Yu Hou, Wen Yang, Fan Yang, Hong-jian Bu, Lin-jie Wang,, Zhi-xing Liang, Bo Sun, Zhi-kun Shen

1 Affiliated Hospital of Hebei University, Baoding, Hebei Province, China

2 The Third Central Hospital of Baoding City, Baoding, Hebei Province, China

INTRODUCTION

The incidence of spinal tuberculosis has continually increased in recent years; this disease commonly occurs in the lumbar spine, lumbar vertebrae, thoracic vertebrae, and cervical vertebrae (Chopra et al., 2016; Izawa and Kitada,2016). The majority of spinal tuberculosis patients present with kyphosis deformity in corresponding segments (Kandwal et al., 2016; Osman et al., 2016; Yu et al., 2016). In spinal tuberculosis patients with severe kyphotic deformity,the key to successful treatment is the individual patient’s response to tuberculosis drugs and the implementation of rational fixation approaches at an appropriate time (Patankar,2016; Wang et al., 2016); good curative effects have been shown using anterior or posterior fixation, followed by posterior debridement and bone graft fusion (Wu et al., 2015).

Surgery via the posterior or anterior approach will be respectively performed in 16 of 32 patients with tuberculosis of the lumbar spine. The spinal cord function of these 32 patients has been assessed as Frankel grade C (n = 7), D(n = 14) and E (n = 11). The primary outcome measure of this study will be the Cobb angle at the thoracic spine segments preoperatively versus 2 years postoperatively, which will be used to evaluate the postoperative change in the thoracic spine curvature. The primary causes of poor healing or recurrence of spinal tuberculosis at the thoracic and lumbar segments are reportedly improper surgical timing,poor debridement, improper selection of internal fixation methods, poor selection of bone graft material or grafting position, irregular anti-tuberculosis bacilli chemotherapy,drug tolerance, poor braking, and not using a brace after surgery (Shen et al., 2011). However, the factors that in fluence curative effects require further investigation.

Pedicle screws are commonly used to repair spine fracture, and therefore they should have good biocompatibility.Cobalt alloy reportedly exhibits good anti-bending and anti-compressive strength, strong impact toughness, good elastic modulus, small thermal expansion coef ficient, and good compatibility with the human body (Sonofuchi et al.,2016). However, few studies have investigated the use of cobalt alloy pedicle screws for treatment of severe kyphosis deformity in spinal tuberculosis.

Main objectives

To investigate whether implantation of cobalt alloy pedicle screws is effective in treating severe kyphosis deformity in spinal tuberculosis, and to determine the factors that are likely to in fluence the curative effects.

Distinguishing features from related studies

Most previous related studies have focused on the curative effects of internal fixation for repair of severe kyphosis deformity in spinal tuberculosis, but few have investigated the factors that in fluence the curative effects.

METHODS/DESIGN

Study design

A prospective, single-center, self-controlled, open-label trial.

Study setting

Af filiated Hospital of Hebei University, Baoding, Hebei Province, China.

Study procedures

This study will include 84 spinal tuberculosis patients with severe kyphosis deformity who will undergo cobalt alloy pedicle screw implantation in the Af filiated Hospital of Hebei University, China. These patients will be followed up for 2 years postoperatively, and will undergo X-ray and MRI examinations at regular intervals to assess vertebral fusion, postoperative kyphosis correction and spinal function recovery. Postoperative functional recovery of the injured spinal cord will be evaluated using the Frankel grade classi fication (Capaul et al., 1994) and factors in fluencing curative effects will be analyzed (Figure 1).

Figure 1: Flow chart of trial protocol.

Inclusion criteria

Patients presenting with all of the following criteria will be considered for study inclusion:

· Meeting the diagnostic criteria of spinal tuberculosis

· Diagnosed with spinal tuberculosis via X-ray or MRI

· Spinal tuberculosis patients with severe kyphosis deformity at the thoracic and lumbar segments and a spinal Cobb angle ≥ 90° complicated by spinal cord compression or neurological dysfunction, spinal stability destruction and paravertebral abscess

· Frankel grade C, D, or E

· Age 24–67 years

· Provision of complete medical data

· Receiving anti-tuberculosis medication for 3 weeks

Exclusion criteria

Patients with one or more of the following conditions will be excluded from this study:

· Inability to tolerate surgery

· Other concomitant spine diseases

· Unable or unwilling to participate in this clinical trial

Baseline evaluation

The baseline information including demographic data and general disease history of the included patients is shown in Table 1.

Table 1: Baseline data of included patients

Sample size

In accordance with our experience, we hypothesized that the thoracic Cobb angle at postoperative 2 years will be narrowed by 45% compared with preoperatively. Taking β = 0.1 and power = 90% with a signi ficance level of α =0.05 (two-sided), the final effective sample size of n = 65 per group was calculated using PASS 11.0 software (NCSS,MD, USA). If we assume a patient loss rate of 20%, we will require 78 patients per group. We aim to include 84 patients in each group.

