Positive suggestions via headphones during general anesthesia for the improvement of vegetative & cognitive postoperative course parameters in elderly orthopedic patients – A randomized controlled double-blinded trial (POSSUDEL)

Positive suggestions via headphones during general anesthesia for the improvement of vegetative & cognitive postoperative course parameters in elderly orthopedic patients – A randomized controlled double-blinded trial (POSSUDEL) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Positive suggestions via headphones during general anesthesia for the improvement of vegetative & cognitive postoperative course parameters in elderly orthopedic patients – A randomized controlled double-blinded trial (POSSUDEL) Lena Heiß, Saskia Neitzert, Ernil Hansen, Hartmuth Nowak, Renate Neitzert, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6058214/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Oct, 2025 Read the published version in Trials → Version 1 posted 6 You are reading this latest preprint version Abstract Background Postoperative delirium and cognitive deficits are significant surgical complications, especially in elderly patients. The reported incidence of postoperative delirium is variable but notably high in cardiothoracic, orthopedic, and general surgery. The etiology of postoperative delirium is known to be multifactorial, with prevention being the most effective strategy currently available. This study aims to explore the potential benefits of positive suggestions delivered via headphones during general anesthesia on the incidence of postoperative delirium and improving postoperative pain, nausea, and cognitive outcomes in elderly orthopedic patients. Methods This randomized controlled double-blinded trial will involve patients aged 60 and above undergoing elective hip or knee surgery under general anesthesia. Participants will be randomized into three groups: a control group receiving no auditory intervention and two intervention groups receiving positive therapeutic suggestions via headphones from either a male or female speaker. The primary outcome is the incidence of postoperative delirium within five days after surgery, that will be assessed by using the 4AT and 3DCAM. Secondary outcomes include pain intensity, medication consumption, postoperative nausea and vomiting, and levels of specific biomarkers. Data will be collected before, during and after surgery as well as three months after surgery. In addition, intraoperative pain is being measured objectively by using the nociception level index (NOL). Discussion This study hypothesizes that positive auditory suggestions can reduce postoperative delirium incidence, lower pain intensity as well as pain medication use, and decrease postoperative nausea, vomiting incidence and severity. Additionally, gender differences in response to male versus female voices will be explored. The findings could offer a non-invasive, cost-effective method to enhance postoperative recovery in elderly patients, potentially leading to changes in perioperative care practices. Trial registration DRKS00030589 prospectively registered 25.10.2022 anesthesia processed EEG elderly headphones nociception level index pain PONV positive suggestions delirium total intravenous anesthesia Administrative information Title {1} Positive suggestions via headphones during general anesthesia for the improvement of vegetative & cognitive postoperative course parameters in elderly orthopedic patients – A randomized controlled double-blinded trial (POSSUDEL) Trial registration {2a and 2b} DRKS00030589 prospectively registered 25.10.2022 Positive Suggestionen mittels Tonträger während Allgemeinanästhesie zur Reduktion von Delir und der Verbesserung vegetativer und kognitiver Verlaufsparameter: Eine multizentrische, doppelblinde randomisierte Interventionsstudie (POSSUDEL) Protocol version {3} 29.08.2022 V1.5 Funding {4} This study is part of the LMU hospital's own funding program Author details {5a} Lena Heiß*, Saskia Neitzert*, Renate Neitzert, Ernil Hansen, Hartmuth Nowak, Thomas Saller * joint first authorship Name and contact information for the trial sponsor {5b} n/a This study is part of the LMU hospital's own funding program Role of sponsor {5c} n/a This study is part of the LMU hospital's own funding program Introduction Background and rationale {6a} Postoperative syndromes with cognitive deficits Postoperative delirium (POD) is an acute neuropsychiatric syndrome. It is characterized by transient disturbances in attention, awareness, and cognition following surgery [1]. It typically manifests within the first few days after an operation and is marked by fluctuating symptoms, including confusion, disorientation, an altered level of consciousness, and impaired memory. POD is more common in elderly patients and those having major surgery. The incidence of POD varies widely and depends on the age of the patient cohort studied and the type of surgical procedure [2]. The highest incidences are found after cardiothoracic procedures, orthopedic and general surgery [3]. While the exact etiology is best described as multifactorial and not fully understood to date [4], it is known to be associated with increased morbidity, prolonged hospital stay, an elevated risk of long-term cognitive decline as well as increased mortality [5]. For example, Moskowitz et al. demonstrated that for elective surgery, in patients 50 or more years of age, 5-year mortality was increased 7.35-fold after the occurrence of POD (95% CI: 1.49 - 36.18) [6]. As the development of POD or long-term postoperative cognitive deficits (POCD) represents the most frequent postoperative complication, mainly affecting elderly patients [7], a further increase of this complication is expected in the future due to demographic change [6]. As prevention has proven most effectively [3], patient’s personal risk factors and possible predictors must be identified and measures to reduce the probability of the occurrence of POD/POCD or neurocognitive disorder (NCD) [8] must be taken. Importance of therapeutic communication Communication plays a special role in the entire field of healthcare. It can accompany and support medical therapies. Appropriate use of language and professional conversation management allow us to discover patients' resources and use them for the process of healing. A randomized, double-blind, multicenter trial showed that audio cues can reduce pain and nausea, consequently reducing the use of analgesics and antiemetics in at-risk groups. The time to reorientation was also shown to be diminished [9]. Due to the age structure of the study, delirium incidence was inherently low, so no conclusions could be drawn regarding the antidelirogenic effect of positive suggestions. Objectified intraoperative pain measurement Measuring pain intensity is usually based on self-reporting by patients. With this method the subjective level of pain can be determined before and after surgery. Since patients cannot be questioned during general anesthesia, it was not possible to measure pain level intraoperatively in the past. Lately, an AI-based algorithm has been developed to generate a Nociception Level Index (NoL) during surgery [10]. The algorithm considers variants of the following four parameters, which can be measured via a single finger electrode: Skin conductance, heart rate variability, accelerometry, and skin temperature. Studies have already shown that the NoL index is suitable for predicting postoperative pain [11]. Thus, this technology seems to be suitable for a more precise analysis of the effect of therapeutic interventions especially on perioperative pain perception. Gender differences: Effect of different voices Gender acts as an independent risk factor for several diseases and disorders. For example, female gender has already been established as a specific risk factor for the occurrence of postoperative nausea and vomiting [12]. The opposite seems to be true for the occurrence of delirium after surgical interventions: In this context, men seem to be more likely to develop POD [13]. With the upcoming awareness for gender sensitive medicine, research has also increasingly focused on the impact of sex differences on the efficacy of therapeutic interventions. For instance, there appear to be discrepancies in the efficacy of hypnosis therapy for smoking cessation when administered to different sexes (Green et al., 2008). However, robust data on gender differences in the effects of suggestive procedures is missing. In particular, no research has been done on gender differences in the effects of hypnotic suggestion when delivered by different voices. Biomarkers to predict cognitive outcome after surgery NCD, particularly POD and POCD represent significant complications following surgical procedures. Given that current therapeutic approaches primarily focus on general factors such as e.g. fluid and electrolyte balance [14], there is a growing emphasis on early diagnosis and prevention of NCD [5]. The identification of high-risk patients in advance is of the utmost importance. For this purpose, biomarkers have been investigated [15]; however, their suitability for routine use is limited due to the invasive nature of the puncture. An alternative approach is to utilize markers in the blood, which can be categorized into three groups: global non-specific markers, established specific markers of neurocognitive functions and markers with less evidence to date. While so far, no single marker on its own has been sufficient for accurate prediction, a targeted combination of different markers could be an effective method for predicting cognitive complications with sufficient sensitivity and specificity [16]. This trial will examine whether suggestions can reduce the probability of occurrence of delirium. Furthermore, it will be examined to what extent intraoperative application of different suggestive statements can reduce the postoperative perceived nausea as well as vomiting and pain, measured by the consumption of analgesics at a defined pain level. Moreover, it will be tested whether patients return to spontaneous breathing more rapidly, regain consciousness faster, are oriented and have less anxiety by listening to a sound recording with suggestions compared to a control group. Potential risk markers for stress, delirium and inflammation are to be investigated by measuring several parameters in the patients' blood. In addition to the standard values determined during orthopedic surgery, cortisol, cortisol derivatives, NT-proCNP, NfL, S-100, pTau and IL-6 will be determined. Beside the above mentioned targets, it will be investigated whether the choice of voice (male vs. female) has an influence on the effects described above. Objectives {7} In the current study we aim to address the following hypotheses: Primary hypothesis: Delirium incidence is lower in the intervention group than in the control group Secondary hypotheses: Pain intensity is lower in the intervention group than in the control group Pain medication consumption p.p. is lower in the intervention group than in the control group Postoperative nausea and vomiting (PONV) incidence is lower in the intervention group than in the control group PONV is less frequent in the intervention group than in the control group The above-mentioned effects differ depending on whether the subjects hear a speaker's voice according to their own gender or not The level of biomarkers indicates the likelihood of occurrence of postoperative delirium Trial design {8} A parallel group design will be applied. The study physician, who is not directly involved in data collection, will randomly assign patients to experimental conditions using software. Every person directly involved will be blinded to the allocation, as will the patients. Included patients will be randomized into 3 groups. In the sense of a balanced design, equal numbers of patients will be assigned to the intervention or control group. The experimental group will be further subdivided. During general anesthesia, patients in both intervention groups will be presented with positive therapeutic content via headphones either from a female or male speaker. Patients in the control group also will receive headphones for general anesthesia, but the track that will be played does not contain any audio content. Otherwise, the treatment will not differ from the verum group. Methods: Participants, interventions and outcomes Study setting {9} All data will be collected in Germany. Leading center of the trial is the hospital of the Munich Ludwig-Maximilians-University (LMU). Further data is planned to be collected in the hospital of the Ruhr University Bochum as well as in the Heidelberg university hospital. Eligibility criteria {10} Patients meeting following criteria will be included: Elective hip or knee surgery (e.g. hip or knee TEP) with a planned duration of 1-3 hours General anesthesia using total intravenous anesthesia (TIVA) Age from 60 years and above German as native language or similar level Sufficient hearing ability (no hearing aid at room volume necessary) Ability to give consent The Following exclusion criteria apply: Patients with hearing loss Diagnosis of dementia or MOCA <17 Preoperative delirium on hospital admission Language barriers Patient refusal If consent for blood collection: hemoglobin < 10 g/dL Who will take informed consent? {26a} Prior to surgery, patients who will undergo knee or hip surgery will be seen by a member of the study team who will ask them for their informed consent. If consent will be given, a short assessment will be conducted to evaluate inclusion and exclusion criteria. Additional consent provisions for collection and use of participant data and biological specimens {26b} n/a (patient data will be specifically used for this study) Interventions Explanation for the choice of comparators {6b} Delirium is a complication that primarily affects patients of older age. Therefore, patients will be recruited who already reached the age of 60 for all three subgroups. The control group will also receive headphones but without the suggestion audio. Intervention description {11a} The study will randomize patients into three groups. The control group will receive just headphones without being exposed to audio content while the other two groups will listen to therapeutic audio content. There will be no further difference in these groups regarding care and measures. Criteria for discontinuing or modifying allocated interventions {11b} Consent to participate in the study can be withdrawn at any time, without giving reasons or obtaining any disadvantages for further medical care. In case of withdrawal from the study, personal data already obtained will be destroyed. Patients for whom there will be a short-term change in the anaesthetic procedure, e.g. to anaesthesia with sevoflurane, will be considered separately due to the increased risk of PONV. Strategies to improve adherence to interventions {11c} n/a (as all patients will be monitored by a study team member during their surgery, no specific strategy to improve adherence to protocol is necessary. Relevant concomitant care permitted or prohibited during the trial {11d} Participation in other delirium-related intervention studies. Provisions for post-trial care {30} n/a (no special post-trial care needed) Outcomes {12} Primary outcome will refer to delirium incidence. Cognitive testing in form of the 4AT [17, 18], as well as the 3DCAM [19] will be performed pre- and postoperatively on all study participants to determine whether the incidence of delirium is lower in the intervention group than in the control group. As secondary outcomes postoperative nausea will be assessed with the Wengritzky PONV score [20], pain will be assessed using the Numerical Rating Scale (NRS) and medication consumption will be documented by analysing the patient’s files. Furthermore, the effect of different speaker voices as well as the possible correlation regarding the occurrence of delirium with the sampled biomarkers in the blood will be investigated. Participant timeline {13} The study duration for all included participants will be defined by the time of surgery until the day of discharge. A follow-up survey of the cognitive function level, including a new blood sample, is planned after three months (Follow Up). Table 1 shows a detailed overview of the course of the study. Table 1 – Participant timeline. STUDY PERIOD Date Prior to surgery Day of surgery Day 1 Day 2 Day 3 Day 4 Day 5 +3 months Timepoint Screening Baseline Pre-OP OP PostOP recovery room PostOP ward Follow-Up Visit-Code SCR V0 V1 V2 V3a V3b V3c V3d V4 V5 V6 V7 V8 V9 ENROLMENT Eligibility criteria ● Informed consent ● Feedback request ● ASSESSMENTS MOCA ● TMT ● Frailty Screening ● PONV risk-score ● Charlson Comorbidity Index ● Permanent medication ● QUESTIONNAIRES iADL ● ● SF36 ● ● GDS ● ● BDI ● Complications ● ALLOCATION Randomized allocation ● SAMPLES Blood sample ● Saliva sample ● ● INTERVENTION Controll group ● SGS intervention group ● DGS intervention group ● OUTCOME VARIABLES 4AT Delirium ● ● ● ● ● ● ● ● ● ● 3DCAM Delirium ● ● ● ● ● ● Pain score (NAS) ● ● ● ● ● ● ● ● ● ● ● Pain medication consumption ● ● ● ● ● ● ● ● Comfort scale (NCS) ● ● ● ● ● ● ● ● ● ● ● PONV wengritzky ● ● ● ● ● ● Sedline ● NOL ● Sample size {14} Based on the primary endpoint analysis, the sample size was calculated as follows: At the university hospital, LMU Munich, a delirium incidence of approx. 25% can be assumed for electively orthopedic surgery. By means of therapeutic suggestion may be reduced by at least 50%. The calculation in G*Power [21] using the z-test "Difference between two independent proportions" results in a sample size of 110 subjects per group for a design in which the intervention group and control group are of equal size, with a required power of at least .8 and a significance level of 5%. This results in a total of 220 subjects. Based on the results of the study by Nowak et al. 2020 [9], we also calculated the sample size needed to detect effects of the intervention on pain expression, which are of great interest in the secondary endpoint analysis: For effects on opioid use, an effect size of d = .36 is assumed. For a required power of .8 at a level of significance at 5%, a group size of at least 101 subjects is needed. For effects on pain intensity, an effect size of .325 can be calculated using G*Power based on the mean values and standard deviations given in the original work. When power is set at 0.8 and significance level at 5% the resulting sample size amounts to a total of 248 subjects. In addition to the effect of the intervention on delirium incidence, the effect on pain severity is also of great interest as a (secondary) endpoint. Hence, the larger calculated sample number (n = 248) is chosen as a further basis for calculation to be able to achieve sufficiently good power for the secondary endpoints as well. To ensure that the calculated minimum power will be achieved there is a need to take possible drop-outs into account. Therefore at least 10% more subjects will be necessary, which results in a total of 273 participants. In consideration of the balanced design, the final target equals in a rounded up total number of 280 patients. Recruitment {15} At the LMU Munich university hospital, participants for the study will be recruited in the anesthesia outpatient clinic. If an eligible patient cannot be included in the anesthesia outpatient clinic, we will attempt to reach them through the orthopedics outpatient clinic. Assignment of interventions: allocation Sequence generation {16a} Included patients will be divided as follows: 1:1 (intervention vs. control group) and within the intervention group 1:1 to a speaker with the same gender (sGS) vs. a speaker with a different gender (dGS). Thus, the only factor influencing assignment is patient gender. Concealment mechanism {16b} Numbered audio players will be used to maintain blinding of the trained junior researchers conducting the intervention and data collection. After the randomization process, the study's PI will notify the relevant parties regarding the designated number of the audio player to be utilized. Those administering the intervention as well as the anesthetists in charge will not have permission to listen to the audio tracks on the different audio players. Implementation {16c} Trained junior researchers will enroll participants, while the allocation sequence will be automatically generated by RedCap. In detail, randomization will be conducted using block randomization, assigning subjects to one of the study conditions listed above. The PI of the study will perform randomization in RedCap. Assignment of interventions: Blinding Who will be blinded {17a} The trained junior researchers, the responsible clinical staff, and the patients themselves will be blinded to avoid any potential influence, whether conscious or unconscious. Procedure for unblinding if needed {17b} n/a (Since our intervention will be supplementary and will not modify the process or medications, identification of blinding is unnecessary.) Data collection and management Plans for assessment and collection of outcomes {18a} Baseline: Patients will be pseudonymized after inclusion. Required data items encompass Montral Cognitive Assessment (MOCA) [22], Frailty-test [23], PONV risk score [20], and continuous medication including pain medication. Additionally, patients will complete the Quality-of-Life questionnaire (SF-36) [24], Geriatric Depression Scale (GDS) [25], and instrumental Activities of Daily Living (iADL) [26]. Before surgery: Directly prior to their scheduled surgery patients will be visited for assessment. The patients' cognitive state will be assessed using the 4AT. Additionally, they will be asked to rate their current level of pain using the NRS, as well as provide a saliva sample for cortisol analysis. Blood samples for cortisol levels and biomarkers will be obtained within the placement of a peripheral venous access, without the need for a separate puncture. Throughout surgery: The following data will be recorded routinely. During anaesthesia depth of anaesthesia will be monitored intraoperative processed EEG, employing devices such as Sedline® [27]. Other crucial parameters are analgesic use, NOL-index [10] evaluated pain levels, overall operating time, and recovery duration, measured from the end of sedation to the time of extubating. After surgery: After extubating objective data will be collected in the recovery room every 15 minutes for a total duration of one hour. Postoperative assessments will include the 4AT score for delirium, pain score measured on NRS, Numerical Comfort Scale (NCS) for assessing comfort, and postoperative nausea rated from 0 to 3. After the patient will have been in the recovery room for one hour, additional assessments will be conducted, including an extended delirium screening (3DCAM), PONV Score antiemetic consumption, and nurse-controlled analgesia consumption for NRS 3. In the regular ward, data will be recorded for the first five days post-surgery. Pain scores (measured using the NRS), analgesic intake via nurse-controlled analgesia (NCA; applicable for NRS of 3 or higher), PONV scores (as per Wengritzky's classification system), antiemetic usage, comfort ratings (using the NCS) and delirium assessments (using both the 4AT score and 3DCAM) will be documented. Follow-up assessments will be conducted three months after the surgery by sending patients a set of questionnaires (iADL, GDS, BDI, SF36) via mail. They will also be asked to provide their pain and comfort levels (NAS and NCS, respectively) and to submit another saliva sample. Any adverse effects that may have occurred will also be investigated and noted. If any cause for concern arises about returned questionnaires, the participants will be contacted and offered further assistance. All study participants may contact us at any time should they have any questions or concerns. Plans to promote participant retention and complete follow-up {18b} To enhance participant retention, trained junior investigators will supervise participants during their clinical stay. Study results as well as personal blood work results will be provided to patients at the study's conclusion if they have agreed to receive them. A 3-month follow-up will yield additional information on participants' well-being, and, when needed, further supportive discussions will be arranged. If participants choose to withdraw from the study, all data collected from them will be eliminated and excluded from the analysis. Withdrawal will be permitted at any point. Data management {19} The RedCap online tool (Vanderbilt University, Texas, USA) will serve as a shared database for all participating centers hosted by the Ruhr University Bochum. Patient data will exclusively be entered using pseudonyms, preventing any conclusions about the individuals without further information. During the study, data will be recorded on paper protocols or directly via RedCap. RedCap supports data quality assurance by enforcing specific data formatting and performing range checks during data entry. After completing data collection, we will conduct plausibility checks. Confidentiality {27} Patients’ confidential information will be protected under medical confidentiality and the German Federal Data Protection Act (BDSG). Pseudonymized proband data may be shared, but original documents will not be accessible to third parties. Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33} On the day of surgery, a blood sample will be drawn to quantify relevant values and biomarkers. After centrifugation and pipetting of the plasma, the cryopreserved biomarkers will be analyzed to assess potential associations between the biomarkers and delirium incidence. In addition, a saliva sample will be taken to analyze preoperative cortisol as a marker for experienced stress. Statistical methods Statistical methods for primary and secondary outcomes {20a} To ensure normal distribution, the Kolmogorov-Smirnov test will be conducted prior to any other analyzation. Comparison of the intervention group with the control group will be evaluated using the following analytical methods (Statistical significance is considered at a p-value < 0.05): A Chi2-Test will be used to compare delirium as well as PONV-incidence. For the comparison of non-parametric variables Mann-Whitney U tests will be conducted. Parametric variables will be compared using Student t-Test. Logistic regression will be utilized to analyse the accuracy of prediction for blood biomarkers. Interim analyses {21b} n/a (An interim evaluation is not intended) Methods for additional analyses (e.g. subgroup analyses) {20b} Gender effects will be explored by comparing the interventions group who listened to sGS with the intervention group who listened to dGS using the above-mentioned tests. Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c} In general, per-protocol analysis will be intended. To address the fact that complete protocol adherence is not always feasible in everyday clinical practice, all relevant cases will be included in the calculations as part of an intention-to-treat analysis. Plans to give access to the full protocol, participant level-data and statistical code {31c} n/a Oversight and monitoring Composition of the coordinating center and trial steering committee {5d} n/a Composition of the data monitoring committee, its role and reporting structure {21a} The study design, inclusion criteria, questionnaire selection, the points at which questioning takes place, together with supplementary monitoring and data-gathering monitors and the documentation tool RedCap were primarily prepared, selected and refined by the main center. In consultation with the other centers, details were negotiated through an iterative process to ensure a unified basis for conducting the study. As the study is self-funded and there are no sponsors involved, there are no competing interests or conflicts of interest. Trained junior researchers of the LMU Munich [24] hospital will monitor the process of data collection and report regularly to their head of trial. Adverse event reporting and harms {22} Adverse events, such as an increase in pain intensity or increased consumption of antiemetics, as well as delayed awakening after prolonged general anesthesia, will be closely monitored continuously and treated immediately. Frequency and plans for auditing trial conduct {23} Regular meetings will be held to review progress and suggest improvements and/or changes. As this will be a multicenter study, consultation and exchange with the other clinics will also be relevant. Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25} No major changes are planned currently. If anything were to change, the ethics committee would be informed immediately so that the vote could be revised. As the trial is self-funded, there is no need to inform sponsors. Dissemination plans {31a} The results will be published in a peer-reviewed medical journal, and the study participants will receive their personal laboratory results and the published article upon request and consent. The participating staff will be informed of the results of the study as part of an educational presentation. Discussion The objective of our study is to examine the impact of positive suggestions on delirium in elderly patients, while also investigating the influence on post-operative pain and nausea. Postoperative delirium (POD) remains a prevalent complication among elderly surgical patients, associated with increased morbidity and mortality [ 28 ]. The management of delirious patients poses substantial challenges for healthcare providers and families, often leading to significant financial burdens due to prolonged care requirements and potential long-term consequences [ 29 ]. Given the aging population and the rising number of surgeries performed on older adults, there is a critical need for effective preventive strategies and methods for early detection of delirium [ 6 ]. Such approaches have the potential to significantly improve clinical outcomes for this vulnerable population. Evidence suggests that targeted interventions, such as positive suggestions, have a beneficial effect on postoperative symptoms such as pain perception, required pain medication and the incidence of postoperative nausea and vomiting (PONV) [ 9 , 30 ]. It has also been shown that medical hypnosis has a favorable impact on individuals experiencing anxiety and stress [ 31 ]. Building upon these findings, this study aims to further investigate the impact of positive suggestions on delirium risk, postoperative pain, and PONV among patients over 60 years undergoing orthopedic procedures. Notably, this investigation incorporates an analysis of gender-specific differences and examines the influence of suggestion delivery by voices of different genders [ 32 ]. A major strength of this study design lies in its well-thought methodology, which was achieved through randomization, double-blinding and a multicenter approach. By specifically avoiding music in the control group and using spoken suggestions without background music in the intervention group, potential effects can be more directly attributed to the use of positive suggestions rather than being influenced by background music effects [ 33 ]. Additionally, to the best of our knowledge, this study is among the first within the field of delirium research to employ objective intraoperative pain assessment via the NOL index [ 10 , 11 ]. This approach provides a more accurate and reliable measure of intraoperative pain, reducing the reliance on subjective patient self-reporting. There are, however, several limitations that warrant consideration. Regular evaluation and delirium screenings throughout the study may themselves influence the neurocognitive state of patients. The necessary personal interactions and cognitive tasks involved in delirium assessments could be seen as a form of cognitive training, which is known to improve overall cognitive outcomes and may consequently affect delirium rates [ 34 , 35 ]. Moreover, due to resource limitations, cultural and linguistic differences were not addressed, although they could offer valuable insights for future research. In conclusion, the POSSUDEL study provides valuable insights into the potential of positive suggestions as a simple yet effective intervention to aid in the prevention of postoperative delirium. The findings may suggest clinically relevant strategies for enhancing treatment outcomes and general well-being in older patients, thus offering a practical tool for improving early detection and prophylaxis of POD in everyday clinical practice. Trial status Enrollment began in November 2022. The study is still enrolling patients and is expected to complete data collection until May 2025. Abbreviations NRS Numerical Rating Scale PONV Postoperative Nausea and Vomiting SF36 Quality of Life Questionnaire NCS Numerical Comfort Scale 4AT The 4 A’s Test:A rapid clinical test for Delirium 3DCAM 3-Minute Diagnostic Interview for CAM-defined Delirium:A rapid clinical test for Delirium NOL Nociception Level (objectively quantify a patient’s physiological pain response during operation for example) Declarations Acknowledgements We cordially thank the patients participating in our study for their support. We also appreciate the daily support of the nurses and anesthesiologists in our anesthesia bay, which helped to prepare the measurements, assisted with blood drawings and wholeheartedly apply positive words and vibes to the patients that need them. This devotion to perceive patients’ needs is key to perform communication based on positive suggestions and enable them to act on patients frightened or in pain. Authors’ contributions {31b} LH*: Conceived the study, led the proposal and protocol development. She as well conducted the statistical and methodological planning. SN*: Conceived the study, led the proposal and protocol development. She was also responsible for the practical implementation of the interventions and the collection of data. TS: Developed the idea for the study, conceived the study, led the proposal and protocol development and supervised all processes. *joint first authorship Funding {4} This trial was funded in parts by of the LMU hospital's Medical Clinician Scientist (MCSP) Advanved funding program. Availability of data and materials {29} Only those directly involved in conducting the study will have access to the original final data of the trial. The data can be made available to the scientific community in anonymized form on reasonable request. Ethics approval and consent to participate {24} The trial is registered under the number DRKS00030589 and has been approved by the Ethics Committee of the LMU Munich (Vote 22-0631, 12/09/2022). Written, informed consent to participate will be obtained from all participants. Consent for publication {32} n/a (No personal information about participating patients will be published) Competing interests {28} The authors declare that they have no competing interests. Authors ’ information (optional) LH*: Before starting medical school, she graduated with a degree in psychology. SN*: Before starting medical school, she graduated with a degree in nursing and still works at an ER. TS: As a senior consultant, specialized in geriatric anesthesia his focus lies in research for delirium and its prevention. Currently, he is principal investigator in a trial of delirium prevention and management at the LMU university hospital and is head of orthogeriatric anesthesia at the university hospital, LMU Munich. * joint first authorship References Rudolph JL, Marcantonio ER. Postoperative Delirium: Acute Change with Long-Term Implications. Anesthesia & Analgesia. 2011;112(5):1202-11. Gallinat J, Möller HJ, Moser RL, Hegerl U. Das postoperative Delir Risikofaktoren, Prophylaxe und Therapie. Der Anaesthesist. 1999;48(8):507-18. Roos P, Goettel N. Epidemiologie des Delirs: Teil 2 – Das postoperative Delir. 2020;17:38-43. Maldonado JR. Neuropathogenesis of Delirium: Review of Current Etiologic Theories and Common Pathways. The American Journal of Geriatric Psychiatry. 2013;21(12):1190-222. Aldecoa C, Bettelli G, Bilotta F, Sanders RD, Audisio R, Borozdina A, et al. European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium. European Journal of Anaesthesiology. 2017;34(4):192-214. Moskowitz EE, Overbey DM, Jones TS, Jones EL, Arcomano TR, Moore JT, et al. Post-operative delirium is associated with increased 5-year mortality. American Journal of Surgery. 2017;214(6):1036-8. Serafim RB, Dutra MF, Saddy F, Tura B, de Castro JE, Villarinho LC, et al. Delirium in postoperative nonventilated intensive care patients: risk factors and outcomes. Ann Intensive Care. 2012;2(1):51. Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, et al. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. British Journal of Anaesthesia. 2018;121(5):1005-12. Nowak H, Zech N, Asmussen S, Rahmel T, Tryba M, Oprea G, et al. Effect of therapeutic suggestions during general anaesthesia on postoperative pain and opioid use: multicentre randomised controlled trial. BMJ. 2020;371. Ben-Israel N, Kliger M, Zuckerman G, Katz Y, Edry R. Monitoring the nociception level: a multi-parameter approach. Journal of Clinical Monitoring and Computing. 2013;27(6):659-68. Ledowski T, Schlueter P, Hall N. Nociception level index: do intra-operative values allow the prediction of acute postoperative pain? Journal of Clinical Monitoring and Computing. 2021. Rüsch D, Eberhart LHJ, Wallenborn J, Kranke P. Übelkeit und Erbrechen nach Operationen in Allgemeinanästhesie. Deutsches Ärzteblatt International. 2010;107(42):733-41. Wang H, Guo X, Zhu X, Li Y, Jia Y, Zhang Z, et al. Gender Differences and Postoperative Delirium in Adult Patients Undergoing Cardiac Valve Surgery. Frontiers in Cardiovascular Medicine. 2021;8. Radtke FM, Franck M, MacGuill M, Seeling M, Lütz A, Westhoff S, et al. Duration of fluid fasting and choice of analgesic are modifiable factors for early postoperative delirium. European Journal of Anaesthesiology | EJA. 2010;27(5):411-6. Hall RJ, Watne LO, Cunningham E, Zetterberg H, Shenkin SD, Wyller TB, et al. CSF biomarkers in delirium: a systematic review. International Journal of Geriatric Psychiatry. 2018;33(11):1479-500. Schaefer ST, Koenigsperger S, Olotu C, Saller T. Biomarkers and postoperative cognitive function: could it be that easy? Current Opinion in Anesthesiology. 