Tacrolimus Monitoring in Liver Transplant Recipients, Posttransplant Cholestasis: A Comparative Between 2 Commercial Immunoassays and a Liquid Chromatography-Tandem Mass Spectrometry Method.

BACKGROUND: Cholestasis commonly occurs after orthotopic liver transplantation. It can be extrahepatic because of mechanical obstruction or intrahepatic because of various causes. During cholestasis episodes, blood concentrations of tacrolimus (TAC) metabolites may increase, potentially affecting TAC concentrations measured by immunoassays. This study aimed to simultaneously evaluate the analytical performance of 2 TAC immunoassays, a quantitative microsphere system (QMS) immunoassay, and chemiluminescence microparticle immunoassay, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) as a reference method in liver transplant recipients. METHODS: This single-center study included 265 patients who underwent orthotopic liver transplantation. In total, 942 blood samples were collected. TAC trough concentrations were measured using LC-MS/MS and 2 immunoassays in parallel. The plasma concentrations of conjugated bilirubin were measured in all samples. The results were analyzed using Bland-Altman plots and Passing-Bablok regressions. RESULTS: The Bland-Altman plot analysis showed that the TAC QMS immunoassay has a significant bias (+37%) compared with LC-MS/MS, and this bias was higher in patients with cholestasis with hyperbilirubinemia (≤+70% in patients with conjugated bilirubin >150 µmol/L). In comparison, the chemiluminescence microparticle immunoassay showed acceptable analytical performance in patients with hyperbilirubinemia (bias <10%). CONCLUSIONS: In agreement with previous findings, the TAC QMS immunoassay showed a positive bias compared with LC-MS/MS. This bias is remarkably high in patients with cholestasis and hyperbilirubinemia, suggesting the cross-reactivity of TAC metabolites with the monoclonal antibody used in the QMS immunoassay.

[Unfractionned heparin wastage at a French university hospital]. / Gaspillage d'héparine sodique dans un centre hospitalo-universitaire français.

OBJECTIVES: In a context of heparin shortage, we studied the wasted quantities in three intensive care units (ICU) of a university hospital where two electric syringe pump (ESP) heparin protocols coexist (20,000UI/48mL used in the cardiology ICU and 25,000UI/50mL use in the medical and surgical ICUs). METHOD: We performed a prospective observational study of patients treated with heparin ESP. We collected the information recorded in the prescription software connected to the ESP (dosage, start time, infusion rate, interruption times, date and time of end of treatment). We observed the ESPs, noted the time of start written on the label and the quantity remaining, and questioned nurses about the constraints that lead for changing the ESPs. RESULTS: Between 23/03/23 and 19/05/23, 164 vials of 25,000UI/5mL were used. The wasted quantity was equivalent 42 vials: 18 vials (43%) of treatment stopped, nurses practices such as changing the ESP in advance 6 vials (14%), application of the rule "discard the ESP 24hours after preparation" 9 vials (21.5%) and 9 vials (21.5%) corresponding to the 45mL discarded for the 45 ESP prepared in the cardiology ICU. CONCLUSION: More than a quarter of the heparin purchased is wasted. The results should lead to policy decisions concerning the medications supply chain, i.e. abandoning the 20,000UI/48mL protocol, supply of ready to use heparin syringes by industry or by the pharmacy. It is essential that these data be fed back to nurses' teams, in order to gather their suggestions before considering any changes of their practices.

[Inability of hospital computerised physician order entry systems to secure the use of concentrated potassium intravenous solutions]. / Incapacité des logiciels d'aide à la prescription hospitaliers à sécuriser l'utilisation des solutions concentrées de potassium injectable.

