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Protocol for the Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study: a prospective, observational, multicentre cohort study of acute spinal cord injury
  1. Wenjian Yuan1,
  2. Jiuxiao Sun1,
  3. Qingyang Li1,
  4. Ruiyuan Zheng1,
  5. Bin Guan1,
  6. Zhuo Chen1,
  7. Jiaming Ding1,
  8. Qingyu Sun1,
  9. Runhan Fu1,
  10. Wei Wang1,
  11. Yuxuan Fan2,
  12. Yi Kang2,
  13. Chao Sun2,
  14. Ang Li3,
  15. Dongjin Wu4,
  16. Dachuan Wang4,
  17. Lei Qi4,
  18. Lingxiao Chen1,5,6,
  19. Shiqing Feng1,2,4,
  20. Hengxing Zhou1,7
  1. 1 Department of Orthopaedics, Qilu Hospital of Shandong University, Shandong University Centre for Orthopaedics, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  2. 2 Department of Orthopaedics, Tianjin Medical University General Hospital, Tianjin Medical University, International Science and Technology Cooperation Base of Spinal Cord Injury, Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin, China
  3. 3 Department of Orthopaedics, Henan Provincial People's Hospital, Zhengzhou, Henan, China
  4. 4 The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  5. 5 Department of Biostatistics, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
  6. 6 Sydney Musculoskeletal Health, The Kolling Institute, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
  7. 7 Center for Reproductive Medicine, Shandong University, Jinan, Shandong, China
  1. Correspondence to Professor Hengxing Zhou; zhouhengxing{at}sdu.edu.cn; Professor Shiqing Feng; shiqingfeng{at}sdu.edu.cn; Dr Lingxiao Chen; lche4036{at}uni.sydney.edu.au

Abstract

Introduction Spinal cord injury (SCI) is a catastrophic event with devastating physical, social and occupational consequences for patients and their families. The number of patients with acute SCI in China continues to grow rapidly, but there have been no large prospective cohort studies of patients with acute SCI. This proposed study aims to establish a multicentre, extensive sample cohort of clinical data and biological samples of patients in China, which would aid the systematisation and standardisation of clinical research and treatment of acute SCI, thus reducing the heavy burden of acute SCI on patients and society.

Methods and analysis The Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) study is an observational, multicentre cohort study of patients with acute SCI admitted to the Qilu Hospital of Shandong University and other participating centres with prospective collection of their clinical data and biological samples. We aim to recruit 2097 patients in this study. Demographics, disease history, emergency intervention information, motor and sensory examinations, surgical information, medication information and rehabilitation evaluation will be recorded. This will facilitate the development of a prediction model for complications and prognosis of patients with acute SCI and an evaluation of the current management of acute SCI. Among these variables, detailed information on surgical treatment will also be used to assess procedures for acute SCI treatment. Outcome measurements, including the International Standard for Neurological Classification of Spinal Cord Injury examinations, the occurrence of complications and death, will be performed repeatedly during follow-up. We will analyse imaging data and blood samples to develop SCI imaging markers and biomarkers.

Ethics and dissemination This study protocol has been approved by the Medical Ethics Committee of the Qilu Hospital of Shandong University and all other participating centres. The findings will be disseminated in peer-reviewed journals and academic conferences.

  • Spine
  • Follow-Up Studies
  • Epidemiology
  • REGISTRIES
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Strengths and limitations of this study

  • This study is a multicentre and large-sized observational cohort study, which allows the collection of motor and sensory examinations, neurophysiological monitoring, blood biochemical indicators, imaging markers and broad electronic medical records.

  • This study contributes to the comparability of spinal cord injury (SCI) lesions, treatments and outcomes among patients, centres and countries through standardised data collection using the International SCI data sets.

  • This research exclusively takes place in China, which may limit the generalisability of the findings.

Introduction

Spinal cord injury (SCI) is a severe traumatic disease with high incidence and disability, caused by various external forces acting on the spinal cord, resulting in neurological impairment.1–5 The number of patients with SCI is rapidly increasing worldwide, and the age-standardised incidence rate of SCI in China increased by 40.81% from 1990 to 2019.1 Several international studies, such as the Transforming Research and Clinical Knowledge in Spinal Cord Injury6 study and the European Multicenter Study on Human Spinal Cord Injury7 have contributed to large-scale observational studies of SCI with high-quality, prospective, multicentre SCI data sets. However, such a cohort study has yet to be reported in China. Therefore, we propose to systematically collect demographic data, blood biomarkers, neuroradiological characteristics, clinical intervention outcomes in patients with acute traumatic SCI and outcomes of neurological function at multiple time points covering multiple centres after the initial injury. We will collect Chinese Real-World Evidence for Acute Spinal Cord Injury (ChiRES) and construct a multicentre, large-sample database of acute SCI clinical information and biospecimens.

