A combined drug for anesthesia and analgesia

Abstract

The present invention provides a combined drug, which contains ropivacaine, adrenaline and glucocorticoid for simultaneous or separate administration in the form of the same or different specification unit preparations, has good local anesthetic and postoperative analgesic effects, and is further supplemented with adjuvants such as magnesium sulfate and sodium bicarbonate, which can prolong the postoperative analgesic effect while ensuring the local anesthetic effect, effectively relieve early pain, accelerate the early recovery after total knee arthroplasty, and has clinical application value.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to a combined drug for anesthesia and analgesia. Background Art

[0002] Total knee arthroplasty (TKA) is the main means to solve end-stage knee joint diseases, relieve knee joint pain and reconstruct knee joint function. More than 60% of TKA patients will experience moderate to severe pain after surgery. Severe pain after surgery often prevents patients from participating in rehabilitation training in the early postoperative stage and may delay recovery by having a negative impact on diet, sleep and mood. Activity limitations caused by pain may lead to complications such as decreased pulmonary ventilation function, gastrointestinal function inhibition, deep vein thrombosis of the lower extremities, pulmonary embolism and cognitive dysfunction after surgery. Therefore, effective control of pain after TKA is an important link in strengthening the concept of rehabilitation surgery and is crucial for promoting early functional exercise of patients, reducing the incidence of complications and improving the surgical effect. Although a large number of studies have explored effective postoperative analgesia methods for TKA, there is still no gold standard that satisfies everyone so far.

[0003] Cocktail therapy is a currently popular analgesic method, that is, a mixed drug in a certain ratio is injected into the soft tissues around the joint during surgery by local infiltration. Its operation is simple, the analgesia is effective, and it can promote early functional exercise of patients after surgery. It can provide satisfactory analgesic effects and help maintain muscle strength without causing complications related to opioid drugs. Although a large number of studies have confirmed the analgesic effect of cocktail therapy in total knee arthroplasty, its optimal drug formula and concentration have not been recognized yet. At present, most cocktail preparations are amide local anesthetics added with adrenaline to reduce its absorption, enhance and prolong its activity, or combined with glucocorticoids.

[0004] Ropivacaine has the advantages of low cardiac toxicity, long duration and wide safety range, and is a long-acting amide local anesthetic widely used in clinical practice. At present, there are reports on the combined application of ropivacaine and adrenaline in local anesthesia during carpal tunnel syndrome surgery; and studies on the analgesic effect of ropivacaine combined with dexamethasone after total hip arthroplasty. However, the effect of the combined use of ropivacaine, adrenaline and dexamethasone has not been reported in the literature.

[0005] In addition, as a natural calcium channel blocker and N-methyl-D-aspartic acid receptor (NMDA) antagonist in the human body, the role of magnesium ions in pain treatment has been widely concerned. The existing research results have confirmed that NMDA receptors are not only present in the central nervous system, but also expressed in the skin, muscles and knee joint cavity. As an adjuvant for local anesthetics, magnesium sulfate is increasingly widely used in peripheral nerve block and local infiltration of incisions. Its effectiveness as an adjuvant may be reflected in the following aspects: (1) Mg2+ blocks the influx of Ca2+, increases the activation threshold of the nerve fiber membrane potential, thereby enhancing the nerve block effect of local anesthetics and prolonging the nerve block time; (2) Mg2+ can enhance the analgesic effect of opioid drugs; (3) Mg2+ can effectively block the activation of peripheral NMDA receptors, reduce the sensitivity of peripheral effector receptors, and reduce the transmission of peripheral stimulation signals to the central nervous system; (4) Magnesium sulfate can promote vascular endothelial cells to release nitric oxide, protect the vascular endothelial dysfunction caused by ischemia-reperfusion, and relieve pain.

[0006] Sodium bicarbonate is an adjuvant that theoretically helps to accelerate the onset time of local anesthesia and increase the block depth of various local anesthetics. Adding sodium bicarbonate increases the pH value of the local anesthetic solution, changes its equilibrium, so that more local anesthetics exist in the unionized form. This is beneficial for the drug to cross the lipid membrane and should result in a faster nerve block effect. It has also been reported that buffering local anesthesia prolongs the duration of local anesthesia. However, the benefits of alkalizing local anesthetics with sodium bicarbonate are unclear and may only be recommended for selected peripheral nerve blocks.

[0007] Currently, there are existing reports on the research of magnesium sulfate and sodium bicarbonate as a cocktail therapy for peri-articular infiltration analgesia. For example: He Qiao et al., "Application of Magnesium Sulfate Combined with Ropivacaine Cocktail in Early Analgesia after Total Hip Arthroplasty" [J], Orthopaedics, 2022, 13(1) disclosed that magnesium sulfate can prolong the analgesic time of the cocktail analgesic mixture. However, they believe that ropivacaine has an obvious vasoconstrictive effect. Considering safety and effectiveness, adrenaline was not added to the mixture, and there was a lack of objective evaluation of whether magnesium sulfate produces side effects in the mixture, and there was also a lack of clinical evidence for whether it can be used in combination with ropivacaine cocktail together with sodium bicarbonate. Summary of the Invention

[0008] The purpose of the present invention is to provide a combined drug for anesthesia and analgesia with good local anesthesia and postoperative analgesia effects and high safety.

