Does the preoperative administration of tranexamic acid reduce perioperative blood loss and transfusion requirements after head neck cancer surgery? A randomized, controlled trial.

BACKGROUND: Head and neck cancer (HNC) surgery is associated with high intraoperative blood loss which may require urgent blood transfusion. Many strategies have been recommended to decrease the need for allogenic transfusion. Use of perioperative tranexamic acid (TA) has a promising role. AIMS: This study was to evaluate the effectiveness of single preoperative bolus dose of TA on blood loss prevention and red blood cell transfusion in patients undergoing HNC surgery. STUDY
DESIGN: A prospective, double-blind, and randomized controlled study.
MATERIALS AND METHODS: From 2007 July to 2010 January; 80 patients, aged (35-55), of American Society of Anesthesiologists II-III scheduled for unilateral HNC surgeries were randomly received either TA (Group T) in a dose of 20 mg/kg diluted to 25 cc with normal saline or an equivalent volume of normal saline (Group C) in a tertiary care hospital. Hemoglobin (Hb) concentration, platelet count, packed cell volume, fibrinogen level, D-dimer level were measured pre- and post-operatively.
RESULTS: Saline (C) Group required more blood, colloid, crystalloid for blood loss. In Group T, 32 patients did not require transfusion of any blood products compared to five patients in Group C (P < 0.0001) and only eight units of blood was transfused in Group T, whereas a total of 42 units of blood was transfused in Group C. Even after numerous transfusions, Hb% after 6 h and 24 h in Group C were significantly low in comparison with Group T (P < 0.05).
CONCLUSION: Thus, TA significantly reduces blood loss and chances of colloid, blood, and crystalloid transfusion caused by HNC surgery.

RCT Entities:   Population Interventions Outcomes

INTRODUCTION

Incidence of head neck cancer (HNC) is high in Asia and other less developed nations. Its prevalence (HNC) with respect to total body malignancy varies from 9.8% to 40%.[12] The morbidity and mortality related to HNC is of lamenting concern to the patients, their relatives and the susceptible community at large.

HNC surgery procedures are often complicated by challenging anatomy, complex reconstructions, and long operative times. Bleeding during HNC surgery is still now a challenge for surgeons and anesthesiologists. Furthermore, majority of the patients undergoing these treatments have medical co-morbidities that complicate their care and may lead to postoperative complications. Since the beginning of last century, neck dissection (ND) has been recognized as an interwoven part of the HNC surgery operations.[3] ND is commonly used in the treatment of cervical lymphatic metastases of malignant disease of the upper aerodigestive tract, thyroid, parotid, and skin of the head and neck.[4] Studies have demonstrated that the operative time and the blood loss are related to the clinical outcomes and the complications in most of head and neck surgery.[56]

New strategies and surgical equipment focused on reducing operative durations, blood loss, hospital bed occupancy and the rate of complications are emerging and the results are encouraging. Bipolar diathermy,[7] harmonic scalpel,[8] packing,[9] local vasoconstrictors,[9] endovascular embolization,[10] head up positioning,[11] induced hypotension,[12] preoperative autologous blood donation with or without erythropoietin,[1314] and antifibrinolytic agents[15] are the most commonly used techniques.

Tranexamic acid (TA), a synthetic antifibrinolytic agent that is approximately 7–10 times more potent than Epsilon-aminocaproic acid, competitively blocks the lysine-binding site of plasminogen, plasmin, and tissue plasminogen activator which prevents their association with fibrin.[15] Thus, plasminogen to plasmin conversion is retarded, and the proteolytic action of plasmin on fibrin monomers and fibrinogen is debarred. Adverse effect of TA are rare and mainly limited to nausea, usually elicited by rapid intravenous (IV) infusion.[16]

Till date no any study is available on the role of TA in the reduction of perioperative blood loss specifically in HNC surgery with ND. Hence, we intended to evaluate the efficacy of single preoperative bolus dose of TA on reduction in blood loss and red blood cell transfusion in patients undergoing unilateral HNC surgery and untoward effects with the use of this drug in our population.

