Effectiveness and safety of Qishe™ for treating postoperative symptoms after surgery for cervical spondylotic myelopathy: A prospective, randomized, controlled clinical trial

doi:10.21203/rs.3.rs-4274452/v1

Objectives: With the increasing incidence and surgical management of cervical spondylotic myelopathy, residual postoperative pain and numbness have become challenging problems. Investigation into reducing postoperative symptoms and improving the quality of life of patients who have undergone surgery for cervical spondylotic myelopathy is urgently required. Qishe™ is a traditional Chinese compound herbal medicine, clinical trials have shown that it reduces limb numbness and pain in patients with cervical spondylosis. We conducted a prospective, randomized, controlled trial to evaluate the effectiveness and safety of Qishe in improving postoperative symptoms after surgery for cervical spondylotic myelopathy.

Methods: We have recruited 72 patients who underwent anterior cervical decompression and fusion in Longhua and Long March Hospitals from December 2019 to August 2020. The study patients were randomly divided into treatment (36 cases) and control groups (36). The treatment group received Qishe and the control group mecobalamin. Trained researchers evaluated the patients at the time of enrollment, and 2, 4, 6 months after surgery. The outcomes included Japanese Orthopaedic Association scores, visual analogue scale, Neck Disability Index, 10-s grip and release test. Adverse reactions and postoperative complications were recorded.

Results: A total of 71 subjects were analyzed (36 subjects in the Qishe group, 35 subjects in the control group). We found that Qishe improved postoperative limb sensation and motor function and reduced severity of pain and cervical dysfunction index scores. Its clinical efficacy was not inferior to that of mecobalamin (P=0.437). There were no serious adverse events in either group.

Conclusion:Qishe is an effective and safe treatment for postoperative symptoms in patients who have undergone surgery for cervical spondylotic myelopathy.

Cervical spondylotic myelopathy

Qishe

Traditional Chinese Medicine

Cervical spondylotic myelopathy (CSM) is caused by degeneration of the cervical spine and adjacent structures, including disc herniation, ligament calcification, cervical facet joint hyperplasia, and osteophyte formation, resulting in spinal cord compression or disturbance of the blood supply. The main manifestations are numbness of limbs, difficulty in fine movement, sensations of girdling in the chest and abdomen and stepping cotton, and instability walking. In severe cases, muscle atrophy, constipation, and paralysis may occur^1,2. The main pathological mechanism is neuronal degeneration caused by spinal cord compression or ischemia, leading to spinal cord conduction dysfunction^3,4. This condition characteristically occurs in 40–60-year-old individuals, accounting for 10–15% of all cases of cervical spondylosis. The incidence has recently been increasing and the onset occurring at younger ages⁵. Because surgical interventions can relieve nerve compression, prevent progression of nerve damage, and improve function and quality of life, increasing numbers of patients are being managed surgically. Although such surgery is usually safe and effective, complications occur in 11–38% of patients. Fehlings et al⁶ found that overall perioperative and delayed date rates were 15.6% and 4.4%, respectively. Most complications are temporary and non-neurological and do not require invasive interventions or prolonged hospital stays. However, some patients have intractable postoperative neck pain, limb numbness, and muscle weakness.

The absence of specific, universally accepted therapies for postoperative symptoms in patients who have undergone surgery for CSM necessitates investigation of possible alternative treatments. Qishe™ (Shanghai Huanghai Pharmaceutical, Shanghai, China), a traditional Chinese medicine, is composed of processed Radix Astragali (the root of Astragalus membranaceus var. mongholicus), muscone, Szechuan lovage rhizome, Radix Stephaniae Tetrandrae, Ovientvine (Sinomenium Acutum), and artificial Calculus Bovis and has the function of regulating qi and promoting blood circulation, regulating collaterals, and relieving pain^7,8. Previous studies have shown that this formulation can relieve cervical pain and numbness, and improve the quality of life of patients with cervical spondylotic radiculopathy⁹. It has been found in clinical practice that Qishe can improve postoperative symptoms after surgery for CSM; however, there is a lack of evidence-based data. Therefore, we designed a multicentre, randomized, controlled trial to demonstrate its efficacy and safety in this setting.

