Sedative Plasma Concentrations and Delirium Risk in Critical Illness

Background: The relationship between plasma concentration of sedatives and delirium is unknown. Objective: We hypothesized that higher plasma concentrations of lorazepam are associated with increased delirium risk, whereas higher plasma concentrations of dexmedetomidine are associated with reduced delirium risk. Methods: This prospective cohort study was embedded in a double-blind randomized clinical trial, where ventilated patients received infusions of lorazepam and dexmedetomidine. Plasma concentrations of these drugs and delirium assessments were measured at least daily. A multivariable logistic regression model accounting for repeated measures was used to analyze associations between same-day plasma concentrations of lorazepam and dexmedetomidine (exposures) and the likelihood of next-day delirium (outcome), adjusting for same-day mental status (delirium, coma, or normal) and same-day fentanyl doses. Results: This critically ill cohort (n = 103) had a median age of 60 years (IQR: 48-66) with APACHE II score of 28 (interquartile range [IQR] = 24-32), where randomization resulted in assignment to lorazepam (n = 51) or dexmedetomidine (n = 52). After adjusting for same-day fentanyl dose and mental status, higher plasma concentrations of lorazepam were associated with increased probability of next-day delirium (comparing 500 vs 0 ng/mL; odds ratio [OR] = 13.2; 95% CI = 1.4-120.1; P = 0.02). Plasma concentrations of dexmedetomidine were not associated with next-day delirium (comparing 1 vs 0 ng/mL; OR = 1.1; 95% CI = 0.9-1.3; P = 0.45). Conclusions: In critically ill patients, higher lorazepam plasma concentrations were associated with delirium, whereas dexmedetomidine plasma concentrations were not. This implies that the reduced delirium risk seen in patients sedated with dexmedetomidine may be a result of avoidance of benzodiazepines, rather than a dose-dependent protective effect of dexmedetomidine.

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Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment

Journal of Psychopharmacology ◽

10.1177/0269881120926673 ◽

2020 ◽

pp. 026988112092667

Author(s):

Anna Borissova ◽

Bart Ferguson ◽

Matthew B Wall ◽

Celia JA Morgan ◽

Robin L Carhart-Harris ◽

...

Keyword(s):

Repeated Measures ◽

Ultimatum Game ◽

Subjective Effects ◽

Plasma Concentrations ◽

Controlled Experiment ◽

Prosocial Behaviour ◽

Cooperative Behaviour ◽

Acute Effects ◽

Double Blind ◽

Bayesian Analyses

Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct to psychotherapy. It may be beneficial to trust, empathy and cooperative behaviour due to its acute prosocial effects. Aim: To test (a) the acute effects of MDMA on measures of empathy, trust and cooperative behaviour, and (b) subacute changes in mood three days after MDMA administration. Methods: Twenty-five participants ( n=7 female), participated in this double-blind, repeated-measures, placebo-controlled experiment. Participants attended two acute sessions, one week apart. Each acute session was followed by a subacute session three days later. Participants received placebo (100 mg ascorbic acid) during one acute session, and MDMA (100 mg MDMA-HCl) at the other, with order counterbalanced. Participants completed the following tasks assessing prosocial behaviour: a trust investment task, a trustworthy face rating task, an empathic stories task, a public project game, a dictator game and an ultimatum game. Participants reported subjective effects. Blood was taken pre-drug, 2 and 4 hours post-drug, and tested for plasma MDMA levels. Results: MDMA acutely increased self-reported ‘closeness to others’ and ‘euphoria’ and increased plasma concentrations of MDMA. MDMA did not significantly change task-based empathy, trust or cooperative behaviour. Using Bayesian analyses, we found evidence that MDMA and placebo did not differ in their effects on empathy and cooperative behaviour. MDMA did not significantly change subacute mood and this was supported by our Bayesian analyses. Conclusion: Despite augmentation in plasma MDMA levels and subjective drug effects, we found no increase in prosocial behaviour in a laboratory setting.

