Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

McNicol,

2016

(individual study characteristics deduced from (Neilipovitz 2001;

Sethna, 2005

))

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search up to (October/2015)

A: Neilipovitz 2001

B: Sethna, 2005

Study design: RCT

Setting and Country:

A: Canada

B: USA

Source of funding:

A: Commercial: Funded by an unrestricted grant from Pharmacia Pharmaceuticals

No description of conflicts of interest

B: Support provided solely from institutional and/or departmental sources.

No description of conflicts of interest

Inclusion criteria SR: studies that evaluated participants 18 years of age or

younger who were undergoing surgery for correction of primary or secondary scoliosis.

Exclusion criteria SR: not reported

9 studies included, however, only 3 studies reported the comparison of interest. Of which 1 (En, 2014) was presented

in abstract form only, with no subsequent full publication. For this reason, this study was not included in the analysis.

Important patient characteristics at baseline:

N, mean age

A: 40 patients,

Tranexamic acid group

Entered/completing: 22/22

Age (mean, SD): 14.1 ± 2.1

Sex (male, %):

12 (55%)

Placebo group

Entered/completing: 18/18

Age (mean, SD): 13.7 ± 2.5

Sex (male, %):

5 (28%)

B: 44 patiënts,

Tranexamic acid group

Entered/completing: 23/23

Age (mean, SD): 13.6 ± 1.8

Sex (male, %):

17 (74%)

Placebo group

Entered/completing: 21/21

Age (mean, SD): 14.0 ± 2.0

Sex (male, %):

13 (62%)

Groups comparable at baseline?

A: preoperative haemoglobin, autologous donors, median levels fused, surgical duration, degree of difficulty, operative field conditions

The tranexamic acid group had a non-significantly larger proportion of participants with secondary scoliosis (P = 0.62). Participants with secondary scoliosis had a significantly

smaller body mass compared with participants with primary scoliosis (38.1 kg versus 58.4

kg; P < 0.001)

B: demographics, operative conditions, distribution of secondary scoliosis. Preoperative

laboratory variables, except PTT values, were comparable between the 2 groups. PTT

was significantly higher in the placebo group (37 ± 6 seconds) than in the tranexamic

acid group (33 ± 6 seconds) (P = 0.02), but the difference was considered not clinically relevant because mean values in both groups were within the reference range of 25 to 37

seconds

Describe intervention:

A: Loading dose given after final patient positioning. Tranexamic acid: loading dose of 10 mg/kg followed by a continuous infusion of 1 mg/kg/h until skin closure. This is considered a low-dose regimen.

Transfusion trigger was Hgb 7 g/dL or clinical symptoms of hypovolaemia

B: Loading dose given after induction of anaesthesia and before skin incision.

Tranexamic acid: loading dose of 100mg/kg (100mg/mL concentration) over 15 minutes

followed by a continuous infusion of 10 mg/kg/h until skin closure. This is considered a high-dose regimen.

Transfusion trigger was a haematocrit decrease to 25%or less, except in some participants with secondary scoliosis for whom treatment was initiated at a haematocrit of 27% to

prevent inadequate oxygenation during rapid bleeding

Describe control:

A: Placebo: nature of placebo not described. Administered as Tranexamic acid.

B: Placebo: 0.9% saline administered as Tranexamic acid

End-point of follow-up:

A: 24 hours after surgery

B: Study duration unclear - appears to be intraoperative period only

For how many participants were no complete outcome data available?

(intervention/control)

A: No missing data

B: No missing data

A: Primary outcome: amount of blood transfused in the perioperative period (up to 24

hours after surgery)

Secondary outcomes:

• Estimated intraoperative blood loss

• AEs

B: Primary outcome: estimated total blood loss intraoperatively

Secondary outcomes:

• Amount of blood transfused

• AEs

Estimated intraoperative blood loss

Effect measure: mean difference (95% CI):

A: -250.00 ( -1123.42, -623.42 )

B: -855.00 ( -1408.15, -301.85 )

Pooled effect (fixed effects model):

-681.81 (95% CI -1149.12 to -214.49) favoring Favours tranexamic acid

Heterogeneity (I²): 24%

Mean total blood transfused (mL)

Effect measure: mean difference (95% CI):

A: -531.00 ( -1032.12, -29.88 )

B: -325.00 ( -685.06, 35.06 )

Pooled effect (fixed effects model):

-395.14 (95% CI -687.55, to -102.73) favoring tranexamic acid

Heterogeneity (I²): 0.0%

Number of participants receiving blood transfusion (both allogeneic and autologous)

Effect measure: Risk Ratio (95% CI):

B: 0.85 ( 0.56, 1.30)

Thrombotic event

Data were insufficient to allow performance of meta-analysis of safety data for any AE outcome; number of participants experiencing specific AEs (i.e. renal insufficiency, hypersensitivity or thrombotic events.

Studies did not report AEs or reported zero events

Facultative:

We rated the quality of evidence for our primary outcome as low on the basis of unclear risk of bias for several domains in most studies and the small total number of participants.

