Hyperbaric oxygen therapy and comprehensive orthopedic treatment for incomplete traumatic spinal cord injury on the qinghai-tibet plateau: Study protocol for an open-label randomized controlled clinical trial
Qing Sun, Jian-feng Bao, Yu-lan An, Hui Lei, Jun Ma
Department of Spine Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai Province, China
|Date of Web Publication||28-Apr-2017|
Department of Spine Surgery, Affiliated Hospital of Qinghai University, Xining, Qinghai Province
Source of Support: This study was supported by a grant from the Qinghai Provincial Health and Family Planning Committee Guidance Project in 2015., Conflict of Interest: None
Background: Apoptosis secondary to ischemia and hypoxia is the main cause of spinal cord dysfunction. Because of the decrease in atmospheric pressure, patients living on the Qinghai-Tibet Plateau are in a hypoxic environment, which is very unfavorable for the recovery of spinal cord injury. Hyperbaric oxygen therapy can improve the postoperative function of patients with incomplete spinal cord injury, and its effect is better on the plateau than at normal altitudes. We performed a prospective randomized controlled clinical trial to observe the effect of hyperbaric oxygen therapy on traumatic spinal cord injury in patients living on the Qinghai-Tibet Plateau and are currently analyzing the results.
Methods/Design: This prospective, open-label, randomized controlled clinical trial was performed at the Department of Spine Surgery, Affiliated Hospital of Qinghai University, China. In total, 164 patients with incomplete traumatic spinal cord injury were equally and randomly assigned to a control group and a hyperbaric oxygen therapy group. Patients in the control group were treated with pedicle screw fixation and decompressive laminectomy. In addition to the surgical treatment performed in the control group, patients in the hyperbaric oxygen group underwent hyperbaric oxygen therapy at 0.2 MPa once a day for four treatment courses. Ten treatment sessions constituted one course, and each course was separated by a 5- to 7-day rest interval. The primary outcome was the modified Barthel index to assess activities of daily living. The secondary outcomes were the American Spinal Injury Association (ASIA) impairment scale grade, sensory score, and motor score. The partial results demonstrated that after four treatment courses (55–61 days), the modified Barthel index and ASIA tactile, pain, and motor scores were higher in the hyperbaric oxygen group than in the control group. The ASIA grades were significantly different between the hyperbaric oxygen group and control group. The proportion of patients with ASIA grades D and E was higher in the hyperbaric oxygen group than in the control group.
Discussion: The study design was finished in May 2012. Patient recruitment began in June 2012 and finished until February 2016.Data analysis will be finished in December 2017. In this trial, we aim to determine the efficacy of hyperbaric oxygen therapy on the treatment of incomplete traumatic spinal cord injury in patients living on the plateau and to provide clinical evidence for treating incomplete traumatic spinal cord injury in these patients.
Trial registration: ClinicalTrials.gov identifier: NCT03112941.
Ethics: The study protocol has been approved by Ethics Committee, Affiliated Hospital of Qinghai University, China in April 2012 (approval number: QHC011K).
Informed consent: Written informed consent was obtained from relatives or legal representatives.
Keywords: clinical trial; traumatic spinal cord injury; hyperbaric oxygen; plateau; modified Barthel index; American Spinal Injury Association impairment scale grading; American Spinal Injury Association impairment scale sensory score; American Spinal Injury Association impairment scale motor score; randomized controlled clinical trial
|How to cite this article:|
Sun Q, Bao Jf, An Yl, Lei H, Ma J. Hyperbaric oxygen therapy and comprehensive orthopedic treatment for incomplete traumatic spinal cord injury on the qinghai-tibet plateau: Study protocol for an open-label randomized controlled clinical trial. Asia Pac J Clin Trials Nerv Syst Dis 2017;2:50-7
|How to cite this URL:|
Sun Q, Bao Jf, An Yl, Lei H, Ma J. Hyperbaric oxygen therapy and comprehensive orthopedic treatment for incomplete traumatic spinal cord injury on the qinghai-tibet plateau: Study protocol for an open-label randomized controlled clinical trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2017 [cited 2019 Jun 26];2:50-7. Available from: http://www.actnjournal.com/text.asp?2017/2/2/50/205194
| Introduction|| |
History and current related studies
Spinal cord injury (SCI) is a serious disabling condition with various causative factors (e.g., trauma, infection) and can lead to paralysis. It is reported that 16 to 40 people per million in developed countries develop SCI every year (Chéhensse et al., 2013; Liu et al., 2016a), while this number in China ranges from 34.3 to 60.0 people per million (Hu et al., 1992; Li et al., 2004; Qiu, 2009). SCI is often caused by physical trauma, such as rotation, compression, or hyperextension of the spine (Sabapathy et al., 2015). This type of SCI is also known as traumatic SCI (TSCI). Many treatments are currently available for TSCI, but the prognosis is poor (Hess and Hough, 2012).
