Adverse drug reactions in dermatology.

Adverse drug reactions (ADRs) - that is, unintended and harmful responses to medicines - are important to dermatologists because many present with cutaneous signs and because dermatological treatments can cause serious ADRs. The detection of ADRs to new drugs is often delayed because they have a long latency or are rare or unexpected. This means that ADRs to newer agents emerge only slowly after marketing. ADRs are part of the differential diagnosis of unusual rashes. A good drug history that includes details of drug dose, time-course of the reaction and factors that may make the patient more susceptible, will help. For example, Stevens-Johnson syndrome with abacavir is much commoner in patients with HLA-B*5701, and has a characteristic time course. Newer agents have brought newer reactions; for example, acneiform rashes associated with epidermal growth factor receptor inhibitors such as erlotinib. Older systemic agents used to treat skin disease, including corticosteroids and methotrexate, cause important ADRs. The adverse effects of newer biological agents used in dermatology are becoming clearer; for example, hypersensitivity reactions or loss of efficacy from antibody formation and progressive multifocal leucoencephalopathy due to reactivation of latent JC (John Cunningham) virus infections during efalizumab treatment. Unusual or serious harm from medicines, including ADRs, medication errors and overdose, should be reported. The UK Yellow Card scheme is online, and patients can report their own ADRs.

The medico-legal significance of pharmacokinetic interactions with ethanol.

In the UK, the maximal permitted ethanol concentration for driving is 80 mg ethanol/100 mL blood, 35 µg ethanol/100 mL breath or 107 mg ethanol/100 mL urine. Drivers exceeding the prescribed limit face severe penalties, which they are often anxious to avoid, either by acquittal or by putting forward 'special reasons' why they should not be disqualified from driving. One frequently explored defence is that the accused was taking prescribed medication. Defence solicitors often ask the question whether the prescribed medication could have caused significantly altered blood ethanol concentrations. This paper reviews the impact of various medications and how they can influence the blood ethanol concentration. Although many drugs can interact with ethanol at a pharmacodynamic level, causing increased impairment, relatively few drugs interact with ethanol pharmacokinetically leading to significantly altered blood ethanol concentrations.

Decision support for sensible dosing in electronic prescribing systems.

WHAT IS KNOWN AND OBJECTIVE: The sensible dosing of medicines can ensure that patients receive neither excessive doses leading to toxicity nor inappropriately low doses leading to undertreatment. Computerized prescribing systems with embedded decision support can check doses during prescription order entry and display alerts when the prescribed doses are out of range. We have been unable to identify any scheme for the systematic addition of dosing information to CPOE systems. We used pharmacological data to design an algorithm for dose range checking that we tested on a subset of medicines in an electronic prescribing system to ensure that the rules could be implemented in practice. METHODS: We drafted an initial algorithm based on pharmacological principles, tested it on a subset of frequently prescribed drugs in an electronic prescribing system and then refined it. We considered which clinical decision support functions systems would require to be maximally effective. RESULTS AND DISCUSSION: The final algorithm contained eleven broad factors. We tested it on 30 drug-route-form combinations, and it accommodated the information for all of these combinations. We also identified a variety of system functions that would be required for comprehensive dosing decision support. WHAT IS NEW AND CONCLUSION: The dose range checking algorithm that we have derived from first principles will allow the clinical workflow and warnings to be constructed more effectively within systems to enhance patient safety. This will form a basis for the development of optimal schemes for adding decision support to prescribing systems.

Laboratory monitoring and adverse patient outcomes with antihypertensive therapy in primary care.

PURPOSE: The monitoring of serum electrolyte and creatinine concentrations in patients treated with antihypertensive therapy is recommended. We wished to examine the relationship between laboratory monitoring and adverse patient outcomes. METHODS: We carried out a retrospective cohort study using the General Practice Research Database (GPRD). Patients aged 18 years or older with newly diagnosed hypertension and prescribed a single antihypertensive agent were included. Monitoring was defined as any laboratory test for serum electrolyte and creatinine (or urea) concentrations within 6 months of starting treatment. RESULTS: We identified 74 096 patients who were newly diagnosed with hypertension and prescribed a single antihypertensive agent. Twenty six thousand nine hundred forty six (36.4%) patients had any biochemical laboratory measurement within 6 months. Three hundred ten patients (0.4%) died, 1451 (2%) were admitted to hospital at least once and 29 749 (40.2%) discontinued their first course of antihypertensive treatment within 6 months. Patients were more likely to be admitted to hospital if their biochemistry had been monitored after beginning treatment (adjusted hazard ratio (HR) 1.37; 95%CI 1.21-1.55). They were also marginally more likely to discontinue treatment (adjusted HR 1.04; 95%CI 1.02-1.07). They were not significantly more likely to die (adjusted HR 1.21; 95%CI 0.87-1.67). CONCLUSIONS: Biochemical testing at baseline and monitoring after starting treatment is often omitted in newly diagnosed hypertensive patients. Those patients who are monitored are more likely to be admitted to hospital and to discontinue initial antihypertensive therapy, but not to die. Many biochemical adverse drug reactions are found only by laboratory monitoring.

