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1.  Improvement in Glycemic Control and Outcome Corresponding to Intensive Insulin Therapy Protocol Development 
Background
Intensive insulin therapy (IIT) has been shown to reduce mortality and morbidity in longer stay, critically ill patients. However, this has been demonstrated in a single site, whereas two multicentric studies have been terminated prematurely mainly due to hypoglycemia. Other difficulties with IIT include efficacy of glycemic control. This report describes how IIT can be improved by protocol simplification and removal of glucose supplementation.
Methods
A clinical information system established at each bedspace guided staff through the IIT algorithms. Time spent within predefined glycemic ranges was calculated assuming a linear trend between successive measurements. Three groups were investigated retrospectively: IIT1 protocol,1 an updated IIT2 version, and intuitive nurse dosing of conventional insulin therapy (CIT).
Results
Fifty consecutive, critically ill patients were included in each study group. Patient characteristics were similar in each group. The frequency of CIT and IIT2 blood glucose measurements were 11.6 and 11.5 measurements per day, respectively, while the IIT1 measurements were more frequent (14.5 measurements per day). The mean proportion of time spent in the target glycemic range (4.4–6.1 mmol/liter) was highest in the IIT2 group (34.9%), as compared to the IIT1 (22.9%) and CIT groups (20.3%) (p <.001). Survival at 28 days was 74.5% for IIT2 (highest), 68% for IIT1, and 48% for CIT (p = .02). There were a similar number of those experiencing a severe hypoglycemic event in each group.
Conclusions
IIT protocol optimization was associated with increased glycemic control and improved 28-day survival. The better optimized IIT2 protocol provided tighter control than either the IIT1 or CIT protocol, without increased sampling or incidence of hypoglycemia. The clinical effectiveness of the IIT algorithm appeared to be improved by simplifying the protocol to meet the needs of the critical care unit.
PMCID: PMC2769749  PMID: 19885203
blood glucose; critically ill; insulin; tight glycemic control
2.  Technical Challenges and Clinical Outcomes of Using a Closed-Loop Glycemic Control System in the Hospital 
According to large randomized trials, results suggest that maintaining normoglycemia postoperatively through tight glycemic control (TGC) and intensive insulin therapy (IIT) can improve surgical outcomes as well as reduce mortality and morbidity in critically ill patients. However, trials examining the effects of TGC have had conflicting results. Systematic reviews and meta-analyses have also led to differing conclusions. The main reason these clinical trials and meta-analyses show negative results for TGC is the high incidence of hypoglycemia induced by IIT. This could not be prevented because there is no reliable technique that can avoid this condition during IIT. The development of accurate, continuous blood glucose monitoring devices and closed-loop systems for computer-assisted blood glucose control in the intensive care unit (ICU) will probably help avoid hypoglycemia in these situations.
The STG closed-loop glycemic control system was introduced to our department to be used and evaluated for strict serum glucose control with no hypoglycemic episodes during IIT in the surgical ICU, to reduce the workload of ICU nurses, and to decrease incidents related to the management of blood glucose levels according to manual conventional venous infusion insulin therapy. The goal of our team was to use the STG closed-loop glycemic control system for perioperative TGC in surgical patients to solve the complications of IIT and reduce risk of hypoglycemia. The challenge at our hospital demonstrated that the STG closed-loop glycemic control system can be expected to achieve TGC with no occurrence of hypoglycemia induced by IIT after surgery.
PMCID: PMC3692238  PMID: 23439182
closed-loop glycemic control system; hypoglycemia; intensive care unit; intensive insulin therapy; liver;  pancreas; STG; surgery; tight glycemic control
3.  Benefits of intensive insulin therapy on neuromuscular complications in routine daily critical care practice: a retrospective study 
Critical Care  2009;13(1):R5.
Introduction
Intensive insulin therapy (IIT) reduced the incidence of critical illness polyneuropathy and/or myopathy (CIP/CIM) and the need for prolonged mechanical ventilation (MV ≥ 14 days) in two randomised controlled trials (RCTs) on the effect of IIT in a surgical intensive care unit (SICU) and medical intensive care unit (MICU). In the present study, we investigated whether these effects are also present in daily clinical practice when IIT is implemented outside of a study protocol.
Methods
We retrospectively studied electrophysiological data from patients in the SICU and MICU, performed because of clinical weakness and/or weaning failure, before and after routine implementation of IIT. CIP/CIM was diagnosed by abundant spontaneous electrical activity on electromyography. Baseline and outcome variables were compared using Student's t-test, Chi-squared or Mann-Whitney U-test when appropriate. The effect of implementing IIT on CIP/CIM and prolonged MV was assessed using univariate analysis and multivariate logistic regression analysis (MVLR), correcting for baseline and ICU risk factors.
Results
IIT significantly lowered mean (± standard deviation) blood glucose levels (from 144 ± 20 to 107 ± 10 mg/dl, p < 0.0001) and significantly reduced the diagnosis of CIP/CIM in the screened long-stay patients (125/168 (74.4%) to 220/452 (48.7%), p < 0.0001). MVLR identified implementing IIT as an independent protective factor (p < 0.0001, odds ratio (OR): 0.25 (95% confidence interval (CI): 0.14 to 0.43)). MVLR confirmed the independent protective effect of IIT on prolonged MV (p = 0.002, OR:0.40 (95% CI: 0.22–0.72)). This effect was statistically only partially explained by the reduction in CIP/CIM.
Conclusions
Implementing IIT in routine daily practice in critically ill patients evoked a similar beneficial effect on neuromuscular function as that observed in two RCTs. IIT significantly improved glycaemic control and significantly and independently reduced the electrophysiological incidence of CIP/CIM. This reduction partially explained the beneficial effect of IIT on prolonged MV.
doi:10.1186/cc7694
PMCID: PMC2688117  PMID: 19166623
4.  Barriers and Facilitators to the Use of Computer-based Intensive Insulin Therapy 
Purpose
Computerized clinical decision support systems (CDSSs) for intensive insulin therapy (IIT) are increasingly common. However, recent studies question IIT’s safety and mortality benefit. Researchers have identified factors influencing IIT performance, but little is known about how workflow affects computer-based IIT. We used ethnographic methods to evaluate IIT CDSS with respect to other clinical information systems and care processes.
