CN116898977A - Combined medicine for anesthesia and analgesia - Google Patents

Abstract

The invention provides a combined medicament which contains ropivacaine, epinephrine and glucocorticoid which are used for simultaneous or separate administration of unit preparations with the same or different specifications, has better local anesthesia and postoperative analgesic effects, is further assisted by magnesium sulfate and sodium bicarbonate adjuvant, can prolong the postoperative analgesic effect while guaranteeing the local anesthesia effect, effectively relieves early pain, accelerates early recovery after total knee replacement operation, and has clinical application value.

Description

Combined medicine for anesthesia and analgesia

Technical Field

The invention belongs to the field of biological medicine, and in particular relates to an anesthetic and analgesic combination medicine.

Background

Total knee arthroplasty (total knee arthroplasty, TKA) is the primary means of resolving end-stage knee joint disease, relieving knee pain, and reestablishing knee function. Over 60% of TKA patients experience moderate to severe pain after surgery, which often makes them unable to participate in rehabilitation training at an early stage after surgery and may delay rehabilitation by negatively affecting diet, sleep and mood. Pain-induced restriction of activity may cause complications such as decreased lung ventilation, gastrointestinal function inhibition, deep vein thrombosis of lower limbs, pulmonary embolism, and cognitive dysfunction. Therefore, effective control of TKA postoperative pain is an important link in enhancing the concept of rehabilitation surgery, and is important for promoting early functional exercises of patients, reducing the incidence of complications, and improving the surgical effect. Although there are a great deal of research exploring effective TKA post-operative analgesic methods, there is no gold standard to date that is satisfactory to all.

The cocktail therapy is a current hot analgesic mode, namely, a mixed medicament with a certain proportion is injected into soft tissues around joints in an operation by adopting a local infiltration method, the operation is simple, the pain is effectively relieved, and the early functional exercise of a patient after the operation can be promoted. It can provide satisfactory analgesic effects and help maintain muscle strength without causing opioid-related complications. Although extensive research has demonstrated the analgesic effect of cocktail therapy in total knee replacement, its optimal pharmaceutical formulation and concentration has not been recognized. Currently, cocktail formulations are mostly amide type local anesthetics with epinephrine added to reduce their absorption, enhance and prolong their activity, or in combination with glucocorticoids.

Ropivacaine has the advantages of low cardiac toxicity, long duration, wide safety range and the like, and is a long-acting amide local anesthetic widely applied to clinic. At present, there are reports on the combined application of ropivacaine and epinephrine to local anesthesia in carpal tunnel syndrome surgery; study of analgesic effects of ropivacaine in combination with dexamethasone following total hip arthroplasty. However, the effect of ropivacaine in combination with epinephrine and dexamethasone has not been reported.

In addition, magnesium ions are of great interest as natural calcium channel blockers and N-methyl-D-aspartate receptor (NMDA) antagonists in humans, whose role in pain management is to be seen. The results of prior studies confirm that NMDA receptors are not only present in the central nervous system, but are also expressed in the skin, muscle and knee cavities. The application of magnesium sulfate as local anesthetic adjuvant in peripheral nerve block and local infiltration of incision is becoming widespread, and the effectiveness of the magnesium sulfate as adjuvant may be represented in the following aspects: (1) Mg2+ blocks Ca < 2+ > inflow and increases the activation threshold of nerve fiber membrane potential, thereby enhancing the nerve blocking effect of local anesthetics and prolonging the nerve blocking time; (2) mg2+ enhances the analgesic effect of opioid; (3) Mg2+ can effectively block the activation of peripheral NMDA receptor, reduce the sensitivity of peripheral effect receptor and reduce the transmission of peripheral stimulation signal to central nervous system; (4) The magnesium sulfate can promote the release of nitric oxide from vascular endothelial cells, protect vascular endothelial dysfunction caused by ischemia reperfusion and relieve pain.

Sodium bicarbonate is an adjuvant that theoretically helps to accelerate the onset of local anesthesia and increase the depth of block of various local anesthetics. The addition of sodium bicarbonate increases the pH of the local anesthetic solution, changing its balance, thereby allowing more local anesthetic to exist in unionized form. This facilitates the drug to pass through the lipid membrane and should result in a faster nerve blocking action. Buffering of local anesthesia has also been reported to extend the duration of local anesthesia. However, the benefits of alkalizing local anesthetics with sodium bicarbonate are ambiguous and may be recommended only for selected peripheral nerve blockages.

Currently, there are reports on studies on magnesium sulfate and sodium bicarbonate as cocktail therapies for periarticular infiltration analgesia. For example: he Qiao et al, magnesium sulfate in combination with Luo Guka for early analgesia after total marrow arthroplasty [ J ], orthopedics department, 2022,13 (1) discloses that magnesium sulfate can prolong the analgesic time of cocktail analgesic cocktail, but Luo Guka is considered to have obvious vasoconstriction effect, epinephrine is not added to cocktail in consideration of safety and effectiveness, objective evaluation is lacking on whether side effect is generated in cocktail of magnesium sulfate, and clinical basis is lacking on whether sodium bicarbonate can be used together with Luo Guka for cocktail.

