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1.  Mild hypoglycemia is independently associated with increased mortality in the critically ill 
Critical Care  2011;15(4):R173.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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
doi:10.1186/cc10322
PMCID: PMC3387616  PMID: 21787410
2.  Mild hypoglycemia is independently associated with increased risk of mortality in patients with sepsis: a 3-year retrospective observational study 
Critical Care  2012;16(5):R189.
Introduction
Mild hypoglycemia is associated with increased mortality in critically ill patients. However, data regarding the association between mild hypoglycemia and patient outcomes among patients with sepsis are limited.
Methods
Patients admitted to a medical ICU for sepsis, as defined by the Surviving Sepsis Campaign guidelines, during a 3-year period were enrolled retrospectively. Data on blood glucose (BG) control parameters and patient outcomes were collected. The primary outcome was the relationship of mild hypoglycemia (defined as minimum BG of 40 to 69 mg/dl during ICU stay) to hospital mortality, and the secondary outcomes were ICU-acquired complication rates, ICU and 1-year mortality rates. A relationship between glucose variability and hypoglycemic events was also investigated.
Results
Three-hundred and thirteen consecutive patients with sepsis were enrolled (mean age, 71.8 ± 11.3 years; male, n = 166; diabetics, n = 102). A total of 14,249 (5.6/day/patient) BG tests were performed, and 175 hypoglycemic events (spontaneous, n = 71; iatrogenic, n = 104) occurred in 80 (25.6%) patients during the ICU stay; severe hypoglycemia (minimum BG level < 40 mg/dl) occurred in 24 (7.7%) patients, and mild hypoglycemia (minimum BG level 40 to 69 mg/dl) was found in 56 (17.9%) patients. The frequency of hypoglycemic events increased with higher glucose variability, and patients with mild hypoglycemia had higher rates of ICU-acquired complications than did those with no hypoglycemia (renal, 36.2% vs. 15.6%, P = 0.003; cardiac, 31.9% vs. 14.3%, P = 0.008; hepatic, 34.0% vs. 18.2%, P = 0.024; bacteremia, 14.9% vs. 4.5%, P = 0.021). Multivariate analysis revealed that mild hypoglycemia was independently associated with increased hospital mortality (odds ratio, 3.43; 95% confidence interval, 1.51 to 7.82), and even a single event was an independent risk factor (odds ratio, 2.98; 95% confidence interval, 1.10 to 8.09). Kaplan-Meier analysis demonstrated that mild hypoglycemia was significantly associated with a lower 1-year cumulative survival rate among patients with sepsis (P < 0.001).
Conclusion
Mild hypoglycemia was associated with increased risk of hospital and 1-year mortality, as well as the occurrence of ICU-acquired complications. Physicians thus need to recognize the importance of mild hypoglycemia in patients with sepsis.
doi:10.1186/cc11674
PMCID: PMC3682291  PMID: 23062226
3.  Hypoglycemia and Outcome in Critically Ill Patients 
Mayo Clinic Proceedings  2010;85(3):217-224.
OBJECTIVE: To determine whether mild or moderate hypoglycemia that occurs in critically ill patients is independently associated with an increased risk of death.
PATIENTS AND METHODS: Of patients admitted to 2 hospital intensive care units (ICUs) in Melbourne and Sydney, Australia, from January 1, 2000, to October 14, 2004, we analyzed all those who had at least 1 episode of hypoglycemia (glucose concentration, <81 mg/dL). The independent association between hypoglycemia and outcome was statistically assessed.
RESULTS: Of 4946 patients admitted to the ICUs, a cohort of 1109 had at least 1 episode of hypoglycemia (blood glucose level, <81 mg/dL). Of these 1109 patients (22.4% of all admissions to the intensive care unit), hospital mortality was 36.6% compared with 19.7% in the 3837 nonhypoglycemic control patients (P<.001). Even patients with a minimum blood glucose concentration between 72 and 81 mg/dL had a greater unadjusted mortality rate than did control patients (25.9% vs 19.7%; unadjusted odds ratio, 1.42; 95% confidence interval, 1.12-1.80; P=.004.) Mortality increased significantly with increasing severity of hypoglycemia (P<.001). After adjustment for insulin therapy, hypoglycemia was independently associated with increased risk of death, cardiovascular death, and death due to infectious disease.
CONCLUSION: In critically ill patients, an association exists between even mild or moderate hypoglycemia and mortality. Even after adjustment for insulin therapy or timing of hypoglycemic episode, the more severe the hypoglycemia, the greater the risk of death.
This study found that an association exists between even mild or moderate hypoglycemia and mortality in critically ill patients; even after adjustment for insulin therapy or timing of hypoglycemic episodes, the more severe the hypoglycemia, the greater the risk of death.
doi:10.4065/mcp.2009.0394
PMCID: PMC2843109  PMID: 20176928
4.  Hemoglobin A1c Levels and Risk of Severe Hypoglycemia in Children and Young Adults with Type 1 Diabetes from Germany and Austria: A Trend Analysis in a Cohort of 37,539 Patients between 1995 and 2012 
PLoS Medicine  2014;11(10):e1001742.
In a cohort study, Beate Karges and colleagues find that the association between low hemoglobin A1C and severe hypoglycemia in children and young adults with type 1 diabetes has decreased over the period between 1995 and 2012.
Please see later in the article for the Editors' Summary
Background
Severe hypoglycemia is a major complication of insulin treatment in patients with type 1 diabetes, limiting full realization of glycemic control. It has been shown in the past that low levels of hemoglobin A1c (HbA1c), a marker of average plasma glucose, predict a high risk of severe hypoglycemia, but it is uncertain whether this association still exists. Based on advances in diabetes technology and pharmacotherapy, we hypothesized that the inverse association between severe hypoglycemia and HbA1c has decreased in recent years.
Methods and Findings
We analyzed data of 37,539 patients with type 1 diabetes (mean age ± standard deviation 14.4±3.8 y, range 1–20 y) from the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative diabetes cohort prospectively documented between January 1, 1995, and December 31, 2012. The DPV cohort covers an estimated proportion of >80% of all pediatric diabetes patients in Germany and Austria. Associations of severe hypoglycemia, hypoglycemic coma, and HbA1c levels were assessed by multivariable regression analysis. From 1995 to 2012, the relative risk (RR) for severe hypoglycemia and coma per 1% HbA1c decrease declined from 1.28 (95% CI 1.19–1.37) to 1.05 (1.00–1.09) and from 1.39 (1.23–1.56) to 1.01 (0.93–1.10), respectively, corresponding to a risk reduction of 1.2% (95% CI 0.6–1.7, p<0.001) and 1.9% (0.8–2.9, p<0.001) each year, respectively. Risk reduction of severe hypoglycemia and coma was strongest in patients with HbA1c levels of 6.0%–6.9% (RR 0.96 and 0.90 each year) and 7.0%–7.9% (RR 0.96 and 0.89 each year). From 1995 to 2012, glucose monitoring frequency and the use of insulin analogs and insulin pumps increased (p<0.001). Our study was not designed to investigate the effects of different treatment modalities on hypoglycemia risk. Limitations are that associations between diabetes education and physical activity and severe hypoglycemia were not addressed in this study.
