1 Introduction
The pediatric patients undergoing cardiac surgery suffer from the high risk of bleeding and transfusion. Perioperative bleeding may lead to end-organ damage and increased complications such as hypotension, metabolic acidosis, infection, and acute respiratory distress.[1–3] [4–7] [8] [8]
Tranexamic acid (TXA), which has been increasingly used for blood conservation in cardiac surgery, is a synthetic antifibrinolytic agent acting by inhibiting tissue plasminogen and plasmin. Results from previous trials have shown that TXA can reduce blood loss and transfusion in patients undergoing cardiac surgery.[9–12] [13]
Furthermore, some biases may exist in the results mentioned above as most of the enrolled patients were White in the current studies. Especially, it has been reported that there are differences in blood coagulation function and fibrinolysis system between the Caucasian and the Asian population,[14,15] [16–18] [19–21] [19] [20] [21]
As the evidence supporting the routine use of TXA in Chinese pediatric patients undergoing cardiac surgery remains weak, we will perform a systemic review and meta-analysis in this paper to systematically evaluate the efficacy of TXA in Chinese pediatric patients undergoing cardiac surgery.
2 Methods and analysis
2.1 Search strategy
We conducted a systemic review according to the Preferred Reporting Items for Systemic Reviews and Meta-Analysis Quality of Reporting of Meta-analysis (PRIMSA) Guidelines.[22] Tranexamic Acid AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR randomly OR trial) AND (China OR Chinese) AND pediatric (Table S1, Supplemental Digital Content, https://links.lww.com/MD2/A928
2.2 Inclusion and exclusion criteria
We included all randomized controlled trials (RCTs) comparing the efficacy of TXA with controls (saline/blank) on Chinese children undergoing cardiac surgery. Primary outcomes of interest included postoperative bleeding, allogeneic transfusion, and reoperation for bleeding. Secondary outcomes of interest included postoperative recovery: mechanical ventilation duration (MVD), lengths of stay (LOS) in the intensive care unit (ICU), LOS in the hospital. Exclusion criteria include studies published as review article, case report or abstract; studies based on animal models; duplicate publications; studies lacking information about outcomes of interest. Two authors (ZYZ and YTY) independently review the titles and abstracts of all identified studies for eligibility, excluding obviously ineligible ones. The eligibility of those remaining studies for final inclusion was further determined by examining the full text.
2.3 Study quality assessment
Two authors (ZYZ and YTY) independently assessed the risk of bias by using the tool described in the Cochrane Handbook for Systematic Reviews of Interventions.[23] [24]
2.4 Data abstraction
Two authors (YTY and LXH) independently performed data extraction: author, year of publication, and journal of included studies; total number of patients, number of patients in TXA, and Control groups, gender, age; surgical procedure; data regarding outcomes of interest. Disagreements were resolved by discussion among all authors during the process of data abstraction.
2.5 Statistical analysis
All data were analyzed by utilizing RevMan 5.3 (Cochrane Collaboration, Oxford, UK). Pooled odds ratio (OR) and 95% confidence interval (CI) were estimated for dichotomous data, and weighted mean difference (WMD) and 95% CI for continuous data, respectively. Each outcome was tested for heterogeneity, and randomized-effects or fixed-effects model was used in the presence or absence of significant heterogeneity (Q -statistical test P < .05). Sensitivity analyses were done by examining the influence of statistical model on estimated treatment effects, and analyses which adopt the fixed-effects model were repeated again by using randomized-effects model and vice versa. In addition, sensitivity analysis also was performed to evaluate the influence of individual study on the overall effects. Subgroup analyses were performed to evaluate possible effects of patient characteristics and control agents on the outcomes, if necessary. Publication bias was explored through visual inspection of funnel plots of the outcomes. All P values were 2-sided, and statistical significance was defined as P < .05.
2.6 Subgroup analysis and investigation of heterogeneity
The trials were divided into 3 subgroups according to the cyanotic CHD, non-cyanotic CHD, and combined cyanotic/non-cyanotic CHD.
2.7 Ethics and dissemination
This study was a meta-analysis of previously published literatures, ethical approval was not necessary under the ethical committee of Fuwai Hospital.
3 Results
3.1 Search results
As depicted in the flowchart (Fig. 1 ), database search identified 22 articles for complete evaluation. Finally, 15[25–39] Table 1 . Of the 15 trials, 2 were performed in the Hebei province,[26,34] [29,35] [38] [35] [37] [27] [28] [30,36,39] [25,32] [31]
Figure 1: Flowchart of the included and excluded studies.