OBJECTIVES: To determine whether hospital computerised physician order entry (CPOE) systems contribute to securing intravenous potassium chloride (KCl) prescriptions with reference to the recommendations issued by French healthcare agencies. METHODS: We sent a questionnaire to the members of the Association pour le Digital et l'Information en Pharmacie. RESULTS: More than three quarters of the 84 responses received involving 23 CPOE systems indicate that it is possible to: prescribe an ampoule of concentrated potassium chloride 10% 10mL intravenously without any diluents (80%); prescribe 4g of KCl in a bag of 500mL of NaCl 0,9% (98%); prescribe a solution that contains 6 grams of KCl per liter (94%); prescribe the administration of an injectable ampoule orally by means of a free text comment (83%). Nearly half of the responses indicate that it is possible to prescribe: concentrated KCl ampoules as administration solvent (50%); an injectable vial to be administered by oral route (52%). CONCLUSION: At least 23 hospital CPOE systems are unable to secure the prescriptions of injectable KCl. This finding lifts the veil on an unthought, namely the role of CPOE systems in securing high-risk medications. In order to solve this problem, it should be mandatory that health information technology vendors pay particular attention to these drugs. With regard to injectable KCl, the utilisation of a dilution vehicle, maximum concentration and maximum infusion flow rate are the first four constraints to be satisfied.

[Translation and adaptation of a tool prescribing errors related to computerized physician order entry coding to the French hospital background]. / Traduction et adaptation au contexte hospitalier français d'un outil de codification des erreurs de prescription liées aux logiciels.

Prescribing errors related to computerized physician order entry are current and may have serious consequences for patients. They can be detected by pharmacists during prescriptions analysis and lead to pharmacist's interventions. In France, few monocentric studies have studied Pharmacist Interventions triggered by prescribing errors identified as System-Related Errors (PISREs) in French hospitals. However, their respective analysis method prevent any comparison between computerized physician order entry systems in order to identify the safest and rule out the most dangerous. A computerized physician prescribing error related to the software is characterized by its causes, consequences and mechanism of occurrence. US researchers have developed and validated a tool to classify and illustrate these three characteristics. The objectives of this article are to present this tool, to propose a French adaptation and to describe the perspectives analyze and understand prescription errors related to computerized physician order entry based on data of Act-IP©. The adaptation was performed using PISREs extracted from the Act-IP© observatory of the French Society of Clinical Pharmacy. Each item of the codification is illustrated with an example of PI. We are considering a training plan in order to allow wide use of this tool. Once adopted this tool, the next step will be to organize a prospective multicenter study including as many computerized prescription order entry systems as possible. The aim of this study will be identifying the safest systems. Consequently, it will then be possible to have arguments to qualify the most dangerous and thus propose their withdrawal from the market.

Curbing proton pump inhibitor overprescribing: Multifaceted strategies in an academic hospital.

WHAT IS KNOWN AND OBJECTIVE: Proton pump inhibitors (PPI) have become essential in the management of upper gastrointestinal disorders, yet they are prescribed without an indication in up to 89% of cases and the number of prescribed PPIs is on the rise. A working group developed several multifaceted strategies in our multihospital trust to curb inappropriate PPI use. We describe herein these strategies and assess their impact on PPI consumption in a hospital belonging to this trust. METHODS: From 2012 to 2019, our actions included the publication and presentation of a review of emergent PPI side effects, the development of an appropriate use leaflet, medication audits, journal club meetings, and prescription analysis. We considered that a decrease in PPI consumption could be a relevant surrogate criterion for the appropriation and acceptance of these interventions; this was assessed from 2012 to 2019 and expressed as defined daily dose (DDD)/1000 patient-days. RESULTS AND DISCUSSION: There was a clear downward trend in the consumption of PPIs, both in medical and surgical wards. The overall PPI use decreased by 17.1% (from 566 to 468 DDD/1000 patient-days). IV PPI consumption dropped by 37.7% (from 146 to 91 DDD/1000 patient-days), while oral PPIs consumption decreased by 10% (from 420 to 378 DDD/1000 patient-days). WHAT IS NEW AND CONCLUSION: Sustained strategies aimed at curbing PPI overprescribing led to a sustained decrease in PPI consumption in our hospital. This decrease encourages us to pursue this strategy and to diversify our actions.

[Injectable concentrated potassium concentrate, emblematic of the lack of safety of the drug use process in French hospitals]. / Le potassium injectable concentré, emblématique de l'insécurité médicamenteuse des hôpitaux français.

