CONTINUING MEDICAL EDUCATION
Continuing Medical Education Activity in Academic Emergency Medicine CME Editor: Corey Heitz, MD Authors: Pratik Doshi, MD, Andrew J. Potter, MD, Daniel De Los Santos, MD, Rosa Banuelos, PhD, Bryan F. Darger, and Yashwant Chathampally, MD Article Title: Prospective Randomized Trial of Insulin Glargine in Acute Management of Diabetic Ketoacidosis in the Emergency Department: A Pilot Study If you wish to receive free CME credit for this activity, please refer to the website: http://www.wileyhealthlearning.com/aem.
Accreditation and Designation Statement: Blackwell Futura Media Services designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Educational Objectives After completing this exercise the participant will be better able to discuss the feasibility of using insulin glargine in the emergency department management of acute DKA.
Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Faculty Disclosures: CME Editor: Corey Heitz, MD has no relevant financial relationships to disclose. Authors: Rosa Banuelos, Yashwant Chathampally, Bryan Darger, Daniel De Los Santos, and Andrew Potter have no relevant financial relationships to disclose. Pratik Doshi discloses non-relevant institutional research support from Vapotherm Incorporated and Zoll Incorporated. This manuscript underwent peer review in line with the standards of editorial integrity and publication ethics maintained by Academic Emergency Medicine. The peer
reviewers have no relevant financial relationships. The peer review process for Academic Emergency Medicine is double-blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. Instructions on Receiving Free CME Credit For information on applicability and acceptance of CME credit for this activity, please consult your professional licensing board. This activity is designed to be completed within an hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Follow these steps to earn credit: • Log on to http://www.wileyhealthlearning.com • Read the target audience, educational objectives, and activity disclosures. • Read the article in print or online format. • Reflect on the article. • Access the CME Exam, and choose the best answer to each question. • Complete the required evaluation component of the activity. This activity will be available for CME credit for twelve months following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months.
ORIGINAL CONTRIBUTION
Prospective Randomized Trial of Insulin Glargine in Acute Management of Diabetic Ketoacidosis in the Emergency Department: A Pilot Study Pratik Doshi, MD, Andrew J. Potter, MD, Daniel De Los Santos, MD, Rosa Banuelos, PhD, Bryan F. Darger, and Yashwant Chathampally, MD
Abstract Objectives: The objective was to determine the efficacy of coadministration of subcutaneous (SQ) insulin glargine in combination with intravenous (IV) insulin for treating diabetic ketoacidosis (DKA). Methods: This was a prospective, randomized, controlled trial comparing coadministration of insulin glargine and IV insulin (experimental) with IV insulin (standard care control). The setting was emergency departments (EDs) in two hospitals in Houston, Texas. Patients presenting with blood sugar ≥ 200 mg/dL, pH ≤ 7.3, bicarbonate (HCO3) ≤ 18 mg/dL, ketonemia or ketonuria, and anion gap ≥ 16 between November 2012 and April 2013 were enrolled. All patients received IV insulin. Additionally, the experimental group was given SQ insulin glargine within 2 hours of diagnosis. Upon closure of anion gap, patients in the control group were subsequently transitioned to long-acting insulin. In the study group, IV insulin was discontinued and long-acting SQ insulin was reinstituted 24 hours after initial introduction. The primary outcome of time to closure of anion gap (TCAG) was compared between groups using a general linear model (GLM), adjusting for initial anion gap, etiology, and presence of comorbidities. Similarly, the secondary outcome hospital length of stay (LOS) was adjusted for age, etiology, and hospital site in the GLM. Rate of hypoglycemia and intensive care unit (ICU) admission was compared using Fisher’s exact test while ICU LOS was compared using Wilcoxon’s two-sample test. Results: A total of 40 patients were enrolled in this pilot trial. The estimated mean TCAG was 10.2 hours (SE 6.8 hours) in the experimental group and 11.6 hours (SE 6.4 hours) in the control group (p = 0.63). The estimated mean hospital LOS was 3.9 days (SE 3.4 days) in the experimental group and 4.8 days (SE 3.6 days) in the control group (p = 0.66). Incidents of hypoglycemia, rates of ICU admission, and ICU LOS were similar between the groups. Conclusions: Coadministration of glargine in combination with an insulin infusion in the acute management of DKA is feasible. Further study is needed to determine the true efficacy in terms of TCAG and hospital LOS. ACADEMIC EMERGENCY MEDICINE 2015;22:658–662 © 2015 by the Society for Academic Emergency Medicine
D
iabetic ketoacidosis (DKA) remains a leading cause of morbidity and mortality in type I diabetic patients and causes significant morbidity in type II diabetic patients.1 The number of hospital visits with DKA has increased from about 80,000 in 1988 to about 140,000
in 2009.2 The challenge is in the comanagement of electrolyte imbalance, dehydration, acidosis, and the underlying etiology of the decompensation. The standard treatment of DKA, while variable at different institutions, has the same multifaceted endpoint: reversal of acidosis, correction of
From the Department of Emergency Medicine, University of Texas Health Science Center at Houston (PD, AJP, DDLS, RB, YC), and the University of Texas Medical School at Houston (BFD), Houston, TX. Received August 20, 2014; revisions received November 21 and December 3, 2014; accepted December 9, 2014. Presented at the ACEP Research Forum, Seattle, WA, October 2013; and the Annual SEC ACEP Regional Conference, Sandestin, FL, June 2013. The authors have no relevant financial information or potential conflicts to disclose. Clinical Trials.Gov Identifier NCT 02006342. Supervising Editor: Steven Smith, MD. Address for correspondence and reprints: Pratik Doshi, MD; e-mail: [email protected].
