Application of Different Doses of Tranexamic Acid Plus Traditional Chinese Medicine in Hip Arthroplasty in Patients with Diabetes and Its Influence on Intraoperative Blood Loss and Postoperative Drainage.

Objective: To evaluate the efficacy of different doses of tranexamic acid plus traditional Chinese medicine (TCM) in hip arthroplasty in diabetic patients and the effect on intraoperative hemorrhage and postoperative drainage.
Methods: One hundred patients admitted to our hospital from January 2019 to September 2021 were randomly divided into group B (n = 50) and group A (n = 50), and tranexamic acid was injected intravenously at a dose of 10 mg/kg and 20 mg/kg 30 min before skin incision, and then tranexamic acid 1.0 g was injected into the joint cavity through the drainage after incision closure, followed by 3 h of drainage clamping. The amount of blood loss, coagulation index, postoperative drainage, and incidence of venous thromboembolism (VTE) were compared between the groups.
Results: Group A had significantly less total blood loss, dominant blood loss, and hidden blood loss than group B (P < 0.05). No significant difference in postoperative coagulation indexes and postoperative drainage flow was found between the two groups (P > 0.05). Serological examination results demonstrated no statistical difference in D-dimer (D-D) levels between the two groups. The absence of VTE in both groups was determined by imaging.
Conclusion: Tranexamic acid is effective in reducing intraoperative hemorrhage in diabetic patients undergoing hip arthroplasty. The dose of 20 mg/kg outperforms 10 mg/kg in terms of clinical efficacy with a favorable safety profile, which can be applied according to the patient's actual condition.

1. Introduction

Hip arthroplasty is the main treatment for femoral neck fracture and hip osteoarthritis, in which the diseased joint is replaced by an artificial prosthesis to restore the function of the hip joint and improve the quality of life of patients. At present, hip arthroplasty is extensively used in clinical practice with clear therapeutic effects. However, due to the rich blood supply around the hip joint, intraoperative soft tissue dissection and intracavitary marrow expansion are associated with intraoperative hemorrhage, which requires blood transfusion to maintain effective circulating blood volume [1-3]. Although blood transfusion relieves the organ burden caused by massive blood loss, patients are predisposed to complications such as immune reaction and autohemolysis [4, 5], especially for those with underlying diseases such as diabetes mellitus where blood transfusion is insufficient to reduce their surgical risk. Diabetic patients generally have poor surgical tolerance due to the long-term hyperglycemia of the organism, and massive intraoperative blood loss leads to cardiac and renal dysfunction and poor wound healing, thereby increasing the perioperative mortality of patients [6, 7]. Therefore, intraoperative bleeding control in diabetic hip arthroplasty patients is crucial to safeguard their prognosis. Mechanical hyperfibrinolysis induced by intraoperative manipulation is a key factor in triggering perioperative hemorrhage. Tranexamic acid (TXA), a synthetic derivative of lysine, achieves hemostasis by preventing the degradation of fibrin by fibrinolytic enzymes [8, 9] and is therefore frequently used in hip arthroplasty. 10 mg/kg is clinically considered the optimal dose for intravenous application, which provides optimal hemostasis with a low risk of venous thromboembolism (VTE) [10]. Knee osteoarthritis (KOA) belongs to the category of “arthritis” in TCM and is mostly caused by deficiency of liver and kidney, lack of Qi and blood, lack of nourishment of muscles and bones, combined with external pathogens causing cold, dampness, phlegm, and blood stasis, or overwork, falling, and fluttering. The principles of TCM treatment are to nourish the liver and kidneys, relieve pain, and activate blood circulation to remove blood stasis, but the clinical evidence should be used dialectically. Nevertheless, the efficiency of 10 mg/kg is uncertain for diabetic patients given their special physical status. Accordingly, this study was to investigate the reasonable dosage of TXA for diabetic hip arthroplasty patients, with the aim of providing a reference for the optimal use of the drug.

2. Materials and Methods

2.1. Inclusion and Exclusion Criteria

The data of patients admitted to our hospital from January 2019 to September 2021 were retrospectively analyzed, and patients were included according to the following criteria: (1) patients who were diagnosed by blood glucose monitoring, X-ray, and computed tomography (CT), and met the diagnostic criteria in the Expert Consensus on the Diagnostic Criteria for Adult Femoral Head Necrosis [11]; (2) without hospital referral; (3) aged over 18 years old; (4) without severe hip deformity; (5) without deep vein thrombosis (DVT) confirmed by color Doppler ultrasound; (6) patients who received hip arthroplasty; (7) with reference to the American College of Rheumatology's diagnostic criteria for osteoarthritis of the knee: frequent recurrent knee pain in the last month; bone rubbing sounds on joint movement; morning stiffness of less than 30 minutes; age older than 40 years; and hypertrophy of the bone ends with osteophytes on examination of the knee.