Methods
We conducted direct observation of and unstructured interviews with nurses using IIT CDSS in the surgical and trauma intensive care units at an academic medical center. We observed 49 hours of intensive care unit workflow including 49 instances of nurses using IIT CDSS embedded in a provider order entry system. Observations focused on the interaction of people, process, and technology. By analyzing qualitative field note data through an inductive approach, we identified barriers and facilitators to IIT CDSS use.
Results
Barriers included (1) workload tradeoffs between computer system use and direct patient care, especially related to electronic nursing documentation, (2) lack of IIT CDSS protocol reminders, (3) inaccurate user interface design assumptions, and (4) potential for error in operating medical devices. Facilitators included (1) nurse trust in IIT CDSS combined with clinical judgment, (2) nurse resilience, and (3) paper serving as an intermediary between patient bedside and IIT CDSS.
Conclusion
This analysis revealed sociotechnical interactions affecting IIT CDSS that previous studies have not addressed. These issues may influence protocol performance at other institutions. Findings have implications for IIT CDSS user interface design and alerts, and may contribute to nascent general CDSS theory.
doi:10.1016/j.ijmedinf.2011.10.003
PMCID: PMC3226863  PMID: 22019280
blood glucose; clinical decision support systems; critical care; electronic medical records; ethnography; hyperglycemia; hypoglycemia; insulin
5.  Tight blood glucose control in trauma patients: Who really benefits? 
Background:
This study was designed to evaluate the effect of intensive insulin control (IIT) on outcomes for traumatically injured patients as a function of injury severity score (ISS) and age.
Patients and Methods:
A retrospective review of 2028 adult trauma patients admitted to the surgical intensive care unit (SICU) in a Level I trauma center was performed. Data were collected from a 48-month period before (Pre-IIT) (goal blood glucose 80–200 mg/dL) and after (Post-IIT) (goal blood glucose level 80–110 mg/dL), an IIT protocol was initiated. Patients were stratified by age and ISS. The primary endpoint was mortality.
Results:
There were 784 Pre-IIT and 1244 Post-IIT patients admitted. There was no significant difference between Pre-IIT vs. Post-IIT for the mechanism of injury or ISS. Values for the Pre-IIT group were significantly higher for mortality (21.5% vs. 14.7%, P<0.001) and hospital, but not ICU length of stay were decreased. A significant improvement in mortality was demonstrated between Pre-IIT vs. Post-IIT stratified within the age groups of 41–50, 51–60, and 61 but not the groups 18–30 and 31–40. Mean glucose levels (mg/dL) decreased significantly after the institution of IIT (144.7±1.4 vs. 130.9±0.9; P<0.001). In addition, the occurrence per patient of blood glucose levels <40 mg/dL increased (0.77% vs. 2.86%; P=0.001) and blood glucose levels greater than 200 mg/dL was similar (39.1% vs. 38.8%; P=0.892) in the Pre-IIT and Post-IIT groups, respectively. Glycemic variability, reflected by the standard deviation of each patient's mean glucose level during ICU stay, as well as mean glucose level were lower in survivors than in nonsurvivors. Finally, multivariable logistic regression analysis identified both mean glucose level and glycemic variability as independent contributors to the risk of mortality.
Conclusions:
The implementation of IIT has been associated with a decrease in both hospital length of stay as well as mortality. Average glucose value and glucose variability are independent predictors of survival. Trauma patients with moderate, severe, and very severe injuries benefit most from IIT. These observational data suggest that patients over 40 years of age benefited a great deal more than their younger counterparts from IIT. This study supports the need for a randomized controlled trial to investigate the role of IIT in traumatically injured patients.
doi:10.4103/0974-2700.83864
PMCID: PMC3162705  PMID: 21887026
Age; glucose; glycemic control; ISS; insulin; intensive insulin control; trauma
6.  Intensive Insulin Therapy in Critically Ill Hospitalized Patients: Making It Safe and Effective 
Intensive insulin therapy (IIT) for hyperglycemia in critically ill patients has become a standard practice. Target levels for glycemia have fluctuated since 2000, as evidence initially indicated that tight glycemic control to so-called normoglycemia (80–110 mg/dl) leads to the lowest morbidity and mortality without hypoglycemic complications. Subsequent studies have demonstrated minimal clinical benefit combined with greater hypoglycemic morbidity and mortality with tight glycemic control in this population. The consensus glycemic targets were then liberalized to the mid 100s (mg/dl).
Handheld POC blood glucose (BG) monitors have migrated from the outpatient setting to the hospital environment because they save time and money for managing critically ill patients who require IIT. These devices are less accurate than hospital-grade POC blood analyzers or central laboratory analyzers.
Three questions must be answered to understand the role of IIT for defined populations of critically ill patients: (1) How safe is IIT, with various glycemic targets, from the risk of hypoglycemia? (2) How tightly must BG be controlled for this approach to be effective? (3) What role does the accuracy of BG measurements play in affecting the safety of this method? For each state of impaired glucose regulation seen in the hospital, such as hyperglycemia, hypoglycemia, or glucose variability, the benefits, risks, and goals of treatment, including IIT, might differ.
With improved accuracy of BG monitors, IIT might be rendered even more intensive than at present, because patients will be less likely to receive inadvertent overdosages of insulin. Greater doses of insulin, but with dosing based on more accurate glucose levels, might result in less hypoglycemia, less hyperglycemia, and less glycemic variability.
