Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis.

BACKGROUND: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable. OBJECTIVE: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV. METHODS: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling. RESULTS: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained. CONCLUSION: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02365272.

Higher versus standard amikacin single dose in emergency department patients with severe sepsis and septic shock: a randomised controlled trial.

Recent studies suggest that intensive care unit patients treated with amikacin frequently do not attain the desired pharmacokinetic/pharmacodynamic (PK/PD) target, i.e. peak amikacin concentration (Cpeak) to minimum inhibitory concentration (MIC) ratio of ≥8, when a single dose of 15 mg/kg is used. No data are available for patients admitted to the emergency department (ED). The aim of this prospective randomised controlled study was to determine PK/PD target attainment in ED patients presenting with severe sepsis or septic shock treated with 15 mg/kg versus 25 mg/kg amikacin. Patients were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg. Amikacin Cpeak values were determined. The primary outcome was target attainment defined as Cpeak/MIC ≥ 8 both using EUCAST susceptibility breakpoints and actually documented MICs as denominator. A total of 104 patients were included. The EUCAST-based target was attained in 76% vs. 40% of patients assigned to the 25 mg/kg vs. 15 mg/kg dose groups (P <0.0001). Target attainment using actual MICs (median of 2 mg/L, documented in 48 isolated Gram-negative pathogens) was achieved in 95% vs. 94% of patients in the 25 mg/kg vs. 15 mg/kg dose groups (P = 0.969). Risk factors associated with PK/PD target failure were identified in the multivariable analysis. At least 25 mg/kg amikacin as a single dose should be used in ED patients with severe sepsis and septic shock to attain the EUCAST-based PK/PD target. However, when using local epidemiology as denominator, 15 mg/kg appears to be sufficient. [ClinicalTrials.gov ID: NCT02365272.

Predictors for unintentional medication reconciliation discrepancies in preadmission medication: a systematic review.

PURPOSE: Discrepancies in preadmission medication (PAM) are common and potentially harmful. Medication reconciliation is able to reduce the discrepancy rate, yet implementation is challenging. In order for reconciliation efforts to be more cost-effective, patients at high risk for reconciliation errors should be identified. The purpose of this systematic review is to identify predictors for unintentional discrepancies in PAM. METHODS: Medline and Embase were searched systematically until June 2017. Only studies concerning adult subjects were retained. Quantitative studies were included if predictors for unintentional discrepancies in the PAM had been determined on hospital admission. Variables were divided into patient-, medication-, and setting-related predictors based on a thematic analysis. Studies on identification of predictors for discrepancies and potentially harmful discrepancies were handled separately. RESULTS: Thirty-five studies were eligible, of which 5 studies focused on potentially harmful discrepancies. The following 16 significant variables were identified using multivariable prediction models: number of preadmission drugs, patient's age, availability of a drug list, patients' understanding of medication, usage of different outpatient pharmacies, number of high-risk drugs, discipline for which the patient is admitted, admitting physician's experience, number and type of consulted sources, patient's gender, type of care before admission, number of outpatient visits during the past year, class of medication, number of reimbursements, use of an electronic prescription system, and type of admission (elective vs emergency). The number of preadmission drugs was identified as a predictor in 20 studies. Potentially harmful discrepancies were ascertained in 5 studies with age found to have a predictive value in all 5 studies. CONCLUSION: Multiple suitable predictors for PAM-related discrepancies were identified of which higher age and polypharmacy were reported most frequently.

Developing a decision rule to optimise clinical pharmacist resources for medication reconciliation in the emergency department.

BACKGROUND: The process of obtaining a complete medication history for patients admitted to the hospital from the ED at hospital admission, without discrepancies, is error prone and time consuming. OBJECTIVES: The goal of this study was the development of a clinical decision rule (CDR) with a high positive predictive value in detecting ED patients admitted to hospital at risk of at least one discrepancy during regular medication history acquisition, along with favourable feasibility considering time and budget constraints. METHODS: Data were based on a previous prospective study conducted at the ED in Belgium, describing discrepancies in 3592 medication histories. Data were split into a training and a validation set. A model predicting the number of discrepancies was derived from the training set with negative binomial regression and was validated on the validation set. The performance of the model was assessed. Several CDRs were constructed and evaluated on positive predictive value and alert rate. RESULTS: The following variables were retained in the prediction model: (1) age, (2) gender, (3) medical discipline for which the patient was admitted, (4) degree of physician training, (5) season of admission, (6) type of care before admission, number of (7) drugs, (8) high-risk drugs, (9) drugs acting on alimentary tract and metabolism, (10) antithrombotics, antihaemorrhagics and antianaemic preparations, (11) cardiovascular drugs, (12) drugs acting on musculoskeletal system and (13) drugs acting on the nervous system; all recorded by the ED physician on admission. The final CDR resulted in an alert rate of 29% with a positive predictive value of 74%. CONCLUSION: The final CDR allows identification of the majority of patients with a potential discrepancy within a feasible workload for the pharmacy staff. Our CDR is a first step towards a rule that could be incorporated into electronic medical records or a scoring system.

