Pharmacokinetics of S-ketamine during prolonged sedation at the pediatric intensive care unit.

BACKGROUND: S-ketamine is the S(+)-enantiomer of the racemic mixture ketamine, an anesthetic drug providing both sedation and analgesia. In clinical practice, significant interpatient variability in drug effect of S-ketamine is observed during long-term sedation. AIMS: The aim of this study was to evaluate the pharmacokinetic variability of S-ketamine in children aged 0-18 years during long-term sedation. Twenty-five children (median age: 0.42 years, range: 0.02-12.5) received continuous intravenous administrations of 0.3-3.6 mg/kg/h S-ketamine for sedation during mechanical ventilation. Infusion rates were adjusted to the desired level of sedation and analgesia based on the COMFORT-B score and Visual Analog Scale. Blood samples were drawn once daily at random time-points, and at 1 and 4 hours after discontinuation of S-ketamine infusion. Time profiles of plasma concentrations of S-ketamine and active metabolite S-norketamine were analyzed using nonlinear mixed-effects modeling software. Clearance and volume of distribution were allometrically scaled using the ¾ power model. RESULTS: A total of 86 blood samples were collected. A 2-compartment and 1-compartment model adequately described the PK of S-ketamine and S-norketamine, respectively. The typical parameter estimates for clearance and central and peripheral volumes of distribution were: CLS-KETAMINE =112 L/h/70 kg, V1S-KETAMINE =7.7 L/70 kg, V2S-KETAMINE =545L/70 kg, QS-kETAMINE =196 L/h/70 kg, and CLS-NORKETAMINE =53 L/h/70 kg. Interpatient variability of CLS-KETAMINE and CLS-NORKETAMINE was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations. CONCLUSION: Substantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation.

Quality of pharmaceutical care in surgical patients.

BACKGROUND: Surgical patients are at risk for preventable adverse drug events (ADEs) during hospitalization. Usually, preventable ADEs are measured as an outcome parameter of quality of pharmaceutical care. However, process measures such as QIs are more efficient to assess the quality of care and provide more information about potential quality improvements. OBJECTIVE: To assess the quality of pharmaceutical care of medication-related processes in surgical wards with quality indicators, in order to detect targets for quality improvements. METHODS: For this observational cohort study, quality indicators were composed, validated, tested, and applied on a surgical cohort. Three surgical wards of an academic hospital in the Netherlands (Academic Medical Centre, Amsterdam) participated. Consecutive elective surgical patients with a hospital stay longer than 48 hours were included from April until June 2009. To assess the quality of pharmaceutical care, the set of quality indicators was applied to 252 medical records of surgical patients. RESULTS: Thirty-four quality indicators were composed and tested on acceptability and content- and face-validity. The selected 28 candidate quality indicators were tested for feasibility and 'sensitivity to change'. This resulted in a final set of 27 quality indicators, of which inter-rater agreements were calculated (kappa 0.92 for eligibility, 0.74 for pass-rate). The quality of pharmaceutical care was assessed in 252 surgical patients. Nearly half of the surgical patients passed the quality indicators for pharmaceutical care (overall pass rate 49.8%). Improvements should be predominantly targeted to medication care related processes in surgical patients with gastro-intestinal problems (domain pass rate 29.4%). CONCLUSIONS: This quality indicator set can be used to measure quality of pharmaceutical care and detect targets for quality improvements. With these results medication safety in surgical patients can be enhanced.

Evidence based development of bedside clinical drug rules for surgical patients.