PMCID: PMC3192642  PMID: 21722591
critical care; glucose; glucose monitoring; glucose variability; hyperglycemia; hypoglycemia; insulin; intensive; intensive care unit; point of care
7.  Comparison of intensive insulin therapy versus conventional glucose control in traumatic brain injury patients on parenteral nutrition: A pilot randomized clinical trial 
Background:
Parenteral nutrition (PN) is a valuable life saving intervention, which can improve the nutritional status of hospitalized malnourished patients. PN is associated with complications including hyperglycemia. This study was conducted to compare two methods of blood glucose control in traumatic brain injury patients on PN.
Materials and Methods:
A randomized, open-label, controlled trial with blinded end point assessment was designed. Traumatic brain injury patients (GCS = 4-9) on PN, without diabetes, pancreatitis, liver disease, kidney complication, were participated. Patients were randomly assigned to receive continuous insulin infusion to maintain glucose levels between 4.4 mmol/l (80 mg/dl) and 6.6 mmol/l (120 mg/dl) (n = 13) or conventional treatment (n = 13). Patients in the conventional group were not received insulin unless glucose levels were greater than 10 mmol/l (>180 mg/dl). These methods were done to maintain normoglycemia in ICU. The primary outcome was hypo/hyperglycemic episodes. Other factors such as C-reactive protein, blood electrolytes, liver function tests, lipid profile and mid-arm circumference were compared.
Results:
Mean glucose concentration were significantly lower in IIT group (118 ± 28 mg/dl) vs conventional group (210 ± 31 mg/dl) (P < 0.01). No hypoglycemic episode occurred in two groups. Triglyceride (P = 0.02) and C-reactive protein (P = 0.001) was decreased in the IIT group, significantly. There were also significant differences in the electrolytes, with magnesium and phosphorus being lower in the IIT group (P = 0.05).
Conclusion:
In this pilot study, blood glucose level, CRP and TG were lower in IIT group. Further data collection is warranted to reach definitive conclusions.
PMCID: PMC4116573  PMID: 25097624
Hyperglycemia; hypoglycemia; intensive insulin therapy; parenteral nutrition
8.  Effect of intensive vs conventional insulin therapy on perioperative nutritional substrates metabolism in patients undergoing gastrectomy 
AIM: To investigate the effect of intensive vs conventional insulin therapy on perioperative nutritional substrates metabolism in patients undergoing radical distal gastrectomy.
METHODS: Within 24 h of intensive care unit management, patients with gastric cancer were enrolled after written informed consent and randomized to the intensive insulin therapy (IIT) group to keep glucose levels from 4.4 to 6.1 mmol/L or the conventional insulin therapy (CIT) group to keep levels less than 10 mmol/L. Resting energy expenditure (REE), respiratory quotient (RQ), resting energy expenditure per kilogram (REE/kg), and the lipid oxidation rate were monitored by the indirect calorimeter of calcium citrate malate nutrition metabolism investigation system. The changes in body composition were analyzed by multi-frequency bioimpedance analysis. Blood fasting glucose and insulin concentration were measured for assessment of Homeostasis model assessment of insulin resistance.
RESULTS: Sixty patients were enrolled. Compared with preoperative baseline, postoperative REE increased by over 22.15% and 11.07%; REE/kg rose up to 27.22 ± 1.33 kcal/kg and 24.72 ± 1.43 kcal/kg; RQ decreased to 0.759 ± 0.034 and 0.791 ± 0.037; the lipid oxidation ratio was up to 78.25% ± 17.74% and 67.13% ± 12.76% supported by parenteral nutrition solutions from 37.56% ± 11.64% at the baseline; the level of Ln-HOMA-IR went up dramatically (P < 0.05, respectively) on postoperative days 1 and 3 in the IIT group. Meanwhile the concentration of total protein, albumin and triglyceride declined significantly on postoperative days 1 and 3 compared with pre-operative levels (P < 0.05, respectively). Compared with the CIT group, IIT reduced the REE/kg level (27.22 ± 1.33 kcal/kg vs 29.97 ± 1.47 kcal/kg, P = 0.008; 24.72 ± 1.43 kcal/kg vs 25.66 ± 1.63 kcal/kg, P = 0.013); and decreased the Ln-HOMA-IR score (P = 0.019, 0.028) on postoperative days 1 and 3; IIT decreased the level of CRP on postoperative days 1 and 3 (P = 0.017, 0.006); the total protein and albumin concentrations in the IIT group were greater than those in the CIT group (P = 0.023, 0.009). Postoperative values of internal cell fluid (ICF), fat mass, protein mass (PM), muscle mass, free fat mass and body weight decreased obviously on postoperative 7th day compared with the preoperative baseline in the CIT group (P < 0.05, respectively). IIT reduced markedly consumption of fat mass, PM and ICF compared with CIT (P = 0.009 to 0.026).
CONCLUSION: There were some benefits of IIT in decreasing the perioperative insulin resistance state, reducing energy expenditure and consumption of proteins and lipids tissue in patients undergoing gastrectomy.
doi:10.3748/wjg.v18.i21.2695
PMCID: PMC3370008  PMID: 22690080
Intensive insulin therapy; Resting energy expenditure; Respiratory quotient; Insulin resistance; Free fat acids; Body composition
9.  Effects of tight computerized glucose control on neurological outcome in severely brain injured patients: a multicenter sub-group analysis of the randomized-controlled open-label CGAO-REA study 
Critical Care  2014;18(5):498.
Introduction
Hyperglycemia is a marker of poor prognosis in severe brain injuries. There is currently little data regarding the effects of intensive insulin therapy (IIT) on neurological recovery.
Methods
A sub-group analysis of the randomized-controlled CGAO-REA study (NCT01002482) in surgical intensive care units (ICU) of two university hospitals. Patients with severe brain injury, with an expected ICU length of stay ≥48 hours were included. Patients were randomized between a conventional glucose management group (blood glucose target between 5.5 and 9 mmol.L−1) and an IIT group (blood glucose target between 4.4 and 6 mmol.L−1). The primary outcome was the day-90 neurological outcome evaluated with the Glasgow outcome scale.
