Variability in the quality of overdose advice in Summary of Product Characteristics (SPC) documents: gut decontamination recommendations for CNS drugs.

AIMS: Deliberate self-poisoning is a major cause of morbidity and mortality. The Summary of Product Characteristics (SPC) document is a legal requirement for all drugs, and Section 4.9 addresses the features of toxicity and clinical advice on management of overdose. The quality and appropriateness of this advice have received comparatively little attention. METHODS: Section 4.9 of the SPC was examined for all drugs in the central nervous system (CNS) category of the British National Formulary. Advice concerning gut decontamination was examined with respect to specific interventions: induced vomiting, oral activated charcoal, gastric lavage, and other interventions. Data were compared with standard reference sources for clinical management advice in poisoning. These were graded 'A' if no important differences existed, 'B' if differences were noted but not thought clinically important, and 'C' if differences were thought to be clinically significant. RESULTS: SPC documents were examined for 258 medications from 67 manufacturers. The overall agreement was 'A' in 23 (8.9%), 'B' in 28 (10.9%) and 'C' in 207 (80.2%). Discrepancies were due to inappropriate recommendation of induced emesis in 21.7% (95% confidence interval 17.1, 27.1), gastric lavage in 38.4% (32.7, 44.4), other gut decontamination in 5.8% (3.6, 9.4) and failure to recommend oral activated charcoal in 57.4% (51.1, 63.4). CONCLUSIONS: Gut decontamination advice in SPC documents with respect to CNS drugs was inadequate. Possible reasons for the observed discrepancies and ways of improving the consistency of advice are proposed.

Renal injury at first presentation as a predictor for poor outcome in severe paracetamol poisoning referred to a liver transplant unit.

BACKGROUND: Paracetamol poisoning remains a leading cause of morbidity and mortality. Identifying indices of poor prognosis at first presentation is key to both improving clinical care and determining targets for intervention. Renal failure is a feature of severe paracetamol poisoning. The aim of this study was to investigate the relationship between renal function (serum creatinine, Cr) at first hospital presentation and time of tertiary referral to outcomes in severe paracetamol poisoning. METHODS: This was a retrospective cohort analysis of patients referred to the Scottish Liver Transplant Unit due to paracetamol poisoning between 1992 and 2004. The relation between degree of renal injury and outcomes, including worst prothrombin time, Kings College Hospital Criteria (KCHC) and death were examined. The effects of age, nature (single or multiple) and stated size of overdose, hepatic enzyme induction (gamma-glutamyl transpeptidase, GGT), degree of liver injury (aspartate aminotransferase, prothrombin time), blood pressure and renal injury were assessed. RESULTS: Data from 522 patients were included. Renal impairment (Cr >120 mmol/l) was present in 48.8% of patients with liver injury at time of first presentation. Creatinine at first admission predicted poorer outcome in terms of worse prothrombin time, KCHC and death (p < 0.001). Associated risk factors for renal dysfunction included later presentation, staggered ingestion, increased age, hypotension and elevated GGT at first admission. CONCLUSIONS: Creatinine at first admission appears to be a predictor of poor outcome in paracetamol overdose. A better understanding of mechanisms involved in causing renal dysfunction may offer potential therapeutic targets for improving outcome in this common poisoning.

Interpretation of clinical guidelines for poisoned patients: positive and negative effects of standard phrases used in TOXBASE.

