strategies for reducing blood loss, and tranexamic acid (TXA) is among the most commonly administered, especially because the conclusions of the Blood Conservation Using Antifibrinolytics in a Randomized Trial study raised concerns about aprotinin.[3] The efficacy of TXA in paediatric cardiac surgery has been demonstrated in several trials [4] and analyses,[5] but the determination of its dosage regimen in such trials was empirical as a consequence of the absence of pharmacokinetic analysis in the paediatric population.

Even if a unique dose was sometimes administered before skin incision,[6] dosing schemes were usually based on a loading dose before incision and another dose in the CPB prime volume, in combination with a continuous infusion throughout surgery or with another bolus after coming off CPB.[7] In addition, a significant variability between practitioners may be observed for each of those doses, as already illustrated with a 10-fold factor in the total dose (i.e., dose ranging from 30–300mg/kg).Some dosing schemes have been inspired from pharmacokinetic data in adults, but the relevance of such an extrapolation may be questioned, because differences in the pharmacokinetics between adults and children undergoing cardiac surgery with CPB have already been reported.[8] Moreover, the prime volume for CPB in infants represents approximately 50–100% of their blood volume and is therefore responsible for an additional impairment of haemostasis related to dilutional effects, which may also affect the pharmacokinetics of antifibrinolytic drugs.

AIMS AND OBJECTIVES

AIMS: To determine the optimum dose of tranexamic acid (TXA) in paediatric cardiac surgery for both non-cyanotic and cyanotic heart disease.

OBJECTIVES: To determine the difference between low dosage and high dosage tranexamic acid (TXA) in relation to activated clotting time (ACT).

Sample Size: 120 Paediatric cardiac surgery patients.

Inclusion:

•              Typically, ages can range from 0-18 years, but the exact range depends on the surgery type and drug metabolism.

•              Patients undergoing open cardiac procedure for congenital heart defect repair.

•              Only Elective procedures are included.

•              Children who are at risk for significant blood loss during surgery, where TXA has a known benefit in reducing bleeding and transfusion requirements.

•              In children, the study will compare high-dose TXA (100 mg/kg) with low-dose TXA (30 mg/kg).

Exclusion:

•              Children with a known hypersensitivity or allergy to tranexamic acid or other antifibrinolytics.

•              Children with severe renal impairment (e.g., creatinine clearance below a certain threshold) where pharmacokinetics may differ, unless the dosing model specifically incorporates such cases.

•              Children with active thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism) or a history of severe thromboembolic events, since TXA may increase the risk of thrombosis in such cases.

•              Children with severe liver dysfunction, as it may affect the metabolism of TXA.

•              Children receiving other anticoagulants or fibrinolytics that may interact with TXA.

•              Exclude children with uncontrolled medical conditions like severe asthma,cardiac arrhythmias,or other life threatening conditions that could interfere with surgery or the effects of tranexamic acid.

•              Children with history of seizures & coagulopathy.

Statistical Analysis: For statistical analysis, data were initially entered into a Microsoft Excel spreadsheet and then analyzed using SPSS (version 27.0; SPSS Inc., Chicago, IL, USA) and GraphPad Prism (version 5). Two-sample t-tests, which compare the means of independent or unpaired samples, were used to assess differences between groups. For comparisons of unpaired proportions, either the chi-square test or Fisher’s exact test was used, depending on the context. To perform t-tests, the relevant formulae for test statistics, which either exactly follow or closely approximate a t-distribution under the null hypothesis, were applied, with specific degrees of freedom indicated for each test. P-values were determined from Student's t-distribution tables. A p-value ≤ 0.05 was considered statistically significant, leading to the rejection of the null hypothesis in favour of the alternative hypothesis.

Table 1: Association between Age in group and Sex: Type of dose TXA with protamine

Table 2 : Association between Diagnosis: Type of dose TXA with protamine

Table 3: Association between Thromboembolism and Seizure: Type of dose TXA with protamine

A total of 120 patients were included in the study, with 60 patients each in the high-dose TXA (100mg/kg) with protamine group and the low-dose TXA (30mg/kg) with protamine group. Among patients aged 0–5 years, 30 (50%) belonged to the high-dose group and 20 (33.3%) to the low-dose group. In the 6–10 years age group, 20 (33.3%) patients were in the high-dose group and 25 (41.6%) in the low-dose group. Among those aged 11–15 years, 10 (16.7%) were in the high-dose group and 15 (25%) in the low-dose group. The chi-square test value for age group distribution was 3.555, with a p-value of 0.169, indicating no statistically significant difference between the two groups with respect to age distribution.

In terms of gender, 16 (26.7%) females and 44 (73.3%) males were in the high-dose group, while 20 (33.3%) females and 40 (66.7%) males were in the low-dose group. The chi-square value for gender distribution was 6.349, with a p-value of 0.425, showing no statistically significant difference between the two groups in terms of sex distribution.