Stability of Drugs Used in Helicopter Air Medical Emergency Services: An Exploratory Study.

OBJECTIVE: Transportation by air exposes drugs used in emergency medical services to vibrations. The aim of the study was to determine whether or not vibrations caused by a helicopter induce the degradation of 5 drugs used in this setting. METHODS: A longitudinal study in an operating medical helicopter along with a worst case was conducted. The studied drugs were 3 drugs labeled for refrigeration (cisatracurium, lorazepam, and succinylcholine) and 2 albumin solutions (human albumin 4% and 20%). These drugs were stored for 4 months according to the following conditions: inside a helicopter, worst case with exposure to extreme vibrations, at room temperature, and according to manufacturers' recommendations. Samples were analyzed with validated high-performance liquid chromatography assay methods. A drug was considered stable if the remaining drug content was above 90% of the label claim. Except for the albumin solutions, visual inspection was used to determine instability by the formation of aggregates. RESULTS: Only the samples stored at room temperature became unstable after 4 months. No difference in extreme foaming was observed in the albumin solutions. CONCLUSIONS: These data suggest that the effect of degradation of drugs caused by vibrations is negligible. Temperature was observed as the main cause of drug degradation.

Exploring the relationship between fall risk-increasing drugs and fall-related fractures.

BACKGROUND: Hospital admissions due to fall-related fractures are a major problem in the aging population. Several risk factors have been identified, including drug use. Most studies often retrieved prescription-only drugs from national databases. These are associated with some limitations as they do not always reliably reproduce the complete patient's active drug list. OBJECTIVE: To evaluate the association between the number of FRIDs intake identified by a standardised medication reconciliation process and a fall-related fracture leading to a hospital admission in older adults. SETTING: The first cohort has been recruited from one traumatology ward of a tertiary teaching hospital in Belgium and the second cohort has been recruited from 11 community pharmacies in Belgium. METHOD: A prospective study with two individually matched cohorts was performed. Adult patients (≥75 years) admitted with an injury due to a fall were included in the first cohort (faller group). The second cohort consisted of patients who did not suffer from a fall within the last 6 months (non-faller group). Matching was performed for age, gender, place of residence and use of a walking aid. In both groups, clinical pharmacists and undergraduate pharmacy students obtained the medication history, using a standardised approach. A list of drugs considered to increase the risk of falling was created. It included cardiovascular drugs and drugs acting on the nervous system. A linear mixed model was used to compare the number of fall risk-increasing drugs between fallers and non-fallers. MAIN OUTCOME MEASURE: The number of fall risk-increasing drugs in a faller versus a non-faller group. RESULTS: Sixty-one patients were matched with 121 non-fallers. Patients received on average 3.1 ± 2.1 and 3.2 ± 1.8 fall risk-increasing drugs in the faller and in the non-faller group, respectively. The mean number of fall risk-increasing drugs was comparable in both groups (p = 0.844), even after adjusting for alcohol consumption, fear of falling, vision and foot problems (p = 0.721). CONCLUSION: In a sample of hospitalised patients admitted for a fall-related injury, no significant difference in the number of fall risk-increasing drugs versus that of an outpatient group of non-fallers was found.

Initiatives promoting seamless care in medication management: an international review of the grey literature.

BACKGROUND: Patients' transition between hospital and community is a high-risk period for the occurrence of medication-related problems. AIM OF THE REVIEW: The objective was to review initiatives, implemented at national and regional levels in seven selected countries, aiming at improving continuity in medication management upon admission and hospital discharge. METHOD: We performed a structured search of grey literature, mainly through relevant websites (scientific, professional and governmental organizations). Regional or national initiatives were selected. For each initiative data on the characteristics, impact, success factors and barriers were extracted. National experts were asked to validate the initiatives identified and the data extracted. RESULTS: Most initiatives have been implemented since the early 2000 and are still ongoing. The principal actions include: development and implementation of guidelines for healthcare professionals, national information campaigns, education of healthcare professionals and development of information technologies to share data across settings of care. Positive results have been partially reported in terms of intake into practice or process measures. Critical success factors identified included: leadership and commitment to convey national and local forces, tailoring to local settings, development of a regulatory framework and information technology support. Barriers identified included: lack of human and financial resources, questions relative to responsibility and accountability, lack of training and lack of agreement on privacy issues. CONCLUSION: Although not all initiatives are applicable as such to a particular healthcare setting, most of them convey very interesting data that should be used when drawing recommendations and implementing approaches to optimize continuity of care.

Impact of temperature exposure on stability of drugs in a real-world out-of-hospital setting.

