Preoperative stress markers as predictors of postoperative neuropsychological disorders in cardiac surgery patients: protocol for a single-centre prospective observational study (CAVALIR)
Authors: Marius Butz, Rolf Meyer, Tibo Gerriets, Carolin Hänsel, Hannah Schmidt, Jana Yasemin Bach, Alicia Marek, Marlene Tschernatsch, Omar Alhaj-Omar, Patrick Schramm, Heidrun H Krämer, Yeong-Hoon Choi, Samuel Sossalla, Till Keller, Markus Schoenburg, Martin Juenemann
Published: 2026

ABSTRACT
AbstractIntroductionPostoperative neuropsychological disorders including delirium, cognitive dysfunction and emotional distress are common after cardiac surgery and are linked to reduced quality of life, morbidity and mortality. Reliable preoperative risk factors remain difficult to identify. This study investigates stress-related parameters as predictors of postoperative neuropsychological disorders in patients undergoing cardiac surgery.Methods and analysisIn this prospective study, 240 patients undergoing elective cardiac surgery (coronary artery bypass grafting: n=120, aortic valve replacement: n=120) with extracorporeal circulation at the Kerckhoff-Clinic Bad Nauheim (Germany) will be enrolled. Preoperative stress factors will be assessed using measures of stress-related personality traits, perceived stress, anxiety, depression, salivary cortisol and heart rate variability. Postoperative neuropsychological disorders will be evaluated through diagnosis of delirium in both the intensive care unit and on the standard ward. Additional neurocognitive dysfunctions and emotional distress will be assessed at hospital discharge and 3 months postoperatively, with corresponding preoperative baseline measurements.DiscussionIf stress measures prove to be predictive, they may enhance understanding of postoperative neurocognitive and emotional disorders and facilitate the development of risk stratification algorithms, enabling more effective preventive strategies for high-risk patients.Ethics and disseminationThe study was approved by the Ethics Committee of Justus Liebig University Giessen (Ref.: 54/24) and is conducted in accordance with the Declaration of Helsinki. Written informed consent will be obtained from the patients. Results will be disseminated through peer-reviewed publications and scientific conferences.Trial registration numberProspectively registered with the German Clinical Trials Register (DRKS00035318).Keywords: Delirium; Cognitive dysfunction; Stress, Physiological; Stress, Psychological; Cardiac surgery

STRENGTHS AND LIMITATIONS OF THIS STUDY

Prospective multimodal assessment linking preoperative stress state (heart rate variability, endocrine and psychological measures) with postoperative delirium and 3-month cognitive and emotional recovery.

Prospective multimodal assessment linking preoperative stress state (heart rate variability, endocrine and psychological measures) with postoperative delirium and 3-month cognitive and emotional recovery.

Comprehensive and standardised neuropsychological evaluation including objective cognitive testing (memory, attention, language), emotional symptoms (depression, anxiety) and delirium screening across intensive care unit and ward settings.

Comprehensive and standardised neuropsychological evaluation including objective cognitive testing (memory, attention, language), emotional symptoms (depression, anxiety) and delirium screening across intensive care unit and ward settings.

Inclusion of two major cardiac surgery populations (coronary artery bypass grafting (CABG) and aortic valve replacement (AVR)) allowing procedure-specific risk analyses.

Inclusion of two major cardiac surgery populations (coronary artery bypass grafting (CABG) and aortic valve replacement (AVR)) allowing procedure-specific risk analyses.

Observational single-centre design may limit generalisability and does not allow causal inference.

Observational single-centre design may limit generalisability and does not allow causal inference.

Heart rate variability analyses may be influenced by perioperative factors (eg, arrhythmias, medication), although predefined subgroup analyses are planned.

Heart rate variability analyses may be influenced by perioperative factors (eg, arrhythmias, medication), although predefined subgroup analyses are planned.

