629985
research-article2016
DSTXXX10.1177/1932296816629985Journal of Diabetes Science and TechnologyDoolin et al
Original Article Journal of Diabetes Science and Technology 2016, Vol. 10(4) 932–938 © 2016 Diabetes Technology Society Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1932296816629985 dst.sagepub.com
Transition From Intravenous to Subcutaneous Insulin in Critically Ill Adults Meagan K. Doolin, PharmD, BCPS1, Todd A. Walroth, PharmD, BCPS, BCCCP1, Serena A. Harris, PharmD, BCPS, BCCCP1, Jessica A. Whitten, PharmD, BCPS, BCCCP1, and Andrew C. Fritschle-Hilliard, PharmD, BCPS, BCCCP1
Abstract Background: Glycemic control decreases morbidity and mortality in critically ill patients. However, limited guidance exists regarding the transition from intravenous (IV) to subcutaneous insulin therapy. A validated protocol for transition is necessary since glycemic variability, hyperglycemia, and hypoglycemia adversely impact patient outcomes. Method: The objective was to determine the safest and most effective method to transition critically ill adults from IV to subcutaneous insulin. This single-center, retrospective, observational study included adults admitted to the burn, medical, or surgical/trauma intensive care units from January 1, 2011, to September 30, 2014. A computer-based program provided a reflection of the patient’s total daily IV insulin requirements. This information was then utilized to stratify patients into groups according to their initial dose of subcutaneous insulin as a percentage of the prior 24-hour IV requirements (group stratification: 0-49%, 50-59%, 60-69%, 70-79%, ≥80%). The primary endpoint was the percentage of blood glucose (BG) concentrations within target range (70-150 mg/dL) 48 hours following transition. Results: One hundred patients with 1394 BG concentrations were included. The 50-59% group achieved the highest rate of BG concentrations in goal range (68%) (P < .001). The 0-49% group, which was the transition method utilized most often, resulted in the lowest rate of goal achievement (46%). Conclusions: This retrospective study suggests critically ill adults may be safely transitioned to 50-59% of their 24-hour IV insulin requirements. A dosing protocol will be implemented to transition to 50-70% subcutaneous insulin. Follow-up data will be reviewed to assess the protocol’s safety and efficacy. Keywords blood glucose, critically ill, insulin, intravenous insulin, subcutaneous insulin, transition Hyperglycemia in the critically ill is a common complication and has been associated with increased morbidity and mortality in a variety of patient populations.1-5 This metabolic response is a component of the acute stress response, which is a complex interplay of endogenous and exogenous factors resulting in increased gluconeogenesis, glycogenolysis, and insulin resistance.1-6 While glycemic control has been shown to decrease morbidity and mortality, conflicting data exists regarding the optimal target range for blood glucose (BG) in critically ill adu lts.1-5,7-9 Due to conflicting results in the literature, professional organizations such as the Society of Critical Care Medicine (SCCM) recommend a moderate approach to managing hyperglycemia in the ICU. The Guidelines for the Use of an Insulin Infusion for the Management of Hyperglycemia in Critically Ill
Patients recommend initiation of insulin therapy for a BG ≥ 150 mg/dL with a goal BG of 100 to 150 mg/dL and absolutely < 180 mg/dL using a protocol that achieves a low rate of hypoglycemia.10 A significant amount of literature supports glycemic control in critically ill adults, which often requires patients to be initiated on continuous intravenous (IV) infusions of insulin. However, there is limited guidance regarding an efficacious 1
Eskenazi Health, Department of Pharmacy, Indianapolis, IN, USA
Corresponding Author: Meagan K. Doolin, PharmD, BCPS, Eskenazi Health, 720 Eskenazi Ave, Sidney & Lois Eskenazi Hospital, 2nd Fl, Indianapolis, IN 46202, USA. Email: [email protected]
933
Doolin et al strategy to transition from IV to subcutaneous insulin. Several prior studies have explored methods of conversion from IV insulin to subcutaneous insulin with conflicting results. Weant and Ladha11 published a retrospective study of 79 adults admitted to a neurosurgical ICU who transitioned to twice-daily subcutaneous NPH. Patients were stratified according to the total dose of subcutaneous NPH insulin as a percentage of their prior 24-hour continuous IV insulin requirement. The primary outcome was the percentage of BG concentrations in goal range defined as 80-150 mg/dL within the first 48 hours after transition in each of the stratified groups. There was statistically significant variance among all patients, with the 60% and 70% groups having the highest percentage of BG concentrations in goal range (73% and 69%, respectively; P < .001). In a subgroup analysis, patients with a history of diabetes mellitus (DM) had the lowest median BG concentration in the group whose subcutaneous dose was higher than 70% of the 24-hour IV requirement (P < .001). There was no significant difference in the rate of hypoglycemia, defined as a BG < 80 mg/dL, between groups. However, the frequency of hypoglycemia was almost twice as high in the group with DM as in those without it (4.2% vs 2.2%). The authors concluded the 60-70% transition method was the safest and most effective. In 2006, Schmeltz et al12 randomized 75 patients in the cardiovascular and surgical ICUs to receive 40%, 60%, or 80% of their 24-hour IV insulin requirement as insulin glargine. The primary outcome was the percentage of BG concentrations in the goal range defined as 80-140 mg/dL within the first 24 hours in each of the stratified groups. The percentage of BG concentrations in the study target range were 43.2%, 34.8%, and 48% in the 40%, 60%, and 80% groups, respectively (P = .09). Secondary analysis with use of a BG target of 80-150 mg/dL and removal of outliers resulted in BG concentrations within range in 58.7%, 44.4%, and 67.6% for the 40%, 60%, and 80% groups, respectively (P = .001). The only patient to have a hypoglycemic event, defined as a BG value < 50 mg/dL, was in the 40% group. The authors concluded insulin glargine at a dose equal to 80% of the 24-hour IV insulin requirement resulted in the highest percentage of BG concentrations in the target range. In 2011, Dungan and colleagues13 performed a similar randomized study in 82 patients who had undergone cardiac surgery. Patients were randomly assigned to insulin detemir at 50%, 65%, or 80% of their 24-hour IV requirement. The primary outcome was the percentage of patients with a morning BG in goal range. The percentage of patients with an initial morning BG concentration of 80-130 mg/dL were 36%, 63%, and 56% for the 50%, 65%, and 80% doses, respectively (P = .12). Of note, 1 patient experienced severe hypoglycemia with a BG < 40 mg/dL in the 80% group. As a result, the authors concluded glycemic targets can be achieved without hypoglycemia with an initial regimen of insulin detemir at a dose of 50% of the 24-hour IV requirement. The SCCM guidelines state stable ICU patients should be transitioned to a protocol-driven basal/bolus insulin
regimen before the IV insulin infusion is stopped to avoid a significant loss of glycemic control.10 However, due to the conflicting results in the literature, there is currently no consensus to facilitate the conversion from IV to subcutaneous insulin.11-13 A validated protocol for this transition is imperative as the complications of an inaccurate subcutaneous insulin dose may impact glycemic control and thus morbidity and mortality. Also, overcorrection may result in hypoglycemia, which can have significant negative sequelae of its own. Therefore, the aim of this study was to determine the safest and most effective method to transition critically ill adults from IV to subcutaneous insulin.
