Early Administration of Insulin Glargine in Patients With Diabetic Ketoacidosis
Phase: PHASE2
Conditions: DKA
Sponsor: HealthPartners Institute

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Early Administration of Insulin Glargine in patients with Diabetic Ketoacidosis  
Summary  
 
Diabetic ketoacidosis (DKA) is a medical emergency that is associated with significant morbidity and mortality for both 
patients with type I and type II diabetes1. DKA is diagnosed with a blood glucose level > 250 mg/dL, pH </= 7.3, sodium  
bicarbonate level of </= 18 mEq/L, an anion gap > 10, and the presence of urine and/or serum ketones. Insulin is one of 
the main treatment modalities for DKA. By correcting hyperglycemia and inhibiting the release of free fatty acids, insulin 
administration leads to decreased ketone formation and resolution of acidosis. Short-acting (Regular) intravenous insulin 
is often preferred to subcutaneous administration for initial management due to its short half-life and ease of titration, but 
patients will eventually need to transition to subcutaneous insulin prior to discharge1. This transition will likely include the 
administration of long-acting, basal insulins such as insulin glargine (Semglee, Lantus® or Basaglar®) or insulin 
deguldec (Tresiba®), which have a slow onset of action and have an extended duration of action2. The timing of initiation 
or resumption of home long-acting subcutaneous insulin is controversial in the treatment of DKA. Traditionally, patients 
are transitioned from IV to subcutaneous insulin once the patient reaches a blood glucose level of < 200 - 250 mg/dl and 
experiences two of the following: anion gap closure (≤ 12 mEq/L), resolution of acidosis (pH > 7.3), and/or a sodium 
bicarbonate level of ≥ 15 mEq/L1. The 2019 American Diabetes Association Standards of Medical Care in Diabetes 
recommend initiation of basal insulin 2 – 4 hours prior to discontinuation of intravenous insulin3. However, the 2014 Joint 
British Diabetes Societies Inpatient Care Group on The Management of Diabetic Ketoacidosis in Adults, recommend 
continuing patient’s subcutaneous basal insulin during the initial management of DKA4. 
 
Small prospective, randomized, controlled, pilot trials have shown early initiation of basal insulin within 2-12 hours of IV 
insulin infusion initiation can prevent rebound hyperglycemia when the insulin infusion is eventually discontinued. These 
trials have also shown trends toward decreased time to anion gap closure, resolution of acidosis, and hospital length of 
stay with no increase in hypoglycemic events5–7. Retrospective studies have also shown decreases in time on insulin 
infusion and trends toward shorter ICU length of stay, resulting in lower costs to the institution8. The optimal dose and 
initial timing of early basal insulin is unknown. Trials have used initial basal insulin dosing ranging from 0.25 to 0.4 units 
per kilogram that was initiated anywhere from 2 to 12 hours after the initiation of IV insulin infusion, but no prospective 
trials have examined resuming the patient’s home basal insulin early in the course of DKA treatment  5–7.  
 
It is currently unknown if resuming a portion or all of the patient’s home basal regimen during the initial treatment phase of 
DKA will provide an impact on patient care. The objective of this study is to evaluate the impact of early glargine 
administration at a dose of 0.2 units/kg if the patient was not previously on basal insulin or resuming the patient’s home 
basal insulin regimen within two hours after the start of the intravenous insulin infusion in addition to usual care. We will 
conduct a prospective, randomized study comparing initiation early glargine administration to current standards of care. 
Outcomes include patient length of hospitalization, ICU length of stay, time to resolution of acidosis and anion gap 
closure, incidence of hypoglycemia, and incidence of rebound hyperglycemia.  
 
One of the major benefits of this study is its utter simplicity. We will only have one intervention, and only in the intervention 
group (starting long-acting insulin early along with IV insulin therapy). The control group (standard of care group (SOC)) 
will be treated as they have been historically using the Regions Hospital DKA treatment protocol. We are not asking for 
more labs or nursing/provider interventions than usual. We are also not asking more of our pharmacists besides making at 
most 1-2 more doses of long-acting insulin for patients in the intervention group. This small intervention can help reduce 
ICU and hospital LOS, time on IV insulin infusion, and total amount of IV insulin administered- all of which will lead to a 
much greater cost reduction than 1-2 extra doses of long-acting insulin. As an added bonus, per preliminary reports 
(discussed below) giving long-acting insulin along with the IV insulin infusion does not lead to any additional adverse 
events, including hypoglycemia. 
 
Study aims  
Primary Outcome: 
1) Does early administration of insulin glargine result in a shorter ICU length of stay when compared to usual care 
for the treatment of diabetic ketoacidosis? 
Hypothesis: Early administration of insulin glargine will result in shorter ICU length of stay when compared to 
usual care in patients with DKA. 
Secondary Outcomes: 
1) Does early administration of insulin glargine result in a shorter hospital length of stay (defined as time between 
start of insulin infusion and discharge from hospital) when compared to usual care for the treatment of diabetic 
ketoacidosis? 

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Hypothesis: Early administration of insulin glargine will result in shorter hospital length of stay when compared to 
usual care in patients with DKA. 
 
2) Does early administration of insulin glargine result in a faster recovery from DKA (defined as blood glucose < 200 
and two of: Anion Gap </= 12, Serum Bicarbonate ≥ 15 mEq/L, or pH > 7.3) when compared to usual care for the 
treatment of diabetic ketoacidosis? 
 