Limited evidence of low to very low quality supports the

use of antifibrinolytic drugs for reducing blood loss and decreasing the risk, and volume, of transfusion in children undergoing scoliosis

surgery. Evidence is insufficient to support the use of a particular agent, although tranexamic acid may be preferred, given its widespread availability. The optimal dose regimen for any of these three agents has not been established. Although adverse events appear to occur infrequently, evidence is insufficient to confirm the safety of these agents, particularly for rare but potentially catastrophic events. No long-term safety data are available.

Faraoni, 2012

(individual study characteristics deduced from (Bulutcu, 2005; Chauhan, 2004; Chauhan, 2003; Chauhan, 2004b; Reid, 1997; Zonis, 1996; Levin, 2000; Shimizu, 2011))

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search up to: not reported. All included studies in this review were found in our own search: search up to: 05-12-2018. We did not limit searches by year of publication

A: Bulutcu, 2005;

B: Chauhan, 2004a; C: Chauhan, 2003;

D: Chauhan, 2004b E: Reid, 1997;

F: Zonis, 1996;

G: Levin, 2000;

H: Shimizu, 2011

Study design: RCT not reported if design of the RCT was parallel or cross-over

Setting and Country:

Review: Belgium, no information about setting and country of the included studies

Source of funding:

Not reported

Inclusion criteria SR:

- children under 18 years old;

- cardiac surgery;

- administration of TXA;

- randomized

controlled trial and - English language publications.

Exclusion criteria SR:

- meta-analyses, review articles and studies that used other antifibrinolytic therapy

8 studies included

Important patient characteristics at baseline:

N, mean age

A: TXA group: 25 patients, Placebo: 24 patients.

47.4 months

B: The study randomized participants over 5 different groups, 1 control group and 4 different dose TXA groups.

Total: TXA group: 120 patients, Placebo: 30 patients.

Between 43.2 and 51.0 months

C: TXA group: 96 patients, Placebo: 24 patients.

51.6 months

D: TXA group: 50 patients, Placebo: 50 patients.

49.8 months

E: TXA group: 20 patients, Placebo: 21 patients.

37.8 months

F: TXA group: 40 patients, Placebo: 42 patients.

57.7 months

G: TXA group: 28 patients, Placebo: 28 patients.

45.8 months

H: TXA group: 81 patients, Placebo: 79 patients.

32.5 months

Sex:

Not reported

Groups comparable at baseline?

Not reported

Describe intervention:

See table 2 in the review

A: 100 mg/kg bolus received at induction, 100 mg/kg bolus administered in the ECC prime and 100 mg/kg reived at the end of ECC.

Transfusion policy: Haematocrit: 30%

B: - Group B received 50 mg.kg(-1) of tranexamic acid at induction of anesthesia.

- Group C received 10 mg.kg(-1) at induction followed by an infusion of 1 mg.kg(-1).h(-1).

- Group D had 10 mg.kg(-1) at induction, 10 mg.kg(-1) on bypass, and 10 mg.kg(-1) after protamine.

- Group E had 20 mg.kg(-1) at induction and again after protamine.

Transfusion policy: Haematocrit: 33%

C: 10 mg/kg bolus received at induction, 10 mg/kg bolus administered in the ECC prime and 10 mg/kg reived at the end of ECC.

Transfusion policy: Not described

D: 10 mg/kg bolus received at induction, 10 mg/kg bolus administered in the ECC prime and 10 mg/kg reived at the end of ECC.

Transfusion policy: Not described

E: 100 mg/kg bolus received at induction, 100 mg/kg reived at the end of ECC and a continuous infusion of 10 mg/kg/h

Transfusion policy: Not described

F: 50 mg/kg bolus received at induction

Transfusion policy: Not described

G: 50 mg/kg bolus received at induction

Transfusion policy: Not described

H: 50 mg/kg bolus received at induction and a continuous infusion of 15 mg/kg/h

Transfusion policy: Haemoglobin level: 12–15

Describe control:

No information about placebo is given

End-point of follow-up:

Only reported for transfusion of blood products at 24h and Postoperative blood losses (ml kg −1) at 24

For how many participants were no complete outcome data available?

(intervention/control)

Not reported

Outcome measure-1

Differences in blood loss (ml kg −1 ) at 24 h after surgery for TXA versus placebo.

Postoperative blood losses (ml kg −1) at 24 h were heteroge-

neously distributed (I 2 =82%, P< 0.0001), precluding further analysis (Fig. 2).

Outcome measure-2

RBC transfusion expressed in ml kg −1 day −1 for TXA versus placebo.

TXA reduced the need for RBC transfusion (Fig. 3A) by 6.4 ml kg −1 day −1 (I 2 = 0%, P= 0.45)

Outcome measure-3

PLT transfusion transfusion expressed in ml kg −1 day −1 for TXA versus placebo.

