The negative impact of vitamin D on antipsychotic drug exposure may counteract its potential benefits in schizophrenia.

AIMS: Patients with schizophrenia frequently show insufficient vitamin D levels, which are associated with somatic comorbidity and may contribute to psychopathology. For many reasons, vitamin D supplementation may be indicated for this patient cohort. However, there is growing evidence for a vitamin D-mediated increase of drug metabolism by induction of cytochrome P450 (CYP) 3A4. Hence, this study aimed to assess vitamin D's impact on both antipsychotic drug concentrations and psychopathology in a non-interventional manner. METHODS: Totals of 107 serum concentrations of different antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine and risperidone), 80 serum concentrations of vitamin D and psychopathological assessments were obtained from 80 patients with schizophrenia. The impact of Vitamin D on antipsychotic drug concentrations and symptomatology was assessed using a generalized linear model, path and correlation analyses. RESULTS: We observed a negative relationship between vitamin D and dose-adjusted antipsychotic drug concentrations, which was particularly pronounced for drugs which are predominantly metabolized via CYP3A4 (i.e., aripiprazole and quetiapine). A path analysis suggested a relieving effect of vitamin D on symptomatology which was, however, counteracted by its negative impact on antipsychotic drug levels. Finally, patients with vitamin D levels above the median exhibited a significantly higher proportion of therapeutically insufficient dose-normalized drug concentrations of aripiprazole and quetiapine. CONCLUSION: Despite vitamin D's potential benefits on physical and mental health, clinicians should be aware of its negative impact on blood concentrations of antipsychotics metabolized by CYP3A4 in patients with schizophrenia. Therefore, when considering its supplementation, therapeutic drug monitoring should be applied to guide dose adjustment.

Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy and concomitant lithium therapy remain a matter of debate because of increased rates of adverse events. Current recommendations include monitoring lithium levels and reducing lithium to minimally effective dose. We present a report on protracted effects of lithium intoxication as electroconvulsive therapy 8 days after intoxication and under normal lithium serum levels resulted in a prolonged seizure. Electroencephalogram recordings before stimulation showed electroencephalogram correlates of subsiding lithium intoxication most likely due to protracted lithium influx and efflux of the central nervous system.

Antidepressants in breast milk; comparative analysis of excretion ratios.

Despite increasing prescription rates of antidepressants in pregnant and breastfeeding women over the past decades, evidence of drug exposure for neonates through lactation is very sparse. Concentrations of three antidepressants citalopram, sertraline, and venlafaxine were measured in maternal blood and breast milk in 17 women receiving antidepressant therapy during breastfeeding period. We also computed concentration-by-dose-ratios (C/D) and milk to serum (plasma) penetration ratios (M/P). Non-parametric tests were applied. Serum concentration of citalopram and daily dosage correlated positively while daily dosage and mother milk concentration did not (rho = 0.939, p = 0.005, and rho = 0.772, p > 0.05 respectively). A significant correlation was also found between serum and milk concentrations (rho = 0.812, p = 0.05). Venlafaxine daily dosage correlated positively with the active moiety milk concentration (rho = 0.949, p = 0.014). No significant correlations were reported for sertraline. The amount of antidepressant concentrations to which neonates may be exposed, assessed as absolute infant dose (AID), was particularly low with the highest median AID being 0.16 mg/kg/day for venlafaxine. No significant difference was detected for the M/P ratios between different drugs (p > 0.05), whereas the comparison of C/D ratios revealed lower values in the sertraline group, with the highest values reported for citalopram group (p = 0.007 for serum concentrations and p = 0.008 for mother milk). Findings suggest that breastfeeding under antidepressant treatment constantly exposes children with measurable drug concentrations. As daily dosage and serum concentration of the antidepressants did not predict drug concentrations in mother milk, measuring of drug concentrations in milk helps to quantify drug exposure during breastfeeding. More data-even data of drug concentrations in breastfed children-are needed to better assess the effects of drug exposure on children's development.