Background

Preoperative anxiety occurs in up to 42% of cardiac surgical patients1 and often leads to sedative use, which may cause adverse effects and itself increase the risk of complications, thereby prolonging recovery and hospital stay.2 3 Anxiety has further been associated with postoperative delirium (POD),4,6 delayed neurocognitive recovery (DNR),7 postoperative neurocognitive disorders (PNCD),8 postoperative anxiety,9 pain,10 11 reduced health-related quality of life,12 morbidity13 14 and mortality.15 Moreover, surgery may trigger preoperative depressive symptoms, which are also linked to several postoperative complications like PNCD,16 agitation17 and pain.18 Pathophysiologically, anxiety and depression as a form of emotional stress may activate the hypothalamic–pituitary–adrenal axis and dysregulate the sympathetic nervous system, fostering systemic inflammation and cerebral endothelial dysfunction. This in turn increases susceptibility to postoperative neuro-inflammation and related cognitive disorders.19,21 Altered autonomic stress responses are also discussed in delirium pathophysiology22 and can be indirectly assessed by heart rate variability (HRV).23 Impaired preoperative stress regulation reflected in HRV parameters may thus indicate increased risk for POD. So far, notably changed HRV has been linked to longer stays at intensive care unit (ICU)24 as well as with morbidity and mortality.25 26 Evidence regarding POD remains scarce,27 and research on posthospital cognitive and emotional dysfunctions are lacking. The primary aim of this study is to identify preoperative HRV markers in cardiac surgery patients to better understand the pathogenesis of POD. Secondary aims are to evaluate the predictive value of preoperative stress markers (HRV, salivary cortisol, emotional stress) for delayed cognitive and emotional dysfunctions.

Methods

Study design

This project is a prospective analysis of preoperative stress markers associated with postoperative neuropsychological disorders. The study is conducted by the Heart & Brain Research Group, a collaboration between the Department of Cardiac Surgery at the Kerckhoff Heart Center (Campus of Justus Liebig University Giessen) and the Department of Neurology at University Hospital Giessen, Germany. The research team includes members of cardiac surgery, neurology, neuropsychology and cardiology, responsible for protocol development, study monitoring and reporting.

Patient and public involvement

Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research.

Trial status

The study is currently enrolling patients and is prospectively registered with the German Clinical Trials Register (DRKS00035318; first posted 18 October 2024), a primary registry in the WHO International Clinical Trials Registry Platform network recognised by ClinicalTrials.gov. Patient recruitment started on 4 March 2025 and is expected to be completed on 4 March 2028. Protocol version: V.5.0 (24–09-2025).

Study procedures

The study coordinator screens elective cardiac surgery cases reported by the participating centre. Eligible patients are informed and consented, typically on the day before surgery, followed by baseline data collection. Preoperative assessment includes age, sex, education, Body Mass Index, alcohol and nicotine use, sleep quality, dyslipidaemia, diabetes, renal insufficiency (creatinine >1.2 mg/dL men; >0.9 mg/dL women), hypertension, arrhythmia, heart failure and left ventricular ejection fraction.28 Preoperative emotional distress is assessed by questionnaires on perceived stress (acute and past month), stress coping, neuroticism, depression and anxiety. Saliva samples are collected for cortisol, alpha-amylase and sex-hormones, followed by a 5 min resting HRV recording. While HRV monitoring continues, a 15 min neuropsychological test battery is administered. This 15 min period is defined as a stress-measurement phase, with the test battery serving as a stress-inducing paradigm. Afterwards, HRV is recorded for an additional 5 min to quantify stress reactivity.29 30 All baseline assessments, including questionnaires, neuropsychological testing, saliva sampling and HRV recordings, are performed during a single preoperative assessment session on the day before surgery. Perioperative data include type and depth of anaesthesia, catecholamine therapy, type of surgery (CABG, aortic valve replacement (AVR)), duration of surgery, cardiopulmonary bypass and aortic cross-clamp time, ventilation time, postoperative complications (arrhythmia, renal insufficiency, Transient Ischemic Attack, stroke, dysarthria, aphasia) and ICU/ward length of stay. Postoperative assessment of delirium is performed on the ICU (three times daily) and normal ward (once daily) using standardised screening tools. At hospital discharge, neuropsychological tests on cognition and emotion are repeated. Follow-up at 3 months consists of a structured telephone interview including cognitive tests, questions on emotional distress and impairments in activities of daily living. An overview of the study procedures is presented in figure 1 and the detailed assessment schedule is in table 1.