TXA reduced the need for PLT transfusion (Fig. 3B)

by 3.7 ml kg −1 day −1 (I 2 =0%, P=0.46)

Outcome measure-4

FFP transfusion expressed in ml kg −1 day −1 for TXA versus placebo.

TXA reduced the need for FFP transfusion (Fig. 3C) by 5.4 ml kg −1 day −1 (I 2 = 0%, P=0.53)

Facultative:

Most data were heterogeneously distributed and could not be analysed. Further, transfusion policies were not well defined for each study. There was marked variability in the dosage and infusion schemes used in different studies

This analysis can be biased by two factors. First, four included studies were published by the same team. Second, one of the studies evolved different TXA schemes compared with a same control group and each TXA scheme was considered as a single study in the meta-analysis. We therefore performed a sensitivity analysis to take into account these possible biases

(Table 4). This sensitivity analysis did not change the results of our first statistical analysis except for blood losses that were significantly reduced by TXA (−5.22 ml kg −1 ; 95% CI: −8.16 to −2.28)

when the studies of Chauhan et al. were excluded (10–12).

In conclusion, the present systematic review shows that TXA reduces blood transfusion requirements significantly in paediatric cardiac surgery although the clinical relevance of these results is not clear. As data on postoperative morbidity and mortality and on TXA-related side effects could not be evaluated in

the available studies, we conclude that the evidence for the routine use of TXA in paediatric cardiac surgery remains weak. Further studies are needed to assess the potential beneficial

effects of TXA on postoperative outcomes and to define the optimal dosage scheme for TXA.

White,

2015

(individual study characteristics deduced from (Duran, 2003; Dadure, 2011; Goobie, 2011

))

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs and case-control studies

Literature search up to: Cochrane library: 12/2012

Medline (via OVID): 1946 to June Week 3 2012. Embase 1974 to 2012 Week 26.

A: Duran, 2003

B: Dadure, 2011

C: Goobie, 2011

Study design: RCT (parallel / cross-over: not reported)

Setting and Country:

Tertiary children’s hospitals. Only countries of economic studies were reported.
B: France

Source of funding:

Not reported

Inclusion criteria SR:

- We considered all comparative studies with a treatment group

and a control group. There was a range of different study types from RCTs to case series with historic controls. These were intervention

versus no intervention or a comparison of 2 different interventions.

- one of the following primary outcome measures had to be reported: allogeneic and autologous blood transfusion measured in donor exposures or milliliters or a postoperative hemoglobin (Hb)

or hematocrit (Hct) level.

Exclusion criteria SR:

Not reported

Aim: The aim of this study was to systematically review the clinical effectiveness and the cost-effectiveness of interventions to reduce blood

transfusions in children undergoing surgery for craniosynostosis.

18 studies included, however, only 3 studies reported the comparison of interest (Duran, 2003; Dadure, 2011; Goobie, 2011).

Important patient characteristics at baseline:

Study size:

A: I (TXA) = 10

C (no intervention) = 10

B: I (TXA + EPO) = 19

C (EPO) = 20

C: I (TXA) = 23

C (no intervention) = 20

Groups comparable at baseline?

Yes: study A and B

No: study C

Describe intervention:

A: TXA (no additional information was given in the review, but is retrieved from the abstract)

15 mg/kg of intravenous TA upon anesthetic induction, every 4 hours during surgery, and every 8 hours throughout the 48 hours after surgery

B: TXA + EPO (no additional information was given)

C: TXA (no additional information was given in the review, but is retrieved from the abstract)

loading dose of 50 mg·kg(-1), followed by an infusion of 5 mg·kg·h(-1) during surgery.

Describe control:

A: No intervention (no information about placebo is given)

B: EPO (no additional information was given)

C: No intervention (no information about placebo is given)

End-point of follow-up:

Not reported

For how many participants were no complete outcome data available?

(intervention/control)

Not reported

volume of allogeneic blood transfused

Defined as: not described

Effect measure: mean difference (95% CI):

A: -73 (-194.07, 48.07)

B: -75 (138.46, -11.54)

C: -279.00 (-468.18, -89.82)

Pooled effect (random effects model):

-111.61 (95% CI -207.13 to -16.10) favoring TXA

Heterogeneity (I²): 51%

Effect measure: standard mean difference (95% CI):

A: -0.51 (-1.40, 0.39)

B: -0.72 (-1.37, -0.07)

C: -0.92 (-1.55, -0.28)

Pooled effect (random effects model):

-0.76 (95% CI -1.16 to -0.53) favoring nor TXA or control

Heterogeneity (I²): 0%

Facultative:

The overall quality for the studies is low. In the RCTs, there was no intention-to-treat analysis. The method of randomization was not always described, and the nature of the blinding (assessor/patient/intervention) was not always clear. The RCTs are at risk for bias because of these factors. Only 1 study that was included showed a negative result; all the other studies presented positive results. The failure to publish negative results may be an additional source of bias to this systematic review.