Hypothesis: Early administration of insulin glargine will result in a faster recovery from DKA (defined as blood 
glucose <200 and two of: Anion Gap </= 12, Serum Bicarbonate ≥ 15 mEq/L, or pH > 7.3) when compared to 
usual care for the treatment of diabetic ketoacidosis. 
 
3) Does early administration of insulin glargine result in a shorter duration of elevated anion gap (defined as time 
with anion gap > 12) when compared to usual care for the treatment of diabetic ketoacidosis? 
 
Hypothesis: Early administration of insulin glargine will result in a shorter duration of elevated anion gap (defined 
as time with anion gap > 12) when compared to usual care for the treatment of diabetic ketoacidosis. 
 
4) Does early administration of insulin glargine result in a shorter duration of time on IV insulin infusion when 
compared to usual care for the treatment of diabetic ketoacidosis? 
 
Hypothesis: Early administration of insulin glargine will result in a shorter duration of time on IV insulin infusion 
when compared to usual care for the treatment of diabetic ketoacidosis. 
 
5) Does early administration of insulin glargine result in a lower prevalence of rebound hyperglycemia, defined as 
blood glucose > 180 mg/dL in the 24 hours after IV insulin infusion discontinuation, when compared to usual care 
for the treatment of diabetic ketoacidosis? 
 
Hypothesis: Early administration of insulin glargine will result in a lower incidence of rebound hyperglycemia, 
defined as blood glucose > 180 mg/dL in the 24 hours after IV insulin infusion discontinuation, when compared to 
usual care for the treatment of diabetic ketoacidosis? 
 
6) What is the prevalence of a hypoglycemic (defined as blood glucose < 70mg/dL) event occurring while on IV 
insulin therapy or in the 24h hours after IV insulin infusion discontinuation with early insulin glargine administration 
compared to usual care?  
 
Hypothesis: The occurrence of a hypoglycemic event occurring while on IV insulin therapy or in the 24h hours 
after IV insulin infusion discontinuation with administration of insulin glargine is comparable to usual care. 
 
7) Does early administration of insulin glargine result in a statistically lower mean blood glucose value in the 24 
hours and (separately) 48 hours after IV insulin infusion discontinuation? 
 
Hypothesis: Early administration of insulin glargine will result in a lower mean value of blood glucose in the 24 and 
48 hours after IV insulin infusion discontinuation. 
 
Background, Rationale, Significance 
In 2014, there were 168,000 hospitalizations for DKA, and the average length of stay was 3.4 days in 20091. The 
estimated annual direct medical expense and indirect cost is 2.4 billion dollars per year1. DKA is a potentially life-
threatening condition due to its ability to cause metabolic acidosis, electrolyte imbalances, and dehydration1. While 
DKA treatment protocols differ from institution to institution, the goals of treatment remain the same --- resolution of 
acidosis, dehydration, and hyperglycemia. Following fluid resuscitation, correction of hyperglycemia with insulin 
therapy is the mainstay of treatment11. Intravenous (IV) insulin infusions with regular insulin are commonly used due 
to its short half-life of 30 to 60 minutes and resulting titratability1. Treatment is then continued with subcutaneous (SC) 
insulin once the acidosis and anion gaps have cleared and the patient’s hemodynamics and electrolytes abnormalities 
have resolved3. At Regions Hospital, the current criteria for transitioning from IV to SC insulin include meeting the 
following criteria: 1) fasting blood glucose levels are stable between 180-250 mg/dL for at least 4 hours, 2) vital signs, 
potassium, and sodium levels are stable and within the normal range, 3) the metabolic acidosis has cleared (anion 

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gap <15, and either arterial pH ≥ 7.3 or venous pH ≥ 7.27), and 4) the patient is able to eat regular meals. 
Traditionally, when SC insulin is initiated, the IV insulin infusion is stopped two hours later. However, the timing of SC 
initiation has becoming more controversial in recent years. The 2019 American Diabetes Association Standards of 
Care recommend transition of patients from IV to SC insulin requires administration of basal insulin 2–4 h prior to the 
intravenous insulin being stopped to prevent recurrence of ketoacidosis and rebound hyperglycemia4. However, the 
2014 Joint British Diabetes Societies Inpatient Care Group recommend continuing a patient’s home basal insulin 
during the initial management of DKA to prevent rebound hyperglycemia and to avoid extending length of stay5. 
Several recent papers have examined early basal insulin administration as adjunct therapies with IV insulin infusions 
for the treatment of hyperglycemia and DKA.  
 