How to Treat Hypertension in Venlafaxine-Medicated Patients-Pharmacokinetic Considerations in Prescribing Amlodipine and Ramipril.

BACKGROUND: Amlodipine (AMLO) and ramipril (RAMI) belong to the most prescribed drugs in patients with hypertension, a condition also encountered in depression. Venlafaxine may worsen hypertension because of noradrenergic properties. Although of special clinical relevance, data on pharmacokinetic interactions between AMLO, RAMI, and venlafaxine (VEN) are lacking. METHODS: Two TDM databases consisting of plasma concentrations of VEN and its active metabolite O-desmethylvenlafaxine (ODVEN) were analyzed. We considered a group of patients comedicated with AMLO, VAMLO (n = 22); a group comedicated with RAMI, VRAMI (n = 20); and a 4:1 control group age matched to the VAMLO group receiving VEN without confounding medications, V0 (n = 88). Plasma concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN); metabolic ratio (ODVEN/VEN); and dose-adjusted plasma concentrations (C/D) were compared using nonparametric tests. RESULTS: Groups did not differ in daily VEN dose, age, or sex. The metabolic ratio (ODVEN/VEN) was lower in the AMLO group (P = 0.029), whereas the RAMI group showed lower values for ODVEN (P = 0.029). All other parameters showed no significant differences. CONCLUSIONS: Significantly lower values for the metabolic ratio in the AMLO group are unlikely to be explained by cytochrome P450 (CYP) 3A4 and weak CYP2D6 inhibition by AMLO. Other factors such as differences in CYP2D6 polymorphisms and metabolizer status may better explain the findings. Ramipril showed modest effects with changes in ODVEN concentrations that did not remain significant after dose-adjusted comparisons.

Association of the Quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) Score With Excess Hospital Mortality in Adults With Suspected Infection in Low- and Middle-Income Countries.

Importance: The quick Sequential (Sepsis-Related) Organ Failure Assessment (qSOFA) score has not been well-evaluated in low- and middle-income countries (LMICs). Objective: To assess the association of qSOFA with excess hospital death among patients with suspected infection in LMICs and to compare qSOFA with the systemic inflammatory response syndrome (SIRS) criteria. Design, Settings, and Participants: Retrospective secondary analysis of 8 cohort studies and 1 randomized clinical trial from 2003 to 2017. This study included 6569 hospitalized adults with suspected infection in emergency departments, inpatient wards, and intensive care units of 17 hospitals in 10 LMICs across sub-Saharan Africa, Asia, and the Americas. Exposures: Low (0), moderate (1), or high (≥2) qSOFA score (range, 0 [best] to 3 [worst]) or SIRS criteria (range, 0 [best] to 4 [worst]) within 24 hours of presentation to study hospital. Main Outcomes and Measures: Predictive validity (measured as incremental hospital mortality beyond that predicted by baseline risk factors, as a marker of sepsis or analogous severe infectious course) of the qSOFA score (primary) and SIRS criteria (secondary). Results: The cohorts were diverse in enrollment criteria, demographics (median ages, 29-54 years; males range, 36%-76%), HIV prevalence (range, 2%-43%), cause of infection, and hospital mortality (range, 1%-39%). Among 6218 patients with nonmissing outcome status in the combined cohort, 643 (10%) died. Compared with a low or moderate score, a high qSOFA score was associated with increased risk of death overall (19% vs 6%; difference, 13% [95% CI, 11%-14%]; odds ratio, 3.6 [95% CI, 3.0-4.2]) and across cohorts (P < .05 for 8 of 9 cohorts). Compared with a low qSOFA score, a moderate qSOFA score was also associated with increased risk of death overall (8% vs 3%; difference, 5% [95% CI, 4%-6%]; odds ratio, 2.8 [95% CI, 2.0-3.9]), but not in every cohort (P < .05 in 2 of 7 cohorts). High, vs low or moderate, SIRS criteria were associated with a smaller increase in risk of death overall (13% vs 8%; difference, 5% [95% CI, 3%-6%]; odds ratio, 1.7 [95% CI, 1.4-2.0]) and across cohorts (P < .05 for 4 of 9 cohorts). qSOFA discrimination (area under the receiver operating characteristic curve [AUROC], 0.70 [95% CI, 0.68-0.72]) was superior to that of both the baseline model (AUROC, 0.56 [95% CI, 0.53-0.58; P < .001) and SIRS (AUROC, 0.59 [95% CI, 0.57-0.62]; P < .001). Conclusions and Relevance: When assessed among hospitalized adults with suspected infection in 9 LMIC cohorts, the qSOFA score identified infected patients at risk of death beyond that explained by baseline factors. However, the predictive validity varied among cohorts and settings, and further research is needed to better understand potential generalizability.

