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.
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).
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.
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.
blood glucose; critically ill; insulin; tight glycemic control
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.
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.
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.
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.
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.
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.
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).
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.
In some studies, tight glycemic control with insulin improved outcomes in adults undergoing cardiac surgery, but these benefits are unproven in critically ill children at risk for hyperinsulinemic hypoglycemia. We tested the hypothesis that tight glycemic control reduces morbidity after pediatric cardiac surgery.
In this two-center, prospective, randomized trial, we enrolled 980 children, 0 to 36 months of age, undergoing surgery with cardiopulmonary bypass. Patients were randomly assigned to either tight glycemic control (with the use of an insulin-dosing algorithm targeting a blood glucose level of 80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) or standard care in the cardiac intensive care unit (ICU). Continuous glucose monitoring was used to guide the frequency of blood glucose measurement and to detect impending hypoglycemia. The primary outcome was the rate of health care–associated infections in the cardiac ICU. Secondary outcomes included mortality, length of stay, organ failure, and hypoglycemia.
A total of 444 of the 490 children assigned to tight glycemic control (91%) received insulin versus 9 of 490 children assigned to standard care (2%). Although normoglycemia was achieved earlier with tight glycemic control than with standard care (6 hours vs. 16 hours, P<0.001) and was maintained for a greater proportion of the critical illness period (50% vs. 33%, P<0.001), tight glycemic control was not associated with a significantly decreased rate of health care–associated infections (8.6 vs. 9.9 per 1000 patient-days, P = 0.67). Secondary outcomes did not differ significantly between groups, and tight glycemic control did not benefit high-risk subgroups. Only 3% of the patients assigned to tight glycemic control had severe hypoglycemia (blood glucose <40 mg per deciliter [2.2 mmol per liter]).
Tight glycemic control can be achieved with a low hypoglycemia rate after cardiac surgery in children, but it does not significantly change the infection rate, mortality, length of stay, or measures of organ failure, as compared with standard care. (Funded by the National Heart, Lung, and Blood Institute and others; SPECS ClinicalTrials.gov number, NCT00443599.)
Hyper- and hypoglycemia are strongly associated with adverse outcomes in critical care. Neurologically injured patients are a unique subgroup, where optimal glycemic targets may differ, such that the findings of clinical trials involving heterogeneous critically ill patients may not apply.
We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing intensive insulin therapy with conventional glycemic control among patients with traumatic brain injury, ischemic or hemorrhagic stroke, anoxic encephalopathy, central nervous system infections or spinal cord injury.
Sixteen RCTs, involving 1248 neurocritical care patients, were included. Glycemic targets with intensive insulin ranged from 70-140 mg/dl (3.9-7.8 mmol/L), while conventional protocols aimed to keep glucose levels below 144-300 mg/dl (8.0-16.7 mmol/L). Tight glycemic control had no impact on mortality (RR 0.99; 95% CI 0.83-1.17; p = 0.88), but did result in fewer unfavorable neurological outcomes (RR 0.91; 95% CI 0.84-1.00; p = 0.04). However, improved outcomes were only observed when glucose levels in the conventional glycemic control group were permitted to be relatively high [threshold for insulin administration > 200 mg/dl (> 11.1 mmol/L)], but not with more intermediate glycemic targets [threshold for insulin administration 140-180 mg/dl (7.8-10.0 mmol/L)]. Hypoglycemia was far more common with intensive therapy (RR 3.10; 95% CI 1.54-6.23; p = 0.002), but there was a large degree of heterogeneity in the results of individual trials (Q = 47.9; p<0.0001; I2 = 75%). Mortality was non-significantly higher with intensive insulin in studies where the proportion of patients developing hypoglycemia was large (> 33%) (RR 1.17; 95% CI 0.79-1.75; p = 0.44).
Intensive insulin therapy significantly increases the risk of hypoglycemia and does not influence mortality among neurocritical care patients. Very loose glucose control is associated with worse neurological recovery and should be avoided. These results suggest that intermediate glycemic goals may be most appropriate.
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.
critical care; glucose; glucose monitoring; glucose variability; hyperglycemia; hypoglycemia; insulin; intensive; intensive care unit; point of care
Control of blood glucose (BG) in critically ill patients is considered important, but is difficult to achieve, and often associated with increased risk of hypoglycemia. We examined the use of a computerized insulin dosing algorithm to manage hyperglycemia with particular attention to frequency and conditions surrounding hypoglycemic events.
