Four-hour acetaminophen concentration estimation after ingested dose based on pharmacokinetic models.

INTRODUCTION: The United Kingdom has recently changed the indications for N-acetylcysteine treatment for acetaminophen intoxication. Any ingestion over 75 mg/kg is now referred to the hospital. A model based on pharmacokinetic parameters was developed to predict 4-h acetaminophen concentration for this and other ingested doses. METHODOLOGY: EMBASE and Medline were searched to obtain values for volume of distribution, absorption, and elimination constants and bioavailability for acetaminophen. Four-hour concentrations were calculated for ingestion doses currently recommended for hospital referral in different countries. Calculated plasma concentrations at 4 h for several doses were plotted against the Rumack-Matthew and the United Kingdom treatment lines. RESULTS: Six articles were used for the calculations (4 adult and 2 pediatric). In order to achieve a 4-h acetaminophen concentration of 100 mg/L, doses (mg/kg ± 99.9CI) of 180.5 ± 43.2 for adults and 396.1 ± 115.5 for children were calculated. DISCUSSION: A dose of 75 mg/kg would likely yield a 4-h acetaminophen concentrations well below 100 mg/L. Medical toxicologists and poison information specialists are left without evidence-based guidance for which patients or which ingestion history would now warrant referral to hospital for acetaminophen concentration measurement. Larger toxicokinetic studies in acetaminophen overdose are needed to define ingestion dose for referral to hospital.

Serotonin toxicity from antidepressant overdose and its association with the T102C polymorphism of the 5-HT2A receptor.

Serotonin toxicity results from serotonin excess in the central nervous system from serotonergic drugs. Previous studies suggest an association between T102C polymorphism of the serotonin 2A (5-hydroxytryptamine 2A) receptor gene and serotonergic adverse effects with serotonergic drugs. We aimed to determine whether there is an association between the T102C polymorphism and serotonin toxicity in patients taking serotonergic drug overdoses. Ninety-five patients presenting with serotonergic drug overdoses were examined for serotonin toxicity and had blood collected for DNA analysis. A diagnosis of serotonin toxicity was made in 14 patients (15%) based on the Hunter Serotonin Toxicology Criteria. Four of the 14 patients (29%) with serotonin toxicity had the C/C genotype compared with 20/81 (25%) without serotonin toxicity. There were no differences in age or sex, but the median defined daily dose taken by patients with serotonin toxicity was 27 (14-84) compared with 18 (2-136) in patients without serotonin toxicity (P=0.06). There was no association between serotonin toxicity and the T102C polymorphism in patients taking a serotonergic drug overdose.

Treating acetaminophen overdose: thresholds, costs and uncertainties.

The United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) modified the indications for N-acetylcysteine therapy of acetaminophen (paracetamol) overdose in September 2012. The new treatment threshold line was lowered to 100 mg/L (662 µmol/L) for a 4 hours acetaminophen concentration from the previous 200 mg/L (1325 µmol/L). This decision has the potential to substantially increase overall costs associated with acetaminophen overdose with unclear benefits from a marginal increase in patients protected from hepatotoxicity, fulminant hepatic failure, death, or transplant. Changing the treatment threshold for acetaminophen overdose also implies that ingestion amounts previously thought not to require acetaminophen concentration measurements would need to be revised. As a result, more individuals will be sent to hospitals in order that everyone with a predicted 4 hours concentration above the 100 mg/L line will have concentrations measured and potentially be treated with N-acetylcysteine. Before others consider adopting this new treatment guideline, formal cost-effectiveness analyses need to be performed to define the appropriate thresholds for referral and treatment.

Oxycodone overdose causes naloxone responsive coma and QT prolongation.