Methods A single-center, retrospective, observational review of adult patients admitted to the burn, medical, or surgical/trauma ICU from January 1, 2011, to September 1, 2014 was performed after obtaining institutional review board approval. Patients who received a continuous IV infusion of regular insulin were identified from the pharmacy medication order entry system. Patients were excluded if they were less than 18 years old, were pregnant, were incarcerated, or had a diagnosis of diabetic ketoacidosis. Patient demographic data including age, gender, height, weight, and serum creatinine were collected. Insulin requirements including average hourly IV insulin 6 hours prior to transition, initial dose of basal subcutaneous insulin, dose change within 48 hours of transition, new dose of subcutaneous basal insulin, and reinitiation of IV insulin were also collected. Confounders analyzed include a history of DM, change in nutritional source, vasopressors, steroids, intubation, extubation, and surgery within 48 hours of transition. Nutrition source (total parenteral nutrition, enteral nutrition, clear liquid diet, regular diet, or nothing by mouth) was collected on the day of transition. A change in nutritional source was defined as a change from one source of nutrition to another. Additional outcomes collected include length of ICU stay and 28-day mortality. All data were collected utilizing the electronic medical record. Current practice for administration of IV insulin therapy at our institution is directed by a computer-based program which calculates the hourly IV insulin requirement based on carbohydrate intake and BG concentrations in relation to a target BG target range. The target BG range on IV insulin was 100-150 mg/dL, with the exception of burn patients who had a target of 90-130 mg/dL. Once the patient has achieved stability on the IV insulin infusion, the program can provide a reflection of the patient’s total daily insulin requirements in a transition to subcutaneous insulin report. In addition, this report provides the patient-specific insulin sensitivity factor (ISF) and carbohydrate ratio (CR), which aides in the dosing of short-acting or rapid-acting insulin. However, no specific dose recommendations are provided to assist with transition
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Table 1. Patient Demographics (N = 100). Percentage transition from continuous to basal insulin Demographic
0-49% (n = 71)
Mean age, years (SD) Male, n (%) Mean height, inches (SD) Median weight, kg (IQR) Median BMI, kg/m2 (IQR) Median CrCl, mL/min (IQR)
50-59% (n = 9)
60-69% (n = 7)
55 (15) 47 (24) 32 (45) 5 (56) 66.0 (3.8) 68.8 (4.4) 89.6 (40.1-218.4) 106.7 (81.1-242.0) 31.2 (17.3-73.2) 33.5 (23.0-66.7) 81 (15-230) 106 (13-255)
70-79% (n = 8)
56 (18) 49 (12) 5 (71) 6 (75) 68.1 (3.2) 68.1 (5.1) 80.0 (54.5-143.2) 101.2 (37.3-240.0) 23.9 (18.8-54.2) 38.3 (16.1-78.1) 56 (20-226) 108 (32-183)
≥80% (n = 5)
P value
57 (11) 2 (40) 64.2 (4.1) 87.8 (66.0-121.0) 34.7 (26.1-38.3) 57 (43-70)
.485 .369 .078 .217 .426 .520
Table 2. Confounders (N = 100). Percentage transition from continuous to basal insulin Confounder (n, %)
0-49% (n = 71)
50-59% (n = 9)
DM Change in nutrition Vasopressors Steroids Intubated Extubated Surgery
45 (63.4) 26 (36.6) 6 (8.5) 18 (25.4) 37 (52.1) 6 (8.5) 4 (5.6)
5 (55.6) 2 (22.2) 0 (0) 1 (11.1) 6 (66.7) 1 (11.1) 0 (0)
and therefore the decision remains at the discretion of the prescriber. Efficacy of transition from IV to subcutaneous insulin was tested by reviewing BG concentrations up to 48 hours following conversion. Patients were stratified into groups according to the initial dose of basal subcutaneous insulin as a percentage of their prior 24-hour IV requirement (group stratification: 0-49%, 50-59%, 60-69%, 70-79%, ≥80%). The 24-hour IV requirement was calculated by averaging the hourly requirement of insulin in the 6 hours prior to transition. The primary endpoint was percentage of BG concentrations within goal range, defined as 70-150 mg/dL, within the first 48 hours following transition. Secondary endpoints included percentage of BG concentrations within the goal range following transition at 0-12 hours and 12-24 hours, incidence of hypoglycemia (200 mg/dL), glucose variability defined as the change in mean absolute glucose per hour in the ICU, percentage of patients requiring dose adjustments after initial transition, and percentage of patients who were restarted on IV insulin. Statistical tests were performed using Minitab® 16 software. A sample size calculation was performed a priori. To provide 80% power and detect a 10% difference in the percentage of BG concentrations within the target range, 388 BG concentrations were needed per group. For data analysis, a chi-square test was performed for nominal data. For
60-69% (n = 7) 4 (57.1) 1 (14.3) 1 (14.3) 4 (57.1) 5 (71.4) 1 (14.3) 0 (0)
70-79% (n = 8) 7 (87.5) 3 (37.5) 0 (0) 1 (12.5) 2 (25.0) 0 (0) 0 (0)
≥80% (n = 5)
P value
5 (0) 2 (40.0) 0 (0) 2 (40.0) 2 (40.0) 0 (0) 0 (0)
.275 .716 NA .211 .347 NA NA
continuous data, the Anderson–Darling normality test was used to determine normality. The Kruskal–Wallis test analyzed nonparametric data and the one-way ANOVA test was utilized for parametric data.
