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Hyponatremia in Acute Internal Medicine Patients

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Hyponatremia in Acute Internal Medicine Patients Hyponatremia in acute internal medicine patients: prevalence and prognosis PhD dissertation Louise Bill Health Aarhus University Department of Clinical Epidemiology, Aarhus University Hospital Department of Endocrinology and Internal Medicine, Aarhus University Hospital Supervisors and Collaborators Jens Otto Lunde Jørgensen, MD, DMSc, professor (main supervisor) Department of Endocrinology and Internal Medicine Aarhus University Hospital, Aarhus, Denmark Henrik Toft Sørensen, MD, PhD, DMSc, professor (project supervisor) Department of Clinical Epidemiology Aarhus University Hospital, Aarhus, Denmark Christian Fynbo Christiansen, MD, PhD, associate professor (project supervisor) Department of Clinical Epidemiology Aarhus University Hospital, Aarhus, Denmark Troels Ring, MD (project supervisor) Department of Nephrology Aalborg University Hospital, Aalborg, Denmark Sinna P. Ulrichsen, MSc (collaborator) Department of Clinical Epidemiology Aarhus University Hospital, Aarhus, Denmark Uffe Heide-Jørgensen, MSc, PhD (collaborator) Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark ii Assessment Committee Søren Rittig, MD, associate professor (chairman) Department of Clinical Medicine and Department of Pediatrics Aarhus University and Aarhus University Hospital, Denmark Michael Fored, MD, PhD, associate professor Clinical Epidemiology Unit, Department of Medicine Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden Jens Faber, MD, DMSc, professor Department of Clinical Medicine Herlev Hospital, Herlev, Denmark iii iv Acknowledgments I would like to express my sincere gratitude to all the inspiring and skilled people who made the work presented in this dissertation possible. I am truly grateful to you all. I am deeply indebted to Henrik Toft Sørensen. You dared invite me onto your team at the Department of Clinical Epidemiology. Thank you for believing in me and for opening the world of research to me, for outstanding mentorship, for patiently teaching me clinical epidemiology and the art of scientific writing. My sincere thanks to Jens Otto Lunde Jørgensen and Troels Ring for generously sharing your extensive clinical knowledge and research experience. Thank you for enthusiastically introducing me to the wonders of hyponatremia and for priceless feedback and guidance throughout the years. A special thanks to Christian Fynbo Christiansen; for always encouraging me, for enduring my many questions, and for always leaving the door open. I could not have done it without your guidance and mentorship. I warmly thank Karin Petersen for inviting me to do research at California Pacific Medical Center Research Institute, and for giving Michael and I the opportunity to experience the fantastic city of San Francisco. Thanks to Maria Danielsen and Karen Abrahamsen for treasured memories and friendship. To all my great colleagues at the Department of Clinical Epidemiology, thank you for creating an inspiring and friendly working environment. Especially thanks to Henrik Gammelager for all your help and always positive attitude; to Sinna Ulrichsen and Uffe Heide-Jørgensen for statistical support; and to Anne Ording, Mary Nguyen Nielsen, Jesper Smit, Charlotte Slagelse and Sandra Kruchov Thygesen; for serious and not so serious office-discussions, and for being there for me. This work was made possible with financial support from the Program for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Foundation and the Novo Nordisk Foundation, Otsuka Pharma Scandinavia AB, the Danish Cancer Society, the Aarhus University Research Foundation, the Clinical Epidemiology Research Foundation, and Aarhus University, Denmark. Finally, I would like to thank family and friends for never-ending support and encouragement; a heartfelt thanks to my parents Dorte and Hardy Bill for teaching me that anything is possible if I set my mind to it, and for helping me see what is truly important in life; and to Michael for always being there, for reassuring me and for your infectious positive nature. Louise Bill, August 2015 v Dissertation Papers Paper I Validity of the International Classification of Diseases, 10th revision Discharge Diagnosis Codes for Hyponatraemia in the Danish National Registry of Patients. Louise Holland-Bill, Christian F. Christiansen, Sinna P. Ulrichsen, Troels Ring, Jens Otto L. Jørgensen, Henrik T. Sørensen. BMJ Open. 2014 Apr 23;4(4):e004956. Paper II Hyponatremia and Mortality Risk: A Danish Cohort Study of 279,508 Acutely Hospitalized Patients. Louise Holland-Bill, Christian F. Christiansen, Sinna P. Ulrichsen, Uffe Heide-Jørgensen, Troels Ring, Jens Otto L. Jørgensen, Henrik T. Sørensen. Eur J Endocrinol. 