Population pharmacokinetics of dexamethasone in critically ill COVID-19 patients:Does inflammation play a role?

Purpose: The aim of this study is to design a population pharmacokinetic study to gain a deeper understanding of the pharmacokinetics of dexamethasone in critically ill COVID-19 patients in order to identify relevant covariates that can be used to personalize dosing regimens. Methods: Blood samples from critically ill patients receiving fixed-dose intravenous dexamethasone (6 mg/day) for the treatment of COVID-19 were sampled in a retrospective pilot study. The data were analyzed using Nonlinear Mixed Effects Modeling (NONMEM) software for population pharmacokinetic analysis and clinically relevant covariates were selected and evaluated. Results: A total of 51 dexamethasone samples from 18 patients were analyzed and a two-compartment model fit the data best. The mean population estimates were 2.85 L/h (inter-individual-variability 62.9%) for clearance, 15.4 L for the central volume of distribution, 12.3 L for the peripheral volume of distribution and 2.1 L/h for the inter-compartmental distribution clearance. The covariate analysis showed a significant negative correlation between dexamethasone clearance and CRP. Conclusions: Dexamethasone PK parameters in ICU COVID patients were substantially different from those from non-ICU non-COVID patients, and inflammation may play an important role in dexamethasone exposure. This finding suggests that fixed-dose dexamethasone over several days may not be appropriate for ICU COVID patients.</p

Intraoperative Music to Promote Patient Outcome (IMPROMPTU):A Double-Blind Randomized Controlled Trial

Introduction: Perioperative music can have beneficial effects on postoperative pain, anxiety, opioid requirement, and the physiological stress response to surgery. The aim was to assess the effects of intraoperative music during general anesthesia in patients undergoing surgery for esophagogastric cancer. Materials and methods: The IMPROMPTU study was a double-blind, placebo-controlled, randomized multicenter trial. Adult patients undergoing surgery for stage II-III esophagogastric cancer were eligible. Exclusion criteria were a hearing impairment, insufficient Dutch language knowledge, corticosteroids use, or objection to hearing unknown music. Patients wore active noise-cancelling headphones intraoperatively with preselected instrumental classical music (intervention) or no music (control). Computerized randomization with centralized allocation, stratified according to surgical procedure using variable block sizes, was employed. Primary endpoint was postoperative pain on the first postoperative day. Secondary endpoints were postoperative pain during the first postoperative week, postoperative opioid requirement, intraoperative medication requirement, the stress response to surgery, postoperative complication rate, length of stay, and mortality, with follow-up lasting 30 d. Results: From November 2018 to September 2020, 145 patients were assessed and 83 randomized. Seventy patients (music n = 31, control n = 39) were analyzed. Median age was 70 [IQR 63–70], and 48 patients (69%) were male. Music did not reduce postoperative pain (numeric rating scale 1.8 (SD0.94) versus 2.0 (1.0), mean difference −0.28 [95% CI -0.76–0.19], P = 0.236). No statistically significant differences were seen in medication requirement, stress response, complication rate, or length of stay. Conclusions: Intraoperative, preselected, classical music during esophagogastric cancer surgery did not significantly improve postoperative outcome and recovery when compared to no music using noise-cancelling headphones.</p

Intraoperative Music to Promote Patient Outcome (IMPROMPTU):A Double-Blind Randomized Controlled Trial

Introduction: Perioperative music can have beneficial effects on postoperative pain, anxiety, opioid requirement, and the physiological stress response to surgery. The aim was to assess the effects of intraoperative music during general anesthesia in patients undergoing surgery for esophagogastric cancer. Materials and methods: The IMPROMPTU study was a double-blind, placebo-controlled, randomized multicenter trial. Adult patients undergoing surgery for stage II-III esophagogastric cancer were eligible. Exclusion criteria were a hearing impairment, insufficient Dutch language knowledge, corticosteroids use, or objection to hearing unknown music. Patients wore active noise-cancelling headphones intraoperatively with preselected instrumental classical music (intervention) or no music (control). Computerized randomization with centralized allocation, stratified according to surgical procedure using variable block sizes, was employed. Primary endpoint was postoperative pain on the first postoperative day. Secondary endpoints were postoperative pain during the first postoperative week, postoperative opioid requirement, intraoperative medication requirement, the stress response to surgery, postoperative complication rate, length of stay, and mortality, with follow-up lasting 30 d. Results: From November 2018 to September 2020, 145 patients were assessed and 83 randomized. Seventy patients (music n = 31, control n = 39) were analyzed. Median age was 70 [IQR 63–70], and 48 patients (69%) were male. Music did not reduce postoperative pain (numeric rating scale 1.8 (SD0.94) versus 2.0 (1.0), mean difference −0.28 [95% CI -0.76–0.19], P = 0.236). No statistically significant differences were seen in medication requirement, stress response, complication rate, or length of stay. Conclusions: Intraoperative, preselected, classical music during esophagogastric cancer surgery did not significantly improve postoperative outcome and recovery when compared to no music using noise-cancelling headphones.</p

Supplementary data for: Missed Diagnoses and Health Problems in Adults With Prader-Willi Syndrome: Recommendations for Screening and Treatment