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ISSN 1069-6563 658 PII ISSN 1069-6563583
© 2015 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12673
ACADEMIC EMERGENCY MEDICINE • June 2015, Vol. 22, No. 6 • www.aemj.org
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was approved by the institutional review board at the University of Texas Health Science Center, and subjects signed written informed consent prior to participation.
Figure 1. Onset of action, peak, and duration of exogenous insulin preparations. NPH = neutral protamine hagedorn (intermediate acting insulin). Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005;352:177.
hypovolemia, and resolution of hyperglycemia.1,3–5 This is mostly accomplished with intravenous (IV) insulin in ranges of 0.25 to 0.1 units/kg/hr, appropriate IV fluids, and close monitoring of electrolytes.6 The number of patients with DKA presenting to the emergency department (ED) continues to rise, and the cost of managing these patients is increasing.7 A large part of this cost depends on the time spent in the intensive care unit (ICU). Previous studies have shown that protocol-driven care is effective in the management of DKA,8 and implementing a treatment algorithm that can further decrease the length of the acidotic state and subsequently lower the need for ICU admission is critical to improve cost of care while maintaining patient safety. To accomplish this, administration of insulin glargine and IV insulin from the onset of DKA management may prove beneficial, based on the pharmacokinetics and pharmacodynamics of insulin glargine, which provides a stable plasma level of insulin with a long half-life when compared to other forms of insulin (Figure 1). This approach was shown to be safe in pediatric patients with DKA.1,8 Current protocols favor prolonged management using IV insulin with transition to subcutaneous (SQ) insulin after the closure of anion gap.9 Insulin glargine has an onset of action at around 2 hours after administration; therefore, using it early in the course of treatment can potentially allow for less time spent on IV insulin and expedite disposition.10 If there is a consistent effect of insulin glargine in addition to IV insulin, then a model can potentially be developed where patients with DKA may be managed safely in a non-ICU setting, resulting in cost avoidance. The objective of this pilot trial was to determine if coadministration of SQ glargine in combination with IV insulin decreases the time to resolution of ketoacidosis, as determined by time to closure of anion gap (TCAG), compared to standard management of DKA. Additionally, we sought to assess the safety of this technique by examining the frequency of hypoglycemia, and the effect of this on ICU admissions and overall length of stay (LOS). We planned to develop preliminary estimates of differences in outcomes using a limited sample size. METHODS Study Design This was a prospective, randomized, single-blind trial (ClinicalTrials.Gov identifier NCT 02006342). This study
Study Setting and Population Eligible patients were enrolled from two hospitals in Houston, Texas: a county ED in a Level III trauma center with approximately 70,000 visits/year and a large tertiary care ED in a Level I trauma center with around 55,000 visits/year. This study enrolled a convenience sample of adult patients diagnosed with DKA from November 2012 through April 2013 using the following inclusion criteria: blood sugar > 200 mg/dL, pH < 7.3, HCO3 < 18 mg/dL, ketonemia or ketonuria, and anion gap (AG) > 16. Patients who required IV inotropic resuscitation including use of vasopressors, were pregnant, had end-stage renal disease, were under 18 years of age, were unwilling to consent to participate in the trial, were currently prisoners, were transferred to another hospital, or required emergent surgery were excluded from this study. Initial inclusion criteria had an AG requirement of ≥16, which is higher than the ADA definition, to assure that all patients enrolled in this small trial had DKA. Study Protocol Subjects were randomized and treated according to the study protocol outlined in Figure 2. Fluid resuscitation began with a crystalloid bolus of 2L and followed with continuous IV fluids at a rate chosen by the provider, over 24 to 48 hours. If the level of glucose reached 250 mg/dL and ketonemia persisted, the fluid selection was changed to D5 1/2NS with appropriate addition of potassium. Patients in both groups received IV insulin at 0.1 units/kg/hr, titrated to maintain a steady decline in the serum glucose. In