Timeline of study-related assessments. On the day of admission to the acute care hospital, baseline data are collected, including heart rate variability (HRV), saliva sampling, cognition and emotion. All preoperative HRV measurements are performed consecutively within a single assessment session. After surgery, daily delirium screenings are conducted. At hospital discharge and 3 months follow-up, assessment of cognition and emotion is performed. Detailed timing, measurement frequency and assessment instruments are provided in table 1.

Table 1Assessment scheduleDomainParameter (instrument)Preoperative baseline sessionICU/wardHospital discharge3-month follow-upPhysiologyHRV (Polar10)Rest-HRVStress-HRVRest-HRVpost-HRVXXXCortisol (Saliva)XEmotionAcute stress (VAS)XXXChronic stress (PSS-10)XPreoperative anxiety (APAIS)XState-Anxiety (STAI-6)XXDepression (DASS-D)XXXPosttraumatic stress (PCL-5)XPersonalityStress coping (Brief-COPE)XEmotion regulation (ERQ)XNeuroticism (Big-Five10)XCognitionGlobal Cognition (MoCA)XXXMemory (MoCA)XXXWord-Fluency (RWT)XXXAttention (TMT)XXInhibition (SPT-7)XXDelirium at ICU (ICDSC)XDelirium at normal ward (3D-CAM)XExpectation (TEX-Q)XSubjective cognition (PNCD-Q)XWell-beingActivity of daily living (IADL)XSleep quality (ISI)XAPAIS, Amsterdam Preoperative Anxiety and Information Scale; Brief-COPE, Coping Orientation to Problems Experienced (short form); DASS-D, Depression, Anxiety and Stress Scales (Subscale Depression); 3D-CAM, 3-Minute Diagnostic Interview for Confusion Assessment Method; ERQ, Emotion Regulation Questionnaire; HRV, heart rate variability; IADL, Instrumental Activities of Daily Living; ICDSC, Intensive Care Delirium Screening Checklist; ICU, intensive care unit; ISI, Insomnia Severity Index; MoCA, Montreal Cognitive Assessment; PCL-5, Posttraumatic Stress Disorder Checklist for DSM-5; PNCD-Q, Postoperative Neurocognitive Disorder Questionnaire; PSS-10, Perceived Stress Scale; RWT, Regensburg Word Fluency Test; SPT-7, Short Performance Test (Subtest 7); STAI-6, Short Form State-Trait Anxiety Inventory; TEX-Q, Treatment Expectation Questionnaire; TMT, Trail Making Test; VAS, visual analogue scale.

Assessment schedule

APAIS, Amsterdam Preoperative Anxiety and Information Scale; Brief-COPE, Coping Orientation to Problems Experienced (short form); DASS-D, Depression, Anxiety and Stress Scales (Subscale Depression); 3D-CAM, 3-Minute Diagnostic Interview for Confusion Assessment Method; ERQ, Emotion Regulation Questionnaire; HRV, heart rate variability; IADL, Instrumental Activities of Daily Living; ICDSC, Intensive Care Delirium Screening Checklist; ICU, intensive care unit; ISI, Insomnia Severity Index; MoCA, Montreal Cognitive Assessment; PCL-5, Posttraumatic Stress Disorder Checklist for DSM-5; PNCD-Q, Postoperative Neurocognitive Disorder Questionnaire; PSS-10, Perceived Stress Scale; RWT, Regensburg Word Fluency Test; SPT-7, Short Performance Test (Subtest 7); STAI-6, Short Form State-Trait Anxiety Inventory; TEX-Q, Treatment Expectation Questionnaire; TMT, Trail Making Test; VAS, visual analogue scale.

Inclusion and exclusion criteria

Patients over 18 years undergoing elective on-pump cardiac surgery (coronary artery bypass grafting (CABG) or AVR), with sufficient German language skills for neuropsychological assessment, and the ability to provide written informed consent are eligible. Exclusion criteria include acute psychiatric or neurological disorders (eg, dementia, depression, stroke), reoperations, emergency procedures, pacemaker or recent cardiac treatment within the past 3 months (eg, stent, Transcatheter Aortic Valve Implantation, myocardial infarction, myocarditis)

Outcomes

The primary outcome is to determine which preoperative HRV markers are associated with the development of POD in patients undergoing CABG. Secondary exploratory outcomes include identifying preoperative HRV markers associated with POD in AVR patients; examining preoperative salivary and emotional stress markers in relation to POD in CABG and AVR patients; and investigating associations between preoperative stress markers (HRV, salivary, emotional) and postoperative neuropsychological disorders (DNR, PNCD and emotional distress) across both surgical groups.