[0009] The present invention provides a combined drug which contains ropivacaine, adrenaline and glucocorticoid for simultaneous or separate administration in the same or different specification unit preparations.

[0010] Further, the above glucocorticoid is dexamethasone, betamethasone, triamcinolone acetonide, methylprednisolone, prednisone acetate, prednisolone acetate, cortisone or hydrocortisone.

[0011] Still further, the above glucocorticoid is dexamethasone.

[0012] Further, the mass ratio of the above ropivacaine, adrenaline, and dexamethasone is (150 - 250):(0.1 - 0.5):(5 - 15).

[0013] Still further, the mass ratio of the above ropivacaine, adrenaline, and dexamethasone is 200:0.2:10.

[0014] Further, the above combined drug is characterized in that it further contains an adjuvant, and the adjuvant is magnesium sulfate and / or sodium bicarbonate.

[0015] Still further, the mass ratio of the above ropivacaine and magnesium sulfate is (150 - 250):(200 - 300).

[0016] Still further, the mass ratio of the above ropivacaine and magnesium sulfate is 200:250.

[0017] Further, the mass ratio of the above ropivacaine and sodium bicarbonate is (0.15 - 0.25):(1 - 2).

[0018] Still further, the mass ratio of the above ropivacaine and magnesium sulfate is 0.2:1.5.

[0019] Further, the above combined drug uses the following components as active ingredients:

[0020] Ropivacaine, adrenaline, and dexamethasone;

[0021] Or, ropivacaine, adrenaline, dexamethasone, and magnesium sulfate;

[0022] Or, ropivacaine, adrenaline, dexamethasone, and sodium bicarbonate;

[0023] Or, ropivacaine, adrenaline, dexamethasone, magnesium sulfate, and sodium bicarbonate.

[0024] Further, the above combined drug uses the following components as active ingredients: ropivacaine, adrenaline, dexamethasone, magnesium sulfate, and sodium bicarbonate.

[0025] Still further, the above combined drug uses the following components in parts by weight as active ingredients:

[0026] 200 parts of ropivacaine, 0.2 parts of adrenaline, 10 parts of dexamethasone, 250 parts of magnesium sulfate, and 1500 parts of sodium bicarbonate.

[0027] Furthermore, the above-mentioned combined medicine is a preparation prepared with the above-mentioned components as active ingredients and added with pharmaceutically acceptable excipients.

[0028] Furthermore, the above-mentioned preparation is a liquid preparation.

[0029] Furthermore, the above-mentioned excipient is physiological saline.

[0030] The present invention also provides the use of the above-mentioned combined medicine in the preparation of anesthetic and / or analgesic agents.

[0031] The combined medicine for anesthesia and analgesia of the present invention combines ropivacaine with adrenaline and dexamethasone, has good local anesthetic and postoperative analgesic effects, high safety, and is further supplemented with adjuvants such as magnesium sulfate and sodium bicarbonate, which can significantly prolong the postoperative analgesic effect while ensuring the local anesthetic effect, effectively relieve early pain, accelerate the early recovery after TKA, and has the value of clinical promotion and application.

[0032] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0033] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. Description of the Drawings

[0034] Figure 1 The process of animal experiments;

[0035] Figure 2 Appearance of each group of cocktails (precipitation can be produced by adding sodium bicarbonate to the local anesthetic; A. The cocktail consists of ropivacaine, adrenaline and dexamethasone; B. The cocktail consists of ropivacaine, adrenaline, dexamethasone and magnesium sulfate; C. The cocktail consists of ropivacaine, adrenaline, dexamethasone and sodium bicarbonate; D. The cocktail consists of ropivacaine, adrenaline, dexamethasone, magnesium sulfate and sodium bicarbonate);

[0036] Figure 3 Composition and microstructure of the cocktail (A. Fourier transform infrared spectroscopy, the sample is the powder obtained by filtering the precipitate after adding magnesium sulfate and sodium bicarbonate to the conventional cocktail and drying; B. Fourier transform infrared spectroscopy, the sample is the powder obtained by filtering the precipitate after adding sodium bicarbonate to the conventional cocktail and drying; C. Low-voltage transmission electron microscopy, the sample is the mixture obtained by adding magnesium sulfate and sodium bicarbonate to the conventional cocktail; scale bar: 200 nm);

[0037] Figure 4 Histological analysis (A. HE staining of the sciatic nerve and surrounding muscle tissue; B. LFB staining of the sciatic nerve);

[0038] Figure 5 Inclusion process of the study patients;

[0039] Figure 6 VAS pain score (A. VAS score at rest; B. VAS score during activity; data are expressed as "mean ± standard deviation"; indicating that there is a statistically significant difference between group A and group B (P < 0.05); indicating that there is a statistically significant difference between group A and group C (P < 0.05); § indicates that there is a statistically significant difference between group A and group D (P < 0.05); indicating that there is a statistically significant difference between group B and group D (P < 0.05);

