{"paper_id":"8a4b6a11-c4e7-4652-a311-7c53de8db57e","body_text":"S T U D Y P R O T O C O L Open Access\nEffects of decompressive cervical surgery\non blood pressure in cervical spondylosis\npatients with hypertension: a time series\ncohort study\nHong Liu 1*, Hai-Bo Wang 2, Lin Wu 3, Shi-Jun Wang 1, Ze-Chuan Yang 1, Run-Yi Ma 4, Kathleen H. Reilly 5,\nXiao-Yan Yan 2, Ping Ji 2 and Yang-feng Wu 2,6*\nAbstract\nBackground: Patients with cervical spondylosis myelopathy (CSM) and complicated with hypertension are often\nexperiencing a blood pressure decrease after taking cervical decompressive surgery in clinical observations, but\nhow this blood pressure reduction is associated with the surgery, which cut cervical sympathetic nervous, has never\nbeen rigorously assessed. Thus, the purpose of this study is to investigate the effect of cervical decompressive\nsurgery on blood pressure among CSM patients with hypertension.\nMethods/Design: The study will be a time series cohort study. Fifty eligible patients will be selected consecutively\nfrom the Peking University First Hospital. Two 24-h ambulatory blood pressure measurement (ABPM) will be taken\nbefore the surgery, apart by at least 3 days. The patients will be followed up for another two ABPMs at 1 and\n3 months after the surgery.\nWe will recruit subjects with cervical spondylosis myelopathy meeting operation indications and scheduled for\nreceiving cervical decompressive surgery, aged 18 –84 years, have a history of hypertension or office systolic blood\npressure ≥140 mmHg on initial screening, and willing to participate in the study and provide informed consent.\nExclusion criteria includes a history of known secondary hypertension, visual analogue scale (VAS) score ≥4, and\nunable to comply with study due to severe psychosis.\nThe change in systolic ABPs over the four times will be analyzed to observe the overall pattern of the blood\npressure change in relation to the surgery, but the primary analysis will be the comparison of systolic ABP between\nthe 2 nd and 3 rd ,4 th measurements (before and after the surgery). We will also calculate the regression-to-the-mean\nadjusted changes in systolic ABP as sensitivity analysis. Secondary endpoints are the changes in 24 h ABPM diastolic\nblood pressure, blood pressure control status, the use and dose adjustment of antihypertensive medication, and the\nincidence of operative complications. Primary outcome analyses will be carried out using analysis of covariance, as\nwell as the first secondary endpoint.\n(Continued on next page)\n* Correspondence: liuhooong@163.com; wuyf@bjmu.edu.cn\nHong Liu, Hai-Bo Wang are co-first authors.\n1Department of Orthopaedic Surgery, Peking University First Hospital,\nXishikuda Street 8#, Xicheng Dist, Beijing 100034, P.R. China\n2Peking University Clinical Research Institute, Xueyuan Rd 38#, Haidian Dist,\nBeijing 100191, P.R. China\nFull list of author information is available at the end of the article\n© 2016 Liu et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0\nInternational License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and\nreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to\nthe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver\n(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\nLiu et al. BMC Surgery  (2016) 16:2 \nDOI 10.1186/s12893-015-0117-y\n\n(Continued from previous page)\nDiscussion: This study will inform us the important knowledge about cervical sympathetic nervous system (SNS)\nand blood pressure. Once confirmed, it may help to produce new method for control of hypertension, which is the\nleading cause of death in the world.\nTrial registration: The study is registered to Clinical Trials.gov (NCT02016768).\nKeywords: Cervical spondylosis myelopathy, Cervical decompressive surgery, Hypertension, 24 h ambulatory blood\npressure measurement\nBackground\nHypertension is a major global health concern. It is esti-\nmated that 30 –40 % of the adult population in the devel-\noped world are suffering from hypertension [1, 2].\nMoreover, incidence and prevalence of hypertension are\nincreasing, especially in developing countries. The effects\nof current pharmacologic treatment of hypertension re-\nmain suboptimal in both developing and developed coun-\ntries [3, 4]. The common causes responsible for the poor\ncontrol of high blood pressure are attributed to physicians ’\nattitudes and patient non-compliance to lifelong pharma-\ncological therapy for asymptomatic hypertension [5 –7].