Pharmaceutical composition for intraoperative brain protection in shoulder arthroscopy surgery

Abstract

The invention relates to a pharmaceutical composition for intraoperative brain protection in shoulder arthroscopy surgery. The pharmaceutical composition comprises midazolam, propofol, sufentanil, succinylcholine and atracurium besylate. According to the invention, rScO2 can be improved, the risk of cerebrovascular events can be reduced, but no obvious influence is generated on the circulation stability in the operation of a patient, the postoperative cognitive impairment and the like.

Description

Technical Field

[0001] The invention relates to a pharmaceutical composition for performing brain protection during shoulder arthroscopic surgery, belonging to the technical field of medicines. Background Art

[0002] Shoulder dysfunction is often caused by trauma and degenerative diseases, such as arthritis, rotator cuff injury, and shoulder instability. Arthroscopic shoulder surgery offers advantages such as minimal trauma to the deltoid muscle, a low risk of axillary nerve injury, shortened operative time, and reduced immediate postoperative pain. It also has a low overall complication and infection rate. Poor intraoperative visibility can hinder surgeons' skill and increase complication rates. Arthroscopic visualization is crucial for ensuring surgical efficiency, effectiveness, and safety. To maintain the patient's normal anatomical position and ensure a clear surgical field of view, surgeons typically use the beach chair position (BCP) and administer controlled hypotension. However, BCP and hypotension are likely to lead to cerebral hypoperfusion. Cerebral hypoperfusion can cause neurological damage, including stroke, spinal cord ischemia, and transient visual loss. Therefore, during BCP shoulder arthroscopic surgery, particular attention must be paid to maintaining cerebral perfusion to prevent intraoperative cerebral ischemia, which can lead to postoperative cognitive impairment and other complications.

[0003] Permissive hypercapnia (PHC) is a lung-protective ventilation strategy that allows for a moderate increase in PaCO2 and a certain degree of acidemia when maintaining adequate gas exchange and reducing ventilation pressure are incompatible. PHC can increase regional cerebral oxygen saturation (rScO2), increase cerebral blood flow, and improve the balance of cerebral oxygen supply and demand in patients undergoing heart valve replacement surgery, but it has no significant effect on the incidence of postoperative cognitive impairment. Therefore, to address the risk of intraoperative cerebral ischemic events in patients undergoing arthroscopic shoulder surgery with back-constriction coronary artery disease (BCP), gradually increasing the patient's PaCO2 during surgery can be considered to alleviate cerebral hypoperfusion caused by body position and anesthesia. Stellate ganglion block (SGB) is commonly used clinically to treat a variety of conditions, such as improving insomnia, regulating autonomic dysfunction, alleviating migraine headaches, and regulating endocrine function. Functional magnetic resonance imaging (fMRI) of the brains of patients with SGB reveals that SGB activation is primarily distributed in the contralateral anterior cingulate cortex and hypothalamus (both of which are responsible for maintaining homeostasis), the ventral putamen (i.e., the γ-aminobutyric acid pathway), and the parahippocampal gyrus. Inhibitory effects are observed in the contralateral ventral occipital thalamus, the dorsal putamen (i.e., part of the dopaminergic pathway), and the ipsilateral caudate nucleus. Therefore, SGB maintains homeostasis while regulating body temperature and inhibiting the sympathetic nervous system. Clinical studies have shown that SGB can inhibit neuroinflammatory responses and glial cell activation, while also reducing the expression of autophagy proteins and improving cognitive impairment, suggesting that SGB has a certain brain-protective effect. Summary of the Invention

[0004] The object of the present invention is to provide a robust high performance liquid chromatography method for monitoring lamotrigine serum therapeutic drug levels.

[0005] To achieve the above-mentioned and other related purposes, the present invention provides a technical solution: a pharmaceutical composition for intraoperative brain protection during shoulder arthroscopic surgery, comprising: midazolam, propofol, sufentanil, succinylcholine and atracurium besylate.

[0006] The preferred technical solution is: the dosage of the pharmaceutical composition is: midazolam 0.04-0.06 mg / kg, propofol 2-3 mg / kg, sufentanil 0.04-0.06 mg / kg, succinylcholine 1-1.5 mg / kg, and atracurium besylate 0.4-0.5 mg / kg.