2015;173(1):71-81 Paper III Preadmission Diuretic Use is Associated with Increased Mortality in Patients with Hyponatremia – a Propensity Score-matched Cohort Study. Louise Holland-Bill, Christian F. Christiansen, Sinna P. Ulrichsen, Troels Ring, Jens Otto L. Jørgensen, Henrik T. Sørensen. (submitted) vi Abbreviations aMRR Adjusted mortality rate ratio ATC Anatomical therapeutic chemical ADH Antidiuretic hormone CCI Charlson Comorbidity Index CI Confidence interval CPR Central person registry CRS Civil registration system DIP Department of internal medicine DM Diabetes mellitus DNHSPD Danish National Health Service Prescription Database DNPR Danish National Patient Registry ED Emergency department eGFR Estimated glomerular filtration rate HA Hospital admission ICD International Classification of Disease ICU Intensive care unit ISE Ion selective electrode LVSD Left ventricular systolic dysfunction MeSH Medical Subject Heading NPV Negative predictive value OR Odds ratio PPV Positive predictive value RR Relative risk SIADH Syndrome of inappropriate antidiuretic hormone SSRI Selective serotonin reuptake inhibitors vii viii Contents 1. Introduction ......................................................................................................................................... 1 2. Background ......................................................................................................................................... 3 2.1 Risk factors and mechanisms for hyponatremia ........................................................................... 3 2.2 Prognosis of hyponatremia............................................................................................................ 5 2.2.1 Established and proposed cellular effects of hyponatremia ...................................................... 5 2.2.2 Hyponatremia and mortality in specific diseases ...................................................................... 6 2.3 Literature review ........................................................................................................................... 7 2.4 Quality of discharge diagnosis for hyponatremia (study I) ......................................................... 14 2.5 Prevalence in patients acutely admitted to departments of internal medicine (study II) ............ 14 2.6 Hyponatremia and mortality in internal medicine patients (study II) ......................................... 15 2.7 Impact of diuretic use on hyponatremia-associated mortality (study III) ................................... 16 2.8 Hypotheses and aims ................................................................................................................... 16 3. Methods .............................................................................................................................................. 18 3.1 Setting ......................................................................................................................................... 18 3.2 Data sources ................................................................................................................................ 18 3.2.1 The Danish National Patient Registry (studies I, II and III) ................................................... 18 3.2.2 The Civil Registration System (studies I, II and III) ............................................................... 18 3.2.3 The LABKA database (studies I, II and III) ........................................................................... 19 3.2.4 The Danish National Health Service Prescription Database (study III) .................................. 21 3.3 Study designs .............................................................................................................................. 21 3.4 Study populations ........................................................................................................................ 21 3.5 Exposures (or diagnostic test) ..................................................................................................... 23 3.5.1 Discharge diagnosis for hyponatremia (study I) ..................................................................... 23 3.5.2 Admission hyponatremia (study II) ........................................................................................ 23 3.5.3 Preadmission diuretic use (study III) ...................................................................................... 23 3.6 Outcomes .................................................................................................................................... 24 3.6.1 Reference standard for hyponatremia diagnosis (study I) ....................................................... 24 3.6.2 All-cause mortality (studies II and III) ...................................................................................
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