Disclosure of Invention

The invention aims to provide an anesthetic and analgesic combination drug with good local anesthesia and postoperative analgesic effects and high safety.

The present invention provides a combination comprising ropivacaine, epinephrine, and glucocorticoid in the same or different unit dosage forms for simultaneous or separate administration.

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

Still further, the glucocorticoid is dexamethasone.

Further, the mass ratio of ropivacaine to epinephrine to dexamethasone is (150-250): 0.1-0.5): 5-15.

Further, the mass ratio of ropivacaine, epinephrine and dexamethasone is 200:0.2:10.

Further, the combination is characterized in that the combination further comprises an adjuvant, wherein the adjuvant is magnesium sulfate and/or sodium bicarbonate.

Further, the mass ratio of ropivacaine to magnesium sulfate is (150-250) (200-300).

Further, the mass ratio of ropivacaine to magnesium sulfate is 200:250.

Further, the mass ratio of ropivacaine to sodium bicarbonate is (0.15-0.25): 1-2.

Further, the mass ratio of ropivacaine to magnesium sulfate is 0.2:1.5.

Further, the combination drug comprises the following components as active ingredients:

ropivacaine, epinephrine, and dexamethasone;

or ropivacaine, epinephrine, dexamethasone, and magnesium sulfate;

or ropivacaine, epinephrine, dexamethasone, and sodium bicarbonate;

or ropivacaine, epinephrine, dexamethasone, magnesium sulfate, and sodium bicarbonate.

Further, the combination is prepared from the following components as active ingredients: ropivacaine, epinephrine, dexamethasone, magnesium sulfate, and sodium bicarbonate.

Further, the combination is prepared from the following components in parts by weight as active ingredients:

200 parts of ropivacaine, 0.2 part of epinephrine, 10 parts of dexamethasone, 250 parts of magnesium sulfate and 1500 parts of sodium bicarbonate.

Furthermore, the combination medicine is a preparation prepared by taking the components as active ingredients and adding pharmaceutically acceptable auxiliary materials.

Still further, the formulation is a liquid formulation.

Further, the auxiliary material is physiological saline.

The invention also provides application of the combined medicine in preparing anesthetic and/or analgesic.

The combined drug for anesthesia and analgesia disclosed by the invention combines ropivacaine with epinephrine and dexamethasone, has good local anesthesia and postoperative analgesia effects, is high in safety, and further is supplemented with magnesium sulfate and sodium bicarbonate adjuvant, so that the postoperative analgesia effect can be obviously prolonged while the local anesthesia effect is ensured, early pain is effectively relieved, early recovery after TKA (TKA) operation is accelerated, and the combined drug has clinical popularization and application values.

It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.

The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.

Drawings

FIG. 1 is a process of animal experiments;

the appearance of each set of cocktails of figure 2 (sodium bicarbonate added to the local anesthetic produced a precipitate; a. Cocktail consisted of ropivacaine, epinephrine, and dexamethasone; b. Cocktail consisted of ropivacaine, epinephrine, dexamethasone, and magnesium sulfate; c. Cocktail consisted of ropivacaine, epinephrine, dexamethasone, and sodium bicarbonate; d. Cocktail consisted of ropivacaine, epinephrine, dexamethasone, magnesium sulfate, and sodium bicarbonate);

FIG. 3 shows the composition and microstructure of a cocktail (A. Fourier infrared spectrogram, sample is obtained by adding magnesium sulfate and sodium bicarbonate to a conventional cocktail, filtering and precipitating, and drying the obtained powder; B. Fourier infrared spectrogram, sample is obtained by adding sodium bicarbonate to a conventional cocktail, filtering and precipitating, and drying the obtained powder; C. Low-voltage transmission electron microscope, sample is obtained by adding magnesium sulfate and sodium bicarbonate to a conventional cocktail, and the proportion is 200 nm);

FIG. 4 histological analysis (A. Sciatic nerve and surrounding muscle tissue HE staining; B. Sciatic nerve LFB staining);

figure 5 study patient inclusion procedure;

figure 6VAS pain scores (A. Resting VAS score; B. Active VAS score; data expressed as "mean.+ -. Standard deviation";indicating that the difference between group A and group B is statistically significant (P<0.05)；/>Indicating that the difference between group A and group C is statistically significant (P<0.05 A) is provided; statistically significant (P) for group A and group D differences<0.05)；/>Indicating that the difference between group B and group D is statistically significant (P<0.05)；

Figure 7 consumption of morphine after surgery (data expressed as "mean ± standard deviation;:. Times. Differences between the two groups are statistically significant; P < 0.05);

FIG. 8 survival analysis-first time remedial analgesia;

fig. 9 inflammatory indicators (data are expressed as "mean ± standard deviation"; statistically significant P <0.05; # indicates statistically significant differences between group a and group D;

fig. 10 first straight leg elevation time and post-operative hospitalization time (data expressed as "median ± 95% confidence interval;:, indicating that group a and group D differences are statistically significant);

Detailed Description

The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.