We previously conducted a comprehensive evaluation of clinical practice guidelines for SCI.8–11 We found that some of the recommendations in diagnosis, treatment and complications management after SCI in the domestic and international guidelines lack rigour and clarity, and the feasibility of guidance for clinical practice is insufficient (eg, the lack of uniform and clear clinical management criteria, optimal imaging criteria and optimal surgical criteria).8–15 To optimise the current clinical treatments for SCI, we need to develop a comprehensive and systematic assessment of the current status of clinical management of SCI. Related guidelines need to be developed in the future. The deficiencies in the process and prehospital emergency, diagnosis, treatment and rehabilitation processes need to be addressed and optimised.

SCI can lead to deficits in motor, sensory and other neurological functions, which often lead to severe complications or even death.16 17 The National Spinal Cord Injury Statistical Center has stated that more than 99% of patients have varying degrees of motor and sensory nerve dysfunction in the extremities and that the mortality rate has not decreased in the last 40 years.16 Data from the North American Clinical Trials Network Clinical Center for the Treatment of Spinal Cord Injury showed that 57.8% of patients with SCI had at least one complication, whereas 46.0% had two or more complications.18 Recent research on SCI complications has focused on the analysis of relevant influencing factors,12 17–20 and the few predictive studies have mostly involved single-outcome prediction modelling of complications.21 However, multiple complications and their potential interactions must be considered simultaneously in clinical practice.12 17–22 Therefore, we will develop a multi-outcome variable prediction model for complications and prognoses of Chinese patients with acute SCI based on the ChiRES database, which will help to construct a clinical decision-aid system for acute SCI.

Some of the biochemical parameters (eg, liver function and electrolytes) in the peripheral blood of patients with acute SCI are considerably abnormal and may reflect their prognoses. In addition, biochemical blood and imaging indicators are objective and easy to quantify.23 They are less likely to be affected by critical conditions, the use of sedatives or SCI combined with brain injury. Thus, these indicators are crucial for early intervention, prognosis improvement and follow-up observation. Currently, the preferred imaging test for SCI is Magnetic Resonance Imaging (MRI). However, conventional MRI results are poorly correlated with functional disability evaluation and are unsuitable for evaluating the functional status of the spinal cord. In contrast, diffusion tensor imaging (DTI) is more sensitive to tissue microstructure and neurological changes than T1-weighted and T2-weighted conventional MRI. The MRI-DTI may have the unique advantages of predicting SCI prognosis, good applicability and development prospects.24–26 The development of biochemical blood and imaging markers for early prediction of acute SCI prognosis can aid individualised clinical management and early intervention for potential poor prognoses in different patient populations.

Surgical treatment is one of the current mainstays of SCI treatment.27–29 Most studies have concluded that early surgical treatment may be more beneficial for neurological repair after SCI,17 19 27 28 30–32 but the time thresholds for early and late stages have not been standardised,17 19 27–30 33 34 and 24 hours,27 28 32 48 hours31 33 and 72 hours19 35 have been considered appropriate by different guidelines. In short, there is no standard for the optimal time of surgery for SCI. It is urgent to clarify the optimal time for surgical treatment and to develop a standardised protocol for surgical treatment of acute SCI.

This project will focus on these critical aspects used in clinical practice for acute SCI, based on the above issues. We will establish an extensive, multicentre database of clinical data and biological samples of acute SCI in China, which will help to promote the systematisation and standardisation of clinical research and treatment of acute SCI. This will reduce the heavy burden of acute SCI on patients and society.

Aim/objectives

The primary objectives of the ChiRES study are:

  1. To establish a large, multicentre database of clinical information and biospecimen samples of patients with acute SCI and to complete at least 1 year of follow-up.

  2. To assess the current state of acute SCI management and to identify gaps in the process through a comparison with current guidelines.

  3. To develop biochemical blood markers and imaging markers for early prediction of the prognosis of acute SCI.

  4. To establish prediction models of multiple outcome variables for complications and prognoses of patients with acute SCI.