Because there is considerable variation in the volume of blood transfused between the 3 studies. In Dadure et al 41 2011, there was a mean of 221 mL across the entire study; in Duran 51 2003, a mean of 82 mL; and in Goobie et al 42 2011, a mean of 506 mL. The use of the mean difference is more accurate because of the small number of studies and the variation between the outcome measure used. Tranexamic acid is clinically effective

in reducing allogeneic blood transfusion.

Some studies presented data for only perioperative transfusion, and some presented data for only postoperative transfusions. Where possible in the data extraction, all transfusions were combined to give a total volume transfused for the patient episode.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Brum,

2012

Type of study:

Randomized, double-blind clinical trial

Setting:

pediatric otolaryngology office of Hospital da Crianc¸a Santo

Antoˆnio of the Complexo Hospitalar Santa Casa de Porto Alegre, RS

Country:

Brazil

Source of funding:

Not reported

Inclusion criteria:

Patients of both sexes, between 4 and 12 years, with indication of adenotonsillectomy due to adenotonsillar hyperplasia and

obstructive symptoms of the upper airways

Exclusion criteria:

previously

diagnosed blood dyscrasia, abnormal coagulation screening,

history of bleeding disorder or spontaneous hematomas, or

evidence of other clinically significant disease

N total at baseline:

Intervention: 47

Control: 48

Important prognostic factors²:

age ± SD:

I: 6.43 (2.23)

C: 7.33 (2.66)

Sex:

I: 55.3% M

C: 62.5% M

weight ± SD:

I: 26.52 (11.36)

C: 32.34 (15.87)

Groups comparable at baseline?

There was no difference between sex of the children in the groups, but despite randomization, the weight and age were lower in the group treated with tranexamic acid (P = 0.07 and 0.04,

respectively)

Describe intervention (treatment/procedure/test):

On the day of surgery, the hospital’s industrial

Pharmacy provided the corresponding dose and volume (calculated based on child’s weight). Three syringes were delivered to the team immediately before the procedure, containing tranexamic acid or normal saline, according to the treatment randomly

allocated for the patient. To maintain the sterility of the solution, the syringes were prepared in a laminar flow hood, and they were refrigerated to maintain stability. In the anesthetic induction room, intravenous tranexamic acid 10 mg/kg was administered. The anesthetic procedure was according to the standardized guidelines, so all patients received the same anesthetic medications. Non-steroidal anti-inflammatory drugs

were avoided. Adenotonsillectomy was performed by eight

otorhinolaryngologists of the service, using the cold technique, without utilization of electrocautery. Hemostasis was by com-

pression with moist gauze in the rhinopharynx and suturing with absorbable sutures in the tonsillar fossa. Eight and 16 h after the first application, the child received a new dose of intravenous tranexamic acid 10 mg/kg

Describe control (treatment/procedure/test):

On the day of surgery, the hospital’s industrial

Pharmacy provided the corresponding dose and volume (calculated based on child’s weight). Three syringes were delivered to the team immediately before the procedure, containing tranexamic acid or normal saline, according to the treatment randomly

allocated for the patient. To maintain the sterility of the solution, the syringes were prepared in a laminar flow hood, and they were refrigerated to maintain stability. In the anesthetic induction room, intravenous placebo 10 mg/kg was administered. The anesthetic procedure was according to the standardized guidelines, so all patients received the same anesthetic medications. Non-steroidal anti-inflammatory drugs

were avoided. Adenotonsillectomy was performed by eight

otorhinolaryngologists of the service, using the cold technique, without utilization of electrocautery. Hemostasis was by com-

pression with moist gauze in the rhinopharynx and suturing with absorbable sutures in the tonsillar fossa. Eight and 16 h after the first application, the child received a new dose of intravenous placebo 10 mg/kg

Length of follow-up:

10 days

Loss-to-follow-up:

Intervention:

N (%) = 1 (2,2%)

Reasons (describe)

No transport from countryside to city

Control:

N (%) = 0

Incomplete outcome data:

Intervention:

N (%) = 8 (17%)

Reasons (describe):

Since two surgeons initially involved in the study could not complete their randomization blocks and because 12 patients did not receive the second and third doses of the treatment for which they were allocated

Control:

N (%) = 9 (18,6%)

Reasons (describe)

Since two surgeons initially involved in the study could not complete their randomization blocks and because 12 patients did not receive the second and third doses of the treatment for which they were allocated

Outcome measures and effect size (include 95%CI and p-value if available):

primary outcome: intraoperative bleeding volume.

measured in: milliliters (mL) in the contents of the aspiration flask. The volume of physiological solution for cleaning the surgical bed was systematically controlled, recording the volume utilized and subtracted from the total volume of the aspiration flask

There was no statistically significant reduction in absolute (mL) bleeding volume with the use of tranexamic acid mean ± standard deviation, 135.13 ± 71.44 (tranexamic acid) versus 158.21 ± 88.09 (placebo); P = 0.195 and relative (mL/kg) intraoperative bleeding (mL/kg):

mean ± standard deviation, 5.84 ± 3.4 (tranexamic acid) versus 5.23 ± 3.29 (placebo); P = 0.381

Secondary outcome:

There were no cases of secondary postoperative bleeding (clinical significant

bleeding with the need of hospital readmission, blood transfusion or surgical reintervention).

