Effects of tranexamic acid on post partum hemorrhage due to uterine atony after cesarean section delivery: a randomized, placebo controlled trial

Jarraya Anouar | Abidi Sofiène | Dammak Abdallah | Louati Doulira | Chaabène Kaïs | Kolsi Kamel |

La tunisie chirurgicale - 2018 ; Vol 2018

Resumé

Background : The purpose of this study was to evaluate the effect of early administration of tranexamic acid (TXA) on post partum hemorrhage caused by uterine atony after cesarean section delivery.    

Methods: This was a randomised, placebo controlled trial including 74 patients. We included ASA1 parturients with correct haemostatic status undergoing cesarean section under spinal anesthesia. The randomization begins after the inefficacy of oxytocin injections and starting up sulprostone perfusion at the request of the surgeon. TXA Group received 10 mg/kg of tranexamic acid as induction dose within 12 minutes and 1mg/Kg/h as maintenance within the 2 following hours. Placebo Group received same volumes of normal saline. We compared blood loss and transfusions in both groups.     

Results: The average of bleeding was 1313 ±1432 ml in TXA group versus 2089 ± 1556 ml in placebo group (p=0.03). The number of patients needed blood transfusion was 9 in TXA group versus 23 in P group (p=0.001) and the average of erythrocyte units  transfused was 0.95 in TXA group versus 2.65 in P group. (p=0.009). In this study, we reported a significant reduction in arterial ligations: 2 in TXA group versus 9 in Placebo group (p=0.001) and only two hysterectomies in placebo group.  We have noted also no clinical or biological side effect of TXA and no deaths in both groups. 

 conclusion: TXA can safely reduce bleeding and blood transfusions in post partum hemorrhage by uterine atony after cesarean section delivery.

Mots Clés

blood loss, cesarean section, tranexamic acid, post partum hemorrhage, uterine atony, transfusions

Introduction :

Obstetric hemorrhage is the leading cause of maternal mortality worldwide [1-3].  It also causes hospital morbidity by increasing the need for transfusions and intensive care stay as well as surgical hemostasis, which can involve the gestational prognosis of women.

Uterine atony, which is the subject of this study, is one of the main causes of PPH as it complicates about 1 in 20 deliveries [4].

Tranexamic acid is an antifibrinolytic drug. It is widely used in cardiac surgery [5], orthopedics [6] and for bleeding trauma patients [7] in order to decrease bleeding and transfusions.  It was recently shown that it may decrease bleeding and maternal mortality due to postpartum hemorrhage after vaginal delivery or cesarean section according to the Woman trial [8].   

The aim of this trial is to study the effect of an early administration of TXA on blood loss and on transfusions requirement after a PPH caused by uterine atony after cesarean section delivery.                                                                                               

Article

Methods

This study is a prospective randomized, double blind, placebo controlled trial. After obtaining local research ethics committee approval and written informed patients consent, 74 parturients were enrolled in the study.

We included ASA1 parturients aged from 20 to 40 with correct preoperative haemostatic status (prothrombine ratio > 60 % and platelet rate >100 .10 3/ml), undergoing a cesarean section under spinal anesthesia complicated with uterine atony needing the introduction of Sulprostone.

Other causes of post partum hemorrhage such as   abnormal placentation , severe pre-eclampsia , coagulopathy  and uterine rupture were not included . We didn’t include also parturients with contra indications to TXA administration as past history of vascular occlusive event, convulsion, and allergy.

We excluded the accidental per operative surgical complications (bladder or colon damage).

The randomization begins after the inefficacy of oxytocin IV injections (clinical uterine atony despite maximal dose of 30 UI of oxytocine in 30 minutes) and the need of starting up Sulprostone perfusion (Nalador) at the request of the surgeon who clinically diagnose the uterine atony.

The TXA group received 10 mg/kg of TXA within 12 minutes as an induction dose followed by the maintenance dose which is 1mg/kg/h within the 2 following hours. The Placebo group received normal saline with the same volumes.  All solutions were prepared in identical 20-ml syringes (1ml=50 mg of TXA or normal saline). The anesthesiologists, operating personnel, and study staff were unaware of the treatment assignment.

After standard monitoring, the anesthetic protocol was standardized for all patients. We administered 500 ml of Ringer Lactate followed by Spinal anesthesia with 10 mg bupivacaïne and 10 µg of Fentanyl.