[0007] Due to the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0008] This study monitored the changes in rScO2 in patients undergoing shoulder arthroscopic surgery and explored the effects of PHC combined with SGB on patients' cerebral blood oxygenation and postoperative cognitive function, providing a reference for intraoperative brain protection in patients undergoing shoulder arthroscopic surgery. DETAILED DESCRIPTION

[0009] The following describes the implementation of the present invention through specific embodiments. People skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in these embodiments.

[0010] Unless otherwise specified, the experimental materials used in the following examples were purchased from conventional biochemical reagent stores.

[0011] Example 1: A pharmaceutical composition for intraoperative brain protection during shoulder arthroscopic surgery

[0012] This implementation method was approved by the hospital ethics committee (SZSLYY202004152), and the patients signed the informed consent. 129 patients who underwent elective shoulder arthroscopic surgery from September 2022 to January 2024 were selected. The patients were of either sex, aged 23 to 65 years, and had a BMI of 21 to 27 kg / m 2 Patients were ASA physical status I or II. Exclusion criteria included preoperative contraindications to SGB puncture (puncture site infection, scarring, and previous surgery), history of local anesthetic poisoning or allergy, preoperative coagulopathy, poorly controlled severe hypertension (preoperative BP >180 / 110 mmHg), history of cerebrovascular disease or cranial surgery, uncontrolled bronchial or pulmonary disease, chronic use of opioid analgesics, sedatives, or anticonvulsants, and known drug allergies. Exclusion criteria included poor SGB block response (ptosis, miosis, conjunctival congestion with nasal congestion and anhidrosis; the presence of more than three of these symptoms constitutes a positive Horner syndrome, indicating successful block), severe intraoperative allergic reaction, uncontrolled intraoperative hypertension, hypotension, or hypoxemia, temporary modification of the surgical technique or position due to medical conditions, severe postoperative delayed recovery, intraoperative hemorrhage (blood loss exceeding 15% of the patient's blood volume), and patient withdrawal from the study. The patients were divided into three groups using the random number table method: blank group (group C), PHC group (group P) and SGB+PHC group (group SP), with 43 cases in each group.

[0013] Anesthesia: Preoperatively, the patient fasted for 6 hours and refrained from drinking for 4 hours. Upon admission, the patient was placed in a supine position and connected to an ECG system. Regional cerebral oxygen saturation (rScO2), HR, BP, and SpO2 were monitored and recorded. A 16-gauge trocar was used to access a peripheral vein on the nonoperative side. During the procedure, a cerebral oximeter was used to monitor rScO2. The patient's forehead was degreased with 75% alcohol, and then the left and right electrodes were applied approximately 1 cm above the superior margin of the eyebrow arch, secured with a film. The radial artery was palpated medially on the nonoperative side of the radial head. After local anesthesia with 0.5–1.0 mL of 2% lidocaine, a radial artery cannula was inserted, the transducer connected, and zeroed to ensure the transducer was aligned with the patient's right atrium. Re-zeroing was required after subsequent changes in position, and the transducer was adjusted to align with the right atrium. The patient's head was tilted toward the uninvolved side, and ultrasound of the operative neck was performed using a high-frequency linear array probe (5–13 MHz) to determine the optimal needle insertion route. The patient's group was then determined to undergo SGB. The patient's neck anatomy was carefully identified under ultrasound, including structures such as the trachea, esophagus, and thyroid gland. The anterior tubercle of the C6 transverse process was located, and the carotid sheath, longus colli muscle, and prevertebral fascia were identified to determine the needle insertion route. An in-plane needle insertion technique was used, and the skin was disinfected with iodine tincture three times in a circular area 15 cm from the insertion site. The ultrasound probe was also disinfected with iodine tincture.