addition, the experimental group received SQ insulin glargine, at 0.3 units/kg, within 2 hours of diagnosis. Continued assessment consisted of bedside serum glucose check every hour and serum basic metabolic panel every 2 hours and venous blood gas with lactate every 4 hours. Upon closure of anion gap, patients in the control group were given long-acting SQ insulin, and IV insulin was continued for 2 more hours, to allow for the long-acting insulin to take effect, prior to discontinuation. In the experimental group, IV insulin was discontinued, and because patients had already received insulin glargine, long-acting SQ insulin was reinstituted 24 hours after initial dose. Due to this difference in management at this point, ideally the providers would have to be unblinded at this time. However, due to the fact this was a pilot trial to obtain preliminary estimates of efficacy and safety, it was felt that performing the entire study in a single-blind fashion, with the patients being blinded to the randomization arm, was adequate. The primary outcome was TCAG (≤12). Secondary outcomes were hospital LOS, ICU LOS, rate of ICU admission, and incidence of hypoglycemia (defined as ≤ 60 mg/dL during 24 hours after AG closure). The predetermined sample size was based on the estimated difference of acidosis correction time between treatment and control groups, from Shankar et al.1; assuming a = 0.05 and b = 0.20, and a 5% attrition rate, the sample size was 40 individuals, with 20 individuals per arm.
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Doshi et al. • GLARGINE IN DKA
Figure 2. Outline of study protocol. AGAP = anion gap; BMP = basic metabolic panel; DKA = diabetic ketoacidosis; IVFs = intravenous fluids; UA = urinalysis; VBG = venous blood gas.
Table 1 Description of Demographic Characteristics and Baseline Variables Characteristics Age, years Male Hispanic Type 1 diabetes Comorbidities present Initial glucose Initial pH Initial serum bicarbonate Initial anion gap Initial serum creatinine Level III trauma center hospital Etiology, infection Etiology, new diagnosis with initial presentation Etiology, noncompliance
Control Group (n = 20)
Experimental Group (n = 20)
p-value*
41.5 (29.0–50.5) 10 (50.0) 9 (45.0) 9 (45.0) 10 (50.0) 542.0 (426.0–676.0) 7.1 (7.1–7.3) 13.0 (8.5–14.0) 19.5 (17.5–21.5) 1.1 (0.9–1.4) 17 (85.0) 2 (10.0) 1 (5.0) 17 (85.0)
38.5 (31.5–45.5) 14 (70.0) 10 (50.0) 7 (35.0) 16 (80.0) 640.5 (476.0–700.0) 7.2 (7.1–7.3) 12.5 (8.0, 14.5) 18.5 (17.5–26.0) 1.6 (1.21–2.3) 14 (70.0) 5 (25.0) 2 (10.0) 13 (65.0)
0.82 0.33 1.00 0.75 0.10 0.28 0.96 0.88 0.94 0.03 0.45 0.41
*p-values were calculated based on the Wilcoxon two-sample test or Fisher’s exact test for continuous and categorical variables, respectively. Data are reported as median (IQR) or n (%).
Data Analysis Patient characteristics and baseline variables were described as medians (interquartile range) and counts (%) with standard error (SE) for continuous and categorical variables, respectively. All categorical variables were compared between groups using Fisher’s exact test and continuous variables with the Wilcoxon twosample test. Differences in the primary outcome (TCAG) and secondary outcome (hospital LOS) were assessed using general linear models (GLM) adjusted for potential
confounding patient characteristics and baseline variables. The analysis was carried out as an intent-to-treat analysis. Statistical significance was assessed using a = 0.05. Data analyses were performed using SAS 9.4. RESULTS Forty patients were enrolled. One patient in the experimental group did not receive insulin glargine; however, the analysis was performed using the intention-to-treat
ACADEMIC EMERGENCY MEDICINE • June 2015, Vol. 22, No. 6 • www.aemj.org
Table 2 Comparison of Outcomes by Group
Outcomes Adjusted GLM TCAG (hours),* mean (SE) Hospital LOS (days),† mean (SE) Unadjusted Hypoglycemic events,‡ n (%) Admitted to ICU, n (%) ICU LOS (days),¶ median (IQR)
Control Group
Experimental Group
p-value
11.6 (6.4)
10.2 (6.8)
0.63
4.6 (3.6)
3.9 (3.4)
0.66
3 (15.0)
2 (10)
1.00
4 (20.0)
6 (30.0)
0.71
1.2 (0.8–1.8)
1.8 (1.6–1.9)
0.47
GLM = general linear model; ICU = intensive care unit; LOS = length of stay; SE = standard error; TCAG = time to closure of anion gap. *Estimated least-squares mean-adjusted for initial anion gap, etiology, and presence of comorbidities. †Estimated least squares mean-adjusted for age, etiology, and hospital. ‡Comparison based on Fisher’s exact test. ¶Based on the four individuals in control and six in experimental group, compared using Wilcoxon two-sample test.