Results
A total of 188 patients were included in this analysis. In total 98 (52%) patients were randomized in the control group and 90 (48%) in the IIT group. The mean Glasgow coma score at baseline was 7 (±4). Patients in the IIT group received more insulin (130 (68 to 251) IU versus 74 (13 to 165) IU in the control group, P = 0.01), had a significantly lower morning blood glucose level (5.9 (5.1 to 6.7) mmol.L−1 versus 6.5 (5.6 to 7.2) mmol.L−1, P <0.001) in the first 5 days after ICU admission. The IIT group experienced more episodes of hypoglycemia (P <0.0001). In the IIT group 24 (26.6%) patients had a favorable neurological outcome (good recovery or moderate disability) compared to 31 (31.6%) in the control group (P = 0.4). There were no differences in day-28 mortality. The occurrence of hypoglycemia did not influence the outcome.
Conclusions
In this sub-group analysis of a large multicenter randomized trial, IIT did not appear to alter the day-90 neurological outcome or ICU morbidity in severe brain injured patients or ICU morbidity.
doi:10.1186/s13054-014-0498-9
PMCID: PMC4174656  PMID: 25189764
10.  Effects of blood glucose transcription mismatches on a computer-based intensive insulin therapy protocol 
Intensive care medicine  2010;36(9):1566-1570.
Purpose
Computerized clinical decision support systems (CDSS) for intensive insulin therapy (IIT) generate recommendations using blood glucose (BG) values manually transcribed from testing devices to computers, a potential source of error. We quantified the frequency and effect of blood glucose transcription mismatches on IIT protocol performance.
Methods
We examined 38 months of retrospective data for patients treated with CDSS IIT in two intensive care units at one teaching hospital. A manually transcribed BG value not equal to a corresponding device value was deemed mismatched. For mismatches we recalculated CDSS recommendations using device BG values. We compared matched and mismatched data in terms of CDSS alerts, blood glucose variability, and dosing.
Results
Of 189,499 CDSS IIT instances, 5.3% contained mismatched BG values. Mismatched data triggered 93 false alerts and failed to issue 170 alerts for nurses to notify physicians. Four of six BG variability measures differed between matched and mismatched data. Overall insulin dose was greater for matched than mismatched [matched 3.8 (1.6–6.0), median (interquartile range, IQR), versus 3.6 (1.6–5.7); p < 0.001], but recalculated and actual dose were similar. In mismatches preceding hypoglycemia, recalculated insulin dose was significantly lower than actual dose [recalculated 2.7 (0.4–5.0), median (IQR), versus 3.5 (1.4–5.6)]. In mismatches preceding hyperglycemia, recalculated insulin dose was significantly greater than actual dose [recalculated 4.7 (3.3–6.2), median (IQR), versus 3.3 (2.4–4.3); p < 0.001]. Administration of recalculated doses might have prevented blood glucose excursions.
Conclusions
Mismatched blood glucose values can influence CDSS IIT protocol performance.
doi:10.1007/s00134-010-1868-7
PMCID: PMC2916042  PMID: 20352190
Intensive insulin therapy; Clinical protocols; Clinical decision support systems; Blood glucose; Insulin; Critical care
11.  Social, Organizational, and Contextual Characteristics of Clinical Decision Support Systems for Intensive Insulin Therapy: A Literature Review and Case Study 
Introduction:
Evaluations of computerized clinical decision support systems (CDSS) typically focus on clinical performance changes and do not include social, organizational, and contextual characteristics explaining use and effectiveness. Studies of CDSS for intensive insulin therapy (IIT) are no exception, and the literature lacks an understanding of effective computer-based IIT implementation and operation.
Results:
This paper presents (1) a literature review of computer-based IIT evaluations through the lens of institutional theory, a discipline from sociology and organization studies, to demonstrate the inconsistent reporting of workflow and care process execution and (2) a single-site case study to illustrate how computer-based IIT requires substantial organizational change and creates additional complexity with unintended consequences including error.
Discussion:
Computer-based IIT requires organizational commitment and attention to site-specific technology, workflow, and care processes to achieve intensive insulin therapy goals. The complex interaction between clinicians, blood glucose testing devices, and CDSS may contribute to workflow inefficiency and error. Evaluations rarely focus on the perspective of nurses, the primary users of computer-based IIT whose knowledge can potentially lead to process and care improvements.
Conclusion:
This paper addresses a gap in the literature concerning the social, organizational, and contextual characteristics of CDSS in general and for intensive insulin therapy specifically. Additionally, this paper identifies areas for future research to define optimal computer-based IIT process execution: the frequency and effect of manual data entry error of blood glucose values, the frequency and effect of nurse overrides of CDSS insulin dosing recommendations, and comprehensive ethnographic study of CDSS for IIT.
doi:10.1016/j.ijmedinf.2009.09.004
PMCID: PMC2818499  PMID: 19815452
intensive insulin therapy; clinical protocols; clinical decision support systems; organizational change; organizational structure; hospital information systems; evaluation; sociology of technology
12.  Characteristics and effects of nurse dosing over-rides on computer-based intensive insulin therapy protocol performance 
Objective
To determine characteristics and effects of nurse dosing over-rides of a clinical decision support system (CDSS) for intensive insulin therapy (IIT) in critical care units.
Design
Retrospective analysis of patient database records and ethnographic study of nurses using IIT CDSS.
Measurements
The authors determined the frequency, direction—greater than recommended (GTR) and less than recommended (LTR)— and magnitude of over-rides, and then compared recommended and over-ride doses' blood glucose (BG) variability and insulin resistance, two measures of IIT CDSS associated with mortality. The authors hypothesized that rates of hypoglycemia and hyperglycemia would be greater for recommended than over-ride doses. Finally, the authors observed and interviewed nurse users.