[0014] During SGB, the needle tip is guided within the plane, avoiding nerves and blood vessels, puncturing the prevertebral fascia to reach the stellate ganglion on the surface of the longus colli muscle. After repeated aspiration by an assistant to confirm the absence of blood, a 5-ml mixture of 0.25% ropivacaine and 1% lidocaine is slowly injected into the SP group. An equal volume of 5-ml saline is slowly injected into the same site in the P and C groups. After the injection, ultrasound can be used to visualize the local anesthetic or saline solution gradually spreading from the surface of the longus colli muscle to the area between the C6 transverse process and the carotid artery. The puncture site is pressed to prevent bleeding and hematoma, and the patient's sensations are assessed. A successful SGB is positive for Horner's syndrome. Immediately after the SGB, the patient's vital signs and any block-related adverse reactions are observed. The anesthesiologist performing the SGB assesses the patient's general condition, and rapid induction of general anesthesia is performed approximately 10 minutes after the patient's vital signs stabilize. After inhaling pure oxygen for 3 to 5 minutes, midazolam 0.04 to 0.06 mg / kg, propofol 2 to 3 mg / kg, sufentanil 0.04 to 0.06 mg / kg, succinylcholine 1 to 1.5 mg / kg, and atracurium besylate 0.4 to 0.5 mg / kg were injected intravenously. Anesthesia was maintained by intravenous-inhalational combined anesthesia with inhalation of 1.5% sevoflurane and infusion of remifentanil 4 to 8 μg·kg. -1 ·h -1 , dexmedetomidine 0.2-0.7 μg·kg -1 ·h -1, intermittently inject 1 / 3 to 1 / 2 of the initial dose of atracurium to maintain muscle relaxation, oxygen flow rate is 2 to 3 L / min, FiO2 80%, and intraoperative fluid infusion volume is 8 to 10 ml / kg / h. After tracheal intubation, change to mechanical volume control mode and set V T 6 ml / kg, RR 8-15 times / min, observe the patient's basic vital signs, maintain MAP>80 mmHg, BIS 40-60. After anesthesia induction, change the patient's position to BCP and begin surgery.

[0015] P ET CO2 target value setting: During surgery, adjust V T and RR gradually controls P ET CO2, P group and SP group P ET CO2 was raised to 50 mmHg under controlled conditions, and P ET CO2 is approximately 40 mmHg. If MAP is <60 mmHg or cerebral desaturation events (CDEs) occur during surgery, immediately administer a single intravenous injection of phenylephrine 50-100 μg, and increase the infusion rate. If bradycardia (HR <50 beats / min) occurs, administer atropine 0.25-0.5 mg intravenously. A CDE is defined as a decrease in rScO2 greater than 20% of the baseline value or an absolute rScO2 value <55% for more than 15 seconds. 30 minutes before the end of surgery, administer 3 mg of granisetron hydrochloride intravenously to prevent postoperative nausea and vomiting. After surgery, transfer the patient to the PACU for recovery and extubation.

[0016] All patients received conventional postoperative analgesia using a patient-controlled intravenous analgesia (PCIA) pump with a formulation of sufentanil 2.5 μg / kg and granisetron 10 mg diluted to 100 mL with normal saline. The pump was operated at a rate of 2 mL / h, with a 0.5 mL bolus and a 15-minute lockout period. The infusion was continued for 48 hours. If the VAS score was >4, the patient was to apply an additional PCIA pressure to relieve pain. If pain persisted, 80–100 mg of tramadol was administered intramuscularly.

[0017] Observation indicators: rScO2, HR, BP, SpO2, P at the time of admission (T0), 10 minutes after SG operation (T1), 5 minutes after BCP (T2), 30 minutes after the start of surgery (T3), 1 hour after the start of surgery (T4), and at the end of surgery (T5) were recorded. ETThe occurrence of intraoperative CDE, intraoperative use of vasoactive drugs, intraoperative use of anesthetics, intraoperative fluid replacement volume, intraoperative blood loss, postoperative nausea and vomiting, dizziness, VAS pain scores before surgery, on the first and second days after surgery, and mini-mental state examination scores (MMSE) before surgery, on the first and seventh days after surgery were recorded.

[0018] Statistical analysis: Based on calculations from a pilot project of 36 patients, at a 5% significance level and 85% power to detect a 10% change in cerebral oxygen supply and demand balance in arthroscopic shoulder surgery with SGB for PHC, assuming α = 0.05 and 1-β = 0.85, the sample size was estimated to be 117 patients. Considering a dropout rate of approximately 10%, 129 patients were selected for inclusion in the study.