INTRODUCTION: Electronic information sources are increasingly relied upon for clinical management advice. TOXBASE is a standardised online resource that offers clinical advice on the management of poisoned patients and is the first point of contact between clinicians and the National Poisons Information Service in the United Kingdom. Advice is delivered using a series of standard phrases. The present study examined how healthcare professionals interpret the phrases and studied their impact on clinical decision-making. METHODS: A structured prospective written questionnaire was offered to healthcare staff in the Lothian region, and an electronic questionnaire issued to TOXBASE users across the United Kingdom. Participants were asked to respond to a variety of scenarios representing acutely poisoned patients. Clinical management advice was offered via TOXBASE using a variety of standard phrases, and participants were asked to express the likelihood that they would then administer gut decontamination treatment. RESULTS: There were 70 respondents to written questionnaires, and 119 respondents to the electronic version. Phrases that included didactic instructions, for example 'give', 'contraindicated', 'do' and 'perform' were associated with strongly positive or strongly negative responses. In contrast, advice that consisted of open phrases such as 'consider', 'benefit uncertain', and 'few data' were associated with inconsistent responses. CONCLUSION: Didactic words and phrases are associated with more consistent interpretation and response than open-ended words and phrases. The choice of words and phrases used in electronic systems can have an independent impact on clinical decision-making and require further consideration.

Patterns and predictors of re-admission to hospital with self-poisoning in Scotland.

OBJECTIVES: To identify factors influencing hospital re-admission with self-poisoning. STUDY DESIGN: Retrospective cohort follow-up study using national linked hospital discharge data. METHODS: All Scottish adult hospital episodes with self-poisoning admissions were captured using NHS Scotland Information Services Division data, and first-time 'index' admissions between 1996 and 2002 were identified. Re-admission rate was defined as the proportion of index admissions who went on to have one or more further self-poisoning admissions within 2 years. The effects of various potential risk factors for re-admission were examined using logistic regression. RESULTS: In total, 50,891 index admissions were identified; of these, 8278 patients were re-admitted. The 1-year re-admission rate was 12.2%. Older patients (>65 years) were least likely to be re-admitted [odds ratio (OR) 0.40, P<0.01, compared with patients aged 15-24 years]. No differences were found between males and females. Previous psychiatric hospital admission was associated with an increased re-admission rate (OR 2.85, P<0.01), with a diagnosis of personality disorder associated with the highest rate of re-admission (OR 4.59, P<0.01). Other factors predicting re-admission were: increased deprivation (quintile 3: OR 1.16, P<0.01; quintile 5: OR 1.15, P<0.01, compared with quintile 1); taking medicines for chronic disease, drug dependency (OR 1.6 and 1.19, P < or = 0.02) or antidepressants (OR 1.11, P=0.01) (compared with paracetamol); and co-ingestion of three or more agents (OR 1.37, P<0.01). CONCLUSION: Younger age, higher deprivation, ingestion of certain drug groups or multiple drug types, and prior psychiatric hospital admission are all risk factors for re-admission with self-poisoning. Personality disorder carried the greatest risk of re-admission. These findings may provide a basis to develop policies to reduce re-admission rates in the future.

The use of atropine in a nerve agent response with specific reference to children: are current guidelines too cautious?

This review examines the potential use of nerve agents by a terrorist organisation against a civilian population, which has become an increasingly apparent threat in the UK. Present guidelines for the use of atropine, particularly in children, following such an event are unclear. No precise agreement exists on the most appropriate dose of atropine, or the frequency with which it should be administered. This uncertainty leaves children vulnerable as potentially life-saving treatment may be crucially delayed. Guidelines must be standardised to allow rapid antidotal delivery and maximise the potential for survivors. This review examines the issues currently surrounding the use of atropine in children following a nerve agent attack and propose strategies for treating exposed children.

Impaired heart rate variability and altered cardiac sympathovagal balance after antidepressant overdose.