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The acute effects of a low and high dose of oral l-arginine supplementation in young active males at rest

Applied Physiology Nutrition and Metabolism ◽

10.1139/h11-035 ◽

2011 ◽

Vol 36 (3) ◽

pp. 405-411 ◽

Cited By ~ 16

Author(s):

Scott C. Forbes ◽

Gordon J. Bell

Keyword(s):

Body Mass ◽

Repeated Measures ◽

Plasma Concentrations ◽

Insulin Response ◽

High Dose ◽

Placebo Condition ◽

Double Blind ◽

Physically Active ◽

Significant Difference ◽

Arginine Supplementation

l-arginine (2-amino-5-guanidinovaleric acid) is a conditionally essential amino acid. Intravenous (IV) administration of l-arginine invokes a large metabolic (nitrate/nitrite (NOx)) and hormonal (growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin) response; however, research examining oral l-arginine supplementation is conflicting, potentially owing to dose. The purpose of this study was examine a low and high dose of oral l-arginine on blood l-arginine, NOx, GH, IGF-1, and insulin response. Fourteen physically active males (age: 25 ± 5 years; weight: 78.0 ± 8.5 kg; height: 179.4 ± 4.7 cm) volunteered to be in a randomized, double-blind, repeated-measures study. Following an overnight fast, an IV catheter was placed in a forearm vein and a resting blood sample was drawn at ∼0800 hours. Each subject was then provided 1 of 3 treatment conditions (placebo, low (0.075 g·kg–1 of body mass), or high (0.15 g·kg–1 of body mass of l-arginine)). Blood samples were drawn at 30, 60, 90, 120, and 180 min after consumption. l-arginine plasma concentrations significantly increased (p < 0.001) to a similar level at any time point in both the low- and high-dose conditions; there was no change over time in the placebo condition. There was no significant difference between conditions for NOx, GH, IGF-1, or insulin. Based on these findings, a low dose of l-arginine was just as effective at increasing plasma l-arginine concentrations as a high dose; however, neither dose was able to promote a significant increase in NOx, GH, IGF-1, or insulin at rest.

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1460. Imipenem/Cilastatin (IMI)/Relebactam (REL) in Hospital-Acquired/Ventilator-Associated Bacterial Pneumonia (HABP/VABP): Subgroup Analyses of Critically Ill Patients in the RESTORE-IMI 2 Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1641 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S732-S732

Author(s):

Luke F Chen ◽

Maria C Losada ◽

Kathryn A Mahoney ◽

Jiejun Du ◽

Michelle L Brown ◽

...

Keyword(s):

Renal Impairment ◽

Clinical Response ◽

Critically Ill ◽

Critically Ill Patients ◽

Severe Renal Impairment ◽

Study Drug ◽

Apache Ii ◽

Apache Ii Score ◽

Double Blind ◽

Mitt Population

Abstract Background HABP/VABP are serious infections associated with high mortality. Critically ill patients (pts) are at particularly high risk of adverse clinical outcomes. In the RESTORE-IMI 2 trial, IMI/REL was non-inferior to PIP/TAZ in primary and key secondary endpoints. We evaluated outcomes specifically in critically ill pts, according to several definitions, from that trial. Methods Randomized, controlled, double-blind, phase 3 trial in adult pts with HABP/VABP. Lower respiratory tract (LRT) specimens were obtained ≤48 hours prior to screening. Pts were randomized 1:1 to IMI/REL 500 mg/250 mg or PIP/TAZ 4 g/500 mg, given IV every 6 h for 7-14 d. The primary endpoint was Day 28 all-cause mortality (ACM) and the key secondary endpoint was clinical response at early follow-up (EFU; 7-14 d after completing therapy) in the modified intent-to-treat (MITT) population (randomized pts with ≥1 dose of study drug, excluding pts with only gram-positive cocci present on baseline Gram stain). This analysis assessed efficacy outcomes specifically in pts in the ICU and in pts with APACHE II score ≥15, both prespecified subgroups. In post-hoc analyses, outcomes were also specifically assessed in the subgroups of pts with moderate/severe renal impairment (creatinine clearance < 60 mL/min) and pts who received vasopressors. Results Of MITT pts (n=531) at baseline, 66.1% (175 IMI/REL, 176 PIP/TAZ) were in the ICU, 47.5% (125 IMI/REL, 127 PIP/TAZ) had APACHE-II score ≥15, and 24.7% (71 IMI/REL, 60 PIP/TAZ) had moderate/severe renal impairment. Further, 20.9% (54 IMI/REL, 57 PIP/TAZ) received vasopressors within 72 h of first dose of study drug and/or during the study. In each subgroup, baseline demographics, clinical characteristics, and causative LRT pathogens (mostly Enterobacterales, P. aeruginosa, and A. calcoaceticus-baumannii complex) were generally comparable between treatment arms. In pts with APACHE-II score ≥15, Day 28 ACM and clinical response rates with IMI/REL were favorable compared to PIP/TAZ (Table). Day 28 ACM was also favorable with IMI/REL in patients receiving vasopressors. Remaining outcomes were similar between treatment arms. Conclusion IMI/REL is an efficacious treatment option for critically ill pts with HABP/VABP. Table. Primary and key secondary efficacy outcomes by subgroup (MITT population) Disclosures Luke F. Chen, MBBS MPH MBA FRACP FSHEA FIDSA, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) Maria C. Losada, BA, Merck & Co., Inc. (Employee, Shareholder) Kathryn A. Mahoney, PharmD, Merck (Employee, Shareholder) Jiejun Du, PhD, Merck & Co., Inc. (Employee, Shareholder) Michelle L. Brown, BS, Merck & Co., Inc. (Employee, Shareholder) Robert Tipping, MS, Merck & Co., Inc. (Employee, Shareholder) Katherine Young, MS, Merck & Co., Inc. (Employee, Shareholder)Merck & Co., Inc. (Employee, Shareholder) C. Andrew DeRyke, PharmD, Merck & Co., Inc. (Employee, Shareholder) Joan R. Butterton, MD, Merck & Co., Inc. (Employee, Shareholder) Amanda Paschke, MD MSCE, Merck & Co., Inc. (Employee, Shareholder)

