Arterial Blood Glucose Research Articles

Do potent immobilising-opioids induce different physiological effects in impala and blesbok?

Potent opioids are known to cause negative alterations to the physiology of immobilised antelope. How these effects differ between species has not been studied. This study aimed to compare time to recumbence and effects of opioid-based immobilisation on the physiology of impala (Aepyceros melampus) and blesbok (Damaliscus pygargus phillipsi). Eight animals of each species were immobilised, with 0.09 mg/kg etorphine and 0.09 mg/kg thiafentanil respectively, in a randomised two-way cross-over study. Variables measured and analysed by means of a linear mixed model included time to recumbence, heart rate, respiratory rate, arterial blood pressure, blood gases, lactate and glucose. In blesbok, mean time to recumbence was not significantly different with either drug (2.5 minutes and 2.2 min, respectively), but in impala thiafentanil achieved a shorter time to recumbence (2.0 min) than etorphine (3.9 min). Mean heart rates of immobilised impala were within reported physiological limits, but lower in immobilised blesbok when both opioids were used (35 beats/min to 44 beats/min vs. 104 ± 1.4 beats/min resting heart rate). Impala developed severe respiratory compromise and hypoxaemia from both opioids (overall mean PaO2 values ranged from 38 mmHg to 59 mmHg over 30 min). In contrast, blesbok developed only moderate compromise. Therefore, significantly different species-specific physiological responses to potent opioid drugs exist in blesbok and impala. Given that these different responses are clinically relevant, extrapolation of immobilising drug effects from one species of African ungulate to another is not recommended.

Effects of Single Dose of Dexamethasone on Perioperative Blood Glucose Levels in Patients Undergoing Surgery for Supratentorial Tumors - An Observational Study.

Introduction:Dexamethasone is commonly administered in intracranial tumors to reduce the cerebral edema. Its administration may be associated with hyperglycemia. The primary objective of this study was to study the magnitude of rise in blood sugar levels following the administration of a single 10 mg dose of dexamethasone.Methods:Seventy patients who underwent various neurosurgical procedures were enrolled in the study. Group D (n = 35 undergoing surgery for intracranial tumors) were administered injection dexamethasone 10 mg while as Group P (n = 35 undergoing surgery for subarachnoid hemorrhage) received placebo. Blood samples were obtained through the arterial line at baseline (before dexamethasone administration), 60, 120, 180, and 240 min after the dexamethasone administration and blood glucose concentrations noted.Results:Glucose concentrations were significantly increased in patients who received dexamethasone compared with those who received placebo (P < 0.05). Blood glucose concentrations at different time intervals were greater when compared with the baseline blood sugar levels in both the placebo and dexamethasone group (P < 0.05). The arterial blood glucose concentration in those who received 10 mg dexamethasone (n = 35) increased from 95.29 ± 13.69 mg.dl−1 to 139.97 ± 10.34 mg.dl−1 over 4 h, compared with a change from 94.74 ± 10.05 mg.dl−1 to 122.34 ± 10.68 mg.dl−1 in those who received placebo (n = 35) (P < 0.05).Conclusion:The administration of a single intravenous dose of 10-mg dose dexamethasone caused a significant increase in the blood glucose concentrations at different point intervals when compared with the placebo over a 4-h period. We recommend intensive monitoring of the blood sugar levels during the intraoperative period to prevent the development of severe hyperglycemia and its associated complications.

Sildenafil citrate long-term treatment effects on cardiovascular reactivity in a SHR experimental model of metabolic syndrome.