How to learn effectively in medical school: test yourself, learn actively, and repeat in intervals.

Students in medical school often feel overwhelmed by the excessive amount of factual knowledge they are obliged to learn. Although a large body of research on effective learning methods is published, scientifically based learning strategies are not a standard part of the curriculum in medical school. Students are largely unaware of how to learn successfully and improve memory. This review outlines three fundamental methods that benefit learning: the testing effect, active recall, and spaced repetition. The review summarizes practical learning strategies to learn effectively and optimize long-term retention of factual knowledge.

Sustainable surgical resource initiative for Haiti: the SSRI-Haiti project.

In response to the 2010 earthquake and subsequent cholera epidemic, St Luke's Medical Center was established in Port-au-Prince, Haiti. Here, we describe its inception and evolution to include an intensive care unit and two operating rooms, as well as the staffing, training and experiential learning activities, which helped St Luke's become a sustainable surgical resource. We describe a three-phase model for establishing a sustainable surgical centre in Haiti (build facility and acquire equipment; train staff and perform surgeries; provide continued education and expansion including regular specialist trips) and we report a progressive increase in the number and complexity of cases performed by all-Haitian staff from 2012 to 2022. The results are generalised in the context of the 'delay framework' to global health along with a discussion of the application of this three-phase model to resource-limited environments. We conclude with a brief description of the formation of a remote surgical centre in Port-Salut, an unforeseen benefit of local competence and independence. Establishing sustainable and collaborative surgery centres operated by local staff accelerates the ability of resource-limited countries to meet high surgical burdens.

Effects of the antidepressant mirtazapine on the swimming behaviour and gene expression rate of Danio rerio embryos - Is the sedating effect seen in humans also evident for fish?

In the last decade, mirtazapine has become an important antidepressant in clinical use and has also been found at many different environmental sampling sites. Several homologies between the zebrafish Danio rerio and humans, combined with a number of advantages for behavioural and gene expression research using zebrafish embryos, make their use for the analysis of mirtazapine appropriate. The sedative effect of mirtazapine in humans was also found for a specific concentration range in zebrafish embryos (1333.4 µg/L - 2666.9 µg/L). Specifically, 116 hpf old zebrafish embryos showed a reduced swimming distance when exposed to 1334.4 µg/L mirtazapine. Furthermore, changes at the gene regulatory level could be measured (1333.4 µg/L), in particular in the superordinate regulatory systems. For selected transporters of all regulatory systems, an up regulation of the genes by a factor of more than five times could be measured at the highest mirtazapine exposure concentration that was tested. Finally, studies on the protein levels demonstrated an increase in acetylcholinesterase activity for several exposure concentrations (83.3 µg/L and 666.7 µg/L). The physiological changes in zebrafish embryos caused by mirtazapine demonstrate the relevance of these types of studies in aquatic non-target organisms. Such neuroactive substances could pose a potential risk for aquatic organisms below the previously considered concentration threshold for morphological effects.

Pregnancy exposure to venlafaxine-Therapeutic drug monitoring in maternal blood, amniotic fluid and umbilical cord blood and obstetrical outcomes.