Results
5.1% (9075) of 179 452 IIT CDSS doses were over-rides. 83.4% of over-ride doses were LTR, and 45.5% of these were ≥50% lower than recommended. In contrast, 78.9% of GTR doses were ≤25% higher than recommended. When recommended doses were administered, the rate of hypoglycemia was higher than the rate for GTR (p=0.257) and LTR (p=0.033) doses. When recommended doses were administered, the rate of hyperglycemia was lower than the rate for GTR (p=0.003) and LTR (p<0.001) doses. Estimates of patients' insulin requirements were higher for LTR doses than recommended and GTR doses. Nurses reported trusting IIT CDSS overall but appeared concerned about recommendations when administering LTR doses.
Conclusion
When over-riding IIT CDSS recommendations, nurses overwhelmingly administered LTR doses, which emphasized prevention of hypoglycemia but interfered with hyperglycemia control, especially when BG was >150 mg/dl. Nurses appeared to consider the amount of a recommended insulin dose, not a patient's trend of insulin resistance, when administering LTR doses overall. Over-rides affected IIT CDSS protocol performance.
doi:10.1136/amiajnl-2011-000129
PMCID: PMC3078667  PMID: 21402737
Health-information exchange; qualitative/ethnographic field study; system implementation and management issues; surveys and needs analysis; social/organizational study; improving the education and skills training of health professionals; machine learning; clinical decision support system; intensive insulin therapy; nurse protocol; critical care; intensive care unit; over-ride
13.  Anemia Causes Hypoglycemia in ICU Patients Due to Error in Single-Channel Glucometers: Methods of Reducing Patient Risk 
Critical care medicine  2010;38(2):471-476.
OBJECTIVE
Intensive insulin therapy (IIT) in the critically ill reduces mortality but carries the risk of increased hypoglycemia. Point-of-care (POC) blood glucose analysis is standard; however anemia causes falsely high values and potentially masks hypoglycemia. Permissive anemia is routinely practiced in most intensive care units (ICUs). We hypothesized that POC glucometer error due to anemia is prevalent, can be mathematically corrected, and correction uncovers occult hypoglycemia during IIT.
DESIGN
The study has both retrospective and prospective phases. We reviewed data to verify the presence of systematic error, determine the source of error, and establish the prevalence of anemia. We confirmed our findings by reproducing the error in an in-vitro model. Prospective data was used to develop a correction formula validated by the Monte Carlo method. Correction was implemented in a burn ICU and results evaluated after nine months.
SETTING
Burn and trauma ICUs at a single research institution.
PATIENTS/SUBJECTS
Samples for in-vitro studies were taken from healthy volunteers. Samples for formula development were from critically ill patients on IIT.
INTERVENTIONS
Insulin doses were calculated based on predicted serum glucose values from corrected POC glucometer measurements.
MEASUREMENTS
Time-matched POC glucose, laboratory glucose, and hematocrit values.
MAIN RESULTS
We previously found that anemia (HCT<34%) produces systematic error in glucometer measurements. The error was correctible with a mathematical formula developed and validated using prospectively collected data. Error of uncorrected POC glucose ranged from 19% to 29% (p<0.001), improving to ≤5% after mathematical correction of prospective data. Comparison of data pairs before and after correction formula implementation demonstrated a 78% decrease in the incidence of hypoglycemia in critically ill and anemic patients treated with insulin and tight glucose control (p<0.001).
CONCLUSIONS
A mathematical formula that corrects erroneous POC glucose values due to anemia in ICU patients reduces the incidence of hypoglycemia during IIT.
doi:10.1097/CCM.0b013e3181bc826f
PMCID: PMC4267684  PMID: 19789438
glucose; insulin; point-of-care systems; hematocrit; glucose oxidase; critical care; ICU; glucometer; glucose measurement: arterial; venous; capillary glucose measurement; anemia; capillary
14.  Multicenter Validation of a Computer-Based Clinical Decision Support Tool for Glucose Control in Adult and Pediatric Intensive Care Units 
Introduction
Hyperglycemia during critical illness is common, and intravenous insulin therapy (IIT) to normalize blood glucose improves outcomes in selected populations. Methods differ widely in complexity, insulin dosing approaches, efficacy, and rates of hypoglycemia. We developed a simple bedside-computerized decision support protocol (eProtocol-insulin) that yields promising results in the development center. We examined the effectiveness and safety of this tool in six adult and five pediatric intensive care units (ICUs) in other centers.
Methods
We required attending physicians of eligible patients to independently intend to use intravenous insulin to normalize blood glucose. We used eProtocol-insulin for glucose control for a duration determined by the clinical caregivers. Adults had an anticipated length of stay of 3 or more days. In pediatric ICUs, we also required support or intended support with mechanical ventilation for greater than 24 hours or with a vasoactive infusion. We recorded all instances in which eProtocol-insulin instructions were not accepted and all blood glucose values. An independent data safety and monitoring board monitored study results and subject safety. Bedside nurses were selected randomly to complete a paper survey describing their perceptions of quality of care and workload related to eProtocol-insulin use.
Results
Clinicians accepted 93% of eProtocol-insulin instructions (11,773/12,645) in 100 adult and 48 pediatric subjects. Forty-eight percent of glucose values were in the target range. Both of these results met a priori-defined efficacy thresholds. Only 0.18% of glucose values were ≤40 mg/dl. This is lower than values reported in prior IIT studies. Although nurses reported eProtocol-insulin required as much work as managing a mechanical ventilator, most nurses felt eProtocol-insulin had a low impact on their ability to complete non-IIT nursing activities.
Conclusions
A multicenter validation demonstrated that eProtocol-insulin is a valid, exportable tool that can assist clinicians in achieving control of glucose in critically ill adults and children.