  5. To clarify the optimal timing of surgical treatment, and to develop a standardised protocol for surgical treatment of acute SCI.

Methods and analysis

Study design and setting

ChiRES is a prospective multicentre cohort study focusing on Chinese patients with acute SCI, approved by the Ethics Committee of the Qilu Hospital of Shandong University and all other participating centres. Patient selection will begin in January 2024, and the patients will be recruited from the Qilu Hospital of Shandong University, the Second Hospital of Shandong University, Tianjin Medical University General Hospital and Henan Provincial People’s Hospital. We will collect clinically relevant information and biological samples from patients with acute SCI and record follow-up data for at least 1 year. The study will be designed, implemented and reported according to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE)36 criteria and Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD)37 criteria. A flow chart of the study procedure is shown in figure 1.

Figure 1

Flow chart of the study procedure. AV, arteriovenous; h, hours; SCI, spinal cord injury.

Participants and eligibility criteria

Before the study, patients or their family members will be given a clear explanation of the purpose of the study and sufficient time to complete the informed consent form. During the study, patient privacy and data security will be ensured. Eligible participants will be enrolled and registered according to the following criteria.

Inclusion criteria:

  1. Patients with SCI in the acute phase (within 24 hours).

  2. Capacity and willingness to give written informed consent.

Exclusion criteria:

  1. Non-traumatic paraplegia or tetraplegia (ie, discusprolaps, tumour, arteriovenous malformation, myelitis) excluding single-event ischaemic incidences.

  2. Previously known dementia or severe reduction in intelligence, leading to reduced capabilities to cooperate or provide consent.

  3. Peripheral nerve lesions above the lesion level (ie, plexus brachialis impairment).

  4. Previously known polyneuropathy.

  5. Severe craniocerebral injury.

Data collection and variables

Demographic and clinical data

The International SCI Data Sets project began in 2002, advocating for developing an internationally recognised and accepted standard data set that would provide a common language for SCI centres worldwide and a working resource of guidelines and data collection forms for widespread use by the international SCI clinical community.38 Standardised data collection facilitates comparability of SCI lesions, treatments and outcomes among patients, centres and countries. We will translate the International SCI Data Sets into Chinese and use the latest Chinese version of the data set as the basis for our clinical data collection. In addition, we will collect detailed information on patient demographics (online supplemental material 1), disease history (eg, medication history, surgical history and comorbidities) and contact information using electronic medical record systems and questionnaire. After admission, detailed information, including emergency intervention information, motor and sensory examinations, surgical information, medication information (eg, types of drugs, the first date of administration, the maximum dose and the date it was received and the duration of intake) and rehabilitation evaluation (eg, the start and end time of rehabilitation, rehabilitation modality, frequency and duration of each rehabilitation performed) will be recorded, based on paper and electronic medical records and on-site assessments. A summary of the data collection plan is provided in table 1. (The complete measurements and timelines can be seen in online supplemental material 2).

Supplemental material

Table 1

Summary of data collection plan in the cohort

Collection of blood samples

Blood samples will be collected 1 day and 4 days after injury. Each collection and processing procedure will be performed by well-trained staff. At each point, 8–10 mL of whole venous blood will be collected in an EDTA tube and gently mixed three to five times. Then, the samples will be kept in an ice box and transported to the laboratory as soon as possible. They may be stored in a refrigerator at 4°C for no more than 4 hours. Samples will be equally transferred to 4°C precooled cryogenic tubes (2 mL), and these tubes will be immediately coded and stored at –80°C until the biochemical assays are performed.

MRI protocol

In addition to the baseline evaluation, the MRI scans will be performed 3 days, 14 days, 3 months, 6 months and 12 months after injury during follow-ups. Enrolled patients will undergo MRI (diffusion, T1 and T2) scanning to obtain imaging characteristics. Detailed MRI information from the participating hospitals has been provided (table 2).

Table 2

Information collection of imaging data

Because MRI parameters will be collected from different centres, a voxelwise algorithm will be used to normalise the diffusion data across sites,39 and reporting by neuroradiologists at the Qilu Hospital of Shandong University will be done to facilitate cross-site analysis.

