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- JMIR Publications
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- Copyright © The Author(s). Licensed under Creative Commons Attribution cc-by 4.0
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- 10.2196/15488
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Abstract
Background: Elderly people are at particular high risk for postoperative delirium (POD) following spine surgery, which is associated with longer hospital stays, higher costs, risk for delayed complications, long-term care dependency, and cognitive dysfunction (POCD). It is insufficiently understood which mechanisms and risk factors contribute to the development of POD and POCD following these major but plannable surgeries. Objective: This study aims to identify modifiable risk factors in spine surgery. A better understanding thereof would help adapt medical management and surgical strategies to individual risk profiles. Methods: This is a single-center observational study jointly conducted by the departments of neurosurgery, neurology, and anesthesiology at a tertiary care hospital in Germany. All patients aged 60 years and older presenting to the neurosurgery outpatient clinic or ward for elective spine surgery are screened for eligibility. Exclusion criteria include presence of neurodegenerative or history of psychiatric disease and medication with significant central nervous system activity (eg, antidepressants, antipsychotics, sedatives). Surgical and anesthetic procedures including duration of surgery as primary end point of this study are thoroughly documented. All patients are furthermore evaluated for their preoperative cognitive abilities by a number of tests, including the Consortium to Establish a Registry for Alzheimer's Disease Plus test battery. Physical, mental, and social health and well-being are assessed using the Patient-Reported Outcome Measurement Information System Profile 29 and Hospital Anxiety and Depression Scale. Patients additionally receive preoperative cerebrovascular ultrasound and structural and functional brain imaging. The immediate postoperative period includes screening for POD using the Nursing Delirium Screening Scale and validation through Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, criteria. We furthermore investigate markers of (neuro)inflammation (eg, interleukins, C-reactive protein, tumor necrosis factor alpha). Preoperative examinations are repeated 3 months postoperatively to investigate the presence of POCD and its mechanisms. Statistical analyses will compare delirious and nondelirious patients for predictors of immediate (POD) and delayed (POCD) cognitive dysfunction. https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 1 (page number not for citation purposes) XSL FO RenderX JMIR RESEARCH PROTOCOLS Müller et al Results: This is the first study to prospectively evaluate risk factors for POD and POCD in spine surgery. Recruitment is ongoing, and data collection is estimated to be finished with the inclusion of 200 patients by mid-2020. Conclusions: The identification of mechanisms, possibly common, underlying POD and POCD would be a major step toward defining effective interventional strategies early in or even before the postoperative period, including the adaptation of surgical strategies to individual risk profiles. Trial Registration: ClinicalTrials.gov NCT03486288; https://clinicaltrials.gov/ct2/show/NCT03486288 (JMIR Res Protoc 2020;9(2):e15488) doi: 10.2196/15488 KEYWORDS postoperative delirium; postoperative cognitive dysfunction; spine surgery; neuroinflammation; magnetic resonance imaging; resting-state connectivity; quality of life postoperative monitoring [27]. Numerous prediction models Introduction have been developed to identify patients at risk, yet recent studies highlight that a general application of these models in It is well established that the proportion of elderly people clinical routine is limited, not least because trajectories of continues to grow at an unprecedented rate in western societies cognitive decline are not independent of the type of surgery [1]. Older patients are at increased risk for an episode of [22,26,28,29]. For example, patients who exhibited POCD delirium following major surgery, but the rate of complex following cardiac surgery improved cognitive function after 1 interventions such as spine surgery in this population is rising year compared with their baseline level, which contradicts [2,3]. Notably, the increase of anterior cervical fusion procedures results from mixed surgical populations [26,29]. Differences in is three times greater than that of general surgery in this preoperative cognitive function and mechanisms underlying population based on the National Hospital Discharge Survey cognitive dysfunction possibly resolve some of the discrepancy, from 1990 to 2004 [4]. Other procedures including lumbar which highlights that surgical type-specific studies are required fusion, laminectomy, and discectomy exhibit an ongoing