Recruitment

Spinal tuberculosis patients with severe kyphosis deformity will be recruited from the clinic and wards of the Af filiated Hospital of Hebei University, China. Potential participants can contact the project manager via telephone or e-mail. After providing informed consent, these potential participants will be screened using the inclusion and exclusion criteria.

Blinding

Patients, physicians and assessors will not be blinded to group information and therapeutic regimen.

Interventions Screw implantation position

Patients will be in prone position during surgery. The position for pedicle screw insertion will be determined according to preoperative imaging data. The pedicle screws(Shandong Weigao Orthopedic Device Company, Shandong Province, China) are made of cobalt alloy, and have good strength and histocompatibility. The screws are 30–50 mm long and 50–60 mm diameter and provide reliable vertebral body reduction.

Implantation methods

· Internal fixation via the posterior approach

After induction of general anesthesia with endotracheal intubation, the patients will be placed in prone position. A median incision will be made, taking the diseased vertebral body as the center. The appropriate incision length will be determined according to the degree of vertebral body destruction and the number of involved vertebral bodies.Bilateral vertebral plates and articular processes will be fully exposed. Pedicle screws will be inserted into the normal segments above and below the lesions. According to preoperative kyphosis deformity, the compressive bracing of the pedicle screw system will be used to correct kyphosis and scoliosis and restore spinal physiological curvature.Dead bone, pus, caseous necrotic tissue and granulation tissue will then be thoroughly cleared. Patients with spinal cord compression will undergo decompression. Autologous bone or autologous bone- filled titanium implants (Pyramesh cages with 25–30 mm diameter anterior plates or TSRH-3D spinal pedicle screws; Medtronic Sofamor Danek,Memphis, TN, USA) will be inserted into the intervertebral space. After repeated flushing, we will perform multiple layer wound closure.

· Internal fixation via the anterior approach

Patients will be placed in lateral position with the side of the most severe lesion facing upward. Following induction of general anesthesia with endotracheal intubation, a thoracic approach will be used to ligate vessels at the thoracic and lumbar segments, and fully expose the diseased vertebral bodies. Dead bone, pus, caseous necrotic tissue and granulation tissue will then be thoroughly cleared. Patients with spinal cord compression will undergo decompression. Internal fixation will be performed, followed by bone grafting. Bone grafts will be bone allografts with good histocompatibility from the State-Level Bone Bank, Hebei Province, China.

Postoperative care

After determination of the position of the pedicle, the surgical area will be washed with a large amount of physiological saline. The vertebral plate cortex will be removed before bone allograft implantation. Of the 84 patients included in this study, 44 will not receive postoperative drainage.In the remaining 40 patients, drainage tubes made of disposable blood transfusion apparatus will be placed in the muscle tissue around the lesion foci (such as the platysma,paraspinal muscles or abdominal muscles) and retained for 1–7 days (average 3.5 days). After removal of the initial drainage tubes, another drainage tube will be inserted and the incisions will be closed in multiple layers. This drainage tube will be removed 48 hours after surgery. After surgery,all patients will be medicated for 6 weeks with quadruple anti-tuberculosis drugs (rifampicin, isoniazid, pyrazinamide and ethambutol) and levo floxacin.

Cobb angle measurement

Anterior-posterior X-ray images of the scoliotic spine will be taken using a digital X-ray scanner. The Cobb angle will be measured twice on X-rays taken with a 1 week interval by two experienced radiologists using conventional methods. During the measurement, each radiologist will use one graduator and marker pen set. The Cobb angle will also be measured twice with a 1 week interval by the same two radiologists using Mimics software (Materialise, Leuven,Belgium, USA). The Mimics software can only measure the angle between two straight lines at 0–90°, while the range of the Cobb angle is 0–180°; therefore, the angle-measuring function of Mimics software can be used to assist in accurate measurement of the Cobb angle.

Outcome measures Primary outcome measure

· Thoracic Cobb angle preoperatively and 2 years postoperatively: This will be used to evaluate the change in the thoracic spine curvature, judge the recovery of severe kyphosis deformity in spinal tuberculosis, and evaluate the Cobb angle at the cervical, thoracolumbar,and lumbar segments. A greater Cobb angle indicates more severe kyphosis deformity (Jiang et al., 2012).

Secondary outcome ures

· Cobb angle at the cervical, thoracolumbar, and lumbar segments preoperatively and 2 years postoperatively:To evaluate the improvement in kyphosis deformity in spinal tuberculosis.

· X-ray or MRI findings preoperatively and 2 years postoperatively: To evaluate screw implantation and vertebral body function.

