Iatrogenic Complications Of Diabetes Mellitus An Examination Of Hospital-Acquired Diabetic Ketoacidosis

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January 2019

Iatrogenic Complications Of Diabetes Mellitus: An

Examination Of Hospital-Acquired Diabetic

Ketoacidosis And Severe Outpatient

Hypoglycemia

Chloe Zimmerman

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Recommended Citation

Zimmerman, Chloe, "Iatrogenic Complications Of Diabetes Mellitus: An Examination Of Hospital-Acquired Diabetic Ketoacidosis

And Severe Outpatient Hypoglycemia" (2019). Yale Medicine Thesis Digital Library. 3546.

https://elischolar.library.yale.edu/ymtdl/3546

Iatrogenic Complications of Diabetes Mellitus: An Examination of Hospital-Acquired

Diabetic Ketoacidosis and Severe Outpatient Hypoglycemia

A Thesis Submitted to the

Yale University School of Medicine

in Partial Fulfillment of the Requirements for the

Degree of Doctor of Medicine

by

Chloe Olivia Zimmerman

2019

Abstract

Patients with diabetes mellitus are at risk for two acute metabolic complications:

severe hyperglycemia and hypoglycemia. These acute complications are costly and

associated with significant morbidity and mortality, but are preventable with delivery of

high-quality care. The purpose of this work is to focus on a subset of these complications

which are iatrogenic, i.e., caused by medical treatment. Hospital-acquired diabetic

ketoacidosis (DKA) is an iatrogenic complication as it occurs when a patient with known

diabetes experiences DKA while hospitalized for other reasons. Hypoglycemia is an

adverse effect of treatment and thus, by definition, all hypoglycemia resulting from the

use of glucose-lowering medications in the outpatient setting is iatrogenic. Reducing the

occurrence of these iatrogenic complications of diabetes can improve patient health

outcomes and reduce costs. However, prevention requires targeted interventions based on

a detailed understanding of precipitating factors. In order to address these iatrogenic

complications, we performed two analyses to examine factors driving their occurrence.

The first analysis is a retrospective chart review of hospitalized adults with

diabetes who developed DKA during a hospital admission at a single local hospital.

Twenty-seven patients were included in this analysis over 5 years. The patients were

predominantly White (70.4%) and middle-aged (average age 53.4 years). Most had a

documented diagnosis of type 1 diabetes (59.3%) and all but 1 patient were on insulin at

home. At the time of DKA, 51.9% were on medicine or neurology services, 33.3% on

surgery or ob/gyn, and 14.8% on podiatry. Using common cause analysis, the most

prevalent reason for DKA was a problem with insulin dosing, including missed doses of

insulin (n=7, 25.9%) and insulin dose reductions of 50% or greater (n=8, 29.6%). The

remaining cases were caused by steroids (n=4, 13.8%), infection (n=4, 13.8%), and acute

stress associated with surgery or shock (n=4, 13.8%).

The second analysis is a retrospective analysis of factors that mediate severe

hypoglycemia requiring an ED visit or hospitalization in an insured population in

California. A total of 305,310 adults with diabetes were included in this analysis. Among

the full cohort, the rate of severe hypoglycemia requiring an ED visit or hospitalization

was 7.4 per 1,000 person-years, but this varied significantly by race. Among Black vs

White patients, the rates were 13.64 vs 9.27 per 1,000 person-years, respectively. Given

the significance of these racial disparities, factors mediating these disparities were further

explored. Differences in insulin use by race were not significant, and racial disparities

persisted among patients on insulin. Rates of hypoglycemia among Black vs White

patients on insulin were 34.72 [95% CI 30.09, 38.87] vs 27.14 [25.38, 28.98] per 1000

person-years, respectively. Factors mediating the racial differences in ED visits and

hospitalizations for severe hypoglycemia were investigated using literature review and

clinical expert input and a directed acyclic graph (DAG) was created to depict the causal

relationships of the proposed mediator variables. Analytic work for this project is

ongoing. To analyze our DAG, we plan to assess the causal impact of each proposed

mediator variable by using inverse probability weighting to estimate counterfactual

disparity measures.