Example 1A combination of the present invention

200mg of ropivacaine, 0.2mg of epinephrine, 10mg of dexamethasone and 78ml of physiological saline are added to prepare a total of 100ml of mixed solution.

Example 2A combination according to the invention

Ropivacaine 200mg, epinephrine 0.2mg, dexamethasone 10mg, magnesium sulfate 250mg, 5wt% sodium bicarbonate 30ml, and physiological saline 47ml are added to prepare a total 100ml mixed solution.

Example 3 pharmaceutical combinations according to the invention

200mg of ropivacaine, 0.2mg of epinephrine, 10mg of dexamethasone, 250mg of magnesium sulfate and 77ml of physiological saline are added to prepare a total of 100ml of mixed solution.

Example 4A combination of the present invention

Ropivacaine 200mg, epinephrine 0.2mg, dexamethasone 10mg, 5% sodium bicarbonate 30ml, and physiological saline 48ml were added to prepare a total of 100ml of a mixture.

The following experiments prove the beneficial effects of the invention.

1. Material

1.1 main reagent for experiment

1.2 Main experiment instrument

The "cocktail" in the following experimental examples refers to a combined drug prepared from main drug components in a certain proportion.

Experimental example 1 safety study of the narcotic analgesic combination according to the invention

1. Method of

1.1 characterization of physicochemical Properties

The composition and microstructure of the cocktails (combination drugs prepared as in examples 1-4) were analyzed by fourier transform infrared spectroscopy (Fourier transform infrared spectroscopy, FTIR) and low voltage transmission electron microscopy (transmission electron microscope, TEM).

(1) FTIR: (1) filtering and drying the sample to prepare uniform powder; (2) placing the sample on an optical path, ensuring the stability of the optical path, and collecting FTIR data; (3) processing the optical data; (4) and (5) spectrum interpretation and result analysis.

(2) Low voltage TEM: (1) preparing a sample and dripping the sample onto a silicon wafer; (2) opening a transmission electron microscope and preheating to enable the transmission electron microscope to reach the working temperature, setting a low-voltage mode and calibrating; (3) moving the sample to the position of the electron beam axis and adjusting the inclination angle; (4) irradiating the sample with an electron beam of low electron energy and recording an electron diffraction image; (5) shooting a transmission electron image: a transmission electron image is formed using an electron beam of low electron energy passing through the sample.

1.2, laboratory animals

Animal experiments were approved by the laboratory animal ethics committee of the university, western medicine institute. SD rats 16, 3 months old, weighing 250-300g, supplied by Chengdu laboratory animal Co., ltd. At the animal experiment center of Huaxi hospital at university of Sichuan, all rats were fed according to standard feeding conditions, including maintaining the temperature between 22-26 ℃, controlling the humidity within 37% -42%, illuminating alternately day and night for 12 hours, and feeding and drinking water freely. All animals were kept in the animal center for 1 week before the start of the experiment.

1.3 rat grouping

16 SD rats were randomly assigned to the modified cocktail group and the control group. Sciatic nerve block was performed on 12 rats using modified cocktail (combination drug prepared as in example 2, 0.4ml single injection). Another 4 rats were given simulated sciatic nerve block (0.4 ml saline solution injected) as a control group.

1.4 rat sciatic nerve block

(1) Rats were anesthetized with 2.0% isoflurane and placed in the right lateral position.

(2) The left hip and its surroundings of the rat were subjected to dehairing treatment and sterilized.

(3) The sciatic nerve was located and the depression between the left ischial tuberosity and the ischial tuberosity was found with the finger, i.e. the location of the sciatic nerve.

(4) The syringe with 23G needle is used to insert the needle from the back outside along the direction of sciatic nerve, and the medicine is injected after the bone is pierced. The lower limb motor ability of the rat is affected, and if the rat cannot support body weight, lameness, cannot kick, and the like, the nerve block effect is good. The experimental process of the animal is shown in figure 1.

1.5 sampling protocol

The modified cocktail group was sacrificed and drawn from 4 rats at 2, 7, and 14 days after injection, respectively. Control groups were sacrificed and material was obtained on day 2 (fig. 1).

(1) The rats were sacrificed by cervical removal and the left hip and surrounding skin preparation.