MATERIALS AND METHODS

After proper approval by the Institutional Ethics Committee, this prospective study was conducted at a tertiary care center over a 30 months period and informed consent was obtained from all patients aged 35–55 years. Eighty patients posted for unilateral HNC surgery (American Society of Anesthesiologists classification II-III) were included in this study. Patient refusal, patients having previous HNC surgery, anemia (hemoglobin [Hb] <10 mg/dl [use system internationale style units expression all around abstract and file text] for women and Hb <12 mg/dl for men), abnormal coagulation profile, aspirin intake within 7 days, hepatorenal insufficiency, cardiopulmonary abnormality, pregnancy, and history of embolic manifestations like deep venous thrombosis, transient ischemic attack, and stroke were excluded from the study.

Preoperative hemostatic assessment included platelet count, bleeding time; activated partial thromboplastin time (aPTT) and prothrombin time (PT) were assessed thoroughly. Computer generated randomization used to receive either TA (Group T) or a placebo (Group C). A ticket marked with the group was drawn and kept in an envelope. The injection syringes were prepared blindly by a resident doctor outside the surgical team. The prepared injection was administered 15 min before induction. After 1 ml test dose, patients received either TA in a dose of 20 mg/kg diluted to 25 cc with normal saline (Group T) or an equivalent volume of normal saline (Group C).

Nurses, resident doctors, staff physicians, and the investigators were blinded to the solution and data gathered throughout the procedure. Data were collected according to the written proforma and the envelopes were opened after the study was completed.

After general and systemic examinations, assessment of the airway was done. Routine fasting guidelines were followed and the patients were prescribed 0.5 mg of alprazolam at the night before surgery to alley anxiety. Aspiration prophylaxis was given with tablet metoclopramide and tablet ranitidine.

Intraoperative monitoring included pulse oximetry, EtCO2, five-lead electrocardiography, temperature, and noninvasive blood pressure (NIBP). We have put central venous cannulation for (subclavian vein on the contralateral side) fluid administration and central venous pressure monitoring. Vital parameters were monitored at every 10 min interval intraoperatively and every 30 min for 1st and 2nd postoperative period.

Before the institution of general anesthesia, the study agent was given to the patients over 5 min through IV route. After 5 min preoxygenation with 100% oxygen, premedication was given with glycopyrrolate (0.01 mg/kg), fentanyl (2 µg/kg). Anesthesia was induced in both the group with IV propofol (2 mg/kg), and intubated with atracurium (0.5 mg/kg).

About 1–2% isoflurane in nitrous oxide and oxygen (ratio 2:1) was used for maintenance of anesthesia. EtCO2 was maintained between 35 ± 5 mm Hg during mechanical ventilation. If both heart rate and NIBP increased >20% from baseline, fentanyl was repeated in the dose of 1 µg/kg intraoperatively despite maintaining adequate depth of anesthesia.

All patients were transferred to surgical Intensive Care Unit (SICU) after extubation. Intramuscular diclofenac was used to provide postoperative analgesia at 8 h interval and IV fentanyl 1 µg/kg was administered as rescue analgesic when the visual analog scale score exceeded 3.

Ondansetron 4 mg was given IV if nausea and/or vomiting occurred. Total antiemetics doses and no of patients receiving it were noted. Occurrence of adverse effects during the first 24 h was noted. After 24 h, patients were assessed for: (a) Need for any analgesic, and (b) surgical complication, if any. If the patients mobilize and reported no on the last two questions, they were assessed as fit for discharge from SICU. Measurements were all recorded by the resident doctors blinded to the study drug.

Intraoperative blood losses were determined by measuring the weight change of moistened surgical gauzes, mops, and observing the fluid level of suction reservoirs were used to assess intraoperative blood loss. The content of the wound drainage system was measured at the end of recovery room phase and until the drains were removed. Drains were removed at the end of first postoperative day if the postoperative status allowed.

Factors associated with perioperative blood losses were kept in mind. Approach and incision type, duration of surgery, blood pressure maintained during surgery, and body temperature achieved were all included in this study. Packed cell volume, Hb, platelet, fibrinogen, and D-dimer levels were all measured preoperatively, in the first 6th and 24th h in the postoperative period.

Ringer lactate solution was a primary replacement solution for half of the calculated blood volume loss and thereafter, equal volume of Ringer's lactate solution and 6% pentastarch were given as needed. The transfusion trigger point was kept hematocrit (Hct) <26. Red cell concentrate (RCC) has replaced the blood loss. After 12 h, Ryles tube feeding had been started. Replacement fluid volume was monitored until the next postoperative day and the number of RCC units transfused was registered.