2.1. Product Description

The experimental drug, Qishe specifications are: 0.15 g per pill and 3.75 g per bag. This product was launched in 2009 and approved by the National Medical Product Administration of China) (Approval number: Z20090978).The control drug was mecobalamin (0.5mg per pill; Hainan Star Pharmaceutical, Hainan, China) (Approval number: H20050997)¹⁰.

2.2 Study design and participants

This multicentre, randomized, clinical trial with two parallel arms (Fig. 1) was conducted in Longhua Hospital Affiliated with Shanghai University of Traditional Chinese Medicine and Long March Hospital Affiliated with the Second Military Medical University from December 2019 to August 2020. The study cohort comprised 72 patients with CSM who had undergone anterior cervical decompression and fusion. All patients who met the inclusion criteria were randomly allocated into a treatment (Qishe) or control group (mecobalamin), the randomization sequences being generated using SPSS 25.0 software. This study was performed according to an Enhanced Recovery after Surgery protocol for anterior cervical surgery proposed in 2019. Antibiotics for infection prevention, hormones, diuretics, and nutritional nerve therapy were routinely given for 3 days after surgery. The allocated study drugs were started on the seventh postoperative day in both groups, the experimental group being given Qishe (25 pills containing 0.15 g per pill twice a day) and the control group mecobalamin (one 0.5 mg pill three times a day). These treatments were given for 3 weeks (one course). One week after ceasing them, the treatment was resumed for one more course, the entire treatment cycle comprising two courses of treatment. During this period, non-steroidal anti-inflammatory drugs could be given orally when the visual analogue score (VAS) was > 4. The frequency and timing of medication were recorded in detail. Trial drugs for both groups were packed and numbered uniformly. The study was approved by the medical Ethics Committee of Longhua Hospital affiliated to Shanghai University of Traditional Chinese Medicine (Approval number: 2019LCSY081). The study protocol was in accordance with the Good Clinical Practice and Declaration of Helsinki guidelines⁹. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR1900028173). All patients provided written informed consent before participating in this study.

2.3 Inclusion criteria

The inclusion criteria were as follows: (1) meet the diagnostic criteria of cervical spondylotic myelopathy: typical cervical spinal cord damage, mainly characterized by limb movement disorders, hypoesthesia and abnormal reflexes; Or there are definite signs of spinal cord compression on imaging examination, which are consistent with clinical symptoms¹¹(2)Meeting the diagnostic criteria of TCM: Syndrome differentiation is Qi deficiency and blood stasis syndrome, symptoms included limb pain, numbness, pain with fixed place, or weakness of limbs, difficult to complete fine movements, easy to hold things off, walking instability, and even inhibited urine and stool; the pulse is astringent and weak or the pulse is heavy fine, the tongue is light red or light violet thin white moss^12,13;(3) age 18–80 years; (4) physical condition can tolerate anterior cervical discectomy, decompression, bone grafting, fusion and internal fixation; (5) no previous minimally invasive or open cervical spine surgery; (6) poor response to conservative treatment or progressive worsening of symptoms over 3 months; and (7) understanding and voluntary acceptance of the trial protocol and provision of written informed consent.

2.4 Exclusion criteria

The exclusion criteria were as follows: (1) hematopoietic or endocrine comorbidities or other serious conditions; (2) spinal tumors, bone metabolic diseases, cerebral infarction, spinal injury, fracture and dislocation, and other diseases affecting limb sensation and function; (3) suspected history of alcohol or drug abuse; (4) breastfeeding or trying to become pregnant; (5) participation in other drug trials; and (6) Poor compliance, unable to cooperate with the trial treatment on time, or due to mental consciousness and emotion regulation disorders, unable to effectively evaluate the relevant indicators of the test.

2.5 Shedding and rejection criteria

The shedding and rejection criteria were as follows: (1) subjects who did not cooperate with randomization and did not receive treatment after randomization; (2) poor compliance of subjects (< 50%, > 120%); (3) subjects received other treatments during the observation period; (4)serious adverse events or complications during the trial should not continue the study; (5) loss of follow-up or other reasons lead to incomplete data, which affects the efficacy and safety judgment.

