Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 8  |  Issue : 1  |  Page : 36-42

Can topical administration of tranexamic acid be a good adjuvant to the intravenous route for decreasing postoperative seizure incidence? A double blinded randomized study


1 Department of Anesthesia and Surgical Intensive Care, Mansoura University Hospital, Mansoura, Egypt
2 Cardiothoracic Surgery Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt

Date of Submission08-Jul-2014
Date of Acceptance22-Nov-2014
Date of Web Publication25-Mar-2015

Correspondence Address:
Hani I Taman
Anesthesia and Surgical Intensive Care Unit, Faculty of Medicine, Mansoura University, 53111 Mansoura
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-7934.153936

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  Abstract 

Background
Antifibrinolytic therapy has become a mainstay in complex cardiac surgical procedures for decreasing bleeding and minimizing transfusion requirements. Tranexamic acid (TA) is an antifibrinolytic agent that can be used both systemically and topically. Current studies and case series reports mention an increased incidence of seizures after administration of high doses of TA (60-260 mg/kg body weight). Thus, we hypothesize that adding a topical dose of TA to a small dose intravenously could reduce postoperative bleeding in patients who have undergone cardiac surgery with subsequent decrease in the overall complications associated with this drug, mainly seizures.
Materials and methods
A total of 120 patients were randomly allocated to two groups, the intravenous TA group (group I) and the topical and intravenous TA group (group II), with 60 patients in each. Every patient in group I received an initial bolus dose of TA consisting of a bolus of 50 mg/kg body weight at the beginning and at the end of cardiopulmonary bypass (CPB), and 100 mg/100 ml priming volume was added to the priming fluid of the CPB system. In group II every patient received an initial bolus dose of TA at 30 mg/kg infused over 15 min followed by a 16 mg/kg/h infusion until chest closure with a 2 mg/kg load within the pump prime; in addition, before sternotomy closure, patients received another 2 g of TA diluted in 500 ml of warm saline (37°C), which was poured into the pericardial cavity.
Results
Hemoglobin concentration, hematocrit value, platelet count, international normalized ratio, bleeding time, activated partial thromboplastin time, total volume of blood loss, and total volume of blood transfused into the patients showed no significant differences between the two groups throughout the study. In contrast, prothrombin time and activated clotting time were significantly higher in group II when compared with group I at 2 h postoperatively. Seizure incidence was significantly lower in group II when compared with group I. However, the number of re-explored cases was insignificant when the two groups were compared.
Conclusion
Topical application of TA in addition to a small intravenous dose in patients undergoing open cardiac surgery using CPB reduces perioperative blood loss and transfusion in those patients to the same extent as sole large intravenous dose with less incidence of seizures.

Keywords: antifibrinolytic therapy, cardiopulmonary bypass, tranexamic acid, topical, intravenous, and seizures


How to cite this article:
Taman HI, Amer GF, Amer SA. Can topical administration of tranexamic acid be a good adjuvant to the intravenous route for decreasing postoperative seizure incidence? A double blinded randomized study. Ain-Shams J Anaesthesiol 2015;8:36-42

How to cite this URL:
Taman HI, Amer GF, Amer SA. Can topical administration of tranexamic acid be a good adjuvant to the intravenous route for decreasing postoperative seizure incidence? A double blinded randomized study. Ain-Shams J Anaesthesiol [serial online] 2015 [cited 2021 Nov 30];8:36-42. Available from: http://www.asja.eg.net/text.asp?2015/8/1/36/153936


  Introduction Top


Bleeding and the subsequent need for blood transfusion is a major contributor to postoperative mortality and morbidity in cardiac surgery [1],[2] .

Antifibrinolytic therapy has become a mainstay in complex cardiac surgical procedures for decreasing bleeding and minimizing transfusion requirements. Tranexamic acid (TA) is an antifibrinolytic agent that is being substituted for more expensive drugs in recent years [3],[4] . It can be used both systemically and topically [5] .

Current guidelines make a class I recommendation for TA use as a blood-conservation strategy during cardiac operations [6] . High-dose TA (total dose ≥100 mg/kg) has been advocated during cardiac operations to reduce bleeding [7],[8] .

Current studies and case series reports mention an increased incidence of seizures after administration of high doses of TA (60-260 mg/kg body weight) [9],[10] . Thus, we hypothesize that adding a topical dose of TA to a small intravenous dose can reduce postoperative bleeding in patients who have undergone cardiac surgery using cardiopulmonary bypass (CPB) with subsequent decrease in the associated incidence of seizures.

