Society of Critical Care Medicine Guidelines on Glycemic Control for Critically Ill Children and Adults 2024.

RATIONALE: Maintaining glycemic control of critically ill patients may impact outcomes such as survival, infection, and neuromuscular recovery, but there is equipoise on the target blood levels, monitoring frequency, and methods. OBJECTIVES: The purpose was to update the 2012 Society of Critical Care Medicine and American College of Critical Care Medicine (ACCM) guidelines with a new systematic review of the literature and provide actionable guidance for clinicians. PANEL DESIGN: The total multiprofessional task force of 22, consisting of clinicians and patient/family advocates, and a methodologist applied the processes described in the ACCM guidelines standard operating procedure manual to develop evidence-based recommendations in alignment with the Grading of Recommendations Assessment, Development, and Evaluation Approach (GRADE) methodology. Conflict of interest policies were strictly followed in all phases of the guidelines, including panel selection and voting. METHODS: We conducted a systematic review for each Population, Intervention, Comparator, and Outcomes question related to glycemic management in critically ill children (≥ 42 wk old adjusted gestational age to 18 yr old) and adults, including triggers for initiation of insulin therapy, route of administration, monitoring frequency, role of an explicit decision support tool for protocol maintenance, and methodology for glucose testing. We identified the best available evidence, statistically summarized the evidence, and then assessed the quality of evidence using the GRADE approach. We used the evidence-to-decision framework to formulate recommendations as strong or weak or as a good practice statement. In addition, "In our practice" statements were included when the available evidence was insufficient to support a recommendation, but the panel felt that describing their practice patterns may be appropriate. Additional topics were identified for future research. RESULTS: This guideline is an update of the guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients. It is intended for adult and pediatric practitioners to reassess current practices and direct research into areas with inadequate literature. The panel issued seven statements related to glycemic control in unselected adults (two good practice statements, four conditional recommendations, one research statement) and seven statements for pediatric patients (two good practice statements, one strong recommendation, one conditional recommendation, two "In our practice" statements, and one research statement), with additional detail on specific subset populations where available. CONCLUSIONS: The guidelines panel achieved consensus for adults and children regarding a preference for an insulin infusion for the acute management of hyperglycemia with titration guided by an explicit clinical decision support tool and frequent (≤ 1 hr) monitoring intervals during glycemic instability to minimize hypoglycemia and against targeting intensive glucose levels. These recommendations are intended for consideration within the framework of the patient's existing clinical status. Further research is required to evaluate the role of individualized glycemic targets, continuous glucose monitoring systems, explicit decision support tools, and standardized glycemic control metrics.

Relative Hypoglycemia and Lower Hemoglobin A1c-Adjusted Time in Band Are Strongly Associated With Increased Mortality in Critically Ill Patients.

OBJECTIVES: To determine the associations of relative hypoglycemia and hemoglobin A1c-adjusted time in blood glucose (BG) band (HA-TIB) with mortality in critically ill patients. DESIGN: Retrospective cohort investigation. SETTING: University-affiliated adult medical-surgical ICU. PATIENTS: Three thousand six hundred fifty-five patients with at least four BG tests and hemoglobin A1c (HbA1c) level admitted between September 14, 2014, and November 30, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were stratified for HbA1c bands of <6.5%; 6.5-7.9%; greater than or equal to 8.0% with optimal affiliated glucose target ranges of 70-140, 140-180, and 180-250 mg/dL, respectively. HA-TIB, a new glycemic metric, defined the HbA1c-adjusted time in band. Relative hypoglycemia was defined as BG 70-110 mg/dL for patients with HbA1c ≥ 8.0%. Further stratification included diabetes status-no diabetes (NO-DM, n = 2,616) and preadmission treatment with or without insulin (DM-INS, n = 352; DM-No-INS, n = 687, respectively). Severity-adjusted mortality was calculated as the observed:expected mortality ratio (O:EMR), using the Acute Physiology and Chronic Health Evaluation IV prediction of mortality. Among NO-DM, mortality and O:EMR, decreased with higher TIB 70-140 mg/dL ( p < 0.0001) and were lowest with TIB 90-100%. O:EMR was lower for HA-TIB greater than or equal to 50% than less than 50% and among all DM-No-INS but for DM-INS only those with HbA1 greater than or equal to 8.0%.Among all patients with hba1c greater than or equal to 8.0% And no bg less than 70 mg/dl, mortality was 18.0% For patients with relative hypoglycemia (bg, 70-110 mg/dl) ( p < 0.0001) And was 0.0%, 12.9%, 13.0%, And 34.8% For patients with 0, 0.1-2.9, 3.0-11.9, And greater than or equal to 12.0 Hours of relative hypoglycemia ( p < 0.0001). CONCLUSIONS: These findings have considerable bearing on interpretation of previous trials of intensive insulin therapy in the critically ill. Moreover, they suggest that BG values in the 70-110 range may be deleterious for patients with HbA1c greater than or equal to 8.0% and that the appropriate target for BG should be individualized to HbA1c levels. These conclusions need to be tested in randomized trials.