2.6 Outcomes

The primary outcomes was the Japanese Orthopaedic Association (JOA) Score¹⁴, which includes motor and sensory function scores. Spinal cord dysfunction is evaluated by assessing limb motor function, limb and trunk sensory function, and bladder function. The higher the score, the better the patient’s condition. The secondary outcomes included the following: (1) VAS¹⁵, in which patients score their own pain from 0 to 10(the higher the score, the more severe the pain); (2) Neck Disability Index(NDI)¹⁶, which assesses the patient's ability to live and work (the higher the value, the more severe the dysfunction); (3) 10-s grip and release test¹⁷, in which the patients performs fist flexion and extension for 10s, thus providing an objective indicator of hand function and flexibility. These indicators were reassessed at baseline and 2, 4, and 6 months postoperatively. During the study, possible adverse reactions to the study drugs were noted and recorded, as was the duration of follow-up, loss to follow-up, and withdrawal of participants.

2.7 Sample size

We calculated the required sample size to be randomly distributed equally between the two groups (Qishe versus mecobalamin) on the basis of JOA scores. We selected JOA scores for this purpose because they cover sensory and motor functions of the limbs and bladder. For the purposes of this calculation, the estimated correlation coefficient of the measurements was ρ = 0.8 and alpha = 0.05. With the JOA scores being 13.68 ± 1.83 and 15.65 ± 1.61 at 6 months postoperatively in the mecobalamin and Qishe groups, respectively, the calculated sample size required was approximately 30 in each group¹⁸. Allowing for 20% loss to follow-up, the total sample size needed to detect a significant difference at a 5% level of significance with a power of 90% was 72 patients.

The formula used for this calculation was:

2.8 Statistical analysis

Quantitative measures can be presented as mean, standard deviation, median, minimum and maximum. Qualitative measures can be provided as tables showing frequencies and ratios. We estimated statistical intervals and tested our hypothesis. All statistical analysis was performed with Statistical Packages of Social Sciences (SPSS) software (version 22.0). In two-sided tests, P < 0.05 was considered to denote statistical significance. We used the mean ± standard deviation to present continuous variables, Student’s t-test to assess normally distributed continuous variables, and the rank sum test to assess non-normally distributed measurement data. Other numerical data were tested by two-sided or non-parametric tests and checked by ridit.

3.1. Baseline characteristics

The 72 study patients were randomly divided into treatment and control groups. One patient in the control group was withdrawn from the study because of poor recovery requiring hospitalization for comprehensive treatment 2 weeks postoperatively. No patients were withdrawn from the treatment group (Fig. 1). Baseline data, including sex, age, and disease type, did not differ significantly between the two groups (P > 0:05) (Tables 1–3).

Table 1

Baseline Characteristics
	QSP Group(n = 36)	Control group(n = 36)	χ²	P value
Gender Male Female	22 14	20 15	--	0.734>0.05
Age(years)	55.11 ± 10.55	54.28 ± 10.40	0.239	0.812>0.05
Course of diease	51.69 ± 70.22	41.14 ± 55.62	0.856	0.395>0.05
Height	168.17 ± 8.72	169.16 ± 8.67	-0.612	0.542>0.05
Weight	69.08 ± 11.21	68.75 ± 12.54	-0.021	0.983>0.05
JOA	12.36 ± 1.88	12.34 ± 1.75	0.042	0.966>0.05
VAS	3.47 ± 2.43	4.14 ± 2.14	-1.231	0.222>0.05
NDI	23.78 ± 15.01	24.91 ± 11.98	-0.352	0.726>0.05
10s-grip Affected side Unaffected side	16.92 ± 5.12 17.97 ± 5.04	17.40 ± 4.37 18.31 ± 5.07	-0.427 -0.285	0.671>0.05 0.776>0.05

Table 2

Comparison of general data between the two groups
	QSP group (n = 36)	Control group (n = 35)	Z	P
The segment of the operation	2(2, 3)	2(1, 3)	-0.286	0.775
TCM syndrome integration	4.5(3.25, 7)	5(4, 7)	-0.111	0.912