Table 1: Characteristic of tranexamic acid studies.
3.2 Included trials characteristics
As shown in Table 1 , 15[25–39] [25–32] [33–37] [38,39] [36] [39]
3.3 Risk of bias in included studies
Details regarding the performance of the studies against each domain were presented in the risk of bias graph (Fig. 2 ). Additionally, a visual summary of judgements about each methodological quality item for each included trial was shown in Fig. 3 . Of the 15 included trials, 6 trials[26,27,31,32,34,39] Table 2 .
Figure 2: Risk-of- bias graph for each included study. Green (+), red (–), and yellow(?) circles indicate low, high, and unclear risk of bias, respectively.
Figure 3: Risk-of-bias summary for each included study. Green (+), red (–), and yellow(?) circles indicate low, high, and unclear risk of bias, respectively.
Table 2 -
Quality assessment of included studies.
Jadad score
Study
Sample size
Randomization
Blindness
Withdrawals
Total
Di 2015
[28]
50
1
0
0
1
Han 2015
[27]
40
2
1
1
4
Huang 2013
[38]
682
1
0
0
1
Liu 2015(1)
[26]
100
2
1
0
3
Liu 2015(2)
[34]
100
2
1
0
3
Ma 1998
[32]
24
1
2
0
3
Qin 2015
[25]
100
0
0
0
0
Tu 2011
[35]
60
1
0
0
1
Wang 2012
[30]
80
1
0
0
1
Wang 2011
[39]
119
2
1
1
4
Wang 2012
[29]
60
1
0
0
1
Xia 2015
[33]
56
2
0
0
2
Xu 2020
[37]
30
1
0
0
1
Yue 2005
[31]
30
2
2
0
4
Zhang 2010
[36]
45
1
0
0
1
3.4 Effects on postoperative 24 hours bleeding volume
As shown in Table 1 , 7 trials[26–32] [33–37] [38,39] P = .03] with heterogeneity [I 2 = 99%, P < .00001]); in cyanotic patients ([WMD = –55.25; 95% CI: –92.58 to –17.92; P = .004] with heterogeneity [I 2 = 91%, P < .00001]) and in combined cyanotic/non-cyanotic patients ([WMD = –27.03; 95% CI: –35.64 to –18.41; P < .00001] with heterogeneity [I 2 = 0%, P = .78]) (Fig. 4 ).
Figure 4: Forest plot of postoperative 24 hours bleeding volume.
3.5 Red blood cell transfusion volume
As depicted in Table 1 , 2 trials[28,32] [33–36] [38,39] P = .01] with heterogeneity [I 2 = 91%, P = .001]); in cyanotic patients ([WMD = –142.70; 95% CI: –266.18 to –19.23; P = .02] with heterogeneity [I 2 = 96%, P < .00001]). TXA did not reduce postoperative RBC transfusion volume in combined cyanotic/non-cyanotic patients ([WMD = 18.57; 95% CI: –137.20 to 174.34; P = .82] with heterogeneity [I 2 = 99%, P < .00001]) (Fig. 5 ).
Figure 5: Forest plot of red blood cell.
3.6 Fresh frozen plasma transfusion volume
As depicted in Table 1 , 3 trials[26,28,29] [33,35,36] [39]
Meta-analysis demonstrated that postoperative FFP transfusion volume were similar between the TXA group and control group in non-cyanotic patients ([WMD = –102.23; 95% CI: –230.58–26.12; P = .12] with heterogeneity [I 2 = 99%, P < .00001]); in cyanotic patients ([WMD = –45.98; 95% CI: –149.72 to 57.76; P = .39] with heterogeneity [I 2 = 95%, P < .00001]). TXA significantly reduced postoperative FFP transfusion volume in combined cyanotic/non-cyanotic patients ([WMD = –44.48; 95% CI: –62.99 to –25.97; P < .00001] with heterogeneity [I 2 = 0%, P = .60]) (Fig. 6 ).
Figure 6: Forest plot of fresh frozen plasma transfusion volume.
3.7 Postoperative recovery
As shown in Table 1 , in non-cyanotic patients 2 trials[25,29] [25,29,30] P = .32] with heterogeneity [I 2 = 100%, P = .32]; postoperative LOS in the ICU [WMD = –0.51; 95% CI: –1.55–0.52; P = .33] with heterogeneity [I 2 = 100%, P = .32]) to control group (Fig. 7 ).
