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Anesth Analg 1999;89:1382
© 1999 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

A Comparative Study of the Postoperative Allogeneic Blood-Sparing Effect of Tranexamic Acid Versus Acute Normovolemic Hemodilution After Total Knee Replacement

Edna Zohar, MD*, Brian Fredman, MB BCh*, Martin Ellis, MB BCh{dagger}, Ilya Luban, MD*, Avraham Stern, MD{ddagger}, and Robert Jedeikin, BSc, MB ChB, FFA(SA)*

Departments of *Anesthesiology and Critical Care, {dagger}Blood Bank, and {ddagger}Orthopedic Surgery, Meir Hospital, Kfar Sava, The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Address correspondence and reprint requests to Robert Jedeikin, BSc, MB ChB, FFA(SA), Department of Anesthesiology and Intensive Care, Meir Hospital, Kfar Saba 44281, Israel.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Both acute normovolemic hemodilution (NVHD) and tranexamic acid (TA) are potentially useful allogeneic blood conservation strategies after total knee replacement. However, the relative efficacy of these blood-sparing techniques is unknown. Therefore, to compare the postoperative allogeneic blood sparing of NVHD and TA after total knee replacement, we investigated 40 patients in a prospective, single-blinded study protocol. In Group TA, 30 min before deflating the limb tourniquet, an IV infusion of TA, 15 mg/kg, was administered over a 30-min period. Thereafter, a constant IV infusion of 10 mg · kg-1 · hr-1 was administered until 12 h after deflation of the limb tourniquet. Before induction of anesthesia, NVHD patients were bled to a target hematocrit of approximately 28%. Intravascular blood volume was maintained with lactated Ringer’s solution. All autologous blood was transfused at the end of the surgery. Postoperatively, hematocrit was measured daily. In all cases, a hematocrit <27% was the postoperative transfusion trigger. Before discharge, deep vein thrombosis was excluded by Echo Doppler. Three months after surgery, the incidence of delayed thrombo-embolic events was assessed. The two groups were demographically comparable. In Group NVHD, 843 mL ± 289 of autologous blood was removed. Despite autologous blood transfusion, during the early postoperative period and until the third postoperative day, the NVHD group had significantly (P < 0.01) lower mean hematocrits when compared with the TA group. Thereafter, because of a significantly (P < 0.0008) greater allogeneic blood requirement in the NVHD group, no statistically significant difference in mean hematocrit recordings was noted among the groups. Blood accumulation in the surgical drain 12 h postoperatively, was significantly (P < 0.0008) higher in the NVHD group (259 mL ± 156) when compared with the TA group (110 mL ± 62). Significantly (P < 0.0008) more allogeneic blood was transfused in the NVHD group (19 U/13 patients) when compared with the TA group (2 U/2 patients). No abnormal Echo Doppler studies were reported. During the 3-mo follow-up period, a deep vein thrombosis and pulmonary embolus were documented in one patient in the NVHD group. We conclude that perioperative hemodynamic stability and allogeneic blood sparing is superior after tranexamic acid administration when compared with normovolemic hemodilution.

Implications: For total knee replacement, when compared with normovolemic hemodilution, tranexamic acid administration is associated with superior perioperative hemodynamic stability and allogeneic blood sparing.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
In an attempt to decrease medical costs and blood transfusion-transmitted disease, alternative transfusion protocols have been sought (1,2). However, these protocols are not without associated problems. Although preoperative autologous blood donation may be performed, this technique is an expensive blood conservation strategy. Furthermore, after predeposit of autologous blood, administrative errors may result in incompatible blood transfusion (1–6). Similarly, hemoglobin solutions, perfluorocarbons, and liposome-encapsulated hemoglobin are expensive, have a limited circulatory half-life, and do not replace the coagulant functions of natural blood products (7,8).

Acute normovolemic hemodilution (NVHD) is a potentially useful blood conservation strategy (2,9). Because autologous blood is ultimately transfused, this simple technique does not require compatibility testing and is not associated with infectious disease transmission. In addition, the decreased blood viscosity and the consequent increase in blood flow associated with NVHD is likely protective against postoperative thromboembolic complications (10,11). However, data regarding the compensatory capacity of elderly patients during NVHD are limited (12,13). Therefore, despite NVHD-associated allogeneic blood sparing, this blood conservation strategy may be unsuitable for many geriatric patients.

Epsilon aminocaproic acid, tranexamic acid (TA), and aprotinin inhibit fibrinolysis. Consequently, these drugs support clot stability and decrease bleeding. In the surgical setting, TA and epsilon aminocaproic acid reduce blood loss and allogeneic blood requirements after tonsillectomy, prostatectomy, cervical conization, coronary artery bypass grafting, and liver transplantation (14–16). However, thromboembolic complications are a significant problem after major surgical procedures (17–19). Therefore, because of concerns that antifibrinolytic drug administration may augment the incidence of this potentially life-threatening complication, the risk/benefit ratio of TA administration has been questioned (20).