There was no difference between sex of the children in the groups, but despite randomization, the weight and age were lower in the group treated with tranexamic acid (P = 0.07 and 0.04, respectively). A significant difference in the volume of bleeding was observed between children of 4–6 years (127,55 mL) and of 10–12 years (178,24 mL) (P = 0.03). Despite this difference, linear

regression analysis including weight, age and treatment did not showed significant difference of bleeding between groups (Table 3).

No difference was observed in the incidence of postoperative bleeding in the 10 postoperative days, but the sample size is insufficient to exclude a type 2 error.

Santosh, 2016

Type of study:

RCT

Setting:

Chigateri district hospital and Bapuji teaching hospital attached to JJM Medical College, Davangere

Country:

India

Source of funding:

No source of funding

Inclusion criteria:

All patients of chronic tonsillitis satisfying ‘’PARADISE CRITERIA’’ for tonsillectomy

Exclusion criteria:

- patients undergoing adenotonsillectomy

- known allergy to tranexamic acid drug

- preoperative use of anticoagulant therapy within 5 days of surgery

- Fibrinolytic disorders requiring intraoperative antifibrinolytic treatment

- hematological diseases (thromboembolic events, coagulopathy, and hemolytic disease).

N total at baseline:

Intervention: 25

Control: 25

Important prognostic factors²:

For example

age ± SD:

I:

C:

Sex:

I: % M

C: % M

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Preoperative intravenous tranexamic acid of doses 10 mg/kg/BW, 3 to 4 hours before surgery. Tonsillectomy was performed under general anesthesia with dissection and snare method. The same surgeon operated on all 50 patients.

Describe control (treatment/procedure/test):

Patients did not receive tranexamic acid. Additional information was not given.

Length of follow-up:

Not described

Loss-to-follow-up:

Intervention: 0

Control: 0

Incomplete outcome data:

Intervention: 0

Control: 0

Outcome measures and effect size (include 95%CI and p-value if available):

Blood loss was calculated by gravimetric method and by measuring the blood collection in the suction jar. For measuring blood in the suction jar, the fluid in the suction jar was poured into a measuring cylinder. The lower edge of the fluid meniscus after the foam had settled was considered for the readings…. Gauze pieces and the swabs to be used for the surgery were weighed before keeping on the surgery tray under strict aseptic precautions. Postsurgery all soiled gauze pieces and swabs were weighed again and the difference was taken as the amount of bleeding with conversion of 1 m = mL of blood.

Mean blood loss tranexamic acid: 66,12 ± 40,95 mL

Control: 106,84 ± 64,72 mL

 (p < 0,01)

Twijfel over Kwaliteit studie, geen titels bij tabellen en figuren lijkt niet de definitieve versie.

Betekenis BW is onduidelijk

Soliman, 2015

Type of study:

RCT

Setting:

King Fahad military hospital, Khamis Mushait

Country:

Saudi Arabia

Source of funding:

There is no fund from persons or company.

Inclusion criteria:

Children (ASA physical status I–II) undergoing elective tonsillectomy

without adenoidectomy. The indications of tonsillectomy were

recurrent acute tonsillitis.

Exclusion criteria:

patients with liver or kidney

dysfunction or patients with inherited coagulopathy or preoperative use of anticoagulant therapy or abnormal coagulation

profiles or allergy to tranexamic acid or neurologic or psychiatric disease.

N total at baseline:

Intervention A: 75

Intervention B: 75

Control: 75

Important prognostic factors²:

Age (year) ± SD:

I - A: 7.14 ± 2.35

I – B: 7.00 ± 2.32

C: 7.10 ± 2.45

Sex:

I -A: 48% M

I -B: 53% M

C: 54% M

Weight (kg) ± SD:

I - A: 17.05 ± 3.92

I – B: 17.00 ± 3.84

C: 16.96 ± 3.97

Groups comparable at baseline?

Yes, there were no significant differences regarding the demographic data,

heart rate, mean arterial blood pressure, temperature and

duration of surgery (p > 0.05) (Table 2).

Describe intervention (treatment/procedure/test):

Group A: The tranexamic acid was given after induction intravenously as 15 mg/kg (single bolus dose) over 10 min.

Group B: The tranexamic acid was given after induction intravenously as 15 mg/kg over 10 min and continued infusion as 5 mg/kg/h during surgery.

The most common extracapsular techniques use a ‘‘cold’’ knife (sharp dissection), bipolar cautery (or bipolar scissors). Extracapsular techniques are used for patients under-

going tonsillectomy as a result of tonsillitis or peritonsillar abscess (7). In the present study, extracapsular technique is

used for all cases.

Describe control (treatment/procedure/test):

Patients did not receive tranexamic acid. Additional information was not given.

