Severe dawn phenomenon predicts long-term risk of all-cause mortality in patients with type 2 diabetes.

AIMS: The dawn phenomenon (DP) is an abnormal early morning blood glucose rise without nocturnal hypoglycaemia, which can be more easily and precisely assessed with continuous glucose monitoring (CGM). This prospective study aimed to explore the association between DP and the risk of all-cause mortality in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 5542 adult inpatients with type 2 diabetes in a single centre were analysed. The magnitude of DP (ΔG) was defined as the increment in the CGM-determined glucose value from nocturnal nadir (after 24:00) to prebreakfast. Participants were stratified into four groups by ΔG: ≤1.11, 1.12-3.33, 3.34-5.55, and >5.55 mmol/L. Cox proportional hazard regression models were used to evaluate the impact of DP on all-cause mortality risk. RESULTS: During a median follow-up of 9.4 years, 1083 deaths were identified. The restricted cubic spline revealed a nonlinear (p for nonlinearity = 0.002) relationship between ΔG and the risk of all-cause mortality. A multivariate-adjusted Cox regression model including glycated haemoglobin A1c (HbA1c) showed that ΔG > 5.55 mmol/L was associated with 30% (95% CI, 1.01-1.66) higher risk of all-cause mortality, as compared with ΔG 1.12-3.33 mmol/L. CONCLUSIONS: Higher ΔG is significantly related to an increased risk of all-cause mortality in type 2 diabetes, suggesting that severe DP should be given more attention as a part of glucose management to reduce the risk of long-term adverse outcomes.

Incidence and predictors of mortality among neonates referred to comprehensive and specialized hospitals in Amhara regional state, North Ethiopia: a prospective follow-up study.

BACKGROUND: Neonatal mortality is a major global public health problem. Ethiopia is among seven countries that comprise 50 % of global neonatal mortality. Evidence on neonatal mortality in referred neonates is essential for intervention however, there is no enough information in the study area. Neonates who required referral frequently became unstable and were at a high risk of death. Therefore, this study aimed to assess the incidence and predictors of mortality among referred neonates. METHOD: A prospective follow-up study was conducted among 436 referred neonates at comprehensive specialized hospitals in the Amhara regional state, North Ethiopia 2020. All neonates admitted to the selected hospitals that fulfilled the inclusion criteria were included. Face-to-face interviews, observations, and document reviews were used to collect data using a semi-structured questionnaire and checklists. Epi-data™ version 4.2 software for data entry and STATA™ 14 version for data cleaning and analysis were used. Variables with a p-value < 0.25 in the bi-variable logistic regression model were selected for multivariable analysis. Multivariable analyses with a 95% confidence level were performed. Variables with P < 0.05 were considered statistically significant. RESULT: Over all incidence of death in this study was 30.6% with 95% confidence interval of (26.34-35.16) per 2 months observation. About 23 (17.83%) deaths were due to sepsis, 32 (24.80%) premature, 40 (31%) perinatal asphyxia, 3(2.33%) congenital malformation and 31(24.03%) deaths were due to other causes. Home delivery [AOR = 2.5, 95% CI (1.63-4.1)], admission weight < 1500 g [AOR =3.2, 95% CI (1.68-6.09)], travel distance ≥120 min [AOR = 3.8, 95% CI (1.65-9.14)], hypothermia [AOR = 2.7, 95% CI (1.44-5.13)], hypoglycemia [AOR = 1.8, 95% CI (1.11-3.00)], oxygen saturation < 90% [AOR = 1.9, 95% (1.34-3.53)] at admission time and neonate age ≤ 1 day at admission [AOR = 3.4, 95% CI (1.23-9.84) were predictors of neonatal death. CONCLUSION: The incidence of death was high in this study. The acute complications arising during the transfer of referral neonates lead to an increased risk of deterioration of the newborn's health and outcome. Preventing and managing complications during the transportation process is recommended to increase the survival of neonates.

The paradox of the glycemic gap: Does relative hypoglycemia exist in critically ill patients?

BACKGROUND & AIMS: Elevated glycemic gap, as the differences between measured glucose and hemoglobin A1c (HbA1c)-derived average glucose (ADAG) levels, is a marker of stress-induced hyperglycemia and is a predictor of mortality in critically ill patients. Whether low glycemic gaps are associated with outcomes in critically ill patients remains unclear. We investigated the association of different glycemic gaps on mortality in critically ill patients. METHODS: Totally 935 patients admitted to intensive care units (ICUs) were enrolled retrospectively after the exclusion of patients with absolute hypoglycemia, extreme hyperglycemia, and incomplete glycemic records. Patients were divided into 3 groups according to their glycemic gaps (<-29.7, -29.7-40, ≧40 mg/dL) at the time of ICU admission. The patients were followed for 1 year or until death. RESULTS: Patients with low glycemic gap (glycemic gap < -29.7 mg/dL), which implied relative hypoglycemia, had lower serum glucose levels, higher HbA1c levels, and greater disease severity. Compared with medium group (glycemic gap -29.7-40 mg/dL), both the low and the high glycemic gap (glycemic gap ≧40 mg/dL) groups had significantly greater 30-day (log-rank p = 0.0464) and 1-year mortality (log-rank p = 0.0016). However, only the low glycemic gap group was independently associated with greater in-hospital mortality after adjusting for comorbidities (adjusted OR 1.78, 95% CI 1.00-3.16, p = 0.048). CONCLUSION: This study revealed the presence of a U-shaped relationship between the glycemic gap and mortality in critically ill patients. Low glycemic gaps suggested relative hypoglycemia at the time of ICU admission, and were associated independently with greater in-hospital mortality.