\nMoreover, hypertension that remains uncontrolled in spite\nof the use of 3 or more antihypertensive drugs has been\ncalled resistant hypertension [8]. Clinical evidence indi-\ncates that the risk of major cardiovascular events is higher\namong patients with resistant hypertension than that\namong patients with controlled blood pressure [5]. Thus,\ndeveloping novel approaches for management of hyper-\ntension, especially for resistant hypertension, is an import-\nant issue for the future of the treatment of hypertension.\nIt is well known that sympathetic nerve fibers are rich\nin cervical spinal tissues [9 –11]. Yamada et al. [9] re-\nported that there was different sympathetic innervation\nbetween the cervical dura mater and the posterior longi-\ntudinal ligament. It seems reasonable that the compres-\nsion or irritation of cervical dura mater and/or posterior\nlongitudinal ligament may cause an increase in blood\npressure or aggravate pre-existing hypertension among\npatients with cervical spondylosis myelopathy.\nTamura [12] found that neck injury, such as whiplash,\nmay lead to the cranial symptoms of the Barré-Lieou\nsyndrome (including a group of symptoms such as head-\nache, vertigo, tinnitus and ocular problems), which may\nresult from irritation of the sympathetic nervous supply.\nWe hypothesize that the cervical sympathetic nerve is\nalso associated with the occurrence of resistant hyper-\ntension and that cervical decompressive surgery may be\nbeneficial in blood pressure control among patients with\ncervical spondylosis myelopathy [13]. The purpose of\nthis study is to investigate the effect of cervical decom-\npressive surgery on resistant hypertension based on a\nnovel mechanistic hypothesis of essential hypertension.\nMethods and design\nStudy design and Setting\nThe study is a time series cohort study. Patients with\nboth cervical spondylosis myelopathy and hypertension\nare invited to participate in the study and subsequently\nreceive cervical decompressive surgery. Patients are re-\ncruited continuously by surgeons at the Department of\nOrthopaedics, Peking University First Hospital in\nwhich there are about 30 –40 patients with both cer-\nvical spondylosis myelopathy and hypertension each\nyear. These subjects will be followed up at 1 and\n3 months post-operation after enrollment. The study\nprocedures and informed consent form have been\napproved by the Institutional Review Boards of the\nPeking University Health Science Center in Beijing,\nChina, and registered at NCT02016768. Figure 1\nshows an overview of the most important procedures\nin the study.\nParticipants\nInclusion criteria\nThe patients to be included in the study should meet the\nfollowing inclusion criteria:\n1. Patients with cervical spondylosis myelopathy,\nsuch as bilateral hand clumsiness and numbness,\nwalking unsteady, weakness in the limbs, muscular\ndystrophy, increasing deep tendon reflex and\npositive Hoffmann and Babinski signs; the\nunderlying diseases including multilevel cervical\nspinal stenosis, ossification of posterior longitudinal\nligaments (OPLL), disc herniation, meeting\noperation indications: spinal neurological symptoms\nfor at least 2 months, which are not cured by\nconservative treatment or in progression, significant\nspinal compression indicated by magnetic resonance\nimaging.\n2. Aged 18 –84 years.\n3. Plans for receiving cervical decompressive surgery.\n4. A history of hypertension or office systolic blood\npressure ≥140 mmHg on initial screening.\n5. Willing to participate in the study and sign informed\nconsent.\nLiu et al. BMC Surgery  (2016) 16:2 Page 2 of 7\n\nExclusion criteria\nIf one of the following criteria is met, patients will be\nexcluded from the study:\n1. A history of known secondary hypertension.\n2. Visual analogue scale (VAS) score ≥4.\n3. Unable to comply with study due to sever\npsychosis.\nRecruitment and consent\nThe patients who suffer from cervical spondylosis myel-\nopathy and plan for receiving cervical decompressive\nsurgery will be selected for potential participation by the\nsurgeons at the Department of Orthopedics. After con-\nsultation with inpatients and outpatients and screening\ntheir clinical information, the principal investigator of\nthe study (the surgeon) informs patients whether they\nFig. 1 Study measures and time points\nLiu et al. BMC Surgery  (2016) 16:2 Page 3 of 7\n\nare eligible for the study. Informed consent is acquired\nimmediately after screening for every subject by the\nprincipal investigator.