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
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.
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.
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.
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.
Age; glucose; glycemic control; ISS; insulin; intensive insulin control; trauma
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
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.
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.
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.
Mismatched blood glucose values can influence CDSS IIT protocol performance.
Intensive insulin therapy; Clinical protocols; Clinical decision support systems; Blood glucose; Insulin; Critical care
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.
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.
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.
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.
blood glucose; clinical decision support systems; critical care; electronic medical records; ethnography; hyperglycemia; hypoglycemia; insulin
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
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) 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.
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.
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.
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.
Tight glucose control in the ICU has been proven difficult with an increased risk for hypoglycaemic episodes. Also the variability of glucose may have an impact on morbidity. An accurate and feasible on-line/continuous measurement is therefore desired. In this study a central vein catheter with a microdialysis membrane in combination with an on-line analyzer for continuous monitoring of circulating glucose and lactate by the central route was tested.
A total of 10 patients scheduled for major upper abdominal surgery were included in this observational prospective study at a university hospital. The patients received an extra central venous catheter with a microdialysis membrane placed in the right jugular vein. Continuous microdialysis measurement proceeded for 20 hours and on-line values were recorded every minute. Reference arterial plasma glucose and blood lactate samples were collected every hour.
Mean microdialysis-glucose during measurements was 9.8 ± 2.4mmol/l.No statistical difference in the readings was seen using a single calibration compared to eighth hour calibration (P =0.09; t-test). There was a close agreement between the continuous reading and the reference plasma glucose values with an absolute difference of 0.6+0.8mmol, or 6.8+9.3% and measurements showed high correlation to plasma readings (r = 0.92). Thelimit of agreement was 23.0%(1.94 mmol/l) compared to arterial plasma values with a line of equality close to zero.However, in a Clarke-Error Grid 93.3% of the values are in the A-area,and the remaining part in the B-area.Mean microdialysis-lactate was 1.3 ± 1.1mmol/l. The measurements showed high correlation to the blood readings (r = 0.93).
Continuous on-line microdialysis glucose measurement in a central vein is a potential useful technique for continuous glucose monitoring in critically ill patients, but more improvements and testingare needed.
Continuous glucose monitoring; intravenous microdialysis; intensive care; hyperglycaemia; hypoglycaemia; lactate
To investigate the long-term effect of continuous insulin infusion for glucose control on cerebral metabolism in aneurysmal subarachnoid hemorrhage (SAH) patients.
Prospective, nonrandomized study of 31 SAH patients in the ICU (52 ± 10 years, WFNS Grade 2.9 ± 1.6). A microdialysis catheter was inserted into the vascular territory of the aneurysm. Metabolic changes during 4 days after onset of insulin infusion were analyzed. Blood glucose levels >140 mg/dL after clinical stabilization were treated with intravenous insulin.
24 patients were treated with intravenous insulin. Though no insulin-induced hypoglycemia occurred, cerebral glucose decreased on days 1–4 after insulin onset without reaching critical levels. Glycerol, a marker of membrane degradation, showed a reversible increase on day 1 while the lactate/pyruvate ratio remained stable and glutamate even decreased indicating absence of severe cerebral crisis following insulin infusion and excluding ischemia as a cause for cerebral glucose depletion.
Concerning cerebral metabolism, long-term continuous insulin infusion appears to be safe as long as cerebral glucose levels do not fall below the physiological range. In view of the high incidence of hyperglycemia and need for insulin treatment, future studies on the effect of insulin on cerebral metabolism in SAH patients are desirable.
glucose; hyperglycemia; insulin; subarachnoid hemorrhage; microdialysis
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
Hyperglycemia after aneurysmal subarachnoid hemorrhage (aSAH) occurs frequently and is associated with delayed cerebral ischemia (DCI) and poor clinical outcome. In this review, we highlight the mechanisms that cause hyperglycemia after aSAH, and we discuss how hyperglycemia may contribute to poor clinical outcome in these patients. As hyperglycemia is potentially modifiable with intensive insulin therapy (IIT), we systematically reviewed the literature on IIT in aSAH patients. In these patients, IIT seems to be difficult to achieve in terms of lowering blood glucose levels substantially without an increased risk of (serious) hypoglycemia. Therefore, before initiating a large-scale randomized trial to investigate the clinical benefit of IIT, phase II studies, possibly with the help of cerebral blood glucose monitoring by microdialysis, will first have to improve this therapy in terms of both safety and adequacy.
diabetes mellitus vasospasm; glucose; hyperglycemia; hypoglycemia; subarachnoid hemorrhage
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.
