Combination of tranexamic acid and dexmedetomidine reduces postoperative blood loss in patients undergoing bilateral total knee replacement - A randomized controlled study

Koramutla Pradeep Kumar¹, J Subhashree², Chittaranjan Sahu^3*, G Jagadesh⁴

{^1,3Associate Professor, ²Assistant Professor,  Department of Anesthesiology} {³Associate Professor, ⁴Director, Department of Orthopedics} Balaji Institute of Surgery Research and Rehabilitation for Disabled, Tirupati, Andhra Pradesh, INDIA.

Email: drpradeep9@gmail.com, drswapnaa@gmail.com, chittusahu@gmail.com

Abstract               Background: Total knee replacement in adults is associated with significant blood loss, often requiring allogenic blood transfusion. Tranexamic acid (TEA) reduces blood loss and red cell transfusions in patients undergoing unilateral total knee arthroplasty (TKA). However, literature is scare regarding the use of combination of tranexamic acid and dexmedetomidine and its effects on post operative blood loss in patients undergoing bilateral TKR in a single stage procedure. With this background this randomized study was taken up to evaluate the combination of tranexamic acid and dexmedetomidine in reducing the postoperative blood loss in elective bilateral total knee replacement. Material and Methods: One hundred and thirty four adult patients with ASA 1 to ASA3 were randomly allocated to 1 of 2 groups using a computer-generated random number table with 67 patients in each group. Group I patients (TAS) received tranexamic acid in a dose of 10 mg/kg and saline in a total volume of 10 mL. Group II (TAD) received tranexamin acid and dexmetomidine 0.5 µg/kg making up the volume to 10 mL. Results: The average blood loss assessed by means of the drain output in the TAD group was significantly lower than the TAS group (376 ml in TAD group vs 710 ml while in the TAS group). The requirement of blood transfusion in the TAD group was significantly lower compared to the group receiving TAS (3.7 units in TAS group vs 2.7 units in TAD group). Conclusion: The combination of Tranexamic acid and dexmedetomidine is effective in reducing total blood loss following bilateral total knee replacement surgery and its efficacy is better when compared to the traditional use of tranexamic acid alone.

Key Words: Tranexamic acid; Dexmetomidine; blood loss; bilateral; total knee replacement.

INTRODUCTION

Total knee replacement (TKR) is a commonly performed surgical procedure performed with an aim to relieve pain and for functional recovery especially in patients suffering from advanced degenerative arthritis or rheumatoid arthritis.¹ TKR procedure in adults can be associated with significant blood loss with the blood loss ranging from 1500-2000mL,^2,3 and often requiring allogenic blood transfusion.⁴ Blood transfusion in turn is associated with complications such as hemolytic reactions, transfusion associated sepsis or even transmitting viral infections.⁵ Hence the aim should be to minimize blood loss and avoid transfusion. Various modalities have been tried to decrease blood loss including use of epoitin injections, platelet rich plasmapheresis, fibrin sealing and anti-fibinolytic drugs and use of hypotensive epidural anaesthesia have been tried with varying success.⁶ Tranexamic acid (TXA), a synthetic antifibrinolytic agent inhibits the activation of plasminogen to plasmin. At higher concentration, TXA directly inhibits plasmin activity at high concentrations.⁷ Tranexamic acid has been uses topically, administered intra-articularly and intravenously in TKA and has been shown to be effective in reducing blood loss and transfusion.^8-10 Dexmedetomidine is a new generation highly selective α2-adrenergic receptor (α2-AR) agonist used in various clinical settings and is a useful sedative agent with analgesic properties, hemodynamic stability and ability to recover respiratory function in mechanically ventilated patients facilitating early weaning.^11,12 However, literature is scare with regard to the use of combination of tranexamic acid and dexmedetomidine and its effects on post operative blood loss in patients undergoing bilateral TKR in a single stage procedure. This randomized study was thus taken up to evaluate the combination of tranexamic acid and dexmedetomidine in reducing the postoperative blood loss in elective bilateral total knee replacement.