Effect of glycemic gap upon mortality in critically ill patients with diabetes.

AIMS/INTRODUCTION: Hyperglycemia, hypoglycemia, and blood glucose fluctuation are associated with the outcome in critically ill patients, but the target of blood glucose control is debatable especially in patients with diabetes regarding the status of blood glucose control before admission to ICU. This study aimed to investigate the association between the glycemic gap which is calculated as the mean blood glucose level during the first 7 days after admission to ICU minus the A1C-derived average glucose and the outcome of critically ill patients with diabetes. METHOD: This study was undertaken in two intensive care units (ICUs) with a total of 30 beds. Patients with diabetes who were expected to stay for more than 24 h were enrolled, the HbA1c was tested within 3 days after admission and converted to the A1C-derived average glucose (ADAG) by the equation: ADAG = [(HbA1c * 28.7) - 46.7 ] * 18-1 , arterial blood glucose measurements were four per day routinely during the first 7 days after admission, the APACHE II score within the first 24 h, the mean blood glucose level (MGL), standard deviation (SD), and coefficient of variation (CV) during the first 7 days were calculated for each person, the GAPadm and GAPmean were calculated as the admission blood glucose and MGL minus the ADAG, respectively, the incidence of moderate hypoglycemia (MH) and severe hypoglycemia (SH), the total dosage of glucocorticoids and average daily dosage of insulin within 7 days, the duration of renal replacement therapy (RRT), ventilator-free hours, and non-ICU stay days within 28 days were also collected. The enrolled patients were divided into a survival group and a nonsurvival group according to survival or not at 28 days and 1 year after admission, and the relationship between parameters derived from blood glucose and mortality in the enrolled critically ill patients was explored. RESULTS: Five hundred and two patients were enrolled and divided into a survival group (n = 310) and a nonsurvival group (n = 192). It was shown that the two groups had a comparable level of HbA1c, the nonsurvivors had a greater APACHE II, MGL, SD, CV, GAPadm , GAPmean , and a higher incidence of hypoglycemia. A lesser duration of ventilator-free, non-ICU stay, and a longer duration of RRT were recorded in the nonsurvival group, who received a lower carbohydrate intake, a higher daily dosage of insulin and glucocorticoid. GAPmean had the greatest predictive power with an AUC of 0.820 (95%CI: 0.781-0.850), the cut-off value was 3.60 mmol/L (sensitivity 78.2% and specificity 77.3%). Patients with a low GAPmean tended to survive longer than the high GAPmean group 1 year after admission. CONCLUSIONS: Glycemic GAP between the mean level of blood glucose within the first 7 days after admission to ICU and the A1C-derived average glucose was independently associated with a 28 day mortality of critically ill patients with diabetes, the predictive power extended to 1 year. The incidence of hypoglycemia was associated with mortality either.

Improvement of glycemic control in type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials.

AIM: Different guidelines provide similar, but not identical, therapeutic targets for HbA1c in type 2 diabetes. These targets can also depend from the different pharmacological strategies adopted for intensifying glycemic control. DATA SYNTHESIS: This meta-analysis includes randomized trials adopting any pharmacological regimen for intensifying glycemic control in T2DM (versus standard of care/placebo), with a trial duration ≥2 years and a between-group HbA1c difference≥0.5%. The primary outcome was to assess the effects of the improvement of glycemic control on major cardiovascular events (MACE), ocular and renal complications, and severe hypoglycemia. Mantel-Haenszel odds ratios (MH-OR) with 95% Confidence Intervals were calculated for all the outcomes considered. We included 13 trials fulfilling the inclusion criteria. The improvement of glycemic control was associated with a lower risk of MACE (MH-OR:0.89 [95%CI 0.85-0.94]) and renal adverse events (MH-OR 0.73 [0.65-0.82]), but not all-cause mortality (MH-OR 0.95 [0.88-1.01]) and ocular adverse complications (MH-OR 0.94 [0.72-1.22]). For glucose-lowering drugs inducing hypoglycemia, a protective effect on the risk of microvascular complications, but not of MACE and all-cause mortality, was observed only for HbA1c ≤ 48 mmol/mol, but with higher risk of severe hypoglycaemia (MH-OR 2.72 [1.79-4.13]). Drugs not inducing hypoglycaemia were associated with a reduction of MACE, renal adverse events, and all-cause mortality, for HbA1c< 7% (no data for lower targets). CONCLUSIONS: The present meta-analysis show that the improvement of glycemic control with drugs not inducing hypoglycemia is associated with a reduction in the risk of long-term chronic vascular and renal complications, and all-cause mortality.

(Ultra-)long-acting insulin analogues for people with type 1 diabetes mellitus.