[0019] SPSS 25.0 software was used for statistical analysis. Normally distributed quantitative data were expressed as mean ± standard deviation. Intergroup comparisons were performed using one-way analysis of variance, and overall comparisons within groups were performed using repeated measures analysis of variance. Pairwise comparisons between groups and at different time points within a group were performed using the LSD-t method. Enumeration data are expressed as cases (%), and intergroup comparisons were performed using the χ2 test. P < 0.05 was considered statistically significant.

[0020] result:

[0021] This study initially enrolled 129 patients. Two patients in the SP group were excluded due to changes in surgical procedure during surgery and one due to an allergic reaction to an anesthetic drug. One patient in the P group was excluded due to changes in surgical procedure during surgery and two due to an allergic reaction to an anesthetic drug. Three patients in the C group declined to participate and were excluded. A total of 120 patients were ultimately included in the analysis, with 40 patients in each group. There were no statistically significant differences in gender, age, height, weight, BMI, hypertension, operative time, anesthesia time, intraoperative fluid replacement, intraoperative blood loss, or anesthetic drug dosage among the three groups (Table 1).

[0022] Table 1 Comparison of general conditions of patients in the three groups

[0023]

[0024] There were no statistically significant differences in HR, MAP, and SpO2 among the three groups at different time points during the operation (Table 2).

[0025] Table 2: Comparison of HR, MAP and SpO2 at different time points during surgery among the three groups of patients

[0026]

[0027]

[0028] There was no statistically significant difference in rScO2 between the three groups on the surgical side between T0 and T2. Compared with group C, the rScO2 on the surgical side of the SP group was significantly increased from T3 to T5 (P < 0.05). There was no statistically significant difference in rScO2 between the surgical side of the C and P groups between T3 and T5. Compared with group C, the rScO2 on the surgical side of the P group was significantly increased from T5 (P < 0.05). Compared with group C, the rScO2 on the non-operative side of the SP group was significantly increased from T5 (P < 0.05). There was no statistically significant difference in rScO2 between the non-operative side of the P and SP groups at T5. The rScO2 on the surgical side of the SP group gradually increased from T3 to T5, with statistically significant differences between T3, T4, and T5 (P < 0.05). The rScO2 on the surgical side of the PH group gradually increased from T3 to T5, with statistically significant differences between T2 and T4, and between T3 and T5 (P < 0.05). (Tables 3, 4, and 5).

[0029] Table 3 Comparison of rScO2 in three groups of patients at different time points

[0030]

[0031]

[0032] Note: Compared with T0 a P<0.05; compared with T1 b P<0.05; compared with T2 c P<0.05; compared with T3 d P<0.05; compared with T4 e P<0.05; compared with group C, fP<0.05; compared with group P, gP<0.05.

[0033] At T3-T5, the PaCO2 and P of patients in the P group and SP group were significantly different. ET CO2, compared with group C, there were statistical differences (P < 0.05); within the group, there were statistical differences (P > 0.05) in group P and group SP at T3-T5 compared with T0, T2, and T3, respectively, and there were no statistical differences in the rest (see Table 4).

[0034] Table 4 P values of patients in the three groups at different time points ET Comparison of CO2 and PaCO2 ( mmHg)

[0035]

[0036] Note: Compared with T0 a P<0.05; compared with T1b P<0.05; compared with T2 c P<0.05; compared with group C d P<0.05

[0037] There were no statistically significant differences in the VAS pain scores before surgery and 1 day and 2 days after surgery, and in the MMSE scores before surgery and 1 day and 7 days after surgery among the three groups (Table 5).

[0038] Table 5 Comparison of VAS pain scores and MMSE scores among the three groups of patients

[0039]

[0040] There were no statistically significant differences in the incidence of intraoperative CDE, use of vasoactive drugs, and postoperative adverse reactions among the three groups (Table 6).