In 2012, a single-center prospective, randomized controlled trial by Hsia et al. compared IV insulin infusion with or 
without early administration of insulin glargine (dose = 0.25 U/kg) in 61 hyperglycemic patients with diabetes. Forty-
one percent (25/61) of the patients enrolled in the trial were admitted with DKA. Those in the early insulin glargine arm 
were to receive the glargine subcutaneous injection within 12 hours of initiation of IV insulin infusion. Patients were 
excluded if they were newly diagnosed with hyperglycemia, critically ill, or pregnant. All other decisions about 
transitioning study subjects to SC insulin was left to primary teams including dose, type of insulin, and timing of 
transition. Those patients that received early glargine had lower prevalence of rebound hyperglycemia when the 
insulin infusion was discontinued (experimental group: 33% vs control group: 93.5%; P < 0.001). The total length of IV 
insulin infusion was similar in the two groups (control group: 35 ± 13h vs experimental group: 42 ± 24h). The mean 
blood glucose levels within the 12-hour study period were significantly lower in the intervention group, while there 
were 3 asymptomatic hypoglycemic measurements in the control group and none in the intervention group6.  
In 2015, Doshi et al. conducted a two-center prospective, randomized controlled trial of 40 patients admitted for DKA. 
Patients were randomized to receive early insulin glargine (dose = 0.3 U/kg) or no glargine in addition to regular care. 
Those in the early insulin glargine arm were to receive the glargine subcutaneous injection within 2 hours of 
diagnosis. Patients were excluded if they required inotropic/vasopressor resuscitation, had ESRD, required emergent 
surgery, or were less than 18 years old, pregnant, unwilling to participate, prisoners, or transferred to another hospital. 
Patients in the control group were given insulin glargine once the anion gap closed and the IV insulin infusion was 
continued for two additional hours. There was no difference in time to anion gap closure (control group: 11.6 ± 6.4h vs 
experimental group: 10.2 ± 6.8 hours; p = 0.63), hospital length of stay (control group: 4.6 ± 3.6 days vs experimental 
group: 3.9 ± 3.4 days; p = 0.66), ICU admissions (control group: 4 admissions vs experimental group: 6 admissions; p 
= 0.71), ICU length of stay (control group: 1.2 days vs experimental group: 1.8 days; p = 0.47), and hypoglycemic 
events (control group: 3 events vs experimental group: 2 events)5–8. 
Also in 2015, Houshyar et al. conducted a single-center, prospective, randomized controlled trial of 40 patients 
admitted for DKA. Patients were randomized to receive early insulin glargine (dose = 0.4 U/kg) or no insulin glargine 
in addition to usual care. Those in the early insulin glargine arm were to receive the glargine subcutaneous injection 
within 3 hours of IV insulin infusion initiation. Patients were excluded if they had hypotension (systolic blood pressure 
< 80 mmHg despite receiving 1000ml NS), acute MI, progressive renal or hepatic failure, or lack of consent. Patients 
in the control group were given insulin glargine once the anion gap closed. There was no difference in duration of 
acidosis (control group: 16.91 ± 6.5h vs experimental group: 13.77 ± 6.1h; p = 0.123). There were higher rates of 
hyperglycemia following discontinuation of the insulin infusion in those that did not receive early glargine (51% vs. 
35% of measurements in the experimental group showed a glucose >8.3 mM or >150 mg/dL; p = 0.046). There was 
no difference in hospital length of stay (control group: 5.9 ± 2.2 days vs experimental group: 5.1± 1.9 days; p = 0.225) 
or rates of hypoglycemia (control group: 7 events in 5 patients vs experimental group: 4 events in 4 patients; no p-
value reported). 
Lastly, Rappaport et al. (2019) conducted a single-center, retrospective cohort study of 106 admissions for DKA 
comparing early vs late initiation of basal insulin. Patients admitted to the MICU who were treated with home-dose 
basal insulin prior to DKA resolution and within 24 hours of IV insulin infusion initiation (n = 33) were compared to 
patients who were initiated on basal insulin within 6 hours before or any time after IV insulin infusion discontinuation (n 
= 73). Transition from IV insulin infusion to subcutaneous insulin was not addressed in a protocol and was left to the 
discretion of the provider. Patients were excluded if they had surgery within 48 hours of IV insulin infusion, were 
pregnant, were in vasopressor dependent shock, or had another indication for insulin therapy. Patients in the early 
group had initial daily doses of basal insulin of 0.48 U/kg (IQR: 0.34 – 0.62) compared to 0.44 U/kg in the late group. 
Patients in the early insulin group had their first dose of basal insulin 2.5 hours (IQR: 0.4 – 6.4) after IV insulin infusion 
initiation. There was no difference in transitional failure (early group: 6% vs late: 10%; p = 0.717), rebound 
hyperglycemia (early: 81% vs late: 88%; OR: 0.59, CI: 0.16 – 2.25), hypoglycemia events (early: 33% vs late: 55%; 
OR: 0.41, CI: 0.16-1.05); time to anion gap closure: (early: 7.8h vs late: 9.1h; p = 0.73), length of ICU stay (early: 34h 
vs late: 33.3h, p = 0.83), or hospital length of stay (early: 2 days vs late: 2 days, p = 0.9). There was a statistically 
significant decrease for time on IV insulin infusion (early: 13.8h vs late: 17.1h, p = 0.04). 