(2) The rats were placed on an operating table in a right lateral recumbent position and cut along the inner sides of the left hip and thigh of the rats with scissors and tissue forceps to expose the sciatic nerve.

(3) The nerve was gently pulled out with tissue forceps and a section of the sciatic nerve (approximately 1.5cm long) and surrounding muscle tissue at the cocktail injection site was excised using a surgical knife. 10% neutral formaldehyde was fixed.

1.6 tissue embedding and sectioning

The fixed tissue is dehydrated by a full-automatic dehydrator (dehydration time length: 75% alcohol 1h,85% alcohol 1h,95% alcohol I50 min,95% alcohol II 50min,100% alcohol I50 min,100% alcohol II 50min, and 100% alcohol: xylene one-to-one mixing for 20min, xylene I25 min, xylene II 25min, paraffin I1 h, paraffin II 2h, paraffin III 3 h), embedded, and sliced.

1.7 dewaxing and rehydration of the sections

The specific operation is as follows: xylene I5-10 min, xylene II 5-10min, absolute ethanol I5 min,95% ethanol 5min,85% ethanol 5min,75% ethanol 5min, and ultrapure water 5min.

1.8 hematoxylin-eosin staining (HE staining)

The sciatic nerve and surrounding muscle tissue of the rat were observed under a light microscope by HE staining, and the injury condition of the sciatic nerve and surrounding muscle tissue was evaluated to determine the safety of the modified cocktail.

(1) Hematoxylin staining: the hematoxylin stain is dripped on the tissue section for 10-20min, and is rinsed for 1-3min by tap water.

(2) Differentiation: hydrochloric acid alcohol is differentiated for 5-10s, and tap water is used for washing for 1-3min.

(3) Returning blue: adding into warm water at 50 ℃ or weak alkaline water solution to turn blue until blue color appears; washing with tap water for 1-3min.

(4) Eosin staining: adding 85% alcohol for 3-5min, dyeing with eosin for 3-5min, washing with water for 3-5s, and gradient alcohol dehydrating.

(5) The xylene was transparent and then mounted with neutral gum.

All of the above specimens were performed according to the pathology test standard procedure.

1.9Luxol Fast Blue (LFB) staining

The sciatic nerve is subjected to LFB staining, the number and the morphology of the sciatic nerve myelin after LFB myelin staining are determined, and the improved cocktail is subjected to safety evaluation, so that a basis is provided for clinical use.

(1) Dewaxing and rehydration of the tissue slices are completed, and 95% ethanol is added for slightly washing.

(2) Adding LFB staining solution, staining for 12-20h at room temperature, and washing off excessive staining solution with 95% ethanol.

(3) Washing with distilled water, adding Luxol differentiation liquid, and separating color for 10-15s.

(4) 70% ethanol was added to the mixture to separate colors for 30s, and the mixture was rinsed with distilled water.

(5) Conventional dewatering, wax-impregnated dewaxed clear liquid (DZ 2011) or xylene clear, and neutral gum sealing.

All of the above specimens were performed according to the pathology test standard procedure.

1.10 histological evaluation

The sciatic nerve and the peripheral muscle tissue injury were evaluated based on the criteria reported in the prior literature (Table 1). The tissue slice analyst is blinded to the grouping.

TABLE 1 criteria for determining damage to nerves and surrounding muscle tissue

2. Results

2.1 physicochemical Properties

The appearance of each set of cocktails is shown in figure 2, and the addition of sodium bicarbonate to ropivacaine solution caused precipitation. The absorption peaks of the two groups of FTIR spectrograms are uniform, which shows that the magnesium sulfate added into the cocktail does not react chemically, and the ropivacaine crystals precipitated after the PH is increased are precipitated, and no new substances are generated (figure 3). The microstructure of the precipitate in the cocktail is shown in the electron microscopy image (FIG. 3).

2.2 histological evaluation

According to the injury judgment standard of sciatic nerve and surrounding muscle tissues, the scores of the two groups of injuries are 0 score. HE staining showed no significant damage to the rat sciatic nerve and surrounding muscle tissue from the 2d,7d and 14d samples. Sciatic nerve LFB staining showed that 2d,7d and 14d were harvested after injection of the modified cocktail, and that sciatic nerve fibers were aligned well and myelin was not significantly shed or dissolved (fig. 4). The improved cocktail is therefore considered to have better safety.

Experimental example 2 study on the effectiveness of the narcotic analgesic combination of the invention

1. Method of

1. Study design

The study was a single-center, prospective, double-blind, randomized controlled trial. The study included 120 osteoarthritis patients with unilateral TKA during joint surgery in the department of western scholariciresis, university of si during the period of 2 months 2022 to 12 months 2022. The clinical trial was approved by the biomedical ethical review Committee of the Huaxi hospital at the university of Sichuan (NO. 2021-1232), and all subjects signed informed consent. The study was completed at the national clinical trial registry (registration number: chiCTR 2200055981) at day 1 and 30 of 2022, according to principles of the declaration of Helsinki, and reported in accordance with the CONSORT statement.