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179 Dasotraline in Children With Attention Deficit Hyperactivity Disorder: Results of a Randomized, Double-Blind, Placebo-Controlled Study

CNS Spectrums ◽

10.1017/s1092852918000615 ◽

2018 ◽

Vol 23 (1) ◽

pp. 102-103

Author(s):

Robert Goldman ◽

Lenard Adler ◽

Thomas Spencer ◽

Robert Findling ◽

Seth C. Hopkins ◽

...

Keyword(s):

Weight Loss ◽

Repeated Measures ◽

Mixed Model ◽

Rating Scale ◽

Plasma Concentrations ◽

Fixed Dose ◽

Controlled Study ◽

Double Blind ◽

Once Daily ◽

Stable Plasma

AbstractObjectivesOnce-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, achieves stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6–12 years (NCT02428088).MethodsPatients were randomized 1:1:1 to 6 weeks of once-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo. The primary efficacy endpoint was change from baseline (CFB) at Week 6 in ADHD Rating Scale Version IV – Home Version (ADHD RS-IV HV) total score, using a mixed model for repeated measures (MMRM) in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety endpoints.ResultsThe mean age of 342 randomized patients was 9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% of patients completed the study. In the ITT population (N=336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day vs placebo(least squares [LS] mean [SE] CFB at Week 6: –17.53 [±1.31] vs –11.36 [±1.29], respectively, p<0.001; effect size [ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/day vs placebo at Week 6 (p=0.001, p=0.003, respectively). Improvement in CGI-S score was statistically significant with dasotraline 4 mg/day vs placebo(LS mean [SE] CFB at Week 6: –1.39 [±0.12] vs –1.04 [±0.12], respectively, p=0.040; ES: 0.29). No significant improvement was observed on the ADHD RS-IV HV total score and the CGI-S score for dasotraline 2 mg/day vs placebo. The most frequent treatment-emergent AEs (≥5% and higher than placebo) were (2 mg/day; 4 mg/day; placebo): insomnia (15.3%; 21.7%; 4.3%, all terms combined), decreased appetite (12.6%; 21.7%; 5.2%), weight loss (5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%), nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%; 5.2%; 2.6%).ConclusionsCompared with placebo, dasotraline 4 mg/day significantly improved ADHD symptoms in children, as assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs were insomnia, decreased appetite, weight loss and irritability.Funding AcknowledgementsStudy sponsored by Sunovion Pharmaceuticals Inc.