Conclusions
The previously strong association of low HbA1c with severe hypoglycemia and coma in young individuals with type 1 diabetes has substantially decreased in the last decade, allowing achievement of near-normal glycemic control in these patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than 380 million people have diabetes, a chronic disorder characterized by high levels of glucose (sugar) in the blood. Blood sugar levels are usually controlled by insulin, a hormone produced by the pancreas. In people with diabetes, blood sugar control fails because they make no insulin (type 1 diabetes) or because the cells that normally respond to insulin by removing sugar from the blood have become insulin-resistant (type 2 diabetes). Type 1 diabetes, which tends to develop in childhood or early adulthood, is responsible for about 10% of cases of diabetes in adults and is treated with injections of insulin. Type 2 diabetes can usually be treated with diet, exercise, and antidiabetic drugs. With both types of diabetes, it is important to keep blood sugar levels within the normal range (good glycemic control) to reduce the long-term complications of diabetes, which include kidney failure, blindness, and an increased risk of cardiovascular disease.
Why Was This Study Done?
Patients with type 1 diabetes can achieve strict glycemic control using intensive insulin therapy, but such treatment is associated with a risk of severe or fatal hypoglycemia (low blood sugar). Past studies have found an association between low levels of hemoglobin A1c (HbA1c, a marker of average blood sugar levels over the past 2–3 months; a low HbA1c percentage indicates good glycemic control) and a high risk of severe hypoglycemia. Because of this inverse association, people at risk of severe hypoglycemia are advised to aim for an HbA1c of 7.5% or less, which puts them at risk of diabetic complications (most adults with diabetes aim for an HbA1c of 6.5% or less; people without diabetes have Hb1Ac readings below 6.05%). With recent improvements in insulin therapy, it is not clear whether the inverse association between the incidence of severe hypoglycemia and HbA1c levels still exists. In this trend analysis, the researchers investigate the association over time between HbA1C levels and the risk of severe hypoglycemia in a large cohort (group) of Austrian and German children and young adults with type 1 diabetes.
What Did the Researchers Do and Find?
The researchers analyzed data on Hb1Ac levels and on incidents of severe hypoglycemia and hypoglycemic coma collected from 37,539 children and young adults with type 1 diabetes between 1995 and 2012 by the DPV (Diabetes Patienten Verlaufsdokumentation) Initiative for diabetes care. The DPV cohort includes around 80% of all children and young adults with type 1 diabetes in Germany and Austria. Over the study period, the use of insulin analogs (compounds related to insulin that keep blood sugar levels steadier than regular insulin injections) and of insulin pumps (which deliver constant amounts of short-acting insulin analogs to the body) increased, and there was an increase in how often patients monitored their blood sugar level. Notably, between 1995 and 2012, the relative risk for severe hypoglycemia per 1% decrease in Hb1Ac declined from 1.28 to 1.05, and the relative risk for hypoglycemic coma per 1% decrease in Hb1Ac declined from 1.39 to 1.01. That is, the strength of the inverse association between severe hypoglycemia or coma and HbA1c decreased during the study period. Expressed another way, between 1995 and 2012, the relative risk for severe hypoglycemia and coma per 1% HbA1c decrease dropped by 1.2% and 1.9%, respectively, each year.
What Do These Findings Mean?
These findings reveal a substantial decrease since 1995 in the previously strong inverse association between low HbA1c levels and severe hypoglycemia and hypoglycemic coma in this cohort of young Germans and Austrians with type 1 diabetes. This decrease mainly occurred because of substantial reductions in the risk of hypoglycemia in patients with HbA1c levels between 6.0% and 7.9%, but the study provides no information about the drivers of this reduction. Moreover, these findings may apply only to young type 1 diabetes patients of European descent, and their accuracy may be limited by other aspects of the study design. However, by showing that HbA1c has become a minor predictor for severe hypoglycemia in this group of patients, these findings suggest that strict glycemic control in young patients with type 1 diabetes has become safer in recent years. Thus, it should now be possible to reduce the risk of long-term diabetic complications in such patients through achievement of near-normal glycemic control without increasing patients' risk of severe hypoglycemia.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001742.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public (in English and Spanish), including information on the HbA1c test and a description of a trial that compared the effects of intensive versus conventional treatment of blood glucose levels on the development of diabetic complications in patients with type 1 diabetes
The UK National Health Service Choices website provides information for patients and carers about type 1 diabetes, including a video that describes parents' experiences caring for a child with type 1 diabetes, and information about treating type 1 diabetes that includes a short video about HbA1c
The charity Diabetes UK provides detailed information about type 1 diabetes for patients and carers
The UK-based non-profit organization Healthtalkonline provides information about type 1 diabetes and young people, including interviews with young people about their experiences of the condition
MedlinePlus provides links to further resources and advice about type 1 diabetes (in English and Spanish)
Information about the DPV Initiative is available (mainly in German)
doi:10.1371/journal.pmed.1001742
PMCID: PMC4188517  PMID: 25289645
5.  The impact of early hypoglycemia and blood glucose variability on outcome in critical illness 
Critical Care  2009;13(3):R91.
Introduction
In critical illness, the association of hypoglycemia, blood glucose (BG) variability and outcome are not well understood. We describe the incidence, clinical factors and outcomes associated with an early hypoglycemia and BG variability in critically ill patients.
Methods
Retrospective interrogation of prospectively collected data from the Australia New Zealand Intensive Care Society Adult Patient Database on 66184 adult admissions to 24 intensive care units (ICUs) from 1 January 2000 to 31 December 2005. Primary exposure was hypoglycemia (BG < 4.5 mmol/L) and BG variability (BG < 4.5 and ≥ 12.0 mmol/L) within 24 hours of admission. Primary outcome was all-cause mortality.