Statistical analysis

Sample size was based on a crossover pilot study of 10 patients and was selected to detect a 25% reduction in the incidence of (100 ml) bleeding with a power of 80% and (α error = 0.05, β error = 0.2), the sample size calculated was 74 patients (37/group) to be able to reject the null hypothesis which will be increased to 80 patients (40/group) for possible dropouts. Student's t-test was applied for variables like age (years), height (cm), weight (kg), and preoperative value of hemostatic status like packed cell volume, hemoglobin, platelet count, aPTT, PT time factors and variable related to duration of operation in minute, bleeding amount (ml), colloid/crystalloid used (ml). Variables related to different type of surgeries on the patient, sex, number of different transfusion given to the patients were compared with Chi-square test. A P < 0.05 was considered statistically significant.

RESULTS

The demographic factors mean age (years), sex ratio, mean weight (kg), mean height (cm), and distribution of cases as shown in Table 1 were comparable between the two groups. Preoperative hemostatic status, mean Hb concentration, PCV, mean platelet concentrations, mean aPTT value in seconds, and value of prothrombin (%) were also comparable in between two groups.

Table 1

Demographic profile and the preoperative hematologic status in both groups

In [Table 2] operative duration in minutes and duration of head extension in minutes, as shown, were similar in both the groups. Different types of NDs were quiet comparable among both the groups.

Table 2

Operative time and type of neck dissection

Intraoperative, postoperative and total blood loss as shown in Table 3 and Figure 1 was significantly higher in Group C than Group T (P = 0.0001).

Table 3

Comparison of blood loss among two group

Figure 1

Comparison of mean perioperative blood loss among two groups

In the Group T less blood, colloid, and crystalloid solutions were used to replace the blood loss [Table 4]. 32 patients in Group T did not require transfusion of any blood products compared to 5 patients in Group C (P < 0.0001) and only eight units of blood was transfused in Group T whereas a total of 42 units of blood was transfused in Group C [Table 4].

Table 4

Comparison of replacement solution used by end of the 1st postoperative day

Changes in Hb%, packed cell volume, platelets, D-dimer, and fibrinogen levels have been shown in Table 5. Even after repeated transfusions, Hb% after 6 h and 24 h in Group C were significantly low in comparison with Group T (P = 0.04 and 0.03) [Table 5]. Though platelet count and fibrinogen levels after 6 h and 24 h in two group were not significantly different, but PCV concentration after 6 h and 24 h in Group C were considerably low (P = 0.0001 and 0.0004) [Table 5]. After 6 h and 24 h D-dimer level among two groups were significantly different (P = 0.01 after 6 h and P < 0.04 after 24 h) [Table 5]. The enrollment, allocation, followup and analysis for the patients are all described in figure-2 as consort diagram.

Table 5

Laboratory data at different time intervals between groups

Figure 2

CONSORT 2010 flow diagram

DISCUSSION

In an HNC surgery, 67% of bleeding episodes required operative intervention; the reported incidence of blood loss ranges from 250 to 500 ml depending on the clinical setting and study design.[17] From the ancient period of time, different methods have been used to define and determine perioperative blood loss are probably the main reasons for this great variation. Several studies have evaluated the effects of various operative techniques, instruments, and treatments on HNC surgery-related blood loss, but until recently quite a few factors have been identified as successful.

During HNC surgery, enhanced intraoperative fibrinolytic activity was observed leading to augmented bleeding episode. The enhanced fibrinolysis is due to vascular endothelium released tissue plasminogen activator. The release is triggered by hypoxia or venous engorgement.[18] This local phenomenon has a protective value against vascular thrombosis which may cause migration of clots and endangering one's life. Some recently published studies focusing on the reduction of blood loss by the use of antifibrinolytic drugs supports this theory.

During head neck surgical procedures Chen et al.[19] showed a significant difference in blood loss as drainage amount and found that TA treated group suffers from less bleeding (49.7 ml vs. 88.8 ml).

Elwatidy et al.[20] conducted another study, on patients undergoing spine surgery, by giving 30 mg/kg body weight of TA after induction of anesthesia. In their study, mean blood loss during spine surgery was 49% less in the TA treated group (n = 32) compared with placebo group (n = 32). During the hospital stay, the treatment (TA) group received 80% less blood transfusion (P < 0.008) than patients who received placebo.