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A single serving of caffeinated coffee impairs postprandial glucose metabolism in overweight men

British Journal Of Nutrition ◽

10.1017/s0007114515002640 ◽

2015 ◽

Vol 114 (8) ◽

pp. 1218-1225 ◽

Cited By ~ 17

Author(s):

Tracey M. Robertson ◽

Michael N. Clifford ◽

Simon Penson ◽

Gemma Chope ◽

M. Denise Robertson

Keyword(s):

Glucose Metabolism ◽

Repeated Measures ◽

Postprandial Glucose ◽

Acute Effects ◽

Double Blind ◽

Beneficial Effects ◽

Decaffeinated Coffee ◽

Caffeinated Coffee ◽

Post Hoc ◽

Dose Dependent

AbstractPrevious studies regarding the acute effects of coffee on glycaemic control have used a single large dose of coffee, typically containing the caffeine equivalent of 2–4 servings of coffee. This study investigates whether the acute effects of coffee are dose-dependent, starting with a single serving. A total of ten healthy overweight males participated in a two-part randomised double-blind cross-over study. In the first part, they ingested 2, 4 or 8 g instant decaffeinated coffee (DC) dissolved in 400 ml water with caffeine added in proportion to the DC (total 100, 200 or 400 mg caffeine) or control (400 ml water) all with 50 g glucose. In the second part, they ingested the same amounts of DC (2, 4, 8 g) or control, but with a standard 100 mg caffeine added to each. Capillary blood samples were taken every 15 min for 2 h after each drink and glucose and insulin levels were measured. Repeated measures ANOVA on glucose results found an effect when caffeine was varied in line with DC (P=0·008). Post hoc analysis revealed that both 2 and 4 g DC with varied caffeine content increased the glycaemic response v. control. There was no effect of escalating doses of DC when caffeine remained constant at 100 mg. These results demonstrate that one standard serving of coffee (2 g) is sufficient to affect glucose metabolism. Furthermore, the amount of caffeine found in one serving (100 mg) is sufficient to mask any potential beneficial effects of increasing other components. No dose-dependent effect was found.

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Vitamin B6 Supplementation Reduces Depression in College Women Taking Oral Contraceptives: A Randomized, Double-Blind Cross-Over Trial

Current Developments in Nutrition ◽

10.1093/cdn/nzaa067_040 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1813-1813

Author(s):

Carol Johnston ◽

Anne Curtin

Keyword(s):

College Women ◽

Beck Depression Inventory ◽

Repeated Measures ◽

Vitamin B6 ◽

Plasma Concentrations ◽

Mood States ◽

Control Treatment ◽

Anthropometric Measures ◽

Double Blind ◽

Increased Risk

Abstract Objectives Oral contraception (OC) use has been linked to an increased risk of depression in college women and to poor micronutrient status. Of note, when compared to non-OC users, OC users have a heightened risk of low plasma concentrations of vitamin B6, a cofactor in the tryptophan-serotonin pathway critical to mood regulation. The purpose of this crossover study was to determine whether vitamin B6 supplementation impacted mood states and depression in college women using OC. Methods Participants were healthy and between 18–25 y, did not smoke or use dietary supplements, and used OC (estrogen with progestin) consistently for at least one year prior to the start of the study. The 12-week, randomized, double-blind crossover trial (4-week treatment periods [B6: 100 mg/d or control: placebo pill/d] separated by a 4-week washout [no pills taken]) was approved by the university Institutional Review Board, and participants provided written consent. Anthropometric measures, blood sampling, and diet and mood assessments were completed at the start of the trial and at weeks 4, 8, and 12. Participants (n = 8) maintained normal exercise and eating patterns the duration of the study and recorded pill consumption daily. The Profile of Mood States (POMS) and Beck Depression Inventory were used to assess affect. Plasma pyridoxal 5′ phosphate (PLP) concentrations were quantified by enzymatic assay. Repeated measures ANOVA was used to assess treatment effects. Results Plasma PLP concentrations averaged 66 ± 32 nmol/L at the start of the trial; one participant presented with marginal vitamin B6 status (20–30 nmol/L). Average vitamin B6 intakes did not vary during the trial (1.2–1.4 mg/d); whereas, vitamin B6 status rose significantly following the B6 supplementation period compared to the other three timepoints. POMS scores were not impacted by treatment; however, Beck Depression Inventory scores were reduced 30% by B6 supplementation in comparison to the control treatment (P = 0.047). Conclusions These preliminary data support a growing literature suggesting the benefits of B6 supplementation for reducing depression in young women using OC. Funding Sources This study was supported in part by the Graduate and Professional Students Association and the Office of the Vice Provost for Research.

