Are Lists of Potentially Inappropriate Medications Associated with Hospital Readmissions? A Systematic Review.

BACKGROUND: Suboptimal prescribing, including the prescription of potentially inappropriate medications (PIM), is frequent in patients aged 65 years and older. PIMs are associated with adverse drug events, which may lead to hospital admissions and readmissions for the most serious cases. Several tools, known as lists of PIMs, can detect suboptimal prescription. OBJECTIVE: This systematic review aimed to identify which lists of PIMs are associated with hospital readmission of older patients. PATIENTS AND METHODS: MEDLINE, the Cochrane Library, EMBASE, and clinicaltrials.gov were searched for the period from 1 January 1991 up to 12 May 2022 to identify original studies assessing the association between PIMs and hospital readmissions or emergency department (ED) revisits within 30 days of discharge in older patients. This study is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Checklist, and the risk of bias was assessed with the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies (NOS) and the revised Cochrane risk-of-bias tool for randomized trials (RoB 2). RESULTS: A total of six studies presenting four different lists of PIMs were included. Readmission rates varied from 4.3 to 25.5% and the odds ratio (OR) between PIMs and hospital readmission varied from 0.92 [95% confidence interval (CI) 0.59; 1.42] to 6.48 [95% CI 3.00; 14.00]. Only two studies found a statistically significant association between a list of PIMs and hospital readmission. These two studies used different tools: the Screening Tool of Older Person's Prescriptions (STOPP) and the Screening Tool to Alert Doctors to Right Treatment (START) and a combination of Beers Criteria® and STOPP and START. CONCLUSION: This systematic review shows that the association between list of PIMs and 30-day unplanned readmissions remains unclear and seems dependent on the PIM detection tool. Further studies are needed to clarify this association. PROSPERO registration number CRD42021252107.

Which Potentially Inappropriate Medications List Can Detect Patients At Risk of Readmissions in the Older Adult Population Admitted for Falls? An Observational Multicentre Study Using a Clinical Data Warehouse.

BACKGROUND AND OBJECTIVE: Hospital readmissions are common in the older adult population and potentially inappropriate medications are known to be involved in these readmissions. Several lists of potentially inappropriate medications have been published in diverse countries in order to adapt the lists to local specificities. Among them, the Beers Criteria® were first published in 1991 in the USA, followed by the French Laroche list, the Norwegian NORGEP criteria, the German PRISCUS list, the Austrian consensus panel list and the European list, EU-7. The main objective was to detect which potentially inappropriate medications list can better detect hospital readmissions within 30 days in the older adult population hospitalised for fall-related injuries. METHODS: We conducted a multicentre, observational, retrospective cohort study. Data from older patients initially hospitalised for falls in 2019 and discharged home were retrieved from the Clinical Data Warehouse. Exposure to potentially inappropriate medications was classified according to the six lists mentioned above. The local ethics committee approved the study protocol (number CER-2020-79). RESULTS: After adjustments using propensity score matching, taking a potentially inappropriate medication as per the Laroche and PRISCUS lists was associated with a 30-day hospital readmission with an odds ratio of 1.58 (95% confidence interval 1.06-2.37) and 1.68 (95% confidence interval 1.13-2.50), respectively, while the other four studied lists showed no associations with readmissions. CONCLUSIONS: Our study evidenced that not all lists published allow the accurate prediction of hospital readmissions to the same extent. We found that the Laroche and PRISCUS lists were associated with increased 30-day all-cause hospital readmissions after an index admission with a fall-related injury.

Safety of Elderly Fallers: Identifying Associated Risk Factors for 30-Day Unplanned Readmissions Using a Clinical Data Warehouse.