2019;32(1):92-100. MacLullich AMJ, Shenkin SD, Goodacre S, Godfrey M, Hanley J, Stíobhairt A, et al. The 4 ‘A’s test for detecting delirium in acute medical patients: a diagnostic accuracy study. 2019;23:40. AT - rapid clinical test for delirium (German version) 2023 [Available from: https://www.the4at.com/4at-deutsche. Marcantonio ER, Ngo LH, O'Connor M, Jones RN, Crane PK, Metzger ED, et al. 3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM-defined delirium: a cross-sectional diagnostic test study. Ann Intern Med. 2014;161(8):554-61. Wengritzky R, Mettho T, Myles PS, Burke J, Kakos A. Development and validation of a postoperative nausea and vomiting intensity scale. British Journal of Anaesthesia. 2010;104(2):158-66. Buchner A, Erdfelder E, Faul F, Lang A-G. G*Power 3.1.9.6 for Mac OS X 10.7 to 12. 3.1.9.6 ed2020. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society. 2005;53(4):695-9. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-56. Morfeld M, Kirchberger I, Bullinger M. SF-36 Fragebogen zum Gesundheitszustand. 2., ergänzte und überarbeitete Auflage ed: Hogrefe; 2011. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey MB, et al. Development and validation of a geriatric depression screening scale: A preliminary report. Journal of Psychiatric Research. 1983;17:37-49. Lawton MP, Brody EM. Assessment of older people: Self-maintaining and intrumental activities of daily living. Gerontologist. 1969;9:179-86. SedLine® Sedation Monitor Quick Reference Guide: Masimo; [Available from: https://professional.masimo.com/siteassets/us/documents/pdf/plm-10355c_quick_reference_guide_sedline_english.pdf. Schenning KJ, Deiner SG. Postoperative Delirium in the Geriatric Patient. Anesthesiol Clin. 2015;33(3):505-16. van Lieshout C, Schuit E, Hermes C, Kerrigan M, Frederix GWJ. Hospitalisation costs and health related quality of life in delirious patients: a scoping review. Z Evid Fortbild Qual Gesundhwes. 2022;169:28-38. Nowak H, Wolf A, Rahmel T, Oprea G, Grause L, Moeller M, et al. Therapeutic Suggestions During General Anesthesia Reduce Postoperative Nausea and Vomiting in High-Risk Patients - A Post hoc Analysis of a Randomized Controlled Trial. Front Psychol. 2022;13:898326. Häuser W, Hagl M, Schmierer A, Hansen E. The Efficacy, Safety and Applications of Medical Hypnosis. Dtsch Arztebl Int. 2016;113(17):289-96. Salazar-Parra M, Guzman-Ramirez BG, Pintor-Belmontes KJ, Barbosa-Camacho FJ, Bernal-Hernández A, Cruz-Neri RU, et al. Gender Differences in Postoperative Pain, Nausea and Vomiting After Elective Laparoscopic Cholecystectomy. World J Surg. 2020;44(12):4070-6. Golubovic J, Neerland BE, Aune D, Baker FA. Music Interventions and Delirium in Adults: A Systematic Literature Review and Meta-Analysis. Brain Sci. 2022;12(5). Jiang Y, Xie Y, Fang P, Shang Z, Chen L, Zhou J, et al. Cognitive Training for Reduction of Delirium in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(4):e247361. Kratz T, Heinrich M, Schlauß E, Diefenbachern A. The prevention of postoperative confusion—a prospective intervention with psychogeriatric liaison on surgical wards in a general hospital. Dtsch Arztebl Int. 2015;112:289–96. Cite Share Download PDF Status: Published Journal Publication published 27 Oct, 2025 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 30 Jun, 2025 Reviewers agreed at journal 25 May, 2025 Reviewers invited by journal 21 May, 2025 Editor invited by journal 29 Apr, 2025 Editor assigned by journal 13 Mar, 2025 First submitted to journal 18 Feb, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6058214","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":459935096,"identity":"c08268d9-31e1-4b51-b7d1-c7556b3b95bd","order_by":0,"name":"Lena Heiß","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYBACPhDB2MDAw8DAfADItGAAMfECNoQWtgQGhgQJ4rUAAY8BkVrYew9+YNxhIyPff+bjY94fEnL8PAcYP3zMwaOF51yyBOOZNB6DG7mbjXkSJIwlexuYJWduw6NFIsdAgrHtMI+BBO82aaCWxA3nGdiYefFpkX9j/IOx7T8P0GHPiNQiwWMGtOUAD8OBHDaIlrMNBLTw5JhZJLYlA/2SZmw4Jw3ol56DzXj9ws9+xvjGxzY7e/n+ww8fvLGxAYZY8sEPH/FoAYMEVC4kmkbBKBgFo2AUUAAAdjpEbRcQdpEAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0003-6200-1164","institution":"LMU Hospital: LMU Klinikum","correspondingAuthor":true,"prefix":"","firstName":"Lena","middleName":"","lastName":"Heiß","suffix":""},{"id":459935097,"identity":"cc028675-7df7-4f70-8eda-69998b3b1083","order_by":1,"name":"Saskia Neitzert","email":"","orcid":"","institution":"LMU Hospital: LMU Klinikum","correspondingAuthor":false,"prefix":"","firstName":"Saskia","middleName":"","lastName":"Neitzert","suffix":""},{"id":459935098,"identity":"d7917f83-db6c-48a0-9237-220990931019","order_by":2,"name":"Ernil Hansen","email":"","orcid":"","institution":"Klinikum der Universitat Regensburg: Universitatsklinikum Regensburg","correspondingAuthor":false,"prefix":"","firstName":"Ernil","middleName":"","lastName":"Hansen","suffix":""},{"id":459935099,"identity":"b929ab3f-bb94-4ca2-a873-ccb2d80d4cc1","order_by":3,"name":"Hartmuth Nowak","email":"","orcid":"","institution":"Ruhr University Bochum: Ruhr-Universitat Bochum","correspondingAuthor":false,"prefix":"","firstName":"Hartmuth","middleName":"","lastName":"Nowak","suffix":""},{"id":459935100,"identity":"06d86dc5-e733-4068-8973-8cda8553894f","order_by":4,"name":"Renate Neitzert","email":"","orcid":"","institution":"LMU Hospital: LMU Klinikum","correspondingAuthor":false,"prefix":"","firstName":"Renate","middleName":"","lastName":"Neitzert","suffix":""},{"id":459935101,"identity":"2256c0b9-dda8-4af1-8969-7b3bb8011bcd","order_by":5,"name":"Thomas Saller","email":"","orcid":"","institution":"LMU Hospital: LMU Klinikum","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Saller","suffix":""}],"badges":[],"createdAt":"2025-02-18 17:19:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6058214/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6058214/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-025-09108-x","type":"published","date":"2025-10-27T15:57:31+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":95041395,"identity":"b0920c65-b82e-42c9-ba8d-38073e25b2ea","added_by":"auto","created_at":"2025-11-03 16:11:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1596581,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6058214/v1/8f90f819-9058-41cb-8903-5eb8c7a84082.pdf"}],"financialInterests":"","formattedTitle":"Positive suggestions via headphones during general anesthesia for the improvement of vegetative \u0026amp; cognitive postoperative course parameters in elderly orthopedic patients – A randomized controlled double-blinded trial (POSSUDEL)","fulltext":[{"header":"Administrative information","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"639\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTitle\u0026nbsp;{1}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003ePositive suggestions via headphones during general anesthesia for the improvement of vegetative \u0026amp; cognitive postoperative course parameters in elderly orthopedic patients \u0026ndash; A randomized controlled double-blinded trial (POSSUDEL)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eTrial registration {2a and 2b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eDRKS00030589 prospectively registered 25.10.2022\u0026nbsp;\u003c/p\u003e\n \u003cp\u003ePositive Suggestionen mittels Tontr\u0026auml;ger w\u0026auml;hrend Allgemeinan\u0026auml;sthesie zur Reduktion von Delir und der Verbesserung vegetativer und kognitiver Verlaufsparameter: Eine multizentrische, doppelblinde randomisierte Interventionsstudie (POSSUDEL)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eProtocol version {3}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003e29.08.2022 V1.5\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eFunding {4}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eThis study is part of the LMU hospital\u0026apos;s own funding program\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eAuthor details {5a}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003eLena Hei\u0026szlig;*, Saskia Neitzert*, Renate Neitzert, Ernil Hansen, Hartmuth Nowak, Thomas Saller\u003c/p\u003e\n \u003cp\u003e*\u0026nbsp;joint first authorship\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eName and contact information for the trial sponsor {5b}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003en/a\u003c/p\u003e\n \u003cp\u003eThis study is part of the LMU hospital\u0026apos;s own funding program\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 218px;\"\u003e\n \u003cp\u003eRole of sponsor {5c}\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 421px;\"\u003e\n \u003cp\u003en/a\u003c/p\u003e\n \u003cp\u003eThis study is part of the LMU hospital\u0026apos;s own funding program\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Introduction","content":"\u003cp\u003e\u003cstrong\u003eBackground and rationale {6a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePostoperative syndromes with cognitive deficits\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostoperative delirium (POD) is an acute neuropsychiatric syndrome. It is characterized by transient disturbances in attention, awareness, and cognition following surgery [1]. It typically manifests within the first few days after an operation and is marked by fluctuating symptoms, including confusion, disorientation, an altered level of consciousness, and impaired memory. POD is more common in elderly patients and those having major surgery. The incidence of POD varies widely and depends on the age of the patient cohort studied and the type of surgical procedure [2]. The highest incidences are found after cardiothoracic procedures, orthopedic and general surgery [3]. While the exact etiology is best described as multifactorial and not fully understood to date [4], it is known to be associated with increased morbidity, prolonged hospital stay, an elevated risk of long-term cognitive decline as well as increased mortality [5]. For example, Moskowitz et al. demonstrated that for elective surgery, in patients 50 or more years of age, 5-year mortality was increased 7.35-fold after the occurrence of POD (95% CI: 1.49 - 36.18) [6]. As the development of POD or long-term postoperative cognitive deficits (POCD) represents the most frequent postoperative complication, mainly affecting elderly patients [7], a further increase of this complication is expected in the future due to demographic change [6]. As prevention has proven most effectively [3], patient’s personal risk factors and possible predictors must be identified and measures to reduce the probability of the occurrence of POD/POCD or neurocognitive disorder (NCD) [8] must be taken.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImportance of therapeutic communication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCommunication plays a special role in the entire field of healthcare. It can accompany and support medical therapies. Appropriate use of language and professional conversation management allow us to discover patients' resources and use them for the process of healing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA randomized, double-blind, multicenter trial showed that audio cues can reduce pain and nausea, consequently reducing the use of analgesics and antiemetics in at-risk groups. The time to reorientation was also shown to be diminished\u0026nbsp;[9]. Due to the age structure of the study, delirium incidence was inherently low, so no conclusions could be drawn regarding the antidelirogenic effect of positive suggestions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectified intraoperative pain measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMeasuring pain intensity is usually based on self-reporting by patients. With this method the subjective level of pain can be determined before and after surgery. Since patients cannot be questioned during general anesthesia, it was not possible to measure pain level intraoperatively in the past.\u0026nbsp; Lately, an AI-based algorithm has been developed to generate a Nociception Level Index (NoL) during surgery [10]. The algorithm considers variants of the following four parameters, which can be measured via a single finger electrode: Skin conductance, heart rate variability, accelerometry, and skin temperature. Studies have already shown that the NoL index is suitable for predicting postoperative pain\u0026nbsp;[11]. Thus, this technology seems to be suitable for a more precise analysis of the effect of therapeutic interventions especially on perioperative pain perception.