Background: Significant improvements in clinical outcome can be achieved by implementing effective strategies to optimise pain management, reduce sedative exposure, and prevent and treat delirium in ICU patients. One important strategy is the monitoring of pain, agitation and delirium (PAD bundle). We hypothesised that there is no sufficient financial benefit to implement a monitoring strategy in a Diagnosis Related Group (DRG)-based reimbursement system, therefore we expected better clinical and decreased economic outcome for monitored patients., Methods: This is a retrospective observational study using routinely collected data. We used univariate and multiple linear analysis, machine-learning analysis and a novel correlation statistic (maximal information coefficient) to explore the association between monitoring adherence and resulting clinical and economic outcome. For univariate analysis we split patients in an adherence achieved and an adherence non-achieved group., Results: In total 1,323 adult patients from two campuses of a German tertiary medical centre, who spent at least one day in the ICU between admission and discharge between 1. January 2016 and 31. December 2016. Adherence to PAD monitoring was associated with shorter hospital LoS (e.g. pain monitoring 13 vs. 10 days; p<0.001), ICU LoS, duration of mechanical ventilation shown by univariate analysis. Despite the improved clinical outcome, adherence to PAD elements was associated with a decreased case mix per day and profit per day shown by univariate analysis. Multiple linear analysis did not confirm these results. PAD monitoring is important for clinical as well as economic outcome and predicted case mix better than severity of illness shown by machine learning analysis., Conclusion: Adherence to PAD bundles is also important for clinical as well as economic outcome. It is associated with improved clinical and worse economic outcome in comparison to non-adherence in univariate analysis but not confirmed by multiple linear analysis., Trial Registration: clinicaltrials.gov NCT02265263, Registered 15 October 2014., Competing Interests: MD has nothing to declare. CS reports grants from Aridis Pharmaceutical Inc., grants from B. Braun Melsungen AG, grants from Drägerwerk AG & Co. KGaA, grants from Grünenthal GmbH, grants from Infectopharm GmbH, grants from Sedana Medical Ltd., grants from Deutsche Forschungsgemeinschaft / German Research Society, grants from Deutsches Zentrum für Luft- und Raumfahrt e. V. (DLR) /German Aerospace Center, grants from Einstein Stiftung Berlin/ Einstein Foundation Berlin, grants from European Society of Anaesthesiology, grants from Gemeinsamer Bundesausschuss / Federal Joint Committee (G-BA), grants from Inneruniversitäre Forschungsförderung / Inner University Grants, grants from Projektträger im DLR / Project Management Agency, grants from Stifterverband/Non-Profit Society Promoting Science and Education, grants from WHOCC, grants from Baxter Deutschland GmbH, grants from Biotest AG, grants from Cytosorbents Europe GmbH, grants from Edwards Lifesciences Germany GmbH, grants from Fresenius Medical Care, grants from Grünenthal GmbH, grants from Masimo Europe Ltd., grants from Medtronic GmbH, grants from Pfizer Pharma PFE GmbH, personal fees from Georg Thieme Verlag, grants from Dr. F. Köhler Chemie GmbH, grants from Sintetica GmbH, grants from European Commission, grants from Stifterverband für die deutsche Wissenschaft Þ.V. / Philips, grants from Stiftung Charité, grants from AGUETTANT Deutschland GmbH, grants from AbbVie Deutschland GmbH & Co. KG, grants from Amomed Pharma GmbH, grants from InTouch Health, grants from Copra System GmbH, grants from Correvio GmbH, grants from Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., outside the current work; In addition, Prof. Spies has a patent 10 2014 215 211.9 licensed, a patent 10 2014 215 212.9 licensed, a patent 10 2018 114 364.8 licensed, and a patent 10 2018 110 275.5 pending. Dr. Bjoern Weiss reports personal fees from Orion Pharma Ltd. Outside the current work; in addition Dr. Weiss reports grants from the European Society of Intensive Care Medicine and the Robert-Koch-Insititute outside the current work. NK has nothing to declare. MJ reports talks or teaching for which she received modest honoraria by the following organizations: German National Association of Statutory Health Insurance Physicians, Dr. Risch Laboratories (Buchs, Switzerland), Health Ministry Baden-Württemberg (Germany), mediX AG(Zurich, Switzerland), VDE e.V. (Germany), Geburtshülfliche Gesellschaft zu Hamburg (Obstetrics Association Hamburg), Landesgesundheitsprojekte e.V. (Germany), Gesundheitsforen Leipzig GmbH (Germany), Deutsche Menopause Gesellschaft e.V. (German Menopause Association), Deutscher Berufsverband für Pflegeberufe (DBfK) Nordwest e.V. (German Nursing Association), Swiss Rheumatism Symposium, Sana Herzchirurgie Stuttgart GmbH (Germany). The Harding Center (MJ's former employer) has received funding from: AOK Insurance (Germany), Helsana Insurance (Switzerland), BKK Viactiv Insurance (Switzerland), German Football Association, Microsoft Research New Work, David Harding (Winton Philanthropies), German Federal Institute for Risk Assessment, ERGO Insurances (Germany), Goethe University of Frankfurt (Germany), German Ministry for Transport and digital Infrastructure, German Ministry for Justice and Consumer Protection, German Aerospace Center. JK has nothing to declare. FB reports grants from Berlin Institute of Health, grants from Einstein Foundation, personal fees from Axon Publishing, grants from Vifor Pharma, grants and personal fees from Clearflow, personal fees and non-financial support from Medtronic outside the current work. I hereby confirm that all patents and personal fees that have been reported by the authors are entirely outside the current work. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.