principle. Demographic characteristics and baseline variables glucose, AG, and serum HCO3 level, were similar between the groups, with the exception of creatinine (Table 1). Adjusting for initial AG, presence of comorbidities, and etiology of DKA, the estimated mean TCAG was 10.2 hours (SE 6.8 hours) in the experimental group, compared to 11.6 hours (SE 6.4 hours) in the control group (p = 0.63). In addition, the estimated mean hospital LOS was 3.9 days (SE 3.4 days) in the experimental group and 4.6 days (SE 3.6 days) in the control group, when adjusting for age, hospital site, and etiology (p = 0.66). Rates of ICU admission and hypoglycemia were similar between the two groups, as was ICU LOS (see Table 2 for detailed analysis).
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limited sample size, this would also need to be confirmed in a larger trial. Results from this pilot study suggest that the two regimens do not differ. Given that the current practice in most hospitals requires the admission of such patients to the ICU with subsequent transition of care to nonICU setting prior to discharge, if the regimen with earlier long-acting insulin can be shown to be equally effective in a consistent manner, it may present an opportunity to manage these patients in a noncritical care setting to begin with, which may result in cost avoidance via decreased ICU utilization and potential improvement in efficiency to discharge, not requiring one more transition of care. Based on the results from this pilot study, if the difference in TCAG was the result of the intervention and not due to chance, a trial with 1,120 patients would be needed to detect such a treatment difference, assuming a 5% significance level and 80% power. LIMITATIONS The primary limitation to this study is that it is a pilot trial planned to develop preliminary estimates of differences in outcomes using a limited sample size. However, based on this trial we do report the size of clinical trial that might be needed to definitively answer the question of whether coadministration of insulin glargine is superior to present standard care. Another limitation is that subjects were enrolled based on availability of the research team, leading to a convenience sample of patients. However, we conducted this trial in less than 6 months, limiting as much selection bias as possible. CONCLUSIONS This was a prospective pilot trial reporting the feasibility of coadministration of insulin glargine with insulin infusion in the acute management of diabetic ketoacidosis in the ED. The results of this trial suggest that this model of treatment is feasible and a larger clinical trial is required to assess the true efficacy of this method.
DISCUSSION This pilot trial suggests that coadministration of insulin glargine with insulin infusion is feasible and may have potential to be an alternate model of treatment in patients presenting with DKA. The primary concern for the use of SQ insulin in acute management of DKA is erratic absorption due to the level of hypovolemia that coexists with this condition. To the best of our knowledge, no study has been performed to determine the rates of absorption and serum levels of insulin glargine in patients with DKA. This study was not designed to answer this question; however, given the similar time frames for closure of AG in both groups, further study is required to determine the validity of this concept. The major concern with providing both IV and SQ insulin simultaneously would be an increased risk for hypoglycemia which may be detrimental; however, in this pilot trial the rates were similar between two groups, suggesting the safety of this approach. However, given the
References 1. Shankar V, Haque A, Churchwell KB, Russell W. Insulin glargine supplementation during early management phase of diabetic ketoacidosis in children. Intensive Care Med 2007;33:1173–8. 2. Centers for Disease Control and Prevention. Number (in thousands) of hospital discharges with diabetic ketoacidosis as first-listed diagnosis, United States, 1988-2009. Available at: http://www.cdc.gov/ diabetes/statistics/dkafirst/fig1.htm. Accessed Mar 12, 2015. 3. Savage MW, Dhatariya KK, Kilvert A, et al. Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. Diabet Med 2011;28:508–15. 4. Bull SV, Douglas IS, Foster M, Albert RK. Mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care unit and
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hospital lengths of stay: results of a nonrandomized trial. Crit Care Med 2007;35:41–6. 5. Ferreri R. Treatment practices of diabetic ketoacidosis at a large teaching hospital. J Nurs Care Qual 2008;23:147–54. 6. Chaithongdi N, Subauste JS, Koch CA, Geraci SA. Diagnosis and management of hyperglycemic emergencies. Hormones (Athens) 2011;10:250–60. 7. Dunger DB, Sperling MA, Acerini CL, et al. ESPE/ LWPES consensus statement on diabetic ketoacidosis in children and adolescents. Arch Dis Child 2004;89:188–94.