Results
The cumulative incidence of hypoglycemia and BG variability were 13.8% (95% confidence interval (CI) = 13.5 to 14.0; n = 9122) and 2.9% (95%CI = 2.8 to 3.0, n = 1913), respectively. Several clinical factors were associated with both hypoglycemia and BG variability including: co-morbid disease (P < 0.001), non-elective admissions (P < 0.001), higher illness severity (P < 0.001), and primary septic diagnosis (P < 0.001). Hypoglycemia was associated with greater odds of adjusted ICU (odds ratio (OR) = 1.41, 95% CI = 1.31 to 1.54) and hospital death (OR = 1.36, 95% CI = 1.27 to 1.46). Hypoglycemia severity was associated with 'dose-response' increases in mortality. BG variability was associated with greater odds of adjusted ICU (1.5, 95% CI = 1.4 to 1.6) and hospital (1.4, 95% CI = 1.3 to 1.5) mortality, when compared with either hypoglycemia only or neither.
Conclusions
In critically ill patients, both early hypoglycemia and early variability in BG are relatively common, and independently portend an increased risk for mortality.
doi:10.1186/cc7921
PMCID: PMC2717463  PMID: 19534781
6.  Hypoglycemia and Clinical Outcomes in Patients With Diabetes Hospitalized in the General Ward 
Diabetes Care  2009;32(7):1153-1157.
OBJECTIVE
Hypoglycemia is associated with adverse outcomes in mixed populations of patients in intensive care units. It is not known whether the same risks exist for diabetic patients who are less severely ill. In this study, we aimed to determine whether hypoglycemic episodes are associated with higher mortality in diabetic patients hospitalized in the general ward.
RESEARCH DESIGN AND METHODS
This retrospective cohort study analyzed 4,368 admissions of 2,582 patients with diabetes hospitalized in the general ward of a teaching hospital between January 2003 and August 2004. The associations between the number and severity of hypoglycemic (≤50 mg/dl) episodes and inpatient mortality, length of stay (LOS), and mortality within 1 year after discharge were evaluated.
RESULTS
Hypoglycemia was observed in 7.7% of admissions. In multivariable analysis, each additional day with hypoglycemia was associated with an increase of 85.3% in the odds of inpatient death (P = 0.009) and 65.8% (P = 0.0003) in the odds of death within 1 year from discharge. The odds of inpatient death also rose threefold for every 10 mg/dl decrease in the lowest blood glucose during hospitalization (P = 0.0058). LOS increased by 2.5 days for each day with hypoglycemia (P < 0.0001).
CONCLUSIONS
Hypoglycemia is common in diabetic patients hospitalized in the general ward. Patients with hypoglycemia have increased LOS and higher mortality both during and after admission. Measures should be undertaken to decrease the frequency of hypoglycemia in this high-risk patient population.
doi:10.2337/dc08-2127
PMCID: PMC2699723  PMID: 19564471
7.  Hypoglycemia, With or Without Insulin Therapy, Is Associated With Increased Mortality Among Hospitalized Patients 
Diabetes Care  2013;36(5):1107-1110.
OBJECTIVE
Hypoglycemia is associated with increased mortality in hospitalized patients. We investigated the relationship between spontaneous hypoglycemia versus insulin-associated hypoglycemia and mortality in hospitalized patients.
RESEARCH DESIGN AND METHODS
Data for this retrospective cohort study were obtained from electronic databases of patients admitted between 1 April 2008 and 30 November 2010. Patients with one or more blood glucose values ≤50 mg/dL on point-of-care glucose testing were considered hypoglycemic. Patients treated with insulin were assumed to have insulin-associated hypoglycemia. Age-, sex-, and race-matched patients with all blood glucose values >70 mg/dL were selected as controls. The Charlson comorbidity index (CCI) was used to control for severity of illness.
RESULTS
There were four groups: 1) noninsulin-treated hypoglycemia (NTH) (n = 135), 2) insulin-treated hypoglycemia (ITH) (n = 961), 3) noninsulin-treated control (NTC) (n = 1,058), and 4) insulin-treated control (ITC) (n = 736). Mortality was higher in the ITH group compared with the ITC group (20.3 vs. 4.5%, P < 0.0001), with a relatively higher CCI (1.8 vs. 1.5%, P < 0.0001), but much higher in the NTH group compared with the NTC group (34.5 vs. 1.1%, P < 0.0001), with much higher CCI (2.4 vs. 1.1%, P < 0.0001). Mortality was higher in the NTH group compared with the ITH group (P < 0.0001) but lower in the NTC group compared with the ITC group (P < 0.0001). After controlling for age, sex, CCI, and admission to the intensive care unit, insulin treatment was associated with a lower mortality among the hypoglycemic patients; hazard ratio of death in the ITH group relative to the NTH group was 0.34 (95% CI 0.25–0.47, P < 0.0001).
CONCLUSIONS
Insulin-associated and spontaneous hypoglycemia are associated with increased mortality among hospitalized patients.
doi:10.2337/dc12-1296
PMCID: PMC3631882  PMID: 23248192
8.  Defective Awakening Response to Nocturnal Hypoglycemia in Patients with Type 1 Diabetes Mellitus 
PLoS Medicine  2007;4(2):e69.
Background
Nocturnal hypoglycemia frequently occurs in patients with type 1 diabetes mellitus (T1DM). It can be fatal and is believed to promote the development of the hypoglycemia-unawareness syndrome. Whether hypoglycemia normally provokes awakening from sleep in individuals who do not have diabetes, and whether this awakening response is impaired in T1DM patients, is unknown.
Methods and Findings
We tested two groups of 16 T1DM patients and 16 healthy control participants, respectively, with comparable distributions of gender, age, and body mass index. In one night, a linear fall in plasma glucose to nadir levels of 2.2 mmol/l was induced by infusing insulin over a 1-h period starting as soon as polysomnographic recordings indicated that stage 2 sleep had been reached. In another night (control), euglycemia was maintained.
Only one of the 16 T1DM patients, as compared to ten healthy control participants, awakened upon hypoglycemia (p = 0.001). In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with increased hormonal counterregulation. In all the study participants (from both groups) who woke up, and in five of the study participants who did not awaken (three T1DM patients and two healthy control participants), plasma epinephrine concentration increased with hypoglycemia by at least 100% (p < 0.001). A temporal pattern was revealed such that increases in epinephrine in all participants who awakened started always before polysomnographic signs of wakefulness (mean ± standard error of the mean: 7.5 ± 1.6 min).
Conclusions
A fall in plasma glucose to 2.2 mmol/l provokes an awakening response in most healthy control participants, but this response is impaired in T1DM patients. The counterregulatory increase in plasma epinephrine that we observed to precede awakening suggests that awakening forms part of a central nervous system response launched in parallel with hormonal counterregulation. Failure to awaken increases the risk for T1DM patients to suffer prolonged and potentially fatal hypoglycemia.