Despite its proven dangers, the ward stock drug distribution system predominates in French hospitals. This system allows 12 million injectable ampoules of concentrated potassium chloride to circulate uncontrolled each year. Such a situation is absurd for the following reasons : 1) injected by mistake, concentrated potassium kills within seconds ; 2) the true incidence of potassium-related fatalities and incidents is unknown ; 3) fatal intravenous injection of potassium produces no specific anatomical changes and subtle, if any, findings at autopsy ; 4) it is used for capital punishment by lethal injection in various countries ; and 5) healthcare worker serial killers benefit from the fact that potassium is not identifiable in post-mortem examinations and that investigations to find the murderer are complex and of uncertain outcome. Other medications classed as high-risk have similar characteristics to those of concentrated potassium solutions. Injectable potassium can therefore be regarded as emblematic of the lack of safety of the drug use process in French hospitals. The priority measure to protect patients from this deadly risk is to remove these drugs from uncontrolled ward stocks and to provide premixed potassium solutions. Evidence of the increased safety of the unit dose drug dispensing system should compel health policy makers to systematically implement it, thus bringing the drug use process into compliance with existing French and European regulations.

Le potassium injectable concentré, emblématique de l'insécurité médicamenteuse des hôpitaux français.

Despite its proven dangers, the ward stock drug distribution system predominates in French hospitals. This system allows 12 million injectable ampoules of concentrated potassium chloride to circulate uncontrolled each year. Such a situation is absurd for the following reasons : 1) injected by mistake, concentrated potassium kills within seconds ; 2) the true incidence of potassium-related fatalities and incidents is unknown ; 3) fatal intravenous injection of potassium produces no specific anatomical changes and subtle, if any, findings at autopsy ; 4) it is used for capital punishment by lethal injection in various countries ; and 5) healthcare worker serial killers benefit from the fact that potassium is not identifiable in post-mortem examinations and that investigations to find the murderer are complex and of uncertain outcome. Other medications classed as high-risk have similar characteristics to those of concentrated potassium solutions. Injectable potassium can therefore be regarded as emblematic of the lack of safety of the drug use process in French hospitals. The priority measure to protect patients from this deadly risk is to remove these drugs from uncontrolled ward stocks and to provide premixed potassium solutions. Evidence of the increased safety of the unit dose drug dispensing system should compel health policy makers to systematically implement it, thus bringing the drug use process into compliance with existing French and European regulations.

[Nurses and prescribers' choice of an electric syringe pump protocol for intravenous heparin administration]. / Choix d'un protocole d'administration d'héparine sodique au pousse-seringue électrique par des infirmières et des prescripteurs.

OBJECTIVES: Several protocols for administering heparin by electric syringe pump can coexist within the same hospital. This puts patients at risk of medication errors. In our hospital trust, two preparation protocols coexist (20000UI/48mL and 25000UI/50mL). The objective is to relate the work carried out with prescribers and nurses to retain only one protocol. METHODS: We questioned prescribers and nurses about the differences between the two protocols in terms of the simplicity of implementation and the risk of error to which nurses are exposed when preparing the syringe. Contextual information (heparin shortage, waste) was given in order to support the answers. RESULTS: According to the 96 nurses and 82 prescribers who responded, the protocol to use is 25000IU/50mL for 98% and 83% of them respectively. The 20000IU/48mL protocol was considered the riskiest due to the possibility of mistakenly collecting 5mL instead of the required 4mL. Given the heparin shortage, the waste inherent to the 20000IU/48mL protocol reinforced this choice. CONCLUSIONS: The consultation of nurses and prescribers allowed the choice of a protocol with very strong agreement. This work also brought to light what appears to be a medical misconception, namely that the non-concerted choice by physicians of a mode of administration of a drug can put nurses in a situation to make preparation errors more frequently. This emphasizes that nurses must be stakeholders in the decision-making processes that affect their practice.

Comparison of the validity, perceived usefulness, and usability of I-MeDeSA and TEMAS, two tools to evaluate alert system usability.