Quantification of stress-induced hyperglycaemia associated with key diagnostic categories using the stress hyperglycaemia ratio.

AIM: Stress-induced hyperglycaemia (SIH) is the acute increase from preadmission glycaemia and is associated with poor outcomes. Early recognition of SIH and subsequent blood glucose (BG) management improves outcomes, but the degree of SIH provoked by distinct diagnostic categories remains unknown. Quantification of SIH is now possible using the stress hyperglycaemia ratio (SHR), which measures the proportional change from preadmission glycaemia, based on haemoglobin A1c (HbA1c ). METHODS: We identified eligible patients for eight medical (n = 892) and eight surgical (n = 347) categories. Maximum BG from the first 24 h of admission for medical, or postoperatively for surgical patients was used to calculate SHR. RESULTS: Analysis of variance indicated differing SHR and BG within both the medical (p < 0.0001 for both) and surgical cohort (p < 0.0001 for both). Diagnostic categories were associated with signature levels of SHR that varied between groups. Medically, SHR was greatest for ST-elevation myocardial infarction (1.22 ± 0.33) and sepsis (1.37 ± 0.43). Surgically, SHR was greatest for colectomy (1.62 ± 0.48) and cardiac surgeries (coronary artery graft 1.56 ± 0.43, aortic valve replacement 1.71 ± 0.33, and mitral valve replacement 1.75 ± 0.34). SHR values remained independent of HbA1c , with no difference for those with HbA1c above or below 6.5% (p > 0.11 for each). BG however was highly dependent on HbA1c , invariably elevated in those with HbA1c  ≥ 6.5% (p < 0.001 for each), and unreliably reflected SIH. CONCLUSION: The acute stress response associated with various medical and surgical categories is associated with signature levels of SIH. Those with higher expected SHR are more likely to benefit from early SIH management, especially major surgery, which induced SIH typically 40% greater than medical cohorts. SHR equally recognised the acute change in BG from baseline across the full HbA1c spectrum while BG did not and poorly reflected SIH.

The Interaction of Acute and Chronic Glycemia on the Relationship of Hyperglycemia, Hypoglycemia, and Glucose Variability to Mortality in the Critically Ill.