Hyperbaric oxygen (HBO) therapy involves the medical use of oxygen at a level higher than atmospheric pressure to treat hypoxic disease (Hu et al., 2016). Secondary injuries such as edema, neuronal necrosis, and blood and spinal cord barrier disorders have been shown to be strongly associated with a large number of inflammatory factors (Chen et al., 2017; Yan et al., 2017). HBO therapy can effectively inhibit the generation of inflammatory factors and promote repair and regeneration of neurons (Lu et al., 2012b; Huang et al., 2013; Geng et al., 2015). Moreover, HBO therapy can relieve hypoxia, protect the surrounding tissue, and reduce mitochondrial dysfunction, bleeding, and edema in the injured area (Lu et al., 2012b; Huang et al., 2013; Geng et al., 2015; Hu et al., 2016). HBO therapy has long been used to treat TSCI. Holbach et al. (1977) first found that HBO therapy improved postoperative dysfunction in patients with TSCI. In recent years, several clinical studies have focused on HBO therapy for TSCI, and the patients recovered well (Lu et al., 2012a; Tan et al., 2016). Atmospheric pressure is very low on the Qinghai-Tibet Plateau, and the oxygen content in the plateau environment is less than that on the plains (Li et al., 2015; Hartman-Ksycinska et al., 2016). Secondary apoptosis induced by ischemia and hypoxia after SCI is the main cause of spinal cord dysfunction. HBO therapy can increase the amount of dissolved oxygen, which is helpful for the recovery of incomplete spinal nerve function (Ma et al., 2015). Therefore, HBO therapy has higher therapeutic value on the plateau than on the plains.
In this study, we are evaluating the modified Barthel index and American Spinal Injury Association (ASIA) impairment scale grade, sensory score, and motor score in patients with incomplete SCI on the plateau using HBO therapy at 0.2 MPa combined with pedicle screw fixation and decompressive laminectomy. The main objective is to determine the effect of HBO therapy on incomplete SCI in patients living on the plateau.
Distinguishing features from related studies
Several clinical trials have been performed to investigate HBO therapy for SCI (Tan et al., 2016), but large-sample prospective randomized controlled clinical trials are lacking. No researchers have focused on the effect of HBO therapy in the plateau environment, and no clinical trials on HBO therapy for incomplete SCI have been registered at ClinicalTrials.gov or in the Chinese Clinical Trial Registry.
| Methods/Design|| |
This prospective, open-label, randomized controlled clinical trial was performed at the Department of Spine Surgery, Affiliated Hospital of Qinghai University, China, and data analysis is ongoing. Patients with incomplete TSCI living on the plateau were recruited from June 2012 to February 2016. After application of the inclusion and exclusion criteria (described below), 164 patients were equally randomized into a control group and an HBO group. Patients in the control group were treated with pedicle screw fixation and decompressive laminectomy. In addition to the above treatment, patients in the HBO group underwent an HBO therapy session at 0.2 MPa once a day for four treatment courses. Ten HBO therapy sessions constituted one course, and each course was separated by a 5- to 7-day rest interval.
The primary outcome was the modified Barthel index for assessing activities of daily living before and after treatment. The secondary outcomes were the ASIA impairment scale grade, sensory score, and motor score. The trial flow chart is shown in [Figure 1].
The study design was finished in May 2012. Patient recruitment began in June 2012 and finished in February 2016. Data analysis will be finished in December 2017.
We recruited patients with incomplete TSCI from the Department of Spine Surgery, Affiliated Hospital of Qinghai University, China.
