James S. Krinsley

Effect of an Intensive Glucose Management Protocol on the Mortality of Critically Ill Adult Patients

OBJECTIVE To assess the effect of an intensive glucose management protocol in a heterogeneous population of critically ill adult patients. PATIENTS AND METHODS This study consisted of 800 consecutive patients admitted after institution of the protocol (treatment group, between February 1, 2003, and January 10, 2004) and 800 patients admitted immediately preceding institution of the protocol (baseline group, between February 23, 2002, and January 31, 2003). The setting was a 14-bed medical-surgical intensive care unit (ICU) in a university-affiliated community teaching hospital. The protocol involved intensive monitoring and treatment to maintain plasma glucose values lower than 140 mg/dL. Continuous intravenous insulin was used if glucose values exceeded 200 mg/dL on 2 successive occasions. RESULTS The 2 groups of patients were well matched, with similar age, sex, race, prevalence of diabetes mellitus, Acute Physiology and Chronic Health Evaluation II scores, and distribution of diagnoses. After institution of the protocol, the mean glucose value decreased from 152.3 to 130.7 mg/dL (P<.001), marked by a 56.3% reduction in the percentage of glucose values of 200 mg/dL or higher, without a significant change in hypoglycemia. The development of new renal insufficiency decreased 75% (P=-.03), and the number of patients undergoing transfusion of packed red blood cells decreased 18.7% (P=.04). Hospital mortality decreased 29.3% (P=.002), and length of stay in the ICU decreased 10.8% (P=.01). CONCLUSION The protocol resulted in significantly improved glycemic control and was associated with decreased mortality, organ dysfunction, and length of stay in the ICU in a heterogeneous population of critically ill adult patients. These results support the adoption of this low-cost intervention as a standard of care for critically ill patients.

Association Between Hyperglycemia and Increased Hospital Mortality in a Heterogeneous Population of Critically Ill Patients

OBJECTIVE To investigate the relationship between hyperglycemia and hospital mortality in a heterogeneous group of critically ill patients. PATIENTS AND METHODS Retrospective data were reviewed for 1826 consecutive patients whose glucose values were obtained during their intensive care unit stay at The Stamford Hospital in Stamford, Conn, between October 1, 1999, and April 4, 2002. RESULTS Mean and maximum glucose values were significantly higher among nonsurvivors than among survivors for the entire group (P < .001) and for each subgroup except for patients with septic shock. The lowest hospital mortality, 9.6%, occurred among patients with mean glucose values between 80 and 99 mg/dL. Hospital mortality increased progressively as glucose values increased, reaching 42.5% among patients with mean glucose values exceeding 300 mg/dL. Within each of 3 groupings of Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (0-14; 15-24; > or = 25), mean and maximum glucose values were higher among nonsurvivors than among survivors. CONCLUSION Even a modest degree of hyperglycemia occurring after intensive care unit admission was associated with a substantial increase in hospital mortality in patients with a wide range of medical and surgical diagnoses. Analysis of glucose values added predictive power above that achieved by APACHE II scores alone. These results have important implications for the glycemic management of critically ill patients.

Severe hypoglycemia in critically ill patients: risk factors and outcomes.