MATERIAL AND METHODS

After obtaining approval from the institutional ethics committee, 134 adult patients with ASA 1 to ASA3 were randomly allocated to 1 of 2 groups using a computer-generated random number table with 67 patients in each group. Group I patients (TAS) received tranexamic acid in a dose of 10 mg/kg and saline in a total volume of 10 mL. Group II (TAD) received tranexamin acid and dexmetomidine 0.5 µg/kg making up the volume to 10 mL. All the surgeries were performed by the senior surgeon. A tourniquet and a bone plug (to block the femoral medullary cavity after the femoral cuts) were always used to decrease the blood loss. Closure was performed after ensuring adequate hemostasis. An intra-articular negative suction drain was used in all the cases to measure postoperative blood loss. Preoperative investigations included hemoglobin (Hb), hematocrit (Hct), and a complete coagulogram. Postoperative Hb levels and Hct were measured 24 hours after surgery. The primary outcome was the total perioperative estimated and calculated blood loss 24 h postoperatively. A negative suction drain was kept for 48 hours and the drain output was recorded for day 0 and day 1. The following parameters were estimated. Preoperative hemoglobin (Hb), PCV, postoperative Hb, prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), total drain output of each limb and number of blood units transfused. All patients received blood transfusion in the form of whole blood depending upon the amount of blood lost as assessed from the drain outputs. Thromboprophylaxis in the form of subcutaneous low molecular weight heparin was given to all patients starting from day 1 and continued till the time of discharge. Additional care in the form of postoperative use of DVT stockings, ankle pumps, and early mobilization was also ensured as a part of thromboprophylaxis which is practiced for all patients routinely.

Premedication: All patients were given 0.5 mg of Alprazolam orally at 9.00 pm on the day before surgery.

Anaesthesia Protocol: Anaesthesia was standardized for all the patients. In all the patients central neuronal blockage (CNB) by continuous spinal epidural technique (CSE) was done. Monitoring included electrocardiogram, noninvasive blood pressure and pulse oximetry. CNB was performed with the patient in sitting position under aseptic precautions. Skin wheal is raised with local anaesthetic and spinal epidural is performed at L3-L4, L4-L5 interspce. Post operatively pain is controlled by continuous epidural infusion of 0.125% of Bupivacaine. Rescue analgesia in the form of 0.5mic /kg of fentanyl or diclofenac 50 mg or paracematol 1 gram were given. Post operatively the following parameters were recorded; systolic and diastolic blood pressures, post operative pain using visual analogue score, amount of rescue analgesics. Side effects like nausea, vomiting, constipation, drowsiness and other complications if any were also recorded.

Statistical Analysis: Data is expressed as mean ± standard deviation for continuous variables and as frequency (number [%]) for categorical variables. Independent samples T test was used to assess the difference in markers between the two groups. All statistical analysis were performed using Microsoft excel spreadsheets (Microsoft, Redmond, WA USA) and Statistical package for social sciences for windows version 16.0 (SPSS Inc., Chicago IL, USA). A ‘p’ value <0.05 was considered as statistically significant.

RESULTS

As shown in table 1, the groups were matching in terms of age and the male female ratio. The mean age was 60.9 years and 59.3 years in the TAS and TAD groups respectively. There were 30 males in the TAS group and 37 males in the TAD group. The baseline haemoglobin levels were similar in both the groups (p=0.631). However, a significantly lower haemoglobin was found in the TAS group postoperatively compared to the TAD group (p=0.006). As shown in Table 2, the average blood loss assessed by means of the drain output in the TAD group was significantly lower than the TAS group (376 ml in TAD group vs 710 ml while in the TAS group). The requirement of blood transfusion in the TAD group was significantly lower compared to the group receiving TAS (3.7 units in TAS group vs 2.7 units in TAD group).