Doshi et al. • GLARGINE IN DKA
8. Nyenwe EA, Kitabchi AE. Evidence-based management of hyperglycemic emergencies in diabetes mellitus. Diabetes Res Clin Pract 2011;94:340–51. 9. Kapellen T, Vogel C, Telleis D, Siekmeyer M, Kiess W. Treatment of diabetic ketoacidosis (DKA) with 2 different regimens regarding fluid substitution and insulin dosage (0.025 vs. 0.1 units/kg/h). Exp Clin Endocrinol Diabetes 2012;120:273–6. 10. Ciardullo AV, Bacchelli M, Daghio MM, Carapezzi C. Effectiveness and safety of insulin glargine in the therapy of complicated or secondary diabetes: clinical audit. Acta Diabetol 2006;43:57–60.
Continuing Medical Education Activity in Academic Emergency Medicine CME Editor: Corey Heitz, MD Authors: Pratik Doshi, MD, Andrew J. Potter, MD, Daniel De Los Santos, MD, Rosa Banuelos, PhD, Bryan F. Darger, and Yashwant Chathampally, MD Article Title: Prospective Randomized Trial of Insulin Glargine in Acute Management of Diabetic Ketoacidosis in the Emergency Department: A Pilot Study If you wish to receive free CME credit for this activity, please refer to the website: http://www.wileyhealthlearning.com/aem.
Accreditation and Designation Statement: Blackwell Futura Media Services designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Educational Objectives After completing this exercise the participant will be better able to discuss the feasibility of using insulin glargine in the emergency department management of acute DKA.
Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Faculty Disclosures: CME Editor: Corey Heitz, MD has no relevant financial relationships to disclose. Authors: Rosa Banuelos, Yashwant Chathampally, Bryan Darger, Daniel De Los Santos, and Andrew Potter have no relevant financial relationships to disclose. Pratik Doshi discloses non-relevant institutional research support from Vapotherm Incorporated and Zoll Incorporated. This manuscript underwent peer review in line with the standards of editorial integrity and publication ethics maintained by Academic Emergency Medicine. The peer
reviewers have no relevant financial relationships. The peer review process for Academic Emergency Medicine is double-blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. Instructions on Receiving Free CME Credit For information on applicability and acceptance of CME credit for this activity, please consult your professional licensing board. This activity is designed to be completed within an hour; physicians should claim only those credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the activity during the valid credit period, which is up to two years from initial publication. Follow these steps to earn credit: • Log on to http://www.wileyhealthlearning.com • Read the target audience, educational objectives, and activity disclosures. • Read the article in print or online format. • Reflect on the article. • Access the CME Exam, and choose the best answer to each question. • Complete the required evaluation component of the activity. This activity will be available for CME credit for twelve months following its publication date. At that time, it will be reviewed and potentially updated and extended for an additional twelve months.
ORIGINAL CONTRIBUTION
Prospective Randomized Trial of Insulin Glargine in Acute Management of Diabetic Ketoacidosis in the Emergency Department: A Pilot Study Pratik Doshi, MD, Andrew J. Potter, MD, Daniel De Los Santos, MD, Rosa Banuelos, PhD, Bryan F. Darger, and Yashwant Chathampally, MD
Abstract Objectives: The objective was to determine the efficacy of coadministration of subcutaneous (SQ) insulin glargine in combination with intravenous (IV) insulin for treating diabetic ketoacidosis (DKA). Methods: This was a prospective, randomized, controlled trial comparing coadministration of insulin glargine and IV insulin (experimental) with IV insulin (standard care control). The setting was emergency departments (EDs) in two hospitals in Houston, Texas. Patients presenting with blood sugar ≥ 200 mg/dL, pH ≤ 7.3, bicarbonate (HCO3) ≤ 18 mg/dL, ketonemia or ketonuria, and anion gap ≥ 16 between November 2012 and April 2013 were enrolled. All patients received IV insulin. Additionally, the experimental group was given SQ insulin glargine within 2 hours of diagnosis. Upon closure of anion gap, patients in the control group were subsequently transitioned to long-acting insulin. In the study group, IV insulin was discontinued and long-acting SQ insulin was reinstituted 24 hours after initial introduction. The primary outcome of time to closure of anion gap (TCAG) was compared between groups using a general linear model (GLM), adjusting for initial anion gap, etiology, and presence of comorbidities. Similarly, the secondary outcome hospital length of stay (LOS) was