BACKGROUND: Hospital readmissions are a major problem in the older people as they are frequent, costly, and life-threatening. Falls among older adults are the leading cause of injury, deaths, and emergency department visits for trauma. OBJECTIVE: The main objective was to determine risk factors associated with a 30-day readmission after index hospital admission for fall-related injuries. METHODS: A retrospective nested case-control study was conducted. Data from elderly patients initially hospitalized for fall-related injuries in 2019, in 11 of the Greater Paris University Hospitals and discharged home, were retrieved from the clinical data warehouse. Cases were admission of elderly patients who subsequently experienced a readmission within 30 days after discharge from the index admission. Controls were admission of elderly patients who were not readmitted to hospital. RESULTS: Among 670 eligible index admissions, 127 (18.9%) were followed by readmission within 30 days after discharge. After multivariate analysis, men sex (odds ratio [OR] = 2.29, 95% confidence interval [CI] = 1.45-3.61), abnormal concentration of C-reactive protein, and anemia (OR = 2.22, 95% CI = 1.28-3.85; OR = 1.85, 95% CI = 1.11-3.11, respectively) were associated with a higher risk of readmission. Oppositely, having a traumatic injury at index admission decreased this risk (OR = 0.47, 95% CI = 0.28-0.81). CONCLUSIONS: Reducing early unplanned readmission is crucial, especially in elderly patients susceptible to falls. Our results indicate that the probability of unplanned readmission is higher for patients with specific characteristics that should be taken into consideration in interventions designed to reduce this burden.

Readmissions of Elder Patients Presenting to Hospital for a Fall (RELIEF): A Systematic Review.

OBJECTIVES: Falls are an important issue in older adults as they are frequent, deleterious, and often lead to repeated consultations at the emergency department (ED) and unplanned hospitalizations. Our principal objective was to provide an inventory of interventions designed to prevent unplanned readmissions or ED visits of older patients presenting to hospital with a fall. DESIGN: Systematic review performed on February 11, 2019 in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science, without date or language restriction. We manually updated this search in August 1, 2019. Study selection, data extraction and risk of bias assessment were conducted independently by 2 reviewers. SETTING AND PARTICIPANTS: We included studies reporting interventions to prevent unplanned readmissions or ED visits of older patients (aged 65 years or over) presenting to hospital because of a fall. RESULTS: We identified 475 unique citations after removing duplicates and included 6 studies (2 observational and 4 interventional studies). The studies were published between 2012 and 2019; they evaluated heterogeneous interventions that were frequently multifaceted and multidisciplinary. The interventions were shown effective in reducing readmissions or ED revisits compared with control groups in 3 studies (relative risk reductions between 30% and 65%), all of which were multifaceted and 2/3 multidisciplinary. CONCLUSIONS AND IMPLICATIONS: With 6 articles showing inconsistent results, our study highlights the need to adequately design and evaluate interventions to reduce the burden of hospital readmissions among older fallers. Retrieved studies are recent, which underlines that hospital readmissions are a current concern for researchers and public health authorities [PROSPERO registration number: CRD42019131965].

Pharmacists' role in antimicrobial stewardship and relationship with antibiotic consumption in hospitals: An observational multicentre study.

OBJECTIVES: Antimicrobial stewardship (AMS) teams around the world include pharmacists; however, their impact is relatively unknown. This study aimed to explore the relationship between pharmacists' actions and antibiotic consumption. METHODS: Hospital pharmacists involved in the French antibiotic consumption surveillance network (ATB-Raisin) were invited to participate in a retrospective observational multicentre study. Collected data were: the previous year's (2016) antibiotic consumption expressed in daily defined dose per 1000 patient-days; AMS measures, including pharmacist-specific actions; and use of a computerised prescription order entry (CPOE) system. Associations between antibiotic consumption and AMS measures were assessed by linear regression, after adjustment for hospital activities. RESULTS: Annual data for 2016 from 77 hospitals (7260000 bed-days in 24000 beds) were analysed. Pharmacists were involved in AMS programs in 73% of hospitals, and were the antibiotic advisor in 25%. Pharmaceutical review of prescriptions was organised in almost all hospitals (97%). The univariable analysis identified five measures associated with lower overall antibiotic consumption: CPOE use (if >80% of prescriptions or 100%), pharmaceutical review (if >80% of beds or 100%) and the antibiotic advisor being a pharmacist (P=0.04, P=0.004 and P=0.003, respectively). In the multivariable analysis, two explanatory variables were significantly and independently associated with a lower overall antibiotic consumption: the antibiotic advisor being a pharmacist and a pharmaceutical review covering all beds (-19.9% [-31.6%; -8.1%], P=0.002 and -18.3% [-34.0%; -2.6%], P=0.03, respectively). CONCLUSIONS: Antibiotic consumption was lower when the antibiotic advisor was a pharmacist and when the pharmaceutical team reviewed all prescriptions. These results highlight that actions initiated by pharmacists have a positive impact and should be supported.