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Preliminary research at Regions Hospital determined that in 40 randomly selected patients admitted for DKA in 2019, 
the mean dose of basal insulin initiated was 0.39 units per kilogram, and it was administered a mean of 22.4 hours 
after initiation of the IV insulin infusion and 1.86 hours prior before discontinuation of IV insulin, which is consistent 
with ADA recommendations1,3 
In summary, previous randomized studies using weight based basal insulin doses have shown that the early initiation 
of basal insulin can prevent rebound hyperglycemia with no increase in hypoglycemia. One retrospective study 
demonstrated a decrease of time on IV insulin infusion in those that received early basal insulin when compared to 
those that did not. These studies have also shown trends toward shorter ICU and hospital length of stay, anion gap 
closure, and time to resolution of acidosis but none have demonstrated statistical significance. However, no 
prospective trials have examined resuming the patient’s home basal insulin early in the course of DKA5–7. It is 
currently unknown if resuming a portion or the entirety of the patient’s home basal regimen will provide an impact on 
patient care. By conducting a prospective study comparing initiation of early glargine administration at the patient’s 
home dose to current standards of care, early administration may lead to shorter ICU and hospital lengths of stay as 
well as shorter duration of acidosis. This could provide significant cost-savings to the institution and benefit patients in 
need of treatment for this serious complication of diabetes. 
Approach 
Study design  
This is a prospective, randomized trial to determine whether a fixed dose of early basal insulin administration is 
superior to standard of care for the treatment of DKA. 
Population 
Inclusion Criteria 
• 
Presented to Regions Hospital ED for chief complaint of DKA, nausea, vomiting, abdominal pain, hyperglycemia, 
or similar 
• 
Meets all below diagnostic criteria for DKA per the American Diabetes Association: 
o 
Arterial or venous pH </= 7.3 
o 
Serum Bicarbonate </= 18 mEq/L 
o 
Ketonuria or ketonemia 
o 
Anion Gap > 10 
o 
Blood sugar > 250 mg/dL 
• 
Receiving IV insulin infusion  
• 
It is feasible to provide insulin glargine within 2 hours (+/- 30 minutes) of IV infusion start 
• 
Will be admitted to the ICU for DKA, or already admitted to the ICU for DKA 
• 
Ability to provide informed consent 
 
Exclusion Criteria 
• 
Age < 18 
• 
End stage renal disease or hepatic disease 
• 
Hypotension requiring IV vasopressors or inotropes at any point during admission (i.e. norepinephrine, 
dobutamine, vasopressin, etc.) 
• 
Need for emergent surgery 
• 
Pregnant patients 
• 
Prisoners 
• 
Indication for insulin therapy other than DKA (hypertriglyceridemia, beta-blocker overdose, hyperglycemia without 
DKA)  
• 
Patients receiving prior to admission insulin pump therapy 
• 
Patients receiving prior to admission combination insulin products (i.e. Novolin® 70/30, Novolog® 70/30, 
Humalog® 75/25, etc.) 
• 
Did not consent to study 
 
Sample size 
From 1/1/2018 to 6/30/2019 there were 399 unique encounters of patients admitted to Regions Hospital with an 
associated ICD-10 code of E10.10 (Type 1 diabetes mellitus with ketoacidosis without coma), E10.11 (Type 1 
diabetes mellitus with ketoacidosis with coma), E11.10 (Type 2 diabetes mellitus with ketoacidosis without coma), 

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E11.11 (Type 2 diabetes mellitus with ketoacidosis with coma), E13.10 (Other specified diabetes mellitus with 
ketoacidosis without coma), or E13.11 (Other specified diabetes mellitus with ketoacidosis with coma). 
We expect patients to present at the same rate, indicating that an estimated 264 patients with one of these eligible 
diagnoses will present over the twelve months of study enrollment. Of those 264, we expect 25% to be ineligible due 
to meeting one of the study exclusion criteria and another 25% to be eligible but decline participation. Therefore, we 
expect to see 132 total eligible subjects (66 in each randomization arm).  Due to our fixed sample-size, in lieu of a 
traditional power analysis to determine the number of subjects needed to detect a difference between the group we 
plugged our fixed sample size into a power analysis and solved for length of stay.  
We ran a power analysis using the same historical data used under the Sample size section of this proposal. Because 
we expect about 132 patients to be enrolled, we inspected length of stay (LOS) from the first 100 cases in our 
historical data. LOS is heavily right-skewed, so we log-transformed it to estimate detectible effect size. We used the 
“proc power” program in SAS 9.4, which has specifications for comparing two log-transformed means. In order to 
achieve 80% power to detect a true difference between two fixed groups of n=66, the ratio of logs would have to be 
about 1.31; when normalized, this translates to about 6.5 hours (alpha = 0.05, coefficient of variation =0.6). So, with 
our sample size, we estimate that the intervention would need to cause a 6.5-hour difference in average length of stay 
between groups in order for us to detect a difference 80% of the time.  
 
Data collection process 
Please see the section titled “Outcome/endpoint and other variable definitions, and instruments used” for a full 
description of this process. 
 
Screening and Enrollment  
 
Screening 
 
Because CCRC research interns provide 24/7 ED coverage, and ED pharmacy is also covered 24/7, there is no 
restriction as to the time of day or day of week when enrollments can take place. However, to enhance investigator 
oversight,  patients will only be enrolled when specific ED Pharmacists are on shift, who are the primary investigators. 
This includes Eric Berg, Adis Keric, and Lisa Manson. If those pharmacists are not at the site, the patient will not be 
enrolled.  
 
ED pharmacists received an Epic alert any time a patient meeting DKA criteria is admitted to the ED. The pharmacist 
will alert the CCRC research intern to confirm inclusion/exclusion and approach the patient for study participation. 
CCRC interns will also watch the ED track board for patients admitted with a chief complaint of DKA, nausea, 
vomiting, abdominal pain, hyperglycemia, or similar. Alternatively, an ED pharmacist or attending physician will notify 
Research of a potential patient by calling the 24/7 intern bat phone.  
 