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGender differences: Effect of different voices\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGender acts as an independent risk factor for several diseases and disorders. For example, female gender has already been established as a specific risk factor for the occurrence of postoperative nausea and vomiting [12]. The opposite seems to be true for the occurrence of delirium after surgical interventions: In this context, men seem to be more likely to develop POD [13]. With the upcoming awareness for gender sensitive medicine, research has also increasingly focused on the impact of sex differences on the efficacy of therapeutic interventions. For instance, there appear to be discrepancies in the efficacy of hypnosis therapy for smoking cessation when administered to different sexes (Green et al., 2008). However, robust data on gender differences in the effects of suggestive procedures is missing. In particular, no research has been done on gender differences in the effects of hypnotic suggestion when delivered by different voices.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBiomarkers to predict cognitive outcome after surgery\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNCD, particularly POD and POCD represent significant complications following surgical procedures. Given that current therapeutic approaches primarily focus on general factors such as e.g. fluid and electrolyte balance [14], there is a growing emphasis on early diagnosis and prevention of NCD [5]. The identification of high-risk patients in advance is of the utmost importance. For this purpose, biomarkers have been investigated [15]; however, their suitability for routine use is limited due to the invasive nature of the puncture. An alternative approach is to utilize markers in the blood, which can be categorized into three groups: global non-specific markers, established specific markers of neurocognitive functions and markers with less evidence to date. While so far, no single marker on its own has been sufficient for accurate prediction, a targeted combination of different markers could be an effective method for predicting cognitive complications with sufficient sensitivity and specificity [16].\u003c/p\u003e\n\u003cp\u003eThis trial will examine whether suggestions can reduce the probability of occurrence of delirium. Furthermore, it will be examined to what extent intraoperative application of different suggestive statements can reduce the postoperative perceived nausea as well as vomiting and pain, measured by the consumption of analgesics at a defined pain level. Moreover, it will be tested whether patients return to spontaneous breathing more rapidly, regain consciousness faster, are oriented and have less anxiety by listening to a sound recording with suggestions compared to a control group.\u003c/p\u003e\n\u003cp\u003ePotential risk markers for stress, delirium and inflammation are to be investigated by measuring several parameters in the patients' blood. In addition to the standard values determined during orthopedic surgery, cortisol, cortisol derivatives, NT-proCNP, NfL, S-100, pTau and IL-6 will be determined.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBeside the above mentioned targets, it will be investigated whether the choice of voice (male vs. female) has an influence on the effects described above.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjectives {7}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the current study we aim to address the following hypotheses:\u003c/p\u003e\n\u003cp\u003e\u003cu\u003ePrimary hypothesis:\u0026nbsp;\u003c/u\u003eDelirium incidence is lower in the intervention group than in the control group\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSecondary hypotheses:\u003c/u\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ePain intensity is lower in the intervention group than in the control group\u003c/li\u003e\n \u003cli\u003ePain medication consumption p.p. is lower in the intervention group than in the control group\u003c/li\u003e\n \u003cli\u003ePostoperative nausea and vomiting (PONV) incidence is lower in the intervention group than in the control group\u003c/li\u003e\n \u003cli\u003ePONV is less frequent in the intervention group than in the control group\u003c/li\u003e\n \u003cli\u003eThe above-mentioned effects differ depending on whether the subjects hear a speaker's voice according to their own gender or not\u003c/li\u003e\n \u003cli\u003eThe level of biomarkers indicates the likelihood of occurrence of postoperative delirium\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eTrial design {8}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA parallel group design will be applied. The study physician, who is not directly involved in data collection, will randomly assign patients to experimental conditions using software. Every person directly involved will be blinded to the allocation, as will the patients. Included patients will be randomized into 3 groups. In the sense of a balanced design, equal numbers of patients will be assigned to the intervention or control group. The experimental group will be further subdivided. During general anesthesia, patients in both intervention groups will be presented with positive therapeutic content via headphones either from a female or male speaker. Patients in the control group also will receive headphones for general anesthesia, but the track that will be played does not contain any audio content. Otherwise, the treatment will not differ from the verum group.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods: Participants, interventions and outcomes","content":"\u003cp\u003e\u003cstrong\u003eStudy setting {9}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data will be collected in Germany. Leading center of the trial is the hospital of the Munich Ludwig-Maximilians-University (LMU). Further data is planned to be collected in the hospital of the Ruhr University Bochum as well as in the Heidelberg university hospital.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria {10}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients meeting following criteria will be included:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eElective hip or knee surgery (e.g. hip or knee TEP) with a planned duration of 1-3 hours\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGeneral anesthesia using total intravenous anesthesia (TIVA)\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eAge from 60 years and above\u003c/li\u003e\n \u003cli\u003eGerman as native language or similar level\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSufficient hearing ability (no hearing aid at room volume necessary)\u003c/li\u003e\n \u003cli\u003eAbility to give consent\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003eThe Following exclusion criteria apply:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003ePatients with hearing loss\u003c/li\u003e\n \u003cli\u003eDiagnosis of dementia or MOCA \u0026lt;17\u003c/li\u003e\n \u003cli\u003ePreoperative delirium on hospital admission\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLanguage barriers\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePatient refusal\u003c/li\u003e\n \u003cli\u003eIf consent for blood collection: hemoglobin \u0026lt; 10 g/dL\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWho will take informed consent? {26a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrior to surgery, patients who will undergo knee or hip surgery will be seen by a member of the study team who will ask them for their informed consent. If consent will be given, a short assessment will be conducted to evaluate inclusion and exclusion criteria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional consent provisions for collection and use of participant data and biological specimens {26b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a (patient data will be specifically used for this study)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExplanation for the choice of comparators {6b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDelirium is a complication that primarily affects patients of older age. Therefore, patients will be recruited who already reached the age of 60 for all three subgroups. The control group will also receive headphones but without the suggestion audio.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention description {11a}\u003c/strong\u003e\u003cbr\u003eThe study will randomize patients into three groups. The control group will receive just headphones without being exposed to audio content while the other two groups will listen to therapeutic audio content. There will be no further difference in these groups regarding care and measures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCriteria for discontinuing or modifying allocated interventions {11b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent to participate in the study can be withdrawn at any time, without giving reasons or obtaining any disadvantages for further medical care. In case of withdrawal from the study, personal\u0026nbsp;data already obtained will be\u0026nbsp;destroyed. Patients for whom there will be a short-term change in the anaesthetic procedure, e.g. to anaesthesia with sevoflurane, will be considered separately due to the increased risk of PONV.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrategies to improve adherence to interventions {11c}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a (as all patients will be monitored by a study team member during their surgery, no specific strategy to improve adherence to protocol is necessary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelevant concomitant care permitted or prohibited during the trial {11d}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParticipation in other delirium-related intervention studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvisions for post-trial care {30}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a (no special post-trial care needed)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{12}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrimary outcome will refer to delirium incidence. Cognitive testing in form of the 4AT [17, 18], as well as the 3DCAM [19] will be performed pre- and postoperatively on all study participants to determine whether the incidence of delirium is lower in the intervention group than in the control group.\u003c/p\u003e\n\u003cp\u003eAs secondary outcomes postoperative nausea will be assessed with the Wengritzky PONV score [20], pain will be assessed using the Numerical Rating Scale (NRS) and medication consumption will be documented by analysing the patient\u0026rsquo;s files.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, the effect of different speaker voices as well as the possible correlation regarding the occurrence of delirium with the sampled biomarkers in the blood will be investigated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline {13}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study duration for all included participants will be defined by the time of surgery until the day of discharge. A follow-up survey of the cognitive function level, including a new blood sample, is planned after three months (Follow Up). Table 1 shows a detailed overview of the course of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1 \u0026ndash; Participant timeline.