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1.  Clinical review: Consensus recommendations on measurement of blood glucose and reporting glycemic control in critically ill adults 
Critical Care  2013;17(3):229.
The management reporting and assessment of glycemic control lacks standardization. The use of different methods to measure the blood glucose concentration and to report the performance of insulin treatment yields major disparities and complicates the interpretation and comparison of clinical trials. We convened a meeting of 16 experts plus invited observers from industry to discuss and where possible reach consensus on the most appropriate methods to measure and monitor blood glucose in critically ill patients and on how glycemic control should be assessed and reported. Where consensus could not be reached, recommendations on further research and data needed to reach consensus in the future were suggested. Recognizing their clear conflict of interest, industry observers played no role in developing the consensus or recommendations from the meeting. Consensus recommendations were agreed for the measurement and reporting of glycemic control in clinical trials and for the measurement of blood glucose in clinical practice. Recommendations covered the following areas: How should we measure and report glucose control when intermittent blood glucose measurements are used? What are the appropriate performance standards for intermittent blood glucose monitors in the ICU? Continuous or automated intermittent glucose monitoring - methods and technology: can we use the same measures for assessment of glucose control with continuous and intermittent monitoring? What is acceptable performance for continuous glucose monitoring systems? If implemented, these recommendations have the potential to minimize the discrepancies in the conduct and reporting of clinical trials and to improve glucose control in clinical practice. Furthermore, to be fit for use, glucose meters and continuous monitoring systems must match their performance to fit the needs of patients and clinicians in the intensive care setting.
See related commentary by Soto-Rivera and Agus,
PMCID: PMC3706766  PMID: 23767816
2.  Glycemic control in the critically ill - 3 domains and diabetic status means one size does not fit all! 
Critical Care  2013;17(2):131.
Hyperglycemia, hypoglycemia, and increased glucose variability have each been shown to be independently associated with increased risk of mortality in the critically ill. Sechterberger and colleagues have completed a large observational cohort study that demonstrates that diabetic status modulates these relationships in clinically meaningful ways. These findings corroborate, in a strikingly consistent manner, those of another very recently published large observational study.
PMCID: PMC3672498  PMID: 23594397
3.  Accuracy and limitations of continuous glucose monitoring using spectroscopy in critically ill patients 
OptiScanner devices, continuous glucose monitoring devices that perform automated blood draws via a central venous catheter and create plasma through centrifugation, measure plasma glucose levels through mid-infrared spectroscopy at the bedside. The objective of this study was to determine accuracy and practicality of the devices in critically ill patients attempting glycemic control.
The plasma glucose level was measured by the devices and in comparative plasma samples using Yellow Springs Instrument (YSI) plasma analyzers. After adding several previously unrecognized interferences in the interference library, we reanalyzed the mid-infrared signals and compared the resulting plasma glucose level with the reference value. Results are presented in Clarke error grids, glucose prediction errors and Bland-Altman plots and expressed as correlation coefficients.
We analyzed 463 comparative samples from 71 patients (median 6 (4 to 9) samples per patient). After calibrating the system, a Clarke error grid showed 100% of the values in zones A or B. The glucose predictor error demonstrated that 86% of the glucose values < 75 mg/dL were within ± 15 mg/dL of the YSI results and 95% ≥ 75 mg/dL were within 20% of the comparative YSI results. Bland-Altman plot showed a bias of −0.6 with limit of agreement of −24.6 to 23.3. The Pearson correlation coefficient was 0.93 and R2 was 0.87. In one third of the patients the devices had to be disconnected prematurely (that is before planned disconnection) because of repeated occlusion alarms suggesting blood draw errors.
The devices needed calibration for several previously unrecognized interferences. Thereafter, accuracy of the device to measure plasma glucose levels in ‘our cohort’ of critically ill patients improved, but external validation is highly recommended. The automated blood draw system of the devices needs further improvement to make this device of value for clinical use (trial registration (Netherlands Trial Register): NTR2864).
PMCID: PMC3975731  PMID: 24598381
Glucose; Spectroscopy; Point-of-care; Monitoring; ICU
4.  Glucose Measurement of Intensive Care Unit Patient Plasma Samples Using a Fixed-Wavelength Mid-Infrared Spectroscopy System 
Glycemic control is a rapidly developing field in intensive care medicine with the aim of reducing mortality, morbidity, and cost. Current intensive care unit (ICU) glucose measurement technologies are susceptible to interference from medications, volume expanders, and other substances present in critically ill patients. We hypothesized that a fixed-wavelength mid-infrared (mid-IR) spectroscopy system would be accurate for measuring glucose levels of ICU patients.