2 inclusion and exclusion criteria

Inclusion criteria: (1) a primary unilateral TKA; (2) The american society of anesthesiologists grade (American Society of Anesthesiologists, ASA) as grade i-iii; (3) Body Mass Index (BMI) 18-36kg/m ² 。

Exclusion criteria: (1) Non-osteoarthritis patients, such as osteoarthritis secondary to suppurative arthritis cure, rheumatoid arthritis, traumatic arthritis, etc.; (2) The knee joint buckling deformation is more than or equal to 30 degrees or the varus and valgus deformation is more than or equal to 30 degrees; (3) allergy to the drugs used in the study; (4) history of narcotic or opioid dependence; (5) a history of surgery for the affected knee; (6) a history of neuromuscular disease; (7) Cognitive impairment, past history of mental illness or inability to communicate in speech.

3 randomization grouping and blind method

All patients were divided into A, B, C, D four groups of 30 cases each using a computer-generated random number list (Excel, microsoft Corporation, redmond, USA). Group a LIA cocktails were: 200mg of ropivacaine, 0.2mg of epinephrine and 10mg of dexamethasone; group B LIA cocktails were: ropivacaine 200mg, epinephrine 0.2mg, dexamethasone 10mg and magnesium sulfate 250mg; group C LIA cocktails were: ropivacaine 200mg, epinephrine 0.2mg, dexamethasone 10mg and 5% sodium bicarbonate 30ml; group D LIA cocktails were: ropivacaine 200mg, epinephrine 0.2mg, dexamethasone 10mg, magnesium sulfate 250mg and 5% sodium bicarbonate 30ml. The four groups of analgesic cocktails are diluted to 100ml in total by adding normal saline. The random numbers are sealed in opaque envelopes, one envelope is selected for each patient on the morning of the procedure, and the patients are divided into four groups according to the numbers in the selected envelope. Prior to surgery, it was ensured that anesthesiologists not involved in the study were prepared a corresponding analgesic cocktail. Ward staff, data collectors, outcome assessors and statistical analysts are blinded to the grouping. The randomized packet result is published after the data analysis is completed.

4 perioperative treatment

Oral celecoxib (200 mg, bid) and pregabalin (150 mg, bid) as prophylactic analgesia starting from the day of admission; loxoprofen sodium (60 mg, tid) is taken if celecoxib is contraindicated. General anesthesia is carried out by anesthesiologists, and after pure oxygen is inhaled, the following anesthetic is intravenous injected, namely midazolam, 2mg/kg; propofol, 2mg/kg; sufentanil, 0.3 μg/kg and cis-atracurium 0.2mg/kg.

All TKA procedures in this study were performed by the same senior physician in joint surgery at the university of huaxi hospital, si. After general anesthesia, the skin is guided to the middle incision through the inner side patella bypass, the bone cement knee joint prosthesis is implanted in the operation, a tourniquet is not used, and a drainage tube is not arranged. All patients were instilled with 1g of tranexamic acid intravenously 30 minutes before skin incision and 3 and 6 hours after surgery. Systemic glucocorticoids are not used.

The intra-operative LIA is performed by a surgeon using a multi-point injection method. The four groups of patients were treated in the same manner except for the different ingredients of the cocktail formulation. Before the implantation of the prosthesis, 20ml of cocktail is injected behind the joint capsule, and 20ml of cocktail is used for infiltration analgesia on the medial collateral ligament and the lateral collateral ligament. After placement of the prosthesis, quadriceps and its ligament tissue were infiltrated with 20ml of cocktail, and then periarticular subcutaneous and adipose tissue was infiltrated with 40ml of cocktail. Sufentanil (5 μg) was intravenously injected 20min before the end of surgery to prevent postoperative pain, while 5mg topiroxone was intravenously injected to prevent postoperative nausea and vomiting.

The patient was subjected to periwound ice after returning to the ward without using an analgesic pump. Celecoxib (200 mg, bid) and pregabalin (150 mg, bid) were orally administered post-operatively to control post-operative pain. The remedial analgesia of opioids is determined by PACU and outcome assessors in the ward. When the patient is difficult to tolerate pain after operation [ pain visual simulation score at rest (visual analogue scale, VAS) is more than or equal to 4 points or VAS score at activity is more than or equal to 6 points ], morphine hydrochloride 10mg is injected subcutaneously as a remedial analgesic.

To prevent venous thromboembolism (venous thromboembolism, VTE), low molecular heparin 2000AXaIU was injected subcutaneously 12 hours after surgery followed by 4000AXaIU at 24 hours intervals until discharge. After discharge, rivaroxaban was changed to 10mg orally, 1 time per day, for up to 2 weeks after surgery. The patient receives the lower limb air pressure treatment after operation and actively performs functional exercises of knee bending and stretching, ankle bending and leg lifting, and performs lower limb strength training. The patient walks under the direction of the caregiver using the walker starting on the first day after surgery.