PMCID: PMC2769731  PMID: 19885199
computerized decision support; critical care; glucose control; intensive insulin therapy
15.  Analysis: Continuous Glucose Monitoring during Intensive Insulin Therapy 
Results of the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) trial, intensive insulin therapy (IIT), and use of a continuous glucose sensor in intensive care units (ICU) were analyzed. The NICE-SUGAR trial was unable to determine if optimal intensive insulin therapy decreases mortality. Continuous glucose monitoring (CGM) technology has the potential to improve glycemic control with low glucose variability and low incidence of hypoglycemia. Interstitial fluid CGM may not be useful in perioperative and ICU settings. Studies evaluating the accuracy and reliability of CGM devices, based on a whole blood sample in perioperative and ICU settings, are needed. Once a reliable CGM sensor for ICU use is identified, a large, prospective, controlled, multicenter study could determine if optimal IIT with a low or zero incidence of hypoglycemic events improves mortality.
PMCID: PMC2769950  PMID: 20144346
continuous glucose sensor; glucose; ICU; intensive insulin therapy; perioperative
16.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
17.  Pilot Study for Assessment of Optimal Frequency for Changing Catheters in Insulin Pump Therapy—Trouble Starts on Day 3 
Background
Continuous subcutaneous insulin infusion (CSII) by means of insulin pump devices is considered to be one of the most optimal therapies to achieve treatment targets in patients with diabetes mellitus. In CSII, the insulin is delivered through Teflon catheters or steel needle infusion sets, which need to be renewed on a regular basis. This pilot study was performed to investigate the optimal change frequency in daily practice and to explore potential problems that may occur when the sets are used for a more prolonged time than the recommended up to 72 hours of usage (Teflon catheters).
Method
Twelve patients with type 1 diabetes participated in the trial [age (mean ± STD): 40.3 ± 12.6 years, body mass index: 26.2 ± 3.3 kg/m², hemoglobin A1c: 6.7 ± 0.6%]. They were asked to wear their infusion set (Comfort™ or Silhouette®) for increasing periods of 1, 2, 3, 4, and 5 days. After each use, patients completed standardized questionnaires regarding technical and medical issues associated with infusion set use. A health care professional investigated the infusion sites and infusion sets and completed an “infusion set inspection” questionnaire. Blood glucose was measured and recorded to assess a potential influence of duration of catheter use on glycemic control.
Results
Infusion set and injection site problems (itching, bruising, swelling, and pain) started to occur in measurable amounts on the 3rd day of catheter use, and about 40% of patients reported significant issues when using a catheter for 5 days. In parallel, there was a consistent increase in mean daily blood glucose levels that correlated with the number of days of catheter use (e.g., day 1: 7.5 ± 3.8 mmol/liter, day 3: 8.4 ± 4.2 mmol/liter, day 5: 9.0 ± 4.0 mmol/liter, day 7: 11.6 ± 2.2 mmol/liter, p < 0.05 vs day 1).
Conclusions
Using the catheters for 2 days resulted in a safe and well-tolerated therapy. Clinically relevant adverse events started to occur during the 3rd day and their incidence increased constantly with longer use. This was associated with undesired changes in mean glycemic control. Data support the recommendation by the drug and device manufacturers that insulin pump catheters should only be used for 48–72 hours to avoid adverse events and potential metabolic deterioration.
PMCID: PMC2909532  PMID: 20663464
CSII; catheter infusion set; duration of use; infusion set failure; insulin pump therapy
18.  Glycemic variability and glucose complexity in critically ill patients: a retrospective analysis of continuous glucose monitoring data 
Critical Care  2012;16(5):R175.
Introduction
Glycemic variability as a marker of endogenous and exogenous factors, and glucose complexity as a marker of endogenous glucose regulation are independent predictors of mortality in critically ill patients. We evaluated the impact of real time continuous glucose monitoring (CGM) on glycemic variability in critically ill patients on intensive insulin therapy (IIT), and investigated glucose complexity - calculated using detrended fluctuation analysis (DFA) - in ICU survivors and non-survivors.
Methods
Retrospective analysis were conducted of two prospective, randomized, controlled trials in which 174 critically ill patients either received IIT according to a real-time CGM system (n = 63) or according to an algorithm (n = 111) guided by selective arterial blood glucose measurements with simultaneously blinded CGM for 72 hours. Standard deviation, glucose lability index and mean daily delta glucose as markers of glycemic variability, as well as glucose complexity and mean glucose were calculated.
Results
Glycemic variability measures were comparable between the real time CGM group (n = 63) and the controls (n = 111). Glucose complexity was significantly lower (higher DFA) in ICU non-survivors (n = 36) compared to survivors (n = 138) (DFA: 1.61 (1.46 to 1.68) versus 1.52 (1.44 to 1.58); P = 0.003). Diabetes mellitus was significantly associated with a loss of complexity (diabetic (n = 33) versus non-diabetic patients (n = 141) (DFA: 1.58 (1.48 to 1.65) versus 1.53 (1.44 to 1.59); P = 0.01).
Conclusions
IIT guided by real time CGM did not result in significantly reduced glycemic variability. Loss of glucose complexity was significantly associated with mortality and with the presence of diabetes mellitus.
doi:10.1186/cc11657
PMCID: PMC3682275  PMID: 23031322
19.  Intensive Insulin Therapy for Septic Patients: A Meta-Analysis of Randomized Controlled Trials 
BioMed Research International  2014;2014:698265.