PURPOSE: Antidepressant overdose may be associated with significant cardiotoxicity, and recent data have shown that acute toxic effects are associated with impaired heart rate variability. This study was designed to examine the feasibility of non-invasive heart rate variability recording in patients that present to hospital after deliberate antidepressant ingestion. METHODS: This was a prospective study of 72 consecutive patients attending the Emergency Department after deliberate antidepressant overdose and 72 age-matched patients that ingested paracetamol, as a control group. Single time-point continuous electrocardiographic recordings were used to allow spectral analyses of heart rate variability determined in low-frequency (LF) and high-frequency (HF) domains. The LF:HF ratio was used to represent overall sympathovagal cardiac activity. RESULTS: Antidepressant overdose was associated with reduced overall heart rate variability: 1329 vs. 2018 ms(2) (P = 0.0239 by Mann-Whitney test). Variability in the LF domain was higher (64.8 vs. 49.8, P = 0.0006), whereas that in the HF domain was lower (24.3 vs. 36.4, P = 0.0001), and the LF:HF ratio was higher in the antidepressant group (2.4 vs. 1.2, P = 0.0003). CONCLUSIONS: Antidepressant overdose is associated with impaired heart rate variability in a pattern consistent with excess cardiac sympathetic activity. Further work is required to establish the significance of these findings and to explore whether the impairment of heart rate variability may be used to predict the development of arrhythmia in this patient group.

Survey of cases of paracetamol overdose in the UK referred to National Poisons Information Service (NPIS) consultants.

BACKGROUND: Paracetamol is the most common means of drug overdose in the UK. Guidance on management is available to junior doctors through TOXBASE, the online resource managed by the UK National Poisons Information Service (NPIS) and in poster form. TOXBASE is supported by NPIS units and further by a UK national rota of clinical toxicologists. A study was undertaken to examine reasons why calls about paracetamol are referred to consultants to better understand issues in managing this common poisoning. METHODS: Calls relating to paracetamol overdose referred by a poisons information specialist to the duty NPIS consultant between 1 May 2005 and 30 April 2006 were identified from the database and the number of TOXBASE accesses during the same time period was determined. Enquiries that resulted in consultant referral were classified into six categories. RESULTS: Calls referred to NPIS consultants pertain mainly to patients who present late, staggered overdoses, adverse reactions to N-acetylcysteine, and interpretation of blood results. This information has been used to inform the development of TOXBASE so that comprehensive advice is readily available to end users. CONCLUSIONS: The operation of a national consultant rota enables information on difficult or unusual cases of poisoning to be pooled so that treatment guidelines can be developed to optimise treatment throughout the UK.

Overdose in young children treated with anti-reflux medications: Poisons enquiry evidence of excess 10-fold dosing errors with ranitidine.

BACKGROUND: Accidental drug overdose is a common problem in young children. We examined the influence of formulation and dose in enquiries for different gastro-oesophageal reflux disease treatments in children under 5 years to the UK's National Poisons Information Service. METHODS: Overdose characteristics with ranitidine, omeprazole or domperidone were compared with those of metoclopramide and the H-1 antagonist chlorphenamine, for the period 1 July 2007 to 30 June 2015. RESULTS: There were a total of 1092 ranitidine, 618 domperidone and 1193 omeprazole cases; 669, 281 and 424, respectively, were single agent enquiries; of these 77% (517) of ranitidine, 52% (145) domperidone and 32% (135) omeprazole cases occurred in children <5 years. In comparison, 17% (34/424) of metoclopramide and 53% (533/1013) of chlorphenamine were <5 years; 79% (410/517) of ranitidine overdose enquiries in children <5 years were under 6 months of age, higher than domperidone (68/145, 47%; p < 0.05), omeprazole (8/135, 6%), chlorphenamine (13/553, 2%) or metoclopramide (1/34, 3%) (all p < 0.01). In children aged <6 months, 101 were 10-fold overdoses, 86 with ranitidine. CONCLUSIONS: Tenfold overdoses in children (<5 years) were a feature of ranitidine enquiries, likely due to the high concentration of the syrup. This has relevance to other liquid formulations used for non-licenced indications in young children. Such therapeutic errors cause significant carer anxiety and healthcare utilization. Assistance is needed from manufacturers and legislators in modifying formulation so that drugs can be safely used in young children. Education of prescribers and carers is also needed to reduce the incidence of such errors that cause significant carer anxiety and healthcare utilization.

Hospital usage of TOXBASE in Great Britain: Temporal trends in accesses 2008 to 2015.