[0040] Figure 7 Postoperative morphine consumption (data are expressed as "mean ± standard deviation"; * indicates that there is a statistically significant difference between the two groups; P < 0.05);

[0041] Figure 8 Survival analysis - time to first rescue analgesia;

[0042] Figure 9 Inflammatory indexes (data are expressed as "mean ± standard deviation"; * indicates that there is a statistically significant difference between group A and group B, P < 0.05; # indicates that there is a statistically significant difference between group A and group D);

[0043] Figure 10 Time to first straight leg raise and postoperative hospital stay (data are expressed as "median ± 95% confidence interval"; * indicates that there is a statistically significant difference between group A and group D); Detailed implementation manner

[0044] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0045] Example 1. Combined drugs of the present invention

[0046] 200 mg of ropivacaine, 0.2 mg of adrenaline, 10 mg of dexamethasone, and 78 ml of normal saline are mixed to prepare a total of 100 ml of mixture.

[0047] Example 2. Combined drugs of the present invention

[0048] 200 mg of ropivacaine, 0.2 mg of adrenaline, 10 mg of dexamethasone, 250 mg of magnesium sulfate, 30 ml of 5 wt% sodium bicarbonate, and 47 ml of normal saline are mixed to prepare a total of 100 ml of mixture.

[0049] Example 3. Combined drugs of the present invention

[0050] 200 mg of ropivacaine, 0.2 mg of adrenaline, 10 mg of dexamethasone, 250 mg of magnesium sulfate, and 77 ml of normal saline were mixed to prepare a total of 100 ml of the mixture.

[0051] Example 4. Combined drugs of the present invention

[0052] 200 mg of ropivacaine, 0.2 mg of adrenaline, 10 mg of dexamethasone, 30 ml of 5% sodium bicarbonate, and 48 ml of normal saline were mixed to prepare a total of 100 ml of the mixture.

[0053] The beneficial effects of the present invention are demonstrated by the following experimental examples.

[0054] 1. Materials

[0055] 1.1 Main experimental reagents

[0056]

[0057]

[0058] 1.2 Main experimental instruments

[0059]

[0060] The "cocktail" in the following experimental examples refers to the combined drugs made of the main drug components in a certain ratio.

[0061] Experimental Example 1 Safety study of the combined drugs for anesthesia and analgesia of the present invention

[0062] 1. Method

[0063] 1.1 Physicochemical property characterization

[0064] The components and microstructure of the cocktail (combined drugs prepared according to Examples 1 to 4) were analyzed by Fourier transform infrared spectroscopy (FTIR) and low-voltage transmission electron microscope (TEM).

[0065] (1) FTIR: ① The sample was filtered and dried to form a uniform powder; ② The sample was placed on the optical path to ensure the stability of the optical path and collect FTIR data; ③ The spectral data was processed; ④ Spectral interpretation and result analysis.

[0066] (2) Low-voltage TEM: ① Prepare the sample and drop it onto a silicon wafer; ② Turn on the transmission electron microscope and preheat it to the operating temperature, set the low-voltage mode and calibrate it; ③ Move the sample to the position of the electron beam axis and adjust the tilt angle; ④ Irradiate the sample with an electron beam of low electron energy and record the electron diffraction image; ⑤ Take a transmission electron image: Use an electron beam of low electron energy to pass through the sample to form a transmission electron image.

[0067] 1.2 Experimental animals

[0068] The animal experiment was approved by the Experimental Animal Ethics Committee of West China Hospital of Sichuan University. Sixteen SD rats, 3 months old and weighing 250 - 300 g, were provided by Chengdu Dashuo Experimental Animal Co., Ltd. At the Experimental Animal Center of West China Hospital of Sichuan University, all rats were raised under standard breeding conditions, including a temperature maintained between 22 - 26 °C, a humidity controlled within the range of 37% - 42%, a 12-hour light-dark cycle, and free access to food and water. Before the experiment began, all animals were adaptively raised in the animal center for 1 week.

[0069] 1.3 Grouping of rats

[0070] Sixteen SD rats were randomly divided into a modified cocktail group and a control group. Twelve rats were given a sciatic nerve block with a modified cocktail (the combined drug prepared according to Example 2, 0.4 ml injected once). Another 4 rats were given a sham sciatic nerve block (injected with 0.4 ml of normal saline solution) as the control group.

[0071] 1.4 Sciatic nerve block in rats

[0072] (1) After the rats inhaled 2.0% isoflurane anesthesia, they were placed in the right lateral position.

[0073] (2) The left hip and its surrounding area of the rats were depilated and disinfected.

[0074] (3) Locate the sciatic nerve. Use a finger to find the depression between the left ischial tuberosity and the ischial eminence, which is the location of the sciatic nerve.

[0075] (4) Use a syringe connected to a 23G needle to insert the needle from the dorsolateral side along the direction of the sciatic nerve. After reaching the bone, inject the drug. If the lower limb motor ability of the rats is affected, such as being unable to support the body weight, limping, or unable to kick, it indicates that the nerve block effect is good. The animal experiment process is as Figure 1 shown.