Labs: in order to confirm inclusion/exclusion criteria, the patient will need to have had the following labs completed 
(which are standard of care for any patient with DKA on the differential diagnosis. These are not extra labs that the 
study investigators want, rather, they will already be collected by any provider for any patient with presumed DKA): 
  
• 
Arterial or venous pH </= 7.3 
• 
Serum Bicarbonate </= 18 mEq/L 
• 
Presence of ketonuria or ketonemia (beta-hydroxybutyrate > 0.27 mmol/L) 
• 
Anion Gap > 10 
• 
Blood sugar > 250 mg/dL 
All patients who present with symptoms of possible DKA should receive these labs under standard of care, per 
Regions Hospital DKA Protocol. Should any of these labs be missing, the patient will not be eligible for the study.  
 
The research intern will confirm inclusion and exclusion criteria using a RedCap screening checklist, and obtain 
permission from the patient’s attending to approach for study consent.  
 
Consent 
 
If fully eligible, research staff will approach the patient for consent, either by calling the patient’s room phone, mobile 
phone, or entering the patient’s room in appropriate PPE. (Please see the “Setting/Environment/Organizational 

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feasibility” section for COVID-19 safety information.) Since DKA can sometimes cause confusion, if a patient is 
deemed by the care team to be incapable of informed consent, a patient’s legally authorized representative may be 
approached instead. The patient or LAR may sign the consent form either on paper or electronically in RedCap.  
 
Randomization 
 
An Excel file with rows numbered 1 through 150 will be populated with a randomization column. Using Excel 
randomization functions, a research staff member who will not be involved in consenting will assign either the number 
1 (control) or 2 (intervention) to each row number, ensuring 75 of each are populated. We chose the number 150 
based on the expected sample size of 132, plus extras in case of higher-than-expected enrollment. The research staff 
member will then black out (black highlight over black font) the randomization column, so other team members are 
blinded to future assignments. Upon consent of an eligible patient, research staff will enter subject information in the 
next available row, and randomization status will be unblinded by removing the black highlight for that row only.  
 
 
Enrollment 
 
Once the patient is randomized, the CCRC intern will notify the ED pharmacist who will determine if patient is 
currently taking basal insulin and, if they are taking basal insulin prior to admission, will verify the home basal dosing. 
CCRC research staff will be notified of the dosing order from the randomization and will place the appropriate order. 
The patient will either receive 0.2 u/kg insulin glargine, current (prior to admission) basal insulin dose, or no additional 
treatment study protocol. CCRC staff will abstract the study data points from the patient’s EMR while the patient is in 
the Emergency Department, throughout their hospital stay, and again at the time of discharge. The ED pharmacist will 
time the insulin glargine dose to be administered optimally within two hours after initiation of the IV insulin infusion.  
 
Interventions and Treatments 
 
Intervention group-specific 
For patients who are randomized to the intervention group, subcutaneous insulin will be ordered as follows: 
Prior to administration basal 
insulin (generic) 
Prior to administration 
basal insulin (brand) 
Dose equivalent of 
insulin glargine 
Insulin glargine 
Lantus; Basaglar, 
Semglee 
1:1 
Insulin degludec 
Tresiba 
1:1 
Insulin detemir 
Levemir 
1:1 
None 
None 
0.2 units/kg 
 
If the patient is in the intervention group, the ED pharmacist and/or research intern will determine if the patient 
was taking basal insulin prior to admission. If the patient was not taking basal insulin prior to admission, the 
patient will receive 0.2 units/kg insulin glargine. If the patient was taking basal insulin prior to admission, the 
patient will receive their home insulin glargine dose. 
 
Once the appropriate dose is determined, the research team will order the randomization dose of study 
medication and the ED pharmacist will time the study medication to begin within 2 hours after initiation of the IV 
insulin infusion. The dose will come from IV pharmacy and dispensed in a 1 mL insulin syringe. These syringes 
are then tubed to the ED.CCRC interns may facilitate this process by picking up the dose from the ED pharmacy 
or watching the tube stations closely for the dose to arrive, as nurses are sometimes too busy to check these 
stations on a regular basis. Once the insulin is provided, the nurse will administer the dose. Since the dose if not 
on basal insulin at baseline is weight-based, a current weight will be taken if not already done at admission. 
Research staff will ask the RN to complete this. 
 
Research interns will complete follow-up evaluation of incidence of hypoglycemia or hyperglycemia after IV insulin 
infusion discontinuation. This step will be done in conjunction with one of the study investigators.  
Control group-specific 
If the patient is in the standard of care (control) group, no orders for SC insulin glargine will be placed for research 
purposes. A consent note and research FYI flag will be placed in the patient’s EMR to alert care teams of study 

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participation and to emphasize the importance of adhering to the Regions Hospital DKA Protocol, namely, to not 
administer long-acting insulin until patient meets all criteria as per Regions Hospital DKA Protocol. In the 
intervention group, the patient will have all of the same labs and medications as they would if they were in the 
control group or if they were not in the study at all. If they are in the intervention group, the timing of SC insulin will 
be earlier than it would if the patient were not in the study, but all components of the protocol are identical 
regardless of arm or study participation. 
 