Background. Studies on the effect of intensive insulin therapy (IIT) in septic patients with hyperglycemia have given inconsistent results. The primary purpose of this meta-analysis was to evaluate whether it is effective in reducing mortality. Methods. We searched PubMed, Embase, the Cochrane Library, clinicaltrials.gov, and relevant reference lists up to September 2013 and including randomized controlled trials that compared IIT with conventional glucose management in septic patients. Study quality was assessed using the Cochrane Risk of Bias Tool. And our primary outcome measure was pooled in the random effects model. Results. We identified twelve randomized controlled trials involving 4100 patients. Meta-analysis showed that IIT did not reduce any of the outcomes: overall mortality (risk ratio [RR] = 0.98, 95% CI [0.85, 1.15], P = 0.84), 28-day mortality (RR = 0.66, 95% CI [0.40, 1.10], P = 0.11), 90-day mortality (RR = 1.10, 95% CI [0.97, 1.26], P = 0.13), ICU mortality (RR = 0.94, 95% CI [0.77, 1.14], P = 0.52), hospital mortality (RR = 0.98, 95% CI [0.86, 1.11], P = 0.71), severity of illness, and length of ICU stay. Conversely, the incidence of hypoglycemia was markedly higher in the IIT (RR = 2.93, 95% CI [1.69, 5.06], P = 0.0001). Conclusions. For patients with sepsis, IIT and conservative glucose management show similar efficacy, but ITT is associated with a higher incidence of hypoglycemia.
doi:10.1155/2014/698265
PMCID: PMC4086473  PMID: 25136614
20.  The use of exenatide in severely burned pediatric patients 
Critical Care  2010;14(4):R153.
Introduction
Intensive insulin treatment (IIT) has been shown to improve outcomes post-burn in severely burnt patients. However, it increases the incidence of hypoglycemia and is associated with risks and complications. We hypothesized that exenatide would decrease plasma glucose levels post-burn to levels similar to those achieved with IIT, and reduce the amount of exogenous insulin administered.
Methods
This open-label study included 24 severely burned pediatric patients. Six were randomized to receive exenatide, and 18 received IIT during acute hospitalization (block randomization). Exenatide and insulin were administered to maintain glucose levels between 80 and 140 mg/dl. We determined 6 AM, daily average, maximum and minimum glucose levels. Variability was determined using mean amplitude of glucose excursions (MAGE) and percentage of coefficient of variability. The amount of administered insulin was compared in both groups.
Results
Glucose values and variability were similar in both groups: Daily average was 130 ± 28 mg/dl in the intervention group and 138 ± 25 mg/dl in the control group (P = 0.31), MAGE 41 ± 6 vs. 45 ± 12 (respectively). However, administered insulin was significantly lower in the exenatide group than in the IIT group: 22 ± 14 IU patients/day in the intervention group and 76 ± 11 IU patients/day in the control group (P = 0.01). The incidence rate of hypoglycemia was similar in both groups (0.38 events/patient-month).
Conclusions
Patients receiving exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels. Exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting.
Trial registration
NCT00673309.
doi:10.1186/cc9222
PMCID: PMC2945137  PMID: 20701787
21.  Glycaemic control in Australia and New Zealand before and after the NICE-SUGAR trial: a translational study 
Critical Care  2013;17(5):R215.
Introduction
There is no information on the uptake of Intensive Insulin Therapy (IIT) before the Normoglycemia in Intensive Care Evaluation and Surviving Using Glucose Algorithm Regulation (NICE-SUGAR) trial in Australia and New Zealand (ANZ) and on the bi-national response to the trial, yet such data would provide important information on the evolution of ANZ practice in this field. We aimed to study ANZ glycaemic control before and after the publication of the results of the NICE-SUGAR trial.
Methods
We analysed glucose control in critically ill patients across Australia and New Zealand during a two-year period before and after the publication of the NICE-SUGAR study. We used the mean first day glucose (Glu1) (a validated surrogate of ICU glucose control) to define practice. The implementation of an IIT protocol was presumed if the median of Glu1 measurements was <6.44 mmol/L for a given ICU. Hypoglycaemia was categorised as severe (glucose ≤2.2 mmol/L) or moderate (glucose ≤3.9 mmol/L).
Results
We studied 49 ICUs and 176,505 patients. No ICU practiced IIT before or after NICE-SUGAR. Overall, Glu1 increased from 7.96 (2.95) mmol/L to 8.03 (2.92) mmol/L (P <0.0001) after NICE-SUGAR. Similar increases were noted in all patient subgroups studied (surgical, medical, insulin dependent diabetes mellitus, ICU stay >48/<48 hours). The rate of severe and moderate hypoglycaemia before and after NICE-SUGAR study were 0.59% vs. 0.55% (P =0.33) and 6.62% vs. 5.68% (P <0.0001), respectively. Both crude and adjusted mortalities declined over the study period.
Conclusions
IIT had not been adopted in ANZ before the NICE-SUGAR study and glycaemic control corresponded to that delivered in the control arm of NICE-SUGAR trial. There were only minor changes in practice after the trial toward looser glycaemic control. The rate of moderate hypoglycaemia and mortality decreased along with such changes.
doi:10.1186/cc13030
PMCID: PMC4056083  PMID: 24088368
22.  Effects of intensive insulin therapy combined with low molecular weight heparin anticoagulant therapy on severe pancreatitis 
The current study explored the effects of intensive insulin therapy (IIT) combined with low molecular weight heparin (LMWH) anticoagulant therapy on severe acute pancreatitis (SAP). A total of 134 patients with SAP that received treatment between June 2008 and June 2012 were divided randomly into groups A (control; n=33), B (IIT; n=33), C (LMWH; n=34) and D (IIT + LMWH; n=34). Group A were treated routinely. Group B received continuous pumped insulin, as well as the routine treatment, to maintain the blood sugar level between 4.4 and 6.1 mmol/l. Group C received a subcutaneous injection of LMWH every 12 h in addition to the routine treatment. Group D received IIT + LMWH and the routine treatment. The white blood cell count, hemodiastase, serum albumin, arterial partial pressure of oxygen and prothrombin time were recorded prior to treatment and 1, 3, 5, 7 and 14 days after the initiation of treatment. The intestinal function recovery time, incidence rate of multiple organ failure (MOF), length of hospitalization and fatality rates were observed. IIT + LMWH noticeably increased the white blood cell count, hemodiastase level, serum albumin level and the arterial partial pressure of oxygen in the patients with SAP (P<0.05). It markedly shortened the intestinal recovery time and the length of stay and reduced the incidence rate of MOF, the surgery rate and the fatality rate (P<0.05). It did not aggravate the hemorrhagic tendency of SAP (P>0.05). IIT + LMWH had a noticeably improved clinical curative effect on SAP compared with that of the other treatments.
doi:10.3892/etm.2014.1694
PMCID: PMC4061186  PMID: 24944612
intensive insulin therapy; low molecular weight heparin anticoagulant therapy; severe acute pancreatitis; albumin; white blood cell; diastase; intestinal function recovery time
23.  Short acting insulin analogues in intensive care unit patients 
World Journal of Diabetes  2014;5(3):230-234.