BACKGROUND: Surgical adverse events constitute a considerable problem. More than half of in-hospital adverse events are related to a surgical procedure. Medication related events are frequent and partly preventable. Due to the complexity and multidisciplinary nature of the surgical process, patients are at risk for drug related problems. Consistent drug management throughout the process is needed. OBJECTIVE: The aim of this study was to develop an evidence-based bedside tool for drug management decisions during the pre- and postoperative phase of the surgical pathway. SETTING: Tool development study performed in an academic medical centre in the Netherlands involving an expert panel consisting of a surgeon, a clinical pharmacist and a pharmacologist, all experienced in quality improvement. METHOD: Relevant medication related problems and critical pharmacotherapeutic decision steps in the surgical process were identified and prioritised by a team of experts. The final selection comprised undesirable effects or unintended outcomes related to surgery (e.g. pain, infection) and comorbidity related hazards (e.g. diabetes, cardiovascular diseases). To guide patient management, a list of bedside surgical drug rules was developed using international evidence-based guidelines. MAIN OUTCOME MEASURE: 55 bedside drug rules on 6 drug categories, specifically important for surgical practice, were developed: pain, respiration, infection, diabetes, cardiovascular diseases and anticoagulation. RESULTS: A total of 29 evidence-based guidelines were used to develop the Bedside Surgical Drug Rules tool. This tool consist of practical tables covering management regarding (1) the most commonly used drug categories during surgery, (2) comorbidities that require dosing adjustments and, (3) contra-indicated drugs in the perioperative period. CONCLUSION: An evidence-based approach provides a practical basis for the development of a bedside tool to alert and assist the care providers in their drug management decisions along the surgical pathway.

Occurrence and preventability of adverse drug events in surgical patients: a systematic review of literature.

BACKGROUND: Adverse drug events (ADEs) are a considerable cause of inhospital morbidity and mortality. Patient flow differs substantially for surgical and nonsurgical patients: surgical patients are subjected to multiple medication changes related to surgical intervention or postoperative care. The objective of this study is to systematically review the occurrence and nature of ADEs in surgical patients. Also, a comparison with nonsurgical patients was made. METHODS: A search was conducted in Embase and Medline identifying studies that reported observational data on the occurrence and nature of ADEs in surgical hospitalised adult patients. If sufficient data were available, the occurrence of (preventable) ADEs was compared between surgical and nonsurgical patients. RESULTS: Six studies fulfilled the inclusion criteria. The occurrence of ADEs in surgical patients ranged from 2.0 to 27.7 per 100 admissions, from 4.7 to 8.9 per 1,000 patient days, or involved 8.9% of the patients. Proportions of preventable ADEs in surgical patients were 18% and 54%, described in two studies. A head-to-head comparison of surgical patients and nonsurgical patients was possible for five of six studies. The occurrence of ADEs in nonsurgical patients was significantly higher than in surgical patients in three studies. CONCLUSIONS: ADEs are a relevant problem in surgical patients and nonsurgical patients, with a high proportion of preventable ADEs. The occurrence of ADEs appears to be higher in nonsurgical patients than in surgical patients. However, studies lack details on the differences in nature of ADEs between hospital populations. To improve medication safety this knowledge is essential.

Adverse drug events in older hospitalized patients: results and reliability of a comprehensive and structured identification strategy.

BACKGROUND: Older patients are at high risk for experiencing Adverse Drug Events (ADEs) during hospitalization. To be able to reduce ADEs in these vulnerable patients, hospitals first need to measure the occurrence of ADEs, especially those that are preventable. However, data on preventable ADEs (pADEs) occurring during hospitalization in older patients are scarce, and no 'gold standard' for the identification of ADEs exists. METHODOLOGY: The study was conducted in three hospitals in the Netherlands in 2007. ADEs were retrospectively identified by a team of experts using a comprehensive and structured patient chart review (PCR) combined with a trigger-tool as an aid. This ADE identification strategy was applied to a cohort of 250 older hospitalized patients. To estimate the intra- and inter-rater reliabilities, Cohen's kappa values were calculated. PRINCIPAL FINDINGS: In total, 118 ADEs were detected which occurred in 62 patients. This ADE yield was 1.1 to 2.7 times higher in comparison to other ADE studies in older hospitalized patients. Of the 118 ADEs, 83 (70.3%) were pADEs; 51 pADEs (43.2% of all ADEs identified) caused serious patient harm. Patient harm caused by ADEs resulted in various events. The overall intra-rater agreement of the developed strategy was substantial (κ = 0.74); the overall inter-rater agreement was only fair (κ = 0.24). CONCLUSIONS/SIGNIFICANCE: The ADE identification strategy provided a detailed insight into the scope of ADEs occurring in older hospitalized patients, and showed that the majority of (serious) ADEs can be prevented. Several strategy related aspects, as well as setting/study specific aspects, may have contributed to the results gained. These aspects should be considered whenever ADE measurements need to be conducted. The results regarding pADEs can be used to design tailored interventions to effectively reduce harm caused by medication errors. Improvement of the inter-rater reliability of a PCR remains challenging.

