Emergency Medicine – PICO #2

Brief description of patient problem/setting (summarize the case very briefly)

As you come into the emergency room for your shift, the other PA gives you the sign off on a patient that came in with diabetic ketoacidosis. You notice the bag of intravenous insulin that is helping offset the DKA, and you wonder if insulin given subcutaneously would also help the patient without possibly having them become hypoglycemic.

Search Question: Clearly state the question (including outcomes or criteria to be tracked)

In patients with diabetic ketoacidosis, how does subcutaneous insulin versus intravenous insulin affect the time to DKA resolution and the incidence of hypoglycemic events?

Question Type: What kind of question is this? (boxes now checkable in Word)

☐Prevalence                             ☐Screening                  ☐Diagnosis

☐Prognosis                              ☒Treatment                 ☒Harms

Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? Please explain your choices.

– If meta-analysis or systematic review are not available, randomized controlled clinical trials will also offer great supporting evidence as they are carefully planned experiments, reduce the potential for bias, and allow for comparison between intervention and control groups.

– Cohort studies could also be used since they allow to follow the patients who have already received a particular treatment forward over time. This is not as reliable as randomized controlled clinical trials since patients might differ in ways other than in the variable that is being observed.

PICO search terms:

PICO
Patients with diabetic ketoacidosisSubcutaneous insulinIntravenous insulinDKA resolution
Diabetic ketoacidosis IV insulinReduction in Hypoglycemic events
DKA   

Search tools and strategy used:

Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.
Explain how you narrow your choices to the few selected articles.

Results found:

TRIP Database

  • Diabetic Ketoacidosis AND Subcutaneous Insulin (last 10 years) – 29
  • Diabetic Ketoacidosis AND Subcutaneous Insulin AND Intravenous Insulin (last 10 years) – 10

PubMed

  • Diabetic Ketoacidosis AND Subcutaneous Insulin AND Intravenous Insulin (last 10 years) – 90
  • Diabetic Ketoacidosis AND Subcutaneous Insulin AND Intravenous Insulin (last 10 years and Meta-analysis and RCTs) – 9

Google Scholar

  • Diabetic Ketoacidosis AND Subcutaneous Insulin AND Intravenous Insulin – 27,000
  • Diabetic Ketoacidosis AND Subcutaneous Insulin AND Intravenous Insulin (last 10 years) – 17,000

Many articles I found were randomized control trials that were done outside of the United States. I decided on using two Retrospective Cohort Studies and two Systematic Reviews and Meta-analysis that dealt with my topic. The Retrospective Cohort Studies had large sample sizes and were done in both a single center, and a multi-center study across the United States. I wanted to include those studies because it showed real world results in whether or not subcutaneous insulin was safe and effective in reducing DKA versus the tired and true usage of intravenous insulin.

Identify at least 4 articles (or other appropriate reputable sources) that answer your specific question with the highest available level of evidence (you will probably need to look at more than 4 articles to get the 4 most focused and highest-level articles to address your question). Please make sure that they are Medline indexed.

Please post the citation and abstract for each article (to include the journal and authors’ names and date) and say why you chose it.
Please also note what kind of article it is (e.g. meta-analysis, cohort study, or independent blind comparison with gold standard of diagnosis, etc.).

At the bottom of each abstract, please comment on what your key points are from this article (including any points or concepts included in the article, but not present in the abstract – i.e. make the concepts understandable to the reader)

Please note that if the evidence is not in the abstract, you must clearly summarize the evidence in your posting.