5 ending index

General data of patients were recorded at admission: sex, age, BMI, weight, height, VAS score under daily activities, surgical side, knee joint mobility, ASA grading, and quadriceps muscle strength.

The primary outcome measures include pain scores, post-operative remedial morphine usage, and first-time remedial analgesia. Postoperative pain was assessed with VAS scores at activity (knee flexion 45) and rest, respectively. VAS scores ranged from 0 to 10, with higher scores representing more severe pain, 0 representing "completely pain free", and 10 representing "pain to the extreme", 0 to 3 for mild pain, 4 to 6 for moderate pain, and 7 to 10 for severe pain. The VAS scores at rest were measured 2h, 6h, 12h, 24h, 48h and 72h post-operatively, and the VAS scores at activity were measured 6h, 12h, 24h, 48h and 72h post-operatively.

Secondary outcome measures include inflammatory measures, knee functional recovery, and post-operative hospitalization time. Inflammatory indicators include interleukin 6 (IL-6) and C-reactive protein (CRP). Fasting blood was collected at day 1, 2, and 3 post-surgery, and IL-6 and CRP levels were determined. The knee function recovery was assessed by quadriceps muscle strength, daily walking distance, knee joint mobility, and first straight leg elevation time. The bare-hand muscle force method is used for measuring the quadriceps muscle force, the patient sits or lies on the back, the knee joint flexes, the patient straightens the knee joint, and the resistance is given to the measurer. Muscle strength grading: grade 0 indicates no muscle contraction; level 1 indicates that there is muscle contraction but no joint movement; level 2 indicates that the limb is movable on a plane but cannot resist gravity; the 3-level indicates that the limb gravity can be resisted, but the external resistance can not be overcome; level 4 indicates that the movement can be completed, partially overcoming the resistance; the 5-level indicates resistance can be fully resisted. The patient walks under the walker in one attempt as long as possible, taking this distance as the daily walking distance. Knee joint mobility was measured at bedside using a joint angle protractor, three times per day, 6 hours apart, and the optimal value was taken as the current day's mobility. The first straight leg lifting time is defined as the time that the patient can actively straighten the knee joint for the first time after operation, and the heel lifts off the bed by 30 to 60 degrees.

Patient time to stay after surgery was recorded. The discharge criteria for the patient included: (1) General conditions such as spirit, diet, sleep, and urination and defecation are good; (2) The concurrent diseases are controlled stably, such as hypertension and diabetes are controlled well; (3) the operation incision heals well, and red swelling and seepage are avoided; (4) the pain of the oral analgesic is well controlled, and the VAS score is less than or equal to 3; (5) the knee joint mobility is good and is more than or equal to 100 degrees; (6) The patient and family members master the correct function exercise method and the daily life skills; (7) The walker is correctly used, and the walking assisting distance is more than or equal to 20m.

Other outcome indicators are the incidence of complications, including: wound complications, nausea, vomiting, neurovascular injury, post-operative infections, venous thromboembolism and post-operative falls. All patients were disconnected 3 weeks post-surgery and were followed 3 months post-surgery to assess function and recovery.

6 statistical analysis

Sample size estimation based on post-operative remedial morphine amounts reported in previous studies, at a bilateral alpha value of 0.05 and a potency (1-beta) of 90%, in order to reduce the post-operative remedial morphine amount by 10mg in the observation group [ incorporating the minimum clinical significance differences reported in the 570 reviews of joint replacement analgesia test systems (minimal clinically important difference, MCID)] ^[43] At least 27 subjects were required for each group. Considering that there may be factors such as patient loss or withdrawal from the study, the study was prepared to include 30 patients per group, for a total of 120 patients.

The study used SPSS software 23.0 (IBM Corp, armonk, NY, USA) to statistically analyze the data. The classification data are expressed in percentages or numbers, and the succession of data are expressed in terms of "mean ± standard deviation", unless specifically indicated otherwise. The significance of the difference will be expressed as P <0.05, i.e. considered statistically significant. Carrying out normal evaluation by adopting a Shapiro-Wilk test; normal distribution data were checked using one-way anova and compared afterwards using LSD. If the data does not fit the normal distribution or for ordered data, a Kruskal-Wallis rank sum test is used and a post-hoc test is performed. P-value correction was performed by Bonferroni method for pairwise comparisons between groups. Analysis of the classification data was performed using Pearson chi-square test or Fisher exact probability method. The first rescue analgesia time is analyzed by adopting a survival analysis (Kaplan-Meier method, log-rank test), and the follow-up visit end point is discharge.

