Hyperlactataemia and clinical severity of acute metformin overdose.

BACKGROUND: Although metformin-associated lactic acidosis is well described, there is less information on metformin overdose and whether it is of similar severity. AIMS: This study aims to describe the clinical features, laboratory investigations and outcome of acute metformin overdoses. METHODS: Retrospective case series of acute metformin overdoses (> 3 g) admitted to a toxicology unit over 20 years. Cases were identified from a prospective database and data extracted included demographics, dose, coingestants, clinical effects, investigations, treatment and outcomes. RESULTS: There were 36 acute metformin overdose cases. Median age 41 years old (15-68 years old); 25 were female. Median ingested dose was 10 g (interquartile range (IQR): 5-16.1 g; range: 3.5-50 g), with coingestants taken in 34 presentations. Gastrointestinal symptoms were present in 12/36, tachycardia in 10, bradycardia in three, hypotension in four and hypoglycaemia in eight. Hypotension and bradycardia were consistent with coingestants taken. Blood pH and lactate levels were available in 25/36. Median lowest pH was 7.35 (IQR: 7.28-7.38) and acidosis (pH < 7.35) occurred in 11/25. Median peak lactate was 3.9 mmol/L (IQR: 2.6-5.2 mmol/L). There was a statistical association between dose and lactate (r = 0.51; P = 0.01) and dose and pH (r = -0.70; P = 0.0001). Hyperlactataemia (lactate > 2 mmol/L) without acidosis occurred in 10/25, and hyperlactataemia with acidosis in 11/25; five had lactic acidosis. The median time to peak lactate in 10 presentations with peak lactate > 2 was 6 h (2-19 h). There were six intensive care unit admissions, one for lactic acidosis, and five related to coingestants. There were no deaths. CONCLUSION: Metformin overdose is characterised by hyperlactataemia and minor gastrointestinal effects, with a few large ingestions progressing to lactic acidosis. Coingestants are common and may dominate toxicity.

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.

Activated Charcoal and Bicarbonate for Aspirin Toxicity: a Retrospective Series.

INTRODUCTION: Aspirin overdose causes acid-base disturbances and organ dysfunction. Management is guided by research reported over 50 years ago when chronic aspirin toxicity was common and accounted for significant morbidity. We investigate our experience of aspirin overdose and the effectiveness of charcoal and bicarbonate administration over 20 years. METHODS: This is a retrospective series of acute aspirin overdose from two toxicology units from January 2000 to September 2019. Acute aspirin ingestions > 3000 mg were identified in each unit's database. Excluded were cases of chronic exposure, hospital presentation > 24 hours after ingestion, and cases without a salicylate concentration. Included in our analysis was demographic data, clinical effects, investigations, complications, and treatment. RESULTS: There were 132 presentations in 108 patients (79 females (73%)). The median age was 28 years (range: 13-93 years). The median dose ingested was 7750 mg (IQR: 6000-14,400 mg). There were 44 aspirin-only ingestions. Mild toxicity (nausea, vomiting, tinnitus or hyperventilation) occurred in 22 with a median dose of 160 mg/kg. Moderate toxicity (acid-base disturbance, confusion) occurred in 16 with a median ingested dose of 297 mg/kg. There were no cases of severe toxicity (coma or seizures) due to aspirin alone. The median peak salicylate concentration was 276 mg/L (IQR: 175-400 mg/L, range: 14-814 mg/L). There was a moderate association between dose ingested and peak concentration (Pearson r = 0.58; 95% CI 0.45-0.68). Activated charcoal was administered in 36 (27%) cases, which decreased the median peak salicylate concentration (34.2 to 24.8 mg/L/g (difference: 9.4, 95% CI: 1.0-13.1)). Bicarbonate was administered in 34 (26%) presentations, decreasing the median apparent elimination half-life from 13.4 to 9.3 h (difference: 4.2 h, 95% CI: 1.0-6.5 h). CONCLUSIONS: Acute aspirin overdose caused only mild to moderate effects in this series. Early administration of activated charcoal decreased absorption and use of bicarbonate enhanced elimination.

Life-threatening triclopyr poisoning due to diethylene glycol monoethyl ether solvent.