Adverse drug events in surgical patients: an observational multicentre study.

BACKGROUND: Errors occurring during different steps of the medication process can lead to adverse drug events (ADEs). Surgical patients are expected to have an increased risk for ADEs during hospitalization. However, detailed information about ADEs in the surgical patient is lacking. OBJECTIVE: In this study, we aim to measure the incidence and nature of (preventable) ADEs, potential risk factors for and outcome parameters of (preventable) ADEs in surgical patients. SETTING: Observational multicentre cohort study in which eight surgical wards participated from three Dutch hospitals, all using computerized physician order entry (CPOE) systems with clinical decision support. METHODS: Electively admitted surgical patients of the participating wards were included from March until June 2009. ADEs were measured using a standardized method with expert judgment. Incidence, severity, preventability and accountable medication were assessed. Poisson regression analysis was applied to determine the associations between possible risk factors and the occurrence of ADEs, expressed as incidence rate ratio (IRR). Also outcomes of ADEs in surgical patients were measured. MAIN OUTCOME MEASURE: The incidence and nature of (preventable) ADEs in surgical patients. RESULTS: A total of 567 surgical patients were included. We found an incidence of 27.5 ADEs and 4.2 preventable ADEs (pADEs) per 100 admissions (15.4 %). A quarter of the pADEs were severe or life-threatening. Opioids and anti-coagulation medication play a major role in the occurrence of ADEs and pADEs respectively. Univariate analysis revealed an American Society of Anesthesiologists classification of III or more as a risk factor for ADEs. Patients older than 65 years [IRR 2.77 (1.14-6.72)], with cardiovascular comorbidity [IRR 2.87 (1.13-7.28)], or undergoing vascular surgery [IRR 2.32 (1.01-5.32)] were at risk for pADEs. Patients experiencing an ADE had a significant longer duration of admission than patients without an ADE. CONCLUSIONS: Surgical patients are at considerable risk of experiencing one or more ADEs during their admission, also in CPOE-hospitals. Risk factors for pADEs are age older than 65 years, cardiovascular comorbidity, and vascular surgery. Intensified monitoring may be needed in patients with a higher than average risk for pADEs.

A targeted method for standardized assessment of adverse drug events in surgical patients.

OBJECTIVES: This study demonstrates the development, reliability and outcome of a targeted method for standardized assessment of adverse drug events (ADEs) in surgical patients. METHODS: Initial practice evaluation of this ADE assessment method was carried out in a prospective single centre cohort study. In total, 262 electively admitted surgical patients were included. The surgical trigger tool was applied to patients' medical records by two independent reviewers, and subsequent assessment of causality, severity and preventability of ADEs was carried out by two independent expert panels consisting of a consultant surgeon and a clinical pharmacologist. The surgical trigger tool and causality assessment method were each tested on reliability in a separate group of 50 randomly selected patients using Fleiss and Cohen's kappa statistics and percentages of agreement. Comparison of this method with an existing trigger tool method for ADEs was performed. RESULTS: Our surgical trigger tool contains 51 triggers. The inter- and intra-rater calculations showed substantial to almost perfect levels of agreement (kappa range 0.71-0.83), with a 97.8-98.5% percentage of agreement. Fair to substantial levels of agreement were calculated for causality, severity and preventability (kappa range 0.38-0.79). The percentages of inter- and intra-rater agreement were 68.9 and 70.5% for causality, 67.0 and 82.0% for severity, and both 98.4% for preventability, respectively. Compared with the existing trigger tool method for ADEs, we found an additional 363 triggers, 18 ADEs (an extra 20%) and 3 preventable ADEs in our surgical cohort. CONCLUSIONS: This targeted trigger tool for standardized assessment of ADEs in surgical patients shows excellent agreement between reviewers. The assessment of medication-related harm had acceptable agreement. Compared with an existing ADE trigger tool method, the present method found almost 20% extra ADEs. This method can be a useful alternative to existing trigger tool methods, in particular to assess medication safety in surgical patients.