adjusted for age, etiology, and hospital site in the GLM. Rate of hypoglycemia and intensive care unit (ICU) admission was compared using Fisher’s exact test while ICU LOS was compared using Wilcoxon’s two-sample test. Results: A total of 40 patients were enrolled in this pilot trial. The estimated mean TCAG was 10.2 hours (SE 6.8 hours) in the experimental group and 11.6 hours (SE 6.4 hours) in the control group (p = 0.63). The estimated mean hospital LOS was 3.9 days (SE 3.4 days) in the experimental group and 4.8 days (SE 3.6 days) in the control group (p = 0.66). Incidents of hypoglycemia, rates of ICU admission, and ICU LOS were similar between the groups. Conclusions: Coadministration of glargine in combination with an insulin infusion in the acute management of DKA is feasible. Further study is needed to determine the true efficacy in terms of TCAG and hospital LOS. ACADEMIC EMERGENCY MEDICINE 2015;22:658–662 © 2015 by the Society for Academic Emergency Medicine
D
iabetic ketoacidosis (DKA) remains a leading cause of morbidity and mortality in type I diabetic patients and causes significant morbidity in type II diabetic patients.1 The number of hospital visits with DKA has increased from about 80,000 in 1988 to about 140,000
in 2009.2 The challenge is in the comanagement of electrolyte imbalance, dehydration, acidosis, and the underlying etiology of the decompensation. The standard treatment of DKA, while variable at different institutions, has the same multifaceted endpoint: reversal of acidosis, correction of
From the Department of Emergency Medicine, University of Texas Health Science Center at Houston (PD, AJP, DDLS, RB, YC), and the University of Texas Medical School at Houston (BFD), Houston, TX. Received August 20, 2014; revisions received November 21 and December 3, 2014; accepted December 9, 2014. Presented at the ACEP Research Forum, Seattle, WA, October 2013; and the Annual SEC ACEP Regional Conference, Sandestin, FL, June 2013. The authors have no relevant financial information or potential conflicts to disclose. Clinical Trials.Gov Identifier NCT 02006342. Supervising Editor: Steven Smith, MD. Address for correspondence and reprints: Pratik Doshi, MD; e-mail: [email protected].
658 658
ISSN 1069-6563 658 PII ISSN 1069-6563583
© 2015 by the Society for Academic Emergency Medicine doi: 10.1111/acem.12673
ACADEMIC EMERGENCY MEDICINE • June 2015, Vol. 22, No. 6 • www.aemj.org
659
was approved by the institutional review board at the University of Texas Health Science Center, and subjects signed written informed consent prior to participation.
Figure 1. Onset of action, peak, and duration of exogenous insulin preparations. NPH = neutral protamine hagedorn (intermediate acting insulin). Adapted from Hirsch IB. Insulin analogues. N Engl J Med 2005;352:177.
hypovolemia, and resolution of hyperglycemia.1,3–5 This is mostly accomplished with intravenous (IV) insulin in ranges of 0.25 to 0.1 units/kg/hr, appropriate IV fluids, and close monitoring of electrolytes.6 The number of patients with DKA presenting to the emergency department (ED) continues to rise, and the cost of managing these patients is increasing.7 A large part of this cost depends on the time spent in the intensive care unit (ICU). Previous studies have shown that protocol-driven care is effective in the management of DKA,8 and implementing a treatment algorithm that can further decrease the length of the acidotic state and subsequently lower the need for ICU admission is critical to improve cost of care while maintaining patient safety. To accomplish this, administration of insulin glargine and IV insulin from the onset of DKA management may prove beneficial, based on the pharmacokinetics and pharmacodynamics of insulin glargine, which provides a stable plasma level of insulin with a long half-life when compared to other forms of insulin (Figure 1). This approach was shown to be safe in pediatric patients with DKA.1,8 Current protocols favor prolonged management using IV insulin with transition to subcutaneous (SQ) insulin after the closure of anion gap.9 Insulin glargine has an onset of action at around 2 hours after administration; therefore, using it early in the course of treatment can potentially allow for less time spent on IV insulin and expedite disposition.10 If there is a consistent effect of insulin glargine in addition to IV insulin, then a model can potentially be developed where patients with DKA may be managed safely in a non-ICU setting, resulting in cost avoidance. The objective of this pilot trial was to determine if coadministration of SQ glargine in combination with IV insulin decreases the time to resolution of ketoacidosis, as determined by time to closure of anion gap (TCAG), compared to standard management of DKA. Additionally, we sought to assess the safety of this technique by examining the frequency of hypoglycemia, and the effect of this on ICU admissions and overall length of stay (LOS). We planned to develop preliminary estimates of differences in outcomes using a limited sample size. METHODS Study Design This was a prospective, randomized, single-blind trial (ClinicalTrials.Gov identifier NCT 02006342). This study
