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American Journal of Critical Care. 2007;16: 599-608
Copyright © 2007 by the American Association of Critical-Care Nurses.
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Adherence to and Efficacy and Safety of an Insulin Protocol in the Critically Ill: A Prospective Observational Study

By Sandra G. Oeyen, MD, Eric A. Hoste, MD, PhD, Carl D. Roosens, MD, Johan M. Decruyenaere, MD, PhD and Stijn I. Blot, PhD. Sandra Oeyen, Eric Hoste, and Carl Roosens are intensivists and work as staff members, Johan Decruyenaere is an intensivist and department head, and Stijn Blot is a research worker in the Department of Intensive Care, Ghent University Hospital, Ghent, Belgium.

Corresponding author: Sandra Oeyen, MD, Department of Intensive Care 1K12 IC, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium (e-mail: Sandra.Oeyen{at}UGent.be).


   Abstract
Top
 Abstract
Methods
 Statistical Analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
Background Blood glucose control during acute illness has been associated with improved outcomes.

Objectives To evaluate adherence to and efficacy and safety of an insulin protocol for critically ill patients with target blood glucose levels between 81 and 110 mg/dL and to determine factors associated with adequate daily blood glucose control.

Methods In a prospective observational study, blood glucose levels were determined in 30 patients in intensive care units of a tertiary care university hospital during a 2-month period. All glucose measurements and corresponding insulin infusion rates were evaluated for adherence to and efficacy and safety of the insulin protocol. Linear regression analysis was used to determine factors associated with adequate daily blood glucose control, defined as time in the target range.

Results A total of 6016 blood glucose measurements were obtained during 352 protocol implementation days. Adherence to the protocol was 71%. Blood glucose levels were in the desired range 42% of the total protocol implementation time. Sixty percent of the patients experienced at least one hypoglycemic event. Adherence to the protocol (P < .001), high bilirubin level (P < .001), low daily insulin dose (P = .002), and low C-reactive protein level (P = .048) were independently associated with adequate daily blood glucose control.

Conclusions Protocol adherence was positively associated with daily time in the target range, but efficacy during the total protocol implementation time remained poor. Because of the frequency of hypoglycemia, protocols to maintain blood glucose levels between 81 and 110 mg/dL in critically ill patients may not be recommended.

From 2000 to 2004, the adverse effects of hyperglycemia in critically ill patients were frequently highlighted.1–7 Possible reasons for the relationship between adverse clinical outcomes and hyperglycemia include attenuation of host defensive mechanisms, endothelial dysfunction, increases in the levels of inflammatory cytokines, and changes in myocardial metabolism.8 Critically ill patients are particularly prone to hyperglycemia because of metabolic and hormonal changes associated with the stress response.8,9 Moreover, patients in the intensive care unit (ICU) are predisposed to elevated blood glucose levels because of common clinical interventions, such as the use of corticosteroids, vasopressors, glucose-containing intravenous fluids, and parenteral or enteral nutrition.

Hyperglycemia at the time of admission to the ICU is an independent risk factor for in-hospital mortality.10 It is also associated with an increased mortality and morbidity in critically ill trauma patients.11,12 It is unknown if hyperglycemia at the time of admission would be as predictive of mortality when tight blood glucose control is maintained during the ICU stay.13

Control of hyperglycemia during acute illness has been associated with improved outcome. Furnary et al14 showed that use of an insulin infusion to maintain glucose levels between 150 and 200 mg/dL (to convert to millimoles per liter, multiply by 0.0555) decreased the risk of sternal wound infection after coronary artery bypass graft surgery in diabetic patients by 58%. In a later study,15 when the target blood glucose level was decreased to less than 150 mg/dL in a cohort of 2612 patients with diabetes who were undergoing coronary artery bypass grafting, compared with historical controls, the absolute mortality was reduced 57%. In a large randomized controlled trial, Van den Berghe et al16 found that intensive insulin therapy, with blood glucose levels kept between 80 and 110 mg/dL, reduced mortality and morbidity in critically ill patients in a surgical ICU (SICU). These findings were confirmed in the medical ICU (MICU) for patients who were admitted for at least 3 days.17 To target and maintain these tight blood glucose ranges, Van den Berghe et al16 developed an insulin protocol for timing of blood glucose measurements and insulin dose. Krinsley18 showed that improved glycemic control—although control was not as stringent as in the studies by Van den Berghe et al16,17—was associated with decreased mortality and morbidity in patients in a medical-surgical ICU. The findings of Finney et al19 and Van den Berghe et al20 suggest that control of blood glucose levels rather than insulin therapy accounts for the mortality benefit associated with intensive insulin therapy.