Blood glucose control in intensive care unit (ICU) patients, addressed to actively maintain blood glucose concentration within defined thresholds, is based on two major therapeutic interventions: to supply an adequate calories load and, when necessary, to continuously infuse insulin titrated to patients needs: intensive insulin therapy (IIT). Short acting insulin analogues (SAIA) have been synthesized to improve the chronic treatment of patients with diabetes but, because of the pharmacokinetic characteristics that include shorter on-set and off-set, they can be effectively used also in ICU patients and have the potential to be associated with a more limited risk of inducing episodes of iatrogenic hypoglycemia. Medical therapies carry an intrinsic risk for collateral effects; this can be more harmful in patients with unstable clinical conditions like ICU patients. To minimize these risks, the use of short acting drugs in ICU patients have gained a progressively larger room in ICU and now pharmaceutical companies and researchers design drugs dedicated to this subset of medical practice. In this article we report the rationale of using short acting drugs in ICU patients (i.e., sedation and treatment of arterial hypertension) and we also describe SAIA and their therapeutic use in ICU with the potential to minimize iatrogenic hypoglycemia related to IIT. The pharmacodynamic and pharmachokinetic characteristics of SAIA will be also discussed.
doi:10.4239/wjd.v5.i3.230
PMCID: PMC4058727  PMID: 24936244
Insulin analogues; Short acting drugs; Intensive insulin therapy; Glycemia management; Intensive care
24.  Clinical Impact of Sample Interference on Intensive Insulin Therapy in Severely Burned Patients: A Pilot Study 
Objective
Severely burned patients benefit from intensive insulin therapy (IIT) for tight glycemic control (TGC). We evaluated the clinical impact of automatic correction of hematocrit and ascorbic acid interference for bedside glucose monitoring performance in critically ill burn patients.
Methods
The performance of two point-of-care glucose monitoring systems (GMS): (a) GMS1, an autocorrecting device, and (b) GMS2, a non-correcting device were compared. Sixty remnant arterial blood samples were collected in a prospective observational study to evaluate hematocrit and ascorbic acid effects on GMS1 vs. GMS2 accuracy paired against a plasma glucose reference. Next we enrolled 12 patients in a pilot randomized controlled trial (RCT). Patients were randomized 1:1 to receive IIT targeting a TGC interval of 111–151 mg/dL and guided by either GMS1 or GMS2. GMS bias, mean insulin rate, and glycemic variability were calculated.
Results
In the prospective study, GMS1 results were similar to plasma glucose results (mean bias: −0.75[4.0] mg/dL, n=60, P=0.214). GMS2 results significantly differed from paired plasma glucose results (mean bias: −5.66[18.7] mg/dL, n=60, P=0.048). Ascorbic acid therapy elicited significant GMS2 performance bias (29.2[27.2], P<0.001). RCT results reported lower mean bias (P<0.001), glycemic variability (P<0.05), mean insulin rate (P<0.001), and frequency of hypoglycemia (P<0.001) in the GMS1 group than the GMS2 group.
Conclusions
Anemia and high dose ascorbic acid therapy negatively impact GMS accuracy and TGC in burn patients. Automatic correction of confounding factors improves glycemic control. Further studies are warranted to determine outcomes associated with accurate glucose monitoring during IIT.
doi:10.1097/BCR.0b013e31829b3700
PMCID: PMC3815489  PMID: 23884048
Ascorbic acid; hematocrit; point-of-care testing
25.  Intensive insulin therapy and mortality in critically ill patients 
Critical Care  2008;12(1):R29.
Introduction
Intensive insulin therapy (IIT) with tight glycemic control may reduce mortality and morbidity in critically ill patients and has been widely adopted in practice throughout the world. However, there is only one randomized controlled trial showing unequivocal benefit to this approach and that study population was dominated by post-cardiac surgery patients. We aimed to determine the association between IIT and mortality in a mixed population of critically ill patients.
Methods
We conducted a cohort study comparing three consecutive time periods before and after IIT protocol implementation in a Level 1 trauma center: period I (no protocol); period II, target glucose 80 to 130 mg/dL; and period III, target glucose 80 to 110 mg/dL. Subjects were 10,456 patients admitted to intensive care units (ICUs) between 1 March 2001 and 28 February 2005. The main study endpoints were ICU and hospital mortality, Sequential Organ Failure Assessment score, and occurrence of hypoglycemia. Multivariable regression analysis was used to evaluate mortality and organ dysfunction during periods II and III relative to period I.
Results
Insulin administration increased over time (9% period I, 25% period II, and 42% period III). Nonetheless, patients in period III had a tendency toward higher adjusted hospital mortality (odds ratio [OR] 1.15, 95% confidence interval [CI] 0.98, 1.35) than patients in period I. Excess hospital mortality in period III was present primarily in patients with an ICU length of stay of 3 days or less (OR 1.47, 95% CI 1.11, 1.93 There was an approximately fourfold increase in the incidence of hypoglycemia from periods I to III.
Conclusion
A policy of IIT in a group of ICUs from a single institution was not associated with a decrease in hospital mortality. These results, combined with the findings from several recent randomized trials, suggest that further study is needed prior to widespread implementation of IIT in critically ill patients.
doi:10.1186/cc6807
PMCID: PMC2374630  PMID: 18312617

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