\nWithdrawal of individual subjects\nSubjects can withdraw from the study at any time for any\nreason without any consequences. The investigator can\nalso decide to release a subject from the study for medical\nreasons. For every subject who decides to withdraw from\nthe study, the reasons for withdrawal will be recorded.\nA total of 18 patients have given informed consent for\nparticipation and been enrolled into the study from July\n2014 to Oct 2015.\nCervical decompressive surgery\nThe cervical decompressive surgery will be done with\none of the following four operating methods: inter-\nnational standard anterior cervical discectomy and fu-\nsion (standard Smith-Robinson technique, intervertebral\ndisc incised and removed to reduce pressure, interbody\nfusion by implanting cervical interbody fusion cage), an-\nterior cervical corpectomy and fusion (cervical corpect-\nomy decompression, interbody fusion by implanting\ntitanium cage), posterior bilateral open-door decompres-\nsion (modified Hemo anchored method) or one-side\nopen door decompression (modified Hirobayashi an-\nchored method). The indications for anterior approach\nare subjects with less than three levels disc herniation,\nwhile for posterior approach are those with multilevel\ncervical spinal stenosis and continuous or mixed OPLL.\nInitial screening, assessment and follow-up\nAfter providing informed consent, potential participants\nwill be asked standardized questions about their demo-\ngraphic characteristics and medical history (especially\nfor the history of hypertension and antihypertensive\ntherapy) at initial screening. In addition, office blood\npressure, VAS score and 24 h ambulatory blood pressure\nmeasurement (ABPM) will also be measured and used\nfor checking inclusion/exclusion criteria (Fig. 2).\nEligible participants will be hospitalized for surgical\ntreatment, and a pre-operation visit and clinical evaluation\nwill be done before surgery, including antihypertensive\nmedication, vital signs, physical examination, laboratory\ntesting, spinal nerve function score and 24 h ABPM\n(Fig. 2). It is required that there is at least 3 days apart be-\ntween initial screening visit and pre-operation visit. As\nsoon as the operation condition is met, these subjects will\nreceive cervical decompressive surgery, and their oper-\nation notes and adverse events will be recorded in detail.\nAll subjects will be followed up at 1 and 3 months\nafter surgical operation, with antihypertensive medica-\ntion recording, measurement of office blood pressure,\n24 h ABPM and adverse events assessment collected at\neach time. In addition, VAS, physical examination and\nspinal nerve function score will be measured and col-\nlected at 3 month follow-up.\nRegular antihypertensive medication therapy will be\ncontinued during the entire study period, however, the\ninvestigator can adjust the antihypertensive medication\nif necessary, according to treatment needs of individual\npatients.\nStudy endpoints\nThe primary endpoint is estimated as the difference be-\ntween systolic ABPM before surgery (2 nd measurement)\nand the systolic ABPM at 1 month and 3 month post-\noperation (3 rd and 4 th measurement).\nFour secondary endpoints were defined as: 1) The differ-\nence between diastolic ABPM before surgery and ABPM\ndiastolic blood pressure at 1 month and 3 month post-\noperation; 2) control status of blood pressure at 1 month\nand 3 month post-operation (blood pressure control is\nachieved if systolic/diastolic blood pressure <140/90 mm\nHg, reducing systolic blood pressure by >20 mm Hg or re-\nducing diastolic blood pressure >5 mm Hg); 3) the use\nand dose adjustment of antihypertensive medication; and\n4) the incidence of operative complications, including\nspinal nerve trauma, incision infection and fluid, pneumo-\nnia and urinary system infection etc.