BACKGROUND: For treatment with psychotropic drugs during pregnancy, extended therapeutic drug monitoring is recommended for individual therapy adjustment. We measured venlafaxine (VEN), O-desmethylvenlafaxine (ODV) and active moiety, AM (sum of VEN+ODV) concentrations in maternal serum, amniotic fluid and umbilical cord blood. METHODS: Concentrations of VEN, ODVEN and AM were measured in nine mother-infant pairs at time of delivery; in five cases, amniotic fluid samples were available. Concentrations are reported as median values, first (Q1) and third (Q3) quartiles and ranges. Penetration ratio was calculated by dividing concentrations of VEN, ODVEN and AM in amniotic fluid and umbilical cord blood by maternal serum concentrations. RESULTS: Median daily dosage of venlafaxine was 75 mg (range 37.5-225 mg). There were no significant correlations between daily dose, maternal serum, umbilical cord blood and amniotic fluid concentrations. Median penetration ratio into amniotic fluid was 2.5 (range 0.56-4.48). Median penetration ratio into fetal circulation was 1.05 (range 0.62-2.08). Median concentration of AM was 223.8 ng/mL, range 33.9-338.0 ng/mL (maternal serum), 789.0 ng/mL, range 309-1052.5 ng/mL (amniotic fluid) and 291.0 ng/mL, range 21.1-448.4 ng/mL (cord blood). DISCUSSION: VEN, ODVEN and AM concentrations in maternal serum, amniotic fluid and umbilical cord blood indicate that the fetus might have been exposed to relatively high concentrations throughout pregnancy. High concentrations in amniotic fluid indicate an increased penetration into and/or accumulation within amniotic fluid and a decreased elimination out of amniotic fluid. Findings indicate that fetal in-utero exposition to venlafaxine is higher compared to other antidepressants.

Using critical care physicians to deliver anesthesia and boost surgical caseload in austere environments: the Critical Care General Anesthesia Syllabus (CC GAS).

BACKGROUND: Despite an often severe lack of surgeons and surgical equipment, the rate-limiting step in surgical care for the nearly five billion people living in resource-limited areas is frequently the absence of safe anesthesia. During disaster relief and surgical missions, critical care physicians (CCPs), who are already competent in complex airway and ventilator management, can help address the need for skilled anesthetists in these settings. METHODS: We provided a descriptive analysis that CCPs were trained to provide safe general anesthesia, monitored anesthesia care (MAC), and spinal anesthesia using a specifically designed and simple syllabus. RESULTS: Six CCPs provided anesthesia under the supervision of a board-certified anesthesiologist for 58 (32%) cases of a total of 183 surgical cases performed by a surgical mission team at St. Luc Hospital in Port-au-Prince, Haiti in 2013, 2017, and 2018. There were no reported complications. CONCLUSIONS: Given CCPs' competencies in complex airway and ventilator management, a CCP, with minimal training from a simple syllabus, may be able to act as an anesthesiologist-extender and safely administer anesthesia in the austere environment, increasing the number of surgical cases that can be performed. Further studies are necessary to confirm our observation.

Influence of Kidney Function on Serum Risperidone Concentrations in Patients Treated With Risperidone.