BACKGROUND: People with type 1 diabetes mellitus (T1DM) need treatment with insulin for survival. Whether any particular type of (ultra-)long-acting insulin provides benefit especially regarding risk of diabetes complications and hypoglycaemia is unknown. OBJECTIVES: To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues to NPH insulin (neutral protamine Hagedorn) or another (ultra-)long-acting insulin analogue in people with type 1 diabetes mellitus. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Scopus, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform and the reference lists of systematic reviews, articles and health technology assessment reports. We explored the US Food and Drug Administration (FDA) and European Medical Agency (EMA) web pages. We asked pharmaceutical companies, EMA and investigators for additional data and clinical study reports (CSRs). The date of the last search of all databases was 24 August 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 24 weeks or more comparing one (ultra-)long-acting insulin to NPH insulin or another (ultra-)long-acting insulin in people with T1DM. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias using the new Cochrane 'Risk of bias' 2 (RoB 2) tool and extracted data. Our main outcomes were all-cause mortality, health-related quality of life (QoL), severe hypoglycaemia, non-fatal myocardial infarction/stroke (NFMI/NFS), severe nocturnal hypoglycaemia, serious adverse events (SAEs) and glycosylated haemoglobin A1c (HbA1c). We used a random-effects model to perform meta-analyses and calculated risk ratios (RRs) and odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) and 95% prediction intervals for effect estimates. We evaluated the certainty of the evidence applying the GRADE instrument. MAIN RESULTS: We included 26 RCTs. Two studies were unpublished. We obtained CSRs, clinical study synopses or both as well as medical reviews from regulatory agencies on 23 studies which contributed to better analysis of risk of bias and improved data extraction. A total of 8784 participants were randomised: 2428 participants were allocated to NPH insulin, 2889 participants to insulin detemir, 2095 participants to insulin glargine and 1372 participants to insulin degludec. Eight studies contributing 21% of all participants comprised children. The duration of the intervention varied from 24 weeks to 104 weeks. Insulin degludec versus NPH insulin: we identified no studies comparing insulin degludec with NPH insulin. Insulin detemir versus NPH insulin (9 RCTs): five deaths reported in two studies including adults occurred in the insulin detemir group (Peto OR 4.97, 95% CI 0.79 to 31.38; 9 studies, 3334 participants; moderate-certainty evidence). Three studies with 870 participants reported QoL showing no true beneficial or harmful effect for either intervention (low-certainty evidence). There was a reduction in severe hypoglycaemia in favour of insulin detemir: 171/2019 participants (8.5%) in the insulin detemir group compared with 138/1200 participants (11.5%) in the NPH insulin group experienced severe hypoglycaemia (RR 0.69, 95% CI 0.52 to 0.92; 8 studies, 3219 participants; moderate-certainty evidence). The 95% prediction interval ranged between 0.34 and 1.39. Only 1/331 participants in the insulin detemir group compared with 0/164 participants in the NPH insulin group experienced a NFMI (1 study, 495 participants; low-certainty evidence). No study reported NFS. A total of 165/2094 participants (7.9%) in the insulin detemir group compared with 102/1238 participants (8.2%) in the NPH insulin group experienced SAEs (RR 0.95, 95% CI 0.75 to 1.21; 9 studies, 3332 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 70/1823 participants (3.8%) in the insulin detemir group compared with 60/1102 participants (5.4%) in the NPH insulin group (RR 0.67, 95% CI 0.39 to 1.17; 7 studies, 2925 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin detemir with NPH insulin was 0.01%, 95% CI -0.1 to 0.1; 8 studies, 3122 participants; moderate-certainty evidence. Insulin glargine versus NPH insulin (9 RCTs): one adult died in the NPH insulin group (Peto OR 0.14, 95% CI 0.00 to 6.98; 8 studies, 2175 participants; moderate-certainty evidence). Four studies with 1013 participants reported QoL showing no true beneficial effect or harmful effect for either intervention (low-certainty evidence). Severe hypoglycaemia was observed in 122/1191 participants (10.2%) in the insulin glargine group compared with 145/1159 participants (12.5%) in the NPH insulin group (RR 0.84, 95% CI 0.67 to 1.04; 9 studies, 2350 participants; moderate-certainty evidence). No participant experienced a NFMI and one participant in the NPH insulin group experienced a NFS in the single study reporting this outcome (585 participants; low-certainty evidence). A total of 109/1131 participants (9.6%) in the insulin glargine group compared with 110/1098 participants (10.0%) in the NPH insulin group experienced SAEs (RR 1.08, 95% CI 0.63 to 1.84; 8 studies, 2229 participants; moderate-certainty evidence). Severe nocturnal hypoglycaemia was observed in 69/938 participants (7.4%) in the insulin glargine group compared with 83/955 participants (8.7%) in the NPH insulin group (RR 0.83, 95% CI 0.62 to 1.12; 6 studies, 1893 participants; moderate-certainty evidence). The MD in HbA1c comparing insulin glargine with NPH insulin was 0.02%, 95% CI -0.1 to 0.1; 9 studies, 2285 participants; moderate-certainty evidence. Insulin detemir versus insulin glargine (2 RCTs),insulin degludec versus insulin detemir (2 RCTs), insulin degludec versus insulin glargine (4 RCTs): there was no evidence of a clinically relevant difference for all main outcomes comparing (ultra-)long-acting insulin analogues with each other. For all outcomes none of the comparisons indicated differences in tests of interaction for children versus adults. AUTHORS' CONCLUSIONS: Comparing insulin detemir with NPH insulin for T1DM showed lower risk of severe hypoglycaemia in favour of insulin detemir (moderate-certainty evidence). However, the 95% prediction interval indicated inconsistency in this finding. Both insulin detemir and insulin glargine compared with NPH insulin did not show benefits or harms for severe nocturnal hypoglycaemia. For all other main outcomes with overall low risk of bias and comparing insulin analogues with each other, there was no true beneficial or harmful effect for any intervention. Data on patient-important outcomes such as QoL, macrovascular and microvascular diabetic complications were sparse or missing. No clinically relevant differences were found between children and adults.