Patients of either sex who met all of the following criteria were considered for study inclusion:
- Incomplete SCI (contusion) as assessed by rectal examination in accordance with International Standards for Neurological Classification of Spinal Cord Injury (Revised 2011) (Kirshblum et al., 2011)
- SCI revealed by computed tomography, X-ray, or magnetic resonance imaging examination (Holtz and Levi, 2010; Wyatt et al., 2012; Office of Communications and Public Liaison National Institute of Neurological Disorders and Stroke, 2013)
- Clear trauma in the spine
- Various degrees of movement, sensation, and sphincter dysfunction below the injured spinal segment
- Living on the plateau for at least 2 years
- Age of ≥ 18 years
Patients with one or more of the following conditions were excluded from this study:
- Brain trauma, combined chest and abdominal injury, unstable vital signs, or disturbance of consciousness
- Coagulation dysfunction
- Hypertension, heart disease, diabetes, stroke, brain damage, or neurological disease
- Lumbar surgery, trauma history, lumbar fracture, infection, tumor, or severe osteoporosis
- Nerve pain, limb cramps, or periarticular heterotopic ossification
- Other diseases that might impact neurological examination
- Participation in other clinical trials
Patients who met one or both of the following criteria during the trial were withdrawn from this study:
- Development of a complication that affected the treatment efficacy and safety or a disease that affected the treatment outcome
- Combined use of other therapies or drugs to speed up the treatment effect
In accordance with our previous experience (Ma et al., 2015), we hypothesized that the modified Barthel index would increase by 32 points in the control group and by 48 points in the HBO group. The standard deviation of the change in the modified Barthel index was 40. Considering a power of 1 – β = 0.8 with a significance level of α = 0.05, a sample size of n = 78 per group was required according to calculations performed using PASS 11.0 software (NSCC, LLC, Kaysville, UT, USA). Assuming a patient loss rate of 20%, we required 94 patients per group for a total of 188 patients. Because of limited time and funds, 162 patients were included in the trial (n = 82 per group). The sample size results were analyzed according to the intention-to-treat principle.
Baseline data were collected from all patients before entering the study ([Table 1]).
Randomization and blinding
An assessor who was blinded to the protocols generated a random number table. The patients were assigned a number according to their order of admission. The starting point was arbitrarily determined on the random number table. The number of samples was selected from the random number table in the same order of sampling. Patients with odd numbers were assigned to the control group, and those with even numbers were assigned to the HBO group. The patients, physicians, and evaluators were not blinded to the group assignment.
Patients in the control group underwent pedicle screw fixation and decompressive laminectomy. The patient was placed in the prone position with the abdomen hanging freely. The injury site was localized with a C-arm X-ray machine (HEXRAY Medical Technology, Nanjing, China). After administration of local anesthesia with 2% lidocaine, a posterior median incision was made to expose the vertebral plate and articular processes. The pedicle screw was inserted, and a Tulip PEEK Semi-rigid Rod Spinal Fixation system (Shandong Weigao Orthopedic Device Company, Weihai, China) was fixed. The puncture site was selected in the anteroposterior position with the C-arm X-ray machine. The puncture site was located at the lateral wall of the pedicle (lateral to the articular process, above the superior border of the transverse process, and 2 to 3 cm lateral to the spinous process). The angle of the puncture needle (Shenzhen Sinowares Technology Co., Ltd., Shenzhen, China) in the sagittal plane was 20°. During the surgery, biplane fluoroscopy was utilized to observe the direction of puncture. Whether the puncture needle arrived at the cortical bone was determined according to the depth of the needle. When the puncture needle did not exceed the pedicle, an effort was made to place the tip in the pedicle. After successful puncture, the guide pin, expansion tube, and work casing were inserted in order. A balloon dilatation system was inserted for expansion. After removal of the balloon dilatation system, bone cement (Leide Muhua Pharmaceutical Technology (Beijing) Co., Ltd., Beijing, China) was inserted using the C-arm X-ray machine, and the direction in which the bone cement was distributed was observed. When the bone cement overflowed the vertebral body, the casing and puncture needle were rotated to prevent cement diffusion.
In addition to the above-described conventional treatment, patients in the HBO group received HBO therapy with a GY3078/0.3-2D multi-person pure oxygen chamber (Yantai Hyperbaric Oxygen Factory, Yantai, Shandong Province, China). The pressure during HBO therapy was 0.2 MPa, and the pressure time was 20 minutes. Oxygen inhalation lasted for 60 minutes, with a 10-minute rest to breathe air in the chamber. Thirty minutes later, the pressure was reduced to atmospheric pressure, and the patients exited the chamber. HBO therapy was conducted once a day for four treatment courses. Ten HBO therapy sessions constituted one course, and each course was separated by a 5- to 7-day rest interval.