Results A total of 100 patients with 1394 BG concentrations were included. Demographic data and confounders for the stratified groups are listed in Table 1 and Table 2, respectively. The stratified groups were well-matched with no significant differences in demographics or confounders. Figure 1 displays the percentage of BG concentrations within goal range 48 hours following transition in each of the stratified groups (P < .001). The 50-59% group achieved the highest rate of BG concentrations in goal range (68%). The 0-49% group, which was the transition method utilized most often, resulted in the lowest rate of goal achievement (46%). The 60-69% group and 70-79% group had similar outcomes with 54% and 57% of BG concentrations in range, respectively. Only 5 patients with 72 BG concentrations were transitioned to ≥80%, resulting in 47% of BG concentrations in goal range. Figure 2 illustrates the rates of hypoglycemia (P = .015), which occurred most often in the ≥80% group (6.9%). This group also resulted in the only event of severe hypoglycemia in the study. The 50-59% and 60-69% groups had no incidents of hypoglycemia. The rates of hyperglycemia (P < .001) are depicted in Figure 3. Of BG concentrations in the 0-49% group, 50%
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Figure 1. BG concentrations within goal range 48 hours following transition (N = 1394, P < .001).
Figure 2. Rates of hypoglycemia (N = 1394, P = .015).
were > 150 mg/dL. The lowest rate of hyperglycemia occurred in the 50-59% group (32%). The rates of severe hyperglycemia are shown in Figure 4 (P = .033). The group transitioned to ≥80% had the highest rate of severe hyperglycemia (28%). There was a statistically significant difference in the percentage of patients requiring dose adjustments within 48 hours of transition (P = .004). Four of the 5 (80%) patients in the ≥80% group required a dose adjustment, the majority of which were a decrease in the insulin dose. In contrast, 5 of the 8 (62.5%) patients transitioned to 70-79% also required a dose adjustment but the majority of these patients required an increase in the insulin dose. Of note, 7 of the 8 (87.5%) patients in this group had a history of DM. This finding is consistent with literature which has shown that patients with
DM may require higher doses of insulin upon transition.11 A secondary analysis found no difference in the percentage of BG concentrations within the target range following transition at 0-12 hours (Figure 5) and 12-24 hours (Figure 6), which is likely due to the small number of BG concentrations in each timeframe. However, a trend is easily detected with the 50-59% group achieving the highest rate of BG concentrations in goal range in both timeframes. There were no statistically significant differences in median glucose variability, median ICU length of stay, or 28-day morality between the groups (Table 3), although the study was not powered to detect any of these secondary outcomes. A post hoc analysis was completed with a BG goal of 70-180 mg/dL based on the guidelines which recommend a goal BG of 100 to 150 mg/dL and absolutely < 180 mg/dL.10
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Figure 3. Rates of hyperglycemia (N = 1394, P < .001).
Figure 4. Rates of severe hyperglycemia (N = 1394, P = .033).
When comparing the groups, there was a statistically significant difference in target achievement (P < .001). The 50-59% and 60-69% groups achieved the highest rates of BG concentrations in this goal range (77% and 76%, respectively) and the 0-49% group resulted in the lowest (62%).
Discussion Despite the literature supporting glycemic control in critically ill adults, little guidance exists when transitioning patients from IV to subcutaneous insulin therapy. Therefore, this study sought to determine the most effective and safe method for transitioning from IV insulin to basal subcutaneous insulin, taking into consideration guidelines for glycemic control by the SCCM. BG concentrations were in range most often when transitioned to 50-59% basal subcutaneous insulin. This
group also had the lowest rate of hyperglycemia. In addition, they did not have any hypoglycemic events, proving its safety. These results are consistent with the findings of Dungan and colleagues.13 Despite the high rate of goal achievement in the 50-59% group, only 9 of the 100 (9%) patients were transitioned via this strategy. The majority of the patients were transitioned to 0-49%, resulting in the lowest rate of target goal achievement. These results demonstrate there is an opportunity for practice improvement at the study institution when critically ill adults are transitioned from IV to subcutaneous insulin. The results of this study contradict the findings of Schmeltz and colleagues, who concluded the 80% group was safe and most effective.12 In the present study, the ≥80% group had the highest rates of hypoglycemia and severe hypoglycemia, raising safety concerns. This group also had
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Doolin et al
Figure 5. BG concentrations within goal range at 0-12 hours (N = 389, P = .099).
