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.

Relative Hyperglycemia Is an Independent Determinant of In-Hospital Mortality in Patients With Critical Illness.

OBJECTIVES: To determine whether relative hyperglycemia was associated with in-hospital mortality in critically ill patients independent of other prognostic variables and whether this association is affected by background glycemia. DESIGN: Prospective observational study. SETTING: Mixed medical-surgical ICU in a metropolitan teaching hospital. PATIENTS: From 2,617 admissions to ICU between January 27, 2016, and March 30, 2017, 1,262 consecutive patients who met inclusion and exclusion criteria were studied. INTERVENTIONS: Glycosylated hemoglobin was used to estimate average glucose concentration over the prior 3 months. Glucose concentration on ICU admission was divided by estimated average glucose concentration to calculate the stress hyperglycemia ratio, an index of relative glycemia. Risk of death score was calculated using data submitted to the Australia and New Zealand Intensive Care Society. MEASUREMENTS AND MAIN RESULTS: In this study, there were 186 deaths (14.7%). Admission glucose was significantly associated with mortality in univariate analysis (odds ratio = 1.08 per mmol/L glucose increment; p < 0.001) but not after adjustment for risk of death score (odds ratio = 1.01; p = 0.338). In contrast, stress hyperglycemia ratio was significantly associated with mortality both in univariate analysis (odds ratio = 1.09 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and after adjustment for risk of death score (odds ratio = 1.03; p = 0.014). Unlike admission glucose concentration, stress hyperglycemia ratio was significantly associated with mortality in patients with glycosylated hemoglobin less than 6.5% (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p < 0.001) and glycosylated hemoglobin greater than or equal to 6.5% (48 mmol/mol) (odds ratio = 1.08 per 0.1 stress hyperglycemia ratio increment; p = 0.005). CONCLUSIONS: Unlike absolute hyperglycemia, relative hyperglycemia, as assessed by the stress hyperglycemia ratio, independently predicts in-hospital mortality in critically ill patients across the glycemic spectrum. Future studies should investigate whether using measures of relative hyperglycemia to determine individualized glycemic treatment targets improves outcomes in ICU.

Treatment of prednisolone-induced hyperglycaemia in hospitalized patients: Insights from a randomized, controlled study.

AIM: Prednisolone causes hyperglycaemia predominantly between midday and midnight. Consequently, glargine-based basal-bolus insulin regimens may under treat daytime hyperglycaemia and cause nocturnal hypoglycaemia. We investigated whether an isophane-based insulin regimen is safer and more effective than a glargine-based regimen in hospitalized patients. MATERIALS AND METHODS: Fifty inpatients prescribed ≥20 mg/day prednisolone acutely with (1) finger prick blood glucose level (BGL) ≥15 mmol/L or (2) BGLs ≥10 mmol/L within the previous 24 hours were randomized to either insulin isophane or glargine before breakfast and insulin aspart before meals. The initial daily insulin dose was 0.5 U/kg bodyweight or 130% of the current daily insulin dose. Glycaemic control was assessed using a continuous glucose monitoring system. RESULTS: On Day 1, there were no significant differences in percentage of time outside a target glucose range of 4 to 10 mmol/L (41.3% ± 5.5% vs 50.0% ± 5.7%, P = .28), mean daily glucose (10.2 ± 0.7 vs 10.8 ± 0.8 mmol/L, P = .57) or glucose <4 mmol/L (2.2% ± 1.1% vs 2.0% ± 1.3%, P = .92) in patients randomized to isophane and glargine. In patients treated for 3 days, the prednisolone dose was reduced ( P = .02) and the insulin dose was increased over time ( P = .02), but the percentage of time outside the 4 to 10 mmol/L glucose range did not differ over time ( P = .45) or between groups ( P = .24). CONCLUSIONS: There were no differences in the efficacy or safety of the isophane and glargine-based insulin regimens. We recommend an initial daily insulin dose of 0.5 units/kg bodyweight if not on insulin, a greater than 30% increase in pre-prednisolone insulin dose and larger insulin dose adjustments in patients with prednisolone-induced hyperglycaemia.

How to manage warfarin therapy.