[0076] 1.5 Sampling plan

[0077] In the modified cocktail group, 4 rats were sacrificed and sampled at 2, 7, and 14 days after injection respectively. The control group was sacrificed and sampled on the 2nd day (Figure 1 )。

[0078] (1) Rats were sacrificed by cervical dislocation, and the left hip and its surrounding area were prepared for skin removal.

[0079] (2) The rats were placed on the operating table in the right lateral position. The left hip and the medial side of the thigh of the rats were incised along with scissors and tissue forceps to expose the sciatic nerve.

[0080] (3) The nerve was gently pulled out with tissue forceps, and a section of the sciatic nerve (about 1.5 cm long) at the cocktail injection site and the surrounding muscle tissue were excised using a scalpel. Fixed in 10% neutral formaldehyde.

[0081] 1.6 Tissue embedding and sectioning

[0082] The fixed tissues were dehydrated by an automatic dehydrator (dehydration duration: 75% alcohol for 1 h, 85% alcohol for 1 h, 95% alcohol I for 50 min, 95% alcohol II for 50 min, 100% alcohol I for 50 min, 100% alcohol II for 50 min, 100% alcohol:xylene 1:1 mixture for 20 min, xylene I for 25 min, xylene II for 25 min, paraffin I for 1 h, paraffin II for 2 h, paraffin III for 3 h), embedded, and sectioned.

[0083] 1.7 Dewaxing and rehydration of sections

[0084] Specific operation: xylene I for 5 - 10 min, xylene II for 5 - 10 min, absolute ethanol I for 5 min, absolute ethanol I for 5 min, 95% alcohol for 5 min, 85% alcohol for 5 min, 75% alcohol for 5 min, soaked in ultrapure water for 5 min.

[0085] 1.8 Hematoxylin - eosin staining (HE staining)

[0086] The sciatic nerve and the surrounding muscle tissue of the rats were observed under a light microscope by HE staining to evaluate the damage of the sciatic nerve and the surrounding muscle tissue and determine the safety of the modified cocktail.

[0087] (1) Hematoxylin staining: Drop hematoxylin stain on the tissue section for 10 - 20 min, and rinse with tap water for 1 - 3 min.

[0088] (2) Differentiation: Differentiate with hydrochloric acid alcohol for 5 - 10 s, and rinse with tap water for 1 - 3 min.

[0089] (3) Blueing: Place it in warm water at 50 °C or a weak alkaline aqueous solution for blueing until blue appears; rinse with tap water for 1 - 3 min.

[0090] (4) Eosin staining: Immerse in 85% alcohol for 3 - 5 min, stain with eosin for 3 - 5 min, wash with water for 3 - 5 s, and dehydrate with gradient alcohol.

[0091] (5) After clearing with xylene, mount with neutral balsam.

[0092] All of the above specimens were processed according to the standard operating procedures for pathological examination.

[0093] 1.9 Luxol Fast Blue (LFB) staining

[0094] Perform LFB staining on the sciatic nerve to determine the number and morphology of the sciatic nerve myelin sheaths after LFB myelin staining, evaluate the safety of the modified cocktail, and provide a basis for clinical use.

[0095] (1) Complete dewaxing and rehydration of the tissue sections, and wash slightly with 95% ethanol.

[0096] (2) Add LFB staining solution and stain at room temperature for 12 - 20 h, then wash off the excess staining solution with 95% ethanol.

[0097] (3) Rinse with distilled water, and add Luxol differentiating solution for color differentiation for 10 - 15 s.

[0098] (4) Add 70% ethanol for color differentiation for 30 s, and rinse with distilled water.

[0099] (5) Dehydrate routinely, clear with immersion wax clearing solution (DZ2011) or xylene, and mount with neutral balsam.

[0100] All of the above specimens were processed according to the standard operating procedures for pathological examination.

[0101] 1.10 Histological evaluation

[0102] Judge the injury of the sciatic nerve and surrounding muscle tissues according to the criteria reported in previous literature (Table 1). The analyst of the tissue sections was unaware of the grouping situation.

[0103] Table 1 Criteria for judging nerve and surrounding muscle tissue injury

[0104]

[0105]

[0106] 2. Results

[0107] 2.1 Physical and chemical properties

[0108] The appearance of each group of cocktails was as Figure 2As shown in the figure, adding sodium bicarbonate to the ropivacaine solution causes precipitation. The absorption peaks of the two groups of FTIR spectra are consistent, indicating that adding magnesium sulfate to the cocktail does not cause a chemical reaction. The precipitate is ropivacaine crystals precipitated after the pH is increased, and no new substances are formed( Figure 3 ). The microstructure of the precipitate in the cocktail is shown in the electron micrograph( Figure 3 ).