Table 3

Symptom frequency was compared between the two groups
Symptoms	QSP Group(n = 36)	Control Group(n = 35)	P
Fine motor dysfunction	13	20	0.915
Walking instability	20	20
Step cotton feeling	19	17
numbness	31	28
Abnormal defecate	4	5
dizzy	9	10
Neck stiffness or acid distension	14	12

3.2. Primary outcome

Postoperatively, JOA scores improved significantly within both groups at each time point (F = 218.647, P < 0.001). At 4 and 6 months of follow-up, the improvement in JOA score was better in the Qishe group than in the mecobalamin group (15.69 ± 1.47 vs. 15.17 ± 1.15, P = 0.031; 16.22 ± 1.21 vs. 15.54 ± 1.22, P = 0.027, respectively) (Table 4). Changes in JOA scores in the two groups at the specified time points are shown in Fig. 2A–C. Specifically, JOA scores for motor function increased significantly in both groups over time (F = 74.234, P<0.001); however, the degree of improvement in JOA scores for motor function did not differ significantly between the Qishe and mecobalamin groups (F = 2.372, P = 0.128). JOA scores for sensory function also increased gradually over time in both groups. However, unlike for motor function, the long-term improvement in limb sensory function was better for Qishe than for mecobalamin at 6 months follow-up (5.25 ± 0.60 vs. 4.94 ± 0.59, P = 0.034 at 4 months follow-up; 5.56 ± 0.61 vs. 5.14 ± 0.73, P = 0.012).

3.3. Secondary outcomes

Changes in VAS scores in the two groups at the specified time points are shown in Fig. 2D. Pain decreased postoperatively in both the Qishe and mecobalamin groups; however, the decreases did not differ significantly between these two groups (Table 5). Changes in NDI scores in the two groups at different time points are shown in Fig. 2E. Postoperative oral administration of either Qishe or mecobalamin was effective in reducing the NDI; however, the difference between the treatment groups was not statistically significant (Table 5). Surgery combined with medication resulted in improvement in 10s grip and release tests bilaterally. Two months postoperatively, improvement on the affected side was better for Qishe than for mecobalamin (Fig. 2F,G; Table 6). The improvement between 2 and 4 months of follow-up was better in the Qishe group than in the mecobalamin group, especially on the healthy side. There was no significant difference in the improvement after surgery, compared with before surgery, between the two groups (P = 0.850).

Table 4

Reults for JOA
Time Post-Treatment	GSP Group (n = 36)			Mecobalamin Group (n = 35)
Time Post-Treatment	JOA	motor function	sensory function	JOA	motor function	sensory function
0 M	12.36 ± 1.88	6.28 ± 1.30	3.17 ± 0.97	12.34 ± 1.75	5.91 ± 1.31	3.57 ± 0.88
2 M	14.67 ± 1.62^a	7.19 ± 0.98^a	4.47 ± 0.88^a	14.22 ± 1.31	6.86 ± 1.00^a	4.40 ± 0.74^a
4 M	15.69 ± 1.47^ab	7.56 ± 0.91^a	5.25 ± 0.60^ab	15.17 ± 1.15^a	6.86 ± 1.00^a	4.94 ± 0.59^a
6M	16.22 ± 1.21^ab	7.67 ± 0.72^a	5.56 ± 0.61^ab	15.54 ± 1.22^a	7.46 ± 0.70^a	5.14 ± 0.73^a
Note: aP < 0.05(compared to baseline); bP < 0.05༈compared to control group༉;There were statistically significant differences at each time point in the group (P < 0.001).

Table 5

Reults for VAS and NDI
Time Post-Treatment	GSP Group (n = 36)		Mecobalamin Group (n = 35)
Time Post-Treatment	VAS	NDI	VAS	NDI
0 M	3.47 ± 2.43	23.78 ± 15.01	4.14 ± 2.14	24.91 ± 11.98
2 M	1.75 ± 1.66^a	14.28 ± 9.99^a	2.02 ± 1.27 ^a	15.14 ± 10.05
4 M	0.833 ± 1.03^a	9.94 ± 8.16^a	0.91 ± 0.87^a	11.89 ± 7.16^a
6M	0.36 ± 0.64^a	7.72 ± 6.81^a	0.31 ± 0.58^a	9.26 ± 6.56^a
Note: Compared with preoperative, aP < 0.05; There were statistically significant differences at each time point in the group (P < 0.001).