This is a retrospective analysis of adult patients with hyperglycemia receiving intravenous (IV) insulin therapy from March 2006 to December 2007 in the intensive care units of 2 tertiary care teaching hospitals. Patients placed on a glycemic control protocol using the Clarian GlucoStabilizer™ IV insulin dosing calculator with a target range of 4.4-6.1 mmol/L were analyzed. Metrics included time to target, time in target, mean blood glucose ± standard deviation, % measures in hypoglycemic ranges <3.9 mmol/L, per-patient hypoglycemia, and BG testing interval.
4,588 ICU patients were treated with the GlucoStabilizer to a BG target range of 4.4-6.1 mmol/L. We observed 254 severe hypoglycemia episodes (BG <2.2 mmol/L) in 195 patients, representing 0.1% of all measurements, and in 4.25% of patients or 0.6 episodes per 1000 hours on insulin infusion. The most common contributing cause for hypoglycemia was measurement delay (n = 170, 66.9%). The median (interquartile range) time to achieve the target range was 5.9 (3.8 - 8.9) hours. Nearly all (97.5%) of patients achieved target and remained in target 73.4% of the time. The mean BG (± SD) after achieving target was 5.4 (± 0.52) mmol/L. Targeted blood glucose levels were achieved at similar rates with low incidence of severe hypoglycemia in patients with and without diabetes, sepsis, renal, and cardiovascular disease.
Glycemic control to a lower glucose target range can be achieved using a computerized insulin dosing protocol. With particular attention to timely measurement and adjustment of insulin doses the risk of hypoglycemia experienced can be minimized.
Perioperative hyperglycemia in critically ill surgery patients increases the risk of postoperative infection (POI), which is a common, and often costly, surgical complication. Hyperglycemia is associated with abnormalities in leukocyte function, including granulocyte adherence, impaired phagocytosis, delayed chemotaxis, and depressed bactericidal capacity. These leukocyte deficiencies are the cause of infection and improve with tight glycemic control, which leads to fewer POIs in critically ill surgical patients. Tight glycemic control, such as intensive insulin therapy, has a risk of hypoglycemia. In addition, the optimal targeted blood glucose range to reduce POI remains unknown. Since 2006, we have investigated tight perioperative blood glucose control using a closed-loop artificial endocrine pancreas system, to reduce POI and to avoid hypoglycemia. In this Topic Highlight, we review the relationship between perioperative glycemic control and POI, including the use of the artificial pancreas.
Glycemic control; Surgical site infection; Artificial pancreas; Insulin therapy; Glucose toxicity
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.
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.
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.
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.
computerized decision support; critical care; glucose control; intensive insulin therapy
Critical illness hyperglycemia (CIH) is common in pediatric and adult intensive care units (ICUs). Children undergoing surgical repair or palliation of congenital cardiac defects are particularly at risk for CIH and its occurrence has been associated with increased morbidity and mortality in this population. Strict glycemic control through the use of intensive insulin therapy (IIT) has been shown to improve outcomes in some adult and pediatric studies, yet these findings have sparked controversy. The practice of strict glycemic control has been slow in extending to pediatric ICUs because of the documented increase in the incidence of hypoglycemia in patients treated with IIT. Protocol driven approaches with more liberal glycemic targets have been successfully validated in general and cardiac critical care pediatric patients with low rates of hypoglycemia. It is unknown whether a therapeutic benefit is obtained by keeping patients in this more liberal glycemic control target. Definitive randomized controlled trials of IIT utilizing these targets in critically ill children are ongoing.
children; congenital heart defects; critical illness; glycemic control; hyperglycemia; insulin
Intensive glycemic control has been associated with reduced morbidity and mortality in critically ill patients. Web-based, patient-specific insulin nomograms may facilitate improved glucose control.
To compare 2 algorithms for individualizing insulin infusion therapy (a web-based system [Glucommander method] and a standard paper-based nomogram) in a cardiovascular surgery intensive care unit (ICU).
In this prospective, before–after cohort study, measures of glycemic control for 50 patients receiving insulin according to the Glucommander system were compared with a control group (n = 50) who received insulin according to the standard paper-based nomogram used in the cardiovascular surgery ICU.