Much evidence indicates that metabolic syndrome is strongly correlated with a decrease in nitric oxide and an increase in oxidative stress leading to cardiovascular alterations. In recent years, gut microbiota has emerged as a new contributor to the metabolic syndrome establishment and associated cardiovascular diseases, but the underlying mechanisms remain unclear. We hypothesized that a positive modulation of cyclic guanosine monophosphate (cGMP) pathway, through phosphodiesterase type 5 (PDE5) inhibition could prevent cardiovascular alterations and gut dysbiosis that may be associated to metabolic syndrome. Spontaneously hypertensive rats (SHR) were randomly divided into 4 groups: control, cafeteria diet (CD) and sildenafil citrate treated groups (5mg/kg per os) were given either a CD or a standard chow diet for 10 weeks. Body weight, arterial blood pressure and glucose tolerance test were monitored. At the 10th week, cardiac inotropy and coronary perfusion pressure were evaluated on isolated heart according to Langendorff method. Cumulative concentration response curves to phenylephrine and acetylcholine were determined on thoracic aorta rings for vascular reactivity evaluation. Faecal samples were collected for the gut microbiota analysis. Compared to the control group, CD-fed rats showed a significant increase in body weight gain, arterial blood pressure and were glucose intolerant. This group showed also a decrease in β-adrenoceptor-induced cardiac inotropy and coronary vasodilation. Gut microbiota analysis revealed a significant reduction in the abundance of Lactobocillus spp in cafeteria diet-fed rats when compared to the control ones. Sildenafil citrate long-term treatment decreased weight gain and arterial blood pressure, improved coronary vasodilation and reduced α1-adrenoceptor-induced vasoconstriction in CD group. However, it did not reverse gut dysbiosis induced by chronic CD feeding. These results suggest that cGMP pathway targeting may be a potential therapeutic strategy for the management of the metabolic syndrome and associated cardiovascular disorders.

Influence of Daytime LED Light Exposure on Circadian Regulatory Dynamics of Metabolism and Physiology in Mice.

Light is a potent biologic force that profoundly influences circadian, neuroendocrine, and neurobehavioral regulation in animals. Previously we examined the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit more light in the blue-appearing portion of the visible spectrum (465 to 485 nm) than do broad-spectrum cool white fluorescent (CWF) light, on the nighttime melatonin amplitude and circadian regulation of metabolism and physiology. In the current studies, we tested the hypothesis that exposure to blue-enriched LED light at day (bLAD), compared with CWF, promotes the circadian regulation of neuroendocrine, metabolic, and physiologic parameters that are associated with optimizing homeostatic regulation of health and wellbeing in 3 mouse strains commonly used in biomedical research (C3H [melatonin-producing], C57BL/6, and BALB/c [melatonin-non-producing]). Compared with male and female mice housed for 12 wk under 12:12-h light:dark (LD) cycles in CWF light, C3H mice in bLAD evinced 6-fold higher peak plasma melatonin levels at the middark phase; in addition, high melatonin levels were prolonged 2 to 3 h into the light phase. C57BL/6 and BALB/c strains did not produce nighttime pineal melatonin. Body growth rates; dietary and water intakes; circadian rhythms of arterial blood corticosterone, insulin, leptin, glucose, and lactic acid; pO₂ and pCO₂; fatty acids; and metabolic indicators (cAMP, DNA, tissue DNA 3H-thymidine incorporation, fat content) in major organ systems were significantly lower and activation of major metabolic signaling pathways (mTOR, GSK3β, and SIRT1) in skeletal muscle and liver were higher only in C3H mice in bLAD compared with CWF. These data show that exposure of C3H mice to bLAD compared with CWF has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing that may influence scientific outcomes. The absence of enhancement in amelatonic strains suggests hyperproduction of nighttime melatonin may be a key component of the physiology.

Metabolic and Nutritional Characteristics of Long-Stay Critically Ill Patients.

Background: insufficient feeding is frequent in the intensive care unit (ICU), which results in poor outcomes. Little is known about the nutrition pattern of patients requiring prolonged ICU stays. The aims of our study are to describe the demographic, metabolic, and nutritional specificities of chronically critically ill (CCI) patients defined by an ICU stay >2 weeks, and to identify an early risk factor. Methods: analysis of consecutive patients prospectively admitted to the CCI program, with the following variables: demographic characteristics, Nutrition Risk Screening (NRS-2002) score, total daily energy from nutritional and non-nutritional sources, protein and glucose intakes, all arterial blood glucose values, length of ICU and hospital stay, and outcome (ICU and 90-day survival). Two phases were considered for the analysis: the first 10 days, and the next 20 days of the ICU stay. Statistics: parametric and non-parametric tests. Results: 150 patients, aged 60 ± 15 years were prospectively included. Median (Q1, Q3) length of ICU stay was 31 (26, 46) days. The mortality was 18% at ICU discharge and 35.3% at 90 days. Non-survivors were older (p = 0.024), tended to have a higher SAPSII score (p = 0.072), with a significantly higher NRS score (p = 0.033). Enteral nutrition predominated, while combined feeding was minimally used. All patients received energy and protein below the ICU’s protocol recommendation. The proportion of days with fasting was 10.8%, being significantly higher in non-survivors (2 versus 3 days; p = 0.038). Higher protein delivery was associated with an increase in prealbumin over time (r2 = 0.19, p = 0.027). Conclusions: High NRS scores may identify patients at highest risk of poor outcome when exposed to underfeeding. Further studies are required to evaluate a nutrition strategy for patients with high NRS, addressing combined parenteral nutrition and protein delivery.