\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"14\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTUDY PERIOD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eDate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003ePrior to surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" valign=\"bottom\"\u003e\n \u003cp\u003eDay of surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eDay 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eDay 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eDay 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eDay 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eDay 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e+3 months\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eTimepoint\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eScreening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eBaseline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003ePre-OP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eOP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"bottom\"\u003e\n \u003cp\u003ePostOP recovery room\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" valign=\"bottom\"\u003e\n \u003cp\u003ePostOP ward\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eFollow-Up\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eVisit-Code\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eSCR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV3a\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV3b\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV3c\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV3d\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eV9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eENROLMENT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eEligibility criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eInformed consent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFeedback request\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eASSESSMENTS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMOCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTMT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFrailty Screening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePONV risk-score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCharlson Comorbidity Index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePermanent medication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eQUESTIONNAIRES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eiADL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSF36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eGDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBDI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eComplications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eALLOCATION\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRandomized allocation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSAMPLES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBlood sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSaliva sample\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eINTERVENTION\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eControll group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSGS intervention group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eDGS intervention group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eOUTCOME VARIABLES\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e4AT Delirium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e3DCAM Delirium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePain score (NAS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePain medication consumption\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eComfort scale (NCS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePONV wengritzky\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eSedline\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eNOL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e●\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eSample size\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{14}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the primary endpoint analysis, the sample size was calculated as follows:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt the university hospital, LMU Munich, a delirium incidence of approx. 25% can be assumed for electively orthopedic surgery. By means of therapeutic suggestion may be reduced by at least 50%. The calculation in G*Power [21] using the z-test \u0026quot;Difference between two independent proportions\u0026quot; results in a sample size of 110 subjects per group for a design in which the intervention group and control group are of equal size, with a required power of at least .8 and a significance level of 5%. This results in a total of 220 subjects.\u003c/p\u003e\n\u003cp\u003eBased on the results of the study by Nowak et al. 2020 [9], we also calculated the sample size needed to detect effects of the intervention on pain expression, which are of great interest in the secondary endpoint analysis: For effects on opioid use, an effect size of d = .36 is assumed. For a required power of .8 at a level of significance at 5%, a group size of at least 101 subjects is needed. For effects on pain intensity, an effect size of .325 can be calculated using G*Power based on the mean values and standard deviations given in the original work. When power is set at 0.8 and significance level at 5% the resulting sample size amounts to a total of 248 subjects.\u003c/p\u003e\n\u003cp\u003eIn addition to the effect of the intervention on delirium incidence, the effect on pain severity is also of great interest as a (secondary) endpoint. Hence, the larger calculated sample number (n = 248) is chosen as a further basis for calculation to be able to achieve sufficiently good power for the secondary endpoints as well.\u003c/p\u003e\n\u003cp\u003eTo ensure that the calculated minimum power will be achieved there is a need to take possible drop-outs into account. Therefore at least 10% more subjects will be necessary, which results in a total of 273 participants. In consideration of the balanced design, the final target equals in a rounded up total number of 280 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRecruitment\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{15}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAt the LMU Munich university hospital, participants for the study will be recruited in the anesthesia outpatient clinic. If an eligible patient cannot be included in the anesthesia outpatient clinic, we will attempt to reach them through the orthopedics outpatient clinic.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: allocation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSequence generation\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{16a}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIncluded patients will be divided as follows: 1:1 (intervention vs. control group) and within the intervention group 1:1 to a speaker with the same gender (sGS) vs. a speaker with a different gender (dGS). Thus, the only factor influencing assignment is patient gender.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConcealment mechanism\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{16b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNumbered audio players will be used to maintain blinding of the trained junior researchers conducting the intervention and data collection. After the randomization process, the study\u0026apos;s PI will notify the relevant parties regarding the designated number of the audio player to be utilized.\u003c/p\u003e\n\u003cp\u003eThose administering the intervention as well as the anesthetists in charge will not have permission to listen to the audio tracks on the different audio players.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImplementation\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{16c}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrained junior researchers will enroll participants, while the allocation sequence will be automatically generated by RedCap. In detail, randomization will be conducted using block randomization, assigning subjects to one of the study conditions listed above. The PI of the study will perform randomization in RedCap.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssignment of interventions: Blinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWho will be blinded\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{17a}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trained junior researchers, the responsible clinical staff, and the patients themselves will be blinded to avoid any potential influence, whether conscious or unconscious.\u003cbr\u003e\u003cstrong\u003eProcedure for unblinding if needed\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{17b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a (Since our intervention will be supplementary and will not modify the process or medications, identification of blinding is unnecessary.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection and management\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for assessment and collection of outcomes\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{18a}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaseline: Patients will be pseudonymized after inclusion. Required data items encompass Montral Cognitive Assessment (MOCA) [22], Frailty-test [23], PONV risk score [20], and continuous medication including pain medication. Additionally, patients will complete the Quality-of-Life questionnaire (SF-36) [24], Geriatric Depression Scale (GDS) [25], and instrumental Activities of Daily Living (iADL) [26].\u003c/p\u003e\n\u003cp\u003eBefore surgery: Directly prior to their scheduled surgery patients will be visited for assessment. The patients\u0026apos; cognitive state will be assessed using the 4AT. Additionally, they will be asked to rate their current level of pain using the NRS, as well as provide a saliva sample for cortisol analysis. Blood samples for cortisol levels and biomarkers will be obtained within the placement of a peripheral venous access, without the need for a separate puncture.\u003c/p\u003e\n\u003cp\u003eThroughout surgery: The following data will be recorded routinely. During anaesthesia depth of anaesthesia will be monitored intraoperative processed EEG, employing devices such as Sedline\u0026reg; [27]. Other crucial parameters are analgesic use, NOL-index [10] evaluated pain levels, overall operating time, and recovery duration, measured from the end of sedation to the time of extubating.\u003c/p\u003e\n\u003cp\u003eAfter surgery: After extubating objective data will be collected in the recovery room every 15 minutes for a total duration of one hour. Postoperative assessments will include the 4AT score for delirium, pain score measured on NRS, Numerical Comfort Scale (NCS) for assessing comfort, and postoperative nausea rated from 0 to 3. After the patient will have been in the recovery room for one hour, additional assessments will be conducted, including an extended delirium screening (3DCAM), PONV Score antiemetic consumption, and nurse-controlled analgesia consumption for NRS 3.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the regular ward, data will be recorded for the first five days post-surgery. Pain scores (measured using the NRS), analgesic intake via nurse-controlled analgesia (NCA; applicable for NRS of 3 or higher), PONV scores (as per Wengritzky\u0026apos;s classification system), antiemetic usage, comfort ratings (using the NCS) and delirium assessments (using both the 4AT score and 3DCAM) will be documented.\u003c/p\u003e\n\u003cp\u003eFollow-up assessments will be conducted three months after the surgery by sending patients a set of questionnaires (iADL, GDS, BDI, SF36) via mail. They will also be asked to provide their pain and comfort levels (NAS and NCS, respectively) and to submit another saliva sample. Any adverse effects that may have occurred will also be investigated and noted. If any cause for concern arises about returned questionnaires, the participants will be contacted and offered further assistance. All study participants may contact us at any time should they have any questions or concerns.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to promote participant retention and complete follow-up\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{18b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo enhance participant retention, trained junior investigators will supervise participants during their clinical stay. Study results as well as personal blood work results will be provided to patients at the study\u0026apos;s conclusion if they have agreed to receive them.\u003c/p\u003e\n\u003cp\u003eA 3-month follow-up will yield additional information on participants\u0026apos; well-being, and, when needed, further supportive discussions will be arranged.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIf participants choose to withdraw from the study, all data collected from them will be eliminated and excluded from the analysis. Withdrawal will be permitted at any point.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData management {19}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe RedCap online tool (Vanderbilt University, Texas, USA) will serve as a shared database for all participating centers hosted by the Ruhr University Bochum. Patient data will exclusively be entered using pseudonyms, preventing any conclusions about the individuals without further information. During the study, data will be recorded on paper protocols or directly via RedCap. RedCap supports data quality assurance by enforcing specific data formatting and performing range checks during data entry. After completing data collection, we will conduct plausibility checks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConfidentiality\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{27}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients\u0026rsquo; confidential information will be protected under medical confidentiality and the German Federal Data Protection Act (BDSG). Pseudonymized proband data may be shared, but original documents will not be accessible to third parties.