INTRODUCTION: Triclopyr is a synthetic auxin-like herbicide. It is considered to have low toxicity and there are few reports of poisoning. We report two cases of life-threatening toxicity following ingestions of 250 mL of 50 g/L triclopyr co-formulated with diethylene glycol monoethyl ether (DEGEE). CASE REPORTS: A 79-year-old male with a background of hypertension and atrial fibrillation presented two hours after ingestion with sedation, a severe high anion gap metabolic acidosis, raised osmolar gap and an aspiration pneumonitis. He was ventilated and dialysed for 10 h with resolution of the acidaemia. He was discharged home on day 33. A 66-year-old male with a past history of alcoholism and hypertension presented following a collapse. He had sedation, a severe high anion gap metabolic acidosis with a raised osmolar gap, acute kidney injury and vasodilatory shock. He was ventilated and received dialysis for 43 h. He had poor neurological recovery and died on day 10. DISCUSSION: Ingestion of triclopyr formulations can produce life-threatening toxicity. In large poisonings of triclopyr co-formulated with DEGEE, a high anion gap metabolic acidosis appears to be due to the glycol ether solvent rather than triclopyr itself. Management should focus on good supportive care including dialysis for significant metabolic acidosis.

A model for venom-induced consumptive coagulopathy in snake bite.

Many snake venoms contain procoagulant toxins that activate the coagulation cascade and cause venom-induced consumptive coagulopathy (VICC). We developed a semi-mechanistic model of the clotting cascade in order to explore the effects of the procoagulant toxin from taipan venom on this system as well as the effects of antivenom. Simulations of the time course in the change of clotting factors were compared to data collected from taipan envenomed patients. The model accurately predicted the observed concentration of clotting factors over time following taipan envenomation. Investigations from the model indicated that the upper limit of the half-life of the procoagulant toxin was 1h. Simulations from the model also suggest that antivenom for Australasian elapids has negligible effect on reducing the recovery time of the coagulation profile unless administered almost immediately after envenomation. The model has generality to be expanded to describe the effects of other venoms and drugs on the clotting cascade.

Pharmacokinetics of quetiapine in overdose and the effect of activated charcoal.

The aim of the study was to investigate the pharmacokinetics of quetiapine overdose and the effect of charcoal. The data set included 204 concentration-time points from 54 quetiapine overdose events (median dose 2,700 mg (300-24,000 mg)). Charcoal was administered 0.5-6 h after 19 overdoses. A fully Bayesian methodology for population pharmacokinetic analysis was used and data were modelled using WinBUGS. Uncertainty in the dose history was considered in model building by estimating dose amount and dose time within a possible range. Inclusion of informative priors stabilized the model and population parameter values could be estimated well. A one-compartment model with first-order input and first-order elimination described the data. The final model included uncertainty in dose time. The median and interquartile range of the half-life for individual patients was 6.6 h (4.9-8.4 h). Charcoal was estimated to reduce fraction absorbed by 35%. Co-ingested CYP3A4 inhibitors appeared to decrease clearance and CYP3A4 inducers increase clearance. Charcoal administration may be beneficial after quetiapine overdose.

Drug-induced QT prolongation and torsades de pointes: evaluation of a QT nomogram.

BACKGROUND: Although QT prolongation is associated with increased risk of torsade de pointes (TdP), the precise relationship is not well defined. AIM: To evaluate the performance of a QT nomogram in assessing the risk of TdP from QT-RR combinations. DESIGN: Systematic review. METHODS: We systematically searched MEDLINE/EMBASE for cases of drug-induced TdP. Controls were patients taking non-cardiotoxic drugs in overdose. Inclusion criteria were definite TdP, normal ECG before or after the event, association with a drug/toxin and QT-RR measurements available. The upper bound of a QT-RR cloud diagram developed from human preclinical studies was converted into a QT nomogram [QT vs. heart rate (HR)]. QT-HR combinations for TdP cases and controls were plotted with the QT nomogram, and curves corresponding to a QTc = 440 ms and QTc = 500 ms for comparison (Bazett's correction). RESULTS: We identified 129 cases of TdP. TdP cases occurred at lower HR values with longer QT intervals, with most cases occurring at HR 30-90 bpm. Controls were more evenly distributed, with HR 40-160 bpm. The sensitivity and specificity of the QT nomogram were 96.9% (95%CI 93.9-99.9) and 98.7% (95%CI 96.8-100), respectively. For Bazett QTc = 440 ms, sensitivity and specificity were 98.5% (95%CI 96.3-100) and 66.7% (95%CI 58.6-74.7), respectively, whereas for Bazett QTc =500 ms they were 93.8% (95%CI 89.6-98.0) and 97.2% (95%CI 94.3-100), respectively. DISCUSSION: The QT nomogram is a clinically relevant risk assessment tool that accurately predicts arrhythmogenic risk for drug-induced QT prolongation. Further prospective evaluation of the nomogram is needed.

An in vivo examination of the stability of venom from the Australian box jellyfish Chironex fleckeri.