Improving medication administration in nursing home residents with swallowing difficulties: sustainability of the effect of a multifaceted medication safety programme.

BACKGROUND: Crushing solid oral dosage forms is an important risk factor for medication administration errors (MAEs) in patients with swallowing difficulties. Nursing home (NH) residents, especially those on psychogeriatric wards, have a high prevalence of such difficulties. CONTEXT: Six different psychogeriatric wards in two Dutch NH facilities, participating over a total period of 1 year divided into preintervention, implementation, and the first and second evaluation period. KEY MEASURES FOR IMPROVEMENT: Number of MAEs per number of observed medication administrations calculated for all and three subtypes of MAEs: crushing-uncrushable-medication, inappropriate-technique, and food-drug interactions. STRATEGIES FOR CHANGE: The intervention included (i) education for nursing staff about crushing medication safely, (ii) a medication administration protocol for patients with swallowing difficulties, (iii) a 'do-not-crush-medication' pocket card for the nursing staff, (iv) screening of medication charts by pharmacy technicians on potential crushing problems, and (v) advices on medication charts on safe medication administration to residents with swallowing problems. EFFECTS OF CHANGE: The number of crushing uncrushable medication errors, an MAE subtype with the highest potential risk for patient harm, was reduced significantly from 19 (9.6%) to 7 (3.0%; first evaluation period), adjusted odds ratio 0.20 (OR = 95%CI, 0.07-0.55). During the second evaluation period, the proportion crushing uncrushable medications errors was the only outcome that remained significantly lower in comparison with the preintervention period (p = 0.045). LESSONS LEARNED: Introduction of a multifaceted medication safety programme in NH facilities by a pharmacy team is a tool towards safer medication administration practice in residents with swallowing difficulties. Commitment on organisational level is, however, vital to achieve sustainable improvements.

Recognition of adverse drug events in older hospitalized medical patients.

OBJECTIVE: To assess medical teams' ability to recognize adverse drug events (ADEs) in older inpatients. METHODS: The study cohort comprised 250 patients aged 65 years or older consecutively admitted to Internal Medicine wards of three hospitals in the Netherlands between April and November 2007. An independent expert team identified ADEs present upon admission or occurring during hospitalization by a structured retrospective patient chart review. For all ADEs identified, the expert team assessed causality, severity, preventability, and recognition by medical teams. RESULTS: The medical teams did not recognize 19.9 % of all ADEs present upon admission {60.4 ADEs [95 % confidence interval (CI) 51.5-70.8] per 100 hospitalizations} and 20.3 % of all ADEs occurring during the hospital stay [47.2 ADEs (95 % CI 39.4-56.5) per 100 hospitalizations]. Unrecognized ADEs were significantly more often ADEs with possible causality (p=0.014, df=1), ADEs caused by medication errors (p<0.001, df=1), and ADEs not manifesting as new symptoms (p<0.001, df=1). The medical teams did not recognize 23.2 % of mild to moderately severe ADEs and 16.5 % of severe, life-threatening, or fatal ADEs. The recognition of ADEs varied with event type. CONCLUSIONS: The recognition of ADEs by medical teams was substantial for those ADEs with evident causality and with clinically apparent and severe consequences. ADEs mimicking underlying pathologies with a lower severity went unrecognized much more often, as did those resulting only in abnormal laboratory values. Tools to improve the recognition of ADEs by medical teams should, therefore, focus on those ADEs that are more challenging to detect.

The effect of an active on-ward participation of hospital pharmacists in Internal Medicine teams on preventable Adverse Drug Events in elderly inpatients: protocol of the WINGS study (Ward-oriented pharmacy in newly admitted geriatric seniors).