Reduction in cardiovascular mortality following severe hypoglycemia in individuals with type 2 diabetes: the role of a pragmatic and structured intervention : Structured intervention for community hypoglycemia.

BACKGROUND: Mortality in individuals with diabetes with severe hypoglycemia requiring ambulance services intervention is high and it is unclear whether this is modifiable. Our aim was to characterise this high-risk group and assess the impact of nurse-led intervention on mortality. METHODS: In this single centre study, patients with diabetes and hypoglycemia requiring ambulance call out were randomized to nurse led support (intensive arm) or managed using existing pathways (standard arm). A third group agreed to have their data collected longitudinally (observational arm). The primary outcome was all-cause mortality comparing intensive with combined standard and observational arms as well as standard arm alone. RESULTS: Of 828 individuals identified, 323 agreed to participate with 132 assigned to intensive, 130 to standard and 61 to observational arms. Mean follow up period was 42.6 ± 15.6 months. Mortality in type 1 diabetes (n = 158) was similar across study arms but in type 2 diabetes (n = 160) this was reduced to 33% in the intensive arm compared with 51% in the combined arm (p = 0.025) and 50% in the standard arm (p = 0.06). Cardiovascular deaths, the leading cause of mortality, was lower in the intensive arm compared with combined and standard study arms (p < 0.01). CONCLUSIONS: Medium-term mortality following severe hypoglycemia requiring the assistance of emergency services is high in those with type 2 diabetes. In individuals with type 2 diabetes, nurse-led individualized intervention reduces cardiovascular mortality compared with standard care. Large-scale multicentre studies are warranted to further investigate this approach. Trial registration The trial was retrospectively registered on http://www.clinicaltrials.gov with reference NCT04422145.

Hipoglicemia grave e fatores de risco em pessoas com diabetes em unidade de internação: estudo caso controle / Severe hypoglycemia in people with diabetes in an inpatient unit: a case-control study

A hipoglicemia é uma das principais complicações frente ao manejo inadequado do diabetes, com destaque para a hipoglicemia grave que configura-se como um problema relevante para a manutenção da qualidade de vida dos indivíduos. Os objetivos do presente estudo foram caracterizar os episódios de hipoglicemia grave em pacientes com diabetes em unidades de internação clínica; analisar a associação entre os fatores de risco e os episódios de hipoglicemia grave de pacientes com diabetes em unidade de internação; estimar o tempo de sobrevida até o episódio hipoglicêmico grave. A metodologia empregada para esse estudo considerou casos episódios hipoglicêmicos graves, definidos por valores glicêmicos abaixo de 50 mg/dL. Foram considerados controles os episódios hipoglicêmicos não graves definidos por valores glicêmicos entre 51 a 70mg/dl. Considerou-se como fatores associados à hipoglicemia grave variáveis propostas pela revisão integrativa de literatura realizada para a construção dessa pesquisa. Ainda, também foi analisado o diagnóstico de enfermagem risco de glicemia instável da nomenclatura NANDA-I e sua pertinência quanto aos fatores de risco associados à ocorrência de episódios de hipoglicemia grave. A coleta de dados desenvolveu-se através de análise documental retrospectiva. Foram observados 47 episódios de hipoglicemia grave e 60 episódios de hipoglicemia não grave, respectivamente caso e controle. Os fatores de risco para hipoglicemia grave com evidências na literatura e que foram validados neste estudo caso- controle foram: escolaridade; terapia insulínica; uso de insulinas associadas; modificação recente da dose; insuficiência renal; outras comorbidades; episódio hipoglicêmico anterior e habilidade deficiente para o autocuidado. Identificou-se que o tempo de sobrevida até o episódio hipoglicêmico configura-se em uma curva descendente.A média de tempo que uma pessoa sobrevive até o desfecho de hipoglicemia grave mostrou que o paciente que tem diabetes e está internado tem chances progressivamente maiores de desenvolver episódio de hipoglicemia grave logo nos primeiros dias de internação. Frente aos resultados obtidos, sugere-se que novos estudos sejam realizados com o objetivo descrever aprofundadamente os mecanismos de associação destas variáveis com o episódio hipoglicêmico grave. A identificação da magnituddos fatores de risco para hipoglicemia grave, apresentada através do estudo caso-controle, fornece bases para a construção de instrumentos padronizados de avaliação adequada de pacientes com diabetes em unidades de internação.