Because total knee replacement (TKR) is performed with an occlusive tourniquet and is associated with minimal intraoperative but extensive postoperative blood loss, this surgical procedure is ideally suited for evaluating the efficacy of blood conservation techniques that decrease postoperative blood loss. Furthermore, after TKR, acute hemodilution is an effective blood conservation strategy (21). In addition, when administered to patients undergoing TKR, TA significantly reduces blood loss and transfusion requirements (20). However, there have been no controlled, prospective, blinded studies designed to assess the blood sparing effects of TA administration when compared with NVHD in patients undergoing TKR. Therefore, we performed a study designed to compare the allogeneic blood-sparing effect of TA versus NVHD in patients undergoing TKR.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Forty healthy (ASA physical status I–III) patients undergoing elective TKR were enrolled in this institutional, review board-approved, randomized, prospective, single-blinded study. Written, informed consent was obtained in all cases.

Patients with a history of severe ischemic heart disease (New York Heart Association Class III, IV), chronic renal failure, liver cirrhosis, bleeding disorders, or current anticoagulant therapy were excluded.

Upon arrival in the operating room (OR) holding area, the radial artery was cannulated and monitoring equipment applied. Throughout the perioperative period, the following variables were recorded at 1- to 5-min intervals: intraarterial blood pressure, electrocardiogram, and peripheral hemoglobin oxygen saturation.

According to a computer-generated randomization table, patients were allocated to one of two treatment groups. In Group TA, approximately 30 min before deflating the limb tourniquet, an IV infusion of TA 15 mg/kg was administered over a 30-min period. Thereafter, a constant IV infusion of 10 mg · kg-1 · hr-1 was administered until 12 h after deflation of the limb tourniquet. In Group NVHD, while in the OR holding area, the patients were bled through a 16-gauge needle placed in the antecubital fossa, to a target hematocrit of approximately 28%, using standard blood-collection sets containing citrate-phosphate-dextrose with adenine (CPDA-1; Teva Medical Laboratories, Ltd., Petah-Tiqua, Israel). Blood volume was maintained with lactated Ringer’s solution in a 1:3 (blood/Ringer’s) replacement ratio such that arterial pressure and heart rate remained unchanged. The volume of blood removed was calculated by weighing the collection bag before and after blood removal and assuming that 1 g represented 1 mL of whole blood. All the collected autologous blood was stored in the OR at room temperature.

A standardized general anesthetic technique was administered. This included IV thiopental, 4–6 mg/kg, and fentanyl 6–10 µg/kg for induction of anesthesia. Thereafter, isoflurane (0.5%–1.5%, end-tidal) and 70% nitrous oxide in oxygen was administered for maintenance of general anesthesia. Tracheal intubation was facilitated by succinylcholine 1.0 mg/kg, IV, and surgical relaxation maintained (monitored by a peripheral nerve stimulator) with IV vecuronium. After induction of anesthesia, end-tidal carbon dioxide concentration was monitored and urinary bladder catheterized.

Before surgical incision, a tourniquet was placed and after limb exsanguination, the operative limb isolated. After placement of the prosthesis, the tourniquet was released and hemostasis performed. Intraoperative blood loss was measured by recording blood accumulation in the suction bottles as well as by weighing the surgical pads.

During the surgical procedure, lactated Ringer’s solution was administered to maintain the heart rate and mean arterial blood pressure within 20% of baseline values as well as a urine output of at least 2 mg · kg-1 · hr-1. No blood was administered intraoperatively.

On arrival in the postanesthesia care unit (PACU), autologous blood was reinfused over a 2-h period. Hematocrit was measured every 2 h for the duration of the PACU admission. Thereafter, from the first postoperative day and throughout the duration of the hospital admission hematocrit was measured daily. If the hematocrit was <28% but >27%, the hematocrit was measured 12 h later. In all cases a hematocrit <27% constituted the postoperative transfusion trigger. The decision to transfuse allogeneic blood was made by an independent observer (M. Ellis) who was blinded to the treatment modality.

One day before surgery, and for the duration of the hospital admission, enoxaparine 40 mg/day was administered for deep vein thrombosis (DVT) prophylaxis. The volume of blood in the surgical drain was measured 12 and 24 h, postoperatively. Thereafter, to decrease possible infection, the drain was removed.

Hemoglobin, prothrombin time, partial thromboplastin time, and platelet count were measured on arrival in the OR, on discharge from the PACU, and once daily for 8 days, postoperatively.