and to identify mechanisms of POD and POCD unique to these similar progression [3,5]. procedures [7,22,28,30]. Postoperative delirium (POD) typically evolves within 72 hours Five prospective studies evaluated POD following spine surgery following surgery and is defined by the Diagnostic and and were unable to identify modifiable risk factors other than Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) intraoperative hypotension [31-35]. Retrospective and secondary as a disturbance in attention and awareness that develops over outcome analyses suggest that less complex and shorter a short period of time, fluctuates, and is accompanied by a interventions such as simple decompressions could be associated change in cognition [6,7]. It is associated with increased with lower POD and complication rates compared with complex complication rates, nursing times per patient, length of hospital fusion and instrumentation procedures, rendering the surgical stay, per-day hospital costs, and 1-year health care costs [8-10]. intervention itself a potentially modifiable risk factor [34,36]. While the full pathophysiology of POD remains to be elucidated, current literature suggests an underlying multicausal model that In this study, we thus investigate the primary hypothesis that includes neuroinflammation, brain network dysfunction, the duration of spine surgery is a predictor of POD incidence endocrine stress response, and neurotransmitter imbalance in spinal surgery, which was not previously tested as a primary [11-15]. POD was long considered a reversible condition, but end point in a prospective and sufficiently powered study. it is now established that affected patients do not return to their Evidence in favor of our hypothesis would justify adaptation prior quality of life and employment [16-18]. Elderly patients of surgical interventions to individual risk profiles as a viable are additionally affected by postoperative cognitive dysfunction means to reduce the incidence and sequelae of POD without (POCD) that persists in about 30% to 50% of cases after withholding necessary surgery from affected elderly patients. resolution of POD or develops independently up to 3 months This study will also evaluate the relationship between POD and following surgery [7,19,20]. While POCD can develop in the POCD in spine surgery, which has not been done before but absence of POD, more severe POD increases the likelihood of was declared one of the most relevant study areas in a recently POCD indicating that both entities share at least some published multinational and interprofessional delirium research underlying mechanisms [21,22]. Supporting the idea of shared agenda [37]. Additional end points include long-term cognitive mechanisms, POD and POCD have both been shown to function, quality of life, activities of daily living, mood, and accelerate the rate of cognitive decline and increase the risk of frailty. Underlying pathophysiological mechanisms will be long-term mild cognitive impairment or dementia, which may investigated through ultrasound of the cerebral vasculature, ultimately lead to long-term care dependency and structural and resting-state functional magnetic resonance institutionalization [20,22-26]. imaging (sMRI, rs-fMRI), markers of (neuro)inflammation, and metabolomics. Knowledge of risk factors for POD and POCD, particularly modifiable risk factors, is therefore imperative to enhance informed patient consent, adjust anesthetic and surgical strategies to individual risk profiles, and facilitate appropriate https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 2 (page number not for citation purposes) XSL FO RenderX JMIR RESEARCH PROTOCOLS Müller et al antidepressants, antipsychotics, sedatives, alpha-1-receptor Methods antagonists), inability to participate in follow-up, participation in an interventional trial, electronic or displaceable metallic Setting and Registration implants, or active neoplasms. Informed consent to participate The Cognitive Dysfunction Following Elective Spine Surgery can only be given by the patient themself. All baseline in Elderly Patients (CONFESS) study is a prospective examinations are scheduled within 14 days prior to surgery single-center observational study jointly conducted by the (V0). The day of surgery (V1) includes documentation of routine Department of Neurosurgery and Neurology in cooperation with procedures and a close follow-up of patients in the the Department of Anesthesiology at the University Hospital postanesthesia care unit (PACU) for at least 2 hours or longer Greifswald, Germany, a 950-bed tertiary care hospital. The trial depending on the clinical situation. Patients are afterward was approved by the institutional review board of the University routinely transferred to the neurosurgical ward or may of Greifswald (BB 192/17) and registered at ClinicalTrials.gov occasionally require intermediate/intensive care treatment. [NCT03486288]. The Standard Protocol Items: Postoperative visits (V2) continue for at least 72 hours