Study design and Setting
The study is a time series cohort study. Patients with both cervical spondylosis myelopathy and hypertension are invited to participate in the study and subsequently receive cervical decompressive surgery. Patients are recruited continuously by surgeons at the Department of Orthopaedics, Peking University First Hospital in which there are about 30–40 patients with both cervical spondylosis myelopathy and hypertension each year. These subjects will be followed up at 1 and 3 months post-operation after enrollment. The study procedures and informed consent form have been approved by the Institutional Review Boards of the Peking University Health Science Center in Beijing, China, and registered at NCT02016768. Figure 1 shows an overview of the most important procedures in the study.
Participants
Inclusion criteria
The patients to be included in the study should meet the following inclusion criteria:
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1.
Patients with cervical spondylosis myelopathy, such as bilateral hand clumsiness and numbness, walking unsteady, weakness in the limbs, muscular dystrophy, increasing deep tendon reflex and positive Hoffmann and Babinski signs; the underlying diseases including multilevel cervical spinal stenosis, ossification of posterior longitudinal ligaments (OPLL), disc herniation, meeting operation indications: spinal neurological symptoms for at least 2 months, which are not cured by conservative treatment or in progression, significant spinal compression indicated by magnetic resonance imaging.
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2.
Aged 18–84 years.
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3.
Plans for receiving cervical decompressive surgery.
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A history of hypertension or office systolic blood pressure ≥140 mmHg on initial screening.
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Willing to participate in the study and sign informed consent.
Exclusion criteria
If one of the following criteria is met, patients will be excluded from the study:
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1.
A history of known secondary hypertension.
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2.
Visual analogue scale (VAS) score ≥4.
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3.
Unable to comply with study due to sever psychosis.
Recruitment and consent
The patients who suffer from cervical spondylosis myelopathy and plan for receiving cervical decompressive surgery will be selected for potential participation by the surgeons at the Department of Orthopedics. After consultation with inpatients and outpatients and screening their clinical information, the principal investigator of the study (the surgeon) informs patients whether they are eligible for the study. Informed consent is acquired immediately after screening for every subject by the principal investigator.
Withdrawal of individual subjects
Subjects can withdraw from the study at any time for any reason without any consequences. The investigator can also decide to release a subject from the study for medical reasons. For every subject who decides to withdraw from the study, the reasons for withdrawal will be recorded.
A total of 18 patients have given informed consent for participation and been enrolled into the study from July 2014 to Oct 2015.
Cervical decompressive surgery
The cervical decompressive surgery will be done with one of the following four operating methods: international standard anterior cervical discectomy and fusion (standard Smith-Robinson technique, intervertebral disc incised and removed to reduce pressure, interbody fusion by implanting cervical interbody fusion cage), anterior cervical corpectomy and fusion (cervical corpectomy decompression, interbody fusion by implanting titanium cage), posterior bilateral open-door decompression (modified Hemo anchored method) or one-side open door decompression (modified Hirobayashi anchored method). The indications for anterior approach are subjects with less than three levels disc herniation, while for posterior approach are those with multilevel cervical spinal stenosis and continuous or mixed OPLL.
Initial screening, assessment and follow-up
After providing informed consent, potential participants will be asked standardized questions about their demographic characteristics and medical history (especially for the history of hypertension and antihypertensive therapy) at initial screening. In addition, office blood pressure, VAS score and 24 h ambulatory blood pressure measurement (ABPM) will also be measured and used for checking inclusion/exclusion criteria (Fig. 2).
Eligible participants will be hospitalized for surgical treatment, and a pre-operation visit and clinical evaluation will be done before surgery, including antihypertensive medication, vital signs, physical examination, laboratory testing, spinal nerve function score and 24 h ABPM (Fig. 2). It is required that there is at least 3 days apart between initial screening visit and pre-operation visit. As soon as the operation condition is met, these subjects will receive cervical decompressive surgery, and their operation notes and adverse events will be recorded in detail.
All subjects will be followed up at 1 and 3 months after surgical operation, with antihypertensive medication recording, measurement of office blood pressure, 24 h ABPM and adverse events assessment collected at each time. In addition, VAS, physical examination and spinal nerve function score will be measured and collected at 3 month follow-up.
Regular antihypertensive medication therapy will be continued during the entire study period, however, the investigator can adjust the antihypertensive medication if necessary, according to treatment needs of individual patients.
Study endpoints
The primary endpoint is estimated as the difference between systolic ABPM before surgery (2nd measurement) and the systolic ABPM at 1 month and 3 month post-operation (3rd and 4th measurement).
Four secondary endpoints were defined as: 1) The difference between diastolic ABPM before surgery and ABPM diastolic blood pressure at 1 month and 3 month post-operation; 2) control status of blood pressure at 1 month and 3 month post-operation (blood pressure control is achieved if systolic/diastolic blood pressure <140/90 mm Hg, reducing systolic blood pressure by >20 mm Hg or reducing diastolic blood pressure >5 mm Hg); 3) the use and dose adjustment of antihypertensive medication; and 4) the incidence of operative complications, including spinal nerve trauma, incision infection and fluid, pneumonia and urinary system infection etc.
Sample size calculation
Based on previous study which explored the efficacy of renal sympathetic denervation in treating hypertension, we assume that for the current study the primary outcome (the change of 24 h ABPM systolic blood pressure from pre-operation to the measurement at 3 months post-operation) has a standard deviation of 15 mm Hg [14]. We wish to be able to detect a difference of 11 mm Hg. Assuming a 20 % drop-out rate, a total of 50 participants are required to provide 90 % power, with the risk of two-sided type І error of 0.01.
Statistical analysis
Analyses will be made using SAS statistical software (version 9.3) by researchers at the Peking University Clinical Research Institute. The change in systolic ABPMs over the four times will be analyzed to observe the overall pattern of the blood pressure change in relation to the surgery, but the primary analysis will be the comparison of systolic ABPM between the 2nd and 3rd, 4th measurements (before and after the surgery). We will also calculate the regression-to-the-mean adjusted changes in systolic ABPMs as sensitivity analysis. Primary endpoint analyses and the change in systolic ABPMs over the four times will be carried out using analysis of covariance, as well as the first secondary endpoint (the change of 24 h ABPM diastolic blood pressure). Descriptive statistics will be used to summarize control status of blood pressure, the use and dose adjustment of antihypertensive medication and the incidence of operative complications.