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{33}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn the day of surgery, a blood sample will be drawn to quantify relevant values and biomarkers. After centrifugation and pipetting of the plasma, the cryopreserved biomarkers will be analyzed to assess potential associations between the biomarkers and delirium incidence. In addition, a saliva sample will be taken to analyze preoperative cortisol as a marker for experienced stress.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical methods for primary and secondary outcomes\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{20a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo ensure normal distribution, the Kolmogorov-Smirnov test will be conducted prior to any other analyzation. Comparison of the intervention group with the control group will be evaluated using the following analytical methods (Statistical significance is considered at a p-value \u0026lt; 0.05):\u003c/p\u003e\n\u003cp\u003eA Chi2-Test will be used to compare delirium as well as PONV-incidence. For the comparison of non-parametric variables Mann-Whitney U tests will be conducted. Parametric variables will be compared using Student t-Test. Logistic regression will be utilized to analyse the accuracy of prediction for blood biomarkers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterim analyses\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{21b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a (An interim evaluation is not intended)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods for additional analyses (e.g. subgroup analyses)\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{20b}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGender effects will be explored by comparing the interventions group who listened to sGS with the intervention group who listened to dGS using the above-mentioned tests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods in analysis to handle protocol non-adherence and any statistical methods to handle missing data\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{20c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn general, per-protocol analysis will be intended. To address the fact that complete protocol adherence is not always feasible in everyday clinical practice, all relevant cases will be included in the calculations as part of an intention-to-treat analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans to give access to the full protocol, participant level-data and statistical code\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{31c}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOversight and monitoring\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the coordinating center and trial steering committee\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{5d}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComposition of the data monitoring committee, its role and reporting structure\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{21a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study design, inclusion criteria, questionnaire selection, the points at which questioning takes place, together with supplementary monitoring and data-gathering monitors and the documentation tool RedCap were primarily prepared, selected and refined by the main center. In consultation with the other centers, details were negotiated through an iterative process to ensure a unified basis for conducting the study. As the study is self-funded and there are no sponsors involved, there are no competing interests or conflicts of interest. Trained junior researchers of the LMU Munich [24] hospital will monitor the process of data collection and report regularly to their head of trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse event reporting and harms\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{22}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAdverse events, such as an increase in pain intensity or increased consumption of antiemetics, as well as delayed awakening after prolonged general anesthesia, will be closely monitored continuously and treated immediately.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFrequency and plans for auditing trial conduct\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{23}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegular meetings will be held to review progress and suggest improvements and/or changes. As this will be a multicenter study, consultation and exchange with the other clinics will also be relevant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePlans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees)\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{25}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo major changes are planned currently. If anything were to change, the ethics committee would be informed immediately so that the vote could be revised. As the trial is self-funded, there is no need to inform sponsors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination plans\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{31a}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results will be published in a peer-reviewed medical journal, and the study participants will receive their personal laboratory results and the published article upon request and consent. The participating staff will be informed of the results of the study as part of an educational presentation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe objective of our study is to examine the impact of positive suggestions on delirium in elderly patients, while also investigating the influence on post-operative pain and nausea.\u003c/p\u003e \u003cp\u003ePostoperative delirium (POD) remains a prevalent complication among elderly surgical patients, associated with increased morbidity and mortality [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The management of delirious patients poses substantial challenges for healthcare providers and families, often leading to significant financial burdens due to prolonged care requirements and potential long-term consequences [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Given the aging population and the rising number of surgeries performed on older adults, there is a critical need for effective preventive strategies and methods for early detection of delirium [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Such approaches have the potential to significantly improve clinical outcomes for this vulnerable population.\u003c/p\u003e \u003cp\u003eEvidence suggests that targeted interventions, such as positive suggestions, have a beneficial effect on postoperative symptoms such as pain perception, required pain medication and the incidence of postoperative nausea and vomiting (PONV) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It has also been shown that medical hypnosis has a favorable impact on individuals experiencing anxiety and stress [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBuilding upon these findings, this study aims to further investigate the impact of positive suggestions on delirium risk, postoperative pain, and PONV among patients over 60 years undergoing orthopedic procedures. Notably, this investigation incorporates an analysis of gender-specific differences and examines the influence of suggestion delivery by voices of different genders [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA major strength of this study design lies in its well-thought methodology, which was achieved through randomization, double-blinding and a multicenter approach. By specifically avoiding music in the control group and using spoken suggestions without background music in the intervention group, potential effects can be more directly attributed to the use of positive suggestions rather than being influenced by background music effects [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Additionally, to the best of our knowledge, this study is among the first within the field of delirium research to employ objective intraoperative pain assessment via the NOL index [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. This approach provides a more accurate and reliable measure of intraoperative pain, reducing the reliance on subjective patient self-reporting.\u003c/p\u003e \u003cp\u003eThere are, however, several limitations that warrant consideration. Regular evaluation and delirium screenings throughout the study may themselves influence the neurocognitive state of patients. The necessary personal interactions and cognitive tasks involved in delirium assessments could be seen as a form of cognitive training, which is known to improve overall cognitive outcomes and may consequently affect delirium rates [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Moreover, due to resource limitations, cultural and linguistic differences were not addressed, although they could offer valuable insights for future research.\u003c/p\u003e \u003cp\u003eIn conclusion, the POSSUDEL study provides valuable insights into the potential of positive suggestions as a simple yet effective intervention to aid in the prevention of postoperative delirium. The findings may suggest clinically relevant strategies for enhancing treatment outcomes and general well-being in older patients, thus offering a practical tool for improving early detection and prophylaxis of POD in everyday clinical practice.\u003c/p\u003e "},{"header":"Trial status","content":"\u003cp\u003eEnrollment began in November 2022. The study is still enrolling patients and is expected to complete data collection until May 2025.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNumerical Rating Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePONV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePostoperative Nausea and Vomiting\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSF36\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eQuality of Life Questionnaire\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNCS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNumerical Comfort Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e4AT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eThe 4 A\u0026rsquo;s Test:A rapid clinical test for Delirium\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e3DCAM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e3-Minute Diagnostic Interview for CAM-defined Delirium:A rapid clinical test for Delirium\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNOL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNociception Level (objectively quantify a patient\u0026rsquo;s physiological pain response during operation for example)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe cordially thank the patients participating in our study for their support. We also appreciate the daily support of the nurses and anesthesiologists in our anesthesia bay, which helped to prepare the measurements, assisted with blood drawings and wholeheartedly apply positive words and vibes to the patients that need them. This devotion to perceive patients’ needs is key to perform communication based on positive suggestions and enable them to act on patients frightened or in pain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{31b}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLH*: Conceived the study, led the proposal and protocol development. She as well conducted the statistical and methodological planning.\u003c/p\u003e\n\u003cp\u003eSN*:\u0026nbsp;Conceived the study, led the proposal and protocol development. She was also responsible for the practical implementation of the interventions and the collection of data.\u003c/p\u003e\n\u003cp\u003eTS: Developed the idea for the study, conceived the study, led the proposal and protocol development\u0026nbsp;and supervised all processes.\u003c/p\u003e\n\u003cp\u003e*joint first authorship\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{4}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis trial was funded in parts by of the LMU hospital's Medical Clinician Scientist (MCSP) Advanved funding program.