Table 6

Reults for 10s grip and release test
Time Post-Treatment	GSP Group (n = 36)		Mecobalamin Group (n = 35)
Time Post-Treatment	Affected Side	Healhy Side	Affected Side	Healhy Side
0 M	16.92 ± 5.12	17.97 ± 5.04	17.40 ± 4.37	18.31 ± 5.07
2 M	19.28 ± 3.90^ab	19.11 ± 4.19^a	17.49 ± 2.86	19.27 ± 3.70^a
4 M	20.28 ± 3.59^a	21.42 ± 3.60^a	19.77 ± 3.65^a	20.34 ± 3.83^a
6M	21.68 ± 3.52^a	22.22 ± 4.04^a	20.31 ± 3.17^a	20.60 ± 3.32^a
Note: Compared with preoperative, aP < 0.05; bP < 0.05(compared to control group);There were statistically significant differences at each time point in the group (P < 0.001).

3.4. Assessment of safety

In the control group, one patient reported occasional pain and nausea in the epigastric region after taking the drug; this resolved spontaneously within 1 week. Another patient had poor relief of postoperative symptoms, with severe neck and shoulder pain. Non-steroidal anti-inflammatory drugs did not result in significant improvement, so this patient was withdrawn from the trial. Three patients reported the sensation of a foreign body in the pharynx postoperatively; this symptom gradually resolved within 1 week.

In the treatment group, three patients reported abdominal pain without nausea or vomiting after their first dose of Qishe; this resolved within half an hour. Because the dose of Qishe comes as 25 pills, the patients were asked to take them half an hour after eating and then gargle with warm boiled water. Two patients reported a sensation of a foreign body in the laryngopharynx that gradually resolved within 1 week after surgery. There is a relatively large amount of sinomenine in Qishe. Sinomenine strongly stimulates release of histamine, promotes secretion of gastric acid, stimulates the intestinal canal, and increases the strength of smooth muscle contraction, accounting for the adverse gastrointestinal reactions that resolved spontaneously in three patients. Considering the short duration of the medication cycle, the study treatment was relatively safe. There were no serious adverse events in the treatment or control group.

Because CSM is tending to present at younger ages, the number of patients undergoing surgical treatment has gradually been increasing. Important factors that affect recovery after surgery for CSM include the severity of spinal cord and ischemia–reperfusion injuries. Ischemic and anoxic changes occur after long-term spinal cord compression. The sudden increase in blood supply after decompression can result in spinal cord ischemia–reperfusion injury, which can manifest as limb pain, numbness, instability walking, paralysis, and defecation disorders. At present, there is no standard or guide-recommended Chinese patent medicine for treating postoperative symptoms after surgery for CSM. We reviewed the existing literature and summarized the experimental studies on the treatment of postoperative symptoms of cervical spondylotic myelopathy with traditional Chinese medicine. A total of 61 relevant literature studies and prescription drugs were reviewed. After data analysis and mining, it was found that the main treatment methods were supplementing qi and removing blood stasis and dredging collaterals, and the main drugs were astragalus membranaceus, Chuanxiong, red peony and Dilong, Most of these studies use VAS and JOA scores as outcome indicators. Qishe has been shown to be effective in quickly reducing neck, shoulder, and limb pain and improving numbness, fatigue and other symptoms. Additionally, it has long-term efficacy, which is an advantage over other drugs used to treat CSM.

In this prospective, randomized, controlled clinical trial, we used JOA scores, VAS scores, NDI index, and the 10s grip and release test to evaluate the effects of Qishe and mecobalamin on the degree of sensation, movement, and pain in patients who had undergone surgery for CSM. Compared with other studies, we further statistical analysis of JOA index movement and sensation, in order to clarify the improvement of postoperative sensation and movement of Qishe pill, and have a certain guiding role in the clinical application of the disease prognosis assessment. We found that Qishe is safe and effective in treating these patients’ postoperative symptoms and is more effective than mecobalamin in improving postoperative sensory function, according to JOA scores. Additionally, we found that Qishe is better than mecobalamin in the short term in achieving improvement in motor function of the hand on the affected side. However, there were no significant differences in JOA-assessed motor function, VAS scores, or NDI index between the two groups.