\nSample size calculation\nBased on previous study which explored the efficacy of\nrenal sympathetic denervation in treating hypertension,\nwe assume that for the current study the primary out-\ncome (the change of 24 h ABPM systolic blood pressure\nfrom pre-operation to the measurement at 3 months\npost-operation) has a standard deviation of 15 mm Hg\n[14]. We wish to be able to detect a difference of 11 mm\nHg. Assuming a 20 % drop-out rate, a total of 50 partici-\npants are required to provide 90 % power, with the risk\nof two-sided type І error of 0.01.\nStatistical analysis\nAnalyses will be made using SAS statistical software\n(version 9.3) by researchers at the Peking University\nClinical Research Institute. The change in systolic\nABPMs over the four times will be analyzed to observe\nthe overall pattern of the blood pressure change in rela-\ntion to the surgery, but the primary analysis will be the\ncomparison of systolic ABPM between the 2 nd and 3rd,4 th\nmeasurements (before and after the surgery). We will also\ncalculate the regression-to-the-mean adjusted changes in\nsystolic ABPMs as sensitivity analysis. Primary endpoint\nanalyses and the change in systolic ABPMs over the four\ntimes will be carried out using analysis of covariance, as\nwell as the first secondary endpoint (the change of 24 h\nABPM diastolic blood pressure). Descriptive statistics will\nLiu et al. BMC Surgery  (2016) 16:2 Page 4 of 7\n\nbe used to summarize control status of blood pressure,\nthe use and dose adjustment of antihypertensive medica-\ntion and the incidence of operative complications.\nDiscussion\nThe etiology and mechanism of essential hypertension re-\nmains unclear. Non-operative methods of essential hyper-\ntension treatment including antihypertensive pharmacologic\ndrugs are still unsatisfactory [5, 8]. In the past several years,\na new procedure named renal denervation had been shown\nto be safe and effective in controlling hypertension, sup-\nporting that the sympathetic nervous system (SNS) activity\nis critical in regulating blood pressure [6, 7]. Recently, we\nhave proposed a novel hypothesis that cervical spondylotic\nmyelopathy may be an important etiology of essential\nhypertension which has been termed as cervicogenic hyper-\ntension [13]. In our previous study, we found that the high\nb l o o dp r e s s u r ei n1 2o u to f3 0( 4 0% )h y p e r t e n s i v ep a t i e n t s\nFig. 2 Observation, assessment, and follow-up schedule\nLiu et al. BMC Surgery  (2016) 16:2 Page 5 of 7\n\nwas reduced to normal levels following the cervical decom-\npressive surgery, which resulted in a termination of the an-\ntihypertensive medications. Furthermore, the high and\nunstable blood pressure in th e other 15 patients became\nstabilized and was well controlled by antihypertensive drugs\nafter cervical decompressive surgery [13]. Recently, Peng\net al. reported two cases of cervical spondylosis with hyper-\ntension [15]. After anterior cervical discectomy and fusion,\nthe blood pressure of both the two patients remain normal\nwithout hypertensive medications [15]. Also, we speculate\nthat renal denervation only destructs the network of SNS,\nand that the diseased cervical SNS has a greater impact on\ninitiating and increasing SNS activity, as it may be closer to\ncentral nervous system than the normal renal SNS.\nThrough long–term clinical observations, we have found\nthat high blood pressure or fluctuated blood pressure\namong many patients decreased substantially or became\nstable post-operatively. Therefore, we infer that cervical\ndecompressive surgery may be a novel alternative in treat-\ning hypertension and will effectively reduce blood pressure\nin patients with cervicogenic hypertension. Therefore, a\nsubstantial number of patients with both hypertension and\ncervical spondylosis may benefit from this approach as the\ndecrease in the quantity and/or dose of antihypertensive\ndrugs would subsequently lead to fewer side effects from\nthem. Regarding the rationale for the reduction on blood\npressure, we speculate that the compression or irritation\nof the dura mater and the posterior longitudinal ligament\nof the cervical spine may increase the sympathetic nervous\nactivation. This discharge may pass through the ganglia\nand the sympathetic trunk to the postganglia fibers arriv-\ning at the target organ, such as the vertebral artery and the\nblood vessels and subsequently induce hypertension.\nDecompressive cervical surgery, either anterior cervical\ndiscectomy and fusion or posterior laminoplasty, may\nwithdraw any compression of the dura and the posterior\nlongitudinal ligament and thus the sympathetic irritation\nwill be relieved leading to a decrease of blood pressure.