Preoperative assessment

Heart rate variability

HRV is measured preoperatively using a heart rate chest strap (Polar H10, Darmstadt, Germany). First, pulse-to-pulse intervals are recorded, followed by analyses in the time, frequency and non-linear domains. In the time domain, mean Normal-to-Normal (NN) and the SD of NN intervals are calculated, as well as RMSSD, mean heart rate (bpm) and pNN50 (the proportion of successive RR intervals differing by >50 ms). In the frequency domain, spectral analysis is performed to derive ultra-low frequency (<0.003 Hz), very-low frequency (VLF 0.003–0.04 Hz), low frequency (LF 0.04–0.15 Hz), high frequency (HF 0.15–0.40 Hz) and total power (TP<0.003–0.40 Hz). In the non-linear domain, Poincaré plots are used to calculate the SD of short-term and long-term diagonal axes. Parasympathetic activity is reflected by RMSSD, NN50, pNN50, HF and HF%, while sympathetic activity is indicated by VLF, VLF%, LF, LF% and the LF/HF ratio.31 HRV analysis and interpretation follows established guidelines.31 32 Data will be analysed using validated professional software (Kubios HRV Scientific, Kuopio, Finland).33

Saliva sample

Saliva samples are collected before preoperative neuropsychological testing using synthetic swabs (Salivette, Sarstedt, Rommelsdorf, Germany).34 35 Samples are labelled with the study code and time, centrifuged at 3500 rpm for 5 min independent of temperature and stored at −20 °C in the central laboratory of the Kerckhoff Clinic until transport. They are retained for up to 2–3 years and transferred under cold chain conditions to the Molecular Genetics/Biochemistry Laboratory at Justus Liebig University Giessen. Elevated preoperative cortisol levels have been identified as a risk factor for POD36 and will, therefore, primarily be analysed together with alpha-amylase, interleukin-6, C reactive protein, sex hormones and oxytocin.

Emotional distress

To examine associations between HRV parameters, perceived stress29 and stress coping,30 patients complete a questionnaire battery. Preoperatively, acute stress is rated on a visual analogue scale. Perceived stress during the past month is assessed with the German-validated Perceived Stress Scale (PSS, 10 items).37 Preoperative surgery-specific anxiety is measured with the Amsterdam Preoperative Anxiety and Information Scale (APAIS, 6 items).38 State anxiety is assessed with the State-Trait Anxiety Inventory–Short Form (STAI-6, 6 items).39 Depressive symptoms during the past 7 days are measured preoperatively with the depression subscale of the Depression–Anxiety–Stress Scales (DASS-D, 7 items).40

Stress personality

Personality-related aspects of emotional distress are assessed with validated self-report measures. Stress coping strategies are measured with the German version of the Brief-COPE (28 items).41 Emotion regulation (suppression and reappraisal) is evaluated with the German-validated Emotion Regulation Questionnaire–Short Form (ERQ-SF, 6 items).42 The personality trait neuroticism, closely related to stress perception43 and identified as a risk factor for POCD,44 is assessed with the German-validated short form of the Big Five Inventory (BFI-10, 10 items).45

Sleep quality

The quality of patients’ sleep is assessed preoperatively using the Insomnia Severity Index, which measures sleep disturbances and their impact on daily activities and quality of life as well as satisfaction with sleep behaviour over the past month.46

Tobacco and alcohol consumption

Information on tobacco use is obtained using standardised questions. Patients are categorised as never smokers, former smokers or current smokers. For former smokers, the period of smoking (start and end year) and the average number of cigarettes per day are recorded. For current smokers, the onset of smoking (year) and the number of cigarettes smoked per day are documented. Alcohol consumption is assessed by asking patients how many glasses of alcohol they consume per week or per month. For standardisation, one glass of alcohol is defined as 0.33 L beer, 0.25 L wine or sparkling wine or 0.02 L spirits.