Primary outcome measure
The primary outcome measure was the modified Barthel index. The difference in this index was assessed before and after treatment. The Barthel index was introduced in 1965 by Mahoney and Barthel from the US and modified in 1989 by Shah et al. from Canada. The Barthel index is mainly used to measure the patient's performance in activities of daily living; thus, it can be used to assess the rehabilitation effect in patients with SCI. The Barthel index contains 10 variables: the presence or absence of fecal incontinence, the presence or absence of urinary incontinence, grooming, toilet use, feeding, transfers (e.g., from chair to bed), walking, dressing, climbing stairs, and bathing. The maximum possible total score is 100. Low scores indicate severe dysfunction (Shah et al., 1989).
Secondary outcome measures
The secondary outcome measures were the ASIA impairment scale grade, sensory score, and motor score.
- ASIA impairment scale grade: Recovery of the spinal nerve function was assessed before and after treatment. ASIA is a set of SCI neurological assessment criteria developed by the ASIA in 1982, and patients are assigned a grade of A to E as follows:
- Grade A: Complete injury. No motor or sensory function is preserved in sacral segment S4 or S5.
- Grade B: Sensory incomplete. Sensory but not motor function is preserved below the level of injury, including the sacral segments.
- Grade C: Motor incomplete. Motor function is preserved below the level of injury, and more than half of muscles tested below the level of injury have a muscle grade of < 3 (see muscle strength scores table).
- Grade D: Motor incomplete. Motor function is preserved below the level of injury, and at least half of the key muscles below the neurological level have a muscle grade of ≥ 3.
- Grade E: Normal. No motor or sensory deficits are present, but deficits existed in the past (American Spinal Injury Association, 2011). In this trial, we identified grades D and E as useful recovery.
- ASIA sensory score: Sensory function was assessed before and after treatment. Twenty-eight key points on the skin were checked on each side of the body. The acupuncture sensation and light touch were checked at each key point. The maximum possible total score on both sides was 112. The evaluation criteria for each sensation at each point were missing (0 point), disorder (1 point), and normal (2 points) (Theaudin et al., 2012).
- ASIA motor score: Motor function was assessed before and after treatment. Elbow flexion, wrist extension, elbow extension, finger flexion, finger abduction, hip flexion, knee extension, ankle dorsiflexion, toe extension, and the ankle plantar flexors were checked on both sides of the body. The maximum possible total score was 100. The evaluation criteria were as follows: No muscle contraction (0 point), muscle flickers (1 point), full range of motion with gravity eliminated (2 points), full range of motion against gravity (3 points), full range of motion against resistance (4 points), and normal strength (5 points) (El Masry et al., 1996).
The schedule of outcome measurement assessments is shown in [Table 2].
The researchers accurately and completely filled out all observation forms in a timely manner. Data managers electronically recorded the data using a double-data entry strategy. The electronic database was collated and locked only by the project manager. The locked electronic database could not be altered. All data regarding this trial were preserved by the Affiliated Hospital of Qinghai University, China. The electronic database was statistically analyzed by a professional statistician. Anonymized trial data will be published at www.figshare.com.
Statistical analysis was performed using SPSS 22.0 software (IBM Corp., Armonk, NY, USA). Measurement data are expressed as the mean ± standard deviation. A normality test and variance homogeneity test were conducted. Normally distributed data with homogeneity were compared using one-way analysis of variance. Non-normally distributed data were compared using Wilcoxon's two-sample rank sum test. Ranked data were analyzed using the rank sum test. A P value of < 0.05 was considered statistically significant. Results followed the intention-to-treat principle.
Identifying information, such as data on the observation forms and informed consent forms, was password-protected and not altered for future reference. No person other than an authorized researcher may access this information.
The study protocol was approved by the Ethics Committee of the Affiliated Hospital of Qinghai University, China (Approval number: QHC011K).
All protocols were performed in accordance with the Ethical Principles for Medical Research Involving Human Subjects in the Declaration of Helsinki.
The writing and editing of the article were performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 1).[Additional file 1]
This trial has been registered at ClinicalTrials.gov (identifier: NCT03112941).