The primary aim of this study was to evaluate the incidence of seizures associated with topical TA added to a small intravenous dose relative to a single large intravenous dose in patients who have undergone cardiac surgery using CPB. The secondary aim was to evaluate the efficacy of topical TA added to a small intravenous dose on reducing the perioperative volume of blood loss and need for blood transfusion in comparison with a large dose of TA.


  Materials and methods Top


Between January 2013 and August 2014, 120 patients admitted to the Cardiothoracic Surgery Unit (Mansoura University Hospital) and Damitta Gastrology and Cardiac Surgery Center and scheduled to undergo open cardiac surgery using CPB were enrolled in this study after obtaining the agreement of our local Institutional Research Ethics Board and informed written consent from all patients.

Patients were randomly assigned to two equal groups (n = 60) using medical registering numbers: odd numbers for intravenous TA (group I) and even numbers for intravenous and topical TA (group II).

Patients who were on pump elective coronary artery bypass graft for the first time or undergoing valvular replacement surgery with left ventricular ejection fraction more than 35% were eligible for inclusion in the study.

Exclusion criteria included age more than 65 years, advanced liver, kidney, lung, or severe peripheral vascular disease, recent myocardial infarction, New York Heart Association class 3 or 4, re-exploration, history of seizure disorder, and hematocrit (Hct) levels lower than 30%.

All patients were premedicated with intramuscular injection of midazolam (1 mg/kg) and morphine (10 mg) 45 min before entering the operating room. Anesthesia in all patients was based on moderate doses of fentanyl (15-20 μg/kg) and midazolam (0.05-0.15 mg/kg), supplemented with isoflurane (MAC <1) for maintenance and propofol infusion (2.5-3 mg/kg/h) during CPB. Tracheal intubation and muscle relaxation were facilitated and maintained with rocuronium at a loading dose of 0.9 mg/kg and infusion at 0.5 mg/kg/h.

Every patient in group I received an initial bolus dose of TA consisting of a bolus of 50 mg/kg body weight at the beginning and at the end of CPB, and 100 mg/100 ml priming volume was added to the priming fluid of the CPB system [11] .

In group II every patient received an initial TA bolus of 30 mg/kg infused over 15 min followed by a 16 mg/kg/h infusion until chest closure with a 2 mg/kg load within the pump prime [12] .

On completion of operation and before sternotomy closure, patients received another 2 g of TA diluted in 500 ml of warm saline (37°C), which was poured into the pericardial cavity. Five minutes later it was cleared out and the sternotomy was closed [13] .

Median sternotomy was performed in all patients, and CPB was instituted through cannulation of the ascending aorta and the right atrium. Aortic palpation was used to detect atherosclerosis and, if present, to select an appropriate site for cannulation and clamping.

Heparin was given at an initial dose of 300 IU/kg to achieve an activated clotting time (ACT) of more than 480 s, and at the end of CPB it was reversed with a full dose of protamine chloride to achieve an ACT of less than 120 s.

In all patients, Custodiol cardioplegic solution at 8°C was used for myocardial protection. The CPB circuit lines were not heparin-coated and included a roller pump (Stockert Instrumente, Munich, Germany), a hollow-fiber membrane oxygenator (Medtronic Inc., Minneapolis, Minnesota, USA), and a 34-μm screen arterial filter (Medtronic Inc.).

Colloid (Voluven, Fresenius Kabi Norge AS, Halden, Norway) without any blood product was used as the priming solution. During CPB, the minimum and maximum allowed Hct levels were 20 and 24%, respectively. Moderate hypothermia (32°C) was used during CPB. During rewarming, the maximum allowed blood temperature at heat exchange was 37.5°C, and the maximum allowed nasopharyngeal temperature was 37°C.

The warming rate was ~1°C/1-2 minutes and the nasopharyngeal temperature was monitored closely during the rewarming time. Perfusion was nonpulsatile, with indexed flows set at 2.4 l/m 2 /min during cooling and rewarming and at 2.0 l/m 2 /min during stable CPB. The mean arterial blood pressure was maintained between 60 and 80 mmHg. α-Stat acid-base management was used for all patients.

Packed red blood cells were administered when Hb decreased to less than 8 g/dl and/or Hct decreased to less than 24% during the procedures, and when Hb decreased to less than 10 g/dl and/or Hct decreased to less than 30% during intensive care. When chest drainage blood increased to more than 150 ml/h or to more than 100 ml/h for two consecutive hours and the international normalized ratio (INR) was greater than 1.5, fresh frozen plasma was administered, and when the platelet count was less than 100 × 109/l platelet concentrate was administered.

Postoperatively, re-exploration was performed when chest drainage was more than 300 ml/h for two consecutive hours or was more than 200 ml/h for 3 h, or when echocardiography confirmed the presence of tamponade.