Recommendations for Interventional Trials (SPIRIT) checklist postoperatively and include detailed documentation of primary is provided as Multimedia Appendix 1. and secondary end points. If patients develop POD within 72 hours, daily follow-ups continue until no signs of POD are Patient Recruitment and Study Design documented over a period of 24 hours or the patient is Patient recruitment began in February 2018, and the study discharged (eg, for rehabilitation). Patients are routinely seen continues enrolling patients presenting to the Department of in the neurosurgical outpatient clinic 3 months postoperatively Neurosurgery for elective spine surgery. All patients seen in and in this context receive additional follow-up examinations neurosurgery outpatient clinics or inpatient wards are screened (V3). Patients who agreed to be contacted via telephone finally for eligibility. Patients can be enrolled if they are at least aged undergo a telephone assessment of their cognitive and functional 60 years, scheduled for elective spine surgery without opening status 1 year following surgery (V4). A synopsis of the visit the dura, can give informed consent themselves, and are German plan is provided in Table 1. Recruitment is planned to be native speakers. Exclusion criteria comprise any diagnosis of completed by December 2019. The last in-hospital follow-up dementia or neurodegenerative disease, psychiatric disease, visit is accordingly scheduled for March 2020, and the last prescription of central nervous system–active medication (eg, telephone interview is anticipated for December 2020. https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 3 (page number not for citation purposes) XSL FO RenderX JMIR RESEARCH PROTOCOLS Müller et al Table 1. Summary of the recruitment process and visit plan according to the Standard Protocol Items: Recommendations for Interventional Trials checklist. Event Study period Enrollment Preoperative Intraoperative Postoperative 3-month follow-up 1-year follow-up –7d±7 0 1d 2d 3d 4d etc 90d±14 365d±14 Eligibility screen x Informed consent x Demographic data x Medical history x x x Cognitive testing x x x Quality of life x x Activities of daily living x x Bispectral index monitoring x Vital parameters x Delirium x x x x x x Medication x x x x x x x x x Pain x x x x x x Mobilization x x x x x x x sMRI/re-fMRI Cerebrovascular ultrasound x Inflammatory markers x x x x Neural injury markers x x x x Brain-derived neurotropic factor x polymorphism sMRI/rs-fMRI: structural magnetic resonance imaging/resting-state functional magnetic resonance imaging. is performed with midazolam (0.1 mg/kg) depending on Routine Surgical Procedures individual levels of preoperative excitement. After placement Patients included in this study suffer from degenerative spinal of a peripheral intravenous line (18- or 20-gauge catheter), diseases including cervical disc herniation and stenosis, anesthesia is induced by intravenous injection of sufentanyl thoracical and lumbar stenosis, and degenerative instability. All (0.3-0.6 mg/kg) and propofol (1.5-2.5 mg/kg). Muscular patients are enrolled in elective spinal surgical procedures relaxation is achieved with intravenous injection of without an anticipated dural opening and with a minimum cisatracurium (1.5 mg/kg). Anesthesia is maintained by a scheduled operative time of 60 minutes. All procedures are balanced anesthesia with sevoflurane. The target range chosen performed by standard neurosurgical guidelines. The operation was 0.8 to 1.0 minimum alveolar concentration. Adequate is always performed by an experienced spine surgeon. The anesthetic depth is verified via continuous monitoring of the patients are optimally positioned on the operating table. All bispectral index and real-time electroencephalography patients are operated on in prone position without compression waveforms along the scalp. Estimated insensitive fluid losses of the abdomen by using proper positioning cushions. Each are replaced isovolemic by intravenous infusion of blood patient is covered with a thermal blanket throughout the isotonic electrolyte solution without lactate. A convective air operation. All operations are performed with the help of an warming system is used to keep the body temperature constant operating microscope and a mobile x-ray device. Typical and normothermic. Patients are endotracheally intubated and procedures include anterior cervical discectomy and fusion, mechanically ventilated (pressure-controlled ventilation, FiO posterior cervical decompression and fusion, multisegmental 0.4-0.6) at a rate of 10 to 18 per minute and a positive thoracical and lumbar decompression, and standard and complex end-expiratory pressure of 5 to 10 cm H O. Tidal volume is multilevel spinal fusion. adjusted individually on the basis of the end-tidal carbon dioxide (capnography) monitoring or blood gas analysis and the Routine Anesthetic Procedures measured PaCO . The preoperative period before the induction of anesthesia is in accordance with international