BACKGROUND: The potential of clinical interventions, aiming at reduction of preventable Adverse Drug Events (preventable ADEs) during hospital stay, have been studied extensively. Clinical Pharmacy is a well-established and effective service, usually consisting of full-time on-ward participation of clinical pharmacists in medical teams. Within the current Hospital Pharmacy organisation in the Netherlands, such on-ward service is less feasible and therefore not yet established. However, given the substantial incidence of preventable ADEs in Dutch hospitals found in recent studies, appears warranted. Therefore, "Ward-Oriented Pharmacy", an on-ward service tailored to the Dutch hospital setting, will be developed. This service will consist of multifaceted interventions implemented in the Internal Medicine wards by hospital pharmacists. The effect of this service on preventable ADEs in elderly inpatients will be measured. Elderly patients are at high risk for ADEs due to multi-morbidity, concomitant disabilities and polypharmacy. Most studies on the incidence and preventability of ADEs in elderly patients have been conducted in the outpatient setting or on admission to a hospital, and fewer in the inpatient setting. Moreover, recognition of ADEs by the treating physicians is challenging in elderly patients because their disease presentation is often atypical and complex. Detailed information about the performance of the treating physicians in ADE recognition is scarce. METHODS/DESIGN: The design is a multi-centre, interrupted time series study. Patients of 65 years or older, consecutively admitted to Internal Medicine wards will be included. After a pre-measurement, a Ward-Oriented Pharmacy service will be introduced and the effect of this service will be assessed during a post-measurement. The primary outcome measures are the ADE prevalence on admission and ADE incidence during hospital stay. These outcomes will be assessed using structured retrospective chart review by an independent expert panel. This assessment will include determination of causality, severity and preventability of ADEs. In addition, the extent to which ADEs are recognised and managed by the treating physicians will be considered. DISCUSSION: The primary goal of the WINGS study is to assess whether a significant reduction in preventable ADEs in elderly inpatients can be achieved by a Ward-Oriented Pharmacy service offered. A comprehensive ADE detection method will be used based on expert opinion and retrospective, trigger-tool enhanced, chart review.

Cost-effectiveness of ward-based pharmacy care in surgical patients: protocol of the SUREPILL (Surgery & Pharmacy In Liaison) study.

BACKGROUND: Preventable adverse drug events (pADEs) are widely known to be a health care issue for hospitalized patients. Surgical patients are especially at risk, but prevention of pADEs in this population is not demonstrated before. Ward-based pharmacy interventions seem effective in reducing pADEs in medical patients. The cost-effectiveness of these preventive efforts still needs to be assessed in a comparative study of high methodological standard and also in the surgical population. For these aims the SUREPILL (Surgery & Pharmacy in Liaison) study is initiated. METHODS/DESIGN: A multi-centre controlled trial, with randomisation at ward-level and preceding baseline assessments is designed. Patients admitted to the surgical study wards for elective surgery with an expected length of stay of more than 48 hours will be included. Patients admitted to the intervention ward, will receive ward-based pharmacy care from the clinical pharmacy team, i.e. pharmacy practitioners and hospital pharmacists. This ward-based pharmacy intervention includes medication reconciliation in consultation with the patient at admission, daily medication review with face-to-face contact with the ward doctor, and patient counselling at discharge. Patients admitted in the control ward, will receive standard pharmaceutical care.The primary clinical outcome measure is the number of pADEs per 100 elective admissions. These pADEs will be measured by systematic patient record evaluation using a trigger tool. Patient records positive for a trigger will be evaluated on causality, severity and preventability by an independent expert panel. In addition, an economic evaluation will be performed from a societal perspective with the costs per preventable ADE as the primary economic outcome. Other outcomes of this study are: severity of pADEs, number of patients with pADEs per total number of admissions, direct (non-)medical costs and indirect non-medical costs, extra costs per prevented ADE, number and type of pharmacy interventions, length of hospital stay, complications registered in a national complication registration system for surgery, number of readmissions within three months after initial admission (follow-up), quality of life and number of non-institutionalized days during follow-up. DISCUSSION: This study will assess the cost-effectiveness of ward-based pharmacy care on preventable adverse drug events in surgical patients from a societal perspective, using a comparative study design. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2258.