STUDY OBJECTIVE: The aim of this study is to determine the content of 5 important emergency medical services (EMS) drugs after being stored at the recommended refrigerated temperature, room temperature, or in an emergency physician transport vehicle operating under real-world working conditions. METHODS: Adrenaline hydrochloride, cisatracurium besylate, lorazepam, methylergonovine maleate, and succinylcholine chloride were stored for 1 year under the 3 conditions. For each storage condition, samples of the drugs were taken after 1, 2, 3, and 4 weeks and after 2, 4, 6, 8, 10, and 12 months. For adrenaline hydrochloride, however, the samples were taken after 1, 2, 4, 6, 8, 10, and 12 months. The samples were analyzed with a validated high-performance liquid chromatography assay. A drug was considered stable if its content was above 90%. RESULTS: Adrenaline hydrochloride and methylergonovine maleate remained stable for 1 year at room temperature and in the emergency physician transport vehicle. At room temperature and in the emergency physician transport vehicle, lorazepam became unstable within 4 weeks. Succinylcholine chloride was stable for 2 months at room temperature and for 1 month in the emergency physician transport vehicle. Cisatracurium besylate became unstable within 4 months at room temperature. However, it remained stable for 4 months in the emergency physician transport vehicle. CONCLUSION: When stored at room temperature or in the emergency physician transport vehicle, lorazepam became unstable within weeks, whereas succinylcholine chloride and cisatracurium besylate became unstable within months. Adrenaline hydrochloride and methylergonovine maleate remained stable for several months, even under room temperature and emergency physician transport vehicle conditions. Thus, real-world EMS working conditions pose challenges for maintaining optimal efficacy of these important EMS drugs.

A venlafaxine and mirtazapine-induced serotonin syndrome confirmed by de- and re-challenge.

CASE DESCRIPTION: A 85 year old woman with a history of severe depression treated with mirtazapine and venlafaxine was admitted to the hospital twice after progressive deterioration of her general condition evolving to unconsciousness. Clinicians diagnosed a metabolic encephalopathy caused by a urinary tract infection which was treated appropriately. Although mirtazapine was stopped during the first hospitalization, the patient's general practitioner restarted mirtazapine four days before readmission. During rehospitalization, she developed extreme restlessness, hyperreflexia and an increased tone in the lower limbs. She was hypertensive and tachycardic. Excessive sweating, elevated creatine kinase levels and bilateral mydriasis were noticed. Urinary analysis showed positive levels of mirtazapine and venlafaxine and both drugs were withdrawn. Symptoms resolved within 48 h after discontinuation of her antidepressants. Conclusion To our knowledge, this is the first case of the serotonin syndrome confirmed by a positive challenge, de-challenge and re-challenge.

A simple tool to improve medication reconciliation at the emergency department.

BACKGROUND: Medication histories acquired upon admission are often incomplete. Using a standardized approach warrants more complete medication reconciliation, however, this is too time consuming to be performed. Other strategies guaranteeing complete medication histories should be explored. We developed a limited list of standardized questions and assessed its impact on completeness of medication histories. METHODS: This prospective study enrolled adults presenting to a tertiary care emergency department. In the control group, medication histories were conducted by physicians of general internal medicine conform standard care. In the intervention group, the physicians were obliged to use, besides the standard care, the 'limited questions list' for medication history acquisition. The clinical pharmacist re-obtained medication histories of the patients in both groups using a standardized approach. The primary outcome was the impact of the use of a 'limited questions list' on the frequency of drug omissions in medication histories. RESULTS: 260 consecutive patients were enrolled: 130 in the intervention group and 130 in the control group. There was a significant reduction of 49.3% in drug omissions in the intervention group. The omission rate per medication history was 1.1 for the control group, which was significantly lower (0.6) in the intervention group. Antithrombotics were most frequently forgotten in the control care group as opposed to dietary supplements in the intervention group. CONCLUSION: Drug omission rate in medication histories can be significantly reduced if a limited list of simple questions is used during anamnesis. Widespread use of this tool should be considered to be implemented.

Pharmacist- versus physician-acquired medication history: a prospective study at the emergency department.

BACKGROUND: Recent literature revealed that medication histories obtained by physicians and nurses are often incomplete. However, the number of patients included was often low. Study objective In this study, the authors compare medication histories obtained in the Emergency Department (ED) by pharmacists versus physicians and identify characteristics contributing to discrepancies. METHODS: Medication histories were acquired by the pharmacist from patients admitted to the ED, planned to be hospitalised. A structured form was used to guide the pharmacist or technician to ensure a standardised approach. Discrepancies, defined as any difference between the pharmacist-acquired medication history and that obtained by the physician, were analysed. RESULTS: 3594 medication histories were acquired by pharmacy staff. 59% (95% CI 58.2% to 59.8%) of medication histories recorded by physicians were different from those obtained by the pharmacy staff. Within these inaccurate medication histories, 5963 discrepancies were identified. The most common type of error was omission of a drug (61%; 95% CI 60.4% to 61.6%), followed by omission of dose (18%; 95% CI 17.6% to 18.4%). Drugs belonging to the class of psycholeptics, acid suppressors and beta blocking agents were related to the highest discrepancy rate. Acetylsalicylic acid, omeprazole and zolpidem were most commonly forgotten. CONCLUSION: This large prospective study demonstrates that medication history acquisition is very often incomplete in the ED. A structured form and a standardised method is necessary. Pharmacists are especially suited to acquire and supervise accurate medication histories, as they are educated and familiar with commonly used drugs.