Burden of Inappropriate Prescription of Direct Oral Anticoagulants at Hospital Admission and Discharge in the Elderly: A Prospective Observational Multicenter Study.

INTRODUCTION: Direct oral anticoagulants (DOACs) were developed to overcome some of the limitations associated with vitamin K antagonists (VKAs), such as interindividual variability or the need for therapeutic drug monitoring. However, the complexity of DOAC dose regimens can still lead to dosing errors and potential bleeding-related or thromboembolic adverse events, especially in the elderly. OBJECTIVE: Our objective was to evaluate the rate of inappropriate preadmission DOAC prescriptions at hospital and to evaluate the ability of hospitals to correct them. METHODS: An observational prospective study was conducted in elderly patients (aged ≥ 65 years) hospitalized in six acute units of three Parisian university hospitals between February and July 2018. DOAC prescriptions prior to admission and at discharge were analyzed according to the guidelines in the summaries of product characteristics. RESULTS: A total of 157 patients were included in the study, with a median age of 84 years (interquartile range [IQR] 77-89). The median glomerular filtration rate, determined with the Cockcroft-Gault equation, was 48 mL/min (IQR 35-61). Apixaban was the most frequently prescribed drug, mainly for atrial fibrillation. Overall, 48 (30.6%) and 34 (22.4%) prescriptions were inappropriate prior to admission and at discharge, respectively, showing a significant decrease (p < 0.001). Hospitals significantly corrected more inappropriate prescriptions (37.5%) than they generated (4.6%) (p < 0.05). The nature of the inappropriate prescribing was underdosing (68.8% and 76.5% prior to admission and at discharge, respectively), followed by overdosing (stable rate at almost 20%) and indication errors. No risk factors for inappropriate use were identified by our analysis. CONCLUSION: One-third of DOAC preadmission prescriptions for elderly patients were inappropriate, indicating that a need remains to strengthen DOAC prescribing guidelines in ambulatory clinical practice. However, the rate of inappropriate prescriptions decreased at patient discharge. Future studies are needed to test actions to promote the proper use of DOACs.

Risk scores identifying elderly inpatients at risk of 30-day unplanned readmission and accident and emergency department visit: a systematic review.

OBJECTIVES: The aim of this systematic review was to describe and analyse the performance statistics of validated risk scores identifying elderly inpatients at risk of early unplanned readmission. DATA SOURCES: We identified potentially eligible studies by searching MEDLINE, EMBASE, COCHRANE and Web of Science. Our search was restricted to original studies, between 1966 and 2018. ELIGIBILITY CRITERIA: Original studies, which internally or externally validated the clinical scores of hospital readmissions in elderly inpatients. DATA EXTRACTION AND SYNTHESIS: A data extraction grid based on Strengthening the Reporting of Observational Studies in Epidemiology and Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis statements was developed and completed by two reviewers to collect general data. The same process was used to extract metrological data of the selected scores. QUALITY ASSESSMENT OF THE INCLUDED STUDIES: Assessment of the quality and risk of bias in individual studies was performed by two reviewers, using the validated Effective Public Health Practice Project quality assessment tool. PARTICIPANTS: Elderly inpatients discharged to home from hospital or returning home after an accident and emergency department visit. RESULTS: A total of 12 studies and five different scores were included in the review. The five scores present area under the receiving operating characteristic curve between 0.445 and 0.69. Identification of Senior At Risk (ISAR) and Triage Risk Screening Tool (TRST) scores were the more frequently validated scores with ISAR being more sensitive and TRST more specific. CONCLUSIONS: The TRST and ISAR scores have been extensively studied and validated. The choice of the most suitable score relies on available patient data, patient characteristics and the foreseen clinical care intervention. In order to pair the intervention with the appropriate clinical score, further studies of external validation of clinical scores, identifying elderly patients at risk of early unplanned readmission, are needed. PROSPERO REGISTRATION NUMBER: CRD42017054516.

Reporting of Organ Support Outcomes in Septic Shock Randomized Controlled Trials: A Methodologic Review-The Sepsis Organ Support Study.