Towards evidence-based pharmacotherapy in children.

In daily practice, it is difficult to find a registered drug for children, because about 70% of the drugs prescribed in children are not studied, off-label or unlicensed in this age group. Clinical trials have usually been performed in adults, and then in daily practice dosages are adjusted for children without proper studies in that age group. In some countries, national formularies are being established to overcome the existing variance in prescribing between physicians. Complicating factors in finding the correct dosage for children include the heterogeneity between different age groups in the developmental stages of the organs influencing the absorption, distribution, metabolism, and excretion as well as differences in body composition during growth. Growth may also influence the effects and adverse effects of a drug used in a child. For oral administration of drugs in children, the bioavailability, the taste, the composition, and the absence of toxic ingredients for that age group are additional important factors. The EU has recently introduced legislation to stimulate the pharmaceutical industry to investigate the pharmacological effect and safety of new medicines in children. In response to this legislation, research networks are being established to provide the optimal infrastructure for pediatric drug investigation. The goals of this paper are to review the current problems in daily practice and to address the needs for evidence based pharmacotherapy in children.

On-ward participation of a hospital pharmacist in a Dutch intensive care unit reduces prescribing errors and related patient harm: an intervention study.

INTRODUCTION: Patients admitted to an intensive care unit (ICU) are at high risk for prescribing errors and related adverse drug events (ADEs). An effective intervention to decrease this risk, based on studies conducted mainly in North America, is on-ward participation of a clinical pharmacist in an ICU team. As the Dutch Healthcare System is organized differently and the on-ward role of hospital pharmacists in Dutch ICU teams is not well established, we conducted an intervention study to investigate whether participation of a hospital pharmacist can also be an effective approach in reducing prescribing errors and related patient harm (preventable ADEs) in this specific setting. METHODS: A prospective study compared a baseline period with an intervention period. During the intervention period, an ICU hospital pharmacist reviewed medication orders for patients admitted to the ICU, noted issues related to prescribing, formulated recommendations and discussed those during patient review meetings with the attending ICU physicians. Prescribing issues were scored as prescribing errors when consensus was reached between the ICU hospital pharmacist and ICU physicians. RESULTS: During the 8.5-month study period, medication orders for 1,173 patients were reviewed. The ICU hospital pharmacist made a total of 659 recommendations. During the intervention period, the rate of consensus between the ICU hospital pharmacist and ICU physicians was 74%. The incidence of prescribing errors during the intervention period was significantly lower than during the baseline period: 62.5 per 1,000 monitored patient-days versus 190.5 per 1,000 monitored patient-days, respectively (P < 0.001). Preventable ADEs (patient harm, National Coordinating Council for Medication Error Reporting and Prevention severity categories E and F) were reduced from 4.0 per 1,000 monitored patient-days during the baseline period to 1.0 per 1,000 monitored patient-days during the intervention period (P = 0.25). Per monitored patient-day, the intervention itself cost €3, but might have saved €26 to €40 by preventing ADEs. CONCLUSIONS: On-ward participation of a hospital pharmacist in a Dutch ICU was associated with significant reductions in prescribing errors and related patient harm (preventable ADEs) at acceptable costs per monitored patient-day. TRIAL REGISTRATION NUMBER: ISRCTN92487665.

Application of the Bow-Tie model in medication safety risk analysis: consecutive experience in two hospitals in the Netherlands.