Figure 6. BG concentrations within goal range at 12-24 hours (N = 355, P = .312).
the highest rate of severe hyperglycemia, which could be attributed to the over correction of hypoglycemic events. In conclusion, the current findings suggest this may not be a safe and effective transition method. The guidelines also suggest glucose variability may be a better end point to assess the impact of BG on patient outcome.10 Glucose variability has been independently associated with short-term ICU mortality.14-16 The mechanism of harm includes oxidative stress, neuronal damage, mitochondrial damage, and coagulation activation.14-17 However, the most appropriate metric to describe glucose variability has not yet been defined.10-14,16 In the present study, there was no difference detected between the groups in terms of glucose variability (P = .895). A notable difference between the majority of prior published studies and the current study is the subcutaneous
insulin regimen utilized upon transition. Our study included patients who transitioned to insulin NPH, insulin glargine, and insulin detemir at variable frequencies. Previous studies have included only patients who transitioned to 1 type of basal insulin, which may impact the findings. In addition, the present study included a variety of critically ill patients. These factors may provide more generalizable results, thus increasing the external validity of our findings. Limitations of this study include the single-center, retrospective study design and small sample size. The majority of patients included for review were transitioned to 0-49%. In addition, the study did not exclude patients who required minimal IV insulin, as defined by the SCCM guidelines, and may not warrant transition to basal subcutaneous insulin.10 Despite the small sample size, significant differences were found between groups which minimizes the risk of a Type II error.
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Table 3. Secondary Outcomes (N = 100). Percentage transition from continuous to basal insulin Secondary outcome
0-49% (n = 71)
50-59% (n = 9)
60-69% (n = 7)
Dose adjustment, n (%) Restarted on IV insulin, n (%) Median glucose variability, units (IQR) Median ICU length of stay, days (IQR) Mortality, n (%)
18 (25.4) 7 (9.9) 0.67 (0.13-1.64)
1 (11.1) 1 (11.1) 0.67 (0.18-2.31)
0 (0) 0 (0) 0.74 (0.48-1.46)
16 (2-150) 4 (5.6)
24 (6-258) 0 (0)
Conclusions In conclusion, the study findings suggest critically ill adults should be transitioned to 50-59% of their 24-hour IV insulin requirements as basal subcutaneous insulin. However, additional studies are needed to validate this finding. The results of this study will be utilized to implement a pharmacy-driven protocol at the study institution to transition critically ill adults from IV to subcutaneous insulin therapy. Based on the safety and efficacy findings, as well as post hoc analysis, patients will be transitioned to 50-70% of their 24-hour IV insulin requirements as basal subcutaneous insulin. Follow-up data will be reviewed to assess the impact of the protocol on the efficacy and safety outcomes we have studied. Abbreviations BG, blood glucose; CR, carbohydrate ratio; DM, diabetes mellitus; ICU, intensive care unit; ISF, insulin sensitivity factor; IV, intravenous; SCCM, Society of Critical Care Medicine.
Acknowledgments The authors would like to Meredith Stefanik, PharmD candidate, for her assistance with data collection.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Badawi O, Waite MD, Fuhrman SA, Zuckerman IH. Association between intensive care unit-acquired dysglycemia and in-hospital mortality. Crit Care Med. 2012;40:3180-3188. 2. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet. 2000;355:773-778. 3. Signal M, Le Compte A, Shaw GM, Chase JG. Glycemic levels in critically ill patients: are normoglycemia and low variability
21 (3-37) 0 (0)
70-79% (n = 8) 5 (62.5) 0 (0) 0.67 (0.19-1.00) 7 (2-46) 0 (0)
≥80% (n = 5) 4 (80.0) 0 (0) 0.67 (0.39-1.28) 14 (6-37) 0 (0)
P value .004 NA .895 .256 NA
associated with improved clinical outcomes? J Diabetes Sci Technol. 2012;6:1030-1037. 4. Gale SC, Sicoutris C, Reilly PM, Schwab CW, Gracias VH. Poor glycemic control is associated with increased mortality in critically ill trauma patients. Am Surg. 2007;73:454-460. 5. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003;78:1471-1478. 6. Dungan K, Braithwaite SS, Preiser JC. Stress hyperglycemia. Lancet. 2009;373:1798-1807. 7. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367. 8. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449-461. 9. NICE-SUGAR Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283-1297. 10. Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. Crit Care Med. 2012;40(12):32513276. 11. Weant KA, Ladha A. Conversion from continuous insulin infusions to subcutaneous insulin in critically ill patients. Ann Pharmacother. 2009;43(4):629-634. 12. Schmeltz R, DeSantis AJ, Schmidt K, et al. Conversion of intravenous insulin infusions to subcutaneously administered insulin glargine in patients with hyperglycemia. Endocr Pract. 2006;12(6):641-650. 13. Dungan K, Hall C, Schuster D, Osei K. Comparison of 3 algorithms for basal insulin in transitioning from intravenous to subcutaneous insulin in stable patients after cardiothoracic surgery. Endocr Pract. 2011;17(5):753-758. 14. Hermanides J, Vriesendorp TM, Bosman RJ, Zandstra DF, Hoekstra JB, Devries JH. Glucose variability is associated with intensive care unit mortality. Crit Care Med. 2010;38(3):838842. 15. Bagshaw SM, Bellomo R, Jacka MJ, et al. The impact of early hypoglycemia and blood glucose variability on outcome in critical illness. Crit Care. 2009;13:R91. 16. Egi M, Bellomo R, Stachowski E, et al. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology. 2006;105:244-252. 17. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615-1625.