OBJECTIVES: Many recent randomized controlled trials in the field of septic shock failed to demonstrate a benefit on mortality. Randomized controlled trials increasingly report organ support duration and organ support-free days as primary or secondary outcomes. We conducted a methodologic systematic review to assess how organ support outcomes were defined and reported in septic shock randomized controlled trials. DATA SOURCES: MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science. STUDY SELECTION: We included randomized controlled trials published between January 2004 and March 2018 that involved septic shock adults and assessed organ support duration and/or organ support-free days for hemodynamic support, respiratory support, or renal replacement therapy. DATA EXTRACTION: For each randomized controlled trial, we extracted the definitions of organ support duration and organ support-free days. We particularly evaluated how nonsurvivors were accounted for. Study authors were contacted to provide any missing information regarding these definitions. DATA SYNTHESIS: We included 28 randomized controlled trials. Organ support duration and organ support-free days outcomes were reported in 17 and 15 randomized controlled trials, respectively, for hemodynamic support, 15 and 15 for respiratory support, and five and nine for renal replacement therapy. Nonsurvivors were included in the organ support duration calculation in 13 of 14 randomized controlled trials (93%) for hemodynamic support and nine of 10 (90%) for respiratory support. The organ support-free days definition for hemodynamic support, respiratory support, and renal replacement therapy was reported in six of 15 randomized controlled trials (40%), eight of 15 randomized controlled trials (53%), and six of nine randomized controlled trials (67%) reporting an organ support-free days outcome, respectively. Of these, one half assigned "0" to nonsurvivors, and the other half attributed one point per day alive free of organ support up to a predefined time point. CONCLUSIONS: This study highlights the heterogeneity and infrequency of organ support duration/organ support-free days outcome reporting in septic shock trials. When reported, the definitions of these outcome measures and methods of calculation are also infrequently reported, in particular how nonsurvivors were accounted for, which may have an important impact on interpretation.

Medication reconciliation: Predictors of risk of unintentional medication discrepancies in the cardiology department.

BACKGROUND: Medication reconciliation is a powerful formal process to decrease medication errors, but it has proved to be complex and time consuming. AIMS: To describe the frequency and types of medication discrepancies (between previous treatment and medication order at admission), and to identify predictors of unintentional medication discrepancies (UMDs). METHODS: This interventional study was carried out in the cardiology department of a French teaching hospital. Medication reconciliation was conducted at admission to the cardiology department over 1 month in 2016 by trained pharmacists for: (1) determination of best possible medication history using multiple sources; (2) comparison with the patient's admission medication order and identification of discrepancies; and (3) classification of discrepancies (intentional/unintentional) with the physician. Associations between UMDs and various factors were examined. RESULTS: Overall, 100 patients were included (mean age 67.6±16.7 years; 56 men). The reconciliation process identified 544 drug discrepancies, 77 of which were UMDs; these occurred in 42 patients. The most common UMD type was omission (70.1%). Inability to speak French (P=0.007), low educational level (P=0.004), admission to a non-intensive care unit (P=0.019), two or more co-morbidities (P=0.001) and eight or more drugs on the admission order (P=0.004) were significantly associated with UMDs. Educational level remained significantly and independently associated with UMDs in a multivariable analysis after adjustment for factors that were statistically significant in the univariate analysis. CONCLUSIONS: This study highlights the high risk of medication discrepancies and the factors associated with UMDs. Our results allowed us to identify patients who should receive priority medication reconciliation in a cardiology department.

Potentially inappropriate prescriptions of antithrombotic therapies in older outpatients: a French multicenter cross-sectional study.

PURPOSE: To assess the prevalence of inappropriate prescriptions of antithrombotic therapies (AT) in older outpatients and examine the associated factors. METHODS: A multicenter cross-sectional study was performed in 75 community pharmacies of 11 French districts. The study included 1178 patients aged ≥ 75 years filling a prescription from a general practitioner (GP) at a community pharmacy (mean [SD] age 83 [± 5.5] years, 59% female, median prescribed drugs 7 [range 5-10]).75 pharmacy students prospectively collected data from structured interviews with patients and from prescriptions into an electronic case report. Updated 2014 STOPP/START criteria regarding AT were applied to each prescription. Factors associated with ≥ 1 AT-STOPP criteria and ≥ 1 AT-START criteria were studied (multivariate analysis). RESULTS: 22.6% patients featured ≥ 1 in AT-STOPP criteria and 12.4% ≥ 1 in AT-START criteria. The most frequent AT-STOPP and AT-START criteria were AT prescription despite a concurrent significant bleeding risk and lack of AT prescription for patients with chronic atrial fibrillation, respectively. Two factors were associated with ≥ 1 AT-STOPP criteria: polymedication (≥ 5 drugs; p < 0.001) and previous hospitalization for a serious adverse drug event (ADE; p = 0.007). The only factor associated with ≥ 1 AT-START criteria was lack of information in the prescription regarding the duration of treatment. CONCLUSION: Suboptimal prescribing of AT is common in GP's prescriptions for older autonomous outpatients. The currently process of prescribing AT to older autonomous patients must be improved. Special attention should be given to those with polymedication and those with a history of severe ADEs.