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Prevalence and Determinants of Dyslipidemia: Data from a Saudi University Clinic

The Open Public Health Journal ◽

10.2174/1874944501811010416 ◽

2018 ◽

Vol 11 (1) ◽

pp. 416-424 ◽

Cited By ~ 3

Author(s):

Yasser Taher Al-Hassan ◽

Eduardo L. Fabella ◽

Edric Estrella ◽

Mohammad Aatif

Keyword(s):

Logistic Regression ◽

Lipid Profile ◽

Odds Ratio ◽

Profile Analysis ◽

Cross Sectional Study ◽

Sectional Study ◽

Multivariable Logistic Regression Model ◽

Cross Sectional ◽

The Relationship ◽

Prevalent Form

Background: Dyslipidemia is a risk factor for cardiovascular diseases. The relationship between demographic factors and dyslipidemia in Saudi Arabia is not completely explored. Objectives: This analytic cross-sectional study was conducted to describe the lipid profile, determine the proportion and identify significant demographic determinants of dyslipidemia among patients who have undergone lipid profile analysis in a university multispecialty clinic. Methods: The results of lipid profile examination of 1,541 King Faisal University clinic patients from 1 April, 2014 to 7 March, 2016 were compiled and subjected to descriptive and analytical statistics using STATA MP version 14. Multivariable logistic regression model using Adjusted Odds Ratio (AOR) and 95% Confidence Interval (CI) was fitted to analyze the independent predictors of dyslipidemia. Results: The prevalence of hypercholesterolemia, hypertriglyceridemia, hypo-HDL-cholesterolemia, and hyper-LDL-cholesterolemia were 13.8%, 17.0%, 40.0% 12.85%, respectively. Logistic regression revealed that in comparison with those who were 20 years old and below, those who were between the age of 40-49 years were 4.5 times more likely to have hypercholesterolemia and 3.5 times more likely to have hyper-LDL-cholesterolemia. Similarly, those who were 30-39 years old were 4.3 times and 3 times more likely to have hypertriglyceridemia and hypercholesterolemia, respectively. The same stage group was 3 times more likely to develop hyper-LDL-cholesterolemia. Females were 1.4 times more like to have hypercholesterolemia; non-Saudis were nearly twice as likely to develop hypertriglyceridemia than Saudis. Conclusion: Hypo-HDL-cholesterolemia was the most prevalent form of dyslipidemia. Age, gender and nationality were significant determinants of specific types of dyslipidemia.

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A Double-blind, Randomized Comparison of IV Lorazepam versus Midazolam for Sedation of ICU Patients via a Pharmacologic Model

Anesthesiology ◽

10.1097/00000542-200108000-00007 ◽

2001 ◽

Vol 95 (2) ◽

pp. 286-298 ◽

Cited By ~ 117

Author(s):

Juliana Barr ◽

Katayoun Zomorodi ◽

Edward J. Bertaccini ◽

Steven L. Shafer ◽

Eran Geller

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Sedation Score ◽

Surgical Intensive Care Unit ◽

Population Pharmacokinetic ◽

Surgical Intensive Care ◽

Double Blind ◽

Icu Patients ◽

Intravenous Infusions

Background Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients. Methods With Institutional Review Board approval, 24 consenting adult surgical patients were given either lorazepam or midazolam in a double-blind fashion (together with either intravenous fentanyl or epidural morphine for analgesia) through target-controlled intravenous infusions titrated to maintain a moderate level of sedation for 12-72 h postoperatively. Moderate sedation was defined as a Ramsay Sedation Scale score of 3 or 4. Sedation scores were measured, together with benzodiazepine plasma concentrations. Population pharmacokinetic and pharmacodynamic parameters were estimated using nonlinear mixed-effects modeling. Results A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation > or = ss) = 50%) values for midazolam (sedation score [SS] > or = n, where n = a Ramsay Sedation Score of 2, 3, ... 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively. Conclusions The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.

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Effect of beta blocker use and type on hypoglycemia risk among hospitalized insulin requiring patients

Cardiovascular Diabetology ◽

10.1186/s12933-019-0967-1 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 2

Author(s):

Kathleen Dungan ◽

Jennifer Merrill ◽

Clarine Long ◽

Philip Binkley

Keyword(s):