BACKGROUND: Although there are limited data on oxycodone overdose, it has been suggested that, in addition to central nervous system (CNS) depression, oxycodone may cause QT prolongation. Given the high prescription rate and increasing use of oxycodone, an understanding of its effects and treatment in overdose is necessary. AIM: To investigate the clinical features, electrocardiogram (ECG) parameters and treatment of oxycodone overdose. DESIGN: Retrospective review of a clinical database. METHODS: One hundred and thirty-seven oxycodone overdoses were identified from admissions to a toxicology unit between January 2001 and May 2011. Demographic information, details of ingestion, clinical effects, ECG parameters [heart rate (HR), QT and QRS], naloxone use and length of stay (LOS) were extracted from a clinical database. QT was measured manually and plotted on a QT nomogram. LOS was extracted for all overdoses over the same period. RESULTS: From 137 oxycodone overdoses, 79 (58%) ingested immediate release (IR) and 58 (42%) ingested sustained release (SR) or a combination of IR and SR. The median age was 40 years [interquartile range (IQR): 33-49 years], and 87 were female (64%). The median ingested dose of IR oxycodone was 70 mg (IQR: 40-100, range: 5-200), compared to 240 mg (IQR: 80-530, range: 30-1600) for SR oxycodone. Benzodiazepines were the most frequent co-ingested drug in 52 (38%) cases. No arrhythmias were recorded. Twenty-four patients (18%) had bradycardia of which five had a HR < 50 beats/min. From 116 available ECGs, the median QRS was 95 ms (IQR: 90-102 ms), and there were 20 (17%) abnormal QT-HR pairs. Naloxone boluses were required in 65 admissions (47%), and 34 (25%) required a naloxone infusion. There was higher overall naloxone use with SR and IR + SR (32/58, 55%) compared to IR oxycodone (33/79, 42%). The median LOS was 18 h (IQR: 12-35), which was greater than the median LOS for all toxicology admissions at 15 h (IQR: 8-24) over the same period. Patients requiring a naloxone infusion had an even greater LOS of 36 h (IQR: 20-62 h). CONCLUSION: In addition to the expected CNS depression, the opioid oxycodone can cause bradycardia and QT prolongation in overdose. The SR formulation is associated with the use of naloxone infusions and a longer LOS.

Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal.

OBJECTIVE: The aim of this study was to describe the clinical effects of promethazine in overdose and explore the relationship between delirium and possible predictor variables. METHODS: A case series of promethazine poisonings was identified from a prospective database of poisoning admissions to a regional toxicology service. Data were extracted including demographics, details of ingestion, clinical features including delirium, complications and medical outcomes. In addition to descriptive statistics, a fully Bayesian approach using logistic regression was undertaken to investigate the relationship between predictor variables and delirium. RESULTS: There were 199 patients with 237 presentations, including 57 patients with 78 promethazine alone overdoses. Of these 57 patients who ingested promethazine alone the median age was 22 years [interquartile range (IQR): 17-31] and 42 were female (74%). The median dose ingested was 625 mg (IQR: 350-1250 mg). Median length of stay was 19 h (IQR: 13-27 h), ten were admitted to the intensive care unit (ICU) and four were ventilated. Delirium occurred in 33 patients (42%), tachycardia (HR>100) occurred on 44 occasions (56%) and hypotension only twice. There were no seizures, dysrhythmias or deaths. Multivariate analysis of 215 presentations (in 181 patients) where dose of promethazine ingested was known demonstrated that dose, administration of charcoal within 2 h and co-ingestants predicted whether patients developed delirium. No relationship was shown for sex and age. A plot of probability that a patient will develop delirium vs. dose was constructed which showed the probability of delirium for 250 mg was 31%, 500 mg was 42% and for 1 g was 55% for promethazine alone overdoses. CONCLUSION: The main feature of promethazine toxicity is delirium, the probability of which can be predicted from the dose ingested. The administration of charcoal and the presence of co-ingestants appears to reduce the probability of delirium in a predictable manner.

Digital mobile telephones and interference of ophthalmic equipment.