OBJECTIVE: Two tools are currently available in the literature to evaluate the usability of medication alert systems, the instrument for evaluating human factors principles in medication-related decision support alerts (I-MeDeSA) and the tool for evaluating medication alerting systems (TEMAS). This study aimed to compare their convergent validity, perceived usability, usefulness, strengths, and weaknesses, as well as users' preferences. METHOD: To evaluate convergent validity, two experts mapped TEMAS' items against I-MeDeSA's items with respect to the usability dimensions they target. To assess perceived usability, usefulness, strengths, and weaknesses of both tools, staff with expertise in their medication alerting system were asked to use French versions of the TEMAS and I-MeDeSA. After the use of each tool, participants were asked to complete the System Usability Scale (SUS) and answer questions about the understandability and usefulness of each tool. Finally, participants were asked to name their preferred tool. Numeric scores were statistically compared. Free-text responses were analyzed using an inductive approach. RESULTS: Forty-five participants from 10 hospitals took part in the study. In terms of convergent validity, I-MeDeSA focuses more on the usability of the graphical user interface while TEMAS considers a wider range of usability principles. Both tools have a fair level of perceived usability (I-MeDeSA' SUS score = 61.85 and TEMAS' SUS score = 62.87), but results highlight that revisions are necessary to both tools to improve their usability. Participants found TEMAS more useful than I-MeDeSA (t = -3.63, p =.005) and had a clear preference for TEMAS to identify problems in formative evaluation (39 of 45; 0.867, p <.001) and to compare the usability of alert systems during the procurement process (36 of 45; 0.8, p <.001). CONCLUSIONS: The TEMAS is perceived as more useful and is preferred by participants. The I-MeDeSA seems more relevant for quick evaluations that focus on the graphical user interface. The TEMAS seems to be more suitable for in-depth usability evaluations of alert systems. Even if both tools are perceived to be equally usable, they suffer from wording, instructional, and organizational problems that hinder their use. The results of this study will be used to improve the design of I-MeDeSA and TEMAS.

[Clinical pharmacy and pharmacovigilance over a period of nine years in hospital]. / Pharmacie clinique et pharmacovigilance à l'hôpital : bilan et perspectives après 9 ans d'expérience.

INTRODUCTION: Underreporting is the main limit in any pharmacovigilance system relying on spontaneous notification. Available data emphasize that pharmacists report few adverse drug reactions (ADRs) in France. OBJECTIVE: To report how the integration of pharmacists in health care units contributes to reporting of ADRs and to study the validity of the reports. METHOD: Over a period of nine years we have prospectively collected and analyzed all ADRs collected by pharmacists in a university hospital setting and notified to the regional center of pharmacovigilance. RESULTS: Over the study period 2017 notifications were sent. Over the past four years the annual number of reports varied between 250 and 350. This amount is approximately ten times the number referred by physicians during the year preceding the beginning of this work. Only 8.6% of the submitted notifications were rejected by the pharmacovigilance center for various reasons: no causal link between the adverse event and taking medication, problem of timing, lack of data... CONCLUSION: The integration of the adverse reaction reporting in the daily activities of the pharmacist is a mean to increase very significantly the number of reports (factor of increase of 9.6 to 13.4).

Characteristics of pharmacist's interventions triggered by prescribing errors related to computerised physician order entry in French hospitals: a cross-sectional observational study.

OBJECTIVES: Computerised physician order entry (CPOE) systems facilitate the review of medication orders by pharmacists. Reports have emerged that show conception flaws or the misuse of CPOE systems generate prescribing errors. We aimed to characterise pharmacist interventions (PIs) triggered by prescribing errors identified as system-related errors (PISREs) in French hospitals. DESIGN: This was a cross-sectional observational study based on PIs prospectively documented in the Act-IP observatory database from January 2014 to December 2018. SETTING: PISREs from 319 French computerised healthcare facilities were analysed. PARTICIPANTS: Among the 319 French hospitals, 232 (72.7%) performed SRE interventions, involving 652 (51%) pharmacists. RESULTS: Among the 331 678 PIs recorded, 27 058 were qualified as due to SREs (8.2%). The main drug-related problems associated with PISREs were supratherapeutic (27.5%) and subtherapeutic dosage (17.2%), non-conformity with guidelines/contraindications (22.4%) and improper administration (17.9%). The PI prescriber acceptation rate was 78.9% for SREs vs 67.6% for other types of errors. The PISRE ratio was estimated relative to the total number of PIs. Concerning the certification status of CPOE systems, the PISRE ratio was 9.4% for non-certified systems vs 5.5% for certified systems (p<0.001). The PISRE ratio for senior pharmacists was 9.2% and that for pharmacy residents 5.4% (p<0.001). Concerning prescriptions made by graduate prescribers and those made by residents, the PISRE ratio was 8.4% and 7.8%, respectively (p<0.001). CONCLUSION: Computer-related prescribing errors are common. The PI acceptance rate by prescribers was higher than that observed for PIs that were not CPOE related. This suggests that physicians consider the potential clinical consequences of SREs for patients to be more frequently serious than interventions unrelated to CPOE. CPOE medication review requires continual pharmacist diligence to catch these errors. The significantly lower PISRE ratio for certified software should prompt patient safety agencies to undertake studies to identify the safest software and discard software that is potentially dangerous.