OBJECTIVES: To determine the relationship between preadmission glycemia, reflected by hemoglobin A1c level, glucose metrics, and mortality in critically ill patients. DESIGN: Retrospective cohort investigation. SETTING: University affiliated adult medical-surgical ICU. PATIENTS: The investigation included 5,567 critically ill patients with four or more blood glucose tests and hemoglobin A1c level admitted between October 11, 2011 and November 30, 2019. The target blood glucose level was 90-120 mg/dL for patients admitted before September 14, 2014 (n = 1,614) and 80-140 mg/dL or 110-160 mg/dL for patients with hemoglobin A1c less than 7% or greater than or equal to 7% (n = 3,953), respectively, subsequently. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were stratified by hemoglobin A1c: less than 6.5.(n = 4,406), 6.5-7.9% (n = 711), and greater than or equal to 8.0% (n = 450). Increasing hemoglobin A1c levels were associated with significant increases in mean glycemia, glucose variability, as measured by coefficient of variation, and hypoglycemia (p for trend < 0.0001, < 0.0001, and 0.0010, respectively). Among patients with hemoglobin A1c less than 6.5%, mortality increased as mean glycemia increased; however, among patients with hemoglobin A1c greater than or equal to 8.0%, the opposite relationship was observed (p for trend < 0.0001 and 0.0027, respectively). Increasing glucose variability was independently associated with increasing mortality only among patients with hemoglobin A1c less than 6.5%. Hypoglycemia was independently associated with higher mortality among patients with hemoglobin A1c less than 6.5% and 6.5-7.9% but not among those with hemoglobin A1c greater than or equal to 8.0%. Mean blood glucose 140-180 and greater than or equal to 180 mg/dL were independently associated with higher mortality among patients with hemoglobin A1c less than 6.5% (p < 0.0001 for each). Among patients with hemoglobin A1c greater than or equal to 8.0% treated in the second era, mean blood glucose greater than or equal to 180 mg/dL was independently associated with decreased risk of mortality (p = 0.0358). CONCLUSIONS: Preadmission glycemia, reflected by hemoglobin A1c obtained at the onset of ICU admission, has a significant effect on the relationship of ICU glycemia to mortality. The different responses to increasing mean glycemia support a personalized approach to glucose control practices in the ICU.

Is it time to abandon glucose control in critically ill adult patients?

PURPOSE OF REVIEW: To summarize the advances in literature that support the best current practices regarding glucose control in the critically ill. RECENT FINDINGS: There are differences between patients with and without diabetes regarding the relationship of glucose metrics during acute illness to mortality. Among patients with diabetes, an assessment of preadmission glycemia, using measurement of Hemoglobin A1c (HgbA1c) informs the choice of glucose targets. For patients without diabetes and for patients with low HgbA1c levels, increasing mean glycemia during critical illness is independently associated with increasing risk of mortality. For patients with poor preadmission glucose control the appropriate blood glucose target has not yet been established. New metrics, including stress hyperglycemia ratio and glycemic gap, have been developed to describe the relationship between acute and chronic glycemia. SUMMARY: A 'personalized' approach to glycemic control in the critically ill, with recognition of preadmission glycemia, is supported by an emerging literature and is suitable for testing in future interventional trials.

Pre-admission functional status impacts the performance of the APACHE IV model of mortality prediction in critically ill patients.

BACKGROUND: Functional status (FS) before intensive care unit (ICU) admission is associated with short-term and long-term outcomes among critically ill patients. However, measures of FS are generally not integrated into ICU-specific mortality prediction models. METHODS: This retrospective cohort study used prospectively collected data from 9638 consecutive patients admitted to a single ICU between 1 October 2005 and 30 September 2015. For each ICU admission, FS was prospectively determined and classified into three discrete categories based on performance of basic daily living activities (FS1 - fully independent; FS2 - partly dependent; FS3 - completely dependent). We prospectively calculated Acute Physiology and Chronic Health Evaluation (APACHE) IV predicted mortality percentage (APIV PM) for each admission and calculated observed-expected mortality ratios (OEMR), stratified by FS category and APIV PM. We calculated area under the receiver operator characteristic curve (AUC) for APIV PM and mortality for the entire cohort and the three FS categories. RESULTS: Patients had a median (IQR) age of 67 (52-80) years and mean (SD) APIV PM was 18.3% (24.3%). Of these, 7714 (80.0%) were classified as FS1, 1728 (17.9%) as FS2 and 196 (2.0%) as FS3. FS1 patients were younger, had less comorbid disease, and lower APIV PM compared to FS2 and FS3. The OEMR were significantly lower for FS1 (0.67) than FS2 (0.93) or FS3 (0.90) (p < 0.0001 for both comparisons). Among patients with APIV PM 0-10%, 10-25%, 25-50% and ≥50% the OEMR for FS1 were 0.33, 0.49, 0.61 and 0.86. The AUC (95% CI) for APIV PM and mortality for FS1, FS2 and FS3 were 0.924 (0.914-0.933), 0.837 (0.816-0.858) and 0.775 (0.705-0.8456), respectively (p < 0.001 for each comparison). Multivariable analysis demonstrated that FS2 (OR 2.18 (1.84-2.57) (p < 0.0001)) and FS3 (OR 1.99 (1.34-2.96) (p = 0.0006)) were independently associated with increased risk of mortality. CONCLUSIONS: Baseline FS prior to critical illness is a strong independent predictor of mortality and impacts the relationship between observed and APIV PM in those with lower illness severity. Future iterations of mortality prediction models should integrate a baseline measure of FS to improve performance.