Citation: Stuhr, K., LeeMaster, R., Hickman, A. W., Reachi, B., Pace, W., & Meek, C. (2023). Subcutaneous Insulin Versus Traditional Intravenous Insulin Infusion in Treatment of Mild to Moderate Diabetic Ketoacidosis. The Journal of emergency medicine, 65(3), e221–e228. https://doi.org/10.1016/j.jemermed.2023.06.004
Type of article: Retrospective multicenter cohort study
Abstract   Background: Intravenous (IV) insulin infusions are the current standard of care for treatment of diabetic ketoacidosis (DKA). Subcutaneous (SQ) insulin, however, may also be a safe and effective alternative.   Objective: The purpose of this study was to compare patient-centered outcomes related to the treatment of mild to moderate DKA using two different protocols: an SQ insulin protocol and an IV insulin infusion protocol with an initial bolus (IVB) or without a bolus (IVNB).   Methods: We retrospectively conducted a multicenter cohort study evaluating SQ vs. IV insulin for the treatment of mild to moderate DKA. The primary outcome was time to DKA resolution. Secondary outcomes included time to glucose correction, hospital length of stay (LOS), intensive care unit LOS, hypoglycemia events, readmission rates, and IV insulin use.   Results: Within the study time frame, 257 patients were included in the multivariate Cox proportional hazards regression analysis. There was no significant difference in the time to DKA resolution between the IVB (p = 0.603) or IVNB (p = 0.269) groups compared with the population who received SQ insulin only. Hospital LOS was significantly longer when comparing the SQ group with the IVNB group (p < 0.001), but not when comparing it with the IVB group (p = 0.259). The IV protocols had significantly more hypoglycemic events compared with the SQ protocol (IVB vs. SQ, p < 0.001; IVNB vs. SQ, p = 0.001).   Conclusions: SQ insulin may be an effective alternative option for treating mild to moderate DKA with fewer hypoglycemic effects.
Key Points: This article was a multi-center retrospective cohort study that had three variables – subcutaneous insulin injection (SQ), IV insulin injection with a bolus (IVB), IV insulin injection without a bolus (IVNB)The primary outcome was time to DKA resolution which was time spent in the ED to a blood glucose level (BGL) under 250 mg/dL and an anion gap under 15Secondary outcomes included any hypoglycemic events (defined as BGL under 70), hospital length of stay, and re-admission for DKA within 30 daysA total of 257 patients were included in the study with 75 being in the SQ group, 62 in the IVB group, and 120 in the IVNB groupThe population was split evenly down with 51% of the population being malePatients in the IVB and IVNB groups had higher initial blood glucose and anion gaps compared to the SQ groupMean time to DKA resolution was shortest for the SQ group, while both the IVB and IVNB groups did not have a significant difference in DKA resolution timeThere was no difference found between the SQ group and the IVB group for hospital length of stay, but the IVNB did have a statistically significant longer stay at the hospitalBoth the IVB and IVNB groups had significantly more hypoglycemic events that the group that took the insulin subcutaneously
Why I chose it: I chose this article because it was the most recent article I could find in regards to treating a DKA with subcutaneous insulin. This study also had the bonus of including a third variable, where the intravenous insulin was given with a bolus, and without a bolus. Even though the sample size was not split evenly among different variables, I think this study really did a great job of showing how much providers could utilize subcutaneous insulin safely and effectively
Citation: Rao P, Jiang S, Kipnis P, et al. Evaluation of Outcomes Following Hospital-Wide Implementation of a Subcutaneous Insulin Protocol for Diabetic Ketoacidosis. JAMA Netw Open. 2022;5(4):e226417. doi:10.1001/jamanetworkopen.2022.6417
Type of article: Retrospective cohort study