BACKGROUND: To improve medication safety effectively, one should systematically analyse and assess the risks for medication errors and determine the possible causes. So far, no risk-analysis instrument exists in healthcare that can be used to analyse and visualize risks, causes and consequences of potential adverse events in a prospective manner. In high-risk industries such as petrochemistry and aviation, the Bow-Tie model is frequently used. This model combines causes, errors, preventive and recovery measures, and consequences in one model and gives insight into the magnitude and causes of existing safety risks. The aim of our project was to study the usefulness of the Bow-Tie model in the hospital setting for prospective analysis of risks in the medication process in order to develop a practicable method. METHODS: The model was first adapted to the clinical setting. Thereafter, the risk-analysis model was applied in a large tertiary teaching hospital in multidisciplinary sessions. The sessions and risk-analysis method were evaluated on the following aspects: applicability, comprehensibility, creation of awareness in and motivation of participants, and the capability of the 'system approach' (the approach taken by the Bow-Tie model, which focuses on the conditions under which individuals work and tries to build defences to avert errors or mitigate their effects, in contrast to a 'person approach', which focuses on errors of individuals, blaming them for forgetfulness, inattention etc.). Based on this evaluation, the risk analysis method was adjusted and consecutively applied in a general teaching hospital. After evaluation of the sessions in the second hospital a recommended method for risk analysis with the Bow-Tie model was defined. RESULTS: The risk-analysis method with the Bow-Tie model in the first hospital gave insight into many medication safety-related risks. However, the method was insufficient on comprehensibility and on the creation of awareness and motivation owing to a great number of determined risks which made thorough analysis, drawing of Bow-Ties and prioritizing difficult. The adjusted method in the second hospital focused more on the in-depth analysis of a small number of important safety issues of a department with specific attention for underlying causes. This approach was considered better in applicability, comprehensibility and the creation of awareness. Furthermore, by analyzing underlying causes, more attention could be paid to latent conditions (which can translate into error-provoking conditions) within the system. CONCLUSION: We found the Bow-Tie to be an appropriate model for prospective risk analysis of medication safety in a hospital. By applying the model in two hospitals consecutively we developed a feasible method for risk-analysis sessions. Key factors of this recommended method are a focus on the prioritized selection of safety issues and specific attention to latent conditions within the system by analysing these safety issues in depth to the root causes with the help of the Bow-Tie model.

Oral antiarrhythmic drugs in converting recent onset atrial fibrillation.

AIM: This article reviews clinical studies on oral antiarrhythmic drugs in converting recent onset atrial fibrillation. An oral loading dose of an antiarrhythmic drug for cardioversion of atrial fibrillation could be an option, due to its simplicity, both for patients admitted to outpatient departments and for episodic treatment by self administration outside the hospital. The latter treatment strategy has recently been pointed out by the American College of Cardiology, the American Heart Association and the European Society of Cardiology as the 'pill in the pocket approach'. METHODS: Articles were identified by Medline 1966 to November 2001 and Embase 1966 to November 2001. Randomized studies of oral antiarrhythmic drugs versus placebo or comparative treatment, which are written in the English language, were selected. Non-randomized or non-comparative studies were selected if the results of an analysis to identify predictors for successful conversion are described. The review of clinical trials is followed by a description of pharmacokinetic parameters of the antiarrhythmic drugs. RESULTS: Studies meeting the inclusion criteria were on propafenone, flecainide, sotalol, amiodarone, quinidine, digoxin and verapamil. Conversion rates of a single oral loading dose of 600 mg propafenone varied between 37% and 41% at 4 h after ingestion. Propafenone was more effective than quinidine, amiodarone and placebo. A single oral dose of 300 mg flecainide restored sinus rhythm in 59% and 68% of patients at 3 h. Flecainide was more effective than amiodarone and placebo. Oral sotalol, digoxin and verapamil were not effective in converting atrial fibrillation to sinus rhythm. CONCLUSION: Propafenone and flecainide are effective in converting recent onset atrial fibrillation. No serious ventricular arrhythmia, other serious proarrhythmic effects or serious non cardiac adverse events were observed. Regular supraventricular tachyarrhythmias with 1:1 AV conduction were rare and were also observed in placebo treated patients. Propafenone and flecainide are more effective in patients with atrial fibrillation of less than 24 h. The association between cardioversion and patient characteristics are not consistent between studies. The pharmacokinetics of flecainide, with lower interindividual variability of absorption kinetics, no genetically determined formation of an active metabolite and a more rapid distribution to myocardial tissue, are more favourable for episodic treatment as compared to propafenone. Both flecainide and propafenone are safe in hospitalized patients. Out of hospital self administration of antiarrhythmic drugs, also described as the 'pill in the pocket approach', could be an option for selected patients, after the treatment has proven to be safe in hospital.