Length of follow-up:

Intraoperatively bleeding is reported

Loss-to-follow-up:

Intervention:

N (%) = 0

Control:

N (%) = 0

Incomplete outcome data:

Intervention:

N (%) = 0

Control:

N (%) = 0

Outcome measures and effect size (include 95%CI and p-value if available):

Blood loss (ml)

Defined as: For measuring blood in the suction jar, the fluid in the suction jar was poured into a measuring cylinder and the quantity of

fluid present before the surgery was subtracted. The lower edge of the fluid meniscus after the foam had settled, was considered for the readings, also by visual estimation of 4 x 4 gauze pads,

if mildly moist from 8 ml, moderately moist from 10 ml and completely moist from 12 ml blood (9–11)

The comparison of blood loss between the three groups is

insignificant and the mean was 46.56 ± 5.92 in Group A

patients, 47.07 ± 5.96 in Group B patients and 47.17 ± 5.36

in Group C patients (p = 0.691).

There are limitations to the present study. First, small study populations of the present study, and second the fibrinolytic activity during tonsillectomy were not measured as the kits for measurement were not available in the laboratory. Furthermore, no information about the randomization procedure is described. No losses to follow-up reported.

Conclusion

The present study showed no effect of tranexamic acid in

decreasing the tonsillectomy-related bleeding and there is no complication related to tranexamic acid. Other studies are recommended to measure the fibrinolytic activity during tonsillectomy and its inhibition by tranexamic acid.

Arantes, 2017

Type of study:

parallel-group, double-blind, randomized clinical trial

Setting:

Facial Defects Awareness Center of the Professor Fernando Figueira

Integral Medicine Institute (CADEFI), Recife

Country:

Brazil

Source of funding:

The study was financed by the Facial Defects Awareness Center of the Professor Fernando Figueira Integral Medicine Institute (CADEFI), which is the workplace of the principal investigator of this study. CADEFI is supported by

public funds from the Brazilian Unified Health System (Sistema Único de Saúde e SUS). The authors did not receive financial sup-

port to participate in this study.

None of the authors have financial interest in this research or a commercial

relation with the pharmaceutical company that produces and distributes the drug used in the study

Inclusion criteria:

All patients who underwent palatoplasty at our institution

during the study period were included

Exclusion criteria:

patients with a platelet count lower than 100,000/mm³, with known or suspected coagu-

lation disorders, family history of coagulopathy, or indication of

secondary palatoplasty for the correction of oronasal fistula

N total at baseline:

Intervention: 35

Control: 35

Important prognostic factors²:

Age (n + %):

Intervention:

<2 years: 18 (54,5)

≥2 years and <5 years: 6 (18.2)

≥5 years and <10 years: 5 (15.1)

≥10 years and <18 years 3 (9.1)

≥18 years 1 (3.0)

Control:

<2 years: 18 (54.5)

≥2 years and <5 years: 7 (21.1)

≥5 years and <10 years: 9 (9.1)

≥10 years and <18 years 4 (12.1)

≥18 years 1 (3.0)

Sex:

I: 57.6% M

C: 48.5% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

20 mL/kg/h for 15 min (10 mg/kg), followed

by 0.5 mL/kg/h (1 mg/kg/h) until the end of surgery.

Palatoplasties were performed by one of the six plastic surgeons working at the department.

The surgical technique followed the service protocols and was not standardized. Almost all surgeons, except one, used the VonLangenbeck technique.

Describe control (treatment/procedure/test):

Control group received a placebo of 10 mL saline

Length of follow-up:

patients were reassessed at the clinic between the 4th and 7th postoperative days and 1 month after surgery to assess for the presence of an oronasal fistula.

Loss-to-follow-up:

Intervention:

N (%) = 3 (8.6)

Reasons (describe):

- Anesthetic complication at the beginning of surgery

- Surgery suspended due to clinical complications

- did not return after surgery

Control:

N (%) = 4 (11.4)

Reasons (describe)

- Surgery suspended due to clinical complications (n=2)

- did not return after surgery (n=2)

Incomplete outcome data:

Intervention:

N (%) = 2

Reasons (describe)

- Anesthetic complication at the beginning of surgery

- Surgery suspended due to clinical complications

Control: 2

N (%)

Reasons (describe)

- Surgery suspended due to clinical complications (n=2)

Outcome measures and effect size (include 95%CI and p-value if available):

Intraoperative blood loss

Defined as: during surgery, an aspiration system with an intermediate container, graduated in milliliters (mL), was used to measure the

aspirated volume. Gauzes used to dry the surgical field were

stored, counted, and weighed. Intraoperative bleeding was calculated by adding the volume of the aspirated blood to the volume contained in the gauzes. Aspirated blood volume was calculated as the difference between the volume of blood present in the container at the end of the surgery and the volume of the

liquid instilled on the surgical field. The volume of the blood in the gauzes was estimated by weighing the used gauzes and subtracting their dry weight. Once the procedures were performed in cephalic hyperextension, blood was not swallowed and there were

no losses in this way. All patients were weighed at admission, and an estimate of the total blood volume was calculated using the parameter 70 mL/kg (Barcelona et al., 2005). Bleeding in each patient was assessed by the ratio between the intraoperative bleeding volume and the

estimated total blood volume of the patient.