Continuous glucose monitoring in the ICU: clinical considerations and consensus.

Glucose management in intensive care unit (ICU) patients has been a matter of debate for almost two decades. Compared to intermittent monitoring systems, continuous glucose monitoring (CGM) can offer benefit in the prevention of severe hyperglycemia and hypoglycemia by enabling insulin infusions to be adjusted more rapidly and potentially more accurately because trends in glucose concentrations can be more readily identified. Increasingly, it is apparent that a single glucose target/range may not be optimal for all patients at all times and, as with many other aspects of critical care patient management, a personalized approach to glucose control may be more appropriate. Here we consider some of the evidence supporting different glucose targets in various groups of patients, focusing on those with and without diabetes and neurological ICU patients. We also discuss some of the reasons why, despite evidence of benefit, CGM devices are still not widely employed in the ICU and propose areas of research needed to help move CGM from the research arena to routine clinical use.

SAFETY AND EFFICACY OF PERSONALIZED GLYCEMIC CONTROL IN CRITICALLY ILL PATIENTS: A 2-YEAR BEFORE AND AFTER INTERVENTIONAL TRIAL.

OBJECTIVE: To determine the safety and efficacy of a change in blood glucose (BG) control protocol from a single target to 2 targets based on diabetes mellitus (DM) status and glycated hemoglobin A1C (A1C) in a cohort of critically ill patients. METHODS: This investigation includes 1,979 patients admitted to a single intensive care unit (ICU) between September 16, 2013 and September 15, 2015. The BG target was 90 to 120 mg/dL in the PRE era and 80 to 140 mg/dL for patients without diabetes (NON) and with DM with A1C <7% and 110 to 160 mg/dL for DM with A1C ≥7% (TIGHT and LOOSE protocols) in the POST era. The primary efficacy outcome was the observed:expected (O:E) mortality ratio. RESULTS: Among NON, the mean BG was slightly lower in the POST era: 118 (106-132) versus 115 (101-120) mg/dL (P = .0003). Among DM, the mean BG was 139 (123-160) mg/dL in the PRE era versus 136 (119-149) and 159 (138-171) mg/dL for TIGHT and LOOSE in the POST era (P = .0668 and .0001, respectively). Overall, 11.0% and 11.8% of patients had at least 1 BG level <70 mg/dL in the 2 eras (P = .68). The O:E mortality ratios for NON and DM for the PRE and POST eras were 0.75 versus 0.74 (P = .51) and 0.69 versus 0.52 (P<.001) respectively, and among DM with A1C ≥7% were 0.74 versus 0.52 (P = .004). CONCLUSION: This hypothesis-generating investigation suggests the need for additional prospective interventional studies assessing the outcomes of patients randomized to personalized glucose targets. ABBREVIATIONS: APACHE = Acute Physiology and Chronic Health Evaluation A1C = glycated hemoglobin A1C BG = blood glucose CV = co-efficient of variation DM = diabetes mellitus ICU = intensive care unit LOS = length of stay NON = patients without DM O:E = observed: expected.