2. Results

1 patient baseline characteristics

A total of 173 osteoarthritis patients were evaluated, 25 of which did not meet inclusion criteria, and 28 were unwilling to participate in the study. Finally, each of the A, B, C, D four groups included 30 patients. Study patients were not interviewed and withdrawn during post-operative outcome assessment (fig. 5). There were no significant differences in pre-operative baseline data and operative time for the four groups of patients (table 2).

Table 2 preoperative baseline characteristics for each group of patients

Note that: continuous data are expressed as "mean ± standard deviation"; the classification data is represented numerically. ^a Single factor analysis of variance; ^b pearson chi-square test; ^c Kruskal-Wallis rank sum test. Abbreviations: BMI, body mass index; VAS, visual simulation scoring; ASA, american society of anesthesiologists.

2 main outcome

(1) VAS pain scoring

The VAS scores were significantly reduced (P < 0.05) at 12h, 24h rest after surgery for patients in groups B, C and D compared to group A; the VAS scores were significantly higher in group A patients at 12h, 24h activity post-surgery than in groups B, C and D (P < 0.05); no significant difference in VAS scores (P > 0.05) between group a patients and group B, C and D patients at other post-operative time points at both activity and rest; there was no significant difference in VAS scores at each time point after surgery for the B, C and D three groups of patients, except that the VAS scores were significantly lower at 24h rest after surgery for the D group of patients than for the B group. The results are shown in Table 3 and FIG. 6.

TABLE 3VAS pain score

Note that: data are expressed as "mean ± standard deviation". ^* Kruskal-Wallis rank sum test; ^a indicating that the difference between group A and group B is statistically significant (P<0.05)； ^b Indicating that the difference between group A and group C is statistically significant (P<0.05)； ^c Indicating that the difference between group A and group D is statistically significant (P<0.05)； ^d Indicating that the difference between group B and group D is statistically significant (P<0.05). Abbreviations: VAS, visual simulation scoring.

(2) Postoperative remedial analgesia

Group B (9.00±6.07 mg), group C (9.50±6.87 mg) and group D (4.33±6.66 mg) were all significantly lower in morphine dose at day 1 post-surgery than group a (15.67±6.40 mg) (P < 0.05). There was no significant difference in morphine usage between groups on postoperative day 2 and 3. The total morphine dose (21.67±10.03 mg) during hospitalization was significantly higher for group a than for group B (14.17±8.31mg, p=0.026), group C (14.00±8.85mg, p=0.027) and group D (9.33±8.78mg, p < 0.001). The amount of morphine used on day 1 after the operation of group D was lower than the total amount of morphine used in groups B and C, but the difference was not statistically significant. The results are shown in Table 4 and FIG. 7.

Compared with group a (12.56±4.04 h), the first-time remedial analgesia time after the operation of group B (17.13±5.07h, p=0.005), group C (17.46±5.88h, p=0.009) and group D (22.94±11.94h, p < 0.001) is significantly prolonged. The first time remedial analgesia time after the operation of the group D is obviously higher than that of the group B (P=0.029) and the group C (P=0.031), and the difference is statistically significant. Group D had significantly higher non-remedial analgesia (40.0%) than group a (10.0%, P < 0.05). The results are shown in Table 4 and FIG. 8.

Table 4 post-operative remedial analgesia

Note that: continuous data are expressed as "mean ± standard deviation"; the classification data are indicated by the number (%). The Kruskal-Wallis rank sum test;survival analysis (Kaplan-Meier method, log-rank test); />Pearson chi-square test; exclude non-remedial analgesic patients. ^a Indicating that the difference between group A and group B is statistically significant (P<0.05)； ^b Indicating that the difference between group A and group C is statistically significant (P<0.05)； ^c Indicating that the difference between group A and group D is statistically significant (P<0.05)； ^d Indicating that the difference between group B and group D is statistically significant (P<0.05)； ^e The difference between group C and group D was statistically significant (P<0.05)。

3 secondary outcomes

(1) Inflammatory index

The inflammatory markers CRP and IL-6 were elevated after surgery in four groups of patients. The mean value of CRP for each group reached a peak at day 2 post-surgery. Compared with group A, the CRP levels of groups B and D were significantly reduced on days 2 and 3 after the operation, and the differences were statistically significant (P < 0.05). The IL-6 levels in each group peaked on day 1 post-operatively and subsequently decreased. IL-6 levels were significantly lower in groups B and D (P < 0.05) at days 2 and 3 post-surgery. There was no statistical difference in CRP and IL-6 levels on day 1 pre-and post-operation for each group. The results are shown in Table 5 and FIG. 9.