The mean intraoperative bleeding was 2.75% (SD = 1.92%) of the estimated total blood volume for the control group and 2.42% (SD = 1.77%) of the estimated total blood volume for the intervention group, corresponding to a 0.33% absolute reduction (95%

CI = -0.58% to 1.24%); a relative reduction a relative reduction of 11.9% was observed, without statistical significance (Table 2).

The occurrence of significant hemorrhagic events

defined as the need to use blood products, the need to redo surgery, or the need to

use antifibrinolytic drugs during the postoperative period to control excessive bleeding, was recorded.

None of the patients required the use of blood products or

reoperation due to hemorrhagic complications. Only one patient from the control group needed antifibrinolytic drugs during the postoperative period to treat bleeding at the surgical site.

This randomized clinical trial assessed the effectiveness of tranexamic acid in the reduction of intraoperative bleeding in palatoplasties.

The reduction was lower than expected and was not

statistically significant. A larger sample size would be required to confirm the difference, but, given the magnitude of the clinical effect observed, the execution of such a study may not be justified

Kim, 2018

Type of study:

prospective, randomized,

double-blind, placebo-controlled study

Setting:

Severance Hospital

of the Yonsei University Health System

Country:

South-Korea

Source of funding:

Severance Hospital

of the Yonsei University Health System

Inclusion criteria:

Children who were scheduled for distraction osteogenesis for

craniosynostosis

Exclusion criteria:

- platelet count (PLT), < 50 × 103/μL;

- prothrombin time (PT) or activated partial thromboplastin time (aPTT) > 1.5

times the reference value;

- history of convulsive seizure, epilepsy, or brain surgery;

- treatment with a

non-steroidal anti-inflammatory agent within the

previous 2 days;

- treatment with aspirin within 14

days prior to surgery;

- known allergy to TXA.

N total at baseline:

Intervention: 25

Control: 25

Important prognostic factors²:

Mean age (interquartile range):

I: 12 (7-22)

C: 14 (8-30)

Sex:

I: 61% M

C: 40% M

Groups comparable at baseline?

Yes

Describe intervention (treatment/procedure/test):

TXA was administered as an

intravenous loading dose of 10 mg/kg over 15 min,

followed by continuous intravenous infusion at 5

mg/kg/h from the beginning of the surgery until skin

closure

Describe control (treatment/procedure/test):

Normal saline was similarly administered throughout the surgery

Length of follow-up:

3 months after surgery

Loss-to-follow-up:

Intervention:

N (%) 2 (8%)

Reasons (describe)

Two patients in the TXA group were excluded from the analysis because of an error in the ROTEMTM analysis

Control:

N (%) 0

Incomplete outcome data:

Intervention:

N (%) 2 (8%)

Reasons:

Two patients in the TXA group were excluded from the analysis because of an error in the ROTEMTM analysis

Control:

N (%) 0

Outcome measures and effect size (include 95%CI and p-value if available):

Intraoperative blood loss:

Intraoperative blood loss was significantly lower

in the TXA group than it was in the control group (80.6 ± 33.3 115.6 ± 43.6 mL/kg; P = 0.003).

Blood transfusion

packed RBC

I: 48.8 ± 16.8 mL/kg

C: 65.2 ± 24.2 mL/kg

P = 0.010;

fresh frozen plasma (FFP)

i: 19.4 ± 13.0

c: 28.1 ± 15.1 mL/kg,

P = 0.038).

Platelet concentrate

I: 5.9 (0-12.9)

C: 10 (2.1-16.9)

P = 0.217

Length of stay

The total lengths of postoperative stay in the

the hospital were comparable between the two groups (Table 3).

I: 10.1 ± 3.6 days

C: 10.9 ± 5.1 days

Mean difference: 0.8 (-3.4 to 1.8) p = 0.542

Thromboembolic event

i: 0

c: 0

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

McNicol, 2016

Yes, objectives:

To assess the efficacy and safety of aprotinin, tranexamic acid and aminocaproic acid in reducing blood loss and transfusion requirements

in children undergoing surgery for correction of idiopathic or secondary scoliosis.

Yes

yes

yes

Not applicable

Yes, GRADE approach to assess the overall quality of the evidence

yes

Yes, publication bias could not be assessed because there were fewer than 10 included studies

Not reported for the systematic review

Faraoni, 2012

Yes, we therefore performed a systematic review with meta-analysis to evaluate the available literature on the efficacy of TXA compared with placebo in reducing blood loss and allogeneic blood transfusion exposure in children undergoing cardiac surgery.

Yes, however, date of search was not reported

Yes

Yes, however, patient characteristics for different intervention and control group were not reported

Not applicable

Yes, the systematic review quality checklist was used. For each study included, it reports the level of evidence and grades of recommendations.