Patients were excluded according to the following criteria: (1) patients with mental disorders or language disorders that prevented communication; (2) with coagulation disorders or high-risk bleeding factors; (3) with a history of vascular embolism; (4) with allergies to TXA; (5) with rheumatism, rheumatoid arthritis, gout, osteoarthrosis, and bone tumors; (6) with a history of deep vein thrombosis or long-term use of hormones; (7) with a history of knee replacement surgery; (8) with a history of bleeding disorders; (9) with serious heart, liver, kidney, and hematopoietic system diseases; (10) those who failed to perform functional exercises and follow-up examinations as prescribed by the doctor and those with incomplete information that affects the evaluation of the efficacy of the treatment.

2.2. General Data of Patients

A total of 100 patients were included according to the inclusion and exclusion criteria, and they were randomly and equally divided into group A (n = 50) and group B (n = 50). There was no statistical difference in the general data of the two groups (P > 0.05), as shown in Table 1.

Table 1

Comparison of general data of patients.

Groups	Group A (n = 50)	Group B (n = 50)	X 2/t	P value
Gender			0.161	0.688
Male	28	26
Female	22	24
Mean age	55.10 ± 3.56	55.20 ± 3.44	0.143	0.887
Mean height	175.65 ± 15.65	176.11 ± 15.40	0.148	0.883
Mean weight (kg)	60.65 ± 2.32	60.84 ± 2.40	0.402	0.688
BMI (kg/m2)	22.77 ± 1.25	22.98 ± 1.33	0.814	0.418
Hemoglobin (g/L)	124.98 ± 12.65	125.10 ± 12.55	0.048	0.962
Erythrocyte volume (L/L)	0.48 ± 0.03	0.49 ± 0.04	1.414	0.161
Replacement
Left	18	20	0.170	0.680
Right	20	19	0.042	0.838
Both	12	11	0.057	0.812
Marital status
Married	30	34	0.694	0.405
Unmarried	12	10	0.233	0.629
Divorced/widowed	8	6	0.332	0.564
Place of residence			0.040	0.841
Urban	28	27
Rural	22	23
Living habits
Smoking	24	20	0.649	0.420
Drinking	22	26	0.641	0.423

2.3. Ethical Considerations

This study was approved by the Liuzhou Municipal Liutie Central Hospital (no. LZ8791/97) and was in accordance with the principles of the Declaration of Helsinki (2013) [12], and the patients had signed an informed consent form.

2.4. Methods

Both groups of patients underwent hip arthroplasty by the same group of surgeons with a posterolateral approach. The TCM treatment of occult blood loss and anemia after TKA mostly adopts the methods of tonifying Qi, promoting blood circulation, and stopping blood stasis according to the pathogenesis of the disease. TKA surgery relieves pain and rebuilds knee function but fails to modify the patient's overall weakness of the spleen and stomach. Siwei Buxue Decoction is a famous traditional formula consisting of Astragalus, Radix Angelicae Sinensis, Corni Fructus, and roasted licorice. All herbs in this formula work together to strengthen the spleen, benefit the Qi, nourish the liver and kidney, and invigorate the blood to replenish the blood. Modern pharmacological studies have shown that Astragalus can promote the renewal of serum and liver proteins, promote cell proliferation and reduce thrombosis; Radix Angelicae Sinensis can significantly promote the production of Hb and RBC; Corni Fructus has enhanced nonspecific immune function, antibacterial, and antiswelling effects; and roasted licorice has antibacterial, anti-inflammatory, gastrointestinal protection, and antiswelling effects. The surgical instruments were supplied from Stryker (Beijing) Medical Equipment Co. Ltd. (State Food and Drug Administration Arms Entry no. 1102637, 2014). TXA (Kaifeng Pharmaceutical Group Co. Ltd., State Drug Administration H20067374) was injected intravenously at a dose of 10 mg/kg in group B and 20 mg/kg in group A 30 min before skin incision. After the closure of the incision, TXA 1.0 g was injected into the joint cavity through the drainage tube, followed by the drainage clamping for 3 h. The drainage tube was connected to an autologous blood transfusion device, and the blood drained from the device was routinely returned to the patient without negative pressure suction 6 h after surgery, and the drainage was removed 48 h after surgery. Patients were given rivaroxaban (Bayer AG, Germany, HJ20200024) at 12 h postoperatively, 1 capsule daily for 35 d. Functional exercise of the lower extremities was performed at 24 h postoperatively.