Hyperglycemia is associated with endothelial dysfunction, increased inflammatory cytokines, and adverse outcomes.

 

Because of this growing body of evidence on the adverse effects of hyperglycemia in critically ill patients, we implemented the insulin protocol described by Van den Berghe et al21 (Table 1Go). The objectives of our study were to evaluate adherence to and efficacy and safety of this insulin protocol during the entire protocol implementation period and to determine factors associated with adequate daily blood glucose control.


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  		Table 1 Summary of the insulin protocol as presented by Van den Berghe and colleagues21

 

   Methods
Top
 Abstract
 Methods
Statistical Analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 
Patients and Setting
A prospective observational pilot study was performed in the 22-bed SICU and the 14-bed MICU of Ghent University Hospital, a tertiary care, university teaching hospital in Ghent, Belgium. The nurse to patient ratio in the unit was 1 to 2. Approval for implementation of the insulin protocol was given by the hospital ethics committee, and informed consent was waived. During a 2-month study period, adherence to and efficacy and safety of the protocol were evaluated. Inclusion criteria were admission to the SICU or MICU, an anticipated ICU stay of at least 72 hours, age more than 16 years, presence of an arterial catheter, and need for insulin therapy. Patients with diabetic ketoacidosis, cardiac surgery patients, patients included in other studies, and patients transferred from other hospitals were excluded.

Implementation of the Insulin Protocol
The insulin protocol as described by Van den Berghe et al21 (Table 1Go) was not changed. Implementation and guidelines of the protocol were discussed with the entire SICU and MICU medical and nursing staff before it was used on the units. No special adjustments were made for use of corticosteroids, parenteral nutrition, or substitution solutions with glucose-containing infusions. All patients received baseline glucose infusions, parenteral or enteral nutrition, or a combination of both while the patients were receiving insulin infusions.

We decided to do a pilot study to guide us in making decisions about blood glucose control in the ICUs. All SICU and MICU nurses got a 1-hour lesson and a 4-week training period on the insulin protocol (Table 2Go). In the prestudy period, no data were collected, and the nurses could familiarize themselves with the new protocol. After this training period, the final study with patients began.


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  		Table 2 Implementation and evaluation of the insulin protocol

 
Because the protocol was completely implemented by nurses, ICU medical staff and physicians did not interfere with decisions about insulin rates. The ICU physicians were physicians in training for anesthesiology, surgery, or internal medicine who worked in the units and were supervised by a member of the ICU medical staff. The physicians were told only that a nurse-implemented protocol for tight blood glucose control was being used and that the physicians might be consulted in cases of severe hypoglycemia. The physicians were instructed to follow the protocol for such cases.

For measurements of blood glucose, the nurses used undiluted heparinized arterial blood and a bedside glucometer (GlucoTouch, LifeScan Benelux, Beerse, Belgium). The glucometers underwent monthly quality control. The rate of the insulin infusion (Humulin Regular, Eli Lilly and Company, Indianapolis, Indiana) and the frequency of blood glucose measurements were exclusively managed by the ICU nurses. Insulin was given by continuous intravenous infusion through a central venous catheter with a 50-mL pump syringe (Asena CC, Alaris Medical Systems, Inc, San Diego, California). The standard concentration of the infusion was 1 IU/mL (50 IU of insulin in 50 mL of isotonic saline).

In order to give the nurses as much support as possible during the study period, a bedside chart containing the protocol guidelines was made. This chart also was used to fill in the date, hour, blood glucose measurement, and corresponding rate of the insulin infusion. Nurses could put remarks on the chart if deviations from the protocol occurred. Use of the protocol ended when a patient was discharged to the general unit or therapy was withdrawn. ICU nurses and physicians were not informed that an observational study was being conducted.