Study Setting and Population Eligible patients were enrolled from two hospitals in Houston, Texas: a county ED in a Level III trauma center with approximately 70,000 visits/year and a large tertiary care ED in a Level I trauma center with around 55,000 visits/year. This study enrolled a convenience sample of adult patients diagnosed with DKA from November 2012 through April 2013 using the following inclusion criteria: blood sugar > 200 mg/dL, pH < 7.3, HCO3 < 18 mg/dL, ketonemia or ketonuria, and anion gap (AG) > 16. Patients who required IV inotropic resuscitation including use of vasopressors, were pregnant, had end-stage renal disease, were under 18 years of age, were unwilling to consent to participate in the trial, were currently prisoners, were transferred to another hospital, or required emergent surgery were excluded from this study. Initial inclusion criteria had an AG requirement of ≥16, which is higher than the ADA definition, to assure that all patients enrolled in this small trial had DKA. Study Protocol Subjects were randomized and treated according to the study protocol outlined in Figure 2. Fluid resuscitation began with a crystalloid bolus of 2L and followed with continuous IV fluids at a rate chosen by the provider, over 24 to 48 hours. If the level of glucose reached 250 mg/dL and ketonemia persisted, the fluid selection was changed to D5 1/2NS with appropriate addition of potassium. Patients in both groups received IV insulin at 0.1 units/kg/hr, titrated to maintain a steady decline in the serum glucose. In addition, the experimental group received SQ insulin glargine, at 0.3 units/kg, within 2 hours of diagnosis. Continued assessment consisted of bedside serum glucose check every hour and serum basic metabolic panel every 2 hours and venous blood gas with lactate every 4 hours. Upon closure of anion gap, patients in the control group were given long-acting SQ insulin, and IV insulin was continued for 2 more hours, to allow for the long-acting insulin to take effect, prior to discontinuation. In the experimental group, IV insulin was discontinued, and because patients had already received insulin glargine, long-acting SQ insulin was reinstituted 24 hours after initial dose. Due to this difference in management at this point, ideally the providers would have to be unblinded at this time. However, due to the fact this was a pilot trial to obtain preliminary estimates of efficacy and safety, it was felt that performing the entire study in a single-blind fashion, with the patients being blinded to the randomization arm, was adequate. The primary outcome was TCAG (≤12). Secondary outcomes were hospital LOS, ICU LOS, rate of ICU admission, and incidence of hypoglycemia (defined as ≤ 60 mg/dL during 24 hours after AG closure). The predetermined sample size was based on the estimated difference of acidosis correction time between treatment and control groups, from Shankar et al.1; assuming a = 0.05 and b = 0.20, and a 5% attrition rate, the sample size was 40 individuals, with 20 individuals per arm.
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Doshi et al. • GLARGINE IN DKA
Figure 2. Outline of study protocol. AGAP = anion gap; BMP = basic metabolic panel; DKA = diabetic ketoacidosis; IVFs = intravenous fluids; UA = urinalysis; VBG = venous blood gas.
Table 1 Description of Demographic Characteristics and Baseline Variables Characteristics Age, years Male Hispanic Type 1 diabetes Comorbidities present Initial glucose Initial pH Initial serum bicarbonate Initial anion gap Initial serum creatinine Level III trauma center hospital Etiology, infection Etiology, new diagnosis with initial presentation Etiology, noncompliance
Control Group (n = 20)
Experimental Group (n = 20)
p-value*
41.5 (29.0–50.5) 10 (50.0) 9 (45.0) 9 (45.0) 10 (50.0) 542.0 (426.0–676.0) 7.1 (7.1–7.3) 13.0 (8.5–14.0) 19.5 (17.5–21.5) 1.1 (0.9–1.4) 17 (85.0) 2 (10.0) 1 (5.0) 17 (85.0)
38.5 (31.5–45.5) 14 (70.0) 10 (50.0) 7 (35.0) 16 (80.0) 640.5 (476.0–700.0) 7.2 (7.1–7.3) 12.5 (8.0, 14.5) 18.5 (17.5–26.0) 1.6 (1.21–2.3) 14 (70.0) 5 (25.0) 2 (10.0) 13 (65.0)
0.82 0.33 1.00 0.75 0.10 0.28 0.96 0.88 0.94 0.03 0.45 0.41
*p-values were calculated based on the Wilcoxon two-sample test or Fisher’s exact test for continuous and categorical variables, respectively. Data are reported as median (IQR) or n (%).