Sedative-hypnotic initiation and renewal at discharge in hospitalized older patients: an observational study.

BACKGROUND: Sedative-hypnotics (SHs) are widely used in France but there are no available data addressing their prescription specifically in hospitalized older patients. The objective is thus to determine the cumulative incidence of sedative-hypnotic (SH) medications initialized during a hospital stay of older patients, the proportion of SH renewal at discharge among these patients and to study associated risk factors. METHODS: We conducted a retrospective observational study in six internal medicine units and six acute geriatric units in eight hospitals (France). We included 1194 inpatients aged 65 and older without SH medications prior to hospitalization. Data were obtained from patients' electronic pharmaceutical records. Primary outcome was the cumulative incidence of SH initiation in the study units. Secondary outcomes were the proportion of SH renewal at discharge and risk factors for SH initiation and renewal at discharge (patient characteristics, hospital organization). A Cox regression model was used to study risk factors for SH initiation. A mixed effects logistic regression was used to study risk factors for SH renewal at discharge. RESULTS: SH initiation occurred in 21.5% of participants 20 days after admission. SH renewal at discharge occurred in 38.7% of patients who had initiated it during their stay and were discharged home and in 56.0% of patients discharged to rehabilitation facilities. Neither patients' characteristics nor hospital organization patterns was associated with SH initiation. SH initiation after the first six days after admission was associated with a lower risk of SH renewal in patients discharged to rehabilitation facilities (OR = 0.19, 95% CI: [0.04-0.80]). CONCLUSIONS: Hospitalization is a period at risk for SH initiation. The implementation of interventions promoting good use of SHs is thus of first importance in hospitals. Specific attention should be paid to patients discharged to rehabilitation facilities.

A systematic review of regulatory and educational interventions to reduce the burden associated with the prescriptions of sedative-hypnotics in adults treated for sleep disorders.

BACKGROUND: The burden of Sedative-Hypnotics (SHs) has been known since the 1980s. Yet, their consumption remains high. A systematic review of the literature should help to assess efficient interventions to improve the appropriate use of SHs in sleep disorders. OBJECTIVES: To identify and assess regulatory and educational interventions designed to improve the appropriate use of SHs for insomnia treatment. METHODS: We conducted a systematic review of the literature according to PRISMA guidelines. A systematic search covering the period 1980-2015 was carried out in Medline, Web of Science, Embase and PsycInfo. We included studies reporting the implementation of regulatory or educational strategies directed towards patients and/or healthcare professionals to improve the appropriate use of SHs to treat insomnia in the community, hospitals and nursing homes. RESULTS: Thirty-one studies were included: 23 assessed educational interventions (recommendations by mail/email, computer alerts, meetings, mass media campaigns, prescription profile), 8 assessed regulatory interventions (prescription rule restriction, end of reimbursement). The most recent was implemented in 2009. Restrictive prescription rules were effective to reduce the consumption of targeted SHs but led to a switch to other non-recommended SHs. Among educational interventions, only 3 studies out of 7 reported positive results of mono-faceted interventions; whereas, 13 out of the 16 multi-faceted interventions were reported as efficient: particularly, the active involvement of healthcare professionals and patients and the spread of information through mass media were successful. The risk of bias was high for 24 studies (mainly due to the design), moderate for 3 studies and weak for 4 studies. CONCLUSION: Educational multifaceted studies are presented as the most efficient. But further better designed studies are needed to make evidence-based results more generalizable.

Monitoring of Potentially Inappropriate Prescriptions in Older Inpatients: A French Multicenter Study.