TABLE 5 inflammatory index

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Note that: data are expressed as "mean ± standard deviation". * And (5) single-factor variance analysis. ^a Indicating that the difference between group A and group B is statistically significant (P<0.05)； ^b Indicating that the difference between group A and group D is statistically significant (P<0.05)。

(2) Knee joint functional recovery

Compared with the group A patients, the group D patients have better knee joint mobility on the 1 st and 2 nd days after operation, the walking distance is longer every day, and the differences are of specific statistical significance (P < 0.05). On postoperative day 3, there was no significant difference in the four groups of knee joint mobility and daily walking distance (P > 0.05). There was no significant difference in quadriceps muscle strength after surgery in the four groups of patients. The hospitalization time of the patients in the group D after operation is obviously shortened compared with that of the patients in the group A (65.43+/-5.79 hvs 71.73+/-6.15 h, P < 0.001). The first straight leg lifting time of the four groups of patients is similar, and the difference has no statistical significance. The results are shown in Table 6 and FIG. 10.

TABLE 6 functional recovery of knee joint

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Note that: data are expressed as "mean ± standard deviation". * Kruskal-Wallis rank sum test. ^a Indicating that the difference between group A and group D is statistically significant (P<0.05)。

4 other outcomes

The incidence of nausea, vomiting and wound-related complications was similar for each group of patients, and the differences were not statistically significant. None of the patients in each group had neurovascular injury, VTE, post-operative infection or post-operative fall occurred (table 7).

TABLE 7 incidence of complications

Note that: data are expressed as numbers (%). * And (5) Pearson chi-square test. Abbreviations: VTE: venous thromboembolism

3. Discussion of the invention

The addition of sodium bicarbonate to the cocktail results in the formation of a precipitate which is a precipitated crystal of ropivacaine, consistent with the report of precipitation caused by basification of local anesthetic solutions. Due to the physicochemical properties of local anesthetics, such precipitation is unavoidable in physiological environments. In animal experiments, all precipitations of the modified cocktail of the present invention were absorbed upon dissection and were not deposited around nerves or muscles (fig. 4). Therefore, the precipitate should be absorbed within 2 days at the time of clinical use. Animal experiments initially show that the precipitate is absorbable, safe and reliable, and no related side effect is observed in the clinical experiments at present and in the past.

The research result shows that the cocktail prepared by combining ropivacaine with epinephrine and dexamethasone has better local anesthesia and postoperative analgesic effect, and the simultaneous addition of magnesium sulfate and sodium bicarbonate in the cocktail can obviously prolong the analgesic duration, has statistical significance, plays a synergistic effect, increases the knee joint mobility and daily walking distance on the 1 st and 2 nd days after operation, and shortens the hospitalization time. And the absolute difference of the knee joint movement ranges exceeds 10 degrees on the 1 st day after operation. The current literature reports that the MCID of knee joint mobility after TKA surgery is 10 degrees. In terms of ERAS, there is an advantage in improving cocktail, which can accelerate early recovery after TKA surgery.

In conclusion, the combined medicine combining ropivacaine, epinephrine and dexamethasone provided by the invention has better local anesthesia and postoperative analgesic effects, and further is supplemented with magnesium sulfate and sodium bicarbonate adjuvant, so that the postoperative analgesic effect can be prolonged while the local anesthesia effect is ensured, early pain is effectively relieved, and early recovery after TKA operation is accelerated.

Claims (10)

1. A combination comprising ropivacaine, epinephrine, and glucocorticoid in the same or different unit dosage forms for simultaneous or separate administration.

2. The combination according to claim 1, wherein the glucocorticoid is dexamethasone, betamethasone, triamcinolone acetonide, methylprednisolone, prednisolone acetate, cortisone or hydrocortisone, preferably dexamethasone.

3. The combination according to claim 1 or 2, wherein the mass ratio of ropivacaine, epinephrine, dexamethasone is (150-250): 0.1-0.5): 5-15, preferably 200:0.2:10.

4. The combination according to claim 1 or 2, further comprising an adjuvant, wherein the adjuvant is magnesium sulfate and/or sodium bicarbonate.

5. The combination according to claim 4, wherein the mass ratio of ropivacaine to magnesium sulfate is (150-250): (200-300), preferably 200:250.

6. The combination according to claim 4, wherein the mass ratio of ropivacaine to sodium bicarbonate is (0.15-0.25): 1-2, preferably 0.2:1.5.

7. The combination according to any one of claims 1 to 6, characterized in that it comprises the following components as active ingredients in parts by weight:

200 parts of ropivacaine, 0.2 part of epinephrine, 10 parts of dexamethasone, 250 parts of magnesium sulfate and 1500 parts of sodium bicarbonate.

8. The combination according to claim 1, wherein the preparation is prepared by adding pharmaceutically acceptable auxiliary materials to the active ingredients of the components; the formulation is a liquid formulation.

9. The combination according to claim 8, wherein the adjuvant is physiological saline.

10. Use of a combination according to any one of claims 1 to 9 for the preparation of an anesthetic and/or analgesic.