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.
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).
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.
The purpose of this study was to assess the relation between glycaemic control and the severity of sepsis in a cohort of patients treated with intensive insulin therapy (IIT).
In a prospective, observational study, all patients in the intensive care unit (ICU) (n = 191) with sepsis, severe sepsis or septic shock were treated with IIT (target blood glucose (BG) level 80 to 140 mg/dl instead of strict normoglycaemia). BG values were analysed by calculating mean values, rate of BG values within different ranges, rate of patients experiencing BG values within different levels and standard deviation (SD) of BG values as an index of glycaemic variability.
The number of patients with hypoglycaemia and hyperglycaemia was highly dependent on the severity of sepsis (critical hypoglycaemia ≤ 40 mg/dl: sepsis: 2.1%, severe sepsis: 6.0%, septic shock: 11.5%, p = 0.1497; hyperglycaemia: >140 mg/dl: sepsis: 76.6%, severe sepsis: 88.0%, septic shock: 100%, p = 0.0006; >179 mg/dl: sepsis: 55.3%, severe sepsis: 73.5%, septic shock: 88.5%, p = 0.0005; >240 mg/dl: sepsis: 17.0%, severe sepsis: 48.2%, septic shock: 45.9%, p = 0.0011). Multivariate analyses showed a significant association of SD levels with critical hypoglycaemia especially for patients in septic shock (p = 0.0197). In addition, SD levels above 20 mg/dl were associated with a significantly higher mortality rate relative to those with SD levels below 20 mg/dl (24% versus 2.5%, p = 0.0195).
Patients with severe sepsis and septic shock who were given IIT had a high risk of hypoglycaemia and hyperglycaemia. Among these patients even with a higher target BG level, IIT mandates an increased awareness of the occurrence of critical hypoglycaemia, which is related to the severity of the septic episode.
Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice.
An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity.
Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity.
Hyperglycaemia following aneurysmal subarachnoid hemorrhage (SAH) is associated with complications and impaired neurological recovery. The aim of this study was to determine the effect of insulin treatment for glucose control on cerebral metabolism in SAH patients.
This prospective, nonrandomized study was conducted in 31 SAH patients in an intensive care unit (age 52 ± 10 years, World Federation of Neurological Surgeons grade 2.9 ± 1.6). A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. Blood glucose levels above 140 mg/dl were treated with intravenous insulin and the microdialysates were analyzed hourly for the first 12 hours of infusion.
No hypoglycaemia occurred. Twenty-four patients were treated with insulin for glucose control. Higher age and World Federation of Neurological Surgeons score were risk factors for need for insulin treatment (P < 0.05). Although blood glucose remained stable after initiation of insulin infusion, insulin induced a significant decrease in cerebral glucose at 3 hours after onset of the infusion until the end of the observation period (P < 0.05), reflecting high glucose utilization. The lactate:pyruvate ratio and glutamate did not increase, excluding ischaemia as possible cause of the decrease in glucose. Glycerol tended toward higher values at the end of the observation period (9 to 12 hours), reflecting either tissue damage after SAH or the beginning of cellular distress after insulin infusion.
Higher SAH grade was among the risk factors for need for insulin. Intensive glycaemic control using insulin induced a decrease of cerebral glucose and a slight increase in glycerol, though blood glucose remained normal. Future studies might detect relevant metabolic derangements when insulin treatment starts at low cerebral glucose levels, and may allow us to design a strategy for avoidance of insulin-induced metabolic crisis in SAH patients.
The second study on tight glycaemia control by intensive insulin therapy (IIT) confirmed in medical intensive care unit patients the decrease in hospital mortality reported by the same team in the first IIT trial in surgical patients. However, methodological concerns, the high rate of hypoglycaemia in spite of the infusion of large doses of parenteral glucose and the frequent use of steroids presently preclude considering these results as recommendations in other intensive care units, but rather argue for the need for large-scale assessment of the IIT approach by multi-centre studies to confirm the efficacy and safety of this therapeutic modality.
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
The objective of this study was to investigate the performance of a newly developed decision support system for the establishment of tight glycemic control in medical intensive care unit (ICU) patients for a period of 72 hours.