CLEO: a multidimensional tool to assess clinical, economic and organisational impacts of pharmacists' interventions.

OBJECTIVES: Clinical pharmacists' interventions (PIs) are an important element in ensuring good pharmaceutical care. We aimed to develop and validate a comprehensive multidimensional tool for assessing the potential impact of PIs for daily practice of medication review. METHODS: Experts of the French Society of Clinical Pharmacy (SFPC) developed the CLinical, Economic and Organisational (CLEO) tool, consisting of three independent dimensions concerning clinical, economic and organisational impact. They were asked to analyse 30 scenarios of PIs, and re-rated 10 PIs with a washout of 1 month (internal validation). Then, seven external experts not involved in the development of the tool rated 60 scenarios collected when using the CLEO in daily practice. Inter- and intra-rater reliabilities were determined by calculation of the intra-class correlation (ICCA,1). Users' satisfaction and acceptability of the tool were assessed on a 7-level Likert scale with a 17-item questionnaire. RESULTS: For internal reliability, the inter-rater reliability for the CLEO tool was good for clinical dimensions (ICCA,1=0.693), excellent for economic dimensions (ICCA,1=0.815) and fair for organisational dimensions (ICCA,1=0.421); and the intra-rater reliability was good for clinical dimensions (ICCA,1=0.822), excellent for economic dimensions (ICCA,1=0.918) and good for organisational dimensions (ICCA,1=0.738). For external reliability, the inter-rater reliability was good for clinical dimensions (ICCA,1=0.649), excellent for economic dimensions (ICCA,1=0.814) and fair for organisational dimensions (ICCA,1=0.500). CLEO was viewed as relevant (mean±SD 4.93±1.27), acceptable (4.81±1.78), practicable (5.56±1.45) and precise (5.38±1.47). CONCLUSIONS: CLEO is a comprehensive tool assessing clinical, economic and organisational impacts of PIs which has been developed, validated and was reliable and feasible for use in routine clinical practice.

Effects of a continuous low-dose clonidine epidural regimen on pain, satisfaction and adverse events during labour: a randomized, double-blind, placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Epidural clonidine has been proposed as an adjunct for anaesthetic mixtures during labour. Administered as a bolus, clonidine may have side effects such as sedation and hypotension; its continuous infusion could be attractive in this respect. We, therefore, conducted a randomized, double-blind trial using patient-controlled epidural analgesia with a background infusion using a low dose of clonidine during labour. METHODS: A total of 128 healthy parturients in active labour received a patient-controlled epidural analgesia solution of 0.0625% levobupivacaine and sufentanil 0.25 microg ml(-1) with or without clonidine 2 microg ml(-1). Ninety-five parturients were analysed. The pain score over time was evaluated as well as drug volume utilization; supplementation bolus and side effects were recorded. The primary endpoint was maternal satisfaction [ClinicalTrials.gov Identifier (NCT00437996)]. RESULTS: Three patients in the control group failed to achieve satisfactory epidural analgesia owing to a technical issue. Although the primary endpoint was not statistically significant, analgesia was more pronounced and obtained earlier in the clonidine group. The area under the curve for the visual analogue pain score was significantly lower in the clonidine group. In this group, hourly doses of levobupivacaine and sufentanil were reduced (13.9 +/- 4.3 vs. 16.3 ml +/- 4.0; P = 0.005) as well as rescue supplementation and pruritus incidence (18 vs. 46%; P = 0.004). Maternal blood pressure was significantly lower, over time, in the clonidine group but remained within the normal range. Sedation was similar in both groups (4.3 vs. 2.0%; not significant). CONCLUSION: The addition of clonidine to epidural levobupivacaine and sufentanil for patient-controlled epidural analgesia in labour improved analgesia, reduced the supplementation rate and reduced pruritus without improvement in maternal satisfaction. Blood pressure was significantly lower in the clonidine group over time but without clinical consequence.

