Jacobus Brouwers

Frequency and determinants of drug administration errors in the intensive care unit

Objective The study aimed to identify both the frequency and the determinants of drug administration errors in the intensive care unit. Design Administration errors were detected by using the disguised-observation technique (observation of medication administrations by nurses, without revealing the aim of this observation to the nurses). Setting Two Dutch hospitals. Patients The drug administrations to patients in the intensive care units of two Dutch hospitals were observed during five consecutive days. Interventions None. Measurements and Main Results A total of 233 medications for 24 patients were observed to be administered (whether ordered or not) or were observed to be omitted. When wrong time errors were included, 104 administrations with at least one error were observed (frequency, 44.6%), and when they were excluded, 77 administrations with at least one error were observed (frequency, 33.0%). When we included wrong time errors, day of the week (Monday, odds ratio [OR] 2.69, confidence interval [CI] 1.42–5.10), time of day (6–10 pm, OR 0.28, CI 0.10–0.78), and drug class (gastrointestinal, OR 2.94, CI 1.48–5.85; blood, OR 0.12, CI 0.03–0.54; and cardiovascular, OR 0.38, CI, 0.16–0.90) were associated with the occurrence of errors. When we excluded wrong time errors, day of the week (Monday, OR 3.14, CI 1.66–5.94), drug class (gastrointestinal, OR 3.47, CI 1.76–6.82; blood, OR 0.21, CI 0.05–0.91; and respiratory, OR 0.22, CI 0.08–0.60), and route of administration (oral by gastric tube, OR 5.60, CI 1.70–18.49) were associated with the occurrence of errors. In the hospital without full-time specialized intensive care physicians (which also lacks pharmacy-provided protocols for the preparation of parenteral drugs), more administration errors occurred, both when we included (OR 5.45, CI 3.04–9.78) and excluded wrong time errors (OR 4.22, CI 2.36–7.54). Conclusions Efforts to reduce drug administration errors in the intensive care unit should be aimed at the risk factors we identified in this study. Especially, focusing on system differences between the two intensive care units (e.g., presence or absence of full-time specialized intensive care physicians, presence or absence of protocols for the preparation of all parenteral drugs) may help reduce suboptimal drug administration.

A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout

Objectives: To compare the efficacy and tolerability of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day used to attain a target serum urate concentration (sUr) ⩽0.30 mmol/l (5 mg/dl). Methods: A randomised, controlled, open-label, multicentre trial in gout patients with renal function defined as a calculated creatinine clearance ⩾50 ml/min. Patients were treated with 300 mg allopurinol or 100 mg benzbromarone once a day (stage 1). If sUr ⩽0.30 mmol/l was not attained after 2 months, the dose was doubled to allopurinol 300 mg twice a day or benzbromarone 200 mg once a day (stage 2). The primary end point was treatment success in either of the two stages, defined as clinical tolerability and attainment of biochemical target sUr. Results: Sixty-five patients were enrolled in stage 1; 36 received allopurinol and 29 received benzbromarone. Fifty-five patients (85%) were analysed at stage 1: the success rates were 8/31 (26%) and 13/25 (52%), respectively, and the difference was −0.26 (95% CI from −0.486 to −0.005), p = 0.049. At stage 2, the success rates were 21/27 (78%) and 18/23 (78%), respectively, and the difference was −0.005 (95% CI from −0.223 to 0.220), p = 1.00. Two patients stopped receiving allopurinol and three stopped receiving benzbromarone because of adverse drug reactions. Conclusions: Increasing the allopurinol dose from 300 to 600 mg/day and the benzbromarone dose from 100 to 200 mg/day according to the target sUr produced significantly higher success rates (both 78% successful in attaining sUr ⩽0.30 mmol/l). No significant differences in treatment success between benzbromarone and allopurinol were found after dose escalation. Trial registration number: ISRCTN49563848).