OBJECTIVES: To determine whether potentially inappropriate medications (PIMs) or potentially inappropriate associations (PIAs) prescribed knowingly are associated with patient monitoring. DESIGN: Prospective observational study. SETTING: Geriatric units (n = 56) in 28 hospitals. PARTICIPANTS: Inpatients aged 75 and older (N = 1,327). MEASUREMENTS: Potentially inappropriate prescriptions (PIP) were defined as a PIM or a PIA selected by an expert board from lists of explicit criteria (Beers, Priscus, Laroche, French Health Agency) using a Delphi process. They were considered to be prescribed knowingly if they were maintained after reassessment by the geriatrician and the clinical pharmacist. Primary outcome was the rate of PIPs maintained (prescribed knowingly) and for which a geriatrician declared that specific monitoring was performed. Secondary outcomes were the parameters monitored and the rate of participants receiving knowingly a PIP. RESULTS: One thousand sixty-three PIPs were detected in 607 participants (46%). After reassessment, 826 (78%) PIPs were maintained in 490 participants (37%), the main reasons being participant's regular treatment and lack of alternative. Psychotropic (36%), cardiovascular (including antithrombotics) (29%), and laxative or antiemetic drugs (16%) were the most-frequent classes prescribed knowingly. The geriatricians declared to perform clinical or biological monitoring for 69% (n = 570) of PIMs or PIAs prescribed knowingly. Three types of specific monitoring were identified: clinical, biological, and follow-up with a specialist. CONCLUSION: Approximately three-quarters of PIMs or PIAs were prescribed knowingly, of which 69% were monitored, with wide variations in occurrence and in quality according to drug classes. This underlines the need for accurate guidelines on PIP monitoring.

An observational study of adult admissions to a medical ICU due to adverse drug events.

BACKGROUND: The objectives of the study were to estimate the incidence of intensive care unit (ICU) admissions due to adverse drug events (ADEs), to assess preventability, severity and costs of the corresponding ADE and to determine the leading causes of preventable ADEs. METHODS: An observational study was conducted in a medical ICU of a teaching hospital from February 2013 to February 2014. RESULTS: A total of 743 consecutive admissions were included, and they involved 701 different patients. The included admissions were categorized into three groups (admissions due to preventable ADE, admissions due to unpreventable ADE and the control group). Among the 743 ICU admissions included during the study period, 173 (23.3 %) were due to ADE, with 102 (13.7 %) related to preventable ADE and 71 (9.6 %) to unpreventable ADE, yielding a preventability rate of ADE of 0.59 (102/173). Admissions due to unpreventable ADE concerned patients with more comorbidities, a greater number of drugs and higher Simplified Acute Physiology Score II than admissions due to preventable ADE and the control group admissions (n = 570). Hospital mortality rates, corresponding costs and length of stay were all similar in the preventable ADE and control groups, whereas they were always significantly higher in the unpreventable ADE group. ICU mortality, length of stay and the corresponding costs were similar in the three groups. Non-compliance was the principal leading cause of preventable ADE (n = 31/102). The 102 preventable ADE-related admissions accounted for a total of 528 days of hospitalization in the ICU, requiring a mean of 1.4 ICU beds per day over the one-year period, with an associated total cost amounting to 747,651 €. CONCLUSIONS: ADE was a major cause of admission in the studied ICU, and in 59 % of the cases, ADEs were preventable. The reported burden of ICU admissions due to ADE advocates for further investigations to explore how the rate of such admissions could be decreased.

A case of melphalan sustained accumulation in an 80-year old patient.

Case We report the case of melphalan accumulation in an 80-year old female with multiple myeloma. Her initial health status was good except for a moderate chronic renal failure (estimated glomerular filtration rate: 31 ml/min) and anemia. Among other drugs, her usual treatment included trimethoprim/sulfamethoxazole and the patient received melphalan from day 1 to day 4 for multiple myeloma. On day 13, she was admitted in intensive care unit for acute renal failure and severe sepsis with pancytopenia. Usual treatments were stopped. Melphalan blood concentrations were 123.6 ng/ml on day 16 and 87.5 ng/ml on day 17 while cerebrospinal fluid concentration was 173.8 ng/ml on day 25. Patient recovered on day 30. Melphalan accumulation may be explained by substrate competition between sulfamethoxazole and melphalan in metabolism pathway and chronic renal failure. Conclusion close clinical and renal monitoring should be performed in patient receiving melphalan and sulfamethoxazole.