Patients were transfused, if needed, in per and also in post operative. The transfusion protocol was also the same for both groups .  We transfused 2 erythrocyte units when  hemoglobin concentration decreases under 7g/dl or if it decreases under 8g/dl with active hemorrhage and also if the bleeding is causing severe or not tolerated anemia.  Frozen plasma was  transfused at the dose of 20ml/kg in case of clinical haemostatic trouble , transfusion of more than 4 erythrocyte units or in case of decrease of prothrombin rate under 50 %. Platelets were transfused if platelet decreases less than 50 000 /mm3 with clinical hemorrhage or in massive transfusions at the dose of one pack for every 10 Kg of patient weight.

The main outcome of this study was the estimation of blood loss. transfusions required.  Secondary judgment criteria were: the transfusions required during 48hours after random, the rate of haemostatic surgery (arterial ligation, hysterectomy), the duration of hospitalization as well as TXA serious side effects like myocardial infarction, Stroke, deep venous thrombosis and renal failure.

We collected data about demographic parameters.  We also assessed the evolution of biological blood analysis :  Blood cell count and prothrombin  ratio were taken the day before the cesarean section (Hi), at the beginning of  our protocol (H0) , 2 hours , 6 hours , 12 hours , 24 hours , 48 hours and 3 to 5 days after delivery for both  groups. The blood loss during the first 48 hours was estimated by using Gross method [8] which seems to be more objective than graduated collectors and witch can estimate the blood loss during the 2 following days.   The total blood volume was multiplied by 1.4 due to physiological changes in pregnancy [9].

Gross‘s formula (adapted to pregnancy):   

Blood loss = 1.4 * total blood volume * weight * (Hte.i – Hte.d2) / ((Hte.i + Hte.d2)/2) + 500ml for every erythrocyte unit transfused.

Hte.i : Preoperative hematocrit   ;   Hte.d2 : 2nd  day post operative hematocrit rate. 

Total blood volume = 65 ml/kg.

The need for blood transfusions (globular sediment, fresh frozen plasma and platelet pack) was assessed during   48hours after delivery.   All patients were examined postoperatively during one month  in weekly consultations  for clinical evidence of deep venous thrombosis. We completed by echographic control every time we suspected the occurrence of veinous occlusive event.  We assessed also the evolution of creatinin levels as well as D-Dimmer at the 1st, 2nd and 5th day after the cesarean section delivery to look for biological side effects of the administration of TXA.

Demographics, laboratory variables, and blood loss were compared between TXA and placebo groups with the two-sample Student t test for mean values and the Fisher exact test for proportions. Analysis of the data was performed using the SPSS statistical program for Windows (version 12.0). All reported P values are two tailed. Continuous variables that were normally distributed are expressed as mean +/- SD. A significant difference can be concluded if p value < 0.05.

Results

We included 74 patients divided in two groups, 37 patients were enrolled in TXA group and the same in Placebo group. No patient was excluded.

The demographic characteristics were similar in the two groups (table I).

The estimation of blood loss, for the first post partum 48 hours, shows that the bleeding was reduced about 38 % from 2089 ± 1556 ml in Placebo group to 1313 ±1432  ml in TXA group. (p=0.03).

The need for blood transfusion (erythrocyte units, fresh frozen plasma and platelet pack) was reduced when using TXA. Results were noted in table II.

The decrease of hemoglobin rate and prothrombin ratio was more important in the placebo group compared with TXA group at the second and the sixth hours (table III, IV). The hematocrit evolution was similar in both groups (table V).

We noted no clinical or biological  serious side effects for TXA. The D-Dimmer and creatinin were similar in both groups (table VI, VII).  Although, the D-Dimmer rates were superior in TXA group, no significant differences were noted.

Concerning surgical hemostasis, Arterial ligation was lower in TXA group as it concerns only 2 patients in TXA group versus 9 patients in Placebo group (p=0.001). Hysterectomy was seen only in 2 cases in Placebo group versus no patient in TXA group.

The average duration of hospitalization was 4.2±1 days in Placebo group versus 3.5±0.9 in TXA group (p=0.010).

No deaths were noted in our study.

DISCUSSION:

The TXA is an anti-fibrinolytic drug that was widely used in many surgeries [5-7, 10] to reduce blood loss and transfusions. In our study, the early administration of tranexamic acid in post partum hemorrhage reduced blood loss by about 38 % in the 2 first post partum days and reduced transfusions rates as well without any increase in serious TXA side effects.