General data: the general data contained patients' gender, age, height, weight, BMI, preoperative hemoglobin, preoperative erythrocyte volume, replacement position, marital status, place of residence, and living habits.

Blood loss: blood loss contains total blood loss (TBL), dominant blood loss (DBL), and hidden blood loss (HBL). Blood volume was calculated preoperatively according to the patient's height and weight (blood volume = k1 × height + k2 × weight + k3), with the constant terms k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041 for male, and k1 = 0.3561, k2 = 0.03308, k3 = 0.1833 for female. DBL was calculated according to the blood volume formula. DBL was the sum of the blood volume drained into the autologous blood retriever and the net weight gain of gauze, and HBL was calculated according to the formula for hidden red blood cell loss proposed by Sehat and Evans [13].

Coagulation indexes: the coagulation indexes of the patients were measured postoperatively with the automatic coagulation analyzer (Coatron 1800, original kit, no. 2402724, 2013), including activated partial thromboplastin time (APTT), prothrombin time (PT), and international normalized ratio (INR).

Postoperative drainage volume: the cumulative drainage volume of patients at 12 h, 24 h, 36 h, and at extubation after surgery was recorded.

Incidence of VTE: patients were screened for VTE 1 week after surgery, i.e., screening for the occurrence of DVT and pulmonary embolism (PTE) in the lower extremities: (1) DVT: D-dimer (D-D) test was performed on the patient with a fully automated coagulation analyzer. DVT was excluded with a negative test, and if positive, lower limb venous ultrasound was performed to determine the presence of DVT. (2) PTE: the D-D test was performed on the patient with a fully automated coagulation analyzer, PTE was excluded with a negative test, and if positive, CT pulmonary angiography (Philips, State Food and Drug Administration Arms Entry 2008 no. 3303600) was performed to determine the presence of PTE.

2.6. Statistical Analyses

SPSS 20.0 was used for data analyses, and GraphPad Prism 7 (GraphPad Software, San Diego, USA) was used for image rendering. The count data were processed by the chi-square test, and the measurement data were analyzed using the t-test. Differences were considered statistically significant at P < 0.05.

3. Results

3.1. Comparison of General Data

The two groups presented comparable general data (P > 0.05), as shown in Table 1.

3.2. Comparison of Blood Loss

Group A had significantly less TBL, DBL, and HBL than group B (P < 0.05), as shown in Figures 1(a)–1(c).

Figure 1

Comparison of TBL, DBL, and HBL in patients (, ml). (a) The abscissa is group A and group B from left to right, and the ordinate is TBL (ml); # indicates P < 0.05. The TBL in group A was significantly less than that in group B (331.50 ± 77.01 vs. 496.12 ± 310.23, P < 0.05). (b) The abscissa is group A and group B from left to right, and the ordinate is DBL (ml); # indicates P < 0.05. The DBL in group A was significantly less than that in group B (254.33 ± 70.61 vs. 283.10 ± 70.25, t = 13.254, P < 0.05. (c) The abscissa is group A and group B from left to right, and the ordinate is HBL (ml); # indicates P < 0.05. The HBL in group A was significantly less than that in group B (30.11 ± 10.23 vs. 56.23 ± 15.65, P < 0.05).

3.3. Comparison of Coagulation Function Indexes

There was no significant difference in the postoperative coagulation function indexes between the two groups of patients (P > 0.05), as shown in Figures 2(a)–2(c).

Figure 2

Comparison of postoperative APTT, PT, and INR of patients (, t/s). (a) The abscissa is group A and group B from left to right, and the ordinate is APTT (t/s). There was no statistical difference in APTT between the two groups (30.12 ± 0.05 vs. 30.45 ± 0.09, P > 0.05). (b) The abscissa is group A and group B from left to right, and the ordinate is PT (t/s). There was no statistical difference in PT between the two groups (9.23 ± 0.07 vs. 9.18 ± 0.08, P > 0.05). (c) The abscissa is group A and group B from left to right, and the ordinate is INR. There was no statistical difference in INR between the two groups (31.98 ± 4.65 vs. 31.00 ± 4.14, P > 0.05).

3.4. Comparison of Postoperative Drainage Volume

No significant difference in postoperative drainage volume was found between the two groups (P > 0.05), as shown in Table 2.

Table 2

Comparison of postoperative drainage volume in patients (, ml).