[0109] 2.2 Histological evaluation

[0110] According to the judgment criteria for sciatic nerve and surrounding muscle tissue injury, the injury scores of both groups were 0 points. HE staining showed that there were no obvious injuries in the sciatic nerve and its surrounding muscle tissues of rats taken at 2d, 7d, and 14d. LFB staining of the sciatic nerve showed that when taken at 2d, 7d, and 14d after injecting the modified cocktail, the sciatic nerve fibers were arranged neatly, and there was no obvious shedding or dissolution of the myelin sheath( Figure 4 ). Therefore, it can be considered that the modified cocktail has good safety.

[0111] Experimental Example 2 Study on the effectiveness of the combined drugs for anesthesia and analgesia of the present invention

[0112] I. Methods

[0113] 1. Research design

[0114] This study is a single-center, prospective, double-blind, randomized controlled trial. A total of 120 osteoarthritis patients who underwent elective unilateral TKA in the Department of Orthopaedics, West China Hospital, Sichuan University from February 2022 to December 2022 were included in the study. This clinical trial was approved by the Biomedical Ethics Review Committee of West China Hospital, Sichuan University (NO. 2021-1232), and all subjects signed informed consent forms. This study was registered on the Chinese Clinical Trial Registry on January 30, 2022 (Registration number: ChiCTR2200055981), conducted in accordance with the principles of the Declaration of Helsinki, and reported in accordance with the CONSORT statement.

[0115] 2 Inclusion and exclusion criteria

[0116] Inclusion criteria: (1) Primary unilateral TKA; (2) American Society of Anesthesiologists (ASA) classification of I-III; (3) Body mass index (BMI) of 18-36 kg / m 2 .

[0117] Exclusion criteria: (1) Patients without osteoarthritis, such as those with secondary osteoarthritis after the cure of suppurative arthritis, rheumatoid arthritis, traumatic arthritis, etc.; (2) Knee joint flexion deformity ≥ 30° or varus / valgus deformity ≥ 30°; (3) Allergy to the drugs used in this study; (4) History of anesthesia or opioid dependence; (5) History of surgery on the affected knee joint; (6) History of neuromuscular diseases; (7) Cognitive impairment, history of previous mental illness or inability to communicate verbally.

[0118] 3 Randomization and blinding

[0119] All patients were divided into four groups, namely Group A, Group B, Group C and Group D, with 30 cases in each group, using a computer-generated random number list (Excel, Microsoft Corporation, Redmond, USA). The LIA cocktail for Group A was: ropivacaine 200 mg, adrenaline 0.2 mg, dexamethasone 10 mg; the LIA cocktail for Group B was: ropivacaine 200 mg, adrenaline 0.2 mg, dexamethasone 10 mg and magnesium sulfate 250 mg; the LIA cocktail for Group C was: ropivacaine 200 mg, adrenaline 0.2 mg, dexamethasone 10 mg and 5% sodium bicarbonate 30 ml; the LIA cocktail for Group D was: ropivacaine 200 mg, adrenaline 0.2 mg, dexamethasone 10 mg, magnesium sulfate 250 mg and 5% sodium bicarbonate 30 ml. The four groups of analgesic cocktails were all diluted with normal saline to a total volume of 100 ml. The random numbers were sealed in opaque envelopes, and each patient selected an envelope on the morning of the surgery day. The patients were divided into four groups according to the numbers in the selected envelopes. Before the surgery, an anesthesiologist not involved in the study prepared the corresponding analgesic cocktails. The ward staff, data collectors, outcome evaluators and statistical analysts were all unaware of the grouping situation. The randomization results were announced after the data analysis was completed.

[0120] 4 Perioperative management

[0121] Starting from the day of admission, oral celecoxib (200 mg, Bid) and pregabalin (150 mg, Bid) were given as prophylactic analgesia; if celecoxib was contraindicated, loxoprofen sodium (60 mg, Tid) was taken. General anesthesia was performed by an anesthesiologist. After inhaling pure oxygen, the following anesthetics were injected intravenously: midazolam, 2 mg / kg; propofol, 2 mg / kg; sufentanil, 0.3 μg / kg and cisatracurium 0.2 mg / kg.

[0122] All TKA surgeries in this study were completed by the same senior doctor in the Department of Orthopaedics, West China Hospital, Sichuan University. After general anesthesia, a midline skin incision was made through the medial parapatellar approach. A cemented knee prosthesis was implanted during the operation without using a tourniquet or placing a drainage tube. All patients were intravenously infused with 1 g of tranexamic acid 30 minutes before skin incision and at 3 and 6 hours after surgery. Systemic glucocorticoids were not used.

[0123] During the operation, the surgeon used the multi-point injection method to perform LIA around the joint. Except for the different components of the cocktail formula, the other treatment methods for the four groups of patients were the same. Before implanting the prosthesis, 20 ml of the cocktail was injected behind the joint capsule, and then 20 ml of the cocktail was used to infiltrate and analgesia the medial and lateral collateral ligaments. After placing the prosthesis, 20 ml of the cocktail was used to infiltrate the quadriceps femoris and its ligament tissues, and then 40 ml of the cocktail was used to infiltrate the subcutaneous and adipose tissues around the joint. Twenty minutes before the end of the operation, sufentanil (5 μg) was intravenously injected to prevent postoperative pain, and at the same time, 5 mg of tropisetron was intravenously injected to prevent postoperative nausea and vomiting.