Data Collection
All data were collected prospectively. Patients’ characteristics were obtained, and the Acute Physiology and Chronic Health Evaluation II22 was used to classify severity of illness. For each patient, caloric intake, feeding regimens, use of corticosteroids, organ dysfunction (assessed by using the Sepsis-Related Organ Failure Assessment23), blood glucose levels with their respective insulin infusion rates, and all rate adaptations were recorded daily during use of the protocol.


Many nurses were afraid of causing hypoglycemia and did not increase insulin rates sufficiently.

 

Evaluation of the Protocol
The protocol was evaluated with respect to adherence, efficacy, and safety. Adherence was defined as a correct adjustment in insulin rate according to the protocol and the individual condition of the patient. Nonadherence was any adjustment in the insulin rate that was not in accordance with the protocol guidelines. The efficacy of the protocol was evaluated by calculating the number of hours spent within each of the prospectively defined glycemia ranges during implementation of the protocol and expressing the result as a percentage of the whole study period.19 The different blood glucose ranges were defined as hypoglycemic (≤60 mg/dL), low (61–80 mg/dL), target (81–110 mg/dL), acceptable (111–150 mg/dL), hyperglycemic (151–200 mg/dL), and severely hyperglycemic (>200 mg/dL). The higher the percentage of total time within the target range, the better was the efficacy. Safety was assessed by determining time spent in the hypoglycemic range, the number of events in which the blood glucose level was 60 mg/dL or less, and the frequency of administration of rescue dextrose. Linear regression analysis was performed to determine factors associated with time daily spent in the target range, which was defined as adequate daily blood glucose control.


Insulin dose was adjusted correctly 71% of the time, whereas blood glucose levels were in the target range 42% of the time.

 


   Statistical Analysis
Top
 Abstract
 Methods
 Statistical Analysis
Results
 Discussion
 Limitations
 Conclusion
 References
 
For univariate analysis, {chi}2 tests and linear regression were used. Multivariate linear regression (enter method) was used to detect independent factors that could have influenced blood glucose control. All confounding factors included in the univariate model were assessed daily during the entire time the protocol was used. These factors were all the worst daily values for white blood cell count, level of C-reactive protein, core temperature, ratio of PaO2 to fraction of inspired oxygen, number of platelets, and levels of bilirubin and creatinine; all the exact daily values for caloric intake, blood glucose measurements, insulin dose, and adherence; and all the daily codes for binary variables (0 = no; 1 = yes) for the use of corticosteroids, ventilatory support, and vasoactive medication. A significance level of P < .25 in the univariate analysis was specified for maintaining variables in the multivariate model. If confounding between variables occurred (eg, white blood cell count or level of C-reactive protein), only the most clinically relevant variable was included in the multivariate analysis.24

Variables that remained significant in the final model were considered to be independently associated with adequate daily blood glucose control, which was defined as hours spent each day within the target range. To assess the relationship between a continuous variable and the outcome, and subsequently to analyze whether a continuous variable needed to be transformed or categorized, we used a smoothing scatter plot (Lowess of fit). SPSS, version 12.0 (SPSS Inc, Chicago, Illinois), was used for all statistical analyses. All clinical data are expressed as median and interquartile range or as percentages. P values less than .05 were considered significant.


   Results
Top
 Abstract
 Methods
 Statistical Analysis
 Results
Discussion
 Limitations
 Conclusion
 References
 
Table 3Go gives patients’ baseline demographics, admission features, illness severity, and outcome. Table 4Go gives data on blood glucose control, dose of insulin administered, and adherence to the protocol.


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  		Table 3 Baseline characteristics, illness severity, and outcome

 

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  		Table 4 Blood glucose control: measurements, insulin dose, and adherence to protocol

 
Adherence
During the 2-month study period, the 30 patients had a total of 352 days of protocol implementation. Of 6016 measurements obtained during those 352 protocol implementation days, 4267 measurements (71%) indicated adherence with the insulin protocol. Most deviations from the protocol (29%) were blood glucose levels in the acceptable (40.5%), hyperglycemic (64.5%), and severe hyperglycemic (43.7%) ranges. Of the 1749 deviations from the protocol, 87 were justified, such as alterations in nutrition or transport of a patient. Many nurses said they were afraid of causing hypoglycemia, but they did not indicate so on the bedside chart.