In this study, we choose a cobalt amine as the control drug because cobalt amines are a form of vitamin B₁₂ with methylation activity, have been shown to improve numbness, and are currently the most commonly used agent for treating peripheral nerve injury. We chose an active drug rather than a placebo to avoid delays in treatment and maximize adherence to the treatment protocol¹⁹. We selected a treatment cycle that allowed for adjusting or discontinuing the study medication if there were any adverse effects, such as loss of appetite, nausea, vomiting, diarrhea and other gastrointestinal reaction in response to mecobalamin, or impaired liver and kidney function in response to Ovientvine, which is a component of Qishe. Our protocol permitted adjusting or discontinuing the study medication at specified times points in the treatment cycle. However, no serious adverse events occurred during the trial. In particular, no patients in the treatment group evidenced liver or kidney injury. These findings indicate that short-term administration of Qishe and mecobalamin is effective and safe.

The combination of active ingredients in Qishe can reduce the risk of spinal cord reperfusion injury and promote regeneration and recovery of nerve cells. Studies in rat models have shown that Qishe can improve blood circulation, promote proliferation and differentiation of Schwann cells, improve their budding ability, create a favorable environment for axonal regeneration, improve the speed of binding of acetylcholine, and shorten the time required for nerve regeneration and repair. In addition, pharmacological studies have found that A. membranaceus improves neural function by anti-lipid peroxidation and antioxidant free radicals^20,21. A. membranaceus also promotes neural stem cell proliferation, has anti-inflammatory and analgesic effects, and reduces blood viscosity²². Tetramethylpyrazine, the main effective component of Ligustrum chuanxiong can improve the microcirculation by promoting release of vasoactive substances from vascular endothelial cells, thereby protecting neurons and mitochondria^23,24. Musk can reduce histamine, 5-hydroxytryptamine, and PGE in animal models of CSM, and thus play a role in reducing inflammation and improving symptoms ^25,26. Alkaloid components, such as tetrandrine and sinomenine, are the main components responsible for the wind-reducing, dehumidifying, diuretic, swelling, and analgesic effects of Qishe.

This trial had some limitations. First, the study was not blind; as a result, this would have increased the degree of bias. Second, the duration of follow-up was short; a 1–2 year or longer follow-up would have enabled assessment of the long-term efficacy of Qishe and its adverse effects. Finally, the outcome indicators were mainly subjective. There were no objective indicators such as imaging evidence of spinal signal impairment, spinal canal changes, and the degree of spinal cord compression despite the fact that many studies have found that changes in findings on imaging between before and after treatment can be very useful for evaluating spinal cord function and prognosis. Therefore, we also conducted follow-up and data collection on cervical magnetic resonance imaging of patients before and after treatment. Some patients with cervical spondylotic myelopathy underwent spinal cord injury repair after surgery. We plan to evaluate the effect of Qishe pills on the disease after surgery through relatively objective imaging analysis. However, imaging changes and recovery require long-term follow-up and observation, which is what we are doing and aiming to provide more detailed data and research results for the related research of cervical spondylotic myelopathy.

In conclusion, future studies investigating the efficacy and mechanism of Qishe should be large, high quality, multicentre, double-blind, randomized controlled clinical trials with a long follow-up and objective outcome indicators.

The authors have no financial conflicts of interest to declare.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.This research proposal was approved by the Ethics Committee of Longhua Hospital Shanghai University of Traditional Chinese Medicine on November 28, 2019.(Ethics Number: 2019LCSY081).

Data sharing statement

We are willing to share individual deidentified participant data. We will share Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Study Protocol, Statistical Analysis Plan, Informed Consent Form, Clinical Study Report, Analytic Code will be made available. Anyone who wishes to access the data can get the above data by sending an email to this email address: [email protected]. These data are available for: beginning 3 months and ending 5 years following article publication.

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No competing interests reported.

Effectiveness and safety of Qishe™ for treating postoperative symptoms after surgery for cervical spondylotic myelopathy: A prospective, randomized, controlled clinical trial

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials and Methods