We have previously characterised the pharmacological activity of a number of jellyfish venoms with a particular emphasis on the profound cardiovascular effects. It has been suggested that jellyfish venoms are difficult to work with and are sensitive to pH, temperature and chemical changes. The current study aimed to examine the working parameters of the venom of the Australian box jellyfish Chironex fleckeri to enable fractionation and isolation of the toxins with cardiovascular activity. C. fleckeri venom was made up fresh each day and subjected to a number of different environments (i.e. a pH range of 5-9 and a temperature range of 4-30 degrees C). In addition, the effect of freeze drying and reconstituting the venom was investigated. Venom (50 microg/kg, i.v.) produced a transient hypertensive response followed by cardiovascular collapse in anaesthetised rats. This biphasic response was not significantly effected by preparation of the venom at a pH of 5, 7 or 9. Similarly, venom (50 microg/kg, i.v.) did not display a loss of activity when exposed to temperatures of 4, 20 or 30 degrees C for 1.5h. However, the cardiovascular activity was abolished by boiling the venom. Freeze drying, and then reconstituting, the venom did not significantly affect its cardiovascular activity. However, repeated freeze drying and reconstituting of extracted venom resulted in a significantly loss of activity. This study provides a more detailed knowledge of the parameters in which C. fleckeri venom can be used and, while supporting some previous studies, contradicts some of the perceived problems of working with the venom.

Safety of i.v. administration of redback spider antivenom.

It is unclear what the risk of allergic reactions is with appropriately given dilute i.v. redback spider antivenom (RBSAV). Ninety-five i.v. administrations of RBSAV referred from January 2001 to November 2006 were reviewed. All patients had local pain, 72% radiating pain, 57% diaphoresis and 39% systemic effects. Four patients (4%) had immediate systemic hypersensitivity reactions: none were severe, one was moderate and three mild. In 32 patients followed up for 2 weeks, three (10%) developed serum sickness. RBSAV given i.v. had a low reaction rate.

Thrombotic microangiopathy from Australian brown snake (Pseudonaja) envenoming.

BACKGROUND: Australian brown snake (genus Pseudonaja) envenoming causes a venom-induced consumptive coagulopathy (VICC). A proportion of cases go on to develop thrombotic microangiopathy characterized by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and acute renal failure (ARF). AIM: The aim of the study was to define better the natural history and empirical treatments for thrombotic microangiopathy in brown snake envenoming. METHODS: A review of brown snake bites recruited to the Australian Snakebite Project (ASP), a national multicentre study of snake envenoming was undertaken. Serial data are recorded on clinical effects and laboratory results, including measurement of venom concentrations. We describe cases of thrombotic microangiopathy and compare these to cases without thrombotic microangiopathy. RESULTS: From 32 cases of brown snake envenoming with severe VICC, four (13%) developed thrombotic microangiopathy, we also included two cases of thrombotic microangiopathy from prior to ASP. All six developed severe thrombocytopenia (<20 x 10(-9)/L), worst 3 days after the bite and resolving over a week, MAHA with fragmented red blood cells on the blood film and five developed anuric ARF requiring dialysis and lasting 2-8 weeks. All six received antivenom, which was delayed compared with other brown snake-envenoming cases. Four were treated with plasmapheresis. The severity and recovery of the thrombocytopenia, anaemia and renal function were similar with and without plasmapheresis. The median length of stay for MAHA cases was 14 days (interquartile range (IQR) 12-14) compared to 1.8 days (IQR 1.3-2) for all other cases. CONCLUSION: Thrombotic microangiopathy resulting from brown snake bite appears to have a good prognosis and management should focus on early antivenom therapy and supportive care including dialysis. The role of plasmapheresis is yet to be defined.

Desvenlafaxine overdose and the occurrence of serotonin toxicity, seizures and cardiovascular effects.