An innovative idea and design scheme of continuous arterial blood glucose monitoring equipment

Hyperglycemia is a common complication of critical patients. Currently, clinical assessment of the changes in the blood glucose of critical patients is mainly based on the intermittent monitoring of peripheral blood glucose at a certain time point. This method cannot get the true blood glucose fluctuation, and it is more difficult to find asymptomatic hyperglycemia and hypoglycemia, so the guiding value of blood glucose control is limited. Arterial blood is the most accurate sample of blood glucose monitoring, so it is urgent to ensure the accuracy of arterial blood sample. A continuous arterial blood glucose monitoring equipment was independently developed by general surgical intensive care unit (ICU) of the First Affiliated Hospital of Nanjing Medical University, and National Utility Model Patent of China was obtained. It could greatly improve the efficiency of medical staff, and provide accurate and dynamic statistic data that would be an important basis for doctors' clinical decision-making. The continuous arterial blood glucose monitoring equipment was mainly composed of arterial pressure measuring monitor, program-controlled dynamic blood glucose meter, wire, electric switch, integrated collecting syringe, electric clip, rotary electric bracket, and blood glucose test strips, etc., which could be continuously and dynamically monitor patient blood glucose levels and perform various additional value-added functions such as automatic recording and alarming.

1074-P: Performance of an Artificial Pancreas System in Swine during Severe Hypo- and Hyperglycemic Provocations

Introduction: Intensive care unit (ICU) patients develop stress induced insulin resistance causing hyperglycemia, large glucose variability and hypoglycemia, all of which increase mortality rates. Tight glucose control (TGC) in the ICU is challenging, and usually significantly increases the risk for treatment induced hypoglycemia. The only way to achieve safe TGC will be through use of an artificial pancreas (AP) system. Our goal with the present study was to assess the safety and performance of an AP system, composed of the EIRUS (Getinge AB) continuous glucose monitor (CGM) and novel artificial intelligence-based (AI-based) glucose control software, in a swine model using unannounced hypo- and hyperglycemia challenges. Methods: Fourteen piglets (6 control, 8 treated) underwent sequential unannounced (to the AP system) hypoglycemic and hyperglycemic challenges with 3 U of insulin aspart and a large glucose infusion over the course of 5 hours. In the control animals an ICU physician used every 30-minute arterial blood glucose values to maintain control to a range of 4.4 - 9 mmol/L through use of 20% dextrose for hypoglycemia and insulin aspart for hyperglycemia. In the treated group the AP system attempted to maintain blood glucose control to a range of 4.4 - 6.6 mmol/L in a fully autonomous mode. Results: Five of six control animals and none of eight treated animals experienced severe hypoglycemia (&amp;lt; 2.22 mmol/L). The area under the curve 3.5 mmol/L was 28.9 (21.1 - 54.2) for control and 4.8 (3.1 - 5.2) for the treated animals. The percent time in range 4.4 - 6.6 mmol/L was 32.8 (32.4 - 47.1) for the control and 55.4 (52.9 - 59.4) for the treated animals. After the start of the experiment the control animals underwent 4 (3-5) human interventions to maintain control whereas the treated animals underwent none. Data are median (25-75). Conclusions The AP system abolished severe hypoglycemia and outperformed the ICU physician both in avoiding hypoglycemic excursions and maximizing time in range. Disclosure J. DeJournett: Employee; Self; Ideal Medical Technologies. L. DeJournett: Stock/Shareholder; Self; Ideal Medical Technologies.

Does umbilical cord blood glucose extraction discriminate the risk of early neonatal hypoglycaemia in at-risk newborns?