Hypoglycemia is one of the main complications in the face of inadequate management of diabetes, where severe hypoglycemia is a relevant problem in terms of maintaining the quality of life of individuals. The objectives of the study were to characterize episodes of severe hypoglycemia in patients with diabetes in clinical inpatient units; to analyze the association between risk factors and episodes of severe hypoglycemia in patients with diabetes in the inpatient unit; estimate the survival time until the severe hypoglycemic episode. The methodology used for this study considered cases of severe hypoglycemic episodes, defined by glycemic values below 50 mg / dL. Non-severe hypoglycemic episodes were defined as controls defined by glycemic values between 51 to 70mg / dl. Factors associated with severe hypoglycemia were considered as variables proposed by the integrative literature review carried out for the construction of this research. Still, the Nursing Diagnosis Risk of Unstable Glycemia of the NANDA-I Nomenclature and its relevance regarding the risk factors associated with the occurrence of episodes of severe hypoglycemia were also analyzed. Data collection was developed through retrospective document analysis. 47 episodes of severe hypoglycemia and 60 episodes of non-severe hypoglycemia were analyzed, case and control, respectively. The risk factors for severe hypoglycemia with evidence in the literature that were validated in this case-control study were: education; insulin therapy; use of associated insulins; recent dose modification; renal insufficiency; other comorbidities; previous hypoglycemic episode and deficient ability for self-care. It was identified that the survival time until the hypoglycemic episode is configured in a descending curve. The average time that a person survives until the outcome of severe hypoglycemia showed that the patient who has diabetes and is hospitalized has a progressively greater chance of developing an episode of severe hypoglycemia in the first days of hospitalization. In view of the results obtained, it is suggested that further studies be carried out in order to describe in depth the mechanisms of association of these variables with the severe hypoglycemic episode. The identification of the magnitude of risk factors for severhypoglycemia, presented through the case-control study, provides the basis for the construction of standardized instruments for adequate assessment of patients with diabetes in inpatient units.

La hipoglucemia es una de las principales complicaciones ante el manejo inadecuado de la diabetes, donde la hipoglucemia severa es un problema relevante en cuanto al mantenimiento de la calidad de vida de los individuos. Los objetivos del estudio fueron caracterizar episodios de hipoglucemia severa en pacientes con diabetes en unidades de internación clínica; analizar la asociación entre factores de riesgo y episodios de hipoglucemia severa en pacientes con diabetes en la unidad de internación; Estime el tiempo de supervivencia hasta el episodio de hipoglucemia grave. La metodología utilizada para este estudio consideró casos de episodios hipoglucémicos graves, definidos por valores glucémicos inferiores a 50 mg / dL. Se consideraron controles los episodios hipoglucémicos no graves definidos como valores glucémicos entre 51 y 70 mg / dl. Los factores asociados a la hipoglucemia severa fueron considerados como variables propuestas por la revisión integradora de la literatura realizada para la construcción de esta investigación. Aún así, también se analizó el Diagnóstico de Enfermería Riesgo de Glucemia Inestable de la Nomenclatura NANDA-I y su relevancia con respecto a los factores de riesgo asociados a la ocurrencia de episodios de hipoglucemia severa. La recolección de datos se desarrolló a través del análisis retrospectivo de documentos. Se analizaron 47 episodios de hipoglucemia severa y 60 episodios de hipoglucemia no severa, caso y control, respectivamente. Los factores de riesgo de hipoglucemia severa con evidencia en la literatura que fueron validados en este estudio de casos y controles fueron: educación; terapia con insulina; uso de insulinas asociadas; modificación reciente de la dosis; insuficiencia renal; otras comorbilidades; episodio hipoglucémico previo y capacidad deficiente para el autocuidado. Se identificó que el tiempo de supervivencia hasta el episodio hipoglucémico se configura en una curva descendente. El tiempo promedio que una persona sobrevive hasta el resultado de una hipoglucemia severa mostró que el paciente que tiene diabetes y está hospitalizado tiene una probabilidad progresivamente mayor de desarrollar un episodio de hipoglucemia severa en los primeros días de hospitalización. A la vista de los resultados obtenidos, se sugiere realizar más estudios con el fin de describir en profundidad los mecanismos de asociación de estas variables con el episodio de hipoglucemia grave. La identificación de la magnitud de los factores de riesgo de hipoglucemia severa, presentada a través del estudio de casos y controles, proporciona la base para la construcción de instrumentos estandarizados para la evaluación adecuada de pacientes con diabetes en unidades de internación.

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.

Effect on mortality of increasing the cutoff blood glucose concentration for initiating hypoglycaemia treatment in severely sick children aged 1 month to 5 years in Malawi (SugarFACT): a pragmatic, randomised controlled trial.