DISCUSSION

Blood loss is a major concern in patients undergoing surgeries related to vascular, cardiac, liver transplantations, hepatic resections and orthopedic procedures.¹³ Blood loss and its replacement in elective total knee replacement is a challenge to the anesthesiologist in the perioperative period. The blood loss ranges from 1500-2000mL^2,3 among patients undergoing bilateral total knee replacement. Of the various blood conservative techniques, Tranexamic acid as an effective antifibrinolytic agent is well established.⁷ More recently, studies have shown that α2-adrenoceptor agonists may be beneficial in the postoperative period owing to their sympatholytic effects. Dexmedetomidine is a highly selective α2-adrenergic receptor (α2-AR) agonist. Its primary clinical use is to act as a sedative agent processing analgesic properties. It produces hemodynamic stability through its action on the central nervous system. This has been attributed to activation of postsynaptic receptors by α2-agonists causing inhibition of sympathetic activity. This in turn causes a decrease in BP and HR.¹¹ The average half life of dexmetomidine is 2 hours. Its average protein binding of dexmedetomidine is 94% and has negligible protein binding displacement by commonly used drugs during anesthesia such as fentanyl, ketorolac, theophylline, digoxin, and lidocaine.¹⁴ Previous studies have shown dextomedetomidine to be effective in decreasing bleeding during tympanoplasty or septorhinoplasty¹⁵ and in patients with hypertensive cerebral hemorrhage during the perioperative period.¹⁶ In our study, the average blood loss assessed by means of the drain output in the TAS group was 710 ml while in the TAD group it was 376 ml (Table 2). A previous study by Hippala ST et al.,¹³ reported a mean blood loss of 689 ml in the group who received tranexamic acid for total knee replacement as against 1508 ml in the control group which received normal saline. MacGillivray et al.,¹⁷ reported a blood loss of 678 ml in patients undergoing bilateral TKR who received a dose of 10mg/kg body weight and only 462 ml among those who received a dose of 15 mg/kg of tranexamic acid. MacGillivray et al.,¹⁷ had measured the intra operative blood loss with the help of special intra-articular drains. This could not be done in our study. However, Dhillon MS et al.,¹⁸ reported a blood loss of 275 ml through a similar assessment of the drain output as was done in our study. In a retrospective study, Sipah YJ et al.,¹⁹ in a south Asian population (Pakistan) reported a blood loss of 1288 ml in patients undergoing bilateral TKR and received tranexamic acid compared to 2695 ml in the group which did not receive tranexamic acid. All the patients received blood transfusion after the procedure (3.7 units in TAS group vs 2.7 units in TAD group). However, the requirement in the TAD group who received combination of tranexamic acid along with dexmetomidine was significantly lower compared to the group receiving TAS alone. Hence, Dexmetomidine is useful as an adjunct to tranexamic acid in decreasing blood loss in patients undergoing bilateral total knee replacement surgery. In a previous study by Hiippala ST et al.,¹³ 22 patients out of the total 39 required transfusion of red cells. The requirement of red cell transfusion was significantly lower in the group which received tranexamic acid compared to the control group in their study. In the study by Dhillon MS et al.,¹⁸ only 25 of their 52 patients who received tranexamic acid required blood transfusion. While, in the retrospective study by Sepah YJ et al.,¹⁹ only 6 (12.76%) out of the 47 patients in the tranexamic acid group required blood transfusion in their analysis. MacGillivray et al.,¹⁷ used autologous reinfusion (from intra-articular drains) strategy. This in turn leading to a lesser allogenic transfusion requirement. This reinfusion technique is not available in our centre and at many other centers in India. There are very few studies which have assessed the effect of dexmetomidine in decreasing blood loss during surgical procedures. Durmus M et al.,¹⁵ showed that dexmetomidine has pro and antiplatelet aggregation properties though the coagulation was found to be within normal ranges. However, another study by Kosea EA et al., reported no effect of therapeutic doses of dexmetomidine in an in vitro experiment.²⁰ In line with this, we did not observe any effect of dexmetomidine over coagulation as evidenced by no change in PT values. Also, none of the patients developed thromboembolic complications postoperatively. Contrary to the reports of Durmus M et al,¹⁵ Mizrak A et al.,²¹ showed that premedication with DEX 0.5 mg/kg was effective in decreasing the postoperative agitation, pain, and analgesic requirement but increased the bleeding slightly in pediatric patients undergoing adenotonsillectomy. Ibraheim OA et al.,²² studied the efficacy of dexmetomidine on intraoperative blood loss compared to esmolol or control group in patients undergoing scoliosis surgeries. The authors found the blood loss to be least among patients who received dexmetomidine (465 ml) compared to the esmolol (667 ml) and control group (782 ml). Dexmetomidine has additional properties like sedation, reduces patient anxiety, maintains hemodynamic stability and decreases requirement of opioid analgesics both in the intra operative as well as postoperative period. This in turn results in rapid recovery from anaesthesia postoperatively.^23,24 Thus, the findings from our study encourage the use of dexmetomidine in combination with the traditionally used tranexamic acid in patients undergoing bilateral total knee replacement surgery.

CONCLUSION

The combination of Tranexamic acid and dexmedetomidine is effective in reducing total blood loss following bilateral total knee replacement surgery and its efficacy is better when compared to the traditional use of tranexamic acid alone.

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