Despite targeting newborns at risk of hypoglycaemia based on clinical characteristics, blood glucose measured at 1 and 4 h of age is frequently normal. Identification of at-risk newborns at the greatest risk of hypoglycaemia would allow more targeted, earlier intervention. We aimed to determine the ability of calculated umbilical cord blood glucose extraction to discriminate hypoglycaemia in at-risk newborns in the first 4 h of life. Newborns with paired arterial and venous cord blood glucose and 1 ± 4 h capillary or venous blood glucose measured using a blood gas analyser (radiometer) were retrospectively identified (n = 154). Hypoglycaemia was defined as a blood glucose ≤2.0 mmol/L. The ability of calculated umbilical cord blood glucose extraction to discriminate risk of hypoglycaemia was determined by an receiver operating characteristic (ROC) curve. Twenty-seven newborns (18%) had a blood glucose ≤2.0 mmol/L at either time point. Neither arterial nor venous cord blood glucose predicted early hypoglycaemia better than chance. The area under the ROC curve for umbilical cord blood glucose extraction (area under the ROC curve = 0.74, (95% confidence interval, 0.65-0.82)) was significantly better than chance and arterial or venous cord blood glucose. An umbilical cord blood glucose extraction of 16% had the best sensitivity (80%) and specificity (55%) for discriminating the risk of early hypoglycaemia. Umbilical cord blood glucose extraction discriminates the risk of early hypoglycaemia at 1 or 4 h of age. However, the clinical utility of this test is limited due to the low sensitivity and specificity. Its predictive value may be greater in specific subsets of at-risk newborns and warrants further investigation.

Postnatal outcomes in lambs exposed antenatally and acutely postnatally to fluoxetine.

Approximately 1/3 of newborns exposed antenatally to selective serotonin reuptake inhibitors (SSRIs) exhibit poor neonatal adaptation. Although several potential mechanisms have been proposed, the actual mechanism has not been elucidated. We investigated outcomes in neonatal lambs exposed prenatally or postnatally to fluoxetine (FX). Daily FX injections (50 mg) were given intravenously (i.v.) to five pregnant ewes via implanted catheters beginning at 131-132 days gestation (term = 147 days) for 2 weeks. In another group, lambs with implanted vascular catheters had sterile water (n = 9) or FX (1 mg/kg, n = 12) injected i.v. on ~postnatal day (PND) 4. Prenatal FX-exposed lambs (n = 7) were hyperactive during PND 4 to 14 and their heart rate variability (HRV) was significantly lower than in control lambs (n = 7) on PND 2. In contrast, arterial pressure, heart rate, electrocardiogram, arterial blood gases, pH, glucose, lactate, cortisol, and sleep-activity cycles were not altered following postnatal FX injection. This abnormal postnatal hyperactivity with antenatal FX exposure may reflect increased maturity in terms of locomotory activity. The results suggest that altered brain development may be involved in the poor neonatal adaptation in human infants exposed to FX in utero.

Cardiovascular effects of two adenosine constant rate infusions in anaesthetized dogs

ObjectiveAdenosine induces vasodilatation. The aim of this study was to investigate cardiovascular effects of two adenosine constant rate infusion (CRI) doses in dogs. Study designExperimental, longitudinal repeated measure design. AnimalsTen healthy purpose-bred Beagle dogs. MethodsEach dog was sedated with butorphanol. Anaesthesia was induced with propofol intravenously and maintained with sevoflurane (inspired oxygen fraction = 47–55%). Controlled mechanical ventilation was used to maintain normocapnia. Two doses of adenosine were administered as CRIs to each dog: 140 μg kg–1 minute–1 (A140) followed by 280 μg kg–1 minute–1 (A280). Pulse rate, invasive arterial pressure and stroke volume (by magnetic resonance phase contrast angiography) were measured at baseline, 3 minutes after starting adenosine and 3 and 10 minutes after discontinuing adenosine. Cardiac output, cardiac index and approximated systemic vascular resistances (approximate SVR) were calculated. Additionally, arterial blood gases, co-oximetry, electrolytes, glucose and lactate were measured and oxygen content and delivery calculated. One-way repeated measures analysis of variance (p < 0.05) was used for data analysis. ResultsA140 and A280 resulted in a significant decrease in arterial blood pressure [systolic (p = 0.008), mean (p = 0.003), and diastolic arterial pressure (p = 0.004)] and approximate SVR (p = 0.008) compared with baseline. No significant changes were detected for the other variables. All values returned to baseline within 3 minutes after adenosine discontinuation. Conclusions and clinical relevanceAdenosine CRI decreases arterial pressure by vasodilatation in healthy dogs. No additional effects were observed with the higher dose. The effects in compromised dogs remain to be investigated.