Proton Pump Inhibitors are Risk Factors for Viral Infections: Even for COVID-19?

During the ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), more attention should be paid to the balance of risks and benefits associated with proton pump inhibitors for the following reasons. One of the main functions of gastric juice is to inactivate swallowed microorganisms, thereby inhibiting infectious agents from reaching the intestine. Studies have documented that proton pump inhibitors are a risk factor for rotavirus, influenza virus, norovirus, and Middle East respiratory syndrome coronavirus infections, and are associated with an increased risk of acute gastroenteritis during periods of highest circulation of enteric viruses. In light of the evidence for gastrointestinal infection implying a fecal-oral transmission of SARS-CoV-2 and given the magnitude of the SARS-CoV-2/coronavirus disease 2019 pandemic, associated with the widespread misuse of proton pump inhibitors, this suggests that we should not rule out the hypothesis that patients treated with proton pump inhibitors may be more at risk of being infected by SARS-CoV-2.

Assessment of clinical pharmacists' interventions in French hospitals: results of a multicenter study.

BACKGROUND: The development of clinical pharmacy activities in most European countries is underway; however, data on these activities are still poorly reported. Multicenter studies are necessary to standardize and demonstrate the value of clinical pharmacy activities in these countries. OBJECTIVE: To document clinical pharmacists' daily routine interventions (PIs) to identify trends of intervention, drugs, and situations most frequently associated with drug-related problems (DRPs) and to estimate physicians' acceptance of PI. METHODS: A prospective study of PIs was conducted in 6 French hospitals. The sample consisted of 300 randomized PIs per hospital, recorded during the medication order validation process when a DRP was identified. We recorded patients' demographic characteristics, drugs involved, wards, DRP description, pharmacists' recommendations, and whether or not the recommendations were accepted by the physicians. RESULTS: A total of 38,626 medication orders were analyzed by 28 clinical pharmacists, leading to 1800 PIs (4.66 PIs per 100 medication orders). Of the 1800 PIs, 25.9% targeted psychotropic drugs, 15.9% targeted antithrombotic drugs, 15.5% targeted digestive and metabolic drugs, and 15.0% targeted cardiovascular drugs. The most commonly identified DRPs were nonconformity to guidelines or contraindication (21.3%), followed by improper administration (20.6%), supratherapeutic dose (19.2%), and drug interaction (12.6%). Nearly half (42.2%) of the pharmacists' recommendations were related to drug choice (drug switch 22.2%, drug discontinuation 16.3%, addition of a new drug 3.7%) followed by dose adjustment (23.8%), optimization of administration (21.9%; change of administration route 10.3%, administration modalities 11.6%), and need for drug monitoring (12.2%). The rate of physicians' acceptance was 73.4% (15.3% refusals, 11.3% not assessable). CONCLUSIONS: In French hospitals, pharmacists contribute to preventing DRPs during medication order validation. This study suggests that a few types of drugs and errors constitute a substantial proportion of PIs. Knowledge of the most frequent DRPs could significantly increase the efficiency of clinical PIs.

[Factors in the occurrence of medication errors and the use of order sets]. / Facteurs de survenue d'erreurs médicamenteuses et emploi de protocoles informatisés.

The packaging of the medication and the writing on the label can be the cause of medication errors. Errors in the intake of sodium chloride and potassium chloride have notably been due to the fact that the label of the infusion solute did not explicitly indicate the quantities present in the 500 mL and 1 000 mL bottles. Moreover, the meaning of the description comprising the term 'q.s.p. 1 000 mL' was not known by some of the nursing staff. These two factors, combined with the possibility of prescribing predefined order sets, have led to medication errors which have given rise to a study of how practices can be improved.