Figure 7: Forest plot of post-operative recovery.
3.8 Sensitivity analyses and publication bias
Sensitivity analysis showed that treatment effects on all the outcomes were not affected by the choice of statistical model (Table 3 ). Sensitivity tests were also performed by exclusion of some studies to analyze the influence of the overall treatment effect on high heterogeneity outcomes (Table 4 ) but no contradictory results were found. No significant publication bias was detected by funnels plot examination for postoperative 24 hours bleeding volume (Fig. 8 ).
Table 3 -
Influence of statistical model on TXA efficacy of primary outcomes.
Post-op bleeding, mL
Post-op RBC(u)
Post-op FFP, mL
MVD, h
LOS in the ICU, d
Subgroup
Statistical model
WMD (95% CI)
WMD (95% CI)
WMD (95% CI)
WMD (95% CI)
WMD (95% CI)
Cyanotic
Fixed effects
−21.30 (−24.06, −18.53)
−81.62 (−101.60, −61.65)
−165.41 (−175.55, −155.27)
–
–
Random effects
−55.04 (−103.92, −6.17)
−103.12 (−182.90, −23.34)
−102.23 (−230.58, 26.12)
–
–
Non-cyanotic
Fixed effects
−51.16 (−56.12, −46.19)
−154.31 (−178.45, −130.17)
−110.16 (−115.44, −104.87)
0.76 (−0.06, 1.57)
0.76 (−0.06, 1.57)
Random effects
−55.25 (−92.58, −17.92)
−142.70 (−266.18, −19.23)
−45.98 (−149.72, 57.76)
21.54 (−21.24, 64.31)
−0.51 (−1.55, 0.52)
Cyanotic and non- cyanotic
Fixed effects
−27.03 (−35.64, −18.41)
108.03 (97.09, 118.96)
−44.48 (−62.99, −25.97)
–
–
Random effects
−27.03 (−35.64, −18.41)
18.57 (−137.20, 174.34)
−44.48 (−62.99, −25.97)
–
–
95% CI = 95%confidence interval, d = day, FFP = fresh frozen plasma, h = hour, LOS in the ICU = lengths of stay in the intensive care unit, mL = milliliter, MVD = mechanical ventilation duration, OR = odds ratio, Post-op = postoperative, RBC = red blood cell, u = unit, WMD = weighted mean difference.
Table 4 -
Sensitivity analyses of high heterogeneity outcome.
Heterogeneity
Subgroup
Heterogeneity outcome
Excluded trials
Group TXA (n)
Group C (n)
I
2 (%)
P
Analysis model
WMD/OR
95% CI
Overall effect P
Non-cyanotic
Post-op bleeding, mL
[28,32]
165
165
99
<.00001
IV, Fixed
−21.18
(−23.95, −18.41)
<.00001
Post-op RBC (u)
[28]
24
24
81
.02
IV, Fixed
−184.99
(−264.34, −105.65)
<.00001
Post-op FFP, mL
[28]
80
80
93
.0002
IV, Fixed
−141.29
(−257.44, −25.15)
.02
Cyanotic
Post-op bleeding, mL
[36]
98
93
94
<.00001
IV, Fixed
−81.31
(−123.56, −39.07)
.0002
Post-op RBC (u)
[36]
83
78
95
<.00001
IV, Fixed
−224.85
(−382.02, −67.68)
.005
Post-op FFP, mL
[36]
58
53
92
.0004
IV, Fixed
−154.16
(−246.18, −62.14)
.001
Cyanotic and non-cyanotic
Post-op bleeding, mL
[38]
80
78
0
.8
IV, Fixed
−32.18
(−49.77, −14.60)
.0003
Post-op RBC (u)
[38]
80
78
0
.33
IV, Fixed
−50.24
(−74.15, −26.34)
<.0001
95% CI = 95% confidence interval, d = day, FFP = fresh frozen plasma, h = hours, mL = milliliter, OR = odds ratio, Post-op = postoperative, RBC = red blood cell, TXA = tranexamic acid , u = unit, WMD = weighted mean difference.
Figure 8: Funnels plot examination for postoperative 24 hours bleeding volume.