Written informed consent was provided by a relative or legal representative of each patient after they had indicated that they fully understood the treatment plan.
| Results|| |
The trial was conducted from June 2012 to December 2016. In total, 164 patients were enrolled and partially followed up. Partial results are as follows:
(1) Modified Barthel index: The modified Barthel index was similar between the two groups before treatment (P > 0.05). After four treatment courses, the modified Barthel index was significantly improved in both groups (P < 0.05). Moreover, the modified Barthel index was significantly higher in the HBO group than control group (P < 0.05) ([Table 3]).
|Table 3: Effects of hyperbaric oxygen therapy on modified Barthel index in patients with incomplete traumatic spinal cord injury living on the plateau|
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(2) ASIA sensory score: The ASIA tactile and pain scores were similar between the two groups before treatment (P > 0.05). After four treatment courses, the ASIA tactile and pain scores were increased in both groups (P < 0.05). Moreover, these scores were higher in the HBO group than control group (P < 0.05) ([Table 4]).
|Table 4: Effects of hyperbaric oxygen therapy on ASIA sensory and motor scores in patients with incomplete traumatic spinal cord injury living on the plateau|
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(3) ASIA motor score: The motor score was similar between the two groups before treatment (P > 0.05). After four treatment courses, the motor score was higher in the HBO group than control group (P < 0.05) ([Table 4]).
(4) ASIA impairment scale grade: The ASIA impairment scale grade was similar between the two groups before treatment (P > 0.05). After four treatment courses, the ASIA impairment scale grade was significantly different between the HBO and control groups (P < 0.05). Moreover, the proportion of patients with grades D and E was higher in the HBO group than control group ([Table 5]).
|Table 5: Effects of hyperbaric oxygen therapy on ASIA impairment scale grade in patients with incomplete traumatic spinal cord injury living on the plateau|
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| Discussion|| |
Significance of this study
SCI not only has serious physical and psychological consequences for patients but also places a huge economic burden upon the whole society. The prevention, treatment, and rehabilitation of SCI have become a major issue in the medical field. The two main principles of HBO therapy are as follows:
(1) Inhibition of apoptosis. HBO therapy has been shown to inhibit cell apoptosis after TSCI (Liu et al., 2016b; Sun et al., 2016). Liu et al. (2009) found that HBO therapy reduced caspase-3 expression possibly through down-regulation of Fas/Fasl, finally inhibiting apoptosis.
(2) Promotion of spinal cord regeneration and repair. Wang and Liu (2004) believed that HBO could enhance the expression of growth-associated protein-43 mRNA in the injured spinal cord, promote the regeneration and repair of injured spinal cord neurons, and protect the injured spinal cord.
Qinghai is located in the northeastern part of the Qinghai-Tibet Plateau; this area is characterized by low pressure and hypoxia, which have adverse effects on the repair of TSCI (Ma et al., 2015). However, HBO therapy helps to promote the repair of TSCI despite the environmental characteristics of the plateau, providing a new treatment method for incomplete SCI in patients living on the plateau.
Advantages and limitations of this study
HBO therapy has been used to treat SCI since the 1970s (Holbach et al., 1977). HBO therapy can mitigate edema and improve the blood oxygen partial pressure and blood microcirculation (Chen et al., 2017; Yan et al., 2017). This is the first prospective open-label randomized controlled trial to address the effects of HBO therapy on SCI in patients living on the plateau. Our results will provide an experimental basis for treating incomplete SCI in patients on the plateau.
Spinal shock generally lasts 3 to 4 weeks but may exceed 6 months in some patients. Upper motor neuron paralysis gradually develops along with increased muscle tension, tendon hyper-reflexia, positive pathological reflexes, and reflex incontinence (Kim and Jwa, 2015). The four courses of HBO therapy in the present study lasted 55 to 61 days. The partial results of this study demonstrate that spinal shock was lessened within 2 weeks of treatment in all patients. Thus, the presence of spinal shock did not impact our results.
In this trial, we only observed the effects of four courses of HBO therapy on the recovery of incomplete TSCI; we did not perform a long-term observation. Therefore, the long-term effect of HBO therapy on TSCI requires further investigation.
Evidence for contribution to future studies
This trial will provide experimental evidence for the treatment of incomplete TSCI using HBO therapy in patients living on the plateau and will support the clinical application of HBO therapy.
Additional file 1: SPIRIT checklist (PDF 48.0 kb).
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Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for 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
Study design, postoperative function evaluation, and data arrangement: QS. Surgical treatment: JM and JFB. Data collection and statistical analysis: YLA. Patient screening: HL.
This paper was screened twice using CrossCheck to verify originality before publication.
This paper was double-blinded and stringently reviewed by international expert reviewers.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]