BACKGROUND: Low blood glucose concentrations are common in sick children who present to hospital in low-resource settings and are associated with increased mortality. The cutoff blood glucose concentration for the diagnosis and treatment of hypoglycaemia currently recommended by WHO (2·5 mmol/L) is not evidence-based. We aimed to assess whether increasing the cutoff blood glucose concentration for hypoglycaemia treatment in severely ill children at presentation to hospital improves mortality outcomes. METHODS: We did a pragmatic, randomised controlled trial at two referral hospitals in Malawi. Severely ill children aged 1 month to 5 years presenting to the emergency department with a capillary blood glucose concentration of between 2·5 mmol/L (3·0 mmol/L in severely malnourished children) and 5·0 mmol/L were randomly assigned (1:1) by a computer-generated randomisation sequence, stratified by study site and severe malnutrition, to receive either an immediate intravenous bolus of 10% dextrose at 5 mL/kg followed by a 24-h maintenance infusion of 10% dextrose at 100 mL/kg for the first 10 kg of bodyweight, 50 mL/kg for the next 10 kg, and 20 mL/kg for each subsequent kg of bodyweight (intervention group) or observation for a minimum of 60 min and standard care (control group). Participants and study personnel were not masked to treatment allocation. The primary outcome was all-cause in-hospital mortality, assessed on an intention-to-treat basis. Safety was also assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02989675. FINDINGS: Between Dec 5, 2016, and Jan 22, 2019, 10 947 children were screened, of whom 332 were randomly assigned, and 322 were included in the final analysis (n=162 in the control group and n=160 in the intervention group). The study was terminated after an interim analysis at 24% enrolment indicated futility. The median age of participants was 2·3 years (IQR 1·4-3·2), 65 (45%) were female, and the baseline characteristics of participants were similar between the two groups. The number of in-hospital deaths from any cause was 26 (16%) in the control group and 24 (15%) in the intervention group, with an absolute mortality difference of 1·0% (95% CI -6·9 to 9·0). Serious adverse events, including hypoglycaemia, hyperglycaemia, convulsions, reduced consciousness, and death, were reported in 47 (29%) children in the control group and 39 (24%) children in the intervention group. INTERPRETATION: Increasing the cutoff blood glucose concentration for hypoglycaemia treatment in severely sick children in Malawi from 2·5 mmol/L to 5·0 mmol/L did not reduce all-cause in-hospital mortality. Our findings do not support changing the cutoff for dextrose administration, and further research on the optimal management of severely ill children who present to the emergency department with low blood glucose concentrations is warranted. FUNDING: Swedish Research Council and Stockholm Country Council.

Impact of low fasting plasma glucose on mortality in the general population.

BACKGROUND: While the association between hypoglycaemia and poor outcomes in diabetes is well established, it is unclear whether such an association is generalizable to those without diabetes. METHODS: A total of 8497 participants free of cardiovascular disease and diabetes from the Third National Health and Nutrition Examination Survey were included. We examined the relationship between baseline low (<80 mg/dL) and high (⩾126 mg/dL) fasting plasma glucose compared to normal levels (80-99 mg/dL). RESULTS: Over a median follow-up of 14 years, 2101 deaths occurred, of which 570 were due to cardiovascular disease. In a model adjusted for sociodemographic and cardiovascular disease risk factors, individuals with low fasting plasma glucose were at increased risk of cardiovascular disease and all-cause mortality [hazard ratio = 1.79 (95% confidence interval = 1.04-3.08) and hazard ratio = 1.35 (95% confidence interval = 1.02-1.78), respectively], compared to those with normal fasting plasma glucose. These associations were stronger among men than women for both cardiovascular disease mortality and all-cause mortality. CONCLUSION: Low fasting plasma glucose in individuals without diabetes is a risk factor for cardiovascular disease and all-cause mortality, especially in men.

A performance score of the quality of inpatient diabetes care is a marker of clinical outcomes and suggests a cause-effect relationship between hypoglycaemia and the risk of in-hospital mortality.

AIMS: To build a tool to assess the management of inpatients with diabetes mellitus and to investigate its relationship, if any, with clinical outcomes. MATERIALS AND METHODS: A total of 678 patients from different settings, Internal Medicine (IMU, n = 255), General Surgery (GSU, n = 230) and Intensive Care (ICU, n = 193) Units, were enrolled. A work-flow of clinical care of diabetes was created according to guidelines. The workflow was divided into five different domains: (a) initial assessment; (b) glucose monitoring; (c) medical therapy; (d) consultancies; (e) discharge. Each domain was assessed by a performance score (PS), computed as the sum of the scores achieved in a set of indicators of clinical appropriateness, management and patient empowerment. Appropriate glucose goals were included as intermediate phenotypes. Clinical outcomes included: hypoglycaemia, survival rate and clinical conditions at discharge. RESULTS: The total PS and those of initial assessment and glucose monitoring were significantly lower in GSU with respect to IMU and ICU (P < .0001). The glucose monitoring PS was associated with lower risk of hypoglycaemia (OR = 0.55; P < .0001), whereas both the PSs of glucose monitoring and medical therapy resulted associated with higher in-hospital survival only in the IMU ward (OR = 6.67 P = .001 and OR = 2.38 P = .03, respectively). Instrumental variable analysis with the aid of PS of glucose monitoring showed that hypoglycaemia may play a causal role in in-hospital mortality (P = .04). CONCLUSIONS: The quality of in-hospital care of diabetes may affect patient outcomes, including glucose control and the risk of hypoglycaemia, and through the latter it may influence the risk of in-hospital mortality.