AIM: To assess the effect of mobile telephone electromagnetic interference on electronic ophthalmic equipment. METHODS: Prospective audit with mobile telephones placed at distances of 3 m, 1 m, and 30 cm from, and in contact with, electronic ophthalmic equipment. Any interruption or cessation of the function of the ophthalmic device was assessed with the mobile telephones in standby, and in dialling or receiving modes. Any alterations of displayed digital figures or numbers were also assessed. RESULTS: A total of 23 electronic ophthalmic devices in two hospital ophthalmology outpatient departments were evaluated. All six mobile telephones used, and 22 (95.7%) of the 23 ophthalmic equipment evaluated had the Conformité Européene (CE) mark. No device showed any interruption or cessation of function. There were no alterations of displayed digital figures or numbers. The only effect of any kind was found with four instruments (1 non-CE marked), where there was temporary flickering on the screen, and only occurred when the mobile telephones were dialling or receiving at a distance of 30 cm or less from the instruments. CONCLUSION: This study shows that among the electronic ophthalmic devices tested, none suffered failure or interruption of function, from mobile telephone interference. Although not comprehensive for all ophthalmic equipment, the results question the need for a complete ban of mobile telephones in ophthalmic departments. It highlights the need for a controlled, objectively measured study of the clinically relevant effects of mobile telephones in the ophthalmology outpatient setting.

Wildlife tuberculosis in South African conservation areas: implications and challenges.

Tuberculosis, caused by Mycobacterium bovis, was first diagnosed in African buffalo in South Africa's Kruger National Park in 1990. Over the past 15 years the disease has spread northwards leaving only the most northern buffalo herds unaffected. Evidence suggests that 10 other small and large mammalian species, including large predators, are spillover hosts. Wildlife tuberculosis has also been diagnosed in several adjacent private game reserves and in the Hluhluwe-iMfolozi Park, the third largest game reserve in South Africa. The tuberculosis epidemic has a number of implications, for which the full effect of some might only be seen in the long-term. Potential negative long-term effects on the population dynamics of certain social animal species and the direct threat for the survival of endangered species pose particular problems for wildlife conservationists. On the other hand, the risk of spillover infection to neighboring communal cattle raises concerns about human health at the wildlife-livestock-human interface, not only along the western boundary of Kruger National Park, but also with regards to the joint development of the Greater Limpopo Transfrontier Conservation Area with Zimbabwe and Mozambique. From an economic point of view, wildlife tuberculosis has resulted in national and international trade restrictions for affected species. The lack of diagnostic tools for most species and the absence of an effective vaccine make it currently impossible to contain and control this disease within an infected free-ranging ecosystem. Veterinary researchers and policy-makers have recognized the need to intensify research on this disease and the need to develop tools for control, initially targeting buffalo and lion.

QTc abnormalities in deliberate self-poisoning with moclobemide.

BACKGROUND: Several medications have been found to prolong the QT interval in overdose. This can predispose to torsade de pointes-type ventricular tachycardia. AIMS: To analyse the effects of moclobemide deliberate self-poisoning on the length of both QT and corrected QT (QTc) intervals. METHODS: Electrocardiograms (ECG) of all patients presenting to a regional toxicology service with moclobemide ingestion were reviewed. Cases where a cardiotoxic agent was coingested were excluded. QT and QTc parameters were compared with a comparison group of patients ingesting paracetamol or benzodiazepines. RESULTS: Of 75 patients where ECG were available, the median ingested dose was 4.5 g (interquartile range (IQR): 2.4-7.5; range: 0.6-18 g) and the median age was 34 years (IQR: 26-44). The mean QT interval was 415 ms (standard deviation (SD): 51 ms) with a mean QTc of 459 ms (SD: 44 ms), and were prolonged compared with the comparison group. Twelve female patients had a QTc > 500 ms and in seven of these causality was established based on a pre- or post-ECG with a QTc < 500 ms. Only 10% of the moclobemide cases had a heart rate (HR) > 100 beats per minute, making overcorrection of HR by Bazett's formula an unlikely cause of the findings. No cardiac arrythmias were observed other than one case of first-degree heart block. CONCLUSIONS: Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done on all moclobemide deliberate self-poisonings. Continuous cardiac monitoring for what is otherwise a relatively benign overdose would appear to be an inappropriate use of resources but can be considered in patients with a QTc > 500 ms or with known risks for QT prolongation.