This was a single-center, open, non-controlled feasibility trial including 10 mechanically ventilated ICU patients. The CS-1 decision support system (interacting infusion pumps with integrated enhanced model predictive control algorithm and user interface) was used to adjust the infusion rate of administered insulin to normalize blood glucose. Efficacy and safety were assessed by calculating the percentage of values within the target range (80–110 mg/dl), hyperglycemic index, mean glucose, and hypoglycemic episodes (<40 mg/dl).
The percentage of values in time in target was 47.0% (±13.0). The average blood glucose concentration and hyperglycemic index were 109 mg/dl (±13) and 10 mg/dl (±9), respectively. No hypoglycemic episode (<40 mg/dl) was detected. Eleven times (1.5% of all given advice) the nurses did not follow and, thus, overruled the advice of the CS-1 system. Several technical malfunctions of the device (repetitive error messages and missing data in the data log) due to communication problems between the new hardware components are shortcomings of the present version of the device. As a consequence of these technical failures of system integration, treatment had to be stopped ahead of schedule in three patients.
Despite technical malfunctions, the performance of this prototype CS-1 decision support system was, from a clinical point of view, already effective in maintaining tight glycemic control. Accordingly, and with technical improvement required, the CS-1 system has the capacity to serve as a reliable tool for routine establishment of glycemic control in ICU patients.
algorithms; critical care nursing; hyperglycemia management; insulin infusion systems
Previous studies comparing the effects of oral, intraportal, and peripheral venous administration of glucose in conscious dogs demonstrated a significant increase in hepatic extraction of insulin only after oral glucose, but similar hepatic uptake of glucose after oral and intraportal glucose, which was greater than that after peripheral intravenous glucose infusion. This study evaluated the effect of atropine blockade of the parasympathetic nervous system on the increased fractional hepatic extraction of insulin and the role of gastric inhibitory polypeptide (GIP) on augmented hepatic uptake of oral glucose in conscious dogs with chronically implanted Doppler flow probes on the portal vein and hepatic artery, and catheters in the portal and hepatic veins and carotid artery. Since atropine infusion decreased absorption of glucose, and in order to achieve comparable portal vein levels of glucose and insulin, the dogs receiving atropine were given 1.9 +/- 0.1 g/kg glucose, compared with the control dogs who received 1.1 +/- 0.1 g/kg. The percentage of the glucose load that was absorbed was greater in the dogs not given atropine (80 +/- 4 vs. 44 +/- 7%), but because of the different loads, the absolute amount of glucose absorbed was similar in both groups (20.2 +/- 1.6 vs. 21.7 +/- 4.1 g). Although delayed by atropine, the peak portal vein glucose and insulin concentrations and the amounts presented to the liver were similar in both groups. However, the increased portal vein plasma flow and fractional hepatic extraction of insulin observed after oral glucose was not observed in the dogs infused with atropine. The net hepatic glucose uptake after oral glucose was significantly less at 10, 20, and 45 min in the atropine-treated dogs, and the area under the curve over the 180-min period was 44% less. However, the latter was not statistically significant. Infusion of GIP with peripheral intravenous glucose did not increase hepatic uptake of glucose or the fractional hepatic extraction of insulin compared with peripheral intravenous glucose alone. These results indicate an important role for parasympathetic innervation in the augmented fractional hepatic extraction of insulin, and increased portal vein plasma flow after oral glucose. Although a relationship between the augmented fractional extraction of insulin and the net hepatic glucose uptake may exist, it does not necessarily indicate that the former is required for the latter. Such parasympathetic innervation may be involved in the greater removal of glucose by the liver after oral compared with peripheral glucose administration. The augmented hepatic uptake of glucose and fractional hepatic extraction of insulin after oral glucose doesn not appear to be mediated by gastric inhibitory polypeptide.
Control of hyperglycemia improves outcomes, but increases the risk of hypoglycemia. Recent evidence suggests that blood glucose variability (BGV) is more closely associated with mortality than either isolated or mean BG. We hypothesized that differences in BGV over time are associated with hypoglycemia and can be utilized to estimate risk of hypoglycemia (<50 mg/dL).