Research Design and Methods
This is a prospective investigation of plasma samples from two different institutions treating a heterogeneous population of ICU patients. The first 292 samples were collected from 86 patients admitted to Stamford Hospital, and the next 352 samples were collected from 75 patients from three ICUs at the University of Maryland. Plasma samples were measured on a Fourier-transform infrared or a proprietary spectrometer, with a glucose prediction algorithm to correct for spectral interference, which were compared with reference measurements taken using a YSI 2300 glucose analyzer.
Glucose values ranged from 24 to 343 mg/dl. Numerous medications and injury/disease states were observed in the patient populations, with metoprolol, fentanyl, and multiple organ failure the most prevalent. Despite these interferents, there was a high correlation (r ≥ 0.94) and low standard error (≤12.8 mg/dl) between the predicted glucose values and those of the YSI 2300 STAT Plus reference instrument in the three studies. A total of 95.1% of the 644 values in the three studies met International Organization for Standardization 15197 criteria.
These results suggest that a fixed-wavelength mid-IR spectrometer can measure glucose accurately in the plasma of ICU patients.
PMCID: PMC3380770  PMID: 22538138
continuous glucose monitoring; intensive care unit; interference; spectroscopy
5.  Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study 
Critical Care  2013;17(2):R37.
Hyperglycemia, hypoglycemia, and increased glycemic variability have each been independently associated with increased risk of mortality in critically ill patients. The role of diabetic status on modulating the relation of these three domains of glycemic control with mortality remains uncertain. The purpose of this investigation was to determine how diabetic status affects the relation of hyperglycemia, hypoglycemia, and increased glycemic variability with the risk of mortality in critically ill patients.
This is a retrospective analysis of prospectively collected data involving 44,964 patients admitted to 23 intensive care units (ICUs) from nine countries, between February 2001 and May 2012. We analyzed mean blood glucose concentration (BG), coefficient of variation (CV), and minimal BG and created multivariable models to analyze their independent association with mortality. Patients were stratified according to the diagnosis of diabetes.
Among patients without diabetes, mean BG bands between 80 and 140 mg/dl were independently associated with decreased risk of mortality, and mean BG bands >140 mg/dl, with increased risk of mortality. Among patients with diabetes, mean BG from 80 to 110 mg/dl was associated with increased risk of mortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. An effect of center was noted on the relation between mean BG and mortality. Hypoglycemia, defined as minimum BG <70 mg/dl, was independently associated with increased risk of mortality among patients with and without diabetes and increased glycemic variability, defined as CV >20%, was independently associated with increased risk of mortality only among patients without diabetes. Derangements of more than one domain of glycemic control had a cumulative association with mortality, especially for patients without diabetes.
Although hyperglycemia, hypoglycemia, and increased glycemic variability is each independently associated with mortality in critically ill patients, diabetic status modulates these relations in clinically important ways. Our findings suggest that patients with diabetes may benefit from higher glucose target ranges than will those without diabetes. Additionally, hypoglycemia is independently associated with increased risk of mortality regardless of the patient's diabetic status, and increased glycemic variability is independently associated with increased risk of mortality among patients without diabetes.
See related commentary by Krinsley,
See related commentary by Finfer and Billot,
PMCID: PMC3733432  PMID: 23452622
6.  What is the optimal rate of failed extubation? 
Critical Care  2012;16(1):111.
Failed extubation (FE), defined as reintubation 48 or 72 hours after planned extubation, occurs in a significant percentage of patients and is associated with a substantial burden of morbidity and mortality. This commentary reviews the literature describing FE rates and the clinical consequences of FE and proposes an 'optimal' rate of FE as well as avenues for future research.
PMCID: PMC3396264  PMID: 22356725
7.  Intensive insulin therapy to control hyperglycemia in the critically ill: a look back at the evidence shapes the challenges ahead 
Critical Care  2010;14(6):330.