Suspected white-tail spider bite and necrotic ulcers.

AIM: To describe the clinical features, investigation, diagnosis and treatment of ulcers attributed to white-tail (WT) spider bites or necrotic arachnidism. METHODS: The study was a prospective case series of patients referred to the Hunter Area Toxicology Service (a tertiary referral toxicology unit servicing a population of 500 000) with an ulcer or skin lesion that had been attributed to either a suspected WT spider bite or necrotic arachnidism. Eleven patients with skin lesions or necrotic ulcers were referred between January 2000 and June 2002. RESULTS: In two patients that were inpatients in other hospitals, investigation and follow up was not possible. In both cases there was no history of spider bite and Staphylococcus aureus was cultured. In nine patients, a diagnosis other than spider bite was made following appropriate investigation and follow up, including: (i) two cases of dermatophytoses, (ii) three staphylococcal infections, (iii) one case of pyoderma gangrenosum, (iv) one case of cutaneous polyarteritis nodosa, (v) one case of Nocardia braziliensis and (vi) one infected diabetic ulcer. There was only one case where the person recalled seeing a spider bite them, but the patient did not collect the spider for identification. The median time to diagnosis was 3 weeks (interquartile range: 3-9 weeks) and 3.5 years in one case. Appropriate treatment was initiated once the correct diagnosis was made and all cases resolved. CONCLUSIONS: In this series, all cases initially referred as WT spider bites or necrotic arachnidism were found to have alternative diagnoses with appropriate investigations. This demonstrates that spider bites are an unlikely cause of necrotic ulcers and that all ulcers should be properly investigated with bacterial, fungal and mycobacterial cultures and skin biopsy for histopathology.

The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity.

BACKGROUND: There are difficulties with the diagnosis of serotonin toxicity, particularly with the use of Sternbach's criteria. AIM: To improve the criteria for diagnosing clinically significant serotonin toxicity. DESIGN: Retrospective analysis of prospectively collected data METHODS: We studied all patients admitted to the Hunter Area Toxicology Service (HATS) following an overdose of a serotonergic drug from January 1987 to November 2002 (n = 2222). Main outcomes were: diagnosis of serotonin toxicity by a clinical toxicologist, fulfillment of Sternbach's criteria and treatment with a serotonin receptor (5-HT(2A)) antagonist. A learning dataset of 473 selective serotonin reuptake inhibitor (SSRI)-alone overdoses was used to determine individual clinical features predictive of serotonin toxicity by univariate analysis. Decision rules using CART analysis were developed, and tested on the dataset of all serotonergic overdose admissions. RESULTS: Numerous clinical features were associated with serotonin toxicity, but only clonus (inducible, spontaneous or ocular), agitation, diaphoresis, tremor and hyperreflexia were needed for accurate prediction of serotonin toxicity as diagnosed by a clinical toxicologist. Although the learning dataset did not include patients with life-threatening serotonin toxicity, hypertonicity and maximum temperature > 38 degrees C were universal in such patients; these features were therefore added. Using these seven clinical features, decision rules (the Hunter Serotonin Toxicity Criteria) were developed. These new criteria were simpler, more sensitive (84% vs. 75%) and more specific (97% vs. 96%) than Sternbach's criteria. DISCUSSION: These redefined criteria for serotonin toxicity should be more sensitive to serotonin toxicity and less likely to yield false positives.

Feasibility of prehospital treatment with activated charcoal: Who could we treat, who should we treat?