Context: Prader-Willi syndrome (PWS) is a complex hypothalamic disorder, combining hyperphagia, hypotonia, intellectual disability, and pituitary hormone deficiencies. Annual mortality of patients with PWS is high (3%). In half of the patients, the cause of death is obesity related and/or of cardiopulmonary origin. Health problems leading to this increased mortality often remain undetected due to the complexity and rareness of the syndrome. Objective: To assess the prevalence of health problems in adults with PWS retrospectively. Patients, Design, and Setting: We systematically screened 115 PWS adults for undiagnosed health problems. All patients visited the multidisciplinary outpatient clinic for rare endocrine syndromes at the Erasmus University Medical Center, Rotterdam, Netherlands. We collected the results of medical questionnaires, interviews, physical xaminations, biochemical measurements, polygraphy, polysomnography, and radiology. Main outcome measures: Presence or absence of endocrine and nonendocrine comorbidities in relation to living situation, body mass index, genotype, and demographic factors. Results: Seventy patients (61%) had undiagnosed health problems, while 1 in every 4 patients had multiple undiagnosed health problems simultaneously. All males and 93% of females had hypogonadism, 74% had scoliosis, 18% had hypertension, 19% had hypercholesterolemia, 17% had type 2 diabetes mellitus, and 17% had hypothyroidism. Unfavorable lifestyles were common: 22% exercised too little (according to PWS criteria) and 37% did not see a dietitian. Conclusions: Systematic screening revealed many undiagnosed health problems in PWS adults. Based on patient characteristics, we provide an algorithm for diagnostics and treatment, with the aim to prevent early complications and reduce mortality in this vulnerable patient group

Ensuring quality in 17OHP mass spectrometry measurement:an international study assessing isomeric steroid interference

Objectives: Interference from isomeric steroids is a potential cause of disparity between mass spectrometry-based 17-hydroxyprogesterone (17OHP) results. We aimed to assess the proficiency of mass spectrometry laboratories to report 17OHP in the presence of known isomeric steroids. Methods:A series of five samples were prepared using a previously demonstrated commutable approach. These samples included a control (spiked to 15.0 nmol/L 17OHP) and four challenge samples further enriched with equimolar concentrations of 17OHP isomers (11α-hydroxyprogesterone, 11β-hydroxyprogesterone, 16α-hydroxyprogesterone or 21-hydroxyprogesterone). These samples were distributed to 38 participating laboratories that reported serum 17OHP results using mass spectrometry in two external quality assurance programs. The result for each challenge sample was compared to the control sample submitted by each participant. Results: Twenty-six laboratories (68 % of distribution) across three continents returned results. Twenty-five laboratories used liquid chromatography-tandem mass spectrometry (LC-MS/MS), and one used gas chromatography-tandem mass spectrometry to measure 17OHP. The all-method median of the control sample was 14.3 nmol/L, ranging from 12.4 to 17.6 nmol/L. One laboratory had results that approached the lower limit of tolerance (minus 17.7 % of the control sample), suggesting the isomeric steroid caused an irregular result. Conclusions: Most participating laboratories demonstrated their ability to reliably measure 17OHP in the presence of the four clinically relevant isomeric steroids. The performance of the 12 (32 %) laboratories that did not engage in this activity remains unclear. We recommend that all laboratories offering LC-MS/MS analysis of 17OHP in serum, plasma, or dried bloodspots determine that the isomeric steroids are appropriately separated.</p

Ensuring quality in 17OHP mass spectrometry measurement:an international study assessing isomeric steroid interference

Objectives: Interference from isomeric steroids is a potential cause of disparity between mass spectrometry-based 17-hydroxyprogesterone (17OHP) results. We aimed to assess the proficiency of mass spectrometry laboratories to report 17OHP in the presence of known isomeric steroids. Methods:A series of five samples were prepared using a previously demonstrated commutable approach. These samples included a control (spiked to 15.0 nmol/L 17OHP) and four challenge samples further enriched with equimolar concentrations of 17OHP isomers (11α-hydroxyprogesterone, 11β-hydroxyprogesterone, 16α-hydroxyprogesterone or 21-hydroxyprogesterone). These samples were distributed to 38 participating laboratories that reported serum 17OHP results using mass spectrometry in two external quality assurance programs. The result for each challenge sample was compared to the control sample submitted by each participant. Results: Twenty-six laboratories (68 % of distribution) across three continents returned results. Twenty-five laboratories used liquid chromatography-tandem mass spectrometry (LC-MS/MS), and one used gas chromatography-tandem mass spectrometry to measure 17OHP. The all-method median of the control sample was 14.3 nmol/L, ranging from 12.4 to 17.6 nmol/L. One laboratory had results that approached the lower limit of tolerance (minus 17.7 % of the control sample), suggesting the isomeric steroid caused an irregular result. Conclusions: Most participating laboratories demonstrated their ability to reliably measure 17OHP in the presence of the four clinically relevant isomeric steroids. The performance of the 12 (32 %) laboratories that did not engage in this activity remains unclear. We recommend that all laboratories offering LC-MS/MS analysis of 17OHP in serum, plasma, or dried bloodspots determine that the isomeric steroids are appropriately separated.</p