An Observational Study of the Impact of a Computerized Physician Order Entry System on the Rate of Medication Errors in an Orthopaedic Surgery Unit.

AIM: To assess the impact of the implementation of a Computerized Physician Order Entry (CPOE) associated with a pharmaceutical checking of medication orders on medication errors in the 3 stages of drug management (i.e. prescription, dispensing and administration) in an orthopaedic surgery unit. METHODS: A before-after observational study was conducted in the 66-bed orthopaedic surgery unit of a teaching hospital (700 beds) in Paris France. Direct disguised observation was used to detect errors in prescription, dispensing and administration of drugs, before and after the introduction of computerized prescriptions. Compliance between dispensing and administration on the one hand and the medical prescription on the other hand was studied. The frequencies and types of errors in prescribing, dispensing and administration were investigated. RESULTS: During the pre and post-CPOE period (two days for each period) 111 and 86 patients were observed, respectively, with corresponding 1,593 and 1,388 prescribed drugs. The use of electronic prescribing led to a significant 92% decrease in prescribing errors (479/1593 prescribed drugs (30.1%) vs 33/1388 (2.4%), p < 0.0001) and to a 17.5% significant decrease in administration errors (209/1222 opportunities (17.1%) vs 200/1413 (14.2%), p < 0.05). No significant difference was found in regards to dispensing errors (430/1219 opportunities (35.3%) vs 449/1407 (31.9%), p = 0.07). CONCLUSION: The use of CPOE and a pharmacist checking medication orders in an orthopaedic surgery unit reduced the incidence of medication errors in the prescribing and administration stages. The study results suggest that CPOE is a convenient system for improving the quality and safety of drug management.

A systematic review of adult admissions to ICUs related to adverse drug events.

Adverse drug events (ADE) may lead to hospital admission, and in some cases admission to an ICU is mandatory. We conducted a systematic review dealing with the incidence of ADE requiring ICU admission in adult patients, the reference population being all ICU admissions. Medline, Embase and Web of Science databases were screened from January 1982 to July 2014, using appropriate key words. Only original articles in English reporting the incidence of ADE requiring ICU admission in adult patients among total ICU admissions were included. Article eligibility was assessed by two independent reviewers, a third being involved in cases of disagreement. All reported characteristics (type of ICU, characteristics of patients, incidence of ADE, severity and preventability, drugs involved, causality) in the selected articles were collected for the review. The quality of studies was independently assessed by two reviewers with a specific score that we developed. A meta-analysis was conducted. Inclusion criteria were fulfilled by 11 studies out of the 4,311 identified in the initial literature search. The median (interquartile) quality score was 0.61 (0.44; 0.69). The reported incidences of ADE requiring ICU admission in adult patients ranged from 0.37 to 27.4%, with an associated mortality rate ranging from 2 to 28.1% and a mean length of stay ranging from 2.3 to 6.4 days. Preventable events accounted for 17.5 to 85.7% of the events. Costs and mechanisms at the root of ADE were investigated in only two and five studies, respectively. The forest plot examining the incidence of ADE requiring ICU admission in adult patients was associated with high heterogeneity (I (2) statistic > 98%), and the shape of the corresponding funnel plot was asymmetric. Heterogeneity across studies concerned many features, including studied populations, events considered, causality assessment methods, definitions of preventability and severity. Despite the heterogeneity of the reports, our review indicates that ICU admission due to ADE is a significant issue that should deserve further interest. The review led us to propose a list of items devoted to the reporting of future studies on ADE requiring ICU admissions.

Disturbed intestinal nitrogen homeostasis in a mouse model of high-fat diet-induced obesity and glucose intolerance.