research-article2016
DSTXXX10.1177/1932296816629985Journal of Diabetes Science and TechnologyDoolin et al
Original Article Journal of Diabetes Science and Technology 2016, Vol. 10(4) 932–938 © 2016 Diabetes Technology Society Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1932296816629985 dst.sagepub.com
Transition From Intravenous to Subcutaneous Insulin in Critically Ill Adults Meagan K. Doolin, PharmD, BCPS1, Todd A. Walroth, PharmD, BCPS, BCCCP1, Serena A. Harris, PharmD, BCPS, BCCCP1, Jessica A. Whitten, PharmD, BCPS, BCCCP1, and Andrew C. Fritschle-Hilliard, PharmD, BCPS, BCCCP1
Abstract Background: Glycemic control decreases morbidity and mortality in critically ill patients. However, limited guidance exists regarding the transition from intravenous (IV) to subcutaneous insulin therapy. A validated protocol for transition is necessary since glycemic variability, hyperglycemia, and hypoglycemia adversely impact patient outcomes. Method: The objective was to determine the safest and most effective method to transition critically ill adults from IV to subcutaneous insulin. This single-center, retrospective, observational study included adults admitted to the burn, medical, or surgical/trauma intensive care units from January 1, 2011, to September 30, 2014. A computer-based program provided a reflection of the patient’s total daily IV insulin requirements. This information was then utilized to stratify patients into groups according to their initial dose of subcutaneous insulin as a percentage of the prior 24-hour IV requirements (group stratification: 0-49%, 50-59%, 60-69%, 70-79%, ≥80%). The primary endpoint was the percentage of blood glucose (BG) concentrations within target range (70-150 mg/dL) 48 hours following transition. Results: One hundred patients with 1394 BG concentrations were included. The 50-59% group achieved the highest rate of BG concentrations in goal range (68%) (P < .001). The 0-49% group, which was the transition method utilized most often, resulted in the lowest rate of goal achievement (46%). Conclusions: This retrospective study suggests critically ill adults may be safely transitioned to 50-59% of their 24-hour IV insulin requirements. A dosing protocol will be implemented to transition to 50-70% subcutaneous insulin. Follow-up data will be reviewed to assess the protocol’s safety and efficacy. Keywords blood glucose, critically ill, insulin, intravenous insulin, subcutaneous insulin, transition Hyperglycemia in the critically ill is a common complication and has been associated with increased morbidity and mortality in a variety of patient populations.1-5 This metabolic response is a component of the acute stress response, which is a complex interplay of endogenous and exogenous factors resulting in increased gluconeogenesis, glycogenolysis, and insulin resistance.1-6 While glycemic control has been shown to decrease morbidity and mortality, conflicting data exists regarding the optimal target range for blood glucose (BG) in critically ill adu lts.1-5,7-9 Due to conflicting results in the literature, professional organizations such as the Society of Critical Care Medicine (SCCM) recommend a moderate approach to managing hyperglycemia in the ICU. The Guidelines for the Use of an Insulin Infusion for the Management of Hyperglycemia in Critically Ill
Patients recommend initiation of insulin therapy for a BG ≥ 150 mg/dL with a goal BG of 100 to 150 mg/dL and absolutely < 180 mg/dL using a protocol that achieves a low rate of hypoglycemia.10 A significant amount of literature supports glycemic control in critically ill adults, which often requires patients to be initiated on continuous intravenous (IV) infusions of insulin. However, there is limited guidance regarding an efficacious 1
Eskenazi Health, Department of Pharmacy, Indianapolis, IN, USA
Corresponding Author: Meagan K. Doolin, PharmD, BCPS, Eskenazi Health, 720 Eskenazi Ave, Sidney & Lois Eskenazi Hospital, 2nd Fl, Indianapolis, IN 46202, USA. Email: [email protected]
933
Doolin et al strategy to transition from IV to subcutaneous insulin. Several prior studies have explored methods of conversion from IV insulin to subcutaneous insulin with conflicting results. Weant and Ladha11 published a retrospective study of 79 adults admitted to a neurosurgical ICU who transitioned to twice-daily subcutaneous NPH. Patients were stratified according to the total dose of subcutaneous NPH insulin as a percentage of their prior 24-hour continuous IV insulin requirement. The primary outcome was the percentage of BG concentrations in goal range defined as 80-150 mg/dL within the first 48 hours after transition in each of the stratified groups. There was statistically significant variance among all patients, with the 60% and 70% groups having the highest percentage of BG concentrations in goal range (73% and 69%, respectively; P < .001). In a subgroup analysis, patients with a history of diabetes mellitus (DM) had the lowest median BG concentration in the group whose subcutaneous dose was higher than 70% of the 24-hour IV requirement (P < .001). There was no significant difference in the rate of hypoglycemia, defined as a BG < 80 mg/dL, between groups. However, the frequency of hypoglycemia was almost twice as high in the group with DM as in those without it (4.2% vs 2.2%). The authors concluded the 60-70% transition method was the safest and most effective. In 2006, Schmeltz et al12 randomized 75 patients in the cardiovascular and surgical ICUs to receive 40%, 60%, or 80% of their 24-hour IV insulin requirement as insulin glargine. The primary outcome was the percentage of BG concentrations in the goal range defined as 80-140 mg/dL within the first 24 hours in each of the stratified groups. The percentage of BG concentrations in the study target range were 43.2%, 34.8%, and 48% in the 40%, 60%, and 80% groups, respectively (P = .09). Secondary analysis with use of a BG target of 80-150 mg/dL and removal of outliers resulted in BG concentrations within range in 58.7%, 44.4%, and 67.6% for the 40%, 60%, and 80% groups, respectively (P = .001). The only patient to have a hypoglycemic event, defined as a BG value < 50 mg/dL, was in the 40% group. The authors concluded insulin glargine at a dose equal to 80% of the 24-hour IV insulin requirement resulted in the highest percentage of BG concentrations in the target range. In 2011, Dungan and colleagues13 performed a similar randomized study in 82 patients who had undergone cardiac surgery. Patients were randomly assigned to insulin detemir at 50%, 65%, or 80% of their 24-hour IV requirement. The primary outcome was the percentage of patients with a morning BG in goal range. The percentage of patients with an initial morning BG concentration of 80-130 mg/dL were 36%, 63%, and 56% for the 50%, 65%, and 80% doses, respectively (P = .12). Of note, 1 patient experienced severe hypoglycemia with a BG < 40 mg/dL in the 80% group. As a result, the authors concluded glycemic targets can be achieved without hypoglycemia with an initial regimen of insulin detemir at a dose of 50% of the 24-hour IV requirement. The SCCM guidelines state stable ICU patients should be transitioned to a protocol-driven basal/bolus insulin