A study of 16 patients with type 1 diabetes and 16 healthy participants showed that the normal awakening response provoked by a fall in plasma glucose was impaired in diabetic individuals.
Editors' Summary
Background.
Hypoglycemia (low blood sugar) is a frequent complication of insulin-treated diabetes, affecting patients with type 1 diabetes mellitus in particular. In individuals who do not have diabetes, insulin secretion is modified naturally and continuously by the body's own regulatory systems, depending on the blood sugar. However, in diabetes patients there is a lack of natural insulin and so manufactured insulin has to be given by injection after blood sugar testing. Hence, it is not possible for patients with diabetes to modify insulin secretion naturally in response to a change in glucose levels, and so blood glucose levels can rise and fall beyond healthy levels. In individuals who have intensive insulin therapy, hypoglycemia can be a particular problem; each year about 25% of patients on intensive insulin therapy have at least one episode of severe hypoglycemia—which requires the assistance of another person.
When hypoglycemia occurs during the day, diabetes patients can recognize it by a variety of symptoms, e.g., feeling sweaty and lightheaded, and they may either seek help from another person or treat themselves with sugar. Hypoglycemia during sleep may be very common—it has been observed to occur in up to half of the nights when patients with diabetes were monitored. The particular problem with hypoglycemia occurring during sleep is that diabetes patients may not be aware of it and hence may not be able to treat themselves or to seek assistance. It is believed to contribute to some instances of sudden death during sleep in patients with diabetes.
Why Was This Study Done?
It has not been clear whether there is a certain level of blood glucose below which a signal is triggered that provokes awakening from sleep in either diabetes patients or in individuals who do not have diabetes. The authors of this study wanted to compare responses to lowered blood glucose in diabetes patients and in individuals who do not have diabetes and to see whether the responses differed. They also wanted to look at whether there were any other hormonal changes that preceded or followed awakening after hypoglycemia.
What Did the Researchers Do and Find?
They treated two groups; 16 type 1 diabetes mellitus patients and 16 healthy control participants. With careful monitoring, on one night once stage 2 sleep (as measured by a method known as polysomnography) had been reached, they gave insulin to lower the blood glucose to a specific level (2.2 mmol/l), which would when awake give symptoms of hypoglycemia. On another night (the control night) normal blood sugar levels were maintained.
They found that only one of the 16 diabetes patients, as compared to ten healthy control participants, woke when hypoglycemia occurred. In the control nights, none of the study participants in either of the two groups awakened during the corresponding time. Awakening during hypoglycemia was associated with substantial hormonal changes, especially with an increase in one hormone, epinephrine (also known as adrenaline), and the increases in this hormone occurred before polysomnographic signs of wakefulness.
What Do These Findings Mean?
It appears that patients with type 1 diabetes mellitus do not awake at a level of hypoglycemia that triggers waking in normal individuals. The hormonal responses that were seen in individuals who awoke may be part of a crucial response system to hypoglycemia. These results help us to understand how diabetes patients respond to hypoglycemia, but further work will need to be done to determine whether it is possible to improve the response. It should be noted, however, that the results are probably not generalizable to patients with type 2 diabetes mellitus, who represent the majority of patients with diabetes.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040069.
A related PLoS Medicine Perspective article by Ilan Gabriely and Harry Shamoon discusses this study and more about hypoglycemia in T1DM
MedlinePlus, the encyclopedia of health information from the US National Library of Medicine, has a collection of pages on hypoglycemia
Wikipedia pages on hypoglycemia (note that Wikipedia is a free online encyclopedia that anyone can edit)
National Diabetes Information Clearinghouse, a service of the US National Institute of Diabetes and Digestive and Kidney Diseases, has information on hypoglycemia
doi:10.1371/journal.pmed.0040069
PMCID: PMC1808097  PMID: 17326710
9.  Computer-assisted glucose control in critically ill patients 
Intensive Care Medicine  2008;34(8):1421-1427.
Objective
Intensive insulin therapy is associated with the risk of hypoglycemia and increased costs of material and personnel. We therefore evaluated the safety and efficiency of a computer-assisted glucose control protocol in a large population of critically ill patients.
Design and setting
Observational cohort study in three intensive care units (32 beds) in a 1,300-bed university teaching hospital.
Patients
All 2,800 patients admitted to the surgical, neurosurgical, and cardiothoracic units; the study period started at each ICU after implementation of Glucose Regulation for Intensive Care Patients (GRIP), a freely available computer-assisted glucose control protocol.
Measurements and results
We analysed compliance in relation to recommended insulin pump rates and glucose measurement frequency. Patients were on GRIP-ordered pump rates 97% of time. Median measurement time was 5 min late (IQR 20 min early to 34 min late). Hypoglycemia was uncommon (7% of patients for mild hypoglycemia, < 3.5 mmol/l; 0.86% for severe hypoglycemia, < 2.2 mmol/l). Our predefined target range (4.0–7.5 mmol/l) was reached after a median of 5.6 h (IQR 0.2–11.8) and maintained for 89% (70–100%) of the remaining stay at the ICU. The number of measurements needed was 5.9 (4.8–7.3) per patient per day. In-hospital mortality was 10.1%.
Conclusions
Our computer-assisted glucose control protocol provides safe and efficient glucose regulation in routine intensive care practice. A low rate of hypoglycemic episodes was achieved with a considerably lower number of glucose measurements than used in most other schemes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-008-1091-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00134-008-1091-y
PMCID: PMC2491417  PMID: 18389221
Insulin; Glucose; Critically ill; Computer decision support
10.  Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation 
PLoS Medicine  2013;10(12):e1001577.
In this paper, Choi and colleagues analyzed levels of mitochondrial DNA in two prospective observational cohort studies and found that increased mtDNA levels are associated with ICU mortality, and improve risk prediction in medical ICU patients. The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients.
Background
Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.
Methods and Findings
Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.
Conclusions
Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Intensive care units (ICUs, also known as critical care units) are specialist hospital wards that provide care for people with life-threatening injuries and illnesses. In the US alone, more than 5 million people are admitted to ICUs every year. Different types of ICUs treat different types of problems. Medical ICUs treat patients who, for example, have been poisoned or who have a serious infection such as sepsis (blood poisoning) or severe pneumonia (inflammation of the lungs); trauma ICUs treat patients who have sustained a major injury; cardiac ICUs treat patients who have heart problems; and surgical ICUs treat complications arising from operations. Patients admitted to ICUs require constant medical attention and support from a team of specially trained nurses and physicians to prevent organ injury and to keep their bodies functioning. Monitors, intravenous tubes (to supply essential fluids, nutrients, and drugs), breathing machines, catheters (to drain urine), and other equipment also help to keep ICU patients alive.