The dose and the duration of administration of TXA are controversial.  Some authors [11, 12, 13] have limited the use of TXA in the operating time and there are others [14,15,16] that prolonged administration of the drug some hours after hemorrhagic surgery. Valter Casati and al who used TXA in cardiopulmonary bypass [17] proposes to extend the administration of tranexamic acid in postoperative for cases with excessive bleeding.

By analogy, bleeding during uterine atony is large enough but for a short period of time, which prompted us to a prolonged administration of TXA for the 2 following hours. In the woman trial [8], TXA was injected at the dose of 1g that can be repeated only one time more in the 24 following hours if bleeding continues. In our study we opted for an induction dose of 10 mg / kg injected immediately after the diagnosis of uterine atony within 12 minutes followed by a maintenance dose of 1 mg / kg within the next 2 hours. This dose used has been discussed in the study of Jan C. Horrow and al [18] who have looked for the optimal minimal dose of TXA that can provide the best haemostatic effect. This study showed that the optimal minimum dose is 10 mg/kg as an induction dose and 1 mg/kg/h as a maintenance dose. In our study we have chosen the same doses. 

Several studies showed that TXA can reduce blood loss and blood transfusions in different kinds of surgeries. The Meta analysis of the Cochrane database [19] found  an average decrease of 262 ml in post operative blood loss after the use of TXA in cardiac surgery. In this analysis, the risk of being transfused is also decreased.

In orthopedic surgery, TXA have proven its efficacy in reducing blood loss and transfusions in total knee arthroplasty [11], total hip arthroplasty[20] and in scoliosis surgery[21].

In trauma patients, administering TXA to patients with clinically suspected ongoing blood loss within eight hours of trauma reduces mortality without worsening the risk of significant vascular occlusive events, blood transfusion requirements or surgical intervention at four weeks [7].

In obstetrics, several studies have shown the efficacy of TXA for reducing blood loss in cases of menorrhagia [22]. However, the use TXA is not common for post partum hemorrhage and there are few studies [23] in this context.

The study of A.S-Ducloy Bouthors and al [23] is the pioneer in using TXA in PPH after vaginal delivery. This study included 144 patients divided into two groups, the first receiving placebo and the other receiving TXA at a dose of 4 g the first hour followed by 1g/hour for the six next hours. The bleeding was reduced by 46% during the first 2 hours (p = 0.026) and 49%over the first 6 hours (p = 0.0012). The duration of bleeding was shorter with the use of TXA: 31 ± 28 versus 65± 95 minutes (P = 0.004).

Mayur Gohel and al [24] used TXA in prophylactic to reduce bleeding during cesarean section delivery.  Blood loss was quantified in two steps: the first time from the delivery to the end of cesarean section and the second time for the two following hours. This study showed that bleeding is reduced in the first time by 133 ml for placebo to 75.71 ml for the TXA (p = 0.001) and in the second time it was reduced by 469.7 ml for placebo to 372.7 ml for the TXA (p=0.003).

Ming-ying Gai [25] concluded Tranexamic acid significantly reduced the quantity of blood from the end of caesarean section to 2 h postpartum: 42.75±40.45 ml in the study group versus 73.98±77.09 ml in the control group (P=0.001). It also significantly reduced the quantity of total blood from placental delivery to 2 h postpartum: 351.57±148.20 ml in the study group, 439.36±191.48 ml in the control group (P=0.002). No complications or side effects were reported in either group.

In a recent study [26], using TXA in prophylactic before the cesarean section delivery, Ali Movafegh and al included 100  pregnant women  who were randomized to receive either 10 mg/kg of TXA or placebo intravenously 20 minutes before incision in a double-blind controlled study. The main goal of this study was to assess the effect TXA  on blood loss during and after cesarean delivery. It showed that mean blood loss was significantly less in the TXA group compared with the control group for both intraoperative bleeding (262.5±39.6 vs 404.7±94.4 mL) and postoperative bleeding (67.1±6.5 vs 141.0±33.9 mL; p=0.001), respectively. Oxytocin administration was significantly less in the tranexamic acid group compared with the control group (39±5.8 vs 43±5.4 units; P=0.001).

In our study bleeding was evaluated quantitatively by calculating the total bleeding referring to the formula of Gross. We added 500 ml for every globular unit transfused as it contains 250 ml with 60% of hematocritwitch is the double of physiological hematocrit. So, the transfusion of one globular unit may compensate 500ml of blood loss. We found a reduction of 38 % in blood loss after post partum hemorrhage by uterine atony.  These results are comparable with the studies of A-S Ducloy Bouthors and al[25] and Mayur Gohel and al[24]. This reduction in bleeding in our study was lower than the study of A-Ducloy Bouthors [23] which showed a reduction in bleeding of more than 40% in the early hours.