CONTEXT: Desvenlafaxine is used to treat major depression. Desvenlafaxine is also the active metabolite of venlafaxine. Venlafaxine overdose can cause serotonin toxicity, seizures and cardiovascular effects, but there is limited information on desvenlafaxine overdose. OBJECTIVE: We aimed at investigating the clinical effects and complications from desvenlafaxine overdose. MATERIALS AND METHODS: This was a retrospective observational study of desvenlafaxine overdoses over a six-year period. Demographic details, dose and timing of the overdose, together with clinical effects, treatment and complications were extracted from a local hospital network database or the medical records of patients following hospital admission with a desvenlafaxine overdose. RESULTS: There were 182 cases of desvenlafaxine overdose included in the study. From the 182 cases, 75 were desvenlafaxine (± alcohol) only ingestions and 107 included one or more co-ingested drugs. In single-agent desvenlafaxine ingestions, median age was 25 years (range: 13-68 years) with a median ingested dose of 800 mg (range: 250-3500 mg; interquartile range (IQR): 600-1400 mg), and 54/75 (72%) were female. The Glasgow Coma Score (GCS) was 15 in 68/74 (92%) patients, 13-14 in 5/74 (7%), and was seven in one patient following aspiration. Mild hypertension (systolic blood pressure [BP] > 140-180 mmHg) occurred in 23/71 patients (32%), and tachycardia occurred in 29/74 (39%) patients. There were no abnormal QT intervals and no QRS >120 m s. Serotonin toxicity was diagnosed by the treating physician in 7/75 (9%) patients, but only one of these met the Hunter Serotonin Toxicity Criteria. None of the 75 patients who took desvenlafaxine only (± alcohol) had seizures, were admitted to intensive care or died. In comparison, the 107 patients taking desvenlafaxine in overdose with other medications developed more pronounced toxicity. Generalised seizures occurred in 5/107 (5%), but in three of these cases co-ingestants were possible proconvulsants. Fifteen patients had a GCS ≤9 and none had an abnormal QT or QRS. Severe effects appeared to be associated with coingestants. CONCLUSION: Desvenlafaxine overdose causes minor effects with mild hypertension and tachycardia. The risk of seizures or serotonin toxicity is low.

Severe Hypertension and Bradycardia Secondary to Midodrine Overdose.

The objective of this case is to describe the pharmacokinetics and toxicity of midodrine in overdose. A 20 year old female ingested up to 350 mg midodrine while recovering in hospital from another overdose. She developed vomiting and severe hypertension (blood pressure [BP], 210/100 mmHg). Remarkable findings included a heart rate with a range of 43-60 beats/min, spontaneous respirations (20 breaths/min), and oxygen saturations of >95 % on FiO2 25 %, and a GS of 8. She was admitted to intensive care and had a normal non-contrast CT brain. She was treated with a glyceryl trinitrate patch (5 mg) and observed for 36 h with subsequent BP reduction to 124/81 mmHg and improved in conscious state. Midodrine and desglymidodrine concentrations were measured with liquid chromatography tandem mass spectrometry and were detected with 2-h post-ingestion at concentrations of 158.4 and 169.7 ng/mL, respectively. The parent drug concentrations rapidly decreased with an elimination of half-life of 1.6 h, and the metabolite initially increased and then decreased. The peak in blood pressure appeared to coincide with peak metabolite concentrations. Midodrine in overdose can potentially cause severe hypertension and reflex bradycardia but given its short half-life treatment with vasodilator agents and supportive care is sufficient.

A randomized controlled trial of fresh frozen plasma for coagulopathy in Russell's viper (Daboia russelii) envenoming.

Essentials Russell's viper envenoming is a major health issue in South Asia and causes coagulopathy. We studied the effect of fresh frozen plasma and two antivenom doses on correcting coagulopathy. Fresh frozen plasma did not hasten recovery of coagulopathy. Low-dose antivenom did not worsen coagulopathy. SUMMARY: Background Russell's viper (Daboia russelii) envenoming is a major health issue in South Asia and causes venom-induced consumption coagulopathy (VICC). Objectives To investigate the effects of fresh frozen plasma (FFP) and two antivenom doses in correcting VICC. Methods We undertook an open-label randomized controlled trial in patients with VICC at two Sri Lankan hospitals. Patients with suspected Russell's viper bites and coagulopathy were randomly allocated (1 : 1) to high-dose antivenom (20 vials) or low-dose antivenom (10 vials) plus 4 U of FFP. The primary outcome was the proportion of patients with an International Normalized Ratio (INR) of < 2 at 6 h after antivenom administration. Secondary outcomes included anaphylaxis, major hemorrhage, death, and clotting factor recovery. Results From 214 eligible patients, 141 were randomized: 71 to high-dose antivenom, and 70 to low-dose antivenom/FFP; five had no post-antivenom blood tests. The groups were similar except for a delay of 1 h in antivenom administration for FFP patients. Six hours after antivenom administration, 23 of 69 (33%) patients allocated to high-dose antivenom had an INR of < 2, as compared with 28 of 67 (42%) allocated to low-dose antivenom/FFP (absolute difference 8%; 95% confidence interval - 8% to 25%). Fifteen patients allocated to FFP did not receive it. Severe anaphylaxis occurred equally frequently in each group. One