[0041] Table 6 Comparison of adverse reactions, CDE and vasoactive drug use among the three groups of patients [cases (%)]

[0042]

[0043] discuss

[0044] To ensure a clear visual field and appropriate anatomical positioning during shoulder arthroscopy, patients are often placed under back pressure control (BCP). Patients undergoing BCP under general anesthesia may experience severe hypotension, which, combined with controlled intraoperative hypotension, can further reduce cerebral perfusion and affect the balance of cerebral oxygen supply and demand. Patients undergoing BCP are more susceptible to complications including stroke, spinal cord ischemia, and transient visual loss. Therefore, maintaining cerebral perfusion during shoulder arthroscopy is crucial. PHC, a lung-protective ventilation strategy, has been demonstrated in numerous studies to have roles in maintaining homeostasis, brain protection, and anti-inflammatory measures. PHC mediates the complex regulation of brain homeostasis through multiple mechanisms, including cerebral microcirculation and oxygen supply and demand balance, brain activity and metabolism, excitatory amino acid and neurotransmitter secretion, free radical-induced damage, inflammatory responses, and apoptotic mechanisms. The neuroprotective mechanism of mild hypercapnia remains unclear, but it may be related to enhanced oxygen delivery, improved cerebral glucose utilization, and oxidative metabolism. Furthermore, it can activate adenosine triphosphate-sensitive potassium channels, maintaining normal neuronal activity during cerebral ischemia. A study using PHC in clinical anesthesia management found that PHC increased rScO2 in patients undergoing general anesthesia and reduced the incidence of CDE. The results of this study showed that compared with group C, the rScO2 on the surgical side of group SP was significantly increased from T3 to T5 (P < 0.05). There was no statistically significant difference in rScO2 on the surgical side between groups C and P from T3 to T5. Compared with group C, the rScO2 on the surgical side of group P was significantly increased at T5 (P < 0.05). Compared with group C, the rScO2 on the non-operative side of group SP was significantly increased at T5 (P < 0.05). These results indicate that PHC has the effect of increasing bilateral rScO2 in patients.

[0045] The stellate ganglion (SG) is located at the level of the first rib in the anterior cervical lamina. Its neurons receive impulses from the intermediolateral nucleus of the spinal cord core from C8 to T5 via the white communicating arbor. These impulses are then delivered to postganglionic SG neurons via a divergent mechanism to innervate the upper trunk. The SG regulates the functions of the regions it directly supplies, including the brain, neck, lungs, heart, and upper limbs, as well as the vascular, interstitial, and immune systems, including microcirculation and endothelial function. These influences the peripheral immune system and also the immune system involved in controlling brain regions, such as intestinal function. This mechanism involves the brain receiving and integrating afferent signals from the gut, both neuronal and non-neuronal (e.g., cytokines), via the vagus and sympathetic nerves. This feedback loop influences the gut and its immune system. Sympathetic nerve blockade via the SG can dilate the blocked cerebral artery, alleviating the risk of cerebral ischemia. Therefore, the SG may represent a novel clinical strategy for reducing the risk of cerebral ischemia in patients undergoing arthroscopic shoulder surgery with BCP. The local anesthetic concentration selected for this study was a 5ml mixture of 0.25% ropivacaine and 1% lidocaine. This concentration was determined based on the needs of multiple clinical trials. It effectively blocks sympathetic and sensory nerves, has little blocking effect on motor nerves, and helps avoid recurrent laryngeal nerve block. The results of this study showed that on the surgical side, the SP group had significantly higher rScO2 than the P group at all time points after position change, indicating that SGB can help improve cerebral hypoperfusion and reduce the risk of cerebral ischemic events. However, there was no significant difference on the non-operative side, indicating that the SGB's effect on increasing rScO2 values is only effective on the surgical side. The rScO2 results of the three groups of patients showed that compared with the C group, the SP group had a significantly higher rScO2 on the non-operative side at T5 (P < 0.05). There was no statistically significant difference in rScO2 on the non-operative side between the P and SP groups at T5. The rScO2 of the surgical side in the SP group gradually increased from T3 to T5, and the difference between rScO2 at T3, T4 and T5 was statistically significant (P < 0.05). The rScO2 of the surgical side in the PH group gradually increased from T3 to T5, and the difference between rScO2 at T2 and T4, and between rScO2 at T3 and T5 was statistically significant (P < 0.05), indicating that SGB combined with PHC can improve the rScO2 value of the surgical side better than PHC alone. In order to study the effect of SGB on cerebral blood oxygen balance in patients under PHC, after the patient changed his position, the rScO2 value was increased by controlling V T and RR gradually control P ETCO2 was raised until it stabilized at 50 mmHg, while PaCO2 was monitored intermittently on blood gas analysis to identify changes in PHC. The primary determinant of cerebral perfusion pressure and cerebral oxygenation is MAP, and a decrease in MAP is closely associated with a decrease in rScO2. Therefore, to minimize the impact of MAP fluctuations on this study, MAP fluctuations were maintained within 20% of baseline values. The results of this study showed that after anesthesia induction and transition from supine to beach-chair positioning, rScO2 decreased significantly on both the operative and nonoperative sides, indicating that BCP affects cerebral perfusion and cerebral oxygen homeostasis. Post-anesthesia hypotension and the gravitational effects of elevated head and feet at heart level contribute to cerebral hypoperfusion and ischemia in patients undergoing shoulder arthroscopy. Numerous approaches have been proposed to address cerebral hypoperfusion under BCP, but each approach has its own drawbacks. Generally speaking, fluid administration is an effective method for preventing hypotension-related cerebral hypoperfusion in patients undergoing BCP. For example, Frey et al. demonstrated that preoperative injection of 500 ml of 6% hydroxyethyl starch 130 / 0.4 and 1000 ml of compound sodium acetate effectively maintained hemodynamic stability in the beach chair position. However, this may lead to hypervolemia-related pulmonary edema. The use of pressors such as phenylephrine can overcome hypotension and increase cerebral perfusion, but this also increases cardiac afterload. Preoperative remote ischemic preconditioning can also improve cerebral desaturation in patients undergoing the beach chair position during shoulder surgery, but this technique is not currently widely available and may increase patient risks. SGB is simple to perform and has the potential to improve cerebral blood circulation and immunomodulatory effects, reducing anxiety and discomfort after shoulder arthroscopic surgery in patients undergoing BCP, accelerating recovery, and potentially making it more widely available. The results of this study showed no statistically significant differences in anesthetic medication consumption, postoperative VAS scores, or MMSE scores among the three groups.