A lot of studies showed that TXA reduces transfusions in orthopedic [27,28,29], cardiac [13] and liver transplantation [30].

The relationship between transfusion and post partum administration of TXA is not yet well established and there are little studies in this context.

Tarek Samir [31] reported the role of TXA in avoiding transfusions in a Jehovah's Witnesses having post partum hemorrhage. 

The study of Ducloy-Bouthors and al (EXADELI study group) [23] showed that the administration of TXA reduces blood loss but this study deduced that there is no significant difference in the need for transfusions. However the total amount of red globular sediment transfused through 42 days were 28 for the TXA group versus 62 for control group (p <0.001). These results were comparable with ours.

The evolution of biological parameters showed that the decrease of hemoglobin and prothrombin was significantly higher in control group at the 2nd and the 6th hour. The hematocrit rate was similar in both groups and was influenced by erythrocytes transfusions.

In our study, The evolution of D-dimer rates was comparable between the two groups which is not the case in EXADELI study [23]. This may be due to the differnece of administred doses because  we used  less important doses comparing with those of EXADELI group study [23].

These results are comparable with those of Kazemi and al [32] who find a significant decrease of hemoglobin after total hip arthroplasty at the 6th and the 24th hour after the intervention although hematocrit rates were similar in placebo and TXA group.

Concerning side effects, we have noted no vascular occlusive event. These results are comparable with previous studies such as the meta-analysis of Zufferey [6] in orthopedics which finds no increased risk of thromboembolic events. It is the same for that of the Henry DA  analysis [19]. Neither the BART study [33] or the meta-analysis of Brown [34], both in cardiac surgery, found no increased stroke or myocardial infarction after the administration of TXA. In obstetrics, as well, Gohel Mayur reported no serious side effects. 

CONCLUSION

We concluded that TXA can safely reduce bleeding and blood transfusions as well as the duration of hospitalization.  It may also decrease arterial ligation and hysterectomy.

Table I: demographic parameters and pre operative blood analysis.

 

TXA Group

n=37

(average +/- SD)

Placebo Group

n=37

(average +/- SD)

p value

Age (years)

30.76

 ± 6.09

30.43

 ± 6.05

0.819

weight (Kg)

73.51

± 12.21

72.73

± 13.9

0.797

Size (cm)

168.19

±  6.35

167.49

±  5.09

0.599

BMI (Kg/m2)

25.75

± 3.47

25.86

± 4.43

0.907

Term  (week)

38.81

± 1.86

39.11

± 1.64

0.470

Hemoglobin rate

(g/dl)

11.21

 ± 1.05

10.88

 ± 1.20

0.223

Hematocrit (%)

33.44

± 3.12

31.92

± 5.25

0.135

Platelet (10 3/ml)

205.18

 ±67.09

187.59

±52.70

0.214

Prothrombin ratio

(%)

97.37

± 7.21

99.10

± 14.2

0.510

n: number of patients, SD: standard deviation , BMI : Body Mass Index, TXA : tranexamic acid.

 

Table II: Transfusions parameters. 

 

TXA group

Placebo group

p

Patients needed erythrocyte units

9 / 37

23/ 37

0.001

Patients needed fresh frozen plasma

5/ 37

12/ 37

0.006

Patients needed platelets pack

1/ 37

3/ 37

-

The Total of erythrocyte units transfused

35

98

0.009

The total of fresh frozen plasma transfused

50

106

0.166

The total of platelet pack transfused

28

47

-

TXA: tranexamic acid.

Table III: evolution of hemoglobin during the first 5 post partum days

Hb(g/dl)

± SD

Hb i

Hb 0

Hb 2

Hb 6

Hb 12

Hb 24

Hb 48

Hb.D5

TXA Group

11.21

±1.12

9.775

±1.61

9.27

±1.86

9.32

±1.47

9.49

±1.48

9.48

±1.40

9.51

±1.27

9.57

±1.26

Placebo Group

10.88

±1.25

9.01

±2.26

8.36

±1.87

8.81

±1.20

9.02

±1.18

9.113

±0.80

9.114

±1.29

9.52

±0.91

p

0.223

0.078

0.019

0.018

0.104

0.105

0.089

0.342

Hb : hemoglobin rate , SD ; standard deviation, TXA : tranexamic acid,

Hbi: preoperative hemoglobin

Hb0 : Hemoglobin rate at the beginning of the protocol

Hb2: Hemoglobin rate 2 hours after the beginning of the protocol

Hb6: Hemoglobin rate 6 hours after the beginning of the protocol

Hb12: Hemoglobin rate 12 hours after the beginning of the protocol

Hb24: Hemoglobin rate 24 hours after the beginning of the protocol

Hb48: Hemoglobin rate 48 hours after the beginning of the protocol

Hb.D5: Hemoglobin rate 5 days after the beginning of the protocol

 

Table IV:  the evolution of prothrombin ratio during the first 5 post partum days.