\nOur study has a number of limitations. This is not a ran-\ndomized controlled clinical trial, factors such as placebo\nand Hawthorne effects cannot be ruled out entirely. How-\never, we tried to measure bl ood pressure two times both\nbefore and after the surgery, t hese multiple measurements\nwould help to better understand if the change in blood\npressure is attributed to the surgery or purely to the regres-\nsion to the mean. Although the ra n d o m i z e dc o n t r o l l e dt r i a l\ni st h eg o l ds t a n d a r ds t u d yd e s ign, it is unethical to conduct\nsuch a trial considering the in appropriateness of treating\nhypertension with a cervical decompressive surgery. In our\nopinion, the study still gains im portant scientific informa-\ntion. Once our hypothesis is approved, it will provide an in-\nnovative mechanism of hypertension development, which\nmay lead to the development of new methods of hyperten-\nsion treatment and prevention.\nCompeting interests\nThe authors declare that they have no competing interests.\nAuthors’ contributions\nHL, HBW, LW, SJW, ZCY, RYM, XYY, PJ and YFW all contributed to the\ndevelopment of the study protocol. HL was the principal investigator and\nmanaged the protocol. HL and HBW was involved in the initial draft of the\nmanuscript and writing it. KHR, XYY, PJ and YFW were involved in critical\nreviewing the manuscript. All authors read and approved the final\nmanuscript.\nAcknowledgements\nThe authors wish to thank Xian Su and Fei Wu for their assistance in the\nProtocol development and project management.\nFunding\nThis research is funded by Peking University Clinical Research Program (grant\nnumber, PUCRP201304) in Peking University Health Science Center. Excess\ntreatment and service support costs incurred by the research are funded by\nthe Peking University First Hospital.\nAuthor details\n1Department of Orthopaedic Surgery, Peking University First Hospital,\nXishikuda Street 8#, Xicheng Dist, Beijing 100034, P.R. China. 2Peking\nUniversity Clinical Research Institute, Xueyuan Rd 38#, Haidian Dist, Beijing\n100191, P.R. China. 3Department of Cardiology, Peking University First\nHospital, Xishenkuda Street 8#, Xicheng Dist, Beijing 100034, P.R. China.\n4Department of Epidemiology and Biostatistics, School of Public Health,\nPeking University Health Science Center, Xueyuan Rd 38#, Haidian Dist,\nBeijing 100191, P.R. China. 5Independent Consultant, New York City, NY, USA.\n6The George Institute for Global Health at Peking University Health Science\nCenter, No. 6 Zhichun Road, Beijing 100083, P.R. China.\nReceived: 12 October 2015 Accepted: 21 December 2015\nReferences\n1. Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K,\net al. Heart disease and stroke statistics –2009 update: a report from the\nAmerican Heart Association Statistics Committee and Stroke Statistics\nSubcommittee. Circulation. 2009;119(3):480 –6.\n2. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J. Global burden\nof hypertension: analysis of worldwide data. Lancet. 2005;365(9455):217–23.\n3. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation\nand treatment. 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Liu H, Ploumis A. Cervicogenic hypertension-A possible etiology and\npathogenesis of essential hypertension. Hypothesis. 2012;10:1.\n14. Symplicity HTNI, Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE,\net al. Renal sympathetic denervation in patients with treatment-resistant\nhypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.\nLancet. 2010;376(9756):1903 –9\n15. Peng B, Pang X, Li D, Yang H. Cervical spondylosis and hypertension:\na clinical study of 2 cases. Medicine. 2015;94(10):e618.\n•  We accept pre-submission inquiries \n  Our selector tool helps you to find the most relevant journal\n  We provide round the clock customer support \n  Convenient online submission\n  Thorough peer review\n  Inclusion in PubMed and all major indexing services \n  Maximum visibility for your research\nSubmit your manuscript at\nwww.biomedcentral.com/submit\nSubmit your next manuscript to BioMed Central \nand we will help you at every step:\nLiu et al. BMC Surgery  (2016) 16:2 Page 7 of 7","source_license":"CC0","license_restricted":false}