Blunted Nighttime Sympathetic Nervous System Response to Stress Among Thai Men with Positive Family History of Sudden Unexplained Nocturnal Death Syndrome.

Sudden unexplained nocturnal death syndrome (SUNDS) is prominent among northeast Thai men. This study tests the hypothesis that Thai men with positive family history of SUNDS display abnormal diurnal, autonomic nervous system responses to stress. Healthy northeast Thai men (20-49 years old) lived in the same rural area were divided into two groups based on their positive (PF) or negative family (NF1) history of SUNDS. A second control included Thai men with an NF history of SUNDS from a non-endemic area (NF2). All data were collected at 4:00-6:00 AM (nighttime) and 4:00-6:00 PM (daytime). All three groups displayed nighttime decreases in mean arterial pressure, heart rate, and blood glucose. Furthermore, all subjects displayed similar glucose tolerance and electrolyte balance. The tachycardic responses to a four-minute step test were similar among groups in the daytime, but the nighttime responses were significantly blunted in the PF group compared to either control group (about 20 bpm less). Tachycardic responses to a cold pressor test tended to decrease more during the nighttime in the PF compared to NF1 and NF2 groups, but the difference was not significant. Arterial pressure responses to the exercise were similar among the three groups during the nighttime, whereas in the NF2, daytime mean arterial pressures increased more than those in the other groups. The present data suggest that Thai men with a PF history of SUNDS display blunted sympathetic nervous system responses to stress during the nighttime, a potential factor that may trigger cardiac arrhythmias and contribute to SUNDS.

Risk factors of metabolic syndrome among adult Sudanese sickle cell anemia patients

BackgroundSickle cell disease is a hereditary disorder characterized by haematological anaemia. Several studies assumed that adult sickle patients might develop metabolic syndrome features as hyperglycaemia, hypertension and dyslipidaemia. The aim of this study was to evaluate the metabolic syndrome risk factors among adult Sudanese with sickle cell anemia in the steady state.MethodsA prospective cross sectional study design was conducted among thirty adult patients with sickle cell anemia Hb SS (mean age 23 ± 6.1 years) and thirty healthy individuals matched for age and gender. Waist and hip circumferences were measured by simple tape. Venous blood sample were analysed to detect blood glucose level, uric acid, total cholesterol, triglycerides, low and high-density lipoprotein after 8 h overnight fasting by spectrophotometer. Blood pressure was measured by sphygmomanometer. National Cholesterol Education Program-Adult Treatment Panel III was utilised to define metabolic syndrome. Statistical analysis was performed SPSS software version 23. Continuous data were expressed using mean ± SD. P-value of < 0.05 (two-tailed) was used to establish statistical significance. Unpaired independent T- test was used.ResultsNo significant difference in mean systolic blood pressure in patients group compared to control (P value = 0.3). Mean value of diastolic blood pressure was significantly low in patients group compared to control (65.4 ± 10. 4 VS72.33 ± 8.27 mmHg, P value< 0.001). Fasting triglycerides level was comparable between patients group and control (P value = 0.56). While high-density lipoprotein was significantly lower in sicklers compared to control (30.2 ± 8.2 mg/dL vs 44.71 ± 1.85 mg/dL, P value< 0.001). Fasting blood glucose was significantly low in sickle compared to control (92.6 ± 13 mg/dL vs 106.83 ± 25.11 mg/dL P value< 0.001). Uric acid level was not statistically differed in patients group compared to control (p value = 0.5).ConclusionThere was significant decrease in fasting High-density lipoprotein, diastolic blood pressure, mean arterial pressure and fasting blood glucose among SCA patients compared to control. There was no significant difference in waist circumference, systolic blood pressure, fasting triglycerides and uric acid levels between patients and control groups.