[0124] After the patients returned to the ward, ice compress was applied around the wound, and analgesia pumps were not used. After surgery, celecoxib (200 mg, Bid) and pregabalin (150 mg, Bid) were orally taken to control postoperative pain. Remedial analgesia with opioid drugs was determined by the outcome evaluators in the PACU and the ward. When the patients could not tolerate the pain after surgery [visual analogue scale (VAS) for pain at rest ≥ 4 points or VAS score for activity ≥ 6 points], 10 mg of morphine hydrochloride was subcutaneously injected as remedial analgesia.

[0125] To prevent venous thromboembolism (VTE), low molecular weight heparin 2000 AXaIU was subcutaneously injected 12 hours after surgery, and then 4000 AXaIU was given at an interval of 24 hours until discharge. After discharge, it was changed to oral rivaroxaban 10 mg once a day for 2 weeks after surgery. The patients received lower limb pneumatic therapy after surgery and actively performed knee joint, ankle joint flexion and extension, and knee extension and leg raising functional exercises, and lower limb strength training. Starting from the first day after surgery, the patients walked on the ground with the help of a walker under the guidance of the nursing staff.

[0126] 5 Outcome indicators

[0127] The general information of the patients was recorded at admission: gender, age, BMI, weight, height, VAS score under daily activities, surgical side, knee joint range of motion, ASA grade, and quadriceps femoris muscle strength.

[0128] The primary outcome measures include pain score, postoperative rescue morphine dosage, and the time to the first rescue analgesia. Postoperative pain was evaluated using the VAS score at rest and during activity (knee flexion at 45°). The VAS score ranges from 0 to 10, with higher scores indicating more severe pain, 0 representing "no pain at all", and 10 representing "the most severe pain". A score of 0 - 3 indicates mild pain, 4 - 6 indicates moderate pain, and 7 - 10 indicates severe pain. The VAS score at rest was measured at 2h, 6h, 12h, 24h, 48h, and 72h after surgery, and the VAS score during activity was measured at 6h, 12h, 24h, 48h, and 72h after surgery.

[0129] The secondary outcome measures include inflammatory indicators, knee joint function recovery, and postoperative hospital stay. Inflammatory indicators include interleukin - 6 (IL - 6) and C - reactive protein (CRP). Fasting blood samples were collected on the morning of the 1st, 2nd, and 3rd days after surgery to measure the levels of IL - 6 and CRP. The recovery of knee joint function was evaluated by quadriceps muscle strength, daily walking distance, knee joint range of motion, and the time to the first straight leg raise. Manual muscle testing was used to measure quadriceps muscle strength. The patient was in a sitting or supine position with the knee flexed, and was instructed to straighten the knee while the measurer applied resistance. Muscle strength grading: grade 0 indicates no muscle contraction; grade 1 indicates muscle contraction but no joint movement; grade 2 indicates the limb can move on a plane but cannot resist gravity; grade 3 indicates the ability to counteract limb weight but cannot overcome additional resistance; grade 4 indicates the ability to complete the movement and partially overcome resistance; grade 5 indicates complete resistance to resistance. The patient walked as far as possible with the aid of a walking aid in one attempt, and this distance was used as the daily walking distance. The knee joint range of motion was measured at the bedside using a goniometer three times a day at 6 - hour intervals, and the best value was used as the range of motion for the day. The time to the first straight leg raise was defined as the time when the patient could first actively straighten the knee after surgery, with the heel lifted 30° to 60° off the bed.

[0130] The postoperative hospital stay of the patients was recorded. The discharge criteria for the patients included: (1) good general conditions such as spirit, diet, sleep, bowel movements, and urination; (2) stable control of co - existing diseases, such as well - controlled hypertension and diabetes; (3) good healing of the surgical incision without redness, swelling, or exudation; (4) good pain control with oral analgesics, VAS score ≤ 3; (5) good knee joint range of motion ≥ 100°; (6) the patient and family members mastered the correct functional exercise methods and daily living skills; (7) correct use of the walking aid and assisted walking distance ≥ 20m.

[0131] The other outcome measure was the complication rate. Complications included wound complications, nausea, vomiting, neurovascular injury, postoperative infection, venous thromboembolism, and postoperative falls. All patients had their sutures removed 3 weeks after surgery and were followed up 3 months after surgery to evaluate function and recovery.

[0132] 6 Statistical analysis

[0133] Sample size estimation was performed based on the reported postoperative rescue morphine dosage in previous studies. When the two-sided α value was 0.05 and the power (1-β) was 90%, in order to reduce the postoperative rescue morphine dosage in the observation group by 10 mg [the minimal clinically important difference (MCID) reported in a systematic review of 570 joint replacement analgesia trials]

[43] , at least 27 subjects were required in each group. Considering factors such as possible patient loss to follow-up or withdrawal from the study, 30 patients were prepared to be included in each group in this study, and a total of 120 patients were included.