The major interventional trials of intensive insulin therapy in critically ill patients have reached divergent results. The present viewpoint article explores some of the potential reasons, including differences in monitoring technology and protocol design and performance, the occurrence of severe hypoglycemia and changes in the standard of care since publication of the landmark single-center trial. Recently published data detailing the deleterious effect of hypoglycemia are discussed, as is the emerging body of literature describing the important impact of glycemic variability on the risk of mortality in heterogeneous populations of acutely ill and severely ill patients. These new findings have important implications for the design of future interventional trials of intensive insulin therapy in the intensive care unit setting.
PMCID: PMC3220034  PMID: 21143774
8.  Mild hypoglycemia is strongly associated with increased intensive care unit length of stay 
Hypoglycemia is associated with increased mortality in critically ill patients. The impact of hypoglycemia on resource utilization has not been investigated. The objective of this investigation was to evaluate the association of hypoglycemia, defined as a blood glucose concentration (BG) < 70 mg/dL, and intensive care unit (ICU) length of stay (LOS) in three different cohorts of critically ill patients.
This is a retrospective investigation of prospectively collected data, including patients from two large observational cohorts: 3,263 patients admitted to Stamford Hospital (ST) and 2,063 patients admitted to three institutions in The Netherlands (NL) as well as 914 patients from the GLUCONTROL trial (GL), a multicenter prospective randomized controlled trial of intensive insulin therapy.
Patients with hypoglycemia were more likely to be diabetic, had higher APACHE II scores, and higher mortality than did patients without hypoglycemia. Patients with hypoglycemia had longer ICU LOS (median [interquartile range]) in ST (3.0 [1.4-7.1] vs. 1.2 [0.8-2.3] days, P < 0.0001), NL (5.2 [2.6-10.3] vs. 2.0 [1.3-3.2] days, P < 0.0001), and GL (9 [5-17] vs. 5 [3-9] days, P < 0.0001). For the entire cohort of 6,240 patients ICU LOS was 1.8 (1.0-3.3) days for those without hypoglycemia and 3.0 (1.5-6.7) days for those with a single episode of hypoglycemia (P < 0.0001). This was a consistent finding even when patients were stratified by severity of illness or survivor status. There was a strong positive correlation between the number of episodes of hypoglycemia and ICU LOS among all three cohorts.
This multicenter international investigation demonstrated that hypoglycemia was consistently associated with significantly higher ICU LOS in heterogeneous cohorts of critically ill patients, independently of severity of illness and survivor status. More effective methods to prevent hypoglycemia in these patients may positively impact their cost of care.
PMCID: PMC3273438  PMID: 22115519
hypoglycemia; intensive care unit; length of stay; resource utilization; APACHE II; mortality; intensive insulin therapy
9.  Mild hypoglycemia is independently associated with increased mortality in the critically ill 
Critical Care  2011;15(4):R173.
Severe hypoglycemia (blood glucose concentration (BG) < 40 mg/dL) is independently associated with an increased risk of mortality in critically ill patients. The association of milder hypoglycemia (BG < 70 mg/dL) with mortality is less clear.
Prospectively collected data from two observational cohorts in the USA and in The Netherlands, and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint.
We analyzed data from 6,240 patients: 3,263 admitted to Stamford Hospital (ST), 2,063 admitted to three institutions in The Netherlands (NL) and 914 who participated in the GLUCONTROL trial (GL). The percentage of patients with hypoglycemia varied from 18% to 65% among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia even after stratification by severity of illness, diagnostic category, diabetic status, mean BG during intensive care unit (ICU) admission and coefficient of variation (CV) as a reflection of glycemic variability. The relative risk (RR, 95% confidence interval) of mortality associated with minimum BG < 40, 40 to 54 and 55 to 69 mg/dL compared to patients with minimum BG 80 to 109 mg/dL was 3.55 (3.02 to 4.17), 2.70 (2.31 to 3.14) and 2.18 (1.87 to 2.53), respectively (all P < 0.0001). The RR of mortality associated with any hypoglycemia < 70 mg/dL was 3.28 (2.78 to 3.87) (P < 0.0001), 1.30 (1.12 to 1.50) (P = 0.0005) and 2.11 (1.62 to 2.74) (P < 0.0001) for the ST, NL and GL cohorts, respectively. Multivariate regression analysis demonstrated that minimum BG < 70 mg/dL, 40 to 69 mg/dL and < 40 mg/dL were independently associated with increased risk of mortality for the entire cohort of 6,240 patients (odds ratio (OR) (95% confidence interval (CI)) 1.78 (1.39 to 2.27) P < 0.0001), 1.29 (1.11 to 1.51) P = 0.0011 and 1.87 (1.46 to 2.40) P < 0.0001) respectively.