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{29}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOnly those directly involved in conducting the study will have access to the original final data of the trial. The data can be made available to the scientific community in anonymized form on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate {24}\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial is registered under the number DRKS00030589 and has been approved by the Ethics Committee of the LMU Munich (Vote 22-0631, 12/09/2022). Written, informed consent to participate will be obtained from all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{32}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003en/a (No personal information about participating patients will be published)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003e{28}\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u003c/strong\u003e\u003cstrong\u003e’\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003einformation (optional)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLH*: Before starting medical school, she graduated with a degree in psychology.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSN*: Before starting medical school, she graduated with a degree in nursing and still works at an ER.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTS:\u0026nbsp;As a senior consultant, specialized in geriatric anesthesia his focus lies in research for delirium and its prevention. Currently, he is principal investigator in a trial of delirium prevention and management at the LMU university hospital and is head of orthogeriatric anesthesia at the university hospital, LMU Munich.\u003c/p\u003e\n\u003cp\u003e* joint first authorship\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRudolph JL, Marcantonio ER. Postoperative Delirium: Acute Change with Long-Term Implications. Anesthesia \u0026amp; Analgesia. 2011;112(5):1202-11.\u003c/li\u003e\n\u003cli\u003eGallinat J, M\u0026ouml;ller HJ, Moser RL, Hegerl U. Das postoperative Delir Risikofaktoren, Prophylaxe und Therapie. Der Anaesthesist. 1999;48(8):507-18.\u003c/li\u003e\n\u003cli\u003eRoos P, Goettel N. Epidemiologie des Delirs: Teil 2 \u0026ndash; Das postoperative Delir. 2020;17:38-43.\u003c/li\u003e\n\u003cli\u003eMaldonado JR. Neuropathogenesis of Delirium: Review of Current Etiologic Theories and Common Pathways. The American Journal of Geriatric Psychiatry. 2013;21(12):1190-222.\u003c/li\u003e\n\u003cli\u003eAldecoa C, Bettelli G, Bilotta F, Sanders RD, Audisio R, Borozdina A, et al. European Society of Anaesthesiology evidence-based and consensus-based guideline on postoperative delirium. European Journal of Anaesthesiology. 2017;34(4):192-214.\u003c/li\u003e\n\u003cli\u003eMoskowitz EE, Overbey DM, Jones TS, Jones EL, Arcomano TR, Moore JT, et al. Post-operative delirium is associated with increased 5-year mortality. American Journal of Surgery. 2017;214(6):1036-8.\u003c/li\u003e\n\u003cli\u003eSerafim RB, Dutra MF, Saddy F, Tura B, de Castro JE, Villarinho LC, et al. Delirium in postoperative nonventilated intensive care patients: risk factors and outcomes. Ann Intensive Care. 2012;2(1):51.\u003c/li\u003e\n\u003cli\u003eEvered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, et al. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. British Journal of Anaesthesia. 2018;121(5):1005-12.\u003c/li\u003e\n\u003cli\u003eNowak H, Zech N, Asmussen S, Rahmel T, Tryba M, Oprea G, et al. Effect of therapeutic suggestions during general anaesthesia on postoperative pain and opioid use: multicentre randomised controlled trial. BMJ. 2020;371.\u003c/li\u003e\n\u003cli\u003eBen-Israel N, Kliger M, Zuckerman G, Katz Y, Edry R. Monitoring the nociception level: a multi-parameter approach. Journal of Clinical Monitoring and Computing. 2013;27(6):659-68.\u003c/li\u003e\n\u003cli\u003eLedowski T, Schlueter P, Hall N. Nociception level index: do intra-operative values allow the prediction of acute postoperative pain? Journal of Clinical Monitoring and Computing. 2021.\u003c/li\u003e\n\u003cli\u003eR\u0026uuml;sch D, Eberhart LHJ, Wallenborn J, Kranke P. \u0026Uuml;belkeit und Erbrechen nach Operationen in Allgemeinan\u0026auml;sthesie. Deutsches \u0026Auml;rzteblatt International. 2010;107(42):733-41.\u003c/li\u003e\n\u003cli\u003eWang H, Guo X, Zhu X, Li Y, Jia Y, Zhang Z, et al. Gender Differences and Postoperative Delirium in Adult Patients Undergoing Cardiac Valve Surgery. Frontiers in Cardiovascular Medicine. 2021;8.\u003c/li\u003e\n\u003cli\u003eRadtke FM, Franck M, MacGuill M, Seeling M, L\u0026uuml;tz A, Westhoff S, et al. Duration of fluid fasting and choice of analgesic are modifiable factors for early postoperative delirium. European Journal of Anaesthesiology | EJA. 2010;27(5):411-6.\u003c/li\u003e\n\u003cli\u003eHall RJ, Watne LO, Cunningham E, Zetterberg H, Shenkin SD, Wyller TB, et al. CSF biomarkers in delirium: a systematic review. International Journal of Geriatric Psychiatry. 2018;33(11):1479-500.\u003c/li\u003e\n\u003cli\u003eSchaefer ST, Koenigsperger S, Olotu C, Saller T. Biomarkers and postoperative cognitive function: could it be that easy? Current Opinion in Anesthesiology. 2019;32(1):92-100.\u003c/li\u003e\n\u003cli\u003eMacLullich AMJ, Shenkin SD, Goodacre S, Godfrey M, Hanley J, St\u0026iacute;obhairt A, et al. The 4 \u0026lsquo;A\u0026rsquo;s test for detecting delirium in acute medical patients: a diagnostic accuracy study. 2019;23:40.\u003c/li\u003e\n\u003cli\u003eAT - rapid clinical test for delirium (German version) 2023 [Available from: https://www.the4at.com/4at-deutsche.\u003c/li\u003e\n\u003cli\u003eMarcantonio ER, Ngo LH, O\u0026apos;Connor M, Jones RN, Crane PK, Metzger ED, et al. 3D-CAM: derivation and validation of a 3-minute diagnostic interview for CAM-defined delirium: a cross-sectional diagnostic test study. Ann Intern Med. 2014;161(8):554-61.\u003c/li\u003e\n\u003cli\u003eWengritzky R, Mettho T, Myles PS, Burke J, Kakos A. Development and validation of a postoperative nausea and vomiting intensity scale. British Journal of Anaesthesia. 2010;104(2):158-66.\u003c/li\u003e\n\u003cli\u003eBuchner A, Erdfelder E, Faul F, Lang A-G. G*Power 3.1.9.6 for Mac OS X 10.7 to 12. 3.1.9.6 ed2020.\u003c/li\u003e\n\u003cli\u003eNasreddine ZS, Phillips NA, B\u0026eacute;dirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society. 2005;53(4):695-9.\u003c/li\u003e\n\u003cli\u003eFried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-56.\u003c/li\u003e\n\u003cli\u003eMorfeld M, Kirchberger I, Bullinger M. SF-36 Fragebogen zum Gesundheitszustand. 2., erg\u0026auml;nzte und \u0026uuml;berarbeitete Auflage ed: Hogrefe; 2011.\u003c/li\u003e\n\u003cli\u003eYesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey MB, et al. Development and validation of a geriatric depression screening scale: A preliminary report. Journal of Psychiatric Research. 1983;17:37-49.\u003c/li\u003e\n\u003cli\u003eLawton MP, Brody EM. Assessment of older people: Self-maintaining and intrumental activities of daily living. Gerontologist. 1969;9:179-86.\u003c/li\u003e\n\u003cli\u003eSedLine\u0026reg; Sedation Monitor Quick Reference Guide: Masimo; [Available from: https://professional.masimo.com/siteassets/us/documents/pdf/plm-10355c_quick_reference_guide_sedline_english.pdf.\u003c/li\u003e\n\u003cli\u003eSchenning KJ, Deiner SG. Postoperative Delirium in the Geriatric Patient. Anesthesiol Clin. 2015;33(3):505-16.\u003c/li\u003e\n\u003cli\u003evan Lieshout C, Schuit E, Hermes C, Kerrigan M, Frederix GWJ. Hospitalisation costs and health related quality of life in delirious patients: a scoping review. Z Evid Fortbild Qual Gesundhwes. 2022;169:28-38.\u003c/li\u003e\n\u003cli\u003eNowak H, Wolf A, Rahmel T, Oprea G, Grause L, Moeller M, et al. Therapeutic Suggestions During General Anesthesia Reduce Postoperative Nausea and Vomiting in High-Risk Patients - A Post hoc Analysis of a Randomized Controlled Trial. Front Psychol. 2022;13:898326.\u003c/li\u003e\n\u003cli\u003eH\u0026auml;user W, Hagl M, Schmierer A, Hansen E. The Efficacy, Safety and Applications of Medical Hypnosis. Dtsch Arztebl Int. 2016;113(17):289-96.\u003c/li\u003e\n\u003cli\u003eSalazar-Parra M, Guzman-Ramirez BG, Pintor-Belmontes KJ, Barbosa-Camacho FJ, Bernal-Hern\u0026aacute;ndez A, Cruz-Neri RU, et al. Gender Differences in Postoperative Pain, Nausea and Vomiting After Elective Laparoscopic Cholecystectomy. World J Surg. 2020;44(12):4070-6.\u003c/li\u003e\n\u003cli\u003eGolubovic J, Neerland BE, Aune D, Baker FA. Music Interventions and Delirium in Adults: A Systematic Literature Review and Meta-Analysis. Brain Sci. 2022;12(5).\u003c/li\u003e\n\u003cli\u003eJiang Y, Xie Y, Fang P, Shang Z, Chen L, Zhou J, et al. Cognitive Training for Reduction of Delirium in Patients Undergoing Cardiac Surgery: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(4):e247361.\u003c/li\u003e\n\u003cli\u003eKratz T, Heinrich M, Schlau\u0026szlig; E, Diefenbachern A. The prevention of postoperative confusion\u0026mdash;a prospective intervention with psychogeriatric liaison on surgical wards in a general hospital. Dtsch Arztebl Int. 2015;112:289\u0026ndash;96.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"anesthesia, processed EEG, elderly, headphones, nociception level index, pain, PONV, positive suggestions, delirium, total intravenous anesthesia","lastPublishedDoi":"10.21203/rs.3.rs-6058214/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6058214/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePostoperative delirium and cognitive deficits are significant surgical complications, especially in elderly patients. The reported incidence of postoperative delirium is variable but notably high in cardiothoracic, orthopedic, and general surgery. The etiology of postoperative delirium is known to be multifactorial, with prevention being the most effective strategy currently available. This study aims to explore the potential benefits of positive suggestions delivered via headphones during general anesthesia on the incidence of postoperative delirium and improving postoperative pain, nausea, and cognitive outcomes in elderly orthopedic patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis randomized controlled double-blinded trial will involve patients aged 60 and above undergoing elective hip or knee surgery under general anesthesia. Participants will be randomized into three groups: a control group receiving no auditory intervention and two intervention groups receiving positive therapeutic suggestions via headphones from either a male or female speaker. The primary outcome is the incidence of postoperative delirium within five days after surgery, that will be assessed by using the 4AT and 3DCAM. Secondary outcomes include pain intensity, medication consumption, postoperative nausea and vomiting, and levels of specific biomarkers. Data will be collected before, during and after surgery as well as three months after surgery. In addition, intraoperative pain is being measured objectively by using the nociception level index (NOL).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study hypothesizes that positive auditory suggestions can reduce postoperative delirium incidence, lower pain intensity as well as pain medication use, and decrease postoperative nausea, vomiting incidence and severity. Additionally, gender differences in response to male versus female voices will be explored. The findings could offer a non-invasive, cost-effective method to enhance postoperative recovery in elderly patients, potentially leading to changes in perioperative care practices.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDRKS00030589 prospectively registered 25.10.2022\u003c/p\u003e","manuscriptTitle":"Positive suggestions via headphones during general anesthesia for the improvement of vegetative \u0026amp; cognitive postoperative course parameters in elderly orthopedic patients – A randomized controlled double-blinded trial (POSSUDEL)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-26 09:59:50","doi":"10.21203/rs.3.rs-6058214/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2025-06-30T12:05:43+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-05-25T10:11:33+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-21T13:50:30+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"Trials","date":"2025-04-29T11:08:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-13T04:29:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Trials","date":"2025-02-18T12:18:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b646a2b4-b501-47d2-9f06-730917314e16","owner":[],"postedDate":"May 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-03T16:10:06+00:00","versionOfRecord":{"articleIdentity":"rs-6058214","link":"https://doi.org/10.1186/s13063-025-09108-x","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2025-10-27 15:57:31","publishedOnDateReadable":"October 27th, 2025"},"versionCreatedAt":"2025-05-26 09:59:50","video":"","vorDoi":"10.1186/s13063-025-09108-x","vorDoiUrl":"https://doi.org/10.1186/s13063-025-09108-x","workflowStages":[]},"version":"v1","identity":"rs-6058214","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6058214","identity":"rs-6058214","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}