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.

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.

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 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 Glycemic Ratio Is Strongly and Independently Associated With Mortality in the Critically Ill.

BACKGROUND: Interventional studies investigating blood glucose (BG) management in intensive care units (ICU) have been inconclusive. New insights are needed. We assessed the ability of a new metric, the Glycemic Ratio (GR), to determine the relationship of ICU glucose control relative to preadmission glycemia and mortality. METHODS: Retrospective cohort investigation (n = 4790) in an adult medical-surgical ICU included patients with minimum four BGs, hemoglobin (Hgb), and hemoglobin A1c (HbA1c). The GR is the quotient of mean ICU BGs (mBG) and estimated preadmission BG, derived from HbA1c. RESULTS: Mortality displayed a J-shaped curve with GR (nadir GR 0.9), independent of background glycemia, consistent for HbA1c <6.5% vs >6.5%, and Hgb >10 g/dL vs <10 g/dL and medical versus surgical. An optimal range of GR 0.80 to 0.99 was associated with decreased mortality compared with GR above and below this range. The mBG displayed a linear relationship with mortality at lower HbA1c but diminished for HbA1c >6.5%, and dependent on preadmission glycemia. In adjusted analysis, GR remained associated with mortality (odds ratio = 2.61, 95% confidence interval = 1.48-4.62, P = .0012), but mBG did not (1.004, 1.000-1.009, .059). A single value on admission was not independently associated with mortality. CONCLUSIONS: The GR provided new insight into malglycemia that was not apparent using mBG, or an admission value. Mortality was associated with acute change from preadmission glycemia (GR). Further assessment of the impact of GR deviations from the nadir in mortality at GR 0.80 to 0.99, as both relative hypo- and hyperglycemia, and as duration of exposure and intensity, may further define the multifaceted nature of malglycemia.