Sweet Spot: Glucose Control in the Intensive Care Unit.

Hyperglycemia, hypoglycemia, and glycemic variability are all independently associated with morbidity and mortality of critically ill patients. A strategy aiming at normoglycemia (so-called tight glycemic control) could improve outcomes of critically ill patients, but results from randomized controlled trials of tight glycemic control are conflicting. Strict glycemic control is associated with an increased risk of hypoglycemia, which could offset the benefit of this intervention. Notably, the risk of hypoglycemia is not necessarily removed with less tight glucose control regimens. The best targets of blood glucose control in critically ill patients, therefore, remain a matter of debate. It should be realized that blood glucose control is a complex intervention, consisting of many critical aspects that have the potential to affect its efficacy and safety. Efficacy, and in particular safety, of blood glucose control could still improve. First, glucose algorithms could overcome the lack of knowledge and skills of nursing staff when they are less experienced in safe and efficient blood glucose control. Several computerized glucose control algorithms have been developed over recent years, but they all need clinical validation. Also, the workload induced by such algorithms should be evaluated. Second, continuous blood glucose monitoring has the potential to improve safety and efficacy. Until recently, blood glucose levels were monitored manually using point-of-care devices with significant inaccuracies. Various continuous monitoring systems have been developed, but studies testing their accuracies and usefulness in an intensive care unit setting are highly needed.

Time in blood glucose range 70 to 140 mg/dl >80% is strongly associated with increased survival in non-diabetic critically ill adults.

INTRODUCTION: Hyperglycemia, hypoglycemia and increased glucose variability are independently associated with increased risk of death in critically ill adults. The relationship between time in targeted blood glucose range (TIR) and mortality is not well described and may be a factor that has confounded the results of the major interventional trials of intensive insulin therapy. METHODS: We conducted a retrospective analysis of prospectively collected data involving 3,297 patients with intensive care unit (ICU) lengths of stay (LOS) of ≥ 1.0 day who were admitted between 1 January 2009 and 31 December 2013 to a single mixed medical-surgical ICU. We investigated the relationship between TIR 70 to 140 mg/dl with mortality and compared outcomes of non-diabetics (NON) and individuals with diabetes mellitus (DM), including stratifying by TIR above (TIR-hi) and below (TIR-lo) the median value for the NON and DM groups. RESULTS: There were 85,799 blood glucose (BG) values for the NON group and 32,651 for the DM group, and we found that 75.5% and 54.8%, respectively, were between 70 and 140 (P < 0.0001). The median (interquartile range) TIR (%) values for the NON and DM groups were 80.6% (61.4% to 94.0%) and 55.0% (35.5% to 71.1%), respectively (P < 0.0001). For the NON group, mortality was 8.47% and 15.71% for TIR-hi and TIR-lo, respectively (P < 0.0001). For the DM group, mortality was 16.09% and 14.44% for TIR-hi and TIR-lo, respectively (P = NS). We observed similar relationships for the NON group when we stratified by ICU LOS or severity of illness, especially in the most severely ill patients. There was a cumulative interaction of indices of hypoglycemia, hyperglycemia or glucose variability with TIR. Multivariable analysis demonstrated, for the NON group, that TIR-hi was independently associated with increased survival (P = 0.0019). For the NON group, the observed-to-expected mortality ratios for TIR-hi and TIR-lo, based on Acute Physiology and Chronic Health Evaluation IV methodology, were 0.53 and 0.78, respectively. In contrast, among those in the DM group, there was no clear relationship between TIR 70 to 140 mg/dl and survival. CONCLUSIONS: Independently of ICU LOS and severity of illness, TIR 70 to 140 mg/dl > 80% is strongly associated with survival in critically ill patients without diabetes. These findings have implications for the design of clinical protocols for glycemic control in critically ill patients as well for the design of future interventional trials of intensive insulin therapy.