OBJECTIVE: Risperidone is one of the most commonly prescribed antipsychotics worldwide. Its main metabolite, 9-hydroxyrisperidone (9-OH-RIS), is excreted renally. The present study examined the relationship of kidney function and serum risperidone concentrations in a large sample of risperidone-treated patients. METHODS: Serum concentrations of risperidone and its active metabolite 9-OH-RIS, as well as creatinine concentrations, from which glomerular filtration rates (GFRs) were estimated, were determined in 175 risperidone-medicated patients (75 female, 100 male). Data were collected between July 2013 and December 2016. Patients were clustered in 4 groups according to their estimated GFR (eGFR) (30-60; > 60-90; > 90-120; and > 120 mL/min/1.73 m²), and serum concentrations of risperidone and 9-OH-RIS and their sum (active moiety [AM]) were compared groupwise. Additionally, serum concentrations were correlated with kidney function. RESULTS: Dose-corrected AM and dose-corrected 9-OH-RIS concentrations were significantly higher in patients with an eGFR of 30-60 mL/min/1.73 m² than in patients with an eGFR > 90-120 mL/min/1.73 m² (P < .001 for dose-corrected AM and P = .001 for dose-corrected 9-OH-RIS) or > 120 mL/min/1.73 m² (P = .036 and .021, respectively). Dose-corrected AM levels were more than doubled in the 30-60 mL/min/1.73 m² group compared to the > 90-120 mL/min/1.73 m² group (mean ± SD = 22.2 ± 14.0 [ng/mL]/[mg/d] vs 10.1 ± 7.7 [ng/mL]/[mg/d]). In the total group, eGFR and dose-corrected 9-OH-RIS and dose-corrected AM were weakly but statistically significantly correlated (Spearman rank correlation coefficient [Rs] = -0.2, P = .004, and Rs = -0.17, P = .01, respectively). CONCLUSIONS: Kidney function is an important determinant of risperidone clearance. These data suggest reducing the risperidone dose by 50% in patients with a GFR below 60 mL/min.

Effect of fluvoxamine augmentation and smoking on clozapine serum concentrations.

BACKGROUND: Clozapine (CLZ) is metabolized via cytochrome P450 CYP1A2 to N-desmethylclozapine (NCLZ). Smoking induces CYP1A2 thereby increasing clozapine metabolism whereas fluvoxamine inhibits CYP1A2. Studies suggest that the beneficial effect of fluvoxamine augmentation in raising serum clozapine concentrations also occurs when serum concentrations are low due to smoking. Yet, little is known about the influence of fluvoxamine augmentation on clozapine serum concentrations in smoking versus non-smoking patients. METHODS: A TDM database was analyzed. Serum concentrations of CLZ, NCLZ, dose-adjusted serum concentrations (C/D) and metabolite-to-parent ratios (MPR) were compared using non-parametrical tests in four groups: clozapine-monotherapy in non-smokers (VNS, n = 28) and smokers (VS, n = 43); combined treatment with clozapine and fluvoxamine in non-smokers (VNS+F, n = 11) and smokers (VS+F, n = 43). RESULTS: The CLZ monotherapy smoking group showed lower values of C/D CLZ of -38.6% (p < 0.001), C/D NCLZ -35.6% (p < 0.001) and a higher MPR (p = 0.021) than in the non-smoking group. The combination of CLZ and fluvoxamine in non-smoking patients led to higher C/D values: C/D CLZ +117.9% (p < 0.001), C/D NCLZ +60.8% (p = 0.029) while the MPR did not differ between groups (p = 0.089). Changes were comparable to fluvoxamine augmentation in the smoking group with increased C/D CLZ of +120.1% (p < 0.001), C/D NCLZ of +85.8% (p < 0.001) and lower MPR (p = 0.006). CONCLUSIONS: Smoking in clozapine monotherapy reduced median dose-adjusted serum concentrations more than a third. Combined treatment with fluvoxamine and clozapine led to higher median C/D values in both, smokers and non-smokers. The opposing effects of CYP1A2 induction by smoking and inhibition by fluvoxamine on clozapine serum concentrations balanced out.

Comprehensive Measurements of Intrauterine and Postnatal Exposure to Lamotrigine.