standards for elective Continuous recording of vital parameters includes 5-lead interventions. Food is withheld for a minimum of 6 hours and electrocardiography, pulse oximetry (SpO ), and noninvasive water for 2 hours before anesthesia starts. Oral premedication https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 4 (page number not for citation purposes) XSL FO RenderX JMIR RESEARCH PROTOCOLS Müller et al blood pressure measurement. Individual patients receive an preoperative analysis of brain-derived neurotropic factor arterial catheter placed in the radial artery depending on their polymorphism is intended [51]. preoperative risk profile to enable close monitoring of Patient-reported quality of life is assessed at V0 and V3 through hemodynamics and arterial blood gas. Hypotensive situations the 36-item Short Form Health Survey and the Patient Records are managed through fluid challenges and continuous medication and Outcome Management Information System 29-item profile with norepinephrine. Recovery from anesthesia was monitored (PROMIS-29) [52,53]. Patients’ relatives are furthermore in the PACU. handed a proxy version of the PROMIS-29 to evaluate agreements of self- and proxy-reported quality of life regarding Primary Outcome Measure individual domains (PROMIS-29 proxy). Proxy reports are a This study’s primary end points are duration of surgery and valuable tool to assess patient outcome when cognitive incidence of delirium. The hypotheses is that the duration of impairment impedes self-report, yet no study previously surgery would predict POD incidence. POD is expected to evaluated if changes of quality of life following surgery are develop within 72 hours following surgery and screening is similarly rated by patients and their proxies [54]. Additional performed every 8 hours within this period in every patient patient-related outcome measures include preoperative levels using the validated Nursing Delirium Screening Scale and postoperative changes of frailty as assessed by the (Nu-DESC) [7,38]. Morning and day shift screenings are Groningen frailty indicator, neck or low back pain–related performed by trained physicians during workdays, other disability using the Oswestry Disability Index, and anxiety and screenings are done by trained nurses. In this study, positive depression rated by the Hospital Anxiety and Depression Scale screening results require confirmation by DSM-5 criteria applied [55-57]. by a trained physician to further increase diagnostic specificity [6]. Training of all personnel involved in the study was sMRI and rs-fMRI have become methods of choice to conducted by a neurologist with expertise in neurocritical care investigate neuronal correlates of pathology-related cognitive and ample research experience in the field. Sufficient screening decline in delirium [58]. While there is a promising prospect performance was guaranteed at the end of the training. for electroencephalography biomarkers to facilitate decision making in clinical situations and investigate neurophysiological Secondary Outcome Measures changes during an episode of delirium, the spatial resolution of POD severity is evaluated using the Confusion Assessment MRI enables the detailed investigation of brain structures and Method (CAM) scoring system severity scale [39]. network interactions associated with the risk for POD and Subsyndromal delirium includes Nu-DESC ratings greater than mechanisms, possibly preventable, leading to POCD and zero that do not fulfill criteria for delirium. Chart-based POD long-term cognitive impairment [13,59]. screening is used to complement POD screening beyond the A recent retrospective analysis found that hemodynamic stenoses Nu-DESC screening period to estimate the overall in-hospital of the cerebral vasculature may predict the incidence of POD POD incidence [40]. in spine surgery [60]. This study includes a prospective Preoperative and postoperative cognitive abilities are evaluated evaluation of this hypothesis and includes an evaluation of at V0 and V3 using the Consortium to Establish a Registry for arterial pulsatility that was suggested as an amply available Alzheimer’s Disease Plus (CERAD-Plus) test battery and biomarker of cognitive reserve capacity [61]. multiple-choice Mehrfach-Wortschatz-Intelligenztest type B Sample Size Calculation and Statistical Methods (MWT-B) word test [41,42]. The CERAD-Plus includes assessments of orientation, visual naming, phonematic speed, The primary hypothesis of this study is that the duration of semantic fluency, verbal episodic memory (encoding, error surgery is a continuous predictor for POD in a binary logistic control, recall, discriminability), nonverbal episodic memory regression model, which has not been previously tested in a (encoding, recall), visuoconstruction abilities, attention, and prospective study. Five studies performed preliminary executive speed and functions. MWT-B results reflect the evaluations of this relationship treating duration of surgery as general intellectual