Confidence Interval ◽

Critically Ill ◽

Beta Blocker ◽

Basal Insulin ◽

Odds Ratio ◽

Beta Blockers ◽

Glucose Monitoring ◽

Hospitalized Patients ◽

The Difference ◽

The Relationship

Abstract Background Although beta blockers could increase the risk of hypoglycemia, the difference between subtypes on hypoglycemia and mortality have not been studied. This study sought to determine the relationship between type of beta blocker and incidence of hypoglycemia and mortality in hospitalized patients. Methods We retrospectively identified non-critically ill hospitalized insulin requiring patients who were undergoing bedside glucose monitoring and received either carvedilol or a selective beta blocker (metoprolol or atenolol). Patients receiving other beta blockers were excluded. Hypoglycemia was defined as any glucose < 3.9 mmol/L within 24 h of admission (Hypo1day) or throughout hospitalization (HypoT) and any glucose < 2.2 mmol/L throughout hospitalization (Hyposevere). Results There were 1020 patients on carvedilol, 886 on selective beta blockers, and 10,216 on no beta blocker at admission. After controlling for other variables, the odds of Hypo1day, HypoT and Hyposevere were higher for carvedilol and selective beta blocker recipients than non-recipients, but only in basal insulin nonusers. The odds of Hypo1day (odds ratio [OR] 1.99, 95% confidence interval [CI] 1.28, 3.09, p = 0.0002) and HypoT (OR 1.38, 95% CI 1.02, 1.86, p = 0.03) but not Hyposevere (OR 1.90, 95% CI 0.90, 4.02, p = 0.09) were greater for selective beta blocker vs. carvedilol recipients in basal insulin nonusers. Hypo1day, HypoT, and Hyposevere were all associated with increased mortality in adjusted models among non-beta blocker and selective beta blocker recipients, but not among carvedilol recipients. Conclusions Beta blocker use is associated with increased odds of hypoglycemia among hospitalized patients not requiring basal insulin, and odds are greater for selective beta blockers than for carvedilol. The odds of hypoglycemia-associated mortality are increased with selective beta blocker use or nonusers but not in carvedilol users, warranting further study.

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Pharmacokinetics and Pharmacodynamics of Meropenem by Extended or Continuous Infusion in Low Body Weight Critically Ill Patients

Antibiotics ◽

10.3390/antibiotics10060666 ◽

2021 ◽

Vol 10 (6) ◽

pp. 666

Author(s):

Sonia Luque ◽

Adela Benítez-Cano ◽

Leire Larrañaga ◽

Luisa Sorlí ◽

María Eugenia Navarrete ◽

...

Keyword(s):

Body Weight ◽

Continuous Infusion ◽

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Apache Ii Score ◽

Therapeutic Drug ◽

Dosing Regimens ◽

Severe Infections ◽

Normal Body Weight

Background: Pathophysiological changes such as extreme body weights in critically ill patients with severe infections may alter the pharmacokinetics (PK) of antimicrobials, leading to treatment failure or toxicity. There are almost no PK data on meropenem in critically ill patients with low body weight (LwBW) and therefore information is lacking on the most appropriate dosing regimens, especially when administered by extended infusion. Objectives: To assess if the current administered doses of meropenem could lead to supratherapeutic concentrations in LwBW patients and to identify the factors independently associated with overexposure. Methods: A matched case-control 1:1 study of surgical critically ill patients treated with meropenem administered by extended or continuous infusion and undergoing therapeutic drug monitoring was conducted. Cases (patients with LwBW (body mass index (BMI) < 18.5 kg/m2)) were matched with normal body weight controls (NBW) (patients with BMI ≥ 18.5 kg/m2 and ≤30 kg/m2)) by age, gender, baseline renal function and severity status (APACHE II score). A 100% fT > MIC was considered an optimal pharmacokinetic/pharmacodynamic (PK/PD) target and 100% fT > 10 × MIC as supratherapeutic exposure. Results: Thirty-six patients (18 cases and 18 controls) were included (median (range) age, 57.5 (26–75) years; 20 (55.6% male)). Meropenem was administered by 6 h (extended) or 8 h (continuous) infusion at a median (range) daily dose of 5 (1–6) g/day. Similar median meropenem trough plasma concentrations (Cmin,ss), measured pre-dose on day three to four of treatment) were observed in the two groups (19.9 (22.2) mg/L vs 22.4 (25.8) mg/L, p > 0.999). No differences in the proportion of patients with an optimal or a supratherapeutic PKPD target between cases and controls were observed. A baseline estimated glomerular filtration rate (eGFR) < 90 mL/min was the only factor independently associated with a supratherapeutic PK/PD target. Conclusions: LwBW seems not to be a risk factor for achieving a supratherapeutic PK/PD target in critically ill patients receiving meropenem at standard doses by extended or continuous infusion.

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