regimen before the IV insulin infusion is stopped to avoid a significant loss of glycemic control.10 However, due to the conflicting results in the literature, there is currently no consensus to facilitate the conversion from IV to subcutaneous insulin.11-13 A validated protocol for this transition is imperative as the complications of an inaccurate subcutaneous insulin dose may impact glycemic control and thus morbidity and mortality. Also, overcorrection may result in hypoglycemia, which can have significant negative sequelae of its own. Therefore, the aim of this study was to determine the safest and most effective method to transition critically ill adults from IV to subcutaneous insulin.
Methods A single-center, retrospective, observational review of adult patients admitted to the burn, medical, or surgical/trauma ICU from January 1, 2011, to September 1, 2014 was performed after obtaining institutional review board approval. Patients who received a continuous IV infusion of regular insulin were identified from the pharmacy medication order entry system. Patients were excluded if they were less than 18 years old, were pregnant, were incarcerated, or had a diagnosis of diabetic ketoacidosis. Patient demographic data including age, gender, height, weight, and serum creatinine were collected. Insulin requirements including average hourly IV insulin 6 hours prior to transition, initial dose of basal subcutaneous insulin, dose change within 48 hours of transition, new dose of subcutaneous basal insulin, and reinitiation of IV insulin were also collected. Confounders analyzed include a history of DM, change in nutritional source, vasopressors, steroids, intubation, extubation, and surgery within 48 hours of transition. Nutrition source (total parenteral nutrition, enteral nutrition, clear liquid diet, regular diet, or nothing by mouth) was collected on the day of transition. A change in nutritional source was defined as a change from one source of nutrition to another. Additional outcomes collected include length of ICU stay and 28-day mortality. All data were collected utilizing the electronic medical record. Current practice for administration of IV insulin therapy at our institution is directed by a computer-based program which calculates the hourly IV insulin requirement based on carbohydrate intake and BG concentrations in relation to a target BG target range. The target BG range on IV insulin was 100-150 mg/dL, with the exception of burn patients who had a target of 90-130 mg/dL. Once the patient has achieved stability on the IV insulin infusion, the program can provide a reflection of the patient’s total daily insulin requirements in a transition to subcutaneous insulin report. In addition, this report provides the patient-specific insulin sensitivity factor (ISF) and carbohydrate ratio (CR), which aides in the dosing of short-acting or rapid-acting insulin. However, no specific dose recommendations are provided to assist with transition
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Table 1. Patient Demographics (N = 100). Percentage transition from continuous to basal insulin Demographic
0-49% (n = 71)
Mean age, years (SD) Male, n (%) Mean height, inches (SD) Median weight, kg (IQR) Median BMI, kg/m2 (IQR) Median CrCl, mL/min (IQR)
50-59% (n = 9)
60-69% (n = 7)
55 (15) 47 (24) 32 (45) 5 (56) 66.0 (3.8) 68.8 (4.4) 89.6 (40.1-218.4) 106.7 (81.1-242.0) 31.2 (17.3-73.2) 33.5 (23.0-66.7) 81 (15-230) 106 (13-255)
70-79% (n = 8)
56 (18) 49 (12) 5 (71) 6 (75) 68.1 (3.2) 68.1 (5.1) 80.0 (54.5-143.2) 101.2 (37.3-240.0) 23.9 (18.8-54.2) 38.3 (16.1-78.1) 56 (20-226) 108 (32-183)
≥80% (n = 5)
P value
57 (11) 2 (40) 64.2 (4.1) 87.8 (66.0-121.0) 34.7 (26.1-38.3) 57 (43-70)
.485 .369 .078 .217 .426 .520
Table 2. Confounders (N = 100). Percentage transition from continuous to basal insulin Confounder (n, %)
0-49% (n = 71)
50-59% (n = 9)
DM Change in nutrition Vasopressors Steroids Intubated Extubated Surgery
45 (63.4) 26 (36.6) 6 (8.5) 18 (25.4) 37 (52.1) 6 (8.5) 4 (5.6)
5 (55.6) 2 (22.2) 0 (0) 1 (11.1) 6 (66.7) 1 (11.1) 0 (0)
and therefore the decision remains at the discretion of the prescriber. Efficacy of transition from IV to subcutaneous insulin was tested by reviewing BG concentrations up to 48 hours following conversion. Patients were stratified into groups according to the initial dose of basal subcutaneous insulin as a percentage of their prior 24-hour IV requirement (group stratification: 0-49%, 50-59%, 60-69%, 70-79%, ≥80%). The 24-hour IV requirement was calculated by averaging the hourly requirement of insulin in the 6 hours prior to transition. The primary endpoint was percentage of BG concentrations within goal range, defined as 70-150 mg/dL, within the first 48 hours following transition. Secondary endpoints included percentage of BG concentrations within the goal range following transition at 0-12 hours and 12-24 hours, incidence of hypoglycemia (200 mg/dL), glucose variability defined as the change in mean absolute glucose per hour in the ICU, percentage of patients requiring dose adjustments after initial transition, and percentage of patients who were restarted on IV insulin. Statistical tests were performed using Minitab® 16 software. A sample size calculation was performed a priori. To provide 80% power and detect a 10% difference in the percentage of BG concentrations within the target range, 388 BG concentrations were needed per group. For data analysis, a chi-square test was performed for nominal data. For
60-69% (n = 7) 4 (57.1) 1 (14.3) 1 (14.3) 4 (57.1) 5 (71.4) 1 (14.3) 0 (0)
70-79% (n = 8) 7 (87.5) 3 (37.5) 0 (0) 1 (12.5) 2 (25.0) 0 (0) 0 (0)
≥80% (n = 5)
P value
5 (0) 2 (40.0) 0 (0) 2 (40.0) 2 (40.0) 0 (0) 0 (0)
.275 .716 NA .211 .347 NA NA
continuous data, the Anderson–Darling normality test was used to determine normality. The Kruskal–Wallis test analyzed nonparametric data and the one-way ANOVA test was utilized for parametric data.