Malglycemia in the critical care setting. Part III: Temporal patterns, relative potencies, and hospital mortality.

INTRODUCTION: The relationship between critical care mortality and combined impact of malglycemia remains undefined. METHODS: We assessed the risk-adjusted relationship (n = 4790) between hospital mortality with malglycemia, defined as hypergycemia (hours Glycemic Ratio ≥ 1.1, where GR is quotient of mean ICU blood glucose (BG) and estimated average BG), absolute hypoglycemia (hours BG < 70 mg/dL) and relative hypoglycemia (excursions GR < 0.7 in those with HbA1c ≥ 8%). RESULTS: Each malglycemia was independently associated with mortality - hyperglycemia (OR 1.0020/h, 95%CI 1.0009-1.0031, p = 0.0004), absolute hypoglycemia (OR 1.0616/h, 95%CI 1.0190-1.1061, p = 0.0043), and relative hypoglycemia (OR 1.2813/excursion, 95%CI 1.0704-1.5338, p = 0.0069). Absolute (7.4%) and relative hypoglycemia (6.7%) exposure dominated the first 24 h, decreasing thereafter. While hyperglycemia had lower risk association with mortality, it was persistently present across the length-of-stay (68-76% incidence daily), making it the dominant form of malglycemia. Relative contributions in the first five days from hyperglycemia, absolute hypoglycemia and relative hypoglycemia were 60%, 21% and 19% respectively. CONCLUSIONS: Absolute and relative hypoglycemia occurred largely in the first 24 h. Relative to all hypoglycemia, the associated mortality from the seemingly less potent but consistently more prevalent hyperglycemia steadily accumulated with increasing length-of-stay. This has important implications for interpretation of study results.

Malglycemia in the critical care setting. Part II: Relative and absolute hypoglycemia.

INTRODUCTION: The relationship between critical care mortality and hypoglycemia, both relative (>30% below average preadmission glycemia) and absolute (blood glucose (BG) <70 mg/dL (<10 mmol/L)) requires further definition. METHODS: We assessed the risk-adjusted relationship between hospital mortality with relative hypoglycemia using the Glycemic Ratio (GR), and with absolute hypoglycemia using BG in a retrospective cohort investigation (n = 4790). RESULTS: Relative hypoglycemia excursions below GR 0.7 with a of 24-h non-exposure period between excursions in those with HbA1c ≥ 8% were independently associated with mortality (n = 373, OR 2.49, 95% CI 1.54-4.04, p = 0.0002) but not those with HbA1c < 8% (n = 4417, OR 0.98 95% CI 0.89-1.08, p = 0.70). Hours below GR 0.7 (1.0037, 0.9995-1.0080, 0.0846) or minimum GR (0.0896, 0.0030-2.6600, 0.1632) were not independently associated with outcome. Absolute hypoglycemia occurred across the HbA1c spectrum in a U-shaped pattern. There was no difference in mortality associated with exposure to BG < 70 mg/dL for HbA1c ≥ 6.5% vs <6.5% (29.7% vs 24.3%, p = 0.77). Hours below 70 mg/dL demonstrated strongest association with outcome, while minimum BG, and excursions below 70 mg/dL were also independently associated. CONCLUSIONS: Relative hypoglycemia represented by excursions below GR 0.7 in those with HbA1c ≥ 8% occurred commonly and was independently associated with mortality. Absolute hypoglycemia had similar association with mortality regardless of HbA1c.

Glycemic control in the critically ill - 3 domains and diabetic status means one size does not fit all!

Hyperglycemia, hypoglycemia, and increased glucose variability have each been shown to be independently associated with increased risk of mortality in the critically ill. Sechterberger and colleagues have completed a large observational cohort study that demonstrates that diabetic status modulates these relationships in clinically meaningful ways. These findings corroborate, in a strikingly consistent manner, those of another very recently published large observational study.

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

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>or=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>or=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.

Brain Glucose Sensing and the Problem of Relative Hypoglycemia.