Various measures will be taken to promote care team compliance with the hospital DKA protocol in the control 
group. These include education of ICU and ED providers, including pharmacists and RNs and careful instructions 
to follow the SOC protocol (with exceptions for the experimental arm) in the FYI flag and consent note. 
Furthermore, CCRC research interns will be involved in each enrollment to ensure that insulin glargine is given in 
the study time window and that SOC labs are completed per the DKA Protocol. Finally, ED pharmacists are on 
service 24 hours per day and will be available for study patient oversight.  
 
Variable list, sources, and data collection 
The variables listed on the below data collection form will be incorporated into a secure REDCap database that 
research staff will use to enter the data. Patients will be assigned study ID numbers in the REDCap database. The 
REDCap database will contain identifying information, however, if de-identified data needs to be shared outside of the 
direct study team, the dataset can be downloaded without identifying variables such as MRN.  
 
Variable Name 
Role of Variable 
Measurement Scale 
Study ID 
Unique identifier  
Continuous (001 – n) 
MRN 
Link to EMR 
String 
Full name 
Link to EMR 
String 
Date of ED presentation 
Link to EMR 
DMY 
Age 
Descriptive 
Continuous 
Race 
Descriptive 
Categorical, as reported in Epic 
Ethnicity 
Descriptive 
Categorical, as reported in Epic 
Sex at birth 
Descriptive 
Categorical, as reported in Epic 
End stage renal disease 
or hepatic disease 
Inclusion/exclusion criteria 
Binary 
Vasopressor dose to treat 
hypotension at any point 
during admission 
Inclusion/exclusion criteria 
Binary 
On insulin pump therapy 
at baseline (prior to ED) 
Inclusion/exclusion criteria 
Binary 
On combination insulin 
products (i.e. Novolin® 
70/30, Novolog® 70/30, 
Humalog® 75/25, etc.) at 
baseline 
Inclusion/exclusion criteria 
Binary 
Presenting pH (prior to 
intervention) 
Inclusion/exclusion criteria 
Continuous 

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Time of first pH 
Calculate time to resolution 
Continuous 
Time of short-acting 
insulin start 
Calculate time to resolution 
Continuous 
Time of first pH > 7.3 
Outcome  
Calculate time to resolution 
Continuous 
Presenting blood glucose 
in mg/dL 
Inclusion/exclusion criteria 
Continuous 
Time of first blood 
glucose < 250 mg/dL 
Outcome  
Calculate time to resolution 
Continuous 
Blood glucose > 180 
mg/dL in the 24 hours 
after IV insulin infusion 
discontinuation 
Outcome  
Binary 
Blood glucose < 70mg/dL 
≥ 1 time at any point 
while on IV insulin 
therapy or in the 24 hours 
after IV insulin infusion 
discontinuation 
Outcome 
Prevalence of AE (hypoglycemia) 
Binary 
Blood glucose < 70mg/dL 
at any point between 
glargine start and 24 
hours after IV insulin 
infusion discontinuation 
(control group only) 
Outcome 
Prevalence of AE that may be 
contributable to study intervention 
(hypoglycemia) 
Binary 
Mean blood glucose in 24 
and 48 hours after IV 
insulin infusion 
discontinuation 
Outcome 
Continuous 
Presenting anion gap 
Inclusion/exclusion criteria 
Continuous 
Time of first anion gap 
Calculate time to resolution 
Continuous 
Time of first anion gap < 
12 
Calculate time to resolution 
Continuous 
Presenting serum 
bicarbonate level in 
mEq/L 
Inclusion/exclusion criteria 
Continuous 
Time of first serum 
bicarbonate < 15 mEq/L 
Calculate time to resolution 
Continuous 
Presence of ketonuria or 
ketonemia on 
presentation 
Inclusion/exclusion criteria 
Binary 
Presenting Beta-
Hydroxybutyrate in 
mmol/L 
Inclusion/exclusion criteria 
Continuous 

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Type I or Type II Diabetes 
Descriptive 
Binary 
Prior to admission history 
of current basal insulin 
usage 
Treatment determination if in 
intervention arm 
Binary 
Home Insulin Dose 
Treatment determination if in 
intervention arm 
Continuous 
Time of IV insulin infusion 
initiation 
Ensure protocol compliance 
Start of outcome measure 
Date/Time 
Time of IV insulin infusion 
discontinuation 
Outcome 
Date/Time 
Time of SC insulin 
glargine administration 
Descriptive 
Ensure protocol compliance 
Date/Time 
Exact dose of SC insulin 
glargine administered  
Descriptive  
Ensure protocol compliance 
Date/Time 
Weight in kg 
Determine insulin glargine dose 
for study order 
Continuous 
Date/time of ICU 
admission 
Calculate ICU LOS post-infusion 
for study outcome 
Date/time 
Date/time of ICU 
discharge (defined as 
time of service switch to 
progressive care or 
general medicine) 
Calculate ICU LOS post-infusion 
for outcome 
Date/time 
Date/time of IV insulin 
infusion start 
Calculate LOS post-infusion for 
study outcome 
Date/time 
Date/time of hospital 
discharge 
Calculate LOS for study outcome 
Date/time 
 