· Frankel grade preoperatively and 2 years postoperatively: To evaluate the recovery of spinal cord function.The Frankel grade classi fication is used to assess the severity of spinal cord injury as follows (Capaul et al.,1994). Grade A: no motor or sensory function detected below the level of the lesion. Grade B: no motor function detected below the level of the lesion, with preservation of some sensory function below the level of the lesion.Grade C: some voluntary motor function preserved below the level of the lesion, but too weak to serve any useful purpose; sensation may or may not be preserved.Grade D: functionally useful voluntary motor function is preserved below the level of the lesion. Grade E: normal motor and sensory function below the level of the lesion,although abnormal re flexes may be present.

Other outcome measures

· Multiple logistic regression analysis of factors that in fluence curative effects: To summarize the factors that in fluence curative effects, including anti-tuberculosis medication, surgical timing, surgical approach and drainage protocol.

· Incidence of adverse events 2 years postoperatively: To evaluate the incidence of postoperative complications.

The schedule of outcome measurement assessments is shown in Table 2.

Adverse events

We will record adverse events, including vertebral body displacement, thoracic and lumbar back muscle injury,nonspeci ficlow back pain, and screw pull out or loosening. If severe adverse events occur, investigators will report details, including the data of occurrence and measures taken to treat the adverse events, to the principle investigator and the institutional review board within 24 hours.

Data collection, management, analysis and open-access Data collection

Case report forms with demographic data, disease diagnosis,accompanying diseases, drug allergy history, and adverse events will be collected, processed using Epidata software(Epidata Association, Odense, Denmark), collated, and then recorded electronically by data managers using a double-data entry strategy.

Table 2: Timing of outcome assessment

Data management

The locked electronic database will be accessible and locked only by the project manager, and will not be altered. All data regarding this trial will be preserved by the Af filiated Hospital of Hebei University, China.

Data analysis

The electronic database will be statistically analyzed by a professional statistician who will create an outcome analysis report that will be submitted to the lead researchers. An independent data monitoring committee will supervise the mange the trial data, ensuring a scienti ficand stringent trial to yield accurate and complete data.

Data open access

Anonymized trial data will be published at www. figshare.com.

Statistical analysis

Statistical analysis will be performed using SPSS 19.0 software (IBM, Armonk, NY, USA), and will follow the intention-to-treat principle. Normally distributed measurement data will be expressed as the mean ± SD, and minimums and maximums. Non-normally distributed measurement data will be expressed as lower quartile (q1), and median and upper quartile (q3). The Wilcoxon matched pairs test will be performed for comparison of the Cobb angle preoperatively versus 2 years postoperatively. The Wilcoxon signed-rank test will be performed for comparison of pre- and postoperative Frankel grade, and McNemar's chi-square test will be used to analyze the incidence of adverse reactions.Multiple logistic regression analysis will be performed to analyze the factors that in fluence curative effects, with calculation of regression coef ficients, odd ratios and 95%con fidence interval. The signi ficance level will be α = 0.05.

Auditing

Trial progression will be reported to the ethics committee of Af filiated Hospital of Hebei University, China every 3 months, and the trial's status will be updated in the registration database.

Confidentiality

Trial outcomes will be transcribed, dated, and uploaded to a dedicated computer by two staff members. Data were scheduled, checked and locked by an investigator,password-protected, and not altered. Data regarding this trial protocol recorded will be preserved by the Af filiated Hospital of Hebei University, China.

TRIAL STATUS

Data analysis at the time of submission.

DISCUSSION

Significance of this study

This study aims to investigate the curative effects of implantation of cobalt alloy pedicle screws with good biocompatibility with the human body in the treatment of severe kyphosis deformity in spinal tuberculosis, based on normalized anti-spinal tuberculosis medication, and analyze the factors that in fluence the curative effects.

Advantages and limitations of this study

Advantages: This is a prospective, single-center, selfcontrolled, open-label trial. All patients will be followed up for 2 years.

Limitations: Trial outcomes are single and the study may be strati fied (for example, via patient age and approach),which may be confounding factors affecting the accuracy of trial outcomes.

Evidence for contribution to future studies

Our 2-year follow-up investigating the factors in fluencing the curative effects of cobalt alloy pedicle screw implantation on severe kyphotic deformity in spinal tuberculosis will aid surgeons in selecting the most appropriate approach to enhance treatment effectiveness.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the form the patient(s) will give his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

None declared.

Author contributions

YH conceived and designed the trial protocol and wrote the manuscript. WY, FY, HJB, LJW, ZXL, BS and ZKS will assist in trial conduction. All authors approved the final version of this manuscript.

Plagiarism check

This paper was screened twice using CrossCheck to verify originality before publication.

Peer review

This paper was double-blinded and stringently reviewed by international expert reviewers.

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