The oligopeptide transporter peptide cotransporter-1 Slc15a1 (PEPT1) plays a major role in the regulation of nitrogen supply, since it is responsible for 70% of the dietary nitrogen absorption. Previous studies demonstrated that PEPT1 expression and function in jejunum are reduced in diabetes and obesity, suggesting a nitrogen malabsorption from the diet. Surprisingly, we reported here a decrease in gut nitrogen excretion in high-fat diet (HFD)-fed mice and further investigated the mechanisms that could explain this apparent contradiction. Upon HFD, mice exhibited an increased concentration of free amino acids (AAs) in the portal vein (60%) along with a selective increase in the expression of two AA transporters (Slc6a20a, Slc36a1), pointing to a specific and adaptive absorption of some AAs. A delayed transit time (+40%) and an increased intestinal permeability (+80%) also contribute to the increase in nitrogen absorption. Besides, HFD mice exhibited a 2.2-fold decrease in fecal DNA resulting from a reduction in nitrogen catabolism from cell desquamation and/or in the intestinal microbiota. Indeed, major quantitative (2.5-fold reduction) and qualitative alterations of intestinal microbiota were observed in feces of HFD mice. Collectively, our results strongly suggest that both increased AA transporters, intestinal permeability and transit time, and changes in gut microbiota are involved in the increased circulating AA levels. Modifications in nitrogen homeostasis provide a new insight in HFD-induced obesity and glucose intolerance; however, whether these modifications are beneficial or detrimental for the HFD-associated metabolic complications remains an open issue.

Rosiglitazone and metformin have opposite effects on intestinal absorption of oligopeptides via the proton-dependent PepT1 transporter.

The intestinal H(+)/peptide cotransporter 1 (PepT1) plays a major role in nitrogen supply to the body by mediating intestinal absorption of di- and tripeptides. Previous studies have reported that in animal models of type 2 diabetes/obesity, PepT1 activity and expression were markedly reduced. This prompted us to investigate the effects of two antidiabetic drugs, rosiglitazone and metformin, on PepT1 activity/expression in a murine diet-induced obesity model. C57BL/6J male mice were fed a high-fat diet (HFD) or a standard chow for 6 weeks and then were treated for 7 days with metformin (250 mg/kg/day) and/or rosiglitazone (8 mg/kg/day). For in vitro studies, Caco-2 enterocyte-like cells were treated for 7 days with metformin (10 mM) and/or rosiglitazone (10 µM). A 7-day rosiglitazone treatment increased PepT1 activity and prevented the 2-fold HFD-induced reduction in PepT1 transport. Metformin alone did not modify PepT1 activity but counteracted rosiglitazone-induced PepT1-mediated transport. As with the in vivo studies, rosiglitazone treatment up-regulated PepT1 transport activity with concomitant induction of S6 ribosomal protein activation in vitro. Furthermore, metformin decreased PepT1 expression (mRNA and protein) and its transport activity. The effect of metformin was linked to a reduction of phosphorylated S6 ribosomal protein (active form) and of phosphorylated 4E-BP1 (inactive form), a translation repressor. These data demonstrate that two antidiabetic drugs exert opposite effects on the PepT1 transport function probably through direct action on enterocytes. In our type 2 diabetes/obesity model, rosiglitazone, a peroxisome proliferator-activated receptor-γ agonist compensated for the HFD-induced PepT1 down-regulation, whereas metformin reversed rosiglitazone activity at the translational level.

Reduced intestinal absorption of dipeptides via PepT1 in mice with diet-induced obesity is associated with leptin receptor down-regulation.

Leptin is a major determinant of energy homeostasis, acting both centrally and in the gastrointestinal tract. We previously reported that acute leptin treatment enhances the absorption of di- and tripeptides via the proton-dependent PepT1 transporter. In this study, we investigated the long term effect of leptin on PepT1 levels and activity in Caco2 cell monolayers in vitro. We then assessed the significance of the regulation of PepT1 in vivo in a model of diet-induced obesity. We demonstrated that 1) leptin regulated PepT1 at the transcriptional level, via the MAPK pathway, and at the translational level, via ribosomal protein S6 activation, in Caco2 cells and 2) this activation was systematically followed by a time- and concentration-dependent loss of leptin action reflecting desensitization. Deciphering this desensitization, we demonstrated that leptin induced a down-regulation of its own receptor protein and mRNA expression. More importantly, we showed, in mice with diet-induced obesity, that a 4-week hypercaloric diet resulted in a 46% decrease in PepT1-specific transport, because of a 30% decrease in PepT1 protein and a 50% decrease in PepT1 mRNA levels. As shown in Caco2 cells, these changes in PepT1 were supported by a parallel 2-fold decrease in leptin receptor expression in mice. Taken together, these results indicate that during induction of obesity, leptin resistance may also occur peripherally in the gastrointestinal tract, disrupting the absorption of oligopeptides and peptidomimetic drugs.