OBJECTIVE: The aim of this study was to measure and investigate correlations of lamotrigine concentrations in maternal as well as umbilical cord blood, amniotic fluid, and breast milk to account for the distribution of the drug. METHODS: Concentrations of lamotrigine were measured in 19 mother-infant pairs at the time of delivery. To account for the penetration ratio into amniotic fluid, cord blood and breast milk, the concentration of lamotrigine in the particular environment was divided by the concentration in maternal serum. A no-intercept model was applied for associations between maternal serum concentrations, amniotic fluid, umbilical cord blood, and breast milk concentrations. RESULTS: The mean daily dosage of lamotrigine was 351.32 mg (range 50-650 mg). We detected associations between maternal serum and amniotic fluid (ß = 0.088, p < 0.001), as well as umbilical cord (ß = 0.939, p < 0.001) and breast milk (ß = 0.964, p < 0.001). The median penetration ratio into amniotic fluid, cord blood, and breast milk was 0.68, 0.92, and 0.77, respectively. CONCLUSIONS: Lamotrigine concentrations in amniotic fluid, cord blood, and breast milk give evidence that the fetus/newborn is constantly exposed to lamotrigine. Maternal serum concentrations predicted exposure via amniotic fluid, umbilical cord, and breast milk. Data suggest that therapeutic drug monitoring can be recommended as part of the clinical routine in psychopharmacotherapy for pregnant or breastfeeding women.

Critical care capacity in Haiti: A nationwide cross-sectional survey.

OBJECTIVE: Critical illness affects health systems globally, but low- and middle-income countries (LMICs) bear a disproportionate burden. Due to a paucity of data, the capacity to care for critically ill patients in LMICs is largely unknown. Haiti has the lowest health indices in the Western Hemisphere. In this study, we report results of the first known nationwide survey of critical care capacity in Haiti. DESIGN: Nationwide, cross-sectional survey of Haitian hospitals in 2017-2018. SETTING: Haiti. SUBJECTS: All Haitian health facilities with at least six hospital beds. INTERVENTIONS: Electronic- and paper-based survey. RESULTS: Of 51 health facilities identified, 39 (76.5%) from all ten Haitian administrative departments completed the survey, reporting 124 reported ICU beds nationally. Of facilities without an ICU, 20 (83.3%) care for critically ill patients in the emergency department. There is capacity to ventilate 62 patients nationally within ICUs and six patients outside of the ICU. One-third of facilities with ICUs report formal critical care training for their physicians. Only five facilities met criteria for a Level 1 ICU as defined by the World Federation of Societies of Intensive and Critical Care Medicine. Self-identified barriers to providing more effective critical care services include lack of physical space for critically ill patients, lack of equipment, and few formally trained physicians and nurses. CONCLUSIONS: Despite a high demand for critical care services in Haiti, current capacity remains insufficient to meet need. A significant amount of critical care in Haiti is provided outside of the ICU, highlighting the important overlap between emergency and critical care medicine in LMICs. Many ICUs in Haiti lack basic components for critical care delivery. Streamlining critical care services through protocol development, education, and training may improve important clinical outcomes.

Differences in Duloxetine Dosing Strategies in Smoking and Nonsmoking Patients: Therapeutic Drug Monitoring Uncovers the Impact on Drug Metabolism.

BACKGROUND: For certain psychotropic drugs, such as clozapine or olanzapine, the influence of smoking on drug metabolism is well studied. Tobacco smoke increases the metabolism of drugs that are substrates for cytochrome P450 (CYP) 1A2 due to CYP induction. The antidepressant duloxetine, acting as a serotonin-norepinephrine reuptake inhibitor, is mainly metabolized via CYP1A2. To date, little is known about the influence of smoking on serum duloxetine concentrations. METHODS: A therapeutic drug monitoring database consisting of plasma concentrations of duloxetine collected from January 2013 to June 2017 was analyzed. A group of nonsmoking patients undergoing treatment with duloxetine (n = 89) was compared to a group of active smokers also receiving duloxetine (n = 36). Serum concentrations of duloxetine and dose-adjusted serum concentrations were compared using non-parametric tests. RESULTS: Groups did not differ concerning sex (P = .063), but the group of active smokers was younger (P < .001) and received higher daily doses of duloxetine (P = .001). Smokers showed significantly lower median serum duloxetine concentrations (38.4% lower, P = .002) and 53.6% lower dose-adjusted serum concentrations (0.325 [ng/mL]/[mg/d] in smokers vs 0.7 [ng/mL]/[mg/d] in nonsmokers, P < .001). CONCLUSIONS: Despite higher daily doses, smokers had considerably lower serum duloxetine concentrations. The induction of CYP1A2 by tobacco smoke is a clinically relevant factor for drugs that are substrates for CYP1A2. Clinicians should actively assess smoking status, inform patients about the effect of smoking on duloxetine metabolism, and anticipate higher serum concentrations in the case of smoking cessation. Therapeutic drug monitoring ensures treatment efficacy by enabling the personalizing of treatment, as smokers need higher duloxetine doses to target serum concentrations within the therapeutic reference range.