Why Was This Study Done?
Although many patients admitted to ICUs recover, others do not. ICU specialists use scoring systems (algorithms) based on clinical signs and physiological measurements to predict their patients' likely outcomes. For example, the APACHE II scoring system uses information on heart and breathing rates, temperature, levels of salts in the blood, and other signs and physiological measurements collected during the first 24 hours in the ICU to predict the patient's risk of death. Existing scoring systems are not perfect, however, and “biomarkers” (molecules in bodily fluids that provide information about a disease state) are needed to improve risk prediction for ICU patients. Here, the researchers investigate whether levels of circulating cell-free mitochondrial DNA (mtDNA) are associated with ICU deaths and whether these levels can be used as a biomarker to improve risk prediction in ICU patients. Mitochondria are cellular structures that produce energy. Levels of mtDNA in the plasma (the liquid part of blood) increase in response to trauma and infection. Moreover, mtDNA activates molecular processes that lead to inflammation and organ injury.
What Did the Researchers Do and Find?
The researchers measured mtDNA levels in the plasma of patients enrolled in two prospective observational cohort studies that monitored the outcomes of ICU patients. In the Brigham and Women's Hospital Registry of Critical Illness study, blood was taken from 200 patients within 24 hours of admission into the hospital's medical ICU. In the Molecular Epidemiology of Acute Respiratory Distress Syndrome study (acute respiratory distress syndrome is a life-threatening inflammatory reaction to lung damage or infection), blood was taken from 243 patients within 48 hours of admission into medical and non-medical ICUs at two other US hospitals. Patients admitted to medical ICUs with a raised mtDNA level (3,200 or more copies of a specific mitochondrial gene per microliter of plasma) had a 7- to 8-fold increased risk of dying within 28 days of admission compared to patients with mtDNA levels of less than 3,200 copies/µl plasma. There was no evidence of an association between raised mtDNA levels and death among patients admitted to non-medical ICUs. The addition of an elevated mtDNA level to a clinical model for risk prediction that included the APACHE II score and biomarkers that are already used to predict ICU outcomes improved the net reclassification index (an indicator of the improvement in risk prediction algorithms offered by new biomarkers) of 28-day mortality among medical ICU patients in both studies.
What Do These Findings Mean?
These findings indicate that raised mtDNA plasma levels are associated with death in medical ICUs and show that, among patients in medical ICUs, measurement of mtDNA plasma levels can improve the prediction of the risk of death from the APACHE II scoring system, even when commonly measured biomarkers are taken into account. These findings do not indicate whether circulating cell-free mtDNA increased because of the underlying severity of illness or whether mtDNA actively contributes to the disease process in medical ICU patients. Moreover, they do not provide any evidence that raised mtDNA levels are associated with an increased risk of death among non-medical (mainly surgical) ICU patients. These findings need to be confirmed in additional patients, but given the relative ease and rapidity of mtDNA measurement, the determination of circulating cell-free mtDNA levels could be a valuable addition to the assessment of patients admitted to medical ICUs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001577.
The UK National Health Service Choices website provides information about intensive care
The Society of Critical Care Medicine provides information for professionals, families, and patients about all aspects of intensive care
MedlinePlus provides links to other resources about intensive care (in English and Spanish)
The UK charity ICUsteps supports patients and their families through recovery from critical illness; its booklet Intensive Care: A Guide for Patients and Families is available in English and ten other languages; its website includes patient experiences and relative experiences of treatment in ICUs
Wikipedia has a page on ICU scoring systems (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001577
PMCID: PMC3876981  PMID: 24391478
11.  Tight Glycemic Control versus Standard Care after Pediatric Cardiac Surgery 
The New England journal of medicine  2012;367(13):1208-1219.
BACKGROUND
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.
METHODS
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.
RESULTS
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]).
CONCLUSIONS
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.)
doi:10.1056/NEJMoa1206044
PMCID: PMC3501680  PMID: 22957521
12.  Hypoglycemia Aggravates Critical Illness–Induced Neurocognitive Dysfunction 
Diabetes Care  2009;33(3):639-644.
OBJECTIVE
Tight glycemic control (TGC) in critically ill patients is associated with an increased risk of hypoglycemia. Whether those short episodes of hypoglycemia are associated with adverse morbidity and mortality is a matter of discussion. Using a case-control study design, we investigated whether hypoglycemia under TGC causes permanent neurocognitive dysfunction in patients surviving critical illness.
RESEARCH DESIGN AND METHODS
From our patient data management system, we identified adult survivors treated for >72 h in our surgical intensive care unit (ICU) between 2004 and 2007 (n = 4,635) without a history of neurocognitive dysfunction or structural brain abnormalities who experienced at least one episode of hypoglycemia during treatment (hypo group) (n = 37). For each hypo group patient, one patient stringently matched for demographic- and disease-related data were identified as a control subject. We performed a battery of neuropsychological tests investigating five areas of cognitive functioning in both groups at least 1 year after ICU discharge. Test results were compared with data from healthy control subjects and between groups.
RESULTS
Critical illness caused neurocognitive dysfunction in all tested domains in both groups. The dysfunction was aggravated in hypo group patients in one domain, namely that of visuospatial skills (P < 0.01). Besides hypoglycemia, both hyperglycemia (r = −0.322; P = 0.005) and fluctuations of blood glucose (r = −0.309; P = 0.008) were associated with worse test results in this domain.
CONCLUSIONS
Hypoglycemia was found to aggravate critical illness–induced neurocognitive dysfunction to a limited, but significant, extent; however, an impact of hyperglycemia and fluctuations of blood glucose on neurocognitive function cannot be excluded.
doi:10.2337/dc09-1740
PMCID: PMC2827523  PMID: 20032274
13.  Hypoglycemia Associated Mortality is Not Drug-associated but Linked to Comorbidities 
The American journal of medicine  2011;124(11):1028-1035.
Objective
Although tight glucose control is widely used in hospitalized patients, there is concern that medication-induced hypoglycemia may worsen patient outcomes. We sought to determine if the mortality risk associated with hypoglycemia in hospitalized non-critically ill patients is linked to glucose-lowering medications (drug-associated hypoglycemia) or if it is merely an association mediated by comorbidities (spontaneous hypoglycemia).
Methods
Retrospective cohort of patients admitted to the general wards of an academic center during 2007. The in-hospital mortality risk of a hypoglycemic group (at least one blood glucose ≤ 70 mg/dl) was compared to that of a normoglycemic group using survival analysis. Stratification by subgroups of patients with spontaneous and drug-associated hypoglycemia was performed.