Abstract Importance: Standard diabetic ketoacidosis care in the US includes intravenous insulin treatment in the intensive care unit. Subcutaneous (SQ) insulin could decrease intensive care unit need, but the data are limited. Objective: To assess outcomes after implementation of an SQ insulin protocol for treating diabetic ketoacidosis. Design, Setting, and Participants: This cohort study is a retrospective evaluation of a prospectively implemented SQ insulin protocol. The study was conducted at an integrated health care system in Northern California. Participants included hospitalized patients with diabetic ketoacidosis at 21 hospitals between January 1, 2010, and December 31, 2019. The pre-implementation phase was 2010 to 2015, and the postimplementation phase was 2017 to 2019. Data analysis was performed from October 2020 to January 2022. Exposure: An SQ insulin treatment protocol for diabetic ketoacidosis. Main Outcomes and Measures: Difference-in-differences evaluation of the need for intensive care, mortality, readmission, and length of stay at a single intervention site using an SQ insulin protocol from 2017 onward compared with 20 control hospitals using standard care. Results: A total of 7989 hospitalizations for diabetic ketoacidosis occurred, with 4739 (59.3%) occurring before and 3250 (40.7%) occurring after implementation. The overall mean (SD) age was 42.3 (17.7) years, with 4137 hospitalizations (51.8%) occurring among female patients. Before implementation, SQ insulin was the first insulin used in 40 intervention (13.4%) and 651 control (14.7%) hospitalizations. After implementation, 98 hospitalizations (80.3%) received SQ insulin first at the intervention site compared with 402 hospitalizations (12.8%) at control sites. The adjusted rate ratio for intensive care unit admission was 0.43 (95% CI, 0.33-0.56) at the intervention sites, a 57% reduction compared with control sites, and was 0.50 (95% CI, 0.25-0.99) for 30-day hospital readmission, a 50% reduction. There were no significant changes in hospital length of stay and rates of death. Conclusions and Relevance: These findings suggest that a protocol based on SQ insulin for diabetic ketoacidosis treatment was associated with significant decreases in intensive care unit need and readmission, with no evidence of increases in adverse events.
Key Points: This retrospective cohort study included the treatment of DKA at 21 hospitals between Jan 1, 2010 and Dec 31, 2019 There was one intervention hospital that used subcutaneous insulin with the other 20 hospitals that were the control group that used the standard intravenous insulinThe pre-implementation period was Jan 1, 2010 until Dec 31, 2015 with 4,739 patientsThe post-implementation period was Jan 1, 2017 until Dec 31, 2019 with 3,250 patientsThere was a total of 7,989 patients who were hospitalized with DKA. The amount of time until the first documented reduction of serum glucose less than 250 mg/dL was similar in both the intervention and control groupsThe amount of time until the anion gap was less than 16 mEq/L was longer in the control groupAt the intervention sites, there was a substantial decrease in hospitalizations where the patient was admitted to the ICU, from 67.8% pre-implementation to 27.9% post-implementationConversely, standard care sites saw a jump in ICU admission from 75.6% pre-implementation to 79.5% post-implementation30-day readmission for DKAs decreased for the intervention sites from 21.1% to 9.8%, while the standard of care sites stayed flat throughoutCases of hypoglycemia were similar for both groups
Why I chose it: I chose this article because it was a massive undertaking for the Kaiser Permanente hospital group. The sample size was close to 8,000 participants, which was great to have. Also, I have not yet seen a study that used a pre and post implementation control and treatment group, so it was great to read through that.
Citation: Andrade-Castellanos, C. A., Colunga-Lozano, L. E., Delgado-Figueroa, N., & Gonzalez-Padilla, D. A. (2016). Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis. The Cochrane database of systematic reviews, 2016(1), CD011281. https://doi.org/10.1002/14651858.CD011281.pub2
Type of article: Systematic review and meta-analysis
Abstract Objectives: To assess the effects of subcutaneous rapid-acting insulin analogues for the treatment of diabetic ketoacidosis. Search methods: We identified eligible trials by searching MEDLINE, PubMed, EMBASE, LILACS, CINAHL, and the Cochrane Library. We searched the trials registers WHO ICTRP Search Portal and ClinicalTrials.gov. The date of last search for all databases was 27 October 2015. We also examined reference lists of included randomized controlled trials (RCTs) and systematic reviews, and contacted trial authors. Selection criteria: We included trials if they were RCTs comparing subcutaneous rapid-acting insulin analogues versus standard intravenous infusion in participants with DKA of any age or sex with type 1 or type 2 diabetes, and in pregnant women. Data collection and analysis: Two review authors independently