There was no significant difference between the 2 groups with respect to time to target blood glucose (5.1–8.0 mmol/L), percentage of time within the target range, or mean amplitude of glucose excursion. Patients in the intervention group spent less time above the target range (p = 0.007) and more time below the target range (p < 0.001), and the mean glucose was lower in this group compared with the control group (7.9 versus 8.6 mmol/L, p = 0.002). The percentage of blood glucose measurements below 4 mmol/L was higher in the intervention group than in the control group (3.7% versus 1.4%, p = 0.003). Satisfaction surveys revealed that the program was well accepted by the nursing staff in the cardiovascular surgery ICU.
A web-based insulin nomogram was an easy-to-use instrument for achieving tighter glucose control for patients in the cardiovascular surgery ICU. Use of the Glucommander system led to lower mean blood glucose but an increase in episodes of hypoglycemia.
tight glycemic control; critically ill patients; régulation serrée de la glycémie; patients gravement malades
Hospital patients recovering from critical illness on general floors often receive insulin therapy based on protocols designed for patients admitted directly to general floors. The objective of this study is to compare glycemic control and insulin dosing in patients recovering from critical illness and those without prior critical illness.
Medical record review of blood glucose measurements and insulin dosing in 25 patients under general ward care while transitioning from the intensive care unit (transition group) and 25 patients admitted directly to the floor (direct floor group).
Average blood glucose did not differ significantly between groups (transition group 9.49 mmol/L, direct floor group 9.6 mmol/L; P = 0.83). Significant differences in insulin requirements were observed between groups with average daily doses of 55.9 units in patients transitioning from the intensive care unit (ICU) versus 25.6 units in the direct floor group (P = 0.004).
Patients recovering from critical illness required significantly larger doses of insulin than those patients admitted directly to the floor. Managing insulin therapy in patients transitioning from the ICU may require greater insulin doses.
hyperglycemia; glycemic control; insulin; critical illness
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.
continuous glucose sensor; glucose; ICU; intensive insulin therapy; perioperative
Hyperglycemia and protein loss are common in critically ill patients. Insulin can be used to lower blood glucose and inhibit proteolysis. The impact of moderate insulin therapy on protein metabolism in critically ill patients has not been evaluated. We compared urinary nitrogen excretion, nitrogen balance, serum albumin concentrations, prealbumin concentrations, and clinical outcomes between patients receiving moderate insulin therapy (MIT) and conventional insulin therapy (CIT) in a medical ICU.
Patients were randomly divided into groups and treated with MIT (glucose target 120 to 140 mg/dl) or CIT (glucose target 180 to 200 mg/dl). Calories and protein intake were recorded each day. On days 3, 7 and 14, the 24-hour urinary nitrogen excretion, nitrogen balance, and serum albumin and prealbumin concentrations were measured. Clinical outcomes data were collected.
A total of 112 medical ICU patients were included, with 55 patients randomized to the MIT group and 57 patients randomized to the CIT group. Patients treated with MIT showed a trend towards increased nitrogen balance (P = 0.070), significantly lower urinary nitrogen excretion (P = 0.027), and higher serum albumin (P = 0.047) and prealbumin (P = 0.001) concentrations than patients treated with CIT. The differences between the two groups were most significant on day 3, when all factors showed significant differences (P < 0.05).
Moderate glucose control results in less negative nitrogen balances in medical ICU patients. Differences are more significant in the early stages compared with the late stages of critical illness.
ClinicalTrial.Gov NCT 01227148
The objective of this study was to investigate the performance of a newly proposed insulin titrating algorithm to achieve tight glycemic control in the critically ill.
A simulation environment with 10 critically ill virtual subjects was employed to evaluate the “I, Pancreas” algorithm proposed by Braithwaite et al. and described in an article in this issue of Journal of Diabetes Science and Technology. The algorithm was coded in MATLAB® and was “plugged in” to a simulation environment to provide glucose control in a 48-hour-long simulated study.
Mean blood glucose was 6.5 ± 0.4 mmol/liter (118 ± 7.8 mg/dl), percentage of time spent in the target glucose range was 38% (32–44%), and the hyperglycemic index was 0.6 (0.4 –1.0) mmol/liter [11.1 (7.7–18.1) mg/dl]. A single episode of mild hypoglycemia at 3.8 mmol/liter (69 mg/dl) was observed during 480 hours of glucose control.