Assessment of postoperative neuropsychological disorders

Perioperative neurocognitive disorders

POD is assessed three times daily during ICU stay using the German-validated Intensive Care Delirium Screening Checklist (ICDSC)47 and once daily on the normal ward using the German-validated 3 min Diagnostic Interview for Confusion Assessment Method (3D-CAM).48 Delirium monitoring is continued until hospital discharge, usually on postoperative day 7. Both tools are recommended by the Enhanced Recovery After Surgery Society.49 Delirium episodes recorded in medical charts are also included in the analysis.

DNR at hospital discharge and PNCD at 3-month follow-up are assessed using a neuropsychological test battery covering Diagnostic and Statistical Manual of Mental Disorders (DSM-5) neurocognitive domains,50 evaluating preoperatively and postoperatively verbal memory, complex attention, verbal fluency and visuoconstructive ability (see table 2). Preoperative neuropsychological assessment serves as a baseline for postoperative classification of DNR and PNCD. Cognitive screening is performed with the German-validated Montreal Cognitive Assessment (MoCA),51 which takes about 10 min and covers visuoconstructive ability (copying a 3D figure), object naming, verbal and working memory, attention, phonemic fluency, abstraction, cognitive flexibility and temporal and spatial orientation. The MoCA raw total score is defined as a variable and is further transformed into a demographically corrected z-score (adjusted for age, education and sex; https://www.mocatest.ch). At the 3-month follow-up, the telephone version (T-MoCA) is administered.52 Verbal memory (delayed recall) is assessed within the MoCA. Patients are read five words two times, asked to repeat them immediately and at a short delay freely. Delayed cued recall is further quantified with the MoCA Memory Index Score.53 Selective attention is measured with the Trail Making Test A (TMT-A),54 where patients must connect numbers in ascending order as quickly as possible. Cognitive inhibition is examined with subtest 7 of the Short Performance Test (SPT-7),55 where patients are required to rename letters (eg, say ‘A’ instead of ‘B’ and vice versa). Semantic verbal fluency is assessed with the Regensburg Word Fluency Test (RWT),56 in which patients generate as many category-specific words as possible within 1 min. Phonemic verbal fluency is also assessed with the RWT as part of the MoCA,51 requiring patients to name as many words as possible within 1 min that begin with a given letter. Visuoconstructive ability is evaluated through the accurate reproduction of the three-dimensional item from the MoCA.51 Parallel test forms are applied to control for practice and learning effects.

Table 2Cognitive domains according to DSM-5 and corresponding neuropsychological test parametersCognitive domainCognitive subdomainCognitive parameterTask (scale of measure)Learning and memoryVerbal free recallMOCA (Wordlist)Recalling items of wordlist (number of correct items)Verbal cued recallMOCA (Memory Index)Recalling items of wordlist (number of correct items)Complex attentionSelective attentionTMT-AConnecting numbers in ascending order (seconds)InhibitionSPT-7Renaming interfering letters, eg, ‘S’ instead of ‘T’ (seconds)SpeechWord fluencyRWT (phonematic)Naming words with a specific initial letter (number of correct words)RWT (semantic)Naming words from a specific category (number of correct words)Perceptive motoricVisuoconstructionMOCA (3-D Figur)Copying a three-dimensional figure (number of correct figures)DSM-5, Diagnostic and Statistical Manual of Mental Disorders; MoCA, Montreal Cognitive Assessment; RWT, Regensburg Word Fluency Test; SPT, Short Performance Test; TMT, Trail Making Test.

Cognitive domains according to DSM-5 and corresponding neuropsychological test parameters

DSM-5, Diagnostic and Statistical Manual of Mental Disorders; MoCA, Montreal Cognitive Assessment; RWT, Regensburg Word Fluency Test; SPT, Short Performance Test; TMT, Trail Making Test.