Pregnancy exposure to quetiapine - Therapeutic drug monitoring in maternal blood, amniotic fluid and cord blood and obstetrical outcomes.

RATIONALE: This prospective study is the first to measure and correlate quetiapine concentrations in maternal blood, amniotic fluid and umbilical cord blood to account for the distribution of quetiapine. METHODS: Concentrations of quetiapine are quantified in seven mother infant pairs at the time of delivery. Data are provided as median values, first (Q1) and third (Q3) quartiles and ranges. To account for the penetration ratio, the concentration of quetiapine in amniotic fluid and cord blood was divided by maternal concentrations. Correlations between daily dosage, maternal serum and umbilical cord blood concentrations were computed for seven patients while calculations for amniotic fluid were only available for six mother-infant pairs. RESULTS: The median daily dosage of quetiapine was 300mg (Q1: 300mg, Q3: 600mg, range 200-800mg). There was a strong and significant correlation between maternal serum and cord blood concentrations (r=0.893, p=0.007). The median penetration ratio into fetal circulation was 0.18 (Q1: 0.16, Q3: 0.32; range 0.13-0.42), suggesting a low penetration. The median penetration ratio into amniotic fluid was 0.44 (Q1: 0.15, Q3: 0.96; range 0.09-1.70). CONCLUSIONS: Quetiapine concentrations in amniotic fluid and cord blood give evidence that quetiapine is constantly accessible to the fetus with a relatively low penetration ratio. A high correlation between maternal serum and umbilical cord blood concentrations highlights a predictive role of quantifying drug concentrations in maternal serum for assessing drug concentrations in fetal circulation. Findings support the important role of therapeutic drug monitoring in supporting the efficacy and safety of psychopharmacological treatment strategies in highly vulnerable populations.

Reduced clearance of venlafaxine in a combined treatment with quetiapine.

Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic interactions between venlafaxine and quetiapine have not been studied yet. A therapeutic drug monitoring database containing serum concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. Two groups of patients were compared: venlafaxine monotherapy V0 (n = 153) and co-medication with quetiapine, VQUE (n = 71). Serum concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN), metabolite to parent compound ratio (ODVEN/VEN) and dose adjusted serum concentrations were compared using non-parametrical tests without information on CYP2D6 genotype. The two groups did not differ in terms of the daily dosage of venlafaxine, age, or sex. Median serum concentrations in the quetiapine group showed significantly, 15.8% and 29.3% higher values for AM and ODVEN (p = 0.002, Cohen's d = 0,41; p = 0.003, d = 0,44), respectively. Dose adjusted serum concentrations of active moiety and ODVEN revealed comparable differences (p = 0.038, d = 0,32; p = 0.015, d = 0,28) with significantly higher values in the co-medicated group. Significantly higher values for ODVEN and AM suggest a reduced clearance of ODVEN and active moiety when quetiapine is co-administered. This may be a consequence of a reduced metabolism of venlafaxine to the inactive metabolite N-desmethylvenlafaxine via CYP3A4, the main metabolizing enzyme for quetiapine, and a shift towards a higher proportion of the active metabolite ODVEN. Therapeutic drug monitoring is recommended in the case of co-medication to ensure clinical efficacy and patient safety. Although the increase of AM is moderate, we consider it relevant for clinicians given the prevalence of concomitant medication of quetiapine and venlafaxine.

Treatment outcomes after implementation of an adapted WHO protocol for severe sepsis and septic shock in Haiti.