In this initial in silico evaluation, the “I, Pancreas” algorithm provided a safe control of glucose in the simulated study and achieved tight glycemic control 38% of the time.
algorithm; critical illness; glucose control; simulation environment
Critically ill patients can develop hyperglycaemia even if they do not have diabetes. Intensive insulin therapy decreases morbidity and mortality rates in patients in a surgical intensive care unit (ICU) and decreases morbidity in patients in a medical ICU. The effect of this therapy on patients in a mixed medical/surgical ICU is unknown. Our goal was to assess whether the effect of intensive insulin therapy, compared with standard therapy, decreases morbidity and mortality in patients hospitalised in a mixed ICU.
This is a prospective, randomised, non-blinded, single-centre clinical trial in a medical/surgical ICU. Patients were randomly assigned to receive either intensive insulin therapy to maintain glucose levels between 80 and 110 mg/dl (4.4 to 6.1 mmol/l) or standard insulin therapy to maintain glucose levels between 180 and 200 mg/dl (10 and 11.1 mmol/l). The primary end point was mortality at 28 days.
Over a period of 30 months, 504 patients were enrolled. The 28-day mortality rate was 32.4% (81 of 250) in the standard insulin therapy group and 36.6% (93 of 254) in the intensive insulin therapy group (Relative Risk [RR]: 1.1; 95% confidence interval [CI]: 0.85 to 1.42). The ICU mortality in the standard insulin therapy group was 31.2% (78 of 250) and 33.1% (84 of 254) in the intensive insulin therapy group (RR: 1.06; 95%CI: 0.82 to 1.36). There was no statistically significant reduction in the rate of ICU-acquired infections: 33.2% in the standard insulin therapy group compared with 27.17% in the intensive insulin therapy group (RR: 0.82; 95%CI: 0.63 to 1.07). The rate of hypoglycaemia (≤ 40 mg/dl) was 1.7% in the standard insulin therapy group and 8.5% in the intensive insulin therapy group (RR: 5.04; 95% CI: 1.20 to 21.12).
IIT used to maintain glucose levels within normal limits did not reduce morbidity or mortality of patients admitted to a mixed medical/surgical ICU. Furthermore, this therapy increased the risk of hypoglycaemia.
clinicaltrials.gov Identifiers: 4374-04-13031; 094-2 in 000966421
Critically ill patients often experience high levels of insulin resistance and stress-induced hyperglycemia, which may negatively impact outcomes. In 2001, Van den Berghe and coauthors used intensive insulin therapy (IIT) to control blood glucose (BG) to normal levels and reported a reduction in intensive care unit (ICU) mortality from 8% to 4.6%. Many studies tried to replicate these results, with some showing reduced mortality, others failing to match these results, and many seeing no clinically significant difference. The interpretation of results is important when drawing conclusions about the benefits and risks of IIT. There is the potential for negative results to be falsely negative due to unintended patient crossover or cohort overlap.
The aim of this study was to investigate the association between the amount of time each critically ill patient experiences good glucose control and hospital mortality.
This study uses BG data from 784 patients admitted to the Christchurch Hospital ICU between January 2003 and May 2007. For each of the 5 days of analysis, all patients with BG data were pooled together in a single cohort before being stratified into two subcohorts based on glycemic performance, determined by cumulative time in band (cTIB). The cTIB metric is calculated per patient/per day and defined here as the percentage of time the patient’s BG levels have been cumulatively in a specific band (72–126 mg/dl) up to and including the considered day. Subcohort A had patients with cTIB ≥ threshold and subcohort B had patients with cTIB < threshold. Three cTIB thresholds were tested: 0.3 (30%), 0.5 (50%), and 0.7 (70%). The odds of living (OL) were then calculated for each subcohort and day, forming the basis of comparison between the subcohorts. A second analysis was run using only the 310 patients with BG data for 5 days or more to assess the impact of patient dropout.
Results show that, across all three cTIB threshold levels (0.3, 0.5, and 0.7) and all 5 days of analysis, patients with a cTIB ≥ threshold have a higher OL than patients with a cTIB < threshold. A cTIB threshold of 0.7 showed the strongest separation between the subcohorts, and on day 5, the OL for subcohort A was 4.4 versus 1.6 for subcohort B. The second analysis showed that patient dropout had little effect on the overall trends. Using a cTIB threshold of 0.7, the OL for subcohort A was 0.8 higher than the OL for subcohort B on day 1, which steadily increased over the 5 days of analysis.