4 Discussion
To our best knowledge, this is the first meta-analysis dedicated to evaluate the efficacy of TXA for Chinese pediatric patients undergoing cardiac surgery. TXA administration can reduce the postoperative 24 hours blood loss in non-cyanotic, cyanotic, and combined cyanotic/non-cyanotic patients, the RBC transfusion in non-cyanotic and cyanotic patients, and the FFP transfusion in non-cyanotic and combined cyanotic/non-cyanotic patients. Our meta-analysis results are consistent with those studies including Asians[40–42] [40] [41] [42]
Evidence has suggested that there might be significant differences among different human races with respect to blood coagulation and fibrinolysis functions.[14,15,19–21] [43] [44]
The inconsistencies in the findings between our meta-analysis and meta-analysis mentioned above are likely caused by the difference in human races of patients. For this reason, in order to complete the objective of this review, we made a comparison with the Caucasian pediatric population to show its relevance or really if this discrepancy exists.
4.1 Comparison with the Caucasian pediatric population:
Database search identified 5 articles[45–49] [45,47,49] [46,47,49] [48,49]
Meta-analysis demonstrated that, TXA administration can reduce the postoperative 24 hours blood loss in cyanotic and combined cyanotic/non-cyanotic Caucasian pediatric patients (Figure S1, Supplemental Digital Content, https://links.lww.com/MD2/A925 https://links.lww.com/MD2/A926 https://links.lww.com/MD2/A927
The results of meta-analysis between the Caucasian and Chinese pediatric populations showing that TXA is effective in reducing the blood loss in both Caucasian and Chinese pediatric cardiac surgery but works inconsistently when it comes to the transfusion requirement.
The efficacy of TXA on postoperative RBC and FFP transfusion requirement are inconsistent between the cyanotic and combined cyanotic/non-cyanotic patients groups, which is mainly caused by the fact that: cyanotic heart disease is often characterized by a complex coagulation disorder that increases both the thrombotic and the hemorrhagic risk in children and adults who undergo cardiac surgery.[37–40] [50] [51,52] [40]
Several factors may explain the high degree of heterogeneity observed between the included studies.
(1) The guideline of applying TXA as well as the pharmacological data of TXA in pediatric cardiac surgery are not yet available.
Since the suspension of aprotinin in 2007, TXA has become the main antifibrinolytic agent for preventing blood loss in cardiac surgery.[53] [54] [55] Table 1 ). After anesthetic induction, some studies used a single bolus that ranged from 10 to 100 mg/ kg.[26,27,38] [25,28–33,35–38] [34]
(2) Allogeneic transfusion protocols inconsistent.
Most of the included studies did not describe the transfusion protocols that have been used. In the absence of this information, the efficacy of TXA is difficult to evaluate.
(3) Several of the published studies are drawn from the same team.
For this reason, we performed a sensitivity analysis to evaluate the impact on the results. The exclusion of these studies reduces the number of patients included in our analysis but did not change the overall results.
4.2 Limitations
This study has some limitations. Meta-analysis can increase the power of analysis by pooling many small low-quality studies, but different administration modalities of TXA (e.g., dose, timing), varied surgical operation types and different clinical practices, quality and heterogeneity issues of included studies may limit the certainty of the findings of meta-analysis. There were significant differences among the 15 clinical trials included in the meta-analysis with respect to sample size, study design, outcome definition, allogeneic transfusion protocols, etc; so the statistical analysis results of the current study should be explained with caution. To confirm this, more well designed and adequately-powered randomized trials are needed.
5 Conclusion
To conclude, TXA is highly effective in reducing the blood loss in Chinese pediatric cardiac surgery, but it works poorly when it comes to the transfusion requirement. To further confirm this, more well-designed and adequately-powered randomized trials are needed.
Acknowledgments
The authors were grateful to Mr Zhong-Yi Zhao for linguistic suggestion.
Author contributions
Conceptualization: Yuntai Yao.
Data curation: Zhiyao Zou, Lixian He.
Formal analysis: Zhiyao Zou, Yuntai Yao.
Investigation: Zhiyao Zou, Yuntai Yao, Lixian He.
Methodology: Zhiyao Zou, Yuntai Yao, Lixian He.
Project administration: Yuntai Yao.
Software: Zhiyao Zou, Yuntai Yao, Lixian He.
Validation: Yuntai Yao.
Writing – original draft: Zhiyao Zou, Lixian He.
Writing – review & editing: Zhiyao Zou, Yuntai Yao.
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