level. a categorical variable and secondary end point. They reported mean delirium incidences of 14% for durations of surgery less Systemic inflammation, neuroinflammation, and neuronal injury than 180 minutes, 33% for 180 to 300 minutes, and 48% for are assessed with blood samples taken at V0, V1 (immediately surgeries lasting longer than 300 minutes [31-35]. We extend after surgery in the PACU), and the first two days of V2 (ie, on these previous findings by using a binary logistic regression the first and second postoperative day). Systemic inflammation model that provides the intriguing perspective to estimate how is characterized by white blood cell count, C-reactive protein, the odds of becoming delirious change with every minute of interleukins, and tumor necrosis factor alpha among others that surgery. We used a well-established simulation-based approach are considered to contribute to the pathogenesis of delirium to estimate an adequate sample size to test our hypothesis [62]. [15,43-45]. Markers of neuroinflammation and neuronal injury The simulation used a representative population of surgical include glial fibrillary acidic protein, neuron specific enolase, patients based on information from the hospital’s clinical and neurofilament levels [46-48]. Neopterin and information system, which included duration, type, and malondialdehyde levels are established surrogate markers of frequency of spine surgeries performed by the Department of oxidative (neuronal) stress [49,50]. Given the increasingly Neurosurgery in 2016. Samples were randomly drawn from this recognized role of genetic predisposition for neuronal plasticity, population and included in repeated study simulations while iteratively increasing sample sizes. This process continued until https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 5 (page number not for citation purposes) XSL FO RenderX JMIR RESEARCH PROTOCOLS Müller et al 80% of simulations run for a given sample size yielded Discussion significant regression coefficients in a 2-tailed Wald test at a 5% alpha level. This approach yielded that 182 patients need Significance of This Study to be tested so that the power to reject the null hypothesis is This is the first study to prospectively evaluate risk factors for 80%. Anticipating a dropout rate of 10%, we plan to enroll 200 POD and POCD in spine surgery including comprehensive pre- patients in this study. Before testing real data, compliance with and postoperative assessments of cognitive function, markers assumptions of a binary regression analysis needs to be of systemic and neuroinflammation, metabolomics, cerebral confirmed, including normal distribution of the data and vasculature, and structural and functional neuroimaging. There homoscedasticity of residuals. are no other ongoing registered studies with a similar focus [67]. Secondary end points will be analyzed using appropriate The few prospective studies that evaluated risk factors and summary measures depending on the distribution of data. mechanisms of POD in the context of spine surgery were already Categorical data will be presented as absolute and relative discussed [31-35], however neither of the studies assessed frequencies. Continuous data will be presented as mean or associations of POD and POCD, which is required to disentangle median values with 95% confidence intervals. Global tests will pathways that promote either one or both postoperative cognitive be performed using analysis of variance for categorial data; disorders. Available retrospective studies do not resolve this binary and continuous data will be analyzed using generalized issue given diagnostic inaccuracies [36,40]. Yet identification linear models with a suitable link function. Post hoc tests will of possibly common mechanisms underlying POD and POCD be performed using Student t tests for normally distributed data, would be a major step toward defining effective interventional Wilcoxon signed-rank test for paired observations, or strategies early in or even before the postoperative period, Mann-Whitney U test for unpaired observations. Categorical including the adaptation of surgical strategies to individual risk values will be compared using χ2 or McNemar. A P value of profiles [37]. Despite the exciting prospect for the application <.05 is denoted statistically significant. Corrections for multiple of possible findings from this study, there are important comparisons and alpha error accumulation will be performed. methodological and conceptual issues that require close attention Statistical analysis will be performed using SPSS Statistics 25 concerning data acquisition, analysis, and interpretation. (IBM Corp) and MATLAB 2018a (The MathWorks Inc). Diagnostic Challenges to Identify Delirium MRI analysis will include quantification of brain atrophy Accurate diagnosis of POD is a major concern in all studies in through estimations of pre- versus postoperative changes of the field. While diagnosing the patient using DSM-5 criteria tissue volumes. To assess