Results show that OL are higher for patients with cTIB ≥ 0.3–0.7 than patients with cTIB < 0.3–0.7, irrespective of how cTIB was achieved. A cTIB threshold of 0.5 was found to be a minimum acceptable threshold based on outcome. If cTIB is used in similar BG studies in the future, cTIB ≥ 0.7 may be a good target for glycemic control to ensure outcomes and to separate patients with good BG control from patients with poor control.
critically ill; glycemic variability; intensive care unit; intensive insulin therapy; mortality; tight glycemic control
To compare two subcutaneous insulin strategies for glycemic management of hyperglycemia in non–critically ill hospitalized patients with diabetes during enteral nutrition therapy (ENT).
RESEARCH DESIGN AND METHODS
Fifty inpatients were prospectively randomized to receive sliding-scale regular insulin (SSRI) alone (n = 25) or in combination with insulin glargine (n = 25). NPH insulin was added for persistent hyperglycemia in the SSRI group (glucose >10 mmol/l).
Glycemic control was similar in the SSRI and glargine groups (mean ± SD study glucose 8.9 ± 1.6 vs. 9.2 ± 1.6 mmol/l, respectively; P = 0.71). NPH insulin was added in 48% of the SSRI group subjects. There were no group differences in frequency of hypoglycemia (1.3 ± 4.1 vs. 1.1 ± 1.8%; P = 0.35), total adverse events, or length of stay.
Both insulin strategies (SSRI with the addition of NPH for persistent hyperglycemia and glargine) demonstrated similar efficacy and safety in non–critically ill hospitalized patients with type 2 diabetes during ENT.
Glycemic control with intensive insulin therapy (IIT) has received widespread adoption secondary to findings of improved clinical outcomes and survival in the burn population. Severe burn as a model for trauma is characterized by a hypermetabolic state, hyperglycemia, and insulin resistance. In this article, we review the findings of a burn center research facility in terms of understanding glucose management. The conferred benefits from IIT, our findings of poor outcomes associated with glycemic variability, advantages from preserved diurnal variation of glucose and insulin, and impacts of glucometer error and hematocrit correction factor are discussed. We conclude with direction for further study and the need for a reliable continuous glucose monitoring system. Such efforts will further the endeavor for achieving adequate glycemic control in order to assess the efficacy of target ranges and use of IIT.
artificial pancreas; burn; computer decision support; continuous glucose monitor; diurnal variation; glucometer; glucose variability; hematocrit effect; hypoglycemia; intensive insulin therapy
The purpose of this research is to provide recommendations for the management of glycemic control in critically ill patients.
Twenty-one experts issued recommendations related to one of the five pre-defined categories (glucose target, hypoglycemia, carbohydrate intake, monitoring of glycemia, algorithms and protocols), that were scored on a scale to obtain a strong or weak agreement. The GRADE (Grade of Recommendation, Assessment, Development and Evaluation) system was used, with a strong recommendation indicating a clear advantage for an intervention and a weak recommendation indicating that the balance between desirable and undesirable effects of an intervention is not clearly defined.
A glucose target of less than 10 mmol/L is strongly suggested, using intravenous insulin following a standard protocol, when spontaneous food intake is not possible. Definition of the severe hypoglycemia threshold of 2.2 mmol/L is recommended, regardless of the clinical signs. A general, unique amount of glucose (enteral/parenteral) to administer for any patient cannot be suggested. Glucose measurements should be performed on arterial rather than venous or capillary samples, using central lab or blood gas analysers rather than point-of-care glucose readers.
Thirty recommendations were obtained with a strong (21) and a weak (9) agreement. Among them, only 15 were graded with a high level of quality of evidence, underlying the necessity to continue clinical studies in order to improve the risk-to-benefit ratio of glucose control.
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.
Retrospective analysis of patient database records and ethnographic study of nurses using IIT CDSS.
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.
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.
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.
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
Hyperglycemia is associated with increased morbidity and mortality in critically ill patients and strict glycemic control has become standard care for adults. Recent studies have questioned the optimal targets for such management and reported increased rates of iatrogenic hypoglycemia in both critically ill children and adults. The ability to provide accurate, real-time continuous glucose monitoring would improve the efficacy and safety of this practice in critically ill patients. The aim of our study is to determine if a continuous, interstitial glucose monitor will correlate with blood glucose values in critically ill children.
We evaluated 50 critically ill children age 6 weeks to 16 years old with a commercially available continuous glucose monitor (CGM; Medtronic Guardian®). CGM values and standard blood glucose (BG) values were compared. During the study, no changes in patient management were made based on CGM readings alone.