Questionnaire on postoperative neurocognitive disorders

To follow the nomenclature for PNCD recommended by Evered et al,57 the patient’s subjective impression of postoperative cognitive decline is considered as an outcome measure and has, for example, been assessed with the question: ‘Is your memory or thinking affecting your daily life?’.58 However, this question does not specifically address surgery and may capture unrelated factors. Deiner et al59 proposed a more precise formulation: ‘Do you feel that the surgery negatively impacted your clarity of thought?’ Responses are rated on a 5-point Likert scale (‘not at all’, ‘slightly’, ‘moderately’, ‘severely’ and ‘completely’.) and dichotomised into yes/no (decline defined as any response other than ‘not at all’). To capture a broader range of cognitive domains potentially affected by surgery, our group developed the Postoperative Neurocognitive Disorder Questionnaire (PNCD-Q). It covers 17 functions, including various forms of attention, memory, planning, decision-making, mental flexibility, language, emotion recognition, visuoconstruction and spatial orientation, each described in plain language (eg, sustained attention: ‘the ability to concentrate on a task or activity over a longer period of time’). Ratings are provided on the same 5-point scale. Subjective postoperative cognitive decline is defined when at least one domain is rated ‘slightly’ or worse. The selection and definitions of cognitive functions are based on DSM-5.50

Postoperative emotional distress

Depressive symptoms during the past 7 days are measured postoperatively at hospital discharge and 3-month follow-up with the depression subscale of the Depression–Anxiety–Stress Scales.40 At 3-month follow-up, patients complete the German-validated Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5, 20 items).60

Instrumental activities of daily living

Instrumental activities of daily living are assessed 3-month postoperative according to Gärtner et al.61 Seven domains are covered: meal preparation, telephone use, shopping, medication management, light housework (eg, dishwashing, tidying, light cleaning), occasional heavy housework (eg, scrubbing floors, window cleaning) and management of finances or administrative tasks. Response options are ‘no difficulty’, ‘some difficulty’, ‘major difficulty’, ‘unable to do’ and ‘not applicable’.

Treatment expectation

To examine whether expectations regarding posthospital rehabilitation affect neuropsychological outcomes, we use the Treatment Expectation Questionnaire (TEX-Q, 15 items).62

Sample-size estimation

In a preoperative HRV analysis of cardiac surgery patients, an association between HF power and the incidence of POD was observed with an effect size of d=0.5.27 The POD rate was 36% (non-POD: n=22; POD: n=14), which is consistent with previous reports.63 Assuming a statistical power of 0.8, an alpha level of 0.05 (one-sided), and a t-test for independent samples, the required sample size per surgical group (AVR vs CABG) is 118 patients (non-POD: n=81; POD: n=37). For both surgical groups combined, the total sample size is 236 patients. The calculation was performed using G*Power Software (V.3.1.9.7).

Planned statistical analysis

POD is defined as the occurrence of at least one delirium episode (ICDSC, 3D-CAM or medical records) during the ICU and normal ward. DNR at hospital discharge57 and PNCD at 3-month follow-up is defined as a decline, and postoperative cognitive improvement (POCI64 as an increase, of at least one SD between preoperative and postoperative testing in ≥20% of all neuropsychological subdomains (see table 2). Z-scores are calculated as the difference between individual raw scores and the baseline group mean, divided by the baseline SD. PNCD is further classified into two severity levels:

Postoperative mild neurocognitive disorder (p-NCD-mild): subjective decline reported in the PNCD-Q and objective decline of 1–2 SD in ≥20% of tested cognitive subdomains.

Postoperative mild neurocognitive disorder (p-NCD-mild): subjective decline reported in the PNCD-Q and objective decline of 1–2 SD in ≥20% of tested cognitive subdomains.

Postoperative major neurocognitive disorder (p-NCD-major): subjective decline reported in the PNCD-Q and objective decline of ≥2 SD in ≥20% of tested cognitive subdomains, with additional impairment in at least one IADL. IADL impairment is defined as reporting at least ‘some difficulty’ in one or more of daily activities due to postoperative cognitive deficits.

Postoperative major neurocognitive disorder (p-NCD-major): subjective decline reported in the PNCD-Q and objective decline of ≥2 SD in ≥20% of tested cognitive subdomains, with additional impairment in at least one IADL. IADL impairment is defined as reporting at least ‘some difficulty’ in one or more of daily activities due to postoperative cognitive deficits.