A Study to Compare Arterial, Capillary and Venous Blood Glucose levels in Patients with Hypotension on Vasopressor versus Normotensive Patients

A Study to Compare Arterial, Capillary and Venous Blood Glucose levels in Patients with Hypotension on Vasopressor versus Normotensive Patients

Effect of different crystalloids on internal environment in patients with septic shock receiving early fluid resuscitation: a prospective randomized controlled trial

To compare the effect of 0.9% NaCl solution, Ringer solution, and acetate sodium potassium magnesium calcium glucose solution (ASPMCG solution) on internal environment in patients with septic shock receiving early fluid resuscitation. A prospective randomized controlled trial was conducted. From June 2016 to January 2018, a total of 280 patients with septic shock admitted to intensive care unit (ICU) of Northern Jiangsu People's Hospital were enrolled. All eligible patients were randomly divided into 0.9% NaCl solution group (group N), Ringer solution group (group L) and ASPMCG solution group (group P) with random number table. In all patients, catheters were placed in the right internal jugular vein or subclavian vein and were infused with 30 mL/kg of corresponding crystalloid within 3 hours after admission. According to fluid responsiveness, the rehydration rate and fluid volume were determined by the researcher within 6 hours. Other treatments were based on the 2012 Surviving Sepsis Campaign (SSC) guidelines during the study. In this study, 6-hour or 24-hour fluid volume and 7-day exogenous insulin use were recorded. The changes in arterial blood pH, base excess (BE), blood glucose (Glu), lactic acid (Lac), and serum Na+, K+, Cl-, Ca2+ were observed at 0, 3, 6, 24 hours, and 3 days and 7 days of resuscitation. In this study, a total of 1 082 patients were admitted to the ICU, and patients who did not meet the diagnostic criteria for septic shock, death or discharge within 24 hours of ICU admission were excluded. Finally, 280 patients with septic shock were enrolled in the analysis, with 94 patients in group N, 94 patients in group L and 92 patients in group P. There was no significant difference in the amount of crystalloid, colloidal fluid, total fluid within 6 hours or 24 hours or exogenous insulin dose within 7 days among the three groups. After fluid resuscitation, blood Cl- concentration in the three groups was increased in different degrees, peaked at 24 hours, but it in group N was significantly higher than that in group L and group P (mmol/L: 107.5±5.6 vs. 106.1±4.8, 105.1±4.2, both P < 0.05). Moreover, blood Ca2+ concentration also showed an increased tendency, it was significantly lower at 3 hours and 6 hours in group N than that in group L and group P (mmol/L: 1.10±0.08 vs. 1.15±0.09, 1.12±0.10 at 3 hours, 1.12±0.10 vs. 1.16±0.08, 1.15±0.09 at 6 hours, all P < 0.05). There was no significant difference in blood Cl- or Ca2+ between groups L and P (both P > 0.05). Arterial blood pH, BE, Glu, Lac, Na+, or K+ at each time point during fluid resuscitation also showed no difference among the three groups. Among patients with septic shock receiving early fluid resuscitation, compared with Ringer solution and ASPMCG solution, 0.9% NaCl solution may cause hyperchloremia and hypocalcemia, but has no significant effect on acid-base balance. Chinese Clinical Trial Registry, ChiCTR-IOR-16009176.

Abstract 3933: Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index

Abstract The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BYL719. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues (adipocytes and muscles). NVP-BYL719 (a selective inhibitor of the class Ia PI3K isoform alpha) given in the morning is facing on-target tolerability challenge (hyperglycemia) in clinical trials limiting the dose being administered to patient (1). As glucose metabolism is highly impacted by circadian rhythms in patients and rodents, we have decided to adopt an integrative circadian-timing approach in our pre-clinical models to interrogate the benefit of morning vs evening dosing for BYL719. By using a newly developed radio-telemetry technology (2), we were able to record in real time and 'around-the-clock' blood glucose levels in stress-free, freely moving rats dosed with NVP-BYL719 at different regimens. The dynamic profile of hyperglycemia observed after active or inactive period dosing of NVP-BYL719 (50 mg/kg qd p.o.) were similar. Dosing before the inactive phase (10 a.m.) allowed blood glucose to normalize in between 2 doses, which could not be achieved when dosing before the active phase (5 p.m.). After treatment discontinuation a significant hyperglycemia remained for a period up to 12h in the group dosed before the active phase (5 p.m.). Circadian “evening” NVP-BYL719 dosing is associated with a better control of glycaemia. Clinically this could potentially translate to better compliance and longer time on treatment hence better efficacy for patient. Based on these findings we could recommend optimized treatment schedules for future combination experiments in the clinic with NVP-BYL719. 1) Juric et al, “Phase I study of the PI3Kα Inhibitor BYL719, as a Single Agent in Patients with Advanced Solid Tumors (AST)”, Annals of Oncology (2014), 25 (Supp. 4) 2) Brockway et al, “Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months”, J Diabetes Sci Technol (2015), 9(4):771-81 Citation Format: Christian R. Schnell, Thomas Ferrat, Daniel Wyss, Walter Tinetto, Sonja Tobler, Christine Fritsch, Michael Jensen. Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3933.