Results A total of 100 patients with 1394 BG concentrations were included. Demographic data and confounders for the stratified groups are listed in Table 1 and Table 2, respectively. The stratified groups were well-matched with no significant differences in demographics or confounders. Figure 1 displays the percentage of BG concentrations within goal range 48 hours following transition in each of the stratified groups (P < .001). The 50-59% group achieved the highest rate of BG concentrations in goal range (68%). The 0-49% group, which was the transition method utilized most often, resulted in the lowest rate of goal achievement (46%). The 60-69% group and 70-79% group had similar outcomes with 54% and 57% of BG concentrations in range, respectively. Only 5 patients with 72 BG concentrations were transitioned to ≥80%, resulting in 47% of BG concentrations in goal range. Figure 2 illustrates the rates of hypoglycemia (P = .015), which occurred most often in the ≥80% group (6.9%). This group also resulted in the only event of severe hypoglycemia in the study. The 50-59% and 60-69% groups had no incidents of hypoglycemia. The rates of hyperglycemia (P < .001) are depicted in Figure 3. Of BG concentrations in the 0-49% group, 50%
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Figure 1. BG concentrations within goal range 48 hours following transition (N = 1394, P < .001).
Figure 2. Rates of hypoglycemia (N = 1394, P = .015).
were > 150 mg/dL. The lowest rate of hyperglycemia occurred in the 50-59% group (32%). The rates of severe hyperglycemia are shown in Figure 4 (P = .033). The group transitioned to ≥80% had the highest rate of severe hyperglycemia (28%). There was a statistically significant difference in the percentage of patients requiring dose adjustments within 48 hours of transition (P = .004). Four of the 5 (80%) patients in the ≥80% group required a dose adjustment, the majority of which were a decrease in the insulin dose. In contrast, 5 of the 8 (62.5%) patients transitioned to 70-79% also required a dose adjustment but the majority of these patients required an increase in the insulin dose. Of note, 7 of the 8 (87.5%) patients in this group had a history of DM. This finding is consistent with literature which has shown that patients with
DM may require higher doses of insulin upon transition.11 A secondary analysis found no difference in the percentage of BG concentrations within the target range following transition at 0-12 hours (Figure 5) and 12-24 hours (Figure 6), which is likely due to the small number of BG concentrations in each timeframe. However, a trend is easily detected with the 50-59% group achieving the highest rate of BG concentrations in goal range in both timeframes. There were no statistically significant differences in median glucose variability, median ICU length of stay, or 28-day morality between the groups (Table 3), although the study was not powered to detect any of these secondary outcomes. A post hoc analysis was completed with a BG goal of 70-180 mg/dL based on the guidelines which recommend a goal BG of 100 to 150 mg/dL and absolutely < 180 mg/dL.10
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Figure 3. Rates of hyperglycemia (N = 1394, P < .001).
Figure 4. Rates of severe hyperglycemia (N = 1394, P = .033).
When comparing the groups, there was a statistically significant difference in target achievement (P < .001). The 50-59% and 60-69% groups achieved the highest rates of BG concentrations in this goal range (77% and 76%, respectively) and the 0-49% group resulted in the lowest (62%).
Discussion Despite the literature supporting glycemic control in critically ill adults, little guidance exists when transitioning patients from IV to subcutaneous insulin therapy. Therefore, this study sought to determine the most effective and safe method for transitioning from IV insulin to basal subcutaneous insulin, taking into consideration guidelines for glycemic control by the SCCM. BG concentrations were in range most often when transitioned to 50-59% basal subcutaneous insulin. This
group also had the lowest rate of hyperglycemia. In addition, they did not have any hypoglycemic events, proving its safety. These results are consistent with the findings of Dungan and colleagues.13 Despite the high rate of goal achievement in the 50-59% group, only 9 of the 100 (9%) patients were transitioned via this strategy. The majority of the patients were transitioned to 0-49%, resulting in the lowest rate of target goal achievement. These results demonstrate there is an opportunity for practice improvement at the study institution when critically ill adults are transitioned from IV to subcutaneous insulin. The results of this study contradict the findings of Schmeltz and colleagues, who concluded the 80% group was safe and most effective.12 In the present study, the ≥80% group had the highest rates of hypoglycemia and severe hypoglycemia, raising safety concerns. This group also had
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Doolin et al
Figure 5. BG concentrations within goal range at 0-12 hours (N = 389, P = .099).
Figure 6. BG concentrations within goal range at 12-24 hours (N = 355, P = .312).
the highest rate of severe hyperglycemia, which could be attributed to the over correction of hypoglycemic events. In conclusion, the current findings suggest this may not be a safe and effective transition method. The guidelines also suggest glucose variability may be a better end point to assess the impact of BG on patient outcome.10 Glucose variability has been independently associated with short-term ICU mortality.14-16 The mechanism of harm includes oxidative stress, neuronal damage, mitochondrial damage, and coagulation activation.14-17 However, the most appropriate metric to describe glucose variability has not yet been defined.10-14,16 In the present study, there was no difference detected between the groups in terms of glucose variability (P = .895). A notable difference between the majority of prior published studies and the current study is the subcutaneous
insulin regimen utilized upon transition. Our study included patients who transitioned to insulin NPH, insulin glargine, and insulin detemir at variable frequencies. Previous studies have included only patients who transitioned to 1 type of basal insulin, which may impact the findings. In addition, the present study included a variety of critically ill patients. These factors may provide more generalizable results, thus increasing the external validity of our findings. Limitations of this study include the single-center, retrospective study design and small sample size. The majority of patients included for review were transitioned to 0-49%. In addition, the study did not exclude patients who required minimal IV insulin, as defined by the SCCM guidelines, and may not warrant transition to basal subcutaneous insulin.10 Despite the small sample size, significant differences were found between groups which minimizes the risk of a Type II error.
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Table 3. Secondary Outcomes (N = 100). Percentage transition from continuous to basal insulin Secondary outcome
0-49% (n = 71)
50-59% (n = 9)
60-69% (n = 7)
Dose adjustment, n (%) Restarted on IV insulin, n (%) Median glucose variability, units (IQR) Median ICU length of stay, days (IQR) Mortality, n (%)
18 (25.4) 7 (9.9) 0.67 (0.13-1.64)
1 (11.1) 1 (11.1) 0.67 (0.18-2.31)
0 (0) 0 (0) 0.74 (0.48-1.46)
16 (2-150) 4 (5.6)
24 (6-258) 0 (0)
Conclusions In conclusion, the study findings suggest critically ill adults should be transitioned to 50-59% of their 24-hour IV insulin requirements as basal subcutaneous insulin. However, additional studies are needed to validate this finding. The results of this study will be utilized to implement a pharmacy-driven protocol at the study institution to transition critically ill adults from IV to subcutaneous insulin therapy. Based on the safety and efficacy findings, as well as post hoc analysis, patients will be transitioned to 50-70% of their 24-hour IV insulin requirements as basal subcutaneous insulin. Follow-up data will be reviewed to assess the impact of the protocol on the efficacy and safety outcomes we have studied. Abbreviations BG, blood glucose; CR, carbohydrate ratio; DM, diabetes mellitus; ICU, intensive care unit; ISF, insulin sensitivity factor; IV, intravenous; SCCM, Society of Critical Care Medicine.
Acknowledgments The authors would like to Meredith Stefanik, PharmD candidate, for her assistance with data collection.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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21 (3-37) 0 (0)
70-79% (n = 8) 5 (62.5) 0 (0) 0.67 (0.19-1.00) 7 (2-46) 0 (0)
≥80% (n = 5) 4 (80.0) 0 (0) 0.67 (0.39-1.28) 14 (6-37) 0 (0)
P value .004 NA .895 .256 NA
associated with improved clinical outcomes? J Diabetes Sci Technol. 2012;6:1030-1037. 4. Gale SC, Sicoutris C, Reilly PM, Schwab CW, Gracias VH. Poor glycemic control is associated with increased mortality in critically ill trauma patients. Am Surg. 2007;73:454-460. 5. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a heterogeneous population of critically ill patients. Mayo Clin Proc. 2003;78:1471-1478. 6. Dungan K, Braithwaite SS, Preiser JC. Stress hyperglycemia. Lancet. 2009;373:1798-1807. 7. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345:1359-1367. 8. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical ICU. N Engl J Med. 2006;354:449-461. 9. NICE-SUGAR Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283-1297. 10. Jacobi J, Bircher N, Krinsley J, et al. Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. Crit Care Med. 2012;40(12):32513276. 11. Weant KA, Ladha A. Conversion from continuous insulin infusions to subcutaneous insulin in critically ill patients. Ann Pharmacother. 2009;43(4):629-634. 12. Schmeltz R, DeSantis AJ, Schmidt K, et al. Conversion of intravenous insulin infusions to subcutaneously administered insulin glargine in patients with hyperglycemia. Endocr Pract. 2006;12(6):641-650. 13. Dungan K, Hall C, Schuster D, Osei K. Comparison of 3 algorithms for basal insulin in transitioning from intravenous to subcutaneous insulin in stable patients after cardiothoracic surgery. Endocr Pract. 2011;17(5):753-758. 14. Hermanides J, Vriesendorp TM, Bosman RJ, Zandstra DF, Hoekstra JB, Devries JH. Glucose variability is associated with intensive care unit mortality. Crit Care Med. 2010;38(3):838842. 15. Bagshaw SM, Bellomo R, Jacka MJ, et al. The impact of early hypoglycemia and blood glucose variability on outcome in critical illness. Crit Care. 2009;13:R91. 16. Egi M, Bellomo R, Stachowski E, et al. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology. 2006;105:244-252. 17. Brownlee M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54:1615-1625.
