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.

Acute and Chronic Glucose Control in Critically Ill Patients With Diabetes: The Impact of Prior Insulin Treatment.

BACKGROUND: Emerging data highlight the interactions of preadmission glycemia, reflected by admission HbA1c levels, glycemic control during critical illness, and mortality. The association of preadmission insulin treatment with outcomes is unknown. METHODS: This observational cohort study includes 5245 patients admitted to the medical-surgical intensive care unit of a university-affiliated teaching hospital. Three groups were analyzed: patients with diabetes with prior insulin treatment (DM-INS, n = 538); patients with diabetes with no prior insulin treatment (DM-No-INS, n = 986); no history of diabetes (NO-DM, n = 3721). Groups were stratified by HbA1c level: <6.5%; 6.5%-7.9% and >8.0%. RESULTS: Among the three strata of HbA1c, mean blood glucose (BG), coefficient of variation (CV), and hypoglycemia increased with increasing HbA1c, and were higher for DM-INS than for DM-No-INS. Among patients with HbA1c < 6.5%, mean BG ≥ 180 mg/dL and CV > 30% were associated with lower severity-adjusted mortality in DM-INS compared to patients with mean BG 80-140 mg/dL and CV < 15%, (P = .0058 and < .0001, respectively), but higher severity-adjusted mortality among DM-No-INS (P = .0001 and < .0001, respectively) and NON-DM (P < .0001 and < .0001, respectively). Among patients with HbA1c ≥ 8.0%, mean BG ≥ 180 mg/dL was associated with lower severity-adjusted mortality for both DM-INS and DM-No-INS than was mean BG 80-140 mg/dL (p < 0.0001 for both comparisons). CONCLUSIONS: Significant differences in mortality were found among patients with diabetes based on insulin treatment and HbA1c at home and post-admission glycemic control. Prospective studies need to confirm an individualized approach to glycemic control in the critically ill.

The complexity of the calretinin-expressing progenitors in the human cerebral cortex.

The complex structure and function of the cerebral cortex critically depend on the balance of excitation and inhibition provided by the pyramidal projection neurons and GABAergic interneurons, respectively. The calretinin-expressing (CalR(+)) cell is a subtype of GABAergic cortical interneurons that is more prevalent in humans than in rodents. In rodents, CalR(+) interneurons originate in the caudal ganglionic eminence (CGE) from Gsx2(+) progenitors, but in humans it has been suggested that a subpopulation of CalR(+) cells can also be generated in the cortical ventricular/subventricular zone (VZ/SVZ). The progenitors for cortically generated CalR(+) subpopulation in primates are not yet characterized. Hence, the aim of this study was to identify patterns of expression of the transcription factors (TFs) that commit cortical stem cells to the CalR fate, with a focus on Gsx2. First, we studied the expression of Gsx2 and its downstream effectors, Ascl1 and Sp8 in the cortical regions of the fetal human forebrain at midgestation. Next, we established that a subpopulation of cells expressing these TFs are proliferating in the cortical SVZ, and can be co-labeled with CalR. The presence and proliferation of Gsx2(+) cells, not only in the ventral telencephalon (GE) as previously reported, but also in the cerebral cortex suggests cortical origin of a subpopulation of CalR(+) neurons in humans. In vitro treatment of human cortical progenitors with Sonic hedgehog (Shh), an important morphogen in the specification of interneurons, decreased levels of Ascl1 and Sp8 proteins, but did not affect Gsx2 levels. Taken together, our ex-vivo and in vitro results on human fetal brain suggest complex endogenous and exogenous regulation of TFs implied in the specification of different subtypes of CalR(+) cortical interneurons.