AIM: To examine temporal trends in accesses to the UK's National Poison Information Service's TOXBASE database in Britain. METHODS: Generalized additive models were used to examine trends in daily numbers of accesses to TOXBASE from British emergency departments between January 2008 and December 2015. Day-of-the-week, seasonality and long-term trends were analysed at national and regional levels (Wales, Scotland and the nine English Government Office Regions). RESULTS: The long-term trend in daily accesses increases from 2.8 (95% confidence interval (CI): 2.6-3.0) per user on 1 January 2008 to 4.6 (95% CI: 4.3-4.9) on 31 December 2015, with small but significant differences in population-corrected accesses by region ( p < 0.001). There are statistically significant seasonal and day of the week patterns ( p < 0.001) across all regions. Accesses are 18% (95% CI: 14-22%) higher in summer than in January and at the weekend compared to weekdays in all regions; there is a 7.5% (95% CI: 6.1-8.9%) increase between Friday and Sunday. CONCLUSIONS: There are consistent in-year patterns in access to TOXBASE indicating potential seasonal patterns in poisonings in Britain, with location-dependent rates of usage. This novel descriptive work lays the basis for future work on the interaction of TOXBASE use with emergency admission of patients into hospital.

Pattern of lithium exposure predicts poisoning severity: evaluation of referrals to a regional poisons unit.

BACKGROUND: Lithium toxicity may result in severe clinical features. There is on-going uncertainty about the significance of serum lithium concentrations in patients with lithium toxicity. AIM: To examine potential relationships between stated quantity of lithium ingested, serum lithium concentrations, and poisoning severity among patients referred to a regional poisons centre. METHODS: Prospective evaluation of enquiries to the Scottish Poisons Information Bureau about lithium toxicity between 2000-2005 inclusive. RESULTS: There were 172 enquiries, relating to acute ingestion (n = 101), acute-on-therapeutic ingestion (n = 38), or chronic poisoning (n = 33). Poisoning severity was moderate or severe in 9.9%, 26.3% (p < 0.05 vs. acute) and 54.5% (p < 0.005 vs. acute) of each group, respectively. Median (IQR) serum lithium concentrations in each group were: 2.4 (1.7-3.3) mmol/l, 2.1 (1.4-3.8) mmol/l, and 2.3 (1.9-3.3) mmol/l, respectively. The median stated quantities ingested in acute and acute-on-therapeutic lithium exposure were 5000 mg (2000-11 050 mg) and 4000 mg (2400-8820 mg), respectively. DISCUSSION: Patients with acute-on-therapeutic and chronic poisoning are at greatest risk of severe toxicity. These differences cannot be explained by either the quantity of lithium ingested or serum lithium concentration alone.

Liver unit admission following paracetamol overdose with concentrations below current UK treatment thresholds.

BACKGROUND: It has been suggested that current UK thresholds for treating paracetamol overdose should be reduced, following case reports of patients developing fatal liver failure after presenting with paracetamol concentrations below these thresholds. AIM: To determine the frequency of severe liver dysfunction following paracetamol overdose when paracetamol concentrations are below current UK antidote thresholds. DESIGN: Retrospective case note review. METHODS: Details were collected from all patients admitted to liver transplant units in Newcastle and Edinburgh with paracetamol-induced hepatotoxicity. RESULTS: Of 696 patients admitted to the two liver units following paracetamol overdose, 14 presented between 4 and 15 h after overdose with paracetamol concentrations below current UK treatment thresholds (estimated annual population rate 0.15/million person-years). Over the period of study, >100 000 presentations with paracetamol overdose would be expected in the catchment populations for these liver units. DISCUSSION: In view of the rarity of this event, this research does not suggest a need to lower the current thresholds for antidotal treatment.

Effect of acute paracetamol overdose on changes in serum and urine electrolytes.