Long-term treatment with warfarin is recommended for patients with atrial fibrillation at risk of stroke and those with recurrent venous thrombosis or prosthetic heart valves. Patient education before commencing warfarin - regarding signs and symptoms of bleeding, the impact of diet, potential drug interactions and the actions to take if a dose is missed - is pivotal to successful use. Scoring systems such as the CHADS2 score are used to determine if patients with atrial fibrillation are suitable for warfarin treatment. To rapidly achieve stable anticoagulation, use an age-adjusted protocol for starting warfarin. Regular monitoring of the anticoagulant effect is required. Evidence suggests that patients who self-monitor using point-of-care testing have better outcomes than other patients.

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.

A pilot cohort study of deprescribing for nursing home patients acutely admitted to hospital.

BACKGROUND: Patients from residential aged care facilities are commonly exposed to inappropriate polypharmacy. Unplanned inpatient admissions can provide an opportunity for review of complex medical regimens and deprescribing of inappropriate or nonbeneficial medications. The aim of this study was to assess the efficacy, safety and sustainability of in-hospital deprescribing. METHODS: We followed a prospective, multi-centre, cohort study design, with enrolment of 106 medical inpatients age 75 years and older (mean age was 88.8 years) who were exposed to polypharmacy prior to admission and with a planned discharge to a nursing home for permanent placement. Descriptive statistics were calculated for relevant variables. The Short Form-8 (SF-8) health survey was used to assess changes in health-related quality of life (HRQOL) at 90-day follow up, in comparison with SF-8 results at day 30. RESULTS: Deprescribing occurred in most, but not all patients. There were no differences between the groups in principal diagnosis, Charlson index, number of medications on admission or number of Beers list medications on admission. At 90 days, mortality and readmissions were similar, though the deprescribed group had significantly higher odds of better emotional wellbeing than the nondeprescribed group [odds ratio (OR) = 5.08, 95% confidence interval (CI): 1.93, 13.39; p = 0.001]. In the deprescribing group, 31% of the patients still alive at 90 days had medications restarted in primary care. One-year mortality rates were similar. CONCLUSIONS: Deprescribing medications during an unplanned hospital admission was not associated with mortality, readmissions, or overall HRQOL.

Relative Hyperglycemia, a Marker of Critical Illness: Introducing the Stress Hyperglycemia Ratio.

CONTEXT: Hyperglycemia in hospitalized patients is associated with increased morbidity and mortality. OBJECTIVE: We examined whether critical illness is more strongly associated with relative or absolute hyperglycemia. DESIGN: The study was an observational cohort study. PATIENTS AND SETTING: A total of 2290 patients acutely admitted to a tertiary hospital. MAIN OUTCOME MEASURE: The relative hyperglycemia (stress hyperglycemia ratio [SHR]) was defined as admission glucose divided by estimated average glucose derived from glycosylated hemoglobin. The relationships between glucose and SHR with critical illness (in-hospital death or critical care) were examined. RESULTS: In univariable analyses, SHR (odds ratio, 1.23 per 0.1 increment [95% confidence interval, 1.18-1.28]; P < .001) and glucose (odds ratio, 1.18 per mmol/L [1.13-1.23]; P < .001) were associated with critical illness. In multivariable analysis, the association was maintained for SHR (odds ratio, 1.20 per 0.1 increment [1.13-1.28]; P < .001), but not glucose (odds ratio, 1.03 per mmol/L [0.97-1.11]; P = .31). Background hyperglycemia affected the relationship between glucose (P = .002) and critical illness, but not SHR (P = .35) and critical illness. In patients with admission glucose ≤ 10 mmol/L, the odds ratio for critical illness was higher in the fourth (2.4 [1.4-4.2]; P = .001) and fifth (3.9 [2.3-6.8]; P < .001) SHR quintiles than in the lowest SHR quintile. CONCLUSIONS: SHR controls for background glycemia and is a better biomarker of critical illness than absolute hyperglycemia. SHR identifies patients with relative hyperglycemia at risk of critical illness. Future studies should explore whether basing glucose-lowering therapy on relative, rather than absolute, hyperglycemia improves outcomes in hospitalized patients.

Brief report: Comparison of continuous glucose monitoring and finger-prick blood glucose levels in hospitalized patients administered basal-bolus insulin.