[0046] P ET The selection of CO2 value was based on previous literature and only 50 mmHg was selected. No multiple PETCO2 gradients were set. Therefore, the optimal P value for SGB brain protection could not be determined. ET In addition, the patients in this study had a short hospital stay and no longer follow-up, which affected the accuracy of the assessment of the patients' postoperative cognitive function.

[0047] In summary, PHC combined with SGB can further improve the patient's cerebral perfusion on the surgical side, increase rScO2, and reduce the risk of cerebrovascular events, but has no obvious effect on the patient's intraoperative circulatory stability and postoperative cognitive impairment.

[0048] Example 2:

[0049] A pharmaceutical composition for intraoperative brain protection during shoulder arthroscopic surgery comprises midazolam, propofol, sufentanil, succinylcholine and atracurium besylate.

[0050] The preferred technical solution is: the dosage of the pharmaceutical composition is: midazolam 0.04 mg / kg, propofol 2 mg / kg, sufentanil 0.04 mg / kg, succinylcholine 1 mg / kg, and atracurium besylate 0.4 mg / kg.

[0051] Example 3:

[0052] A pharmaceutical composition for intraoperative brain protection during shoulder arthroscopic surgery comprises midazolam, propofol, sufentanil, succinylcholine and atracurium besylate.

[0053] The preferred technical solution is: the dosage of the pharmaceutical composition is: midazolam 0.06 mg / kg, propofol 3 mg / kg, sufentanil 0.06 mg / kg, succinylcholine 1.5 mg / kg, and atracurium besylate 0.5 mg / kg.

[0054] The above description is only used to explain the preferred embodiments of the present invention and is not intended to limit the present invention in any form. Therefore, any modifications or changes made to the present invention under the same inventive spirit should still be included in the scope of protection intended by the present invention.

Claims

1. A pharmaceutical composition for brain protection during shoulder arthroscopic surgery, characterized in that: include: midazolam, propofol, sufentanil, succinylcholine, and atracurium besylate.

2. The robust lamotrigine serum therapeutic drug monitoring high performance liquid chromatography assay method according to claim 1, characterized in that: The dosage of the pharmaceutical composition is: midazolam 0.04-0.06 mg / kg, propofol 2-3 mg / kg, sufentanil 0.04-0.06 mg / kg, succinylcholine 1-1.5 mg / kg, and atracurium besylate 0.4-0.5 mg / kg.

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