Objective:To determine the risk factors for development of severe hypoglycemia (defined as glucose <40 mg/dL) in critically ill patients and define the outcomes of this complication. Design:Retrospective database review, including a case-control analysis that matched each patient with severe hypoglycemia with three controls. Setting:Adult intensive care unit of a university-affiliated community hospital. Patients:A total of 102 patients with at least one episode of severe hypoglycemia extracted from a series of 5,365 medical, surgical, and cardiac patients admitted consecutively between October 1, 1999, and June 15, 2006. Interventions:A program of intensive glycemic monitoring and management, or tight glycemic control, was implemented on February 1, 2003; 2,666 patients were treated before and 2,699 after this date. Measurements and Main Results:Multivariable logistic regression analysis identified diabetes, septic shock, renal insufficiency, mechanical ventilation, severity of illness, reflected by Acute Physiology and Chronic Health Evaluation II score with the age component deleted, and treatment in the tight glycemic control period as independent risk factors for the development of severe hypoglycemia. Mortality was 55.9% among the 102 patients with severe hypoglycemia and 39.5% among the 306 controls (p = .0057). Multivariable logistic regression analysis identified severe hypoglycemia as an independent predictor of mortality for the entire cohort (odds ratio, 2.28; 95% confidence interval, 1.41–3.70; p = .0008). Among patients with severe hypoglycemia, only modified Acute Physiology and Chronic Health Evaluation II score and mechanical ventilation were identified as independent predictors of mortality. A sensitivity analysis was constructed that suggested that quadrupling the rate of severe hypoglycemia and doubling the mortality attributable to severe hypoglycemia would negate the survival benefit of tight glycemic control in this series. Conclusions:Case-control methodology and multivariable logistic regression analysis concurred that even a single episode of severe hypoglycemia was independently associated with increased risk of mortality. Safe implementation of tight glycemic control requires appropriate monitoring to reduce the risk of this complication.

Glycemic variability: A strong independent predictor of mortality in critically ill patients*

Objectives:To determine the effect of glycemic variability, assessed by the standard deviation of each patient’s mean glucose level, on mortality in a population of critically ill adult patients. Design:Retrospective review of a large cohort of prospectively evaluated patients. Setting:Fourteen-bed medical surgical adult intensive care unit of a university affiliated community hospital. Patients:Three thousand two hundred fifty-two patients consecutively admitted between October 1999 and October 2007 with at least three venous glucose samples. Interventions:None. Measurements and Main Results:The mean (sd) Acute Physiology and Chronic Health Evaluation II score of the 3252 patients was 20.0 (8.9) and their mortality was 24.4%, ranging from 18.1% among patients with mean glucose level 70 mg/dL to 99 mg/dL to 35.9% among patients with mean glucose level 180+ mg/dL. The relationship between glycemic variability and mortality was strongest in the euglycemic range. For the 410 patients with mean glucose level 70 mg/dL to 99 mg/dL, mortality ranged from 5.9% in the first quartile of glycemic variability to 30.1% in the fourth; for the 1031 patients with mean glucose level 100 mg/dL to 119 mg/dL the corresponding range was 9.7% to 31.0%. Mortality among patients in the entire cohort with the lowest quartile of glycemic variability was 12.1%, increasing to 19.9%, 27.7%, and 37.8% in the second, third, and fourth quartiles. Intensive care unit length of stay was shorter among patients in the first quartile compared with those in the other three (p < .001). Conclusions:This study demonstrates that increasing glycemic variability conferred a strong independent risk of mortality in this heterogeneous population of critically ill patients. Previously published interventional studies of glycemic control may be reinterpreted using the metric of glycemic variability. Measures to ensure a low degree of glycemic variability may improve outcomes in intensive care unit’s implementing glycemic control. Finally, ongoing and future investigations should consider including this new metric in their study design.

Guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients.