Results
Among 31,970 patients, 3,349 (10.5%) had at least one episode of hypoglycemia. Patients with hypoglycemia were older, had more comorbidities, and received more antidiabetic agents. Hypoglycemia was associated with increased in-hospital mortality (HR: 1.67, 95% CI, 1.33 to 2.09, p<0.001). However, this greater risk was limited to patients with spontaneous hypoglycemia (HR: 2.62, 95% CI, 1.97 to 3.47, p<0.001), not to those with drug-associated hypoglycemia (HR: 1.06, 95% CI, 0.74 to 1.52, p=0.749). After adjustment for patient comorbidities, the association between spontaneous hypoglycemia and mortality was eliminated (HR: 1.11, 95% CI, 0.76 to 1.64, p=0.582).
Conclusions
Drug-associated hypoglycemia was not associated with increased mortality risk in patients admitted to the general wards. The association between spontaneous hypoglycemia and mortality was eliminated after adjustment for comorbidities, suggesting that hypoglycemia may be a marker of disease burden rather than a direct cause of death.
doi:10.1016/j.amjmed.2011.07.011
PMCID: PMC3200530  PMID: 22017781
Hypoglycemia; mortality; hypoglycemia in general ward patients
14.  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.
Introduction
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.
Methods
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.
Results
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.
Conclusions
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, http://ccforum.com/content/17/2/131
See related commentary by Finfer and Billot, http://ccforum.com/content/17/2/134
doi:10.1186/cc12547
PMCID: PMC3733432  PMID: 23452622
15.  Intensive insulin therapy and mortality in critically ill patients 
Critical Care  2008;12(1):R29.
Introduction
Intensive insulin therapy (IIT) with tight glycemic control may reduce mortality and morbidity in critically ill patients and has been widely adopted in practice throughout the world. However, there is only one randomized controlled trial showing unequivocal benefit to this approach and that study population was dominated by post-cardiac surgery patients. We aimed to determine the association between IIT and mortality in a mixed population of critically ill patients.
Methods
We conducted a cohort study comparing three consecutive time periods before and after IIT protocol implementation in a Level 1 trauma center: period I (no protocol); period II, target glucose 80 to 130 mg/dL; and period III, target glucose 80 to 110 mg/dL. Subjects were 10,456 patients admitted to intensive care units (ICUs) between 1 March 2001 and 28 February 2005. The main study endpoints were ICU and hospital mortality, Sequential Organ Failure Assessment score, and occurrence of hypoglycemia. Multivariable regression analysis was used to evaluate mortality and organ dysfunction during periods II and III relative to period I.
Results
Insulin administration increased over time (9% period I, 25% period II, and 42% period III). Nonetheless, patients in period III had a tendency toward higher adjusted hospital mortality (odds ratio [OR] 1.15, 95% confidence interval [CI] 0.98, 1.35) than patients in period I. Excess hospital mortality in period III was present primarily in patients with an ICU length of stay of 3 days or less (OR 1.47, 95% CI 1.11, 1.93 There was an approximately fourfold increase in the incidence of hypoglycemia from periods I to III.
Conclusion
A policy of IIT in a group of ICUs from a single institution was not associated with a decrease in hospital mortality. These results, combined with the findings from several recent randomized trials, suggest that further study is needed prior to widespread implementation of IIT in critically ill patients.
doi:10.1186/cc6807
PMCID: PMC2374630  PMID: 18312617
16.  Intensive Care Unit Hypoglycemia Predicts Depression during Early Recovery from Acute Lung Injury 
Critical care medicine  2008;36(10):2726-2733.
Objective
To evaluate the association between intensive care unit (ICU) blood glucose levels and depression following acute lung injury (ALI)
Design
Prospective cohort study
Setting
Twelve ICUs in 4 hospitals in Baltimore, MD
Patients
Consecutive ALI survivors (n = 104) monitored during 1,717 ICU patient-days and screened for depression at three months after ALI
Interventions
None
Measurements and Main Results
The prevalence of a positive screening test for depression (Hospital Anxiety and Depression [HAD] depression sub-scale score ≥8) at follow-up was 28%. After adjustment for confounders, patients with a mean daily minimum ICU glucose <100 mg/dL had significant increases in mean depression score [2.1 points, 95% confidence interval (CI) 0.6 – 3.7] and in the likelihood of a positive depression screening test [relative risk (RR) 2.6, 95% CI 1.2 – 4.2]. Patients with documented hypoglycemia <60 mg/dL during their ICU stay also had greater symptoms of depression (2.0 points, 95% CI 0.5 – 3.5; RR 3.6, 95% CI 1.8 – 5.1). Other factors independently associated with a positive depression screening test included body mass index >40 kg/m2 (RR 3.3, 95% CI 1.2 – 4.2), baseline depression/anxiety (RR 3.9, 95% CI 1.5 – 6.5), and mean daily ICU benzodiazepine dose >100mg of midazolam-equivalent (RR 2.4, 95% CI 1.1 – 3.8).
Conclusions
Hypoglycemia in the ICU is associated with an increased risk of positive screening for depression during early recovery from ALI. Baseline depressive symptoms, morbid obesity, and ICU benzodiazepine dose were also associated with post-ALI depressive symptoms. These findings warrant increased glucose monitoring for ICU patients at risk for hypoglycemia and further research on how patient and ICU management factors may contribute to post-ICU depression.
doi:10.1097/CCM.0b013e31818781f5
PMCID: PMC2605796  PMID: 18766087
hypoglycemia; depression; intensive care units; respiratory distress syndrome; adult; critical care; blood glucose
17.  Increasing Blood Glucose Variability Heralds Hypoglycemia in the Critically Ill 
The Journal of surgical research  2011;170(2):257-264.
Background
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jss.2011.03.008
PMCID: PMC3154465  PMID: 21543086
Blood glucose variability; hypoglycemia; glycemic control; critical illness
18.  Glycemic Variability and Mortality in Critically Ill Patients: The Impact of Diabetes 
Background
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.
Methods
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%+).
Results
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%.
Conclusions
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
19.  Variability of insulin sensitivity during the first 4 days of critical illness: implications for tight glycemic control 
Background
Effective tight glycemic control (TGC) can improve outcomes in critical care patients, but it is difficult to achieve consistently. Insulin sensitivity defines the metabolic balance between insulin concentration and insulin-mediated glucose disposal. Hence, variability of insulin sensitivity can cause variable glycemia. This study quantifies and compares the daily evolution of insulin sensitivity level and variability for critical care patients receiving TGC.