BACKGROUND: Previous studies have assessed the efficacy of basal-bolus insulin (BBI) in hospitalized patients by measuring four finger-prick blood glucose levels (BGLs) per day. The aim of this study was to investigate whether this BGL monitoring regimen provides an accurate reflection of glycemia in hospitalized patients administered BBI. We hypothesized that, as three of four readings are preprandial, finger-prick BGLs would underestimate the mean glucose concentration. SUBJECTS AND METHODS: Twenty-six consecutive consenting subjects with type 1 (n=3) or type 2 (n=23) diabetes mellitus admitted to the hospital and administered insulin glargine once daily and rapid-acting insulin before meals underwent continuous glucose monitoring for up to 72 h. Finger-prick BGLs were performed before each main meal (0700, 1200, and 1700 h) and at 2100 h. RESULTS: Mean daily glucose concentration was not significantly different when assessed by continuous glucose monitoring and finger-prick BGLs (9.6±2.4 vs. 9.6±2.7 mmol/L, P=0.84). A Bland-Altman plot revealed some variability but no bias between the two methods of measurement of glucose concentration. There were 88 postprandial hyperglycemic excursions recorded on continuous glucose monitoring; 61 (69%) were identified by finger-prick BGL monitoring. There were 10 glucose excursions <4 mmol/L during continuous glucose monitoring; only one was detected by finger-prick BGL monitoring. CONCLUSIONS: Traditional finger-prick BGL monitoring provides a reasonable approximation of mean daily glucose concentration in the majority of hospitalized patients receiving BBI but underestimates the prevalence of postprandial hyperglycemia and hypoglycemia.

Continuous monitoring of circadian glycemic patterns in patients receiving prednisolone for COPD.

CONTEXT: Endogenous glucocorticoid excess (Cushing's syndrome) predominantly increases postprandial glucose concentration. The pattern of hyperglycemia induced by prednisolone has not been well characterized. OBJECTIVE: Our objective was to define the circadian effect of prednisolone on glucose concentration to optimize management of prednisolone-induced hyperglycemia. DESIGN AND SETTING: This was a cross-sectional study in a teaching hospital. PARTICIPANTS: Participants included 60 consecutive consenting subjects with chronic obstructive pulmonary disease admitted to hospital: 13 without known diabetes admitted for other indications and not treated with glucocorticoids (group 1), 40 without known diabetes admitted with an exacerbation of chronic obstructive pulmonary disease and treated with prednisolone (group 2, prednisolone = 30 ± 6 mg/d), and seven with known diabetes treated with prednisolone (group 3, prednisolone = 26 ± 9 mg/d). MAIN OUTCOME MEASURE: Interstitial glucose concentration was assessed during continuous glucose monitoring. RESULTS: Significantly more subjects in group 2 [21 of 40 (53%), P = 0.02] and group 3 [seven of seven (100%), P = 0.003] recorded a glucose of at least 200 mg/dl (≥11.1 mmol/liter) during continuous glucose monitoring than in group 1 [one of 13 (8%)]. The mean glucose concentration between 2400-1200 h for group 3 (142 ± 36 mg/dl) was significantly greater than in the other two groups (P < 0.005), whereas mean glucose concentrations between 2400-1200 h in group 1 (108 ± 16 mg/dl) and group 2 (112 ± 22 mg/dl) were not significantly different. In contrast, the mean glucose concentrations between 1200-2400 h for group 2 (142 ± 25 mg/dl) and group 3 (189 ± 32 mg/dl) were both significantly greater than group 1 (117 ± 14 mg/dl, P < 0.05 for both comparisons). CONCLUSIONS: Prednisolone predominantly causes hyperglycemia in the afternoon and evening. Treatment of prednisolone-induced hyperglycemia should be targeted at this time period.

Clinical decision support implemented with academic detailing improves prescribing of key renally cleared drugs in the hospital setting.

OBJECTIVE: Lack of dose adjustment for renally cleared drugs in the presence of poor renal function is a common problem in the hospital setting. The absence of a clinical decision support system (CDSS) from direct clinician workflows such as computerized provider order entry (CPOE) hinders the uptake of CDSS. This study implemented CDSS in an environment independent of CPOE, introduced to prescribers via academic detailing, to address the dosing of renally cleared drugs. DESIGN: GFR+ was designed to automatically calculate and update renal function, doses of key drugs adjusted for renal function, and highlight clinically significant decreases in renal function. Prescribers were made aware of GFR+, its navigation, and surrounding clinical issues, using academic detailing. MEASUREMENT: The rate of dosing conformity and management for key renally cleared drugs in hospitalized patients, before and after GFR+ implementation. RESULTS: Improvements were seen in dosing conformity for enoxaparin (from 68% to 86%, p=0.03), gentamicin (63-87%, p=0.01), and vancomycin (47-77%, p=0.07), as well as the appropriate use of gentamicin therapeutic drug monitoring (70-90%, p=0.02). During episodes of acute renal impairment, renally cleared drugs were held on 38% of instances in the pre-intervention period compared with 62% post-intervention (p=0.01). CONCLUSION: Clinical decision support implemented with academic detailing improved dosing conformity and management of key renally cleared drugs in a hospitalized population. Academic detailing should be strongly considered to facilitate the introduction of CDSS systems that cannot be placed directly into the clinician workflow.

Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors: implications for bone metastases.

BACKGROUND: Lytic bone metastases occur frequently in cancer patients and present major clinical issues including lack of effective therapies. The mechanism of lytic bone metastases involves interactions between tumor cells, bone matrix, and bone cells. Both focal adhesion kinase (FAK) and Pyk2 are implicated in the biology and physiology of bone and cancer. METHODS: The efficacy of PF-562,271 was evaluated using MDA-MB-231 cells implanted in the tibia of nude rats. The drug was administered orally at a dose of 5 mg/kg, 7 days per week for 28 days. Serum and urine biomarkers, imaging, and histologic techniques were deployed to monitor tumor take rate, disease progression, and response to therapy. RESULTS: The compound was well tolerated. Both compound-treated groups demonstrated significant and similar increases in osteocalcin and cancellous bone parameters. Radiographic evaluation of tumor-bearing tibiae revealed tumor expansion in nontreated rats compared with a decrease in tumor growth and signs of bone healing in rats treated with PF-562,271. Tartrate-resistant acid phosphatase and fluorescent in situ hybridization analysis revealed that the majority of bone resorption at the tumor site was performed by osteoclasts of rat origin. CONCLUSIONS: The oral administration of PF-562,271 at a dose of 5 mg/kg suppressed the growth and local spread of intratibial tumors and restored tumor-induced bone loss. The unique ability of PF-562,271 to both curb tumor growth and safely increase bone formation may be an effective therapy for many cancer patients with bone metastases and cancer-associated osteoporosis.

Postoperative nausea and vomiting are strongly influenced by postoperative opioid use in a dose-related manner.

We prospectively examined the incidence of postoperative nausea and vomiting (PONV) in a group of 193 elderly surgical inpatients receiving no postoperative antiemetic prophylaxis. Risk factors for PONV and detailed data on postoperative opioid use were recorded. The overall postoperative vomiting (POV) rate was 23.8%, whereas postoperative nausea (PON) was 51.3%. Opioid use (P = 0.025), and female gender (P = 0.038) were identified as significantly influencing POV in this relatively small population. There was a strong logarithmic dose-response relationship between postoperative opioid dose and POV (r2= 0.98, P < 0.01), as well as PON (r2= 0.98, P = 0.01). Use of patient-controlled analgesia or epidural analgesia was a marker for large-dose opioid use (P < 0.001) and was associated with POV in the 24-h postoperative period of 41% and 31% respectively, compared with 11% for other patients (P < 0.001). Future studies defining risk factors for POV should treat postoperative opioid use as a continuous variable, rather than treat it as a dichotomous variable.

Assessment of an age-adjusted warfarin initiation protocol.

OBJECTIVE: To examine the time taken to reach a stable international normalized ratio (INR), as well as the incidence of overanticoagulation of an age-adjusted warfarin initiation protocol. METHODS: Inpatients and outpatients commencing warfarin therapy at 2 teaching hospitals were dosed according to the age-adjusted protocol. Data were collected prospectively. MAIN OUTCOME MEASURES: Time to reach a stable INR of 2-3 and the number of patients experiencing an INR > or =4 during the first week of warfarin therapy. RESULTS: Seventy-three patients were assessed; at the completion of the 4-day titration protocol, 63% had achieved a stable INR. After an additional 2 days of empiric dosage adjustment by the attending physician, 86% of the subjects demonstrated a stable INR. Five patients (7%) experienced an INR > or =4. These patients had a nonsignificant trend toward a lower plasma albumin level compared with other patients (p = 0.057, Student's t-test). The INR-driven dose adjustments on days 3 and 4 of this protocol coped with other variables that have been shown to affect maintenance warfarin dosing. These included weight, gender, pharmacologic factors affecting clearance, and the presence of certain predesignated risk factors. CONCLUSIONS: The age-adjusted dosing protocol rapidly achieved a stable INR with minimal overanticoagulation. Patients with low serum albumin levels (<3.0 g/dL) may be sensitive to the effects of warfarin during the loading phase.