Hiippala et al.[21] conducted a study on knee arthroplasty where patients receive either TA (n = 39) or equal volume of normal saline (n = 38). Before deflation of the tourniquet, 15 mg/kg of TA was given IV followed by two l0 mg/kg additional doses. Total blood loss (mean ± standard deviation) was 689 ± 289 ml in the TA Group and 1509.5 ± 643 ml in the NS Group (P < 0.0001). The mean number of transfused red cell units in the TA Group was 1.0 ± 1.2 compared to 3.1 ± 1.6 in the NS Group (P < 0.0001).

While doing a study on advanced ovarian cancer surgery, Lundin et al.[22] found, that total blood loss volume and transfusion rate were significantly lower in the TA treated group compared with placebo. Average blood loss was 520 and 730 ml, respectively (P = 0.03). 30% and 44% patients, respectively received transfusions (P = 0.02).

In cases of total knee arthroplasty, Tanaka et al. studied to determine the optimum protocol for the administration of TA in order to reduce blood loss.[23] Out of two TA injections, one given preoperatively (10 mg/kg) and one on deflation of the tourniquet (10 mg/kg) and found that TA works better when administered before operation rather than during deflation of the tourniquet. Thus, fibrinolysis suppression from the beginning of the operation may be more efficacious than only at the time of the peak of hyperfibrinolysis later.

From different pharmacokinetic studies, it was found that a dose of 10 mg/kg of TA is appropriate for cancer surgery. Since therapeutic levels of TA can be maintained for approximately 8 h after operation, which covers the period of hyperfibrinolysis in cases of enhanced blood loss.[24]

While comparing and reviewing the literature of recent studies we found that Low et al.[25] observed with 1 g per oral, QID dosing of TA had reduced nonarterial bleeding of the upper aerodigestive tract tumors in a case series of four consecutive cases. But on the other hand, Langille et al.[26] in a study on chronic rhinosinusitis ± polyposis undergoing endoscopic sinus surgery found that IV TA did not appear to result in a clinically meaningful reduction in blood loss. In a meta-analysis, Ker et al.[27] concluded that IV TA reduced blood transfusion in surgery. Gupta et al.[28] in their study on modified radical mastectomy and Wertheim's operation found that 1 g IV TA administered prophylactically 20 min before skin incision reduced the blood loss and transfusion requirement without any side effect.

Our present study confirms the beneficial effects of TA on blood loss associated with HNC surgery. The short-term TA therapy reduced blood loss by more than two-third compared to controls.

In our study, there was difference in blood loss between the Group T and Group C during surgery (52.34 ± 10.2 ml vs. 110.24 ± 13.4 ml), (P = 0.0001). Even in the postoperative surgical ward, after 24 h Group C bled more than the Group T (250.28 ± 36.6 ml vs. 150.16 ± 30.4 ml) (P = 0.0001). Moreover, if we consider the total blood loss in Group T it was 202.5 ± 20.3 whereas in Group C it was 360.52 ± 26.2 (P < 0.0001).

In the present study, blood loss in the control group was nearly identical to the formerly reported interventions.[1920212223] In the test group, transfusion requirement was radically decreased. While comparing, the number of transfused units was reduced by 80.95% and the number of transfused patients by 84.37% compared to controls [Table 4]. Though test group received fewer transfusions, the postoperative Hb in the treatment group was still higher compared to controls [Table 4]. The number of patients maintained without any transfusions would have been substantially higher if the transfusion trigger had been lower. One or two units of red cells were ordered for transfusion if the Hct level decreased to <26.

The major limitation of our study is that we had compared TA with placebo based on its known optimal as well as safe premedicating doses for extensive cancer surgery without the knowledge of their disease-specific pharmacodynamic change in doses. However, a larger study with large sample size needs to be conducted to establish the author's point of view with solidarity.

We do conclude that preoperative administration of single bolus dose of TA in a dose of 20 mg/kg significantly reduces blood loss caused by HNC surgery. One limitation of our study is that we compared TA with control based on the known optimal doses from our previous researchers. However, a larger study with large sample size needs to be conducted to establish the actual optimum dose for TA in HNC surgery. The study being conducted in a developing country, the authors could not measure some of the biochemical parameters of bleeding episodes like blood group antigens and the A9 antigen/alpha 6 beta 4 integrin, cytokines, growth factors, and tumor antigens.

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Nil.

Conflicts of interest

There are no conflicts of interest.