Motor and sensory examinations

The International Standard for Neurological Classification of Spinal Cord Injury (ISNCSCI) has been published by the American Spinal Injury Association (ASIA) to assess motor and sensory dysfunction and to classify patients according to different injury severities.40 The ISNCSCI examination consists of rules for the determination of the location (levels), severity (ASIA Impairment Scale) and extent (zones of partial preservation) of an SCI. The classification will be performed based on a sensory examination of light touch appreciation and pinprick discrimination along 28 dermatomes per body side, as well as via a manual muscle test for 10 ‘key’ muscles per body side and an anorectal examination for deep anal pressure sensation and voluntary anal contraction. We will use the ISNCSCI examination to obtain neurological function measurements and to record motor and sensory scores. The entire measurement process will be performed by physicians, nurses and assistants with experience in SCI examination and classification.

Neurophysiological monitoring

Neurophysiological monitoring (including motor-evoked potentials, somatosensory-evoked potentials and electromyogram results) can reflect the status of the efferent and afferent pathways in the spinal cord, and may have potentially unique prognostic value in predicting neurological recovery after acute SCI.7 41 42 We will collect data of these neurophysiological assessments in all patients with acute SCI at baseline and at follow-up phase of 3 days, 14 days, 3 months, 6 months and 12 months after injury and analyse the association between parameters of neurophysiological assessments (eg, amplitude and latency of motor-evoked potentials and somatosensory-evoked potentials, and nerve conduction velocity, latency and amplitude of electromyograms) and outcomes in the subsequent studies.

Follow-up

Point-of-care follow-up will be conducted at each participating centre during hospitalisation. After discharge, follow-ups will be conducted through a combination of on-site assessments, phone calls, WeChat, web questionnaires and post-questionnaires. To ensure reliability, the web follow-up system will record the time of questionnaire completion. Paper questionnaires will be mailed before the follow-up time, and each patient’s condition will be confirmed by telephone on the follow-up day. The primary outcome of prediction models for complications and prognostic factors of acute SCI, as well as the primary outcome indicators for biological and imaging markers, will be measured at 3 days, 14 days, 3 months, 6 months and 12 months after injury. Similarly, the primary outcome of surgical treatments will be measured at 3 days, 14 days, 3 months, 6 months and 12 months after intervention.

Management of acute SCI

Using an established biomarker cohort database for acute SCI, we will evaluate prehospital first aid, diagnosis, treatment and rehabilitation. Based on previous work on the evaluation of SCI guidelines, we will identify deficiencies in current management and provide evidence to inform clinical practice. When there are clear recommendations, we will calculate the rate of implementation. We will describe the status quo for those not mentioned in any guidelines or for those for which there is insufficient evidence.

Predictive model for complications and prognostic factors of acute SCI

Based on the ChiRES cohort, we will set baseline risk factors (eg, demographics, aetiology and behavioural characteristics) and incorporate risk factors for primary outcomes of complications and prognoses. This will be used to establish predictive models for multiple outcome variables of complications and prognoses in patients with acute SCI. We will then construct a clinical decision-aid system for acute SCI to achieve personalised management of complications and early intervention for possible poor prognoses for different patient populations.

Outcome measures

The primary outcome measures for the complication prediction model will include the occurrence of all complications and severe complications in patients with acute SCI. The primary outcome measures for the prognosis prediction model will include ISNCSCI examinations, occurrences of complications and the occurrence of death.

Statistical analysis

We will follow the modelling strategy proposed by Frank Harrell,43 which includes two steps. During step one, full models will be developed (ie, no variable selection will be performed), and during step two, we will approximate the full model and generate final simplified models. Internal validation through bootstrap resampling will be performed. The model’s performance will be assessed via discrimination and calibration. The reporting on the predictive model will follow TRIPOD.37

Imaging markers and biomarkers for predicting acute SCI prognosis

According to available imaging data, several types of variables will be classified. The result of conventional MRI will be a binary variable with a compressed spinal cord, with high signal intensity on T2-weighted images constituting the exposure group, and SCI without radiographic abnormality will comprise the control group. The apparent diffusion coefficient and fractional anisotropy will be continuous variables and will not be grouped. The Brain and Spinal Injury Center (BASIC) score can assess the outcome of conventional MRI, and it is a multi-category variable. BASIC1, BASIC2 and BASIC3 will serve as the exposure groups, and BASIC0 will be the control group. All these variables will be combined and modelled by machine learning (supervised, semi-supervised and unsupervised learning) to construct new features according to the Checklist for Artificial Intelligence in Medical Imaging. This protocol aims to quantify novel and established biomarkers related to SCI pathophysiology in blood, including proteins associated with neuronal and glial structure and function (Glial fibrillary acidic protein, Ubiquitin C-terminal hydrolase L1, etc), microRNAs, genetic traits, phenomics and metabolomics. These blood biomarkers are continuous variables, so we will not group them.