Data Analysis Patient characteristics and baseline variables were described as medians (interquartile range) and counts (%) with standard error (SE) for continuous and categorical variables, respectively. All categorical variables were compared between groups using Fisher’s exact test and continuous variables with the Wilcoxon twosample test. Differences in the primary outcome (TCAG) and secondary outcome (hospital LOS) were assessed using general linear models (GLM) adjusted for potential
confounding patient characteristics and baseline variables. The analysis was carried out as an intent-to-treat analysis. Statistical significance was assessed using a = 0.05. Data analyses were performed using SAS 9.4. RESULTS Forty patients were enrolled. One patient in the experimental group did not receive insulin glargine; however, the analysis was performed using the intention-to-treat
ACADEMIC EMERGENCY MEDICINE • June 2015, Vol. 22, No. 6 • www.aemj.org
Table 2 Comparison of Outcomes by Group
Outcomes Adjusted GLM TCAG (hours),* mean (SE) Hospital LOS (days),† mean (SE) Unadjusted Hypoglycemic events,‡ n (%) Admitted to ICU, n (%) ICU LOS (days),¶ median (IQR)
Control Group
Experimental Group
p-value
11.6 (6.4)
10.2 (6.8)
0.63
4.6 (3.6)
3.9 (3.4)
0.66
3 (15.0)
2 (10)
1.00
4 (20.0)
6 (30.0)
0.71
1.2 (0.8–1.8)
1.8 (1.6–1.9)
0.47
GLM = general linear model; ICU = intensive care unit; LOS = length of stay; SE = standard error; TCAG = time to closure of anion gap. *Estimated least-squares mean-adjusted for initial anion gap, etiology, and presence of comorbidities. †Estimated least squares mean-adjusted for age, etiology, and hospital. ‡Comparison based on Fisher’s exact test. ¶Based on the four individuals in control and six in experimental group, compared using Wilcoxon two-sample test.
principle. Demographic characteristics and baseline variables glucose, AG, and serum HCO3 level, were similar between the groups, with the exception of creatinine (Table 1). Adjusting for initial AG, presence of comorbidities, and etiology of DKA, the estimated mean TCAG was 10.2 hours (SE 6.8 hours) in the experimental group, compared to 11.6 hours (SE 6.4 hours) in the control group (p = 0.63). In addition, the estimated mean hospital LOS was 3.9 days (SE 3.4 days) in the experimental group and 4.6 days (SE 3.6 days) in the control group, when adjusting for age, hospital site, and etiology (p = 0.66). Rates of ICU admission and hypoglycemia were similar between the two groups, as was ICU LOS (see Table 2 for detailed analysis).
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limited sample size, this would also need to be confirmed in a larger trial. Results from this pilot study suggest that the two regimens do not differ. Given that the current practice in most hospitals requires the admission of such patients to the ICU with subsequent transition of care to nonICU setting prior to discharge, if the regimen with earlier long-acting insulin can be shown to be equally effective in a consistent manner, it may present an opportunity to manage these patients in a noncritical care setting to begin with, which may result in cost avoidance via decreased ICU utilization and potential improvement in efficiency to discharge, not requiring one more transition of care. Based on the results from this pilot study, if the difference in TCAG was the result of the intervention and not due to chance, a trial with 1,120 patients would be needed to detect such a treatment difference, assuming a 5% significance level and 80% power. LIMITATIONS The primary limitation to this study is that it is a pilot trial planned to develop preliminary estimates of differences in outcomes using a limited sample size. However, based on this trial we do report the size of clinical trial that might be needed to definitively answer the question of whether coadministration of insulin glargine is superior to present standard care. Another limitation is that subjects were enrolled based on availability of the research team, leading to a convenience sample of patients. However, we conducted this trial in less than 6 months, limiting as much selection bias as possible. CONCLUSIONS This was a prospective pilot trial reporting the feasibility of coadministration of insulin glargine with insulin infusion in the acute management of diabetic ketoacidosis in the ED. The results of this trial suggest that this model of treatment is feasible and a larger clinical trial is required to assess the true efficacy of this method.
DISCUSSION This pilot trial suggests that coadministration of insulin glargine with insulin infusion is feasible and may have potential to be an alternate model of treatment in patients presenting with DKA. The primary concern for the use of SQ insulin in acute management of DKA is erratic absorption due to the level of hypovolemia that coexists with this condition. To the best of our knowledge, no study has been performed to determine the rates of absorption and serum levels of insulin glargine in patients with DKA. This study was not designed to answer this question; however, given the similar time frames for closure of AG in both groups, further study is required to determine the validity of this concept. The major concern with providing both IV and SQ insulin simultaneously would be an increased risk for hypoglycemia which may be detrimental; however, in this pilot trial the rates were similar between two groups, suggesting the safety of this approach. However, given the
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