Descriptive data will be reported as mean with SD, median with IQR or frequency with percentage. Baseline group differences will be analysed using Student’s t-test, Mann–Whitney U-test, Pearson’s χ2 test, or Fisher’s exact test, as appropriate. Assessment parameters within and between groups will be analysed using analyses of variance or non-parametric approaches. For repeated measures, analyses of covariance (ANCOVA) are conducted with the postassessment score as the dependent variable, group as a fixed factor and the preassessment score as covariate. Assumptions for parametric tests are checked with Levene’s test for homogeneity of variance and the Shapiro–Wilk test, supported by visual inspection of distribution plots. For categorical outcomes, logistic regression will be applied; for continuous outcomes, linear or multiple regression analyses. Potential confounding variables identified in the literature or between-group statistics are included in ANCOVA or regression models. If participants drop out and complete datasets are missing, multiple imputation will be applied using the fully conditional specification method (Markov Chain Monte Carlo, 10 iterations), if the amount of dropout not compromise analytical validity.65 Fifty imputations will be generated, and the average is used to replace missing values.

Subgroup analyses will be performed in patients with preoperative arrhythmias potentially affecting HRV interpretation (eg, atrial fibrillation or atrial flutter). Furthermore, intraoperative variables including type and depth of anaesthesia, catecholamine therapy, duration of surgery, cardiopulmonary bypass and aortic cross-clamp time, ventilation time and perioperative complications will be extracted and considered as potential confounders in exploratory analyses where appropriate.

All statistical results are reported with p values, and statistical significance is set at p<0.05. Scientific and clinical conclusions are based not only on statistical significance but also on effect sizes,66 which are reported with CIs where appropriate. Analyses of secondary outcomes are considered exploratory and hypothesis-generating. For exploratory global hypotheses involving multiple tests, p values are controlled using false discovery rate correction to adjust for type I error inflation.

Data management and confidentiality

The collection, pseudonymisation, storage and access to study data lie solely with members of the Heart & Brain Research Group at the Kerckhoff Clinic, Bad Nauheim, in strict compliance with medical confidentiality. Data from paper files, electronic patient records, saliva and HRV measurements are pseudonymised and transferred into a password-protected secure electronic database without personal identifiers. Paper-based test data and questionnaires are stored separately in a locked cabinet. Each participant receives a unique study code (CAV+running number); the key linking codes to identities are stored separately in a password-protected file on a secure server accessible only to authorised group members.

Discussion

This study addresses the early identification of cardiac surgery patients at risk for POD and postoperative cognitive and emotional dysfunctions. These conditions, also called postintensive care syndrome, are common after cardiac surgery and are associated with reduced health-related quality of life.67 While preoperative anxiety and depression are contributors to adverse outcomes,47,13 15 valid biological markers for risk stratification remain limited. HRV represents a non-invasive and dynamic marker of autonomic regulation,31 while emotional stress parameters, including perceived stress, coping strategies, neuroticism and stress-related hormones, may capture important preoperative vulnerabilities. By integrating these measures with validated cognitive tests and subjective patient-reported outcomes, this study provides a comprehensive and multidimensional approach to predicting postoperative neuropsychological disorders. Earlier work suggested associations between HRV and POD, but lacked sufficient sample size, differentiation between CABG and AVR, stress correlates or long-term follow-up.27 The CAVALIR-trial has the potential not only to clarify the pathophysiology between HRV and postoperative neuropsychological dysfunctions but also to lay the foundation for stress marker-driven risk algorithms and targeted preventive strategies68 69 to protect high-risk patients and improve recovery after cardiac surgery.

Ethics and dissemination

The study involving human participants complies with the Declaration of Helsinki and was reviewed and approved by the Ethics Committee of the Justus Liebig University Giessen (Ref.: 54/24). All changes to the study protocol will be submitted to the Ethics Committee. Written informed consent will be obtained from the patients. Our aim is to make the study results accessible to the public, healthcare providers, and the scientific community by disseminating them through press releases, conference presentations, and peer-reviewed journal articles. Findings will be reported regardless of effect size or direction.

Footnotes

Prepublication history for this paper is available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2026-118458).

Data availability free text: Deidentified participants’ data analysed during the current study are available from the corresponding author on reasonable request.

Patient consent for publication: Not applicable.

Provenance and peer review: Not commissioned; externally peer-reviewed.

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

References