Efficacy
At the start of the protocol, 8 of the 30 patients (27%) had blood glucose levels in the target and acceptable ranges, 7 (23%) had levels between 150 and 200 mg/dL, and 15 (50%) had levels greater than 200 mg/dL. After a median of 20 hours (interquartile range, 11–36 hours), the target range was reached. Only 42% of the total protocol implementation time was spent in the desired range. For 36.9%, 8.2%, 1.8%, and 0.3% of this time, blood glucose level was in the acceptable, hyperglycemic, severe hyperglycemic, and hypoglycemic range, respectively (see FigureGo). Even in nonadherence with the protocol, 28% of total protocol implementation time was spent in the target range. This time increased, however, to 65% when nurses were compliant with the protocol (P < .001), with a 4.9 (95% confidence interval, 3.1–7.6) higher chance of attaining adequate daily blood glucose control.


Figure 1
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  		Figure Efficacy of the insulin protocol. Box-and-whisker plots are marked by the first and third quartile of overall time spent in a specific blood glucose range. Median values are represented in the box. The whiskers extend to points that are 1.5 times the interquartile range below the first or above the third quartile. {circ} = outliers that are >1.5 times the interquartile range above the third quartile. Blood glucose ranges (mg/dL; to convert to millimoles per liter, multiply by 0.0555) are defined as hypoglycemic, ≤60; low, 61–80; target, 81–110; acceptable, 111–150; hyperglycemic, 151–200; severe hyperglycemic, >200.

 
Safety
In the 6016 measurements, hypoglycemia was detected 111 times (1.8%) in 18 patients (60%), with a maximum of 25 hypoglycemic events out of 775 blood glucose measurements (3.2%) in 1 patient. A total of 34 episodes of hypoglycemia (0.6%) in 11 patients (37%) resulted in the administration of a rescue bolus of dextrose. A total of 7 blood glucose values (0.1%) in 6 different patients (2%) were 40 mg/dL or less, with a minimum of 34 mg/dL. One hypoglycemic event lasted 1 hour, one 30 minutes, and the others 15 minutes or less. None of these hypoglycemic events led to complications or resulted in clinically important consequences.

Linear Regression Analysis
Multivariate linear regression analysis revealed that adherence with the insulin protocol, a higher bilirubin level, a lower daily insulin dose, and a lower level of C-reactive protein were independently associated with increased time daily spent within the target range (Table 5Go).


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  		Table 5 Linear regression analysis to assess relationships between variables and adequate daily blood glucose control (R2 = 0.366)
 
Insulin Therapy and Feeding
The median insulin infusion dose during the study period was 2.0 IU/h (interquartile range, 1.0–4.0 IU/h), with a maximum of 20.0 IU/h; the maximum rate was needed only in one patient who had severe septic shock. Patients were given enteral and/or parenteral formula during 73% and 46%, respectively, of the study period. Patients received a median of 1640 kcal/d (interquartile range, 1323–1973).

Organ Failure
A high proportion of patients received mechanical ventilation (73%), corticosteroids (47%), or vasopressors (35%). Hyperbilirubinemia (bilirubin ≥1.2 mg/dL; to convert to micromoles per liter, multiply by 17.104) occurred during 100 of the 352 protocol implementation days (28.4%) in patients who had septic shock (65%), liver transplantation (20%), resuscitation (11%), stroke (2%), and heart decompensation (2%).


Sixty percent of patients experienced at least one hypoglycemic event, but without clinically important consequences.

 


   Discussion
Top
 Abstract
 Methods
 Statistical Analysis
 Results
 Discussion
Limitations
 Conclusion
 References
 
More than two-thirds of the blood glucose measurements indicated adherence with the protocol for tight blood glucose control. Even so, only 42% of the total study time was spent in the targeted blood glucose range, and hypoglycemia occurred frequently. Overall adherence with the protocol was 71%, similar to the percentage of adherence in other studies. Taylor et al25 reported an adherence of 53% during study circumstances when the blood glucose target level was 80 to 110 mg/dL, and Rood et al26 found 56% adherence when a paper-based guideline was used for an insulin-dosing protocol. In our study, only a minority of deviations from the protocol were justified. Because many nurses feared causing hypoglycemia, most of the deviations occurred in patients who were in the hyperglycemic and severe hyperglycemic ranges because insulin rates had not been increased sufficiently.