Methods
This is a retrospective analysis of data from the SPRINT TGC study involving patients admitted to a mixed medical-surgical ICU between August 2005 and May 2007. Only patients who commenced TGC within 12 hours of ICU admission and spent at least 24 hours on the SPRINT protocol were included (N = 164). Model-based insulin sensitivity (SI) was identified each hour. Absolute level and hour-to-hour percent changes in SI were assessed on cohort and per-patient bases. Levels and variability of SI were compared over time on 24-hour and 6-hour timescales for the first 4 days of ICU stay.
Results
Cohort and per-patient median SI levels increased by 34% and 33% (p < 0.001) between days 1 and 2 of ICU stay. Concomitantly, cohort and per-patient SI variability decreased by 32% and 36% (p < 0.001). For 72% of the cohort, median SI on day 2 was higher than on day 1. The day 1–2 results are the only clear, statistically significant trends across both analyses. Analysis of the first 24 hours using 6-hour blocks of SI data showed that most of the improvement in insulin sensitivity level and variability seen between days 1 and 2 occurred during the first 12–18 hours of day 1.
Conclusions
Critically ill patients have significantly lower and more variable insulin sensitivity on day 1 than later in their ICU stay and particularly during the first 12 hours. This rapid improvement is likely due to the decline of counter-regulatory hormones as the acute phase of critical illness progresses. Clinically, these results suggest that while using TGC protocols with patients during their first few days of ICU stay, extra care should be afforded. Increased measurement frequency, higher target glycemic bands, conservative insulin dosing, and modulation of carbohydrate nutrition should be considered to minimize safely the outcome glycemic variability and reduce the risk of hypoglycemia.
doi:10.1186/2110-5820-2-17
PMCID: PMC3464183  PMID: 22703645
Critical care; Hyperglycemia; Insulin resistance; Mathematical model; Algorithms
20.  Hypoglycemia in Critically Ill Children 
Background
The practice of glycemic control with intravenous insulin in critically ill patients has brought clinical focus on understanding the effects of hypoglycemia, especially in children. Very little is published on the impact of hypoglycemia in this population. We aimed to review the existing literature on hypoglycemia in critically ill neonates and children.
Methods
We performed a systematic review of the literature up to August 2011 using PubMed, Ovid MEDLINE and ISI Web of Science using the search terms “hypoglycemia or hypoglyc*” and “critical care or intensive care or critical illness”. Articles were limited to “all child (0–18 years old)” and “English”.
Results
A total of 513 articles were identified and 132 were included for review. Hypoglycemia is a significant concern among pediatric and neonatal intensivists. Its definition is complicated by the use of a biochemical measure (i.e., blood glucose) for a pathophysiologic problem (i.e., neuroglycopenia). Based on associated outcomes, we suggest defining hypoglycemia as <40–45 mg/dl in neonates and <60–65 mg/dl in children. Below the suggested threshold values, hypoglycemia is associated with worse neurological outcomes, increased intensive care unit stay, and increased mortality. Disruptions in carbohydrate metabolism increase the risk of hypoglycemia incritically ill children. Prevention of hypoglycemia, especially in the setting of intravenous insulin use, will be best accomplished by the combination of accurate measuring techniques, frequent or continuous glucose monitoring, and computerized insulin titration protocols.
Conclusion
Studies on hypoglycemia in critically ill children have focused on spontaneous hypoglycemia. With the current practice of maintaining blood glucose within a narrow range with intravenous insulin, the risk factors and outcomes associated with insulin-induced hypoglycemia should be rigorously studied to prevent hypoglycemia and potentially improve outcomes of critically ill children.
PMCID: PMC3320821  PMID: 22401322
blood glucose; blood glucose meter; epidemiology; intensive care; outcome; risk factors
21.  Finding the sweet spot: Identification of optimal glucose levels in critically injured patients 
The Journal of trauma  2011;71(5):1108-1114.
Background
Conflicting data exist regarding optimal glycemic control in critically ill trauma patients. We therefore compared glucose parameters and outcomes among three different glycemic control regimens in a single trauma ICU, hypothesizing that a moderate regimen would yield optimal avoidance of hyper- and hypoglycemia with equivalent outcomes when compared to a more aggressive approach.
Methods
We retrospectively reviewed 1422 trauma patients with at least 3-day ICU stay and 5 glucose measurements from May 2001 – January 2010, spanning three non-overlapping, sequential glucose control protocols: ‘relaxed’, ‘aggressive’, and ‘moderate’. For each, we extracted mean blood glucose, hypoglycemic and hyperglycemic event frequency, and glucose variability, and investigated their association with outcomes.
Results
Mortality was associated with elevated mean glucose (135.6 vs. 126.2 mg/dL), more frequent hypoglycemic (2.67 ± 7 vs. 1.28 ± 5) and hyperglycemic (30.6 ± 28 vs. 16.0 ± 22 per 100 patient-ICU-days) events, and higher glucose variability (37.1 ± 20 vs. 29.4 ± 20; all p < 0.001). Regression identified hyperglycemic episodes (p < 0.05) as an independent predictor of mortality. The ‘moderate’ regimen had rare hyperglycemia, low glucose variability, and intermediate mean blood glucose range and frequency of hypoglycemia. Multiorgan failure and mortality did not differ between groups.
Conclusions
Hyperglycemic events (glucose > 180 mg/dL) most strongly predicted mortality. Of glucose control protocols analyzed, the ‘moderate’ protocol had fewest hyperglycemic events. As outcomes were otherwise equivalent between ‘moderate’ and ‘aggressive’ protocols, we conclude that hyperglycemia can be safely avoided using a moderate glycemic control protocol without inducing hypoglycemia.
doi:10.1097/TA.0b013e318232e35b
PMCID: PMC3217206  PMID: 22071916
Glucose; critical care
22.  Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data 
Background
Hyperglycemia is associated with increased mortality in critically ill patients. Randomized trials of intensive insulin therapy have reported inconsistent effects on mortality and increased rates of severe hypoglycemia. We conducted a meta-analysis to update the totality of evidence regarding the influence of intensive insulin therapy compared with conventional insulin therapy on mortality and severe hypoglycemia in the intensive care unit (ICU).
Methods
We conducted searches of electronic databases, abstracts from scientific conferences and bibliographies of relevant articles. We included published randomized controlled trials conducted in the ICU that directly compared intensive insulin therapy with conventional glucose management and that documented mortality. We included in our meta-analysis the data from the recent NICE-SUGAR (Normoglycemia in Intensive Care Evaluation — Survival Using Glucose Algorithm Regulation) study.