An analysis and comparison of commonly available United Kingdom prescribing resources.

BACKGROUND AND OBJECTIVE: Safe prescribing requires accurate and practical information about drugs. Our objective was to measure the utility of current sources of prescribing guidance when used to inform practical prescribing decisions, and to compare current sources of prescribing guidance in the UK with idealized prescribing guidance. METHODS: We developed 25 clinical scenarios. Two independent assessors rated and ranked the performance of five common sources of prescribing guidance in the UK when used to answer the clinical scenarios. A third adjudicator facilitated review of any disparities. An idealized list of contents for prescribing guidance was developed and sent for comments to academics and users of prescribing guidance. Following consultation an operational check was used to assess compliance with the idealized criteria. The main outcome measures were relative utility in answering the clinical scenarios and compliance with the idealized prescribing guidance. RESULTS: Current sources of prescribing guidance used in the UK differ in their utility, when measured using clinical scenarios. The British National Formulary (BNF) and EMIS LV were the best performing sources in terms of both ranking [mean rank 1·24 and 2·20] and rating [%excellent or adequate 100% and 72%]. Current sources differed in the extent to which they fulfilled criteria for ideal prescribing guidance, but the BNF, and EMIS LV to a lesser extent, closely matched the criteria. DISCUSSION: We have demonstrated how clinical scenarios can be used to assess prescribing guidance resources. Producers of prescribing guidance documents should consider our idealized template. Prescribers require high-quality information to support their practice. CONCLUSION: Our test was helpful in distinguishing between prescribing resources. Producers of prescribing guidance should consider the utility of their products to end-users, particularly in those more complex areas where prescribers may need most support. Existing UK prescribing guidance resources differ in their ability to provide assistance to prescribers.

Republished paper: Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis.

OBJECTIVE: To investigate the overall probability of error in preparing and administering intravenous medicines; to identify at which stage of the process an error is most likely to occur; and to determine the impact of error correction on the error probability. Design Systematic review and random-effects Bayesian conditional independence modelling. METHODS: Medline and EMBASE were searched for studies on intravenous medicines. The error rates of each stage were extracted. These, expert estimates, and error rates from generic tasks, were used in a Bayesian conditional independence model to find error 'hot-spots.' The main outcome measure was the probability of at least one error occurring during intravenous therapy. RESULTS: Nine published studies were identified for inclusion in the systematic review and meta-analysis. The overall probability of making at least one error in intravenous therapy was 0.73 (95% credible interval (CrI) 0.54 to 0.90). If error-checking was introduced at each stage of the process, the overall rate fell to 0.22 (95% CrI 0.14 to 0.31). Errors were most likely in the reconstitution step. Removing the reconstitution step by providing preprepared injections would reduce the overall error rate to 0.17 (95% CrI 0.09 to 0.27). CONCLUSIONS: Intravenous therapy is complex and error-prone. Error-checking at each stage could reduce the error probability. The use of preprepared injections may help by eliminating errors in the reconstitution of drug and diluent. However, it will be important to ensure that benefits are not outweighed by practical disadvantages such as an increase in selection errors.

[18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNSTs) are difficult to detect in neurofibromatosis 1 (NF1) individuals. The purpose was to evaluate [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and PET computed tomography (CT) as a diagnostic tool for MPNST in NF1 patients with symptomatic plexiform neurofibromas and to verify the diagnosis by pathology and clinical follow-up. PATIENTS AND METHODS: NF1 individuals with symptomatic plexiform neurofibromas underwent clinical evaluation and magnetic resonance imaging. Qualitative FDG PET and PET CT associated with semi-quantitative maximum standard uptake value (SUVmax) assessed possible malignant change. Excision/biopsy verified the diagnosis when possible and clinical follow-up was undertaken in all patients. RESULTS: In all, 116 lesions were detected in 105 patients aged 5-71 years, including 80 plexiform neurofibromas, five atypical neurofibromas, 29 MPNST and two other cancers. Biopsy confirmed the findings in 59 tumours and no MPNST was diagnosed on clinical follow-up of 23 lesions diagnosed as benign on FDG PET and PET CT. FDG PET and PET CT diagnosed NF1-associated tumours with a sensitivity of 0.89 [95% confidence interval (CI) 0.76-0.96] and a specificity of 0.95 (CI 0.88-0.98), but the SUVmax level did not predict tumour grade. CONCLUSION: FDG PET and PET CT is a sensitive and specific diagnostic tool for NF1-associated MPNST. Other PET tracers will be required to solve the problem of predicting tumour grade.