PURPOSE: The World Health Organization (WHO) has developed a simplified algorithm specific to resource-limited settings for the treatment of severe sepsis emphasizing early fluids and antibiotics. However, this protocol's clinical effectiveness is unknown. We describe patient outcomes before and after implementation of an adapted WHO severe sepsis protocol at a community hospital in Haiti. MATERIALS AND METHODS: Using a before-and-after study design, we retrospectively enrolled 99 adult Emergency Department patients with severe sepsis from January through March 2012. After protocol implementation in January 2014, we compared outcomes to 67 patients with severe sepsis retrospectively enrolled from February to April 2014. We defined sepsis according to the WHO's Integrated Management of Adult Illness guidelines and severe sepsis as sepsis plus organ dysfunction. RESULTS: After protocol implementation, quantity of fluid administered increased and the physician's differential diagnoses more often included sepsis. Patients were more likely to have follow-up vital signs taken sooner, a radiograph performed, and a lactic acid tested. There were no improvements in mortality, time to fluids or antimicrobials. CONCLUSIONS: Use of a simplified sepsis protocol based primarily on physiologic parameters allows for substantial improvements in process measures in the care of severely septic patients in a resource-constrained setting.

Sepsis in Haiti: Prevalence, treatment, and outcomes in a Port-au-Prince referral hospital.

PURPOSE: Developing countries carry the greatest burden of sepsis, yet few descriptive data exist from the Western Hemisphere. We conducted a retrospective cohort study to elucidate the presentation, treatment, and outcomes of sepsis at an urban referral hospital in Port-au-Prince, Haiti. MATERIALS AND METHODS: We studied all adult emergency department patient encounters from January through March 2012. We characterized presentation, management, and outcomes using univariable and multivariable analyses. RESULTS: Of 1078 adult patients, 224 (20.8%) had sepsis and 99 (9.2%) had severe sepsis. In-hospital mortality for severe sepsis was 24.2%. Encephalopathy was a predictor of intravenous fluid administration (adjusted odds ratio [OR], 5.63; 95% confidence interval [CI], 1.46-21.76; P=.01), and lower blood pressures predicted shorter time to fluid administration. Increasing temperature and lower blood pressures predicted antibiotic administration. Encephalopathy at presentation (adjusted OR, 6.92; 95% CI, 1.94-24.64; P=.003), oxygen administration (adjusted OR, 15.96; 95% CI, 3.05-83.59; P=.001), and stool microscopy (adjusted OR, 45.84; 95% CI, 1.43-1469.34; P=.03) predicted death in severe sepsis patients. CONCLUSIONS: This is the first descriptive study of sepsis in Haiti. Our findings contribute to the knowledge base of global sepsis and reveal similarities in independent predictors of mortality between high- and low-income countries.

Remote tele-mentored ultrasound for non-physician learners using FaceTime: A feasibility study in a low-income country.

PURPOSE: Ultrasound (US) is a burgeoning diagnostic tool and is often the only available imaging modality in low- and middle-income countries (LMICs). However, bedside providers often lack training to acquire or interpret US images. We conducted a study to determine if a remote tele-intensivist could mentor geographically removed LMIC providers to obtain quality and clinically useful US images. MATERIALS AND METHODS: Nine Haitian non-physician health care workers received a 20-minute training on basic US techniques. A volunteer was connected to an intensivist located in the USA via FaceTime. The intensivist remotely instructed the non-physicians to ultrasound five anatomic sites. The tele-intensivist evaluated the image quality and clinical utility of performing tele-ultrasound in a LMIC. RESULTS: The intensivist agreed (defined as "agree" or "strongly agree" on a five-point Likert scale) that 90% (57/63) of the FaceTime images were high quality. The intensivist felt comfortable making clinical decisions using FaceTime images 89% (56/63) of the time. CONCLUSIONS: Non-physicians can feasibly obtain high-quality and clinically relevant US images using video chat software in LMICs. Commercially available software can connect providers in institutions in LMICs to geographically removed intensivists at a relatively low cost and without the need for extensive training of local providers.