The following time intervals were recorded and compared: anesthetic time (time from induction of anesthesia until extubation), surgical time (skin incision until skin closure), tourniquet time (time from inflation until deflation), and hospital admission.

All patients were examined daily for signs of lower limb DVT. Furthermore, in all cases, bilateral lower limb Echo Doppler was performed on the fifth postoperative day. All patients were interviewed 3 mo after hospital discharge and the incidence of DVT, pulmonary embolus, myocardial infarction, transient ischemic attack, and stroke were recorded.

Data are expressed as mean values ± SD or SEM. In all cases, normality was assessed with the Kolmogorov-Smirnov test (using the Lilliefors’ modification). Depending on the results of the Kolmogorov-Smirnov analysis, either parametric or nonparametric analysis was performed. Descriptive variables were analyzed using {chi}2 tests. Continuous variables were analyzed using analysis of variance (with Bonferroni’s correction for multiple comparisons). In all comparisons P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The two groups were comparable in age, weight, height, sex, and ASA physical status (Table 1). The anesthetic time, surgical time, tourniquet time, and hospital admission time were similar among the groups (Table 2). In Group NVHD, to achieve the target hematocrit of approximately 28%, 843 ± 289 mL of blood was removed. During blood removal, two patients experienced profound hypotension with associated nausea and vomiting. As a result of the study design, crystalloid administration (crystalloid administered to replace blood removed plus crystalloid administered to replace intraoperative losses) was significantly (P <= 0.01) higher in the NVHD group (63.3 ± 15.5 mL/kg versus 37 ± 11.2 mL/kg for the NVHD and TA Groups, respectively). By contrast, during the postoperative period, crystalloid administration was similar among the groups. Despite hemodilution there was no significant difference in perioperative urine output (Table 3). After induction of anesthesia, the incidence of hypotension and ephedrine administration was significantly (P < 0.01) higher in the NVHD group (Table 3). There was no difference in intraoperative blood loss among the groups (281 ± 139 mL versus 280 ± 130 mL for the NVHD and TA Groups, respectively).


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  		Table 1. Patient Characteristics in the Two Treatment Groups
 

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  		Table 2. Time Intervals in the Two Treatment Groups
 

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  		Table 3. Fluid Balance and Drug Administration in the Two Treatment Groups
 
In accordance with the study design, immediately before induction of anesthesia, hematocrit values in the NVHD group were significantly (P < 0.05) lower than the TA group. Similarly, on PACU arrival, a significantly (P < 0.05) higher mean hematocrit was recorded in the TA group (Fig. 1). During the PACU admission, despite autologous blood transfusion, the NVHD group was associated with significantly lower mean hematocrit when compared with the TA group. This significant difference in hematocrit was noted until the third postoperative day. Thereafter, because of a significantly (P < 0.0008) larger allogeneic blood requirement in the NVHD group (Table 4), no statistically significant difference in mean hematocrit recordings was noted among the groups (Fig. 1).



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  		Figure 1. Perioperative hematocrit in the normovolemic hemodilution (triangles) and tranexamic acid (squares) study groups. *P < 0.05.

 

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  		Table 4. Postoperative Allogeneic Blood Administration in the Two Treatment Groups
 
Twelve hours postoperatively, blood accumulation in the surgical drain was significantly (P < 0.0008) higher in the NVHD group (259 mL ± 156) when compared with the TA group (110 mL ± 62). However, 12 h thereafter (24 h postoperatively), additional blood accumulation in the surgical drain was statistically comparable among the groups (99 ± 46 mL versus 132 ± 123 mL for Groups TA and NVHD, respectively).

During the postoperative period allogeneic blood transfusion was significantly (P < 0.0008) larger in the NVHD group (13 patients received 19 U) when compared with the TA group (two patients each received 1 U) (Table 4).

Skin discoloration and subcutaneous hematoma were noted in six patients in each study group. A clinical DVT was suspected in one patient in the NVHD study group. However, no abnormal Echo Doppler studies were reported.

Preoperative platelet count, prothrombin time, and partial thromboplastin time were similar among the groups. After hemodilution and throughout the postoperative period, evaluation of these variables revealed no significant difference among the groups.