Cerebral Metabolic Changes Related to Oxidative Metabolism in a Model of Bacterial Meningitis Induced by Lipopolysaccharide.

Cerebral mitochondrial dysfunction is prominent in the pathophysiology of severe bacterial meningitis. In the present study, we hypothesize that the metabolic changes seen after intracisternal lipopolysaccharide (LPS) injection in a piglet model of meningitis is compatible with mitochondrial dysfunction and resembles the metabolic patterns seen in patients with bacterial meningitis. Eight pigs received LPS injection in cisterna magna, and four pigs received NaCl in cisterna magna as a control. Biochemical variables related to energy metabolism were monitored by intracerebral microdialysis technique and included interstitial glucose, lactate, pyruvate, glutamate, and glycerol. The intracranial pressure (ICP) and brain tissue oxygen tension (PbtO2) were also monitored along with physiological variables including mean arterial pressure, blood glucose, lactate, and partial pressure of O2 and CO2. Pigs were monitored for 60min at baseline and 240min after LPS/NaCl injection. After LPS injection, a significant increase in cerebral lactate/pyruvate ratio (LPR) compared to control group was registered (p=0.01). This increase was due to a significant increased lactate with stable and normal values of pyruvate. No significant change in PbtO2 or ICP was registered. No changes in physiological variables were observed. The metabolic changes after intracisternal LPS injection is compatible with disturbance in the oxidative metabolism and partly due to mitochondrial dysfunction with increasing cerebral LPR due to increased lactate and normal pyruvate, PbtO2, and ICP. The metabolic pattern resembles the one observed in patients with bacterial meningitis. Metabolic monitoring in these patients is feasible to monitor for cerebral metabolic derangements otherwise missed by conventional intensive care monitoring.

Pulse pressure is associated with plasma amyloid-β transport dysfunction.

Increased pulse pressure (PP) has been implicated in the development and progression of Alzheimer's disease in middle-aged and elderly adults. Considering the close relationship between peripheral amyloid-β clearance and brain amyloid-β deposition, we investigated the potential association between PP and plasma amyloid-β transport function. In this cross-sectional study, a total of 1118 participants underwent a health assessment and quantification of plasma amyloid-β and amyloid-β transporter expression. Relationships between plasma levels of amyloid-β1-40, amyloid-β1-42, soluble low-density lipoprotein receptor-related protein-1 (sLRP1), soluble receptor for advanced glycation end products (sRAGE), and PP were determined using multiple linear regressions. PP was a significant determinant of amyloid-β1-40 level (β = 0.059, P = 0.036) and log-transformed sRAGE (β = -0.002, P = 0.029) independent of age, sex, body mass index, pulse rate, mean arterial pressure, blood glucose, blood lipids, lifestyle, and medical history. Additionally, log-transformed soluble low-density lipoprotein receptor-related protein-1 and log-transformed sRAGE were positively associated with plasma amyloid-β1-40 level (β = 3.610, P < 0.001; β = 2.573, P = 0.001). Similar associations were observed between log-transformed sRAGE and plasma amyloid-β1-42 level (β = 1.350, P = 0.022). An elevation in PP is associated with increased plasma amyloid-β1-40 and decreased log-transformed sRAGE among individuals not taking antihypertensive medication. The underlying mechanism of this effect may be relevant to peripheral amyloid-β clearance.

Rapid Response: To Scan or Not to Scan? The Utility of Noncontrast CT Head for Altered Mental Status.