Post-mortem clinical pharmacology.

Clinical pharmacology assumes that deductions can be made about the concentrations of drugs from a knowledge of the pharmacokinetic parameters in an individual; and that the effects are related to the measured concentration. Post-mortem changes render the assumptions of clinical pharmacology largely invalid, and make the interpretation of concentrations measured in post-mortem samples difficult or impossible. Qualitative tests can show the presence of substances that were not present in life, and can fail to detect substances that led to death. Quantitative analysis is subject to error in itself, and because post-mortem concentrations vary in largely unpredictable ways with the site and time of sampling, as a result of the phenomenon of post-mortem redistribution. Consequently, compilations of 'lethal concentrations' are misleading. There is a lack of adequate studies of the true relationship between fatal events and the concentrations that can be measured subsequently, but without such studies, clinical pharmacologists and others should be wary of interpreting post-mortem measurements.

Should doctors who make clinical errors be charged with manslaughter? A survey of medical professionals and members of the public.

If a doctor is grossly negligent and the patient dies as a result, the doctor can be charged with manslaughter. We have investigated the difference in opinion between medical professionals and the public on whether doctors should face criminal charges following different fatal medical errors. We conducted a survey of 40 medical professionals and 40 members of public, using a set of questions about negligence and manslaughter relating to four real-life cases of doctors charged with manslaughter where eventual outcomes were known. Medical professionals and the public agreed that lessons could be learnt from all four cases and that an independent review of each case should be carried out. However, across all cases, the public were more likely to respond that the doctor should be charged with manslaughter (OR = 2.1; 95% CI = 1.3-3.2). The public and, to a lesser extent, medical professionals still hold individuals responsible following a death due to medical error. This has implications for those who advocate a systems-based approach for assessing the root causes of medical errors, where there is a limited focus on individual accountability.

Cervical cord compression from plexiform neurofibromas in neurofibromatosis 1.

Cervical cord compression from cervical root neurofibromas represents an important clinical problem in patients with neurofibromatosis type 1 (NF1), but is rarely reported. The aim of this study was to describe the clinical presentation and follow-up of children and adults with NF1 and cervical cord compression. A retrospective review of clinical records and neuroimaging studies from two large tertiary care centres between 1996 and 2006 was performed. 13 patients with NF1 and cervical cord compression were identified. Age at presentation ranged from 9 to 61 years. The most common presentation was progressive quadriparesis. 11 of 13 patients underwent cervical decompression and subtotal resection of the associated neurofibroma. The majority of patients had recovery of neurological function and no further clinical progression. Progressive neurological deficit (typically quadriparesis), rather than neuroimaging appearances, should dictate the need for surgery.

Identification of novel deletion breakpoints bordered by segmental duplications in the NF1 locus using high resolution array-CGH.

BACKGROUND: Segmental duplications flanking the neurofibromatosis type 1 (NF1) gene locus on 17q11 mediate most gene deletions in NF1 patients. However, the large size of the gene and the complexity of the locus architecture pose difficulties in deletion analysis. We report the construction and application of the first NF1 locus specific microarray, covering 2.24 Mb of 17q11, using a non-redundant approach for array design. The average resolution of analysis for the array is approximately 12 kb per measurement point with an increased average resolution of 6.4 kb for the NF1 gene. METHODS: We performed a comprehensive array-CGH analysis of 161 NF1 derived samples and identified heterozygous deletions of various sizes in 39 cases. The typical deletion was identified in 26 cases, whereas 13 samples showed atypical deletion profiles. RESULTS: The size of the atypical deletions, contained within the segment covered by the array, ranged from 6 kb to 1.6 Mb and their breakpoints could be accurately determined. Moreover, 10 atypical deletions were observed to share a common breakpoint either on the proximal or distal end of the deletion. The deletions identified by array-CGH were independently confirmed using multiplex ligation-dependent probe amplification. Bioinformatic analysis of the entire locus identified 33 segmental duplications. CONCLUSIONS: We show that at least one of these segmental duplications, which borders the proximal breakpoint located within the NF1 intron 1 in five atypical deletions, might represent a novel hot spot for deletions. Our array constitutes a novel and reliable tool offering significantly improved diagnostics for this common disorder.

Doctors charged with manslaughter in the course of medical practice, 1795-2005: a literature review.

