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P T. 2012;37(5): 283-286, 306

Evaluation of an Adult Insulin Infusion Protocol At an Academic Medical Center

Katerina I. Petrov PharmD
Tammy L. Burns PharmD, BCPS
Andjela Drincic MD

Objective:

Acknowledging evidence of possible detrimental effects of tightly controlled blood glucose levels, the American Association of Clinical Endocrinologists and the American Diabetes Association published a consensus statement recommending less strict control for most diabetic patients. As a result of these recommendations, our academic center at Creighton University Medical Center revised its adult insulin infusion protocol to target blood glucose levels ranging from 120 to 180 mg/dL for regular (standard) glycemic control and 80 to 120 mg/dL for tight control; previous targets had ranged from 80 to 180 mg/dL and 70 to 110 mg/dL, respectively. The primary objective was to evaluate the time that blood glucose values were within the target range for patients receiving the new protocol, compared with patients receiving the previous protocol.

Methods:

Our study was designed to evaluate the effectiveness and safety of the revised protocol. Using a retrospective chart review, we collected data for 4 months from patients on the old insulin protocol (May to August 2009) and for 4 months from patients on the new protocol (September to December 2009). Secondary endpoints included the number of hypoglycemic episodes (blood glucose below 70 mg/dL) and severe hypoglycemic episodes (blood glucose 40 mg/dL or lower) experienced by patients receiving the new insulin protocol compared with those receiving the former protocol.

Results:

Patient characteristics were similar at baseline. Blood glucose values stayed within the target range for a significantly shorter time with the new protocol than with the former protocol (44.6% vs. 56.8%, respectively; P < 0.001), probably because of the narrower target range in the revised protocol. No statistically significant differences in hypoglycemia were observed after the protocol was changed. Hypoglycemia occurred in 31% of the former-protocol patients compared with 18% of the revised-protocol patients. Severe hypoglycemia was experienced by 2.1% of patients on the old protocol and by 3.1% of patients on the new protocol. Rates of severe hypoglycemia were low (2.6%) with the original protocol.

Conclusion:

Patients’ blood glucose levels were within the target range for a shorter time with the new protocol. Fewer episodes of hypoglycemia were recorded with the new protocol, but rates of severe hypoglycemia were similar with both protocols.

INTRODUCTION

Hyperglycemia, whether a result of stress or illness, is common among hospitalized patients and has been associated with adverse outcomes.1 Early studies suggested that interventions to reduce blood glucose levels resulted in improved clinical outcomes, but these studies were weakened by retrospective designs and other methodological concerns.2

In a landmark study published by Van den Berghe et al. in 2001, a 42% reduction in the relative risk of mortality was observed in surgical intensive-care unit (ICU) patients who were treated with intensive rather than conventional glucose control (Table 1).3 Five years later, the same investigators reported no mortality benefit from intensive glucose control in a prospective, randomized study in critically ill medical patients at the same institution.4 These patients, however, experienced reductions in other measures of morbidity, such as a lower incidence of newly acquired kidney disease, less need for continuing with a mechanical ventilator, and shorter stays in the ICU or hospital.

Primarily on the basis of these two Van den Berghe trials, many hospitals pursued intensive glucose control as a standard of care to improve patient outcomes. Professional organizations also recommended glycemic control not only in critically ill patients but in all hospitalized patients as well.5

More recently, two studies have raised questions about the results of the Van den Berghe trials. Davos et al.6 and Brunkhorst et al.7 reported unacceptably high rates of hypoglycemia and did not observe reduced mortality rates with intensive insulin therapy. In addition, two meta-analyses of intensive insulin therapy, published by Pittas et al.8 and Wiener et al.,9 indicated considerable variability in target blood glucose concentrations and in the investigational methods used to evaluate the usefulness of strict blood glucose control.

Adding to the controversy was the conclusion of the multinational Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE–SUGAR) trial.10 Investigators randomly assigned 6,104 ICU patients to receive either intensive insulin therapy (target blood glucose range, 81–108 mg/dL) or conventional insulin therapy (target blood glucose goal, below 180 mg/dL). The results contrasted with those of preceding studies. An absolute increase in the rate of the primary endpoint (death at 90 days) was observed with intensive glycemic control (27.5%), compared with conventional control (24.9%) (odds ratio, 1.14; P = 0.02). Moreover, severe hypoglycemia occurred in significantly more intensive-control patients than in conventional-control patients (6.8% vs. 0.5%, respectively; P < 0.001).