Results
We included 26 trials involving a total of 13 567 patients in our meta-analysis. Among the 26 trials that reported mortality, the pooled relative risk (RR) of death with intensive insulin therapy compared with conventional therapy was 0.93 (95% confidence interval [CI] 0.83–1.04). Among the 14 trials that reported hypoglycemia, the pooled RR with intensive insulin therapy was 6.0 (95% CI 4.5–8.0). The ICU setting was a contributing factor, with patients in surgical ICUs appearing to benefit from intensive insulin therapy (RR 0.63, 95% CI 0.44–0.91); patients in the other ICU settings did not (medical ICU: RR 1.0, 95% CI 0.78–1.28; mixed ICU: RR 0.99, 95% CI 0.86–1.12). The different targets of intensive insulin therapy (glucose level ≤ 6.1 mmol/L v. ≤ 8.3 mmol/L) did not influence either mortality or risk of hypoglycemia.
Interpretation
Intensive insulin therapy significantly increased the risk of hypoglycemia and conferred no overall mortality benefit among critically ill patients. However, this therapy may be beneficial to patients admitted to a surgical ICU.
doi:10.1503/cmaj.090206
PMCID: PMC2665940  PMID: 19318387
23.  Impaired Awareness of Hypoglycemia in a Population-Based Sample of Children and Adolescents With Type 1 Diabetes 
Diabetes Care  2009;32(10):1802-1806.
OBJECTIVE
To determine the prevalence and clinical associations of impaired awareness of hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes.
RESEARCH DESIGN AND METHODS
A validated questionnaire was administered to 656 patients with type 1 diabetes over a 6-month period to determine hypoglycemia awareness status. Case ascertainment was 79% of the clinic population. The rate of severe hypoglycemia was determined by data collected prospectively in the preceding year.
RESULTS
Impaired awareness of hypoglycemia was present in 29% of patients. Patients with impaired awareness of hypoglycemia had an earlier onset of diabetes (P < 0.001), were younger (P < 0.001), and had lower mean levels of A1C since diabetes onset (P = 0.006) and at their last visit (P = 0.001). The overall rate of severe hypoglycemia was 24.5 episodes per 100 patient-years in the preceding year. The severe hypoglycemia rate was higher in those with impaired awareness of hypoglycemia (37.1 vs. 19.3 episodes per 100 patient-years, P < 0.001). Among patients aged <6 years (n = 46), 59% of care providers reported impaired awareness of hypoglycemia, and the rate of severe hypoglycemia was significantly higher in those reporting impaired awareness (33.3 vs. 52 episodes per 100 patient-years, P = 0.02). More patients with recurrent hypoglycemia reported impaired awareness of hypoglycemia (47 vs. 28%, P = 0.03).
CONCLUSIONS
A significant proportion of children and adolescents with type 1 diabetes have impaired awareness of hypoglycemia. Screening for impaired awareness is an important component of routine diabetes care and can identify patients at increased risk of a severe hypoglycemic event.
doi:10.2337/dc09-0541
PMCID: PMC2752917  PMID: 19587370
24.  Effects of tight computerized glucose control on neurological outcome in severely brain injured patients: a multicenter sub-group analysis of the randomized-controlled open-label CGAO-REA study 
Critical Care  2014;18(5):498.
Introduction
Hyperglycemia is a marker of poor prognosis in severe brain injuries. There is currently little data regarding the effects of intensive insulin therapy (IIT) on neurological recovery.
Methods
A sub-group analysis of the randomized-controlled CGAO-REA study (NCT01002482) in surgical intensive care units (ICU) of two university hospitals. Patients with severe brain injury, with an expected ICU length of stay ≥48 hours were included. Patients were randomized between a conventional glucose management group (blood glucose target between 5.5 and 9 mmol.L−1) and an IIT group (blood glucose target between 4.4 and 6 mmol.L−1). The primary outcome was the day-90 neurological outcome evaluated with the Glasgow outcome scale.
Results
A total of 188 patients were included in this analysis. In total 98 (52%) patients were randomized in the control group and 90 (48%) in the IIT group. The mean Glasgow coma score at baseline was 7 (±4). Patients in the IIT group received more insulin (130 (68 to 251) IU versus 74 (13 to 165) IU in the control group, P = 0.01), had a significantly lower morning blood glucose level (5.9 (5.1 to 6.7) mmol.L−1 versus 6.5 (5.6 to 7.2) mmol.L−1, P <0.001) in the first 5 days after ICU admission. The IIT group experienced more episodes of hypoglycemia (P <0.0001). In the IIT group 24 (26.6%) patients had a favorable neurological outcome (good recovery or moderate disability) compared to 31 (31.6%) in the control group (P = 0.4). There were no differences in day-28 mortality. The occurrence of hypoglycemia did not influence the outcome.
Conclusions
In this sub-group analysis of a large multicenter randomized trial, IIT did not appear to alter the day-90 neurological outcome or ICU morbidity in severe brain injured patients or ICU morbidity.
doi:10.1186/s13054-014-0498-9
PMCID: PMC4174656  PMID: 25189764
25.  Glycemic variability and outcome in critically ill 
Background:
Acute hyperglycemia, hypoglycemia and glycemic variability (GV) have been found to be the three principal domains of glycemic control, which can adversely affect patient outcome. GV may be the confounding factor in tight glycemic control trials in surgical and medical patient.
Objective:
This study was conducted to establish if there was any relationship between GV and intensive care unit (ICU) mortality in the Indian context.
Study Design:
A retrospective review of a large cohort of prospectively collected database.
Setting:
Adult Medical/Surgical/Trauma/Neuro ICU of a tertiary care hospital.
Patient Population:
All patients who had four or more blood glucose measured during the ICU stay.
Outcome:
ICU mortality.
Result:
2208 patients with a total of 11,335 blood glucose values were analyzed. GV measured by the standard deviation (SD) of mean blood glucose and glycemic lability index (GLI), both were significantly (P < 0.001) associated with ICU mortality. This relationship was maintained (odds ratio (OR): 2.023, 95% confidence interval (CI): 1.483-2.758) even after excluding patients with hypoglycemia (<60 mg/dl). Patients with blood glucose values in the euglycemic range but highest SD had higher mortality (54%) compared to mortality (24%) in patients above the euglycemic range. Similarly patients with blood sugar values below the average for study cohort and high GLI, another marker of GV had higher mortality (OR: 5.62, CI: 3.865-8.198) than compared to patients in the hyperglycemic range, reflecting the importance of GV as a prognostic marker in patients with blood sugar in the euglycemic range.
Conclusion:
This study demonstrated that high glucose variability is associated with increased ICU mortality in a large heterogeneous cohort of ICU patients. This effect was particularly evident among patients in the euglycemic range.
doi:10.4103/0972-5229.132484
PMCID: PMC4047689  PMID: 24914256
Critically ill; glycemic lability index; glycemic variability; hypoglycemia; intensive care unit mortality

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