[0134] In this study, SPSS software version 23.0 (IBM Corp, Armonk, NY, USA) was used for statistical analysis of the data. Categorical data were expressed as percentages or numbers, and continuous data were expressed in the form of "mean ± standard deviation", unless otherwise specified. Statistical significance of differences was indicated by P < 0.05, which was considered statistically significant. The Shapiro-Wilk test was used for normality assessment; one-way analysis of variance was used to test normally distributed data, and the LSD method was used for post hoc comparison. If the data did not conform to the normal distribution or for ordinal data, the Kruskal-Wallis rank sum test was used and post hoc tests were performed. The Bonferroni method was used for P-value correction in pairwise comparisons between groups. Pearson's chi-square test or Fisher's exact probability method was used to analyze categorical data. Survival analysis (Kaplan-Meier method, log-rank test) was used to analyze the time to the first rescue analgesia, and the follow-up endpoint was discharge.

[0135] II. Results

[0136] 1 Patient baseline characteristics

[0137] A total of 173 patients with osteoarthritis were evaluated, among whom 25 did not meet the inclusion criteria and 28 were unwilling to participate in the study. Finally, 30 patients were included in each of the four groups A, B, C, and D. There were no patients lost to follow-up or withdrawn from the study during the postoperative outcome assessment ( Figure 5 ). There were no significant differences in the preoperative baseline data and operation time among the four groups (Table 2).

[0138] Table 2 Preoperative baseline characteristics of patients in each group

[0139]

[0140]

[0141] Note: Continuous data are expressed as "mean ± standard deviation"; categorical data are expressed as numbers. a One-way analysis of variance; b Pearson chi-square test; c Kruskal-Wallis rank sum test. Abbreviations: BMI, body mass index; VAS, visual analogue scale; ASA, American Society of Anesthesiologists.

[0142] 2 Primary outcomes

[0143] (1) VAS pain score

[0144] Compared with group A, the VAS scores of patients in groups B, C, and D at rest at 12 h and 24 h after surgery were significantly decreased (P < 0.05); the VAS scores of patients in group A during activity at 12 h and 24 h after surgery were significantly higher than those in groups B, C, and D (P < 0.05); there were no significant differences in the VAS scores of patients in group A and groups B, C, and D during activity and at rest at other time points after surgery (P > 0.05); except that the VAS score of patients in group D at rest at 24 h after surgery was significantly lower than that in group B, there were no obvious differences in the VAS scores of patients in groups B, C, and D at each time point after surgery. The results are shown in Table 3 and Figure 6 as follows.

[0145] Table 3 VAS pain score

[0146]

[0147]

[0148] Note: Data are expressed as "mean ± standard deviation". * Kruskal-Wallis rank sum test; a indicates that there is a significant difference between group A and group B (P < 0.05); b indicates that there is a significant difference between group A and group C (P < 0.05); c indicates that there is a significant difference between group A and group D (P < 0.05); d indicates that there is a significant difference between group B and group D (P < 0.05). Abbreviation: VAS, visual analogue scale.

[0149] (2) Rescue analgesia after surgery

[0150] The morphine consumption on the first day after surgery in Group B (9.00 ± 6.07 mg), Group C (9.50 ± 6.87 mg), and Group D (4.33 ± 6.66 mg) was significantly lower than that in Group A (15.67 ± 6.40 mg) (P < 0.05). There was no significant difference in morphine consumption among groups on the second and third days after surgery. The total morphine consumption during hospitalization in Group A (21.67 ± 10.03 mg) was significantly higher than that in Group B (14.17 ± 8.31 mg, P = 0.026), Group C (14.00 ± 8.85 mg, P = 0.027), and Group D (9.33 ± 8.78 mg, P < 0.001). The morphine consumption on the first day after surgery and the cumulative total morphine consumption after surgery in Group D were lower than those in Group B and Group C, but the differences were not statistically significant. The results are shown in Table 4 and Figure 7 as follows.

[0151] Compared with Group A (12.56 ± 4.04 h), the time to the first rescue analgesia after surgery in Group B (17.13 ± 5.07 h, P = 0.005), Group C (17.46 ± 5.88 h, P = 0.009), and Group D (22.94 ± 11.94 h, P < 0.001) was significantly prolonged. The time to the first rescue analgesia after surgery in Group D was significantly higher than that in Group B (P = 0.029) and Group C (P = 0.031), and the differences were statistically significant. The number of patients without rescue analgesia in Group D (40.0%) was significantly higher than that in Group A (10.0%, P < 0.05). The results are shown in Table 4 and Figure 8 as follows.

[0152] Table 4 Rescue analgesia after surgery

[0153]

[0154]

[0155] Note: Continuous data are expressed as "mean ± standard deviation"; categorical data are expressed as numbers (%). *Kruskal-Wallis rank sum test; Survival analysis (Kaplan-Meier method, log-rank test); Pearson chi-square test; § Excluding patients without rescue analgesia. a Indicates a statistically significant difference between Group A and Group B (P < 0.05); b Indicates a statistically significant difference between Group A and Group C (P < 0.05); c Indicates a statistically significant difference between Group A and Group D (P < 0.05); d Indicates a statistically significant difference between Group B and Group D (P < 0.05); e Indicates a statistically significant difference between Group C and Group D (P < 0.05).