Outcome measures

The primary outcome measures for the imaging markers and biomarkers for predicting the prognosis of acute SCI will include ISNCSCI examinations and the occurrences of complications or death.

Statistical analysis

We will perform our analysis based on the framework of causal inference.44 Potential confounders will be selected based on clinical knowledge and prior literature. The final included confounders will be chosen based on a causal diagram. The reporting will follow Prognosis Research Strategy 2: Prognostic Factor Research.45

Surgical treatment of acute SCI

We will include patients treated with surgery in the ChiRES cohort and collect the clinical data and biospecimen database of this subset of patients with acute SCI. Following the causal inference analysis process, we will use various study subgroups to elucidate the effects of surgical treatment on the primary and secondary outcome indicators of acute SCI prognoses and to clarify the optimal timing of surgical treatment. This will result in the development of standardised protocols for surgical treatment of acute SCI and will optimise the current clinical treatments used for SCI. The study subgroups are shown in table 3.

Table 3

Subgroups for surgical treatment of acute spinal cord injury (SCI)

Outcome measures

The primary outcome measures of surgical treatment of acute SCI will include data from the ISNCSCI examinations; secondary outcome measures will include the occurrences of complications and death.

Statistical analysis

We will perform the analysis based on the framework of target trial emulation.46 The potential heterogeneity of treatment effects will be explored via the causal forest method.47

Sample size

We used the four-step method provided by Riley et al 48 for calculating the sample size of a prediction model. The largest sample size among the four steps was the one we needed. We referenced the data from the previous prediction model of complication in patients with SCI,49 with an anticipated proportion of the presence of complication was 0.4 and the R2 cs was 0.12. We set the predictor parameters to 30 and the shrinkage to 0.9. The largest sample size in the four steps was 2097, which was the minimum sample size for our study.

Quality control

Before recruitment, researchers will receive training in the standard operation processes for clinical data and biological sample collection. There will be dedicated individuals responsible for managing all data to ensure the preservation, safety and reliability of the original data. In addition, a committee composed of experts in clinical medicine, epidemiology and health statistics, scientific research management and other fields will review and validate the designs and implementation plans of this protocol under the guidelines of the Academic Council of Shandong University Clinical Research Center. This will ensure data quality and improve the management system to protect the privacy of the patients.

Patient and public involvement

Patients and the public will not be involved in the formulation of research questions, measurement of outcomes, survey design or data interpretation.

Ethics and dissemination

Ethical approval

The protocol was approved by the Medical Ethics Committee of the Qilu Hospital of Shandong University and all other participating centres following the Declaration of Helsinki and other similar ethical standards.

Informed consent

Each patient, or their legal guardian, if necessary, will give informed consent in writing.

Dissemination

Results will be disseminated through peer-reviewed publications and to patients, medical and health service administrators, clinicians and other researchers at conferences. We will also provide feedback to clinicians through peer reviews to develop optimal treatment strategies. The observational study will be reported using STROBE, and the multi-outcome prediction models for individual prognoses and diagnoses will be reported using TRIPOD.

We welcome researchers from all over the world to contact us (HZ: zhouhengxing@sdu.edu.cn) if they are interested in becoming involved in ChiRES, especially for the colleagues who wish to collaborate with us for contributing to the SCI community in a prospective way.

Ethics statements

Patient consent for publication

References

Footnotes

  • WY, JS and QL contributed equally.

  • Contributors Conceptualisation: LC, HZ and SF. Methodology: LC, HZ and SF. Project administration: LC, HZ and SF. Writing—original draft: WY and JS. Writing—review and editing: WY, JS, QL, RZ, BG, ZC, JD, QS, RF, WW, YF, YK, CS, AL, DWu, DWa, LQ, LC, HZ and SF. Supervision: LC, HZ and SF. All authors have read and approved the final manuscript.

  • Funding This work was funded by ECCM Program of Clinical Research Center of Shandong University (No.2021SDUCRCC002), Clinical Research Center of Shandong University (No.2020SDUCRCA008), Clinical Medical Research Program of Tianjin Medical University General Hospital (No.22ZYYLCZD01) and the Taishan Scholars Program of Shandong Province-Young Taishan Scholars (tsqn201909197). LC is funded by the International Postdoctoral Exchange Fellowship Program (Talent-Introduction Program, YJ20220294).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.