Reducing mortality from severe malaria in Sierra Leonean children by applying the World Health Organization's standard malarial protocol with additional sublingual glucose: A continuous quality improvement report.

OBJECTIVES: To reduce childhood mortality from severe malaria by implementing the World Health Organization's standardized malarial treatment protocol. DESIGN: Observational study comparing the mortality rate from malaria before and after the intervention. SETTING: Inpatient pediatric ward in a district referral hospital of Sierra Leone. PARTICIPANTS: A total of 1298 pediatric patients (ages 0-13 years, male and female) received the intervention, representing 100% of the pediatric patients admitted with severe malaria during the dates of implementation (there were no exclusion criteria). INTERVENTIONS: We implemented the World Health Organization's standardized malarial protocol on September 30, 2015. Based on monthly run reports of mortality and root cause analysis, we adapted the malaria protocol by adding sublingual glucose as a treatment to target hypoglycemia complications in March 2016. MAIN OUTCOME MEASURES: The primary outcome was a change in monthly percent mortality from severe malaria, and the secondary outcome was the percent of mortality attributed to hypoglycemia. RESULTS: The monthly average percent mortality from severe malaria dropped from 9% to 3.6% after the intervention, which was borderline statistically significant (p 0.06, CI 95% 1.5 to 5.6). The secondary outcome, percent of malarial deaths attributable to hypoglycemia via chart reviews, dropped from 83% to 44% across the study period. There was an increase in the average number of admissions for severe malaria from 71 to 153 children per month in the second half of the year (range from 49-212 per month). CONCLUSION: Implementing the WHO malaria treatment protocol with bedside tracking of protocol steps reduced malaria mortality and improved our ward's efficiency without adding any human or medical resources.

Risk of Major Adverse Cardiovascular Events, Severe Hypoglycemia, and All-Cause Mortality for Widely Used Antihyperglycemic Dual and Triple Therapies for Type 2 Diabetes Management: A Cohort Study of All Danish Users.

OBJECTIVE: The vast number of antihyperglycemic medications and growing amount of evidence make clinical decision making difficult. The aim of this study was to investigate the safety of antihyperglycemic dual and triple therapies for type 2 diabetes management with respect to major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in a real-life clinical setting. RESEARCH DESIGN AND METHODS: Cox regression models were constructed to analyze 20 years of data from the Danish National Patient Registry with respect to effect of the antihyperglycemic therapies on the three end points. RESULTS: A total of 66,807 people with type 2 diabetes were treated with metformin (MET) plus a combination of second- and third-line therapies. People on MET plus sulfonylurea (SU) had the highest risk of all end points, except for severe hypoglycemia, for which people on MET plus basal insulin (BASAL) had a higher risk. The lowest risk of major adverse cardiovascular events was seen for people on a regimen including a glucagon-like peptide 1 (GLP-1) receptor agonist. People treated with MET, GLP-1, and BASAL had a lower risk of all three end points than people treated with MET and BASAL, especially for severe hypoglycemia. The lowest risk of all three end points was, in general, seen for people treated with MET, sodium-glucose cotransporter 2 inhibitor, and GLP-1. CONCLUSIONS: Findings from this study do not support SU as the second-line treatment choice for patients with type 2 diabetes. Moreover, the results indicate that adding a GLP-1 in people treated with MET and BASAL could be considered, especially if those people suffer from severe hypoglycemia.

Impact of blood glucose abnormalities on outcomes and disease severity in patients with severe sepsis: An analysis from a multicenter, prospective survey of severe sepsis.

BACKGROUND: Dysglycemia is frequently observed in patients with sepsis. However, the relationship between dysglycemia and outcome is inconsistent. We evaluate the clinical characteristics, glycemic abnormalities, and the relationship between the initial glucose level and mortality in patients with sepsis. METHODS: This is a retrospective sub-analysis of a multicenter, prospective cohort study. Adult patients with severe sepsis (Sepsis-2) were divided into groups based on blood glucose categories (<70 (hypoglycemia), 70-139, 140-179, and ≥180 mg/dL), according to the admission values. In-hospital mortality and the relationship between pre-existing diabetes and septic shock were evaluated. RESULTS: Of 1158 patients, 69, 543, 233, and 313 patients were categorized as glucose levels <70, 70-139, 140-179, ≥180 mg/dL, respectively. Both the Acute Physiological and Chronic Health Evaluation II and Sequential Organ Failure Assessment (SOFA) scores on the day of enrollment were higher in the hypoglycemic patients than in those with 70-179 mg/dL. The hepatic SOFA scores were also higher in hypoglycemic patients. In-hospital mortality rates were higher in hypoglycemic patients than in those with 70-139 mg/dL (26/68, 38.2% vs 43/221, 19.5%). A significant relationship between mortality and hypoglycemia was demonstrated only in patients without known diabetes. Mortality in patients with both hypoglycemia and septic shock was 2.5-times higher than that in patients without hypoglycemia and septic shock. CONCLUSIONS: Hypoglycemia may be related to increased severity and high mortality in patients with severe sepsis. These relationships were evident only in patients without known diabetes. Patients with both hypoglycemia and septic shock had an associated increased mortality rate.