OBJECTIVES: To investigate the feasibility and potential risk benefit of prehospital administration of activated charcoal. METHODS: Review of deliberate self poisoning presentations to the emergency department (ED) of a toxicology unit by ambulance over six years. Data were extracted from a standardised prospective database of poisonings. Outcomes included: number of patients attended by ambulance and number arriving in emergency within one hour. Cases were stratified by ingestion type, based on toxicity and sedative activity. RESULTS: 2041 poisoning admissions were included. The median time to ambulance attendance was 1 h 23 min (IQR 37 min-3 h) and to hospital attendance was 2 h 15 min (IQR 1 h 25 min-4 h). In 774 cases (38%) ambulance attendance occurred within one hour, but in only 161 (8%) did ED attendance occur within one hour. Non-sedating, highly toxic substances were ingested in 55 cases, 24 (23 with GCS>14) with ambulance attendance, and five with ED attendance, within one hour. Conversely 439 patients ingested a less toxic, sedative agent, 160 with ambulance attendance, and 32 with ED attendance, within one hour. Limiting decontamination to patients ingesting highly toxic, non-sedating compounds (GCS<14) reduces the proportion requiring treatment to 23 of the 774 (3.0%), an additional 18 patients. CONCLUSION: More patients could potentially be decontaminated if all patients attended by ambulance within one hour received charcoal. However, this would expose 128 patients with sedative, low risk poisonings to the risk of aspiration, and only treat 18 extra high risk poisonings. This small potential benefit of prehospital charcoal is unlikely to justify the expense in training and protocols required to implement it

Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been regarded as less toxic in overdose than tricyclic antidepressants (TCAs). Within the TCAs, dothiepin has greater toxicity. Venlafaxine may be more toxic than SSRIs. AIM: To assess the toxicity in overdose of venlafaxine and SSRIs compared to TCAs, and of dothiepin compared to other TCAs. DESIGN: Cohort study of prospectively collected data from the Hunter area, NSW, Australia. METHODS: First admissions with antidepressant deliberate self-poisoning (DSP) (November 1994 to April 2000) were identified; the presence of seizures, life-threatening arrhythmias, coma, serotonin toxicity or ICU admission, and QRS duration were noted. RESULTS: There were 538 admissions, with no deaths. The odds ratio (OR) for seizures with dothiepin vs. other TCAs was 3.4 (95%CI 1.2-9.9). Seizures occurred in 7/51 (14%) venlafaxine overdoses; all patients with seizures consumed > or =900 mg. The OR for seizures vs. TCAs was 4.4 (95%CI 1.4-13.8). Coma was less likely with venlafaxine and SSRIs. SSRIs, but not venlafaxine, were less likely to prolong the QRS to > or =100 ms. ICU admission was less likely for SSRIs. Serotonin toxicity was much more common with venlafaxine and SSRIs. DISCUSSION: Venlafaxine and dothiepin are pro-convulsant in overdose. Venlafaxine is more likely to cause serotonin toxicity, but less likely to cause coma than TCAs. SSRIs are less likely to cause coma, require ICU admission, or prolong the QRS, but are more likely to cause serotonin toxicity. Antidepressants other than TCAs or venlafaxine should be considered in patients at risk of seizure or suicide.

Treatment of anticholinergic-induced ileus with neostigmine.

A 33-year-old man with a history of recreational benztropine abuse presented to the emergency department with confusion, abdominal pain, and distention. An abdominal radiograph revealed gross fecal loading. He was initially treated with intravenous fluids and opiate analgesia. Subsequently, a diagnosis of anticholinergic poisoning was made, based on tachycardia, delirium, dry mucosa, and reduced bowel sounds. Treatment with tacrine reversed the delirium, and a history of repeated benztropine use was obtained. Persistent ileus was treated with repeated doses of neostigmine, and gastrointestinal motility returned with prompt defecation. Neostigmine appears to be useful in reversing ileus caused by anticholinergic drug overdose. Theoretically, it may be useful in reversing anticholinergic ileus resulting from acute drug overdose, allowing or enhancing decontamination, but the safety and potential efficacy of neostigmine in this scenario have not been established.