Yes, furthermore a sensitivity analysis was performed to take into account the following aspects: four included studies were published by the same team. Second, one of the studies evolved different TXA schemes compared with a

same control group and each TXA scheme was considered as a

single study in the meta-analysis. We therefore performed a sensitivity analysis to take into account these possible biases. In addition to this, these studies applied low TXA doses compared to the other included studies.

Yes, publication bias could not be assessed because there were fewer than 10 included studies

Not reported for the individual studies

White, 2015

Yes, aim: to systematically review the clinical effectiveness and the cost-effectiveness of interventions to reduce blood transfusions in children undergoing surgery for craniosynostosis.

Yes

Yes

Yes, however, information is very scarce

Not applicable

Yes, risk of bias table

Yes

Yes, publication bias could not be assessed because there were fewer than 10 included studies

Not reported for the individual studies

Study reference

(first author, publication year)

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Brum, 2012

Study used randomized blocks. Prior to the beginning of the

study, an independent investigator established randomized blocks of four patients: 2 of the placebo group and 2 of the intervention group. These were distributed randomly within the block. Positions within the blocks were given increasing numbers, and this number identified a sealed opaque envelope containing treatment group. Each surgeon received his/her randomized blocks. The 4 patients of the same block were operated by the same surgeon. At the time of surgery, the team contacted the pharmacy of the hospital, providing the patient’s information and the name of the surgeon. The pharmacist in charge opened the corresponding envelope, which contained the type of treatment (saline or tranexamic acid) and of sent the recipients for the study. Treatment was kept blind, revealed only after the completion of the study.

Blinding was kept in a manner in which the surgeon, the main

investigator, and patient/family had no knowledge of who was

receiving the intervention or placebo. Placebo was normal saline maintaining the identical volume, coloration, texture and vial as tranexamic acid, and it was prepared in the hospital pharmacy.

Unlikely

Unlikely

Unlikely

Unlikely

Unlikely, authors reported all outcomes that were reported at https://clinicaltrials.gov/ were described

Unlikely, loss to follow up doesn’t differ between groups. Reasons are also reported

Unlikely, ITT analysis performed

Santosh, 2016

Not described

Unclear, method of randomization is not described

Unclear if patients, care providers or outcome assessors were blinded

Unclear if patients, care providers or outcome assessors were blinded

Unclear if patients, care providers or outcome assessors were blinded

Unlikely, trial not registered at clinicaltrial.gov. However, all outcomes listed in the methods section were reported in the results section

Unlikely, no losses to follow-up

Unlikely, participants included in the analysis are exactly those who were randomized into the trial.

Soliman, 2015

Not described

Unclear, method of randomization is not described

Unclear if patients, care providers or outcome assessors were blinded

Unclear if patients, care providers or outcome assessors were blinded

Unclear if patients, care providers or outcome assessors were blinded

Unlikely, trial not registered at clinicaltrial.gov. However, all outcomes listed in the methods section were reported in the results section

Unlikely, no losses to follow-up

Unlikely, participants included in the analysis are exactly those who were randomized into the trial.

Arantes, 2017

Randomization was performed after inclusion of the patients in

the study by an independent physician, and numbered packages were distributed to the two groups by an author using RAS ® (RandomAllocation Software 1.0, Mahmood Saghaei, Isfahan University of Medical Sciences, Isfahan, Iran). Packages were used sequentially, and each patient had the same probability of being allocated to the control group as to the intervention group. During surgery, the anesthesia care team received a package that could contain drug or placebo.

Palatoplasties were performed by one of the six plastic surgeons

working at the department. The authors did not participate in the

surgical procedures.

Unlikely

Unlikely

Unlikely, the surgical team received a previously diluted solution for infusion, which could contain saline (240 mL) with 10 mL Transamin ® (50 mg/mL tranexamic acid, Zydus Nikkho Farmaceutica Ltda, RJ, Brazil) or 10 mL saline. Because the drug is colorless,

whether the package had the drug or not was not possible to determine by observation

Unlikely

Unlikely, authors reported all outcomes that were reported at clinicaltrials.gov were described

Unlikely, loss to follow up doesn’t differ between groups. Reasons are also reported

Unlikely, ITT analysis performed

Kim, 2018

Patients were evenly assigned to two groups (TXA or control) using computer-generated randomized

tables. The group allocations were noted in sequentially numbered, sealed, and opaque

envelopes.

Unlikely

Unlikely, a research assistant who was not a study investigator opened the envelopes and prepared the infusions according to the group allocations. Besides the designated research assistant who prepared the study drugs, all study participants and care providers were blinded to the randomization.

Unlikely

Unlikely

Unlikely, authors reported all outcomes that were reported at clinicaltrials.gov were described. More outcomes were reported than were described at clinicaltrials.gov, however these were both statistically and not statistically significant outcomes.

Unlikely, 2/25 patients of the intervention group were lost to follow up because of an error in the ROTEM^TM analysis.

Unlikely