Drug-Related Problems in Hospitalised Patients

Drug-related problems include medication errors (involving an error in the process of prescribing, dispensing, or administering a drug, whether there are adverse consequences or not) and adverse drug reactions (any response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function). Furthermore, adverse drug events can be defined as an injury — whether or not causally-related to the use of a drug.Drug-related problems are relatively common in hospitalised patients and can result in patient morbidity and mortality, and increased costs. In order to get an overview of studies on drug-related problems in hospitalised patients, with specific attention to the incidence of drug-related problems and their costs, to the possibilities of prevention and to the effect of these interventions, we performed a literature search.Incidences of medication errors reported in studies vary widely. The range of reported incidences of adverse drug reactions is even wider. These wide ranges can be largely explained by the different study methods and definitions used.Problems related to drug therapy may be averted by preventive interventions. Several possibilities for prevention exist, especially for the prevention of medication errors. Prescribing, transcription and interpretation errors can be reduced by using computerised physician order entry. Together with the use of automated dispensing systems and bar-code technology, this will aid in the reduction of both dispensing and administration errors. Education of nursing staff involved in the process of drug distribution is another important measure for preventing medication errors. Finally, the introduction of systems for the early detection of adverse drug reactions may help to reduce problems related to drug therapy. Identifying risk factors that contribute to the development of adverse drug reactions, may aid in the prevention of these reactions.

Chlorpromazine equivalents versus defined daily doses: How to compare antipsychotic drug doses?

Classic chlorpromazine (CPZ) equivalents can be used to chart relative antipsychotic potencies of antipsychotic drugs. Values of CPZ equivalents per drug are ambiguous in literature. In drug use evaluation studies, antipsychotic doses are frequently compared by use of the defined daily dose (DDD). The DDD is the assumed average maintenance dose per day for a drug if used for its main indication in adults. The DDD is based on review of the available older and recent literature. In this report, we evaluated discrepancy between CPZ-equivalent values and DDD-equivalent values. We plotted CPZ-equivalent values against DDD-equivalent values and performed linear regression to determine the mean relationship between the 2 methods. About 67% of the DDD-equivalent values demonstrated lower potencies for antipsychotic drug compared with CPZ-equivalent values. The slope of the regression line was 0.68 (r2 = 0.81). Because we found a great discrepancy between these 2 methods of comparing antipsychotic drug doses, we think further research is necessary to develop a standardized way of antipsychotic drug comparison.

Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon

Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of the VKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 and VKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect of VKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anticoagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.

Determination of moxifloxacin in dried blood spots using LC-MS/MS and the impact of the hematocrit and blood volume.

Moxifloxacin (MFX) is a potential oral agent use in the treatment of multidrug-resistance tuberculosis (MDR-TB). Due to variability in pharmacokinetics and in vitro susceptibility of causative bacteria, therapeutic drug monitoring (TDM) of MFX is recommended. Conventional plasma sampling for TDM is facing logistical challenges, especially in limited resource areas, and dried blood spots (DBS) sampling may offer a chance to overcome this problem. The objective of this study was to develop a LC-MS/MS method for determination of MFX in dried blood spots (DBS) that is applicable for TDM. The influence of paper type, the hematocrit (Hct) and the blood volume per spot (V(b)) on the estimated blood volume in a disc (V(est)) was investigated. The extracts of 8mm diameter discs punched out from DBS were analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS) with cyanoimipramin as internal standard. The method was validated with respect to selectivity, linearity, accuracy, precision, sensitivity, recovery and stability. The effect of Hct and V(b) on LC-MS/MS analytical result was also investigated. The relationship between MFX concentrations in venous and finger prick DBS and those in plasma was clinically explored. V(est) was highly influenced by Hct while the effect of V(b) appeared to be different among paper types. Calibration curves were linear in the range of 0.05-6.00 mg/L with inter-day and intra-day precisions and biases of less than 11.1%. The recovery was 84.5, 85.1 and 92.6% in response to blood concentration of 0.15, 2.50 and 5.00 mg/L, respectively. A matrix effect of less than 11.9% was observed. MFX in DBS was stable for at least 4 weeks at room condition (temperature of 25°C and humidity of 50%). A large range of Hct value produced a significant analytical bias and it can be corrected with resulting DBS size. A good correlation between DBS and plasma concentrations was observed and comparable results between venous DBS and finger prick DBS was attained. This fully validated method is suitable for determination of MFX in dried blood spot and applicable for TDM.

Meta-analysis: comparing the efficacy of proton pump inhibitors in short-term use

Background:  Proton pump inhibitors have a prominent role in the management of acid‐related diseases. Controlling expenses on proton pump inhibitors would yield great economic benefits for Dutch health care.