In the high-dose TXA with protamine group, 5 (8.3%) patients had AP window PM VSD, 5 (8.5%) complete atrioventricular (AV) canal defect, 1 (1.7%) had doubly committed VSD, 2 (3.3%) had Inlet VSD, 1 (1.7%) had partial AV canal defect, 18 (30%) had perimembranous VSD, 11 (18.3%) had Tetralogy of Fallot (TOF), 3 (5%) had TOF with absent pulmonary valve, and 12 (20%) had muscular VSD. In the low-dose TXA with protamine group, 5 (8.3%) patients had ASD, 45 (71.4%) had perimembranous VSD, 6 (10%) had subaortic VSD, 2 (3.4%) had TOF, 1 (1.7%) had VSD, and 1 (1.7%) had VSD with DCRV. The association between diagnosis and TXA dosage was statistically significant ( chi square = 99.4225, p < 0.0001. In High Dose Txa with Protamine, the mean Activated Clotting Time (Act) Before Heparin (Seconds) (mean± s.d.) of patients was 115.2333 ± 20.8260. In Low Dose Txa with Protamine, the mean Activated Clotting Time (Act) Before Heparin (Seconds) (mean± s.d.) of patients was 120.0667 ±23.4531. Distribution of mean Activated Clotting Time (Act) Before Heparin (Seconds) with Group was not statistically significant (p = 0.2344). In High Dose Txa with Protamine, the mean ACT 5 minutes after heparin (mean± s.d.) of patients were 650.3333 ±20. In Low Dose Txa with Protamine, the mean ACT 5 minutes after heparin (mean± s.d.) of patients were 858.9833 ±50. Distribution of mean ACT 5 Minutes after Heparin with Group was not statistically significant (p =0.8951).We found that mean ACT after Low Dose Txa with Protamine (133.6000± 16.7864)  is more as compared to  High Dose Txa with Protamine (92± 4.0 ) but this was statistically significant (p< 000.1).

Gertler Ret al [9] (2017) found that,a two‐compartment model was fitted, with the main covariates being allometrically scaled bodyweight, CPB, Intercompartmental clearance (Q), peripheral volume (V2), systemic clearance, (CL) and the central volume (V1) were calculated. Typical values of the PK parameter estimates were as follows: CL = 3.78 [95 % confidence interval (CI) 2.52, 5.05] l h–1; central volume of distribution = 13.6 (CI 11.7, 15.5) l; Q = 16.3 (CI 13.5, 19.2) l h–1; V2 = 18.0 (CI 16.1, 19.9) l. Independently of age, 10 mg kg–1 TXA as a bolus, a subsequent infusion of 10 mg kg–1 h–1, then a 4 mg kg−1 bolus into the prime and a reduced infusion of 4 mg kg–1 h–1 after the start of CPB are required to maintain TXA concentrations continuously above 20 μg ml–1, the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the ‘10‐10‐4‐4 rule’).

Gruber M et al [10] (2017) observed that,Independently of age, 10 mg kg–1 TXA as a bolus, a subsequent infusion of 10 mg kg–1 h–1, then a 4 mg kg−1 bolus into the prime and a reduced infusion of 4 mg kg–1 h–1 after the start of CPB are required to maintain TXA concentrations continuously above 20 μg ml–1, the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the ‘10-10-4-4 rule’).

We observed that, mean Activated Clotting Time (Act) Before Heparin (Seconds) was more in Low Dose Txa with Protamine [858.9833± 50.9609] compared to High Dose Txa with Protamine[650.3333± 20.8260] and this was  not statistically significant (p=0.2344).

Strauss ER et al [11] (2022) showed that, the authors’ institutional TXA regimen is a non weight-based, double-bolus plus infusion regimen, which was designed to target a TXA level of at least 15 µg/L and to achieve a higher TXA level at the time of heparin reversal to coordinate a higher antifibrinolytic effect, with a predictable time point during cardiac surgery when fibrin formation peaks.

We showed that, mean ACT 5 minutes after heparin was more in Low Dose Txa with Protamine [858.9833± 50.8472] compared to High Dose TXA with Protamine [650.3333± 20.8228] and this was not statistically significant (p=0.8951).

In our study, mean Act After High Dose TXA with Protamine was low (92.6167±4.61) as compared to Low Dose Txa with Protamine (133.6± 16.4) and  this was statistically significant (p<0.0001).

Taam J et al [12] (2020) showed that, Tranexamic acid reduces blood loss and transfusion requirements with no significant thrombotic adverse effects. Postoperative seizures have been seen in cardiac surgical patients in association with patient (advanced age, underlying neurologic disease, chronic kidney disease); surgical (open cardiac procedures, long bypass times); and drug (high tranexamic acid dose) risk factors.

Based on population pharmacokinetics, this study offers a useful dosage schedule for tranexamic acid (TXA) in children having heart surgery. The pharmacokinetic diversity across various paediatric age groups and weight is properly taken into account in the established dosage regimen. It guarantees the best possible therapeutic doses while lowering the possibility of side effects from both under and overdose. With its ability to be tailored to clinical practise,the program gives medical professionals a dependable ,evidence based method of administering TXA to its high risk patient group.To improve the dosage plan and validate its clinical effectiveness and safety,more validation through clinical studies will be necessary.

To conclude high dose TXA is highly effective in indian paediatric cardiac surgery patients in comparison to low dose TXA without showing any adverse effects.To further confirm this more well designed and adequately powered randomised trials are needed.

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