 
Statistical analysis plan  
The primary outcome and secondary outcomes 1-4 and 7 will follow the same analysis plan to study the difference in 
the distribution of time to an endpoint. First, the distributions for each of these outcomes will be evaluated to 
determine if the distribution is normal or non-parametric. If the distribution is normal, that outcome will be analyzed 
using a two-tailed unpaired t-test. If the distribution is non-parametric, that outcome will be analyzed using a Wilcoxen 
rank sum test. We expect length of stay data to follow a non-parametric distribution. In secondary outcome 2, the 
outcome measured is the time at which all of the necessary criteria are hit for the first time simultaneously, which 
accounts for the transient nature of some of these measures.  
Secondary outcomes 5-6 will measure the prevalence of each of these outcomes. Prevalence was chosen over 
incidence in order to account for multiple instances of rebound hyperglycemia or hypoglycemia occurring within the 
specified timeframe for each and also the amount of time it takes to clinically reverse these conditions. For both of 
these outcomes, a two-proportion z test will be run to find the difference in the amount of time each treatment arm 
cumulatively spent with the specified condition. Finally, for the outcomes relying on certain lab values, we will examine 
time from IV insulin infusion start to outcome labs in both groups. If there is significant variability between the 
experimental and SOC arms, we will adjust for this statistically. Group randomization should ensure that variability is 

V3.0 28APR2022 
 
10 
equally distributed between groups, however, there is a chance of bias (e.g., if the experimental group fares better 
and thus are slower to get nursing checks.) 
 
Strengths and limitations 
One strength of this study includes the 24/7 availability of the CCRC Research Intern and the ED Clinical Pharmacist 
to assist with patient enrollment. This will allow patients to be enrolled on all shifts. The biggest strength in this study 
is the potential to provide a data set more than double the size of the previous studies on early basal insulin 
administration in DKA. This study will also follow the patient throughout their hospital stay and look at potential 
practice changes to decrease the overall length of stay for patients with DKA. We have worked with all relevant 
departments (ED, Critical Care, Endocrinology, Pharmacy) to ensure that this research will fit into the current workflow 
for DKA patients without impeding patient care. 
The biggest limitation is that while our sample size is larger than the previous publications on this topic, it is still a 
small pilot study and effects will be somewhat limited to our local setting and practices. This is also a single-center 
study and not all Emergency Departments have 24/7 ED Clinical Pharmacists available so these practices may not be 
easily duplicated. Not all patients who are eligible will agree to be in the study, which may cause participation bias. To 
avoid research bias, a staff member who will not be involved in consent will set up the randomization scheme, so 
enrollers will be unaware of the next randomization assignment when they approach patients  
Furthermore, since this is a pragmatic study in the real-world setting of a functioning, busy ED, research has limited 
control over components such as timing of standard of care labs and study intervention. We will report and statistically 
correct for any large variation in timing of outcome labs, such as post-intervention glucose checks.  
 
 
 
Setting/Environment/Organizational feasibility 
The study will be conducted at Regions Hospital. The study will primarily take place while the patient is in the ED, but 
the study intervention may take place in the ICU if the patient is quickly admitted. The ED pharmacists can oversee 
ICU medication orders, and the ICU pharmacists will also be trained about this study. This location is appropriate as 
this study is designed to assess the efficacy and safety of early basal insulin administration versus standard of care 
for the treatment of DKA. The department heads for endocrinology, emergency medicine, critical care, internal 
medicine and pharmacy were contacted and have endorsed providing support for this study. The Department of 
Endocrinology was consulted on providing recommendations for both the dosing of basal insulin as well as the timing 
of basal insulin initiation in relation to starting the IV insulin infusion. Furthermore, the ED pharmacists, ICU 
pharmacists, and floor pharmacists have a close working relationship, and communicate with each other daily. All 
three study investigators have spent time working as ICU pharmacists.  
Due to the ongoing COVID-19 pandemic, additional actions will be taken to ensure the safety of patients and research 
staff. Research staff will follow the same PPE protocols as each patient’s care team. Room entries for patient who 
have been ruled out for COVID will require a surgical mask. If a patient’s COVID status is unknown, but COVID is not 
suspected, research staff will attempt to contact the patient via phone, or have a care team member who is entering 
the room for cares ask if the patient is interested in speaking with research, before entering the patient’s room 
themselves. In this case, the research team will follow the same PPE routine as care team members who are entering 
the room. CCRC staff has permission to use PPE from the ED for research purposes. To reduce strain on ED PPE, 
CCRC staff has been instructed to retain N-95 masks and reuse for the equivalent of 5 full shifts per the current 
Worksite Health recommendation, and each CCRC staff member has their own reusable face shields.  If the patient is 
COVID-positive, patients will not enter the patient’s room, and will instead attempt to contact the patient via phone. If a 
paper consent form needs to be signed, a member of the care team in full PPE will bring it in to the patient at the time 
of other cares. Patients and LARs will be offered the option to sign a digital consent form, sent to their personal device 
via RedCap, as this will avoid a Research room entry. 
 