the impact of cortical atrophy, brain applied by a trained specialist (eg, psychiatrist, neurologist, grey matter volume will be included as an additional covariate intensivist) is considered the method of choice, this approach in statistical analyses [63]. Preoperative extent and postoperative is impractical in clinical routine and challenging even in study changes of white matter lesions will be quantified using the environments given the high prevalence of delirium and its age-related white matter changes score [64]. Resting-state fluctuating character that requires multiple assessments per day analyses will be conducted as previously published and [6,68,69]. The use of screening tools, which are time efficient particularly include the default mode network (DMN), and can be applied by trained nurses or physicians, is hence an task-positive network (TPN), salience, and dorsal attention important step toward timely diagnosis and effective treatment network [13,65,66]. Regression analyses will be used to correlate of delirious patients [27,70]. A recent review of established network changes with alterations in domains of cognitive delirium screening tools found psychometric properties to be dysfunction. best for the Nu-DESC and CAM, and both tools are recommended to be used by the European Society of Results Anesthesiology guideline on POD [70,71]. This study uses the Nu-DESC since the CAM was recently shown to be difficult to Recruitment began in April 2018, and the study is currently implement in practice and the Nu-DESC can be performed in enrolling patients. Data collection is expected to be finished by less than 2 minutes and is suitable for screening by trained April 2020. This study does not receive funding from third party nurses [71-73]. Interrater reliability is not a concern using the organizations but is supported through research budgets of Nu-DESC since it was reported to be substantial to excellent involved departments. This approach was chosen to [71]. expeditiously establish a status quo supporting applications for subsequent interventional trials since the burden of POD In order to achieve a balanced trade-off between feasibility and significantly impacts clinical routine. accuracy of diagnostic tools, we chose a combination of methods for the detection of POD regarding our primary end point. First results of primary end point evaluations are expected Screening for POD is performed using the Nu-DESC with a between June and July 2020. If the primary hypothesis turns cutoff of 2 points, which provides a sensitivity and specificity out to be true (ie, duration of surgery is a predictor of POD), of about 80% [71]. Lack of specificity is counterbalanced by funding for an interventional trial will be applied for by the subsequent confirmation of positive screening results by DSM-5 third quarter of 2020 and, if funding is granted, a corresponding criteria [6]. While this strict approach may miss subsyndromal trial to be started in 2021. and mild cases of POD, we argue that it will provide robust results that are not susceptible to confounding variance introduced by cases of marginal delirium. In this context, it is https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 6 (page number not for citation purposes) XSL FO RenderX JMIR RESEARCH PROTOCOLS Müller et al important to note that current diagnostic criteria are based on production mediated through vagal afferents [96,97]. While phenotypes and do not reflect neurobiological endotypes, which opening of the blood barrier induced by anesthesia is an inevitably includes the possibility that none of the available intriguing and prevailing explanation, cerebrospinal fluid levels diagnostic methods will sufficiently discriminate POD endotypes and serum concentration of markers of inflammation are not from variants of physiological brain states or altered brain states correlated, suggesting additional involvement of other of other causes [37,74,75]. Given this uncertainty, we will run mechanisms that remain to be elucidated [47,98]. secondary analyses on subsyndromal cases of POD based on Structural and Functional Imaging Nu-DESC screening and chart-review and evaluate whether Studying the pathophysiology of POD and POCD using MRI associated pathophysiological changes are continuous with provides numerous opportunities to asses brain structure and endotypes of full POD. function. Previous studies investigating sMRI changes found Contribution of Anesthesia to Neuronal Injury that preoperative white matter hyperintensities (WMH) were Anesthesia is considered one of the major contributors to the predictors of POD [99-101]. These studies, however, evaluated development of POD and POCD and therefore requires close patients undergoing cardiac surgery or being treated in ICU, attention in every study in the field [76,77]. It is well established which limits their generalizability. As outlined above, cognitive that the cumulative dose of anesthetics applied during surgery trajectories in cardiac surgery can be expected