Incidence and nature of medication errors in neonatal intensive care with strategies to improve safety - A review of the current literature

Neonates are highly vulnerable to medication errors because of their extensive exposure to medications in the neonatal intensive care unit (NICU), the general lack of evidence on pharmacotherapeutic interventions in neonates and the lack of neonate-specific formulations. We searched PubMed and EMBASE to identify relevant original studies published in the English language. Eleven studies were identified on the frequency of medication errors in the NICU. The highest rate was 5.5 medication errors per 100 prescriptions; however, medication error rates varied widely between studies, partly due to differences in the definition of an error and the rigor of the method used to identify medication errors. Furthermore, studies were difficult to compare because medication error rates were calculated differently. Most studies did not assess the potential clinical impact of the errors. The majority of studies identified dose errors as the most common type of error. Computerised physician order entry and interventions by clinical pharmacists (e.g. the participation of pharmacists in ward rounds and review of patients’ prescriptions prior to dispensing) were the most common interventions suggested to improve medication safety in the NICU. However, only very limited data were available on evaluation of the effects of such interventions in NICUs. More research is needed to determine the frequency and types of medication errors in NICUs and to develop evidence-based interventions to improve medication safety in the NICU setting. Some of these research efforts need to be directed to the establishment of clear definitions of medication errors and agreement on the methods that should be used to measure medication error rates and their potential clinical impact.

Cost-Benefit Analysis of the Detection of Prescribing Errors by Hospital Pharmacy Staff

AbstractObjective: Prescribing errors are a major cause of iatrogenic patient morbidity and therefore interventions aimed at preventing the adverse outcomes of these errors are likely to result in cost reduction. However, it is unclear whether the costs associated with these preventive measures are outweighed by the cost reductions (benefits). Therefore, a study was set up to analyse costs and benefits of detecting prescribing errors by hospital pharmacy staff. Design: During 5 consecutive days in two Dutch hospitals in February 2000 all medication orders, in which prescribing errors were detected, were analysed. A cost-benefit analysis was performed, based on direct medical costs only. The benefit-to-cost ratio was calculated by taking into account the net time hospital pharmacy staff needed for the prevention of the error (this included potential time saving for nursing staff, when an error was prevented by hospital pharmacy staff instead of nursing staff), as well as taking into account the possible consequences of the prescribing error (were the error not prevented). Results: A total of 3540 orders, of which 351 contained prescribing errors (9.9%), were analysed. During the 1-week period investigated, time-investment of the pharmacy staff had net costs of EUR285 (2000 values). During the same period estimated benefits related to this investment were EUR9867. The finding of higher benefits than costs was robust in sensitivity analysis. Conclusions: From this study it can be concluded that prevention of prescribing errors by hospital pharmacy staff results in higher benefits than the costs related to the net time investment.

Pharmacokinetic-Pharmacodynamic Drug Interactions with Nonsteroidal Anti-Inflammatory Drugs

SummaryThe nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic interactions, the use of these compounds should be avoided where possible.Acidic NSAIDs interact with bile acid-binding resins, resulting in decreased concentrations of NSAIDs in the blood. In earlier reports it was suggested that the absorption of NSAIDs was affected by antacids and sucralfate. More recently, it was shown that there is delayed absorption of these drugs, but there is no difference in the extent of absorption.Only salicylates had their urinary secretion enhanced by antacids, which increase the urinary pH to values >7. Histamine H2-receptor antagonists can be combined safely with NSAIDs. The concomitant administration of probenecid increased the blood concentration of NSAIDs, so an enhanced anti-inflammatory effect can be expected when these 2 drugs are combined.More importantly, NSAIDs can cause pharmacokinetic drug-drug interactions with other drugs. As can be expected, interactions with drugs that have a small therapeutic window are most likely to be of clinical significance. For example, lithium, medium to high dose methotrexate and, to a lesser extent, cyclosporin may be affected by concomitant administration of an NSAID.Aspirin (acetylsalicylic acid) and/or pyrazoles interact with oral anticoagulants, oral antihyperglycaemic agents and the anticonvulsants phenytoin and valproic acid (sodium valproate). Elevation of blood concentrations of these agents can be potentially dangerous.Similarly, NSAIDs interact with digoxin. This interaction is most likely to occur in the elderly, in neonates or in patients with renal impairment.Indomethacin can influence the blood concentrations of aminoglycosides in neonates. Unfortunately, this effect seems unpredictable, so practical therapeutic recommendations cannot be made.When NSAIDs are combined with salicylates or diflunisal, the blood concentrations of the salicylate or diflunisal may increase. However, the clinical relevance of this increase in drug concentration seems to be of minor importance. Gastrointestinal bleeding caused by NSAIDs is the most dangerous when it results from a mixed pharmacokinetic/pharmacodynamic interaction; however, patients are also at risk when pharmacodynamic interactions only are involved.