The aims of the study were the following: (1) to determine how often computed tomography (CT) scans of the head are obtained on rapid responses called for altered mental status (AMS), (2) to determine whether CT imaging of the head is required during all rapid responses called for AMS, (3) to determine which patients would benefit from CT scans of the head in this setting, (4) to note whether an adequate neurologic exam was documented, (5) to determine the cost of CT scans that did not change management, and (6) to examine the role of medications leading to AMS. The study was a retrospective chart review at Abington Jefferson Hospital. Data collected included the age, sex, time of rapid response, clinical condition of the patient, whether an arterial blood gas and blood glucose were done, and whether a neurological exam was documented in the resident's rapid response team note. The patien's medications were also reviewed. Computed tomography scan findings as well as changes made in a patient's care as a result of the scan were recorded. Any findings that did not lead to a change in management were considered a "negative" scan. Overall, 610 rapid responses were activated from January to August 2016. One hundred four (17.04%) of the total rapid responses were for AMS and 83 (79.8%) of these patients underwent noncontrast CT scan of the head. The mean (SD) age of the patients was 74.7 (13.6) years. A total of 56.6% were female. The most frequent clinical conditions documented at the time of rapid responses were noted as confused (33.7%, 28/83), either lethargic or unconscious (32.5%, 27/83), and concern for stroke (21.7%, 18/83). A total of 96.4% (80/83) of the CT scans done were negative for any acute changes. The three patients with positive scans (3/83) had a change in management as a result of the scans. If patients with symptoms concerning for stroke and unconscious patients are excluded, the total number of remaining patients is 56. Of these, zero patients had a positive scan. A total of 64.7% of the rapid response teams were activated either in the afternoon (31.3%) or at night (33.7%). A total of 33.7% had a complete neurological exam documented. A total of 66.2% were either incomplete (34.9%) or absent (31.3%). Sixty percent of the patients who had a CT head for AMS also had a blood sugar checked at bedside. Thirty-eight percent had an arterial blood gas. More than half the patients were taking one or more sedating medications (45/83, 57.8%). Most patients were not on anticoagulants (79.5%). The findings of this study suggest that CT scan of the head is useful in older patients, patients with symptoms concerning for stroke, or cases of sudden onset of impaired consciousness. Noncontrast CT scans of the head are not useful for other presentations of AMS.

Comparison of Glycemic Control between Continuous Regular Insulin Infusion and Single-dose Subcutaneous Insulin Glargine Injection in Medical Critically Ill Patients.

Background and Aims:This study aimed to compare glycemic control between continuous intravenous regular insulin infusion and single-dose subcutaneous insulin glargine injection in medical critically ill patients.Subjects and Methods:A prospective noninferiority study was conducted in medical critically ill patients who developed hyperglycemia and required regular insulin infusion by the Intensive Care Unit glycemic control protocol. The eligible patients were switched from the daily regular insulin requirement to single-dose subcutaneous insulin glargine injection by a 100% conversion dose. Arterial blood glucose was checked every 2 h for 24 h. Success cases were blood glucose levels of 80–200 mg/dL during the study period. The mean time-averaged area under the curves (AUCs) of blood glucose levels between the two types of insulin were compared by t-test.Results:Of 20 cases, 14 cases (70%) were successful. The mean time-averaged AUCs of blood glucose levels between the two types of insulin were not significantly different (155.91 ± 27.54 mg/dL vs. 151.70 ± 17.07 mg/dL, P = 0.56) and less than the predefined noninferior margin. No severe hypoglycemic cases were detected during the study period.Conclusions:Single-dose subcutaneous insulin glargine injection was feasibly applied for glycemic control in medical critically ill patients. The glycemic control in the critically ill patients by a single dose of subcutaneous insulin glargine was comparable to standard intravenous regular insulin infusion. A conversion dose of 100% of the daily requirement of regular insulin is suggested.

A non-invasive approach for the diagnosis of Type 2 diabetes using HRV parameters

As per the records of World Health Organisation, diabetes is currently one of the major diseases faced by the world community. This necessitates the introduction of screening tools for diabetes. In this paper, a non-invasive approach is proposed to diagnose the presence of Type 2 diabetes by analysing the relationship between the Heart Rate Variability (HRV) parameters and the arterial blood glucose changes. The HRV analysis is performed using non-linear methods such as Detrended Fluctuation Analysis (DFA) and Poincare plot. A few parameters derived from these non-linear methods are used to introduce two metrics named as Standard Deviation Ratio (SDR) and alpha-ratio. These two metrics are given as input to a machine learning classifier to categorise the subjects as diabetic or non-diabetic. The accuracy analysis of the classification results shows that 94.7% of the subjects are categorised correctly. Therefore, the proposed metrics can be considered as non-invasive screening tools in predicting the presence of Type 2 diabetes.