Groups	Group A (n = 50)	Group B (n = 50)	t	P value
12 h	182.65 ± 12.55	185.98 ± 15.65	1.174	0.243
24 h	210.65 ± 23.65	215.22 ± 25.98	0.920	0.360
48 h	289.65 ± 20.65	292.65 ± 30.55	0.575	0.566
At extubation	344.48 ± 23.65	350.65 ± 36.99	0.994	0.323

3.5. Comparison of VTE Incidence

The results of the serological examination showed no statistical difference in D-D levels between the two groups (732.65 ± 13.65 vs. 735.98 ± 15.44, P > 0.05), and the presence of DVT and PTE in both groups was excluded by imaging, i.e., no occurrence of VTE in both groups.

4. Discussion

Several studies have shown that comorbid diabetes increases the risk of surgical procedures, especially in patients with a long course of diabetes and usually combined with cardiovascular and cerebrovascular diseases such as coronary heart disease and hypertension. These patients typically have poor organism tolerance and a higher surgical risk than nondiabetic patients [14-16]. Godshaw et al. revealed that perioperative blood loss is the main risk for diabetic patients [17] and that massive blood loss may lead to cardiac and renal dysfunction, thereby resulting in poor prognosis. Notwithstanding the standardization and formalization of hip arthroplasty, surgical exposure, acetabular polishing, and femoral expansion are associated with excessive intraoperative blood loss, and hidden blood loss has been frequently reported [18, 19], due to a large amount of blood leaking into the tissue spaces and joint cavities during surgery, with total bleeding in patients reaching more than 2000 ml. Blood transfusion is the most common solution for blood loss during hip arthroplasty, but with blood resources shortage in China and the risk of hemolysis, the exploration of more effective measures to reduce intraoperative bleeding remains a major clinical issue to be addressed.

In 1976, a study reported the use of TXA in orthopedic treatment to reduce bleeding in patients [20]. Recent literature confirms that surgical trauma leads to the release of tissue-type fibrinogen activators, which degrades fibrin and multiple coagulation factors, decreasing their plasma levels and activity [21]. The mechanism of action of TXA is to prevent fibrin degradation by fibrinolytic enzymes. TXA binds saturated to the lysine binding site of fibrinogen and competitively inhibits fibrinogen activation and fibrinolytic enzyme binding proteins to achieve hemostasis. Previous research concluded that 10 mg/kg is the most effective and safe dose in hip arthroplasty [22], but the dosage for diabetic patients remains poorly understood. In the present study, 20 mg/kg TXA was applied by intravenous injection, and it was found that TBL, DBL, and HBL in group A were significantly less than those in group B (P < 0.05), indicating a better hemostatic effect by high-dose TXA in diabetic patients. Notably, the two groups had similar postoperative drainage volumes (P > 0.05), which may be attributed to the blocking saturation of the fibrinogen, fibrinolytic enzyme, and tissue-type fibrinogen activator lysine binding sites by TXA in the two groups, resulting in virtually equivalent postoperative trauma bleeding volumes in the two groups.

Consensus on the optimal application of TXA has yet to be developed in academia. Though most scholars proved the availability of TXA for systemic administration, there is a high risk for intravenous injections in elderly patients with comorbid underlying diseases, and there is also a risk of postoperative DVT in patients [23]. It has been found that the application of TXA in intra-articular cavity injection can further enhance the hemostatic effect because intra-articular TXA targets active bleeding sites and increases the stability of the fibrin clot, thereby avoiding blood loss from the tissue surface [24]. It has been reported that intra-articular injection did not increase the incidence of VTE [25]; however, uncertainties remain on the risk of complications associated with intravenous injection. In the present study, both intravenous and intra-articular injections were performed, and no significant differences were found between the two groups in terms of postoperative coagulation indexes (P > 0.05), serological examination showed no statistical differences in D-D levels between the two groups, and the absence of VTE in both groups was confirmed by imaging, indicating no increase in the probability of thrombosis in diabetic patients with intravenous high-dose TXA.

The presence of anemia in patients after knee arthroplasty impairs postoperative joint function recovery and compromises their quality of life. Hemostasis of the intramedullary cancellous bone surface is difficult in patients treated with total knee arthroplasty, and postoperative anemia is relatively common in elderly and frail patients. In this regard, the treatment efficacy of conventional Western medical treatment is unfavorable. The Siwei Buxue Decoction can improve patients' postoperative anemia by benefiting Qi and nourishing the blood. In clinical practice, ferrous sulfate tablets are used to treat iron deficiency anemia, and malnutrition. In the treatment of patients with anemia after knee arthroplasty, the application of Siwei Buxue Decoction can mitigate the patient's anemia symptoms and promote the recovery of limb function after knee arthroplasty.

In conclusion, tranexamic acid is effective in reducing intraoperative hemorrhage in diabetic patients undergoing hip arthroplasty. The dose of 20 mg/kg outperforms 10 mg/kg in terms of effectiveness, with a favorable safety profile, which can be applied according to the patient's actual condition.