"Relative hypoglycemia" is an often-overlooked complication of diabetes characterized by an increase in the glycemic threshold for detecting and responding to hypoglycemia. The clinical relevance of this problem is linked to growing evidence that among patients with critical illness, higher blood glucose in the intensive care unit is associated with higher mortality among patients without diabetes but lower mortality in patients with preexisting diabetes and an elevated prehospitalization HbA1c. Although additional studies are needed, the cardiovascular stress associated with hypoglycemia perception, which can occur at normal or even elevated glucose levels in patients with diabetes, offers a plausible explanation for this difference in outcomes. Little is known, however, regarding how hypoglycemia is normally detected by the brain, much less how relative hypoglycemia develops in patients with diabetes. In this article, we explore the role in hypoglycemia detection played by glucose-responsive sensory neurons supplying peripheral vascular beds and/or circumventricular organs. These observations support a model wherein relative hypoglycemia results from diabetes-associated impairment of this neuronal glucose-sensing process. By raising the glycemic threshold for hypoglycemia perception, this impairment may contribute to the increased mortality risk associated with standard glycemic management of critically ill patients with diabetes.

Malglycemia in the critical care setting. Part I: Defining hyperglycemia in the critical care setting using the glycemic ratio.

INTRODUCTION: Stress-induced hyperglycemia (SIH) is conventionally represented by Blood Glucose (BG) although recent evidence indicates the Glycemic Ratio (GR, quotient of mean BG and estimated preadmission BG) is a superior prognostic marker. We assessed the association between in-hospital mortality and SIH, using BG and GR in an adult medical-surgical ICU. METHODS: We included patients with hemoglobin A1c (HbA1c) and minimum four BGs in a retrospective cohort investigation (n = 4790). RESULTS: A critical SIH threshold of GR 1.1 was identified. Mortality increased with increasing exposure to GR ≥ 1.1 (r2 = 0.94, p = 0.0007). Duration of exposure to BG ≥ 180 mg/dL demonstrated a less robust association with mortality (r2 = 0.75, p = 0.059). In risk-adjusted analyses, hours GR ≥ 1.1 (OR 1.0014, 95%CI (1.0003-1.0026), p = 0.0161) and hours BG ≥ 180 mg/dL (OR 1.0080, 95%CI (1.0034-1.0126), p = 0.0006) were associated with mortality. In the cohort with no exposure to hypoglycemia however, only hours GR ≥ 1.1 was associated with mortality (OR 1.0027, 95%CI (1.0012-1.0043), p = 0.0007), not BG ≥ 180 mg/dL (OR 1.0031, 95%CI (0.9949-1.0114), p = 0.50) and this relationship remained intact for those who never experienced BG outside the 70-180 mg/dL range (n = 2494). CONCLUSIONS: Clinically significant SIH commenced above GR 1.1. Mortality was associated with hours of exposure to GR ≥ 1.1 which was a superior marker of SIH compared to BG.

The impact of premorbid diabetic status on the relationship between the three domains of glycemic control and mortality in critically ill patients.

PURPOSE OF REVIEW: Hyperglycemia, hypoglycemia and increased glycemic variability are independently associated with increased risk of mortality in critically ill patients. The purpose of this review is to evaluate the evidence from interventional trials of intensive insulin therapy, as well as observational cohort studies, relating premorbid diabetic status and these three domains of glycemic control to mortality. RECENT FINDINGS: Hyperglycemia has a stronger association with mortality in critically ill patients without diabetes than in those with diabetes. Hypoglycemia is independently associated with increased risk of mortality in both populations. Limited data suggest that increased glycemic variability may have a stronger association with mortality in patients without diabetes than in those with diabetes. SUMMARY: Premorbid diabetic status impacts the relationship of the three domains of glycemic control to risk of mortality in critically ill patients. The data presented in this review are hypothesis generating; future trials of IIT in the critically ill should stratify management and outcomes by premorbid diabetic status.