Materials & Methods
Patients treated with intravenous insulin in the Surgical Intensive Care Unit of a tertiary care center formed the retrospective cohort. Exclusion criteria included death within 24 hours of admission. We describe BGV in patients over time and its’ temporal relationship to hypoglycemic events. The risk of hypoglycemia for each BG measurement was estimated in a multivariable regression model. Predictors were measures of BGV, infusions of dextrose and vasopressors, patient demographics, illness severity, and BG measurements.
66,592 BG measurements were collected on 1392 patients. Hypoglycemia occurred in 154 patients (11.1%). Patient BGV fluctuated over time, and increased in the 24 hours preceding a hypoglycemic event. In crude and adjusted analyses, higher BGV was positively associated with a hypoglycemia (OR 1.41, p<0.001). Previous hypoglycemic events and time since previous BG measurement were also positively associated with hypoglycemic events. Severity of illness, vasopressor use, and diabetes were not independently associated with hypoglycemia.
BGV increases in the 24 hours preceding hypoglycemia, and patients are at increased risk during periods of elevated BG variability. Prospective measurement of variability may identify periods of increased risk for hypoglycemia, and provide an opportunity to mitigate this risk.
Blood glucose variability; hypoglycemia; glycemic control; critical illness
The effect of diazepam on blood glucose concentration (BGC) was investigated in a double-blind cross-over study in 10 healthy and 10 non-insulin-dependent diabetic subjects taking oral hypoglycemic drugs. In the first session, fasting blood samples were taken for blood glucose and glycosylated hemoglobin estimation and at 60, 80, 95, 125, and 155 minutes thereafter for glucose estimation. In another 2 sessions, a venous sample was taken immediately before premedication (5 mg diazepam or placebo randomly given during breakfast). One hour later a blood sample was taken, and the volunteers were submitted to periodontal treatment after injection of 1.8 mL of 2% mepivacaine with 1:100,000 adrenaline. Venous blood samples were taken at 15, 30, 60, and 90 minutes after injection. The changes in BGC were analyzed using analysis of variance (ANOVA) for repeated measures; the means were compared using Tukey test (P = .05). Statistically significant differences in the BGC were observed between diabetic and nondiabetic groups (P = .00003). However, there were no significant differences among the sessions of the same group (P = .29). The results of this study show that a single dose of 5 mg diazepam before dental treatment does not influence BGC in nondiabetic and non-insulin-dependent diabetic subjects.
A young woman had severe brittle diabetes mellitus that was critically unmanageable with all conventional insulin treatment. Continuous subcutaneous and intramuscular infusions of insulin also failed to control her metabolic instability. Use of a continuous intravenous infusion, however, whereby a portable, variable-rate, battery-operated syringe pump delivered insulin through a subcutaneously tunnelled central venous catheter, resulted in good control. When she was receiving hourly intramuscular insulin injections (a mean of 778 IU daily) mean blood glucose concentrations had been 22.1 +/- 1.4 mmol/l (398 +/- 25 mg/100 microliters). After she had received the intravenous infusion for one month as an outpatient mean blood glucose concentration was 8.2 +/- 0.46 mmol/l (148 +/- 8 mg/100 microliters) and only 80 IU insulin daily was required. Follow-up after over five months of use showed that few complications had occurred. The system is simple to use and safe, and the diabetes had been stabilised such that she could enjoy a near-normal life style.
Many neurosurgery patients may have unrecognized diabetes or may develop stress-related hyperglycemia in the perioperative period. Diabetes patients have a higher perioperative risk of complications and have longer hospital stays than individuals without diabetes. Maintenance of euglycemia using intensive insulin therapy (IIT) continues to be investigated as a therapeutic tool to decrease morbidity and mortality associated with derangements in glucose metabolism due to surgery. Suboptimal perioperative glucose control may contribute to increased morbidity, mortality, and aggravate concomitant illnesses. The challenge is to minimize the effects of metabolic derangements on surgical outcomes, reduce blood glucose excursions, and prevent hypoglycemia. Differences in cerebral versus systemic glucose metabolism, time course of cerebral response to injury, and heterogeneity of pathophysiology in the neurosurgical patient populations are important to consider in evaluating the risks and benefits of IIT. While extremes of glucose levels are to be avoided, there are little data to support an optimal blood glucose level or recommend a specific use of IIT for euglycemia maintenance in the perioperative management of neurosurgical patients. Individualized treatment should be based on the local level of blood glucose control, outpatient treatment regimen, presence of complications, nature of the surgical procedure, and type of anesthesia administered.