BackgroundWhile in vitro and animal studies have shown reduced cytochrome P450 (CYP) 3A activity due to obesity, clinical studies in (morbidly) obese patients are scarce. As CYP3A activity may influence both clearance and oral bioavailability in a distinct manner, in this study the pharmacokinetics of the CYP3A substrate midazolam were evaluated after semi-simultaneous oral and intravenous administration in morbidly obese patients, and compared with healthy volunteers.MethodsTwenty morbidly obese patients [mean body weight 144 kg (range 112–186 kg) and mean body mass index 47 kg/m2 (range 40–68 kg/m2)] participated in the study. All patients received a midazolam 7.5 mg oral and 5 mg intravenous dose (separated by 159 ± 67 min) and per patient 22 samples over 11 h were collected. Data from 12 healthy volunteers were available for a population pharmacokinetic analysis using NONMEM®.ResultsIn the three-compartment model in which oral absorption was characterized by a transit absorption model, population mean clearance (relative standard error %) was similar [0.36 (4 %) L/min], while oral bioavailability was 60 % (13 %) in morbidly obese patients versus 28 % (7 %) in healthy volunteers (P < 0.001). Central and peripheral volumes of distribution increased substantially with body weight (both P < 0.001) and absorption rate (transit rate constant) was lower in morbidly obese patients [0.057 (5 %) vs. 0.130 (14 %) min–1, P < 0.001].ConclusionsIn morbidly obese patients, systemic clearance of midazolam is unchanged, while oral bioavailability is increased. Given the large increase in volumes of distribution, dose adaptations for intravenous midazolam should be considered. Further research should elucidate the exact physiological changes at intestinal and hepatic level contributing to these findings.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-014-0166-x) contains supplementary material, which is available to authorized users.

This study shows that cefazolin tissue distribution is lower in morbidly obese patients and reduces with increasing body weight, and that dose adjustments are required in this patient group.

The assistance of third-year medical students (MS3) may be an easy, inexpensive, educational method to decrease physical and emotional stress among first-year medical students (MS1) on the first day of gross anatomy dissection. In the academic years 2000-2001 and 2001-2002, a questionnaire on the emotional and physical reactions on the first day of dissection was distributed to 84 MS1 at Mayo Medical School (Rochester, MN); 74 (88%) responded. Student perceptions were assessed on a 5-point Likert scale. The 42 second-year medical students (MS2) whose first academic year was 1999-2000 were used as a control group, because they had not had assistance from MS3. MS2 completed the same questionnaire (59% response rate). Data were collected from MS1 on the day of their first gross anatomy dissection. The most frequent reactions were headache, disgust, grief or sadness, and feeling light-headed. Significant differences (alpha < 0.05) were found with use of the chi(2) test to compare the emotional and physical reactions of MS1 and MS2. MS1 had significantly fewer physical reactions (64% vs. 88%), reporting lower levels of anxiety (23% vs. 48%), headache (14% vs. 36%), disgust (9% vs. 20%), feeling light-headed (11% vs. 24%), and reaction to the smell of the cadaver and laboratory (8% vs. 52%). MS1 commented that having MS3 at the dissection table was extremely helpful. They relied less on their peers and felt they learned more efficiently about the dissection techniques and anatomical structures. Using MS3 as assistants is one method to reduce fear and anxiety on the first day of gross anatomy dissection.

BackgroundDuring resuscitation in severe sepsis and septic shock, several goals are set. However, usually not all goals are equally met. The aim of this study is to determine the relative importance of the different goals, such as mean arterial pressure (MAP), lactate, central venous oxygen saturation (ScvO2) and central to forefoot temperature (delta-T), and how they relate to intensive care unit (ICU) and hospital mortality.MethodsIn a retrospective cohort study in a 20-bed mixed medical and surgical ICU of a teaching hospital we studied consecutive critically ill patients who were admitted for confirmed infection and severe sepsis or septic shock between 2008 and 2014. All validated MAP, lactate levels, ScvO2 and delta-T for the first 24 hours of ICU treatment were extracted from a clinical database. Logistic regression analyses were performed on validated measurements in the first hour after admission and on mean values over 24 hours. Patients were categorized by MAP (24-hour mean below or above 65 mmHg) and lactate (24-hour mean below or above 2 mmol/l) for Cox regression analysis.ResultsFrom 837 patients, 821 were eligible for analysis. All had MAP and lactate measurements. The delta-T was available in 812 (99 %) and ScvO2 was available for 193 out of these patients (23.5 %). Admission lactate (p < 0.001) and admission MAP (p < 0.001) were independent predictors of ICU and hospital mortality. The 24-hour mean values for lactate, MAP and delta-T were all independent predictors of ICU mortality. Hospital mortality was independently predicted by the 24-hour mean lactate (odds ratio (OR) 1.34, 95 % confidence interval (CI) 1.30–1.40, p = 0.001) mean MAP (OR 0.96, 95 % CI 0.95–0.97, p = 0.001) and mean delta-T (OR 1.09, 95 % CI 1.06–1.12, p = 0.001). Patients with a 24-hour mean lactate below 2 mmol/l and a 24-hour mean MAP above 65 mmHg had the best survival, followed by patients with a low lactate and a low MAP.ConclusionsAdmission MAP and lactate independently predicted ICU and hospital mortality. The 24-hour mean lactate, mean MAP and mean delta-T independently predicted hospital mortality. A Cox regression analysis showed that 24-hour mean lactate above 2 mmol/l is the strongest predictor for ICU mortality.