AIMS: To investigate the effects of acute paracetamol overdose on renal function, serum and urine electrolyte excretion in man. METHODS: Two studies were performed in patients admitted with paracetamol overdose: a retrospective study examining changes in serum electrolytes, and a prospective study evaluating changes in serum and urine electrolytes. A control group with SSRI overdose was included in the prospective study. RESULTS: There was a significant dose-dependent relationship between admission (4 h) paracetamol concentration and fall in serum potassium in the retrospective study (P < 0.01) and a significant positive relationship between serum paracetamol at 4 h and fractional excretion of potassium at 12 h postingestion (P < 0.01) in the prospective study. No changes were seen in the control group. No cases developed renal failure. CONCLUSIONS: Paracetamol overdose is associated with dose-related hypokalaemia, and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose perhaps via cyclo-oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol.

Impact of legislative changes on patterns of antipsychotic prescribing and self-poisoning in Scotland: 2000-06.

Recently, national guidelines have advocated greater use of atypical rather than typical antipsychotics in the treatment of schizophrenia. In addition, there have been safety concerns regarding the potential cardiotoxicity of certain antipsychotics taken in overdose. This has led regulatory authorities in the United Kingdom to restrict the use of thioridazine. The overall impact of these legislative changes on patterns of antipsychotic prescribing has received comparatively little attention. Therefore, we sought to examine the effects on community prescribing practices, and to determine whether this was accompanied by changes in patterns of antipsychotic poisoning. Between 2000-03, there was a rapid decline in the use of typical antipsychotics, whereas the use of atypical antipsychotics increased. The prevalence of atypical and typical antipsychotic prescribing has been approximately equal between 2003-06. During the same study period, hospital admissions due to typical antipsychotic poisoning also declined, however, the effects lagged behind changes in prescribing practice by 2-3 years. These data indicate that legislative changes that restrict the use of thioridazine and other typical antipsychotics are associated with a measurable reduction in the number of hospital admissions due to overdose with these agents.

Hemodynamic effects of methadone and dihydrocodeine in overdose.

BACKGROUND: Opioid overdose is an increasing health problem worldwide. The cardiovascular toxicity of opioids contributes to morbidity and mortality in overdose but the hemodynamic effects of opioids reported in animal and human studies are contradictory. METHODS: We performed a prospective observational study of patients admitted to hospital following an overdose of methadone, dihydrocodeine, or low dose paracetamol (10 each). Basic cardiovascular indices including peripheral blood pressure, pulse rate, radial augmentation index and derived measures of aortic systolic, diastolic, pulse, and mean and end systolic pressures were measured every six hours for up to 18-23 hours after exposure or until hospital discharge. RESULTS: Dihydrocodeine and methadone significantly reduced peripheral and aortic systolic, mean and end systolic pressures. Both opioids significantly decreased peripheral pulse pressure, but only methadone decreased aortic blood pressure. Dihydrocodeine reduced systemic and aortic diastolic blood pressure, an effect not induced by methadone. Methadone significantly reduced peripheral pulse pressure. Augmentation index and heart rate, however, did not change. Both opioids decreased arterial oxygen saturation. CONCLUSION: These results suggest that dihydrocodeine and methadone in overdose both have a significant effect on central and peripheral hemodynamics. These effects might be expected to reduce cardiac afterload, providing a pharmacological explanation for the apparent benefit of opioids in cardiovascular diseases.

Alerting and Surveillance Using Poisons Information Systems (ASPIS): outcomes from an international working group.

BACKGROUND: In recent years, awareness of the risks of chemical and poison exposure has increased, and a number of highly publicized terrorist events have heightened community fears. In particular, there is concern surrounding the potential risk of a covert release, which underpins the need to develop robust methods of population surveillance. AIMS AND METHODS: This article outlines the proceedings of a working group and focuses on the need for greater international cooperation and understanding of existing toxicological surveillance systems in a variety of countries. Poison control centers have well-established local networks and experienced staff, which make them well-placed to detect chemical and poison release. This needs further development to ensure timely detection of signals, which might be better achieved by robust international networks and consistent use of data collection tools. We illustrate some of the strengths and weaknesses of existing surveillance methods, and present a position statement on the minimum dataset required by future surveillance systems. CONCLUSIONS: Poison control centers provide a useful platform for developing surveillance activity. Having proposed a number of common aims and objectives, it is hoped that these consensus statements will inform decision makers and stimulate discussion of how international toxicological surveillance programs might best be developed.