OBJECTIVES: To quantify the number of doctors charged with manslaughter in the course of legitimate medical practice and to classify cases, as mistakes, slips (or lapses), and violations, using a recognized classification of human error system. DESIGN: We searched newspaper databases, Medline, Embase, and the Wellcome library catalogue to identify relevant cases from 1795 to December 2005. SETTING: Medical practice in the United Kingdom. MAIN OUTCOME MEASURE: Number of doctors charged with manslaughter in the course of medical practice. RESULTS: We identified 85 doctors charged with manslaughter since 1795. The number of doctors charged was relatively high in the mid-19th century and the inter-war years, and has dramatically increased since 1990. Sixty of the doctors were acquitted, 22 were convicted, and three pleaded guilty. Most doctors were charged as a consequence of mistakes (37) or slips (17), and a minority because of alleged violations (16). CONCLUSIONS: The number of doctors prosecuted for manslaughter has risen steeply since 1990, but the proportion of doctors convicted remains low. Prosecution for deliberately violating rules is understandable, but accounts for only a minority of these cases. Unconscious errors--mistakes and slips (or lapses)--are an inescapable consequence of human actions and prosecution of individuals is unlikely to improve patient safety. That requires improvement to the complex systems of health care.

Chemical disasters.

Chemical disasters are sufficiently common that plans are needed to prevent them, or to mitigate their effects should they occur. However, they are sufficiently rare that any individual is likely to have little or no experience of them. This article reviews chemical disasters which have been reported in the medical literature, and briefly discusses plans for medical involvement in the prevention and tackling of such events.

Neurofibromatous neuropathy in neurofibromatosis 1 (NF1).

BACKGROUND: Neurofibromatosis 1 (NF1) is a common, autosomal dominant, neurocutaneous disease that is clinically and genetically distinct from the rare condition neurofibromatosis 2 (NF2). Neurofibromatous neuropathy has been regarded as a common feature of NF2, but is an unusual and unexplained complication of NF1. The clinical and histological features of the NF1 neuropathy are distinct from those encountered in NF2. We describe eight patients with a symmetrical polyneuropathy, which has been called neurofibromatous neuropathy. METHODS: Clinical assessments, laboratory investigations, neuroimaging, and neurophysiology were undertaken in eight individuals with neurofibromatous neuropathy. None were referred because of neuropathic symptoms. Two subjects underwent sural nerve biopsy and three agreed to mutational analysis. RESULTS: The patients had an indolent symmetrical predominantly sensory axonal neuropathy and unusually early development of large numbers of neurofibromas. The biopsied nerves showed diffuse neurofibromatous change and disruption of the perineurium. Two patients developed a high grade malignant peripheral nerve sheath tumour. Disease causing mutations were detected in two individuals and molecular studies did not reveal any whole gene deletions. CONCLUSIONS: Neurofibromatous neuropathy occurred in 1.3% of 600 patients with NF1. Its cause may be a diffuse neuropathic process arising from inappropriate signalling between Schwann cells, fibroblasts, and perineurial cells.

The relationship between the pharmacokinetics and pharmacodynamic effects of oral hypoglycaemic drugs.

Oral hypoglycaemic drugs have widely differing pharmacokinetic properties. Possible pharmacodynamic benefits include greater efficacy and fewer adverse effects. In general, it has not been possible to demonstrate unequivocal differences in clinical efficacy between the sulphonylureas during long term use, although there are clear differences in potency. These differences have been emphasised to the extent that the term 'second-generation' has been used for the most potent sulphonylureas, but there is little to suggest that potency is of any therapeutic significance. Trials to study differences in efficacy have rarely been of acceptable design. They have often used fixed doses of drugs, begging the question of whether true potency ratios have been established for chronic treatment. They have rarely involved substantial numbers of patients in double-blind crossover studies with a suitable washout period. Trials which show that there is a clear relationship between drug concentrations in blood and drug effects (whether therapeutic effects or adverse effects such as severe hypoglycaemia) are generally lacking. Qualitative and semiquantitative analysis of adverse effects supports the concept that drugs with a long half-life (e.g. chlorpropamide), renally excreted active metabolites (e.g. acetohexamide) or unusual properties (e.g. glibenclamide, which accumulates progressively in islet tissue) are more likely to cause prolonged hypoglycaemia, which may be fatal. The major adverse effect of treatment with biguanides is lactic acidosis, and this probably occurs more commonly in patients treated with phenformin than those treated with metformin because of pharmacogenetic variation in phenformin metabolism. The available evidence therefore favours the use of drugs with a short elimination half-life which are extensively metabolised and which have no active metabolites.

Comparative tolerability profiles of oral antidiabetic agents.

The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.

Oral hypoglycemic agents.

The sulfonylureas remain the most important oral agents, although their chronic hypoglycemic actions are still unexplained and the evidence on their relative efficacy is inconclusive. Data on relative safety suggest that chlorpropamide is the most toxic sulfonylurea but glyburide causes dangerous hypoglycemia as often as chlorpropamide. For many patients, good blood glucose control will be achieved by taking tolbutamide or another sulfonylurea 30 minutes before breakfast and the main evening meal. The biguanide metformin, which is as safe as glyburide, is of use in treating overweight diabetic patients who do not have cardiovascular, hepatic, or renal dysfunction.