As recommended by Finney et al,19 we evaluated efficacy by calculating the time spent in each of the prospectively defined blood glucose ranges. Although our ranges and those of Finney et al were not identical, time spent in the various glycemic ranges was comparable. A median of 42% of total protocol implementation time was spent within the desired range, and an additional 36.9% was spent in the acceptable range.

Perhaps adherence and efficacy would have been better if the time between implementation and evaluation of the protocol had been longer. Efficacy also may vary according to each patient’s characteristics, because a protocol may not fit every patient. Poor glucose control occurs more often in patients who are older, have diabetes, or take corticosteroids and in certain subgroups of critically ill patients.27,28 In our study, adherence with the protocol was associated with a significant increase in efficacy and a 4.9 (95% confidence interval, 3.1–7.6) higher chance of achieving adequate daily blood glucose control. Perhaps the use of computerized guidelines for tight glucose control could improve adherence and efficacy.26

We defined hypoglycemia as a blood glucose level of 60 mg/dL or less because this is the level at which secretion of counterregulatory hormones increases.29 Other investigators defined hypoglycemia as a blood glucose level of 40 mg/dL or less16–18 or as less than 45 mg/dL.30 In this range, however, patients may be at risk for cognitive dysfunction, which can be misdiagnosed in critically ill patients.29

Multivariate linear regression indicated that adherence with the insulin protocol was positively associated with adequate daily blood glucose control. This finding is not surprising, because the protocol already had been successfully used by Van den Berghe and colleagues. It remains to be seen whether blood glucose control can be improved further in such a tight target range for severely ill patients. A high bilirubin level also was positively associated with a better daily blood glucose control. The exact reason for this observation remains unclear. In our study, 65% of all patients with hyperbilirubinemia experienced septic shock, were severely ill, and had long stays in the ICU. Possibly, insulin resistance decreased and glycemia could be better regulated in these patients. Also, patients with higher bilirubin levels may have had a greater tendency for lower blood glucose values because of liver failure and, as a consequence, had better blood glucose control.


Evaluation of this tight glucose control protocol resulted in elevation of the blood glucose target to < 150 mg/dL.

 

The finding that an adequate daily blood glucose control was independently related to a lower daily amount of insulin probably reflects the association between blood glucose control and insulin resistance. When the protocol began, only 2 patients had blood glucose levels in the target range, and 9 patients had blood levels of 300 mg/dL or more. When insulin resistance decreased, lower insulin rates could maintain tighter blood glucose levels. Rady et al27 reported that poor glycemic control in nondiabetic critically ill patients was associated with increased insulin requirements and increased mortality. Taylor et al25 found that a similar mean insulin dose was given in different study phases in which the target blood glucose levels ranged from liberal to 120 to 150 mg/dL to 80 to 110 mg/dL.

Lower levels of C-reactive protein also were independently associated with a better glycemic control. Hansen et al31 found a significantly more pronounced decrease in levels of C-reactive protein in SICU patients with target glycemia between 80 and 110 mg/dL than in conventionally treated patients in whom blood glucose levels were kept between 180 and 200 mg/dL. Intensive insulin therapy in MICU patients significantly decreased the incidence of hyperinflammation, defined as levels of C-reactive protein greater than 15 mg/dL.17

Although the total number of hypoglycemic events and time spent in the hypoglycemic range were negligible, 60% of our patients experienced at least one hypoglycemic event, and 31% (34/111) of these events resulted in rescue dextrose boluses. The discomfort and the uncommon situation of targeting these tight blood glucose values could have played important roles in the high frequency of blood glucose measurements, and the prompt adaptations in insulin rates probably even decreased the number of hypoglycemic events.