Preoperative data, including Hb concentration, Hct value, platelet count, and coagulation profile [INR, bleeding time, prothrombin time (PT), activated partial thromboplastin time (APTT), and ACT], were taken to obtain baseline values before surgery, and at 2, 12, and 24 h after admission to the ICU. Intraoperative and postoperative amount of blood loss and total amount of transfused whole blood were recorded. Incidence of seizures was recorded. A seizure was considered to have occurred in the case of sudden clonic movement of the patient. The suspicion of a clinical seizure was immediately reported by the specially trained nursing staff to the responsible physician who confirmed the diagnosis [14] . Re-explored cases were also recorded.

Sample size calculation

The sample size was calculated on the basis of the incidence of seizures. We expected a difference of 30% between the two groups. Using the χ-test for comparison and setting α-value to 0.05, we needed a minimum of 53 cases in each arm to detect a similar difference with 80% power. We increased the sample to 60 cases in each arm to compensate for possible dropouts. Calculations were made using PS software Windows (G*Power 3.01 programme).

Statistical analysis

Data were first tested for normality by means of the Kolmogorov-Smirnov test. Normally distributed continuous data were analyzed using the Student t-test. Non-normally distributed continuous and ordinal data were analyzed using the Mann-Whitey U-test. Categorical data were analyzed by means of the χ2 -test or Fisher's exact test as appropriate. The results were presented as mean (SD) or number and percentage of patients as appropriate. A P value less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS for Windows, version 18 (SPSS Inc., Chicago, Illinois, USA).


  Results Top


Between January 2013 and August 2014, 120 patients who have undergone open cardiac surgery using CPB were enrolled in the study; 60 patients were assigned to group I and 60 to group II. Demographic data and duration of CPB showed no significant differences between the two groups ([Table 1]).
Table 1 Demographic data and duration of cardiopulmonary bypass in the studied groups

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Hemoglobin concentration, Hct value, platelet count, INR, bleeding time, and APTT showed no significant differences between the two groups throughout the study. In contrast, PT and ACT were significantly higher in group II when compared with group I at 2 h postoperatively ([Table 2] [Table 3] [Table 4], respectively).
Table 2 Hemoglobin concentration (g/dl) and hematocrit value (%) in the studied groups

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Table 3: Perioperative platelets count, international normalized ratio (%), and bleeding time in the studied groups

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Table 4: Perioperative prothrombin time (s), activated partial thromboplastin time (s), and activated clotting time (s) in the studied groups

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Total volume of blood loss and total volume of blood transfused to the patients showed no significant difference between the two groups perioperatively ([Table 5]).
Table 5 Perioperative blood loss (ml) and blood transfusion requirements (ml) in the studied groups

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The incidence of seizures and re-explored cases are summarized in [Table 6]; seizure incidence was significantly lower in group II when compared with group I. However, the number of re-explored cases was insignificant when the two groups were compared together ([Table 6]).
Table 6 Perioperative incidence of seizures and number of re-explored cases in the studied groups

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  Discussion Top


Postoperative bleeding increases morbidity and mortality in cardiac surgery [15] . Therefore, different techniques have been used to reduce bleeding after cardiac surgery, such as autotransfusion, hemodilution, and antifibrinolytic agents such as aprotinin, desmopressin, TA, and e-aminocaproic acid [16] .

TA (a lysine analog) has traditionally been considered a safe drug with a reported low incidence of adverse events. More recently, several investigators have suggested high-dose TA to be etiological in postoperative seizures following cardiac surgery, especially in patients with renal dysfunction [17] .

TA has been used topically to decrease postoperative bleeding after major surgical procedures, but further data are needed on the safety of this hemostatic approach [18] .

Seizure incidence was significantly lower in group II when compared with group I. Also, PT and ACT were significantly higher in group Π when compared with group I at 2 h postoperatively.

However, hemoglobin concentration, Hct value, platelet count, bleeding time, INR, APTT, total volume of blood loss, total volume of blood transfused to the patients, and incidence of re-exploration showed no significant differences between the two groups across the study.

TA is composed of C8H15N02; it has a short half-life of about 2-3 h and is rapidly excreted through the kidneys [19] .

It competitively inhibits the activation of plasminogen, thereby reducing the conversion of plasminogen to plasmin, an enzyme that degrades fibrin clots, fibrinogen, and other plasma proteins, including the procoagulant factors V and VIII [20] .

At higher doses, TA directly inhibits plasmin activity [11],[21] . Thus, it inhibits fibrinolysis, a putative mechanism of bleeding after CPB.