Risks and Benefits  
Potential risks to the patient include hypoglycemia with the administration of both basal and regular insulin 
administration, however, no study that has examined early basal insulin in combination with IV insulin has shown an 
increase in the risk of hypoglycemia5–8. Standard of care for patients with DKA includes an overlap of basal and 
regular insulin for approximately two hours; this ensures that the basal insulin has time to start working before 
stopping the regular insulin. In our study, patients will have a longer duration of overlap of basal and regular insulin as 
the basal insulin will be given earlier in the patient’s treatment course. Patients with DKA who are receiving IV insulin 

V3.0 28APR2022 
 
11 
infusions, whether participating in this study or not, undergo frequent blood glucose monitoring and have the IV insulin 
infusion titrated appropriately to prevent hypoglycemia. Potential benefits to the patient and society include shorter 
hospital and ICU lengths of stay, faster time to resolution of DKA, and less rebound hyperglycemia.  
For study patients randomized to the SOC group, the only potential for change in standard care would be if a provider 
who would have deviated from the Regions Hospital DKA Protocol were the patient not in the study does not deviate 
from it if the patient is in the study, due to education about the importance of adhering to the SOC DKA Protocol. (For 
example, a physician might give SC glargine before the patient meets all criteria for it in the DKA Protocol.) However, 
as the DKA Protocol is evidence-based, peer-reviewed, and created for optimal patient safety and outcomes, this 
should not be considered a risk. If, for whatever reason, a study patient in the SOC arm needs treatment that directly 
contradicts the SOC DKA Protocol, the patient will be withdrawn from the study to ensure patient care and safety are 
the first priority. In looking at existing data to inform this study protocol, only 3 of 45 patients with DKA at Regions 
Hospital received SC glargine prior to what the protocol dictates.  
All adverse events and serious adverse events will be reported to the IRB within the required time windows.  
 
Data Confidentiality and Privacy  
This study involves only minimum necessary data Study results that are shared outside the study team will be de-
identified and in aggregate form. Data will be entered and stored in an HP secure REDCap database, accessible only 
be study team members. All electronic identifiers will be destroyed from Regions Hospital computers at the time of 
study close-out.  
Timeline  
Milestones 
2021 
2022 
M J 
J 
A 
S 
O 
N 
D 
J 
F 
M A 
M J 
J 
A 
S 
O N 
D 
- develop study 
protocol 
 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- IRB approval 
process 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- enroll patients 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
- data analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
- draft publications 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Dissemination/Sharing Results/Integration and Impact  
We plan to publish our results following study completion. The target journals include the American Journal of 
Emergency Medicine, Critical Care Medicine, and The Journal of Clinical Endocrinology & Metabolism. One of the ED 
pharmacists or pharmacy residents will be presenting preliminary results at the Midwest Pharmacy Residency 
Conference, to the pharmacy staff at Regions Hospital, and to the Emergency Medicine and Critical Care 
departments. Our goal is for the data to be incorporated in the development of future policy changes regarding the 
treatment of DKA. 
 
 
 
References 
1.         Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic Crises in Adult Patients With Diabetes. Diabetes 
Care. 2009;32(7):1335-1343. doi:10.2337/dc09-9032 
2.         Hirsch IB. Insulin analogues. The New England journal of medicine. 2005;352(2):174-183. 
doi:10.1056/NEJMra040832 
3.         American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in 
diabetes—2019. Diabetes Care. doi:10.1111/j.1526-4610.2008.01171.x 
4.         Dhatariya K, Savage M. The Management of Diabetic ketoacidosis in adults. Joint British Diabetes Societies 
Inpatient care group. 2013;(September):10,20. http://www.diabetes.org.uk/Documents/About Us/What we 
say/Management-of-DKA-241013.pdf. 

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5.         Hsia E, Seggelke S, Gibbs J, et al. Subcutaneous Administration of Glargine to Diabetic Patients Receiving Insulin 
Infusion Prevents Rebound Hyperglycemia. The Journal of Clinical Endocrinology & Metabolism. 2012;97(9):3132-
3137. doi:10.1210/jc.2012-1244 
6.         Doshi P, Potter AJ, de Los Santos D, Banuelos R, Darger BF, Chathampally Y. Prospective Randomized Trial of 
Insulin Glargine in Acute Management of Diabetic Ketoacidosis in the Emergency Department: A Pilot Study. 
Smith S, ed. Academic Emergency Medicine. 2015;22(6):657-662. doi:10.1111/acem.12673 
7.         Houshyar J, Bahrami A, Aliasgarzadeh A. Effectiveness of Insulin Glargine on Recovery of Patients with Diabetic 
Ketoacidosis: A Randomized Controlled Trial. Journal of clinical and diagnostic research : JCDR. 2015;9(5):OC01-
5. doi:10.7860/JCDR/2015/12005.5883 
8.        Rappaport SH, Endicott JA, Gilbert MP, Farkas JD, Clouser RD, McMillian WD. A Retrospective Study of Early vs 
Delayed Home Dose Basal Insulin in the Acute Management of Diabetic Ketoacidosis. Journal of the Endocrine 
Society. 2019;3(5):1079-1086. doi:10.1210/js.2018-00400 
9.         2017 National Diabetes Fact Sheet. Atlanta, GA: Centers for Disease Control and Prevention. 
https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed August 6, 2019. 
10.       Gosmanov AR, Gosmanova E, Dillard-Cannon E. Management of adult diabetic ketoacidosis. Diabetes, Metabolic 
Syndrome and Obesity: Targets and Therapy. June 2014:255. doi:10.2147/DMSO.S50516 
11.        Humulin R (insulin regular) [prescribing information]. Indianapolis, IN: Eli Lilly and Company; May 2018.