%

PR.i

PR.0

PR.2

PR.6

PR.12

PR.24

PR.48

PR.D5

TXA

Group

97.3

± 7.2

94.18

± 8.5

92.12

± 10

94.87

± 9.04

95.63

± 8.9

96.95

± 8.7

97.18

± 8.6

97.40

± 8.1

Placebo

Group

99.10

± 14.2

89.40

± 12.4

83.26

± 19

89.56

± 12.5

92.55

± 11.2

95.62

± 8.9

95.54

± 9.3

96.18

± 12

p

0.510

0.061

0.016

0.020

0.093

0.517

0.434

0.613

PR : Prothrombin ratio  , SD ; standard deviation, TXA : tranexamic acid,

PRi: preoperative Prothrombin ratio

PR0 : Prothrombin ratio at the beginning of the protocol

PR2: Prothrombin ratio 2 hours after the beginning of the protocol

PR6: Prothrombin ratio 6 hours after the beginning of the protocol

PR12: Prothrombin ratio 12 hours after the beginning of the protocol

PR24: Prothrombin ratio 24 hours after the beginning of the protocol

PR48: Prothrombin ratio 48 hours after the beginning of the protocol

PR.D5: Prothrombin ratio 5 days after the beginning of the protocol

 

Table V : the evolution of hematocrit rate (%)

Ht ± SD

Ht.i

Ht.0

Ht.2

Ht.6

Ht.12

Ht.24

Ht.48

Ht.J5

TXA Group

 

33.4

±3.12

29.64

±4.71

29.12

±3.83

29.16

±3.41

29.39

±3.35

29.41

±2.87

29.86

±2.44

30.06

±2.70

Placebo Group

 

31.92

±5.25

28.6

±4.94

27.68

±4.00

27.18

±2.48

29.08

±2.33

29.16

±2.59

29.62

±2.69

30.28

±3.72

p

0.135

0.356

0.119

0.164

0.648

0.691

0.682

0.773

Ht : hematocrit rate  , SD ; standard deviation, TXA : tranexamic acid,

Ht.i: preoperative Prothrombin ratio

Ht.0 : hematocrit rate at the beginning of the protocol

Ht.2: hematocrit rate 2 hours after the beginning of the protocol

Ht.6: hematocrit rate 6 hours after the beginning of the protocol

Ht.12: hematocrit rate 12 hours after the beginning of the protocol

Ht.24: hematocrit rate 24 hours after the beginning of the protocol

Ht.48: hematocrit rate 48 hours after the beginning of the protocol

Ht.D5: hematocrit rate 5 days after the beginning of the protocol

 

Table VI: the evolution of post operative D-Dimmer rates.

D-Dimmer rate ± SD

D-D.H24

D-D.H48

D-D.D5

TXA group

791.13

± 659

807.81

± 672

835.86

± 713

Placebo group

568.86

± 302

577.67

± 264

602.08

± 276

p

0.061

0.057

0.67

SD ; standard deviation, TXA : tranexamic acid,

D-D.H24 : D-Dimmer rate 1 day after delivery

D-D.H48 : D-Dimmer rate 2 days after delivery

D-D.D5 : D-Dimmer rate 5 days after delivery

 

Table VII: the evolution of creatinin rates during the first 5 post partum days.

Creatinin rate ±SD

Créatinin d1

(µmol/L)

Créatinin d2

(µmol/L)

Créatinin d5

(µmol/L)

TXA

72.35

± 44.2

68.31

± 22.4

66.16

± 15.9

Placebo

67.81

± 12.1

67.50

± 13.7

64.50

± 7.7

P

0.551

0.853

0.571

SD ; standard deviation, TXA : tranexamic acid,

Creatinin d1 : Creatinin rate 1 day after delivery

Creatinin d2: Creatinin rate 2 days after delivery

Creatinin d5: Creatinin rate 5 days after delivery

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