to differ from and the depth of sedation are modifiable risk factors for other conditions given their unique hemodynamic situation that perioperative brain injury [78]. This study therefore includes possibly affects cerebrovascular autoregulation [7]. continuous bispectral index monitoring for depth of anesthesia, Development of ICU delirium is associated with several risk which allows retrospective adjustment of the statistical model factors that are rarely present in patients following spine surgery for confounding variance [79]. Possible mechanisms underlying such as continuous sedation, ventilation, noisy environment, nocuous effects of anesthetics include disruption of neuronal sleep deprivation, compromised hemodynamics, and repeated oscillations, importantly those associated with amyloid cleavage painful invasive procedures, all of which limit the interpretation [80], induction of tau hyperphosphorylation [81], initiation of of WMH as an independent risk factor [20,102]. In support of apoptotic cell-death pathways via caspase activation [82], and this limitation, Cavallari et al [103] examined WMH as a risk disruption of cholinergic transmission regulating microglia factor in a surgical population that mainly comprised orthopedic activity [83,84]. While these mechanisms were identified using patients not treated in ICU and found no significant association single anesthetics, there is no proven benefit from using one with delirium. A recent review concluded that prospective drug over another (eg, sevoflurane or propofol) on the incidence studies are needed to resolve current uncertainties regarding the of POD [85,86]. In the context of this preliminary evidence, we significance of structural abnormalities, particularly vascular chose to standardize the anesthetic procedure using the same abnormalities, in sMRI [104]. The situation is similar concerning drugs in all patients unless the regimen needs to be changed for the role of preexisting cortical atrophy on the risk of developing medical reasons (eg, due to allergies or contraindications). POD. Some studies reported that generalized or focal (temporal lobe, limbic system) grey matter atrophy increases the risk for Role of Inflammatory Pathways delirium while others did not find this association [105,106]. A Investigating the role of mediators of systemic and recent review interpreted differences in structural imaging to neuroinflammation has become one of the cornerstones of POD be mainly due to the focus on cardiac surgery and ICU patients, and POCD research [37]. Research in animal models brought who are difficult to generalize [58]. Our study provides several about exciting results, including upregulation of several potential benefits regarding mentioned limitations. We focus inflammatory pathways and decreased neuronal plasticity in on a population less confounded by critical illness and also hippocampal regions while cortical regions were generally include pre- and postoperative imaging to overcome variance spared, which is in line with cognitive deficits observed in in the general population that limits cross-sectional comparisons humans [14,15,30,87,88]. This motivated studies in humans to controls. We expect that these benefits and concomitant that assessed the association of markers of inflammation with evaluations of cognitive and inflammatory profiles will help POD and POCD, yet findings were ambiguous. While some elucidate the role of sMRI changes for POD and POCD. studies reported that systemic levels of interleukins, particularly There are no studies that performed fMRI before surgery to interleukin-6, and C-reactive protein were predictors of brain identify brain network properties that predispose for the injury, delirium, and subsequent cognitive impairment [44,89], development of POD and POCD [58]. This is surprising given others did not find similar associations [44,90,91]. Possible the broad acceptance of models that consider cognitive resilience reasons for this discrepancy are that some studies included cases a relevant protective mechanism and that fMRI is the method of intensive care unit (ICU) delirium, concentrations of markers of choice to investigate neurobiological substrates underlying of inflammation vary substantially between types of surgery resilience [107-109]. This study aims to fill this gap by [30,92], and neuroinflammatory effects seem to depend on the correlating functional data with perioperative cognitive profiles. extent of preexisting neurodegeneration, which was rarely The combination of pre- and postoperative rs-fMRI will controlled for [14,93]. Another unresolved issue is how systemic furthermore help to disentangle brain networks that are affected and neuroinflammation interact to cause brain injury [84]. by the surgical procedure and lead to sequel cognitive deficits Several possible mechanisms were studied in animal models [74]. There are currently only a few studies that provide and include passive diffusion through leaky blood brain barrier cross-sectional data