Poisons admissions in Edinburgh 1981-2001: agent trends and predictors of hospital readmissions.

Self-poisoning is a major public health problem. This study describes patterns of admissions and readmissions from self-poisoning to the Royal Infirmary of Edinburgh from 1981 to 2001. A database on hospital discharges with a diagnosis (ICD-9/10) of poisoning between 1981 and 2001 was used. Annual admissions were described for seven main drug categories, and proportions of patients readmitted within 1-5 years from first admission, were computed for each category. Cox proportional hazards regression was used to evaluate prognostic factors for readmission risk over 1981-2001. For both sexes, admissions increased from the early to mid 1990s, and declined thereafter. The proportion readmitted varied with the drug taken at first admission, from 11.9% (95% CI: 10.8-13%) for non-opiate analgesics, to 17.6% (16.5-18.7%) for benzodiazepines. Deprivation was positively related to readmission risk after first admissions with paracetamol (P < 0.001) and benzodiazepines (P < 0.001). Timing of first admissions involving paracetamol (P < 0.01), benzodiazepines (P < 0.001), antidepressants (P < 0.001), non-opiate analgesics (P < 0.001), and opiates (P < 0.05), was inversely associated with readmission risk. In patients admitted for drug overdose, readmission risk is influenced by type of drug taken at first admission. Information on drug type used in self-poisoning may assist in identifying patients at risk for future events, and in reducing hospital readmissions.

Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury.

Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery (n = 116) and validation (n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making.

Olanzapine overdose is associated with acute muscle toxicity.

Olanzapine is an atypical antipsychotic that is reported to cause myopathy and raised creatine kinase (CK) levels. The prevalence and severity of acute myopathy after deliberate olanzapine ingestion are unclear. Therefore, we reviewed case notes from 64 consecutive patients admitted to our institution after olanzapine overdose. Overall, serum CK was higher than five times the upper limit of normal in 17% of patients. The prevalence of raised CK values was positively correlated with the stated quantity of olanzapine ingested, suggesting a dose-dependent relationship for acute muscle toxicity. There was an apparent delay of 12 hours or more between olanzapine ingestion and the occurrence of maximum CK. Despite the high prevalence of acute muscle toxicity after olanzapine ingestion, none of the patients developed renal failure.

Five years of poisons information on the internet: the UK experience of TOXBASE.

INTRODUCTION: In 1999, the UK adopted a policy of using TOXBASE, an internet service available free to registered National Health Service (NHS) departments and professionals, as the first point of information on poisoning. This was the first use worldwide of the internet for provision of clinical advice at a national level. We report the impact on database usage and NPIS telephone call loads. METHODS: Trends in the pattern of TOXBASE usage from 2000-2004 are reported by user category. Information on the monographs accessed most frequently was also extracted from the webserver and sorted by user category. The numbers of telephone calls to the National Poisons Information Service (NPIS) were extracted from NPIS annual reports. RESULTS: Numbers of database logons increased 3.5 fold from 102,352 in 2000 to 368,079 in 2004, with a total of 789,295 accesses to product monographs in 2004. Registered users increased almost tenfold, with approximately half accessing the database at least once a year. Telephone calls to the NPIS dropped by over half. Total contacts with NPIS (web and telephone) increased 50%. Major users in 2004 were hospital emergency departments (60.5% of logons) and NHS public access helplines (NHS Direct and NHS24) (29.4%). Different user groups access different parts of the database. Emergency departments access printable fact sheets for about 10% of monographs they access. CONCLUSION: Provision of poisons information by the internet has been successful in reducing NPIS call loads. Provision of basic poisons information by this method appears to be acceptable to different professional groups, and to be effective in reducing telephone call loads and increasing service cost effectiveness.