Hyponatremia in acute internal medicine patients

144 Pages·2015·3.65 MB·English

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

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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

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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

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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)

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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

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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) .................................................................................... 24
3.7 Covariates ................................................................................................................................... 24
3.7.1 Demographic information ....................................................................................................... 24
3.7.2 Department and year of admission .......................................................................................... 24
3.7.3 Preexisting morbidity and the Charlson Comorbidity Index .................................................. 25
3.7.4 Discharge diagnosis related to the current hospitalization ...................................................... 25
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3.7.5 Estimated glomerular filtration rate (eGFR) ........................................................................... 25
3.7.6 Concurrent drug use ................................................................................................................ 25
3.8 Statistical analyses ...................................................................................................................... 26
3.8.1 Data quality measures (study I) .............................................................................................. 26
3.8.2 Prevalence (study II) ............................................................................................................... 27
3.8.3 Mortality (studies II and III) ................................................................................................... 27
3.8.4 Sensitivity analyses (studies I–III) .......................................................................................... 28
3.8.5 Additional information ............................................................................................................ 29
4. Results ................................................................................................................................................ 30
4.1 Quality of ICD-10 codes for hyponatremia (study I) .................................................................. 30
4.2 Prevalence of admission hyponatremia (study II) ....................................................................... 31
4.3 Hyponatremia and mortality (study II) ....................................................................................... 31
4.4 Impact of diuretic use on hyponatremia-associated mortality (study III) ................................... 36
5. Discussion........................................................................................................................................... 38
5.1 Main conclusions ........................................................................................................................ 38
5.2 Comparison with existing literature ............................................................................................ 38
5.2.1 Quality of ICD-10 codes for hyponatremia (study I) .............................................................. 38
5.2.2 Prevalence of admission hyponatremia (study II) ................................................................... 39
5.2.3 Hyponatremia and mortality (study II) ................................................................................... 40
5.2.4 Impact of diuretic use on hyponatremia-associated mortality (study III) ............................... 41
5.3 Methodological considerations ................................................................................................... 42
5.3.1 Precision .................................................................................................................................. 42
5.3.2 Selection bias .......................................................................................................................... 43
5.3.3 Information bias ...................................................................................................................... 44
5.3.4 Confounding ........................................................................................................................... 45
5.3.5 Statistical analysis ................................................................................................................... 46
5.4 Clinical implications ................................................................................................................... 47
5.5 Perspective .................................................................................................................................. 48
6. Summary ............................................................................................................................................ 50
7. Dansk resume .................................................................................................................................... 52
8. References .......................................................................................................................................... 54
9. Appendices ......................................................................................................................................... 67

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