and allow for a hypothesis of involved [94], carrier-mediated transport [95], and de novo central networks including a loss of anticorrelation between the TPN https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 7 (page number not for citation purposes) XSL FO RenderX JMIR RESEARCH PROTOCOLS Müller et al and DMN, decreased DMN functional connectivity, reduced suggest studies in the field should include investigations of both functional network integration and efficiency, and decreased POD and POCD to elucidate their relationship and disentangle functional connectivity between the posterior cingulate and shared mechanisms [37,70]. Cognitive testing should comprise superior frontal gyrus [13,110-112]. pre- and postoperative assessments to account for baseline differences, examine a broad spectrum of cognitive domains, Investigation of Perioperative Cognitive Function and account for ceiling effects in good performers and floor The association between POD and POCD is an ongoing matter effects in bad performers [114,115]. This study uses the of debate [22]. While POD may accelerate the trajectory of MWT-B, which allows for adjustment for baseline intelligence. cognitive decline, it is also possible that POD is a marker of The CERAD-Plus test battery enables repeated measurements rapid cognitive decline but does not accelerate it or that both of cognitive abilities in multiple domains, and normative age-, conditions are unrelated [113]. Recent consensus statements education-, and gender-specific databases are available [41]. Acknowledgments We acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 393148499) and the Open Access Publication Fund of the University of Greifswald. Authors' Contributions JM, SN, AV, SR, TU, AF, JUM, and RF designed the study and wrote the initial protocol. BvS, ER, SS, HK, KH, and HWSS provided advice and input into the protocol. All authors read and approved the final manuscript. Conflicts of Interest None declared. Multimedia Appendix 1 Standard Protocol Items: Recommendations for Interventional Trials checklist. [PDF File (Adobe PDF File), 188 KB-Multimedia Appendix 1] References 1. US Census Bureau. 2016. An aging world—2015: international population reports URL: https://www.census.gov/content/ dam/Census/library/publications/2016/demo/p95-16-1.pdf [accessed 2019-12-11] 2. Fong TG, Tulebaev SR, Inouye SK. Delirium in elderly adults: diagnosis, prevention and treatment. 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[doi: 10.1097/ALN.0000000000002253] [Medline: 29771710] Abbreviations CAM: Confusion Assessment Method CERAD-Plus: Consortium to Establish a Registry for Alzheimer’s Disease Plus CONFESS: Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients DMN: default mode network DSM-5: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ICU: intensive care unit MWT-B: Mehrfach-Wortschatz-Intelligenztest type B Nu-DESC: Nursing Delirium Screening Scale PACU: postanesthesia care unit POCD: postoperative cognitive dysfunction POD: postoperative delirium PROMIS-29: Patient Records and Outcome Management Information System rs-fMRI: resting-state functional magnetic resonance imaging sMRI: structural magnetic resonance imaging SPIRIT: Standard Protocol Items: Recommendations for Interventional Trials TPN: task-positive network WMH: white matter hyperintensity Edited by G Eysenbach; submitted 14.07.19; peer-reviewed by A Mengel, K Chen; comments to author 21.08.19; revised version received 12.10.19; accepted 29.10.19; published 13.02.20 Please cite as: Müller J, Nowak S, Vogelgesang A, von Sarnowski B, Rathmann E, Schmidt S, Rehberg S, Usichenko T, Kertscho H, Hahnenkamp K, Flöel A, Schroeder HWS, Müller JU, Fleischmann R Evaluating Mechanisms of Postoperative Delirium and Cognitive Dysfunction Following Elective Spine Surgery in Elderly Patients (CONFESS): Protocol for a Prospective Observational Trial JMIR Res Protoc 2020;9(2):e15488 URL: https://www.researchprotocols.org/2020/2/e15488 doi: 10.2196/15488 PMID: 32053113 ©Jonas Müller, Stephan Nowak, Antje Vogelgesang, Bettina von Sarnowski, Eiko Rathmann, Sein Schmidt, Sebastian Rehberg, Taras Usichenko, Harry Kertscho, Klaus Hahnenkamp, Agnes Flöel, Henry WS Schroeder, Jan-Uwe Müller, Robert Fleischmann. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 13.02.2020. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Research Protocols, is properly cited. The complete bibliographic information, a link to the original publication on http://www.researchprotocols.org, as well as this copyright and license information must be included. https://www.researchprotocols.org/2020/2/e15488 JMIR Res Protoc 2020 | vol. 9 | iss. 2 | e15488 | p. 14 (page number not for citation purposes) XSL FO RenderX
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JMIR Research Protocols – JMIR Publications
Published: Feb 13, 2020
Keywords: postoperative delirium; postoperative cognitive dysfunction; spine surgery; neuroinflammation; magnetic resonance imaging; resting-state connectivity; quality of life