In the past, many investigators have studied the pharmacokinetics of TA, and the results of these studies have formed the basis of several dosing regimen recommendations [12],[22] . Although the optimum dose of TA has been a subject of debate, a recommended dosing regimen, the BART dose, remains a popular choice in high-risk cardiac surgery [11] .

The BART dose of TA is based on the two-compartment pharmacokinetic model developed by Dowd et al. [12] . Thus, there is the need to define the optimal dose with a clearer understanding of the pharmacokinetics of TA before during and after CPB in cardiac surgery [22] .

The present study depends on the fact that TA decreases perioperative bleeding and the need for blood transfusion. This fact was proved by Alvarez et al. [23] and Hiippala et al. [24] , who showed that intravenous TA significantly reduces blood loss and transfusion units compared with placebo.

Also a study by Mehr-Aein et al. [25] conducted on patients undergoing off-pump coronary artery bypass surgery proved that TA effectively reduces postoperative blood loss and the need for allogeneic blood products after surgery, which supports our findings.

Two separate recently conducted meta-analyses, by Tan et al. [26] and Adler Ma et al. [27] , confirmed the effectiveness of intravenous TA in reducing blood loss and transfusion units while having no significant risk for deep vein thrombosis or pulmonary embolism.

Application of topical TA helps to decrease perioperative bleeding and thus the need for blood transfusion. As topical application of TA can directly target the source of bleeding, it can be considered a safer method of delivery while decreasing potential systemic effects [28] .

Such inhibited local fibrinolytic activity will help prevent fibrin clot dissolution and increase its volume and strength at raw surgical surfaces, thus enhancing microvascular hemostasis and decreasing bleeding [29] .

The advantage of topical application of TA is minimal systemic absorption. In a study conducted by Nilsson [30] , the plasma levels of TA detected in patients who received topical TA were significantly (70%) lower than an equivalent dose of intravenously administered TA.

When used topically, TA did not increase mortality or even morbidity, nor complications such as myocardial infarction, grand mal fits, or renal failure [16] .

In our study topical application of TA was seen to facilitate reduction in both perioperative bleeding and its side effects when given in a large dose intravenously. Studies conducted by Dryden et al. [31] and Fawzy et al. [32] are compatible with ours.

Also Abrishami et al. [33] demonstrated advantages of topical use of antifibrinolytic drugs after open heart surgery in reducing postoperative bleeding and transfusion requirements, but they recommended further clinical trials.

De Bonis et al. [34] proved that the use of blood products was not statistically significantly different between the study (topical TA) and control groups.

Frequency of seizures was significantly lower in group II when compared with group I. TA has a direct effect on central nervous system cells by inhibiting the GABA receptor [35] .

Many studies support our findings. Murkin et al. observed an increase in the incidence of postoperative seizures following administration of high-dose TA (up to 259 mg/kg) at centers in Canada and the UK. They further observed that TA dose reduction resulted in a decrease in the incidence of seizures [35] .

Also Murkin et al. [36] proved that high-dose TA (61-259 mg/kg) was associated with nonischemic clinical seizures in cardiac surgical patients. This is likely because TA exerts a direct effect on central nervous system cells by inhibiting the GABA receptor [35] .

In the present study, the PT and ACT were significantly longer in group II when compared with group I at 2 h postoperatively. This may be attributed to the fact that TA is a synthetic antifibrinolytic drug that prevents the plasmin-mediated conversion of fibrinogen to fibrinogen split products through the inhibition of lysine-binding sites on plasminogen and fibrinogen, preserving the coagulation factors and thus helping to decrease PT and ACT values [37],[38],[39] .

The high PT and ACT values in our study are consistent and comparable with the findings of previous studies conducted by Verstraete [37] , Katoh et al. [38] , and Horrow et al. [39] , which demonstrated that patients treated intravenously with a large dose of TA (>60 mg/kg) had reduced PT and ACT values.

Our study has limitations. Although the objective of this study was to compare the efficacy of adding topical TA to the intravenous route in decreasing both perioperative bleeding and the incidence of complications, mainly seizures and thrombosis, concentrations of the drug could not be assessed as we lack this facility, and therefore we could not judge whether the doses we used were effective therapeutic levels. Thus, further study may be needed to combine the therapeutic level, dose given, and efficacy of that drug to determine the effective dose with the fewest side effects.


  Conclusion Top


Topical application of TA in addition to a small intravenous dose in patients undergoing open cardiac surgery using CPB reduces perioperative blood loss and transfusion in those patients to the same extent as sole large intravenous dose with less incidence of seizures.


  Acknowledgements Top


Conflicts of interest

None declared.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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