In the 3-mo follow-up, two patients (one patient in each group) were not located. Of the remaining 38 (95%) patients, one patient in the NVHD group was documented as having developed a DVT and consequent pulmonary embolus. After a short hospital admission the patient was discharged on oral anticoagulant therapy. In the TA group no postoperative thromboembolic events were documented.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of our study suggest that, when compared with NVHD, TA administration constitutes a superior allogeneic blood-sparing strategy when performed for TKR. This suggestion is supported by the fact that during the late recovery period, patients who underwent hemodilution received significantly more allogeneic blood to maintain the predefined target hematocrit. Furthermore, 12 hours postoperatively, blood accumulation in the surgical drain was significantly lower in the TA group when compared with the NVHD group. In addition, during the postoperative period, NVHD was associated with consistently lower hematocrit recordings when compared with those of patients in the TA group. This finding is of particular importance because, in the NVHD group, all autologous blood was replaced after PACU admission. Because the decision to administer allogeneic blood was made by a blinded investigator (M. Ellis) and a postoperative hematocrit of <27% constituted the only transfusion trigger, we believe that these results are a true reflection of the relative efficacy of the two blood conservation strategies.

In addition to inferior allogeneic blood conservation, NVHD was associated with an increased incidence of perioperative hemodynamic complications. First, during blood removal, 2 (10%) patients in the NVHD group experienced profound hypotension with associated nausea and vomiting. Second, after induction of anesthesia, the incidence of hypotension and ephedrine administration (by a nonblinded investigator) was significantly (P < 0.01) higher in the NVHD group (70% vs 30% for the NVHD and TA groups, respectively). Although hemodilution has been shown to be well tolerated in elderly patients with no known cardiac disease (11), the incidence of hemodynamic instability was unacceptably high in our NVHD group. However, in our investigation, this high incidence of hemodynamic instability may have been study design-induced. We suspect that, before induction of anesthesia, optimizing intravascular volume by monitoring central venous or pulmonary occlusion pressure may have resulted in improved cardiovascular stability. Furthermore, because undiagnosed cardiovascular disease is common in geriatric patients undergoing TKR, it may be prudent to confirm a negative history of cardiovascular disease using objective investigations before performing hemodilution. However, extensive investigations and invasive monitoring would likely negate the financial advantages of hemodilution as a blood-sparing technique.

The superior blood sparing associated with TA administration is likely the result of the mechanisms whereby TA and hemodilution facilitate allogeneic blood sparing. It has been postulated that the application of a pneumatic tourniquet (and consequent tissue hypoxia) increases tissue plasminogen activator secretion from the vascular endothelium (22,23). As a result, there is increased fibrinolytic activity in the operative limb. Because excessive fibrinolysis increases bleeding, the postoperative bleeding associated with TKR may be attributed to fibrin depletion. TA inhibits fibrinolysis by saturating lysine binding sites on the plasminogen molecule. As a result, plasminogen is displaced from the fibrin surface. Because plasmin (the activated form of plasminogen) controls fibrin degradation, TA is a potent inhibitor of fibrinolysis. By contrast, NVHD has no direct antifibrinolytic effect. The allogeneic blood sparing associated with hemodilution is multifactorial. First, because NVHD decreases hematocrit, blood with a low red cell mass is lost into the extravascular compartment (20). Second, it has been postulated that hemodilution results in improved blood flow in the microcirculation, and thus decreases coagulopathies and postoperative bleeding (24,25). Finally, fresh autologous blood has preserved platelets and clotting factors. Thus, when compared with the control, NVHD is associated with significant allogeneic blood conservation (20). However, the results of our study demonstrate that, when compared with TA, NVHD is a less effective blood-sparing strategy for TKR. We hypothesize that the postoperative bleeding associated with TKR is secondary to extensive tourniquet-induced fibrinolysis in the operative limb. Because autologous blood has hemostatic but no specific antifibrinolytic effect, hemodilution is a relatively ineffective allogeneic blood-sparing technique for TKR. Furthermore, the volume of clotting factors and platelets reinfused after NVHD is limited by a combination of the patient’s preoperative hematocrit, cardiovascular compensatory capacity, as well as the desired target hematocrit after blood removal.

This study might be criticized because of the absence of a control group. However, in view of previous studies describing blood transfusion requirements after TKR (20,21), randomizing patients into a treatment group that would probably be exposed to greater allogeneic blood requirements (and blood-induced complications) was ethically unacceptable. A second possible criticism is the fact that the sample size studied was insufficient to compare the relative incidence of thrombo-embolic adverse effects. However, in patients receiving DVT prophylaxis, the incidence of venographically confirmed DVT after TKR is 30%–40% (26,27). To reliably evaluate the effect of a particular blood conservation strategy on postoperative thrombotic complications, a multicenter study would be required. However, despite the relatively small number of patients in our study, it is interesting to note that the 3-mo follow-up revealed a low incidence of thrombo-embolic events.

In conclusion, using our treatment protocol for TKR, TA administration is associated with superior perioperative hemodynamic stability and allogeneic blood sparing when compared with NVHD. However, the effect of this antifibrinolytic drug on the incidence of thrombo-embolic phenomena requires further investigation.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication July 27, 1999.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press