Although no standard method is used to evaluate the quality of blood glucose control in ICU patients and even though target ranges or definitions of hypoglycemia often differ, our results can be compared with those of other studies.18,25,28,30,32–36 After we evaluated the protocol and considered the current recommendations in the literature, we decided to target blood glucose levels according to the Surviving Sepsis Campaign guidelines,37 which recommend levels less than 150 mg/dL. The same consideration was initially made by Goldberg et al.34 They implemented a safe and effective nurse-run insulin protocol in the MICU in which target blood glucose levels were held between 100 and 139 mg/dL. An earlier attempt to implement tight glycemia control was unsuccessful because MICU nurses were uncomfortable with the blood glucose levels and lacked experience to manage intensive insulin infusions.34


Although adherence to the protocol was strongly associated with adequate daily blood glucose control, total protocol implementation time spent in the target range remained low.

 

Our main concern was a high incidence of hypoglycemia. Hypoglycemia seemed to be the most important practical barrier and the major barrier to implementing tight blood glucose control in many centers.30,34 Recently, 2 large-scale multicenter randomized trials of tight blood glucose control, the German Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (NCT00135473 [ClinicalTrials.gov] at http://clinicaltrials.gov) and the European Glucontrol Study (NCT00107601 [ClinicalTrials.gov] at http://clinicaltrials.gov), were interrupted because of a high incidence of hypoglycemia and no mortality benefit in the intensive insulin groups.38,39 Some centers prefer to use less stringent blood glucose ranges to minimize the risk for hypoglycemia but still prevent hyperglycemia.18,28,30,32–34,36,40 Although no adverse effects due to hypoglycemia have been reported when insulin protocols were used, Van den Berghe et al17 found that hypoglycemia was an independent predictor of mortality when MICU patients received intensive insulin therapy.


   Limitations
Top
 Abstract
 Methods
 Statistical Analysis
 Results
 Discussion
 Limitations
Conclusion
 References
 
Our study has several limitations. First, adherence depended on the ICU nurses and may reflect inadequate training before the study began. Many nurses were afraid of causing hypoglycemia, and this fear could have influenced nonadherence with the protocol. Goldberg et al41 found that tight blood glucose control was better accepted after nurses had spent years using a less stringent insulin protocol.

Second, compared with patients in other studies,16–19 our patients had higher scores on the Acute Physiology and Chronic Health Evaluation II. A high percentage of our patients received vasoactive medications, corticosteroids, and parenteral nutrition and had several episodes of sepsis during the evaluation of the protocol. Possibly, the tight blood glucose levels in our protocol would be easier to target and to maintain in patients with lower scores on the Acute Physiology and Chronic Health Evaluation II.

Third, accuracy of bedside glucometers for measurements of lower blood glucose levels has been questioned.42 To prevent disparities caused by different glucose-measuring methods, we preferred a standard well-known procedure that could be performed at the bedside. Arterial blood gas analysis would have been preferable to glucometry.

Finally, our results might not be applicable in other hospitals that do not have the typical organizational, structural, and clinical performance features of a tertiary university teaching hospital. Nevertheless, Goldberg et al33 reported that their insulin protocol was just as effective in a community teaching hospital as in an academic tertiary care center.


   Conclusion
Top
 Abstract
 Methods
 Statistical Analysis
 Results
 Discussion
 Limitations
 Conclusion
References
 
Adherence to and the efficacy and safety of an insulin protocol designed to target blood glucose levels between 81 and 110 mg/dL in SICU and MICU patients were evaluated. Adherence, which occurred in more than two-thirds of the blood glucose measurements, was strongly associated with adequate daily blood glucose control, but still only 42% of total protocol implementation time was spent within the target range. Hypoglycemia occurred frequently; 60% of our patients had at least a single hypoglycemic event. On the basis of these results, we recommend targeting blood glucose levels in a less tight range as described in the Surviving Sepsis Campaign guidelines.37


   ACKNOWLEDGMENTS
 
We thank the SICU and MICU nurses of Ghent University Hospital.

FINANCIAL DISCLOSURES
None reported.

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 Abstract
 Methods
 Statistical Analysis
 Results
 Discussion
 Limitations
 Conclusion
 References
 

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Increasing Compliance With Intensive Insulin Therapy
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