Clinico-pathological features, treatments and survival of malignant insulinomas: a multicenter study.

INTRODUCTION: Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series. AIM OF THE STUDY: To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma. MATERIALS AND METHODS: Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017. RESULTS: The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level <60 µU/mL (P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients. CONCLUSIONS: Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases.

Effect of Chronic Pancreatitis on Complications and Mortality in DM Patients: A 10-year Nationwide Cohort Study.

CONTEXT: Chronic pancreatitis (CP), is a long-term inflammation of the pancreatic parenchyma, and might increase risk of a hyperglycemia crisis or hypoglycemia in patients with diabetes mellitus (DM); however, the relationship has not been previously investigated. OBJECTIVE: To investigate the risk of diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS), hypoglycemia, and long-term outcomes in DM patients with CP. DESIGN: A population-based cohort study. SETTING AND PARTICIPANTS: Tapping Taiwan's National Health Insurance Research Database, we identified 506 DM patients with newly diagnosed CP from 1999 to 2010 and created a control cohort consisting of 5060 age- and sex-matched DM patients without CP from the same time period. We followed those 2 cohorts from the index date to occurrence of outcomes, the date of death or 31 December 2012. MAIN OUTCOME MEASURES: DKA, HHS, hypoglycemia and mortality. RESULTS: DM patients with CP, who were predominantly male (88%) and younger (60% < 45 years old), had a 9.5-, 5.0-, and 3.0-fold higher risk for DKA (95% confidence interval [CI]: 6.51-13.91), HHS (95% CI: 2.85-8.62), and hypoglycemia (95% CI: 2.23-4.08), respectively. They also had lower 1-, 5-, and 10-year cumulative survival rates (98.4% vs 99.0%, 87.7% vs 96.6%, and 78.7% vs 93.6%, respectively) (log-rank test: P < .001), and a 2.43-fold higher risk for death (HR: 2.43, 95% CI: 1.82-3.27). CONCLUSIONS: In Taiwan, DM patients with CP have a higher incidence of DKA, HHS, hypoglycemia, and mortality. More attention is needed for preventing hyperglycemia crisis and hypoglycemia prevention in this population.

Impact of Glycemic Variability and Hypoglycemia on the Mortality and Length of Hospital Stay among Elderly Patients in Brazil.

BACKGROUND: Glycemic variability (GV) is an alternative diabetes-related parameter that has been associated with mortality and longer hospitalization periods. There is no ideal method for calculating GV. In this study, we used standard deviation and coefficient of variation due to their suitability for this sample and ease of use in daily clinical practice. OBJECTIVE: This study aimed to investigate the association between GV, hypoglycemia, and the 90-day mortality and length of hospital stay (LOS) among non-critically ill hospitalized elderly patients. METHODS: The medical records of 2,237 elderly patients admitted to the Zilda Arns Elderly Hospital over a 2.5-year period were reviewed. Hypoglycemia was defined as a glucose level <70 mg/dL (hypoglycemia alert value) and represented by the proportion of days in which the patient presented with this condition relative to the LOS. The Charlson comorbidity index was used to evaluate prognosis. Data were analyzed using multiple linear and logistic multivariate regression analyses. RESULTS: Adjusted analysis of 687 patients (305 men [44.4%] and 382 women [55.6%], mean age of 77.86±9.25 years) revealed that GV was associated with a longer LOS (p=0.048). Mortality was associated with hypoglycemia (p=0.005) and mean patient-day blood glucose level (p=0.036). Variables such as age (p<0.001), Charlson score (p<0.001), enteral diet (p<0.001), and corticosteroid use (p=0.007) were also independently associated with 90-day mortality. CONCLUSION: Increased GV during hospitalization is independently associated with a longer LOS and hypoglycemia in non-critically ill elderly patients, while the mean patient-day blood glucose is associated with increased mortality.

Diabetes and Heart Failure: Is it Hyperglycemia or Hyperinsulinemia?

The cardiac effects of exogenously administered insulin for the treatment of diabetes (DM) have recently attracted much attention. In particular, it has been questioned whether insulin is the appropriate treatment for patients with type 2 diabetes mellitus and heart failure. While several old and some new studies suggested that insulin treatment has beneficial effects on the heart, recent observational studies indicate associations of insulin treatment with an increased risk of developing or worsening of pre-existing heart failure and higher mortality rates. However, there is actually little evidence that the associations of insulin administration with any adverse outcomes are causal. On the other hand, insulin clearly causes weight gain and may also cause serious episodes of hypoglycemia. Moreover, excess of insulin (hyperinsulinemia), as often seen with the use of injected insulin, seems to predispose to inflammation, hypertension, dyslipidemia, atherosclerosis, heart failure, and arrhythmias. Nevertheless, it should be stressed that most of the data concerning the effects of insulin on cardiac function derive from in vitro studies with isolated animal hearts. Therefore, the relevance of the findings of such studies for humans should be considered with caution. In the present review, we summarize the existing data about the potential positive and negative effects of insulin on the heart and attempt to answer the question whether any adverse effects of insulin or the consequences of hyperglycemia are more important and may provide a better explanation of the close association of DM with heart failure.