Objective:To evaluate the literature and identify important aspects of insulin therapy that facilitate safe and effective infusion therapy for a defined glycemic end point. Methods:Where available, the literature was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology to assess the impact of insulin infusions on outcome for general intensive care unit patients and those in specific subsets of neurologic injury, traumatic injury, and cardiovascular surgery. Elements that contribute to safe and effective insulin infusion therapy were determined through literature review and expert opinion. The majority of the literature supporting the use of insulin infusion therapy for critically ill patients lacks adequate strength to support more than weak recommendations, termed suggestions, such that the difference between desirable and undesirable effect of a given intervention is not always clear. Recommendations:The article is focused on a suggested glycemic control end point such that a blood glucose ≥150 mg/dL triggers interventions to maintain blood glucose below that level and absolutely <180 mg/dL. There is a slight reduction in mortality with this treatment end point for general intensive care unit patients and reductions in morbidity for perioperative patients, postoperative cardiac surgery patients, post-traumatic injury patients, and neurologic injury patients. We suggest that the insulin regimen and monitoring system be designed to avoid and detect hypoglycemia (blood glucose ⩽70 mg/dL) and to minimize glycemic variability.Important processes of care for insulin therapy include use of a reliable insulin infusion protocol, frequent blood glucose monitoring, and avoidance of finger-stick glucose testing through the use of arterial or venous glucose samples. The essential components of an insulin infusion system include use of a validated insulin titration program, availability of appropriate staffing resources, accurate monitoring technology, and standardized approaches to infusion preparation, provision of consistent carbohydrate calories and nutritional support, and dextrose replacement for hypoglycemia prevention and treatment. Quality improvement of glycemic management programs should include analysis of hypoglycemia rates, run charts of glucose values <150 and 180 mg/dL. The literature is inadequate to support recommendations regarding glycemic control in pediatric patients. Conclusions:While the benefits of tight glycemic control have not been definitive, there are patients who will receive insulin infusion therapy, and the suggestions in this article provide the structure for safe and effective use of this therapy.

Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study.

IntroductionHyperglycemia, hypoglycemia, and increased glycemic variability have each beenindependently associated with increased risk of mortality in critically illpatients. The role of diabetic status on modulating the relation of these threedomains of glycemic control with mortality remains uncertain. The purpose of thisinvestigation was to determine how diabetic status affects the relation ofhyperglycemia, hypoglycemia, and increased glycemic variability with the risk ofmortality in critically ill patients.MethodsThis is a retrospective analysis of prospectively collected data involving 44,964patients admitted to 23 intensive care units (ICUs) from nine countries, betweenFebruary 2001 and May 2012. We analyzed mean blood glucose concentration (BG),coefficient of variation (CV), and minimal BG and created multivariable models toanalyze their independent association with mortality. Patients were stratifiedaccording to the diagnosis of diabetes.ResultsAmong patients without diabetes, mean BG bands between 80 and 140 mg/dl wereindependently associated with decreased risk of mortality, and mean BG bands> 140 mg/dl, with increased risk of mortality. Among patients withdiabetes, mean BG from 80 to 110 mg/dl was associated with increased risk ofmortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. Aneffect of center was noted on the relation between mean BG and mortality.Hypoglycemia, defined as minimum BG <70 mg/dl, was independently associatedwith increased risk of mortality among patients with and without diabetes andincreased glycemic variability, defined as CV > 20%, was independentlyassociated with increased risk of mortality only among patients without diabetes.Derangements of more than one domain of glycemic control had a cumulativeassociation with mortality, especially for patients without diabetes.ConclusionsAlthough hyperglycemia, hypoglycemia, and increased glycemic variability is eachindependently associated with mortality in critically ill patients, diabeticstatus modulates these relations in clinically important ways. Our findingssuggest that patients with diabetes may benefit from higher glucose target rangesthan will those without diabetes. Additionally, hypoglycemia is independentlyassociated with increased risk of mortality regardless of the patients diabeticstatus, and increased glycemic variability is independently associated withincreased risk of mortality among patients without diabetes.See related commentary by Krinsley,http://ccforum.com/content/17/2/131See related commentary by Finfer and Billot,http://ccforum.com/content/17/2/134

Clinical review: Consensus recommendations on measurement of blood glucose and reporting glycemic control in critically ill adults

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, http://ccforum.com/content/17/3/155

Glycemic Variability and Mortality in Critically 111 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.

Mild hypoglycemia is independently associated with increased mortality in the critically ill

IntroductionSevere 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.MethodsProspectively 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.ResultsWe 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.ConclusionsMild 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

Moving beyond tight glucose control to safe effective glucose control

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.