Mild hypoglycemia was associated with a significantly increased risk of mortality in an international cohort of critically ill patients. Efforts to reduce the occurrence of hypoglycemia in critically ill patients may reduce mortality
PMCID: PMC3387616  PMID: 21787410
10.  Glycemic Variability and Mortality in Critically Ill Patients: The Impact of Diabetes 
Glycemic variability (GV) has recently been associated with mortality in critically ill patients. The impact of diabetes or its absence on GV as a risk factor for mortality is unknown.
A total of 4084 adult intensive care unit (ICU) patients admitted between October 15, 1999, and June 30, 2009, with at least three central laboratory measurements of venous glucose samples during ICU stay were studied retrospectively. The patients were analyzed according to treatment era and presence or absence of diabetes: 1460 admitted before February 1, 2003, when there was no specific treatment protocol for hyperglycemia (“PRE”) and 2624 patients admitted after a glycemic control protocol was instituted (“GC”). 3142 were patients without diabetes (“NON”), and 942 were patients with diabetes (“DM”). The coefficient of variation (CV) [standard deviation (SD)/mean glucose level (MGL)] of each patient was used as a measure of GV. Patients were grouped by MGL (mg/dl) during ICU stay (70–99, 100–119, 120–139, 140–179, and 180+) as well as by CV (<15%, 15–30%, 30–50%, and 50%+).
Patients with diabetes had higher MGL, SD, and CV than did NON (p < .0001 for all comparisons). Mean glucose level was lower among both GC groups compared to their corresponding PRE groups (p < .0001), but CV did not change significantly between eras. Multivariable logistic regression analysis demonstrated that low CV was independently associated with decreased risk of mortality and high CV was independently associated with increased risk of mortality among NON PRE and GC patients, even after exclusion of patients with severe (<40 mg/dl) or moderate (40–59 mg/dl) hypoglycemia. There was no association between CV and mortality among DM using the same multivariable model. Mortality among NON from the entire cohort, with MGL 70–99 mg/dl during ICU stay, was 10.2% for patients with CV < 15% versus 58.3% for those with CV 50%+; for NON with MGL 100–119 mg/dl, corresponding rates were 10.6% and 55.6%.
Low GV during ICU stay was associated with increased survival among NON, and high GV was associated with increased mortality, even after adjustment for severity of illness. There was no independent association of GV with mortality among DM. Attempts to minimize GV may have a significant beneficial impact on outcomes of critically ill patients without diabetes.
PMCID: PMC2787029  PMID: 20144383
diabetes; glucose; intensive care unit; mortality; variability
11.  Hypoglycemia in the Critically Ill: How Low Is Too Low? 
Mayo Clinic Proceedings  2010;85(3):215-216.
PMCID: PMC2843119  PMID: 20176927
12.  The severity of sepsis: yet another factor influencing glycemic control 
Critical Care  2008;12(6):194.
The present commentary provides a brief overview of the evolving literature on glycemic management in critically ill patients. Recent interventional studies have been plagued by high rates of severe hypoglycemia among patients, particularly those with sepsis. The investigation by Waeschle and colleagues adds to our knowledge about the relationship between the severity of sepsis and glycemic dysregulation. The severity of sepsis is shown to correlate with the risk of sustaining hyperglycemia as well as critical hypoglycemia.
PMCID: PMC2646348  PMID: 19040779
13.  Moving beyond tight glucose control to safe effective glucose control 
Critical Care  2008;12(3):149.
The impressive benefits related to the use of tight glucose control by intensive insulin therapy have not been reproduced until now in multicenter large-scale prospective randomized trials. Although the reasons for these failures are not entirely clear, we suggest the use of a stepwise approach – Safe, Effective Glucose Control – that will essentially target an intermediate blood glucose level. As compared with genuine tight glucose control, Safe, Effective Glucose Control – already used in many intensive care units worldwide – is intended to decrease the rate of hypoglycemia and the workload, while reducing the adverse effects of severe hyperglycemia.
PMCID: PMC2481442  PMID: 18495050

Results 1-13 (13)