Together, these projects demonstrate the importance of thorough analysis of

factors that mediate and precipitate iatrogenic complications. In the case of hospital￾acquired DKA, interventions targeting inappropriate insulin dosing among hospitalized

patients with diabetes could potentially prevent over 50% of cases. For severe outpatient

hypoglycemia, quantifying the causal impact of each proposed mediator variable in the

DAG will reveal high-yield opportunities to address disparities in hypoglycemia.

Ongoing work on both projects continues to improve understanding of these problems

and will ultimately facilitate implementation of targeted prevention strategies.

Acknowledgements

I would like to thank Dr. Kasia Lipska for her support and mentorship over the past four

years. She has generously welcomed my contributions to her research, facilitated

relationships with her collaborators, and encouraged me to pursue my own independent

projects. I will continue to look to her for inspiration and guidance as I move forward in

my medical training.

I would also like to thank Dr. Andrew Karter and Margaret Wharton for their essential

input on the clinical assumptions and statistical analyses in the severe outpatient

hypoglycemia analysis.

I would like to thank Alex Friedman for his help with the design and initiation of the

hospital-acquired DKA project.

I owe this thesis to the patience and unwavering support of my friends and family,

without whom I would not have made it to this point.

Finally, I would like to thank Yale School of Medicine for the opportunity to explore my

research interests during my time here.

Research reported in this publication was supported by the National Institute on Diabetes

and Digestive and Kidney Diseases of the National Institutes of Health under Award

Number T35DK104689.

Table of Contents

Introduction......................................................................................................................... 1

Diabetes and its Complications....................................................................................... 1

Hospital-Acquired Diabetic Ketoacidosis ...................................................................... 2

Severe Outpatient Hypoglycemia ................................................................................... 4

Implications of this Research.......................................................................................... 5

Statement of Purpose and Hypotheses................................................................................ 8

Aim 1: Hospital-Acquired DKA..................................................................................... 8

Aim 2: Severe Outpatient Hypoglycemia ....................................................................... 9

Methods............................................................................................................................. 11

Aim 1: Hospital-Acquired DKA................................................................................... 11

Overall Design: Root Cause vs Common Cause Analysis ....................................... 11

Setting and Participants............................................................................................. 12

Main Outcome Measures.......................................................................................... 13

Statistical Analysis.................................................................................................... 14

Aim 2: Severe Outpatient Hypoglycemia ..................................................................... 15

Overall Design: Directed Acyclic Graphs and Mediation Analysis ......................... 15

Mediator Variable Selection ..................................................................................... 18

Inverse Probability Weighting and Counterfactual Disparity Measures .................. 18

Setting and Study Population.................................................................................... 20

Statistical Analysis.................................................................................................... 22

Results............................................................................................................................... 23

Aim 1: Hospital-Acquired DKA................................................................................... 23

Aim 2: Severe Outpatient Hypoglycemia ..................................................................... 28

Study Population....................................................................................................... 28

Rate of Severe Hypoglycemia, Overall and by Race................................................ 28

Insulin Use, Overall and by Race ............................................................................. 29

Directed Acyclic Graphs........................................................................................... 31

Future Results ........................................................................................................... 36

Discussion......................................................................................................................... 37

Aim 1: Hospital Acquired DKA ................................................................................... 37

1. Transition to inpatient management.................................................................. 37

2. Communication between co-managing teams .................................................. 39

3. Labile blood sugars........................................................................................... 40

Limitations................................................................................................................ 41

Next Steps................................................................................................................. 42

Aim 2: Severe Outpatient Hypoglycemia ..................................................................... 43

Limitations................................................................................................................ 45

Next Steps................................................................................................................. 45

Conclusions................................................................................................................... 46

Appendices........................................................................................................................ 47