extracted data, assessed studies for risk of bias, and evaluated overall study quality utilizing the GRADE instrument. We assessed the statistical heterogeneity of included studies by visually inspecting forest plots and quantifying the diversity using the IM statistic. We synthesized data using random-effects model meta-analysis or descriptive analysis, as appropriate. Main results: Five trials randomized 201 participants (110 participants to subcutaneous rapid-acting insulin analogues and 91 to intravenous regular insulin). The criteria for DKA were consistent with the American Diabetes Association criteria for mild or moderate DKA. The underlying cause of DKA was mostly poor compliance with diabetes therapy. Most trials did not report on type of diabetes. Younger diabetic participants and children were underrepresented in our included trials (one trial only). Four trials evaluated the effects of the rapid-acting insulin analogue lispro, and one the effects of the rapid-acting insulin analogue aspart. The mean follow-up period as measured by mean hospital stay ranged between two and seven days. Overall, risk of bias of the evaluated trials was unclear in many domains and high for performance bias for the outcome measure time to resolution of DKA. No deaths were reported in the included trials (186 participants; 3 trials; moderate- (insulin lispro) to low-quality evidence (insulin aspart)). There was very low-quality evidence to evaluate the effects of subcutaneous insulin lispro versus intravenous regular insulin on the time to resolution of DKA: mean difference (MD) 0.2 h (95% CI -1.7 to 2.1); P = 0.81; 90 participants; 2 trials. In one trial involving children with DKA, the time to reach a glucose level of 250 mg/dL was similar between insulin lispro and intravenous regular insulin. There was very low-quality evidence to evaluate the effects of subcutaneous insulin aspart versus intravenous regular insulin on the time to resolution of DKA: MD -1 h (95% CI -3.2 to 1.2); P = 0.36; 30 participants; 1 trial. There was low-quality evidence to evaluate the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin on hypoglycemic episodes: 6 of 80 insulin lispro-treated participants compared with 9 of 76 regular insulin-treated participants reported hypoglycemic events; risk ratio (RR) 0.59 (95% CI 0.23 to 1.52); P = 0.28; 156 participants; 4 trials. For insulin aspart compared with regular insulin, RR for hypoglycemic episodes was 1.00 (95% CI 0.07 to 14.55); P = 1.0; 30 participants; 1 trial; low-quality evidence. Socioeconomic effects as measured by length of mean hospital stay for insulin lispro compared with regular insulin showed a MD of -0.4 days (95% CI -1 to 0.2); P = 0.22; 90 participants; 2 trials; low-quality evidence and for insulin aspart compared with regular insulin 1.1 days (95% CI -3.3 to 1.1); P = 0.32; low-quality evidence. Data on morbidity were limited, but no specific events were reported for the comparison of insulin lispro with regular insulin. No trial reported on adverse events other than hypoglycemic episodes, and no trial investigated patient satisfaction. Authors’ conclusions: Our review, which provided mainly data on adults, suggests on the basis of mostly low- to very low-quality evidence that there are neither advantages nor disadvantages when comparing the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin for treating mild or moderate DKA.
Key Points: This systematic review and meta-analysis looked at 5 randomized control trials with 201 participantsThere were 110 participants in the subcutaneous insulin groupThe intravenous insulin group had 91 participantsFour of the trials looked at the effects of rapid-acting insulin lispro, while the fifth study looked at rapid-acting insulin aspartThe mean difference for the time to resolution of DKA was similar in both groups, as well as the time to reach a glucose level under 250 mg/dL There was no difference in mean length of stay between both groupsThere was also no statistically significant difference in hypoglycemic events between the treatment and control groups
Why I chose it: I chose this article because it was the only systematic review and meta-analysis that I could find within the last 10 years that pertained to my topic. This article negated everything that I had talked about previously from the other two articles, but the sample size was very small, and this article was close to a decade old (while the other two articles I discussed were much more recent). The biggest takeaway I got from this article was that there was not a huge significant difference between using subcutaneous insulin and intravenous insulin, which shows that either route of administration was regarded as being as effective as the other.