[0156] 3 Secondary outcomes

[0157] (1) Inflammatory markers

[0158] Postoperatively, the inflammatory markers CRP and IL-6 increased in all four groups of patients. The mean value of CRP in each group reached its peak on the 2nd postoperative day. Compared with group A, the CRP levels in groups B and D were significantly lower on the 2nd and 3rd postoperative days, and the differences were statistically significant (P<0.05). The IL-6 levels in each group reached their peaks on the 1st postoperative day and then decreased. The IL-6 levels in groups B and D were significantly lower than those in group A on the 2nd and 3rd postoperative days (P<0.05). There were no statistically significant differences in the CRP and IL-6 levels between the preoperative period and the 1st postoperative day in each group. The results are shown in Table 5 and Figure 9 as follows.

[0159] Table 5 Inflammatory markers

[0160]

[0161]

[0162] Note: Data are expressed as "mean ± standard deviation". *One-way ANOVA. a Indicates a statistically significant difference between group A and group B (P<0.05); b Indicates a statistically significant difference between group A and group D (P<0.05).

[0163] (2) Knee joint function recovery

[0164] Compared with the patients in group A, the patients in group D had better knee joint mobility and walked a longer daily distance on the 1st and 2nd postoperative days, and the differences were statistically significant (P<0.05). On the 3rd postoperative day, there were no obvious differences in the knee joint mobility and the daily walking distance among the four groups (P>0.05). There were no significant differences in the quadriceps muscle strength among the four groups of patients postoperatively. The postoperative hospital stay of the patients in group D was significantly shorter than that of the patients in group A (65.43±5.79h vs 71.73±6.15h, P<0.001). The first straight leg raise times of the four groups of patients were similar, and the differences were not statistically significant. The results are shown in Table 6 and Figure 10 as follows.

[0165] Table 6 Knee joint function recovery

[0166]

[0167]

[0168] Note: Data are expressed as "mean ± standard deviation". *Kruskal-Wallis rank sum test. a Indicates a statistically significant difference between group A and group D (P<0.05).

[0169] 4 Other outcomes

[0170] The incidence rates of nausea, vomiting, and wound-related complications were similar among the groups, and the differences were not statistically significant. None of the patients in each group had neurovascular injury, VTE, postoperative infection, or postoperative falls (Table 7).

[0171] Table 7 Incidence rates of complications

[0172]

[0173] Note: Data are presented as numbers (%). *Pearson chi-square test. Abbreviation: VTE: Venous thromboembolism

[0174] III. Discussion

[0175] Adding sodium bicarbonate to the cocktail in the present invention led to the formation of precipitation, which is consistent with the reported precipitation caused by alkalization of the local anesthetic solution. The precipitation is the crystallization of ropivacaine. Due to the physicochemical properties of local anesthetics, this precipitation is inevitable in the physiological environment. In animal experiments, all the precipitation of the modified cocktail in the present invention had been absorbed during dissection and did not deposit around nerves or muscles ( Figure 4 ). Therefore, the precipitation should also be absorbed within 2 days during clinical use. Preliminary animal experiments showed that the precipitation is absorbable, safe and reliable, and no related side effects have been observed in current and previous clinical trials.

[0176] The results of this study showed that the cocktail prepared by combining ropivacaine with adrenaline and dexamethasone had good local anesthetic and postoperative analgesic effects. Adding magnesium sulfate and sodium bicarbonate to the cocktail could significantly prolong the analgesic duration, and it had statistical significance, playing a synergistic effect, increasing the knee joint mobility and daily walking distance on the 1st and 2nd days after surgery, and shortening the hospital stay. And the absolute difference in the knee joint range of motion on the 1st day after surgery exceeded 10 degrees. The minimally clinically important difference (MCID) of knee joint mobility after TKA reported in the current literature is 10 degrees. In terms of enhanced recovery after surgery (ERAS), the modified cocktail has advantages and can accelerate the early recovery after TKA.

[0177] In summary, the combined drug provided by the present invention, which combines ropivacaine with adrenaline and dexamethasone, has good local anesthetic and postoperative analgesic effects. Further supplemented with adjuvants such as magnesium sulfate and sodium bicarbonate, it can prolong the postoperative analgesic effect while ensuring the local anesthetic effect, effectively relieve early pain, and accelerate the early recovery after TKA.

Claims

1. A combined drug, characterized in that, It uses the following components in parts by weight as active ingredients: 200 parts of ropivacaine, 0.2 part of adrenaline, 10 parts of dexamethasone, 250 parts of magnesium sulfate, and 1500 parts of sodium bicarbonate.

2. The combined medicament according to claim 1, wherein, It is a preparation prepared with the above components as active ingredients plus pharmaceutically acceptable excipients; the preparation is a liquid preparation.

3. The combined medicament according to claim 2, wherein The excipient is physiological saline.

4. Use of the combined drug according to any one of claims 1 to 3 in the preparation of an anesthetic and / or an analgesic.

Images