Forty-seven patients had analyzable CGM data. A total of 1,555 CGM and routine BG measurements were compared using Clarke error grid and Bland-Altman analysis. For all readings, 97.9% were within clinically acceptable agreement. The mean absolute relative difference between CGM and BG readings was 15.3%. For the 1,555 paired CGM and BG measurements, there is a statistically significant linear relationship between CGM values and BG (P <.0001). A high degree of clinical agreement existed in three subpopulation analyses based on age, illness severity, and support measures. This included some of our smallest patients (that is, <12 months old), those who required vasopressors, and those who were treated for critical illness hyperglycemia.
In one of the largest studies to date, in a highly vulnerable ICU population, CGM values have a clinically acceptable correlation with the BG values now used diagnostically and therapeutically. Our data contest the theoretical concerns posed by some regarding CGM use in the ICU. The existing medical evidence may now support a role for CGM devices in the identification and management of hyperglycemia in diverse ICU settings.
A single centre has reported that implementation of an intensive insulin protocol, aiming for tight glycaemic control (blood glucose 4.4 to 6.1 mmol/l), resulted in significant reduction in mortality in longer stay medical and surgical critically ill patients. Our aim was to determine the degree to which tight glycaemic control can be maintained using an intensive insulin therapy protocol with computerized decision support and to identify factors that may be associated with the degree of control.
At a general adult 22-bed intensive care unit, we implemented an intensive insulin therapy protocol in mechanically ventilated patients, aiming for a target glucose range of 4.4 to 6.1 mmol/l. The protocol was integrated into the computerized information management system by way of a decision support program. The time spent in each predefined blood glucose band was estimated, assuming a linear trend between measurements.
Fifty consecutive patients were investigated, involving analysis of 7,209 blood glucose samples, over 9,214 hours. The target tight glycaemic control band (4.4 to 6.1 mmol/l) was achieved for a median of 23.1% of the time that patients were receiving intensive insulin therapy. Nearly half of the time (median 48.5%), blood glucose was within the band 6.2 to 7.99 mmol/l. Univariate analysis revealed that body mass index (BMI), Acute Physiology and Chronic Health Evaluation (APACHE) II score and previous diabetes each explained approximately 10% of the variability in tight glycaemic control. BMI and APACHE II score explained most (27%) of the variability in tight glycaemic control in the multivariate analysis, after adjusting for age and previous diabetes.
Use of the computerized decision supported intensive insulin therapy protocol did result in achievement of tight glycaemic control for a substantial percentage of each patient's stay, although it did deliver 'normoglycaemia' (4.4 to about 8 mmol/l) for nearly 75% of the time. Tight glycaemic control was difficult to achieve in critically ill patients using this protocol. More sophisticated methods such as continuous blood glucose monitoring with automated insulin and glucose infusion adjustment may be a more effective way to achieve tight glycaemic control. Glycaemia in patients with high BMI and APACHE II scores may be more difficult to control using intensive insulin therapy protocols. Trial registration number 05/Q0505/1.
High glycemic variability, rather than a mean glucose level, is an important factor associated with sepsis and hospital mortality in critically ill patients. In this retrospective study we analyze the blood glucose data of 172 nondiabetic patients 18–60 yrs old with second and third-degree burns of total body surface area greater than 30% and 5%, respectively, admitted to ICU in 2004–2008. The analysis identified significant association of increasing daily glucose excursion (DELTA) accompanied by evident episodes of hyperglycemia (>11 mmol/l) and hypoglycemia (<2.8 mmol/l), with sepsis and forthcoming death, even when the mean daily glucose was within a range of acceptable glycemia. No association was found in sepsis complication and hospital mortality with doses of intravenous insulin and glucose infusion. A strong increase in DELTA before sepsis and death is treated as fluctuation amplification near the onset of dynamical instability.
People on insulin therapy are challenged with evaluation of numerous factors affecting the blood glucose in order to select the optimal dose for reaching their glucose target. Following medical recommendations precisely still results in considerable blood glucose unpredictability, often resulting in frustration in the short term due to hypoglycemia and hyperglycemia, and, in the long term, will likely result in complications.
The kinetics of insulin do indeed vary significantly and have become an important focus when developing new insulin analogues and delivery systems; however, numerous of other factors impact glycemic variability. These have different dependences and interactions and are therefore difficult to characterize. Some of the factors are highly dependent and influenced by the type of insulin and devices used in therapy. Development of future therapy products is therefore highly focused on how to minimize glycemic variability.
diabetes; glucose prediction; insulin; variability