Citation: Vincent, M., & Nobécourt, E. (2013). Treatment of diabetic ketoacidosis with subcutaneous insulin lispro: a review of the current evidence from clinical studies. Diabetes & metabolism, 39(4), 299–305. https://doi.org/10.1016/j.diabet.2012.12.003
Type of article: Systematic Review
Abstract Aim: Low-dose intravenous infusions of regular insulin, usually initiated in the emergency department and continued in the intensive care unit (ICU), are the standard care for patients with diabetic ketoacidosis (DKA) to ensure rapid resolution of hyperglycaemia and ketoacidosis. Several studies have evaluated whether subcutaneous injections of the rapid-acting analogue insulin lispro may be an alternative to intravenous insulin infusion for avoiding ICU admissions of uncomplicated DKA cases.\ Methods: This review summarizes the current clinical evidence for the effectiveness and safety of subcutaneous insulin lispro injections in non-severe DKA patients. Relevant studies were identified by a systematic literature search through the PubMed database. Results: To date, four small randomized studies (156 patients overall; three studies in adults and one in pediatric patients with diabetes) have directly compared subcutaneous insulin lispro injections every 1–2 h vs continuous intravenous infusions of regular insulin. Patients with severe complications were excluded. In all studies, the mean time to resolution of DKA was similar in both treatment groups [range (three studies): lispro 10–14.8 h; regular insulin 11–13.2 h]. The mean time to resolution of hyperglycemia, total insulin doses required, number of hospitalization days and number of hypoglycemic episodes were similar in both treatment groups; no severe complications or DKA recurrences were reported, and one study showed a 39% cost reduction for the insulin lispro group. Conclusion: In patients with mild-to-moderate DKA, subcutaneous injections of insulin lispro every 1–2 h offer a feasible alternative to continuous intravenous infusions of regular insulin, and should now be evaluated in larger, more appropriately powered studies.
Key Points: The authors of this systematic review looked through the PubMed database and found four randomized control trialsThere was a total of 156 patientsThe treatment group consisted of 80 patients that took the subcutaneous lispro insulinThe control group had 76 patients and were given intravenous insulinThree of the studies had 110 adults, while the last study had 46 childrenNone of the four studies showed a statistically significant differences in the speed of blood glucose reduction or resolution of DKA symptoms between both groupsThere were no statistically significant reports of hypoglycemia in either groupThe length of stay was lower for the treatment group in comparison to the control groupThe subcutaneous insulin groups were either sent to the floor or step-down units, while the intravenous insulin groups were taken to the ICU, extending their hospital stays
Why I chose it: I chose this article because it was another systematic review. Although the sample size was smaller, I think the information that was extracted was very valuable. As the other articles that were discussed, length of stay for the treatment group was lower than it was for patients who were given intravenous insulin. This was also the first study that accounted for children with DKA.

What is the clinical “bottom line” derived from these articles in answer to your question?

Diabetic ketoacidosis is an acute, potentially life-threatening complication for patients with diabetes. Traditionally, through the United States DKA guidelines, intravenous insulin is prescribed to patients. Subcutaneous insulin has been started to be used to assist in decreasing blood glucose levels in patients that came into the emergency room to much success in reducing BGLs, decreased mean time to DKA resolution, reducing hospital length of stay and curbing any hypoglycemic events. If asked, I would say using subcutaneous insulin is just as good, if not better, than using intravenous insulin in resolving DKA symptoms in the Emergency Room. There are reduced health care costs that are attributed to using subcutaneous insulin, and it keeps the patient out of the ICU with reduced mortality after 30 days.

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