In light of the evidence suggesting a possible detrimental effect of tight glycemic control, the American Association of Clinical Endocrinologists (AACE) and the American Diabetes Association (ADA) agreed on less strict control for most patients. These organizations recommended initiating insulin when blood glucose levels exceeded 180 mg/dL and titrating the dose to maintain a target glucose range of 140 to 180 mg/dL for most critically ill patients.11

Following the AACE/ADA consensus statement, our institution (Creighton University Medical Center) revised its adult insulin infusion protocol to require a blood glucose target range of 120 to 180 mg/dL for regular glycemic control and a target range of 80 to 120 mg/dL for tight control. The former protocol was originally adapted from the University of Washington in Seattle, with goals of 80 to 180 mg/dL for regular control and 70 to 110 mg/dL for tight control.

The new lower limit, 120 mg/dL, was chosen over 140 mg/dL because earlier experience with the insulin infusion protocol at our institution suggested that mean blood glucose levels tended to be near the middle of the target range. In addition, the target patient population for tight glucose control was changed to consist of selected surgical patients only, and regular control was recommended for most other patients. Although the titration algorithm was not modified, additional instructions for nurses to adjust for changes in dietary status were added.

Our study sought to compare the revised insulin infusion protocol with the original protocol in terms of efficacy and safety. The primary objective was to evaluate the percentage of time patients’ blood glucose levels remained in the target range with the previous insulin protocol compared with the revised protocol. Secondary endpoints included the number of hypoglycemic episodes (blood glucose below 70 mg/dL) and severe hypoglycemic episodes (blood glucose 40 mg/dL or below) that patients experienced in the old and new protocols.

METHODS

Our study was a retrospective chart review, and the protocol was approved by our institutional review board. Data were retrieved from the hospital’s electronic medical records, and patients were identified by screening records for insulin charges. We collected information from May 1 to August 31, 2009, for patients on the old protocol and from September 1 to December 31, 2009 for patients on the new protocol.

We included data for all adult patients (19 years of age or older) whose insulin infusion lasted for 12 hours or longer. Exclusion criteria included the addition of insulin to a concomitant total parenteral nutrition order, an addition of subcutaneous insulin, blood glucose target ranges modified by the physician, and incomplete or missing insulin infusion orders.

In addition to collating data on insulin infusion and hypoglycemia, we collected information related to patient demographics, comorbidities, and concurrent hospital medications and treatments. Medications that we considered to have an effect on blood glucose levels included corticosteroids, anti-psychotic agents, beta blockers, and hydrochlorothiazide. We calculated the total time that each patient spent receiving the insulin drip, the percentage of time during which blood glucose values were within the target range, the number of hypoglycemic episodes experienced, and the number of severe hypoglycemic episodes.

We used IBM SPSS software (version 18) to conduct the statistical analysis. Student’s t-test was used to compare the means of continuous variables for all endpoints. We used chi-square tests or Fisher’s exact test to compare categorical variables. A P value of less than 0.05 was considered to be statistically significant.

RESULTS

A total of 543 patients received an insulin infusion during the study period. Of these patients, 344 met the inclusion criteria. A total of 156 patients were treated with the new protocol, and 188 patients were treated with the old protocol. We identified these patients by screening for insulin infusion charges in the hospital billing rcords.

Baseline demographic characteristics were similar for the two groups (Table 2). More patients who received insulin infusions via the old protocol were on dialysis and were taking concurrent medications that affected blood glucose levels, compared with patients receiving the new protocol. More patients on the new protocol were also receiving insulin before admission than patients receiving the old protocol, and requests for endocrine consultations were more frequent with the new protocol than with the old protocol. Tight blood glucose control (i.e., target range, 80–120 mg/dL) was used significantly less often with the new protocol.

With the revised protocol, blood glucose levels remained within their target range for a significantly shorter time compared with the previous protocol and the incidence of hypoglycemia (blood glucose, below 70 mg/dL) was reduced (Table 3). However, severe hypoglycemia (blood glucose, 40 mg/dL or lower) did not differ significantly between the two protocols (see Table 3).

A separate analysis of tight glycemic control did not reveal any statistically significant differences for any endpoints (Table 4). Similarly, patients treated with standard or tight blood glucose control showed no differences in the incidence of hypoglycemia. With the revised standard-control protocol, however, blood glucose levels were maintained for a significantly shorter time within the target range compared with glucose levels that were measured in the previous protocol (Table 5).

DISCUSSION

Blood glucose levels were maintained within the newly specified target range for a significantly shorter time with the revised insulin infusion protocol than with the former protocol. Statistically significant differences were noted only with regular (standard) glycemic control, probably because of the narrower range on the revised regular-control protocol (120–180 mg/dL vs. 80–180 mg/dL). Because our study focused on the time that blood glucose levels remained within the target range, levels between 80 and 119 mg/dL were considered to be out of range, although these values are desirable in practice.

Severe hypoglycemia is a potentially devastating adverse event related to intensive insulin therapy. The revisions to the insulin infusion protocol resulted in a significant overall re duction in the number of hypoglycemic episodes. In fact, no episodes of severe hypoglycemia occurred with the revised tight-control protocol. The overall incidence of severe hypoglycemia was low (2.6%) for both old and new protocols, a substantially lower rate than the rates reported in larger, published trials.610

The total number of insulin infusions was lower with the new protocol, as expected, because infusions were not initiated until blood glucose levels exceeded 180 mg/dL. Previously, infusions were started when orders were written as long as glucose levels exceeded the lower limit of the target range. In addition, the percentage of insulin infusions that were ordered for tight control declined. The new protocol recommends that tight control be reserved for selected surgical patients, but a prescriber may still select tight control for critically ill patients if preferred. This suggests that prescribers accepted and adhered to the recommendations to maintain blood glucose levels below 180 mg/dL instead of trying to achieve super-tight glycemic control.

Our sample did not include patients with diabetic ketoacidosis (DKA). Patients with diabetic ketoacidosis receive a separate protocol with different therapy goals and instructions for insulin infusions.

STUDY LIMITATIONS

Our study might have been limited by several factors, primarily because of its retrospective design. For example, we did not measure nurses’ execution of the insulin protocol. We also assumed that execution of the new protocol was consistent over time because the titration nomogram did not change. Therefore, adherence should have a minimal effect on the final results.

Our analysis focused on the number of hypoglycemic episodes that occurred with the revised protocol because of its clinical importance. Therefore, we did not collect data related to the time during which blood glucose levels exceeded the therapeutic range and the number of occurrences during which they exceeded 180 mg/dL. Having access to glucose data on a continuous basis would be ideal for calculating the time that these values are within the target range, but this is not a realistic expectation in practice. To minimize errors, we calculated the percentage of time that glucose values for all patients stayed consistently within the target range.

CONCLUSION

Patients receiving the revised insulin protocol had lower rates of hypoglycemia compared with those receiving insulin infusions via the former protocol. The overall incidence of severe hypoglycemia was low (2.6%) with the old and new protocols, a substantially lower rate than that in a number of trials. In our study, the revision of an existing protocol, which had been designed to maintain tighter blood glucose control, resulted in lower hypoglycemia rates while still providing acceptable glycemic control.

Tables

Randomized Clinical Studies of Intensive and Conventional Insulin Therapy

Trial Name No. of Patients Type of Patient Intensive Glucose Control (mg/dL) Conventional Glucose Control (mg/dL) Primary Endpoint Result for Intensive Glucose Control (%) Result for Conventional Glucose Control (%) Odds Ratio (95% CI)
Leuven 13 1,548 Surgical 80–110 180–200 Death in ICU 4.6 8.0 0.58 (0.38–0.78)
Leuven 24 1,200 Medical 80–110 180–200 Death in hospital 37.3 40.0 0.94 (0.84–1.06)
Glucontrol6 1,101 General 80–110 140–180 Death in ICU 16.7 15.2 1.10 (0.84–1.44)
VISEP7 537 General 80–110 180–200 Death at 28 days 24.7 26.0 Not reported
NICE–SUGAR10 6,104 General 81–108 144–180 Death at 90 days 27.5 24.9 1.14 (1.02–1.28)

CI = confidence interval; ICU = intensive care unit; NICE–SUGAR = Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation; VISEP = Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis.

Baseline Demographic Characteristics of Patients Receiving Revised and Previous Insulin Infusion Protocols

New Protocol (n = 156) Old Protocol (n = 188) P Value
Age (years), mean ± SD 60.3 ± 14.7 61.6 ± 14.9 NS
Male, n (%) 93 (60.0) 120 (64.5) NS
Weight (kg), mean ± SD 90.9 ± 27.2 92.7 ± 27.3 NS
Hospital length of stay (days), mean ± SD 12.7 ± 26.2 13.5 ± 13.8 NS
History of diabetes mellitus, n (%) 77 (50.3) 83 (45.8) NS
No. of comorbidities, mean ± SD 3.3 ± 2.0 3.17 ± 1.9 NS
Concurrent drugs that affect blood glucose, n (%) 86 (55.8) 132 (71.4) 0.003
Prior insulin therapy, n (%) 48 (31.4) 35 (19.2) 0.010
Dialysis, n (%) 3 (1.95) 18 (9.73) 0.038
Endocrine consultations, n (%) 27 (18.1) 18 (10.2) 0.026
Regimen:
  Tight, n (%)
  Regular, n (%)

53 (34.0)
103 (66.0)

105 (55.8)
83 (44.2)

< 0.001

NS = not significant; SD = standard deviation.

Overall Glucose Control and Hypoglycemia With Revised and Previous Insulin Infusion Protocols

New Protocol (n = 156) Old Protocol (n = 188) P Value
% of time blood glucose was within target range, mean ± SD 44.6 ± 21.4 56.8 ± 29.0 < 0.001
Hypoglycemic episodes (<70 mg/dL) per patient, mean ± SD 0.29 ± 0.71 0.54 ± 1.31 0.023
Hypoglycemic episodes per patient per day, mean ± SD 0.11 ± 0.31 0.15 ± 0.33 NS
Severe hypoglycemic episodes (40 mg/dL) per patient, mean ± SD 0.03 ± 0.26 0.02 ± 0.14 NS
Severe hypoglycemic episodes per patient per day, mean ± SD 0.01 ± 0.10 0.004 ± 0.03 NS
Severe hypoglycemia (40 mg/dL), n (%) 5 (3.1) 4 (2.1) NS

NS = not significant; SD = standard deviation.

Tight Glucose Control in the Revised and Previous Insulin Infusion Protocols

New Protocol (n = 56) Old Protocol (n = 104) P Value
% of time blood glucose was within target range, mean ± SD 49.0 ± 19.4 46.1 ± 24.9 NS
Total time on insulin drip (minutes), mean ± SD 4,376 ± 5,114.5 5,682.8 ± 6,428.1 NS
Hypoglycemic episodes (<70 mg/dL) per patient, mean ± SD 0.21 ± 0.53 0.57 ± 1.28 NS
Hypoglycemic episodes per patient per day, mean ± SD 0.07 ± 0.17 0.13 ± 0.32 NS
Severe hypoglycemic (40 mg/dL) episodes per patient, mean ± SD 0 (0) 0.02 ± 0.137 0.03
Severe hypoglycemic episodes per patient per day, mean ± SD 0 (0) 0.002 ± 0.01 0.03

NS = not significant; SD = standard deviation.

Regular Glucose Control in the Revised and Previous Insulin Infusion Protocols

New Protocol (n = 103) Old Protocol (n = 83) P Value
% of time blood glucose was within target range, mean ± SD 42.3 ± 22.1 70.5 ± 28.2 < 0.001
Total time on insulin drip (minutes), mean ± SD 4,125 ± 3,965.1 4,911.4 ± 4,697.6 NS
Hypoglycemic episodes (<70 mg/gL) per patient, mean ± SD 0.34 ± 0.79 0.51 ± 1.06 NS
Hypoglycemic episodes per patient per day, mean ± SD 0.14 ± 0.36 0.17 ± 0.34 NS
Severe hypoglycemic episodes (40 mg/dL) per patient, mean ± SD 0.05 ± 0.28 0.02 ± 0.15 NS
Severe hypoglycemic episodes per patient per day, mean ± SD 0.02 ± 0.13 0.008 ± 0.05 NS

NS = not significant; SD = standard deviation.

Author bio: 
Dr. Petrov is a Clinical Staff Pharmacist at the INOVA Fairfax Hospital in Falls Church, Va. At the time of the study, she was an Adjunct Assistant Professor and a former PGY1 Pharmacy Practice Resident at Creighton University Medical Center in Omaha, Neb. Dr. Burns is a Research Manager and a Clinical Assistant Professor at the Cardiac Center of Creighton University Medical Center. She was formerly a Pharmacy Clinical Coordinator at the medical center. Dr. Drincic is an Associate Professor in the University of Nebraska’s College of Medicine, Department of Internal Medicine, and Medical Director of the Diabetes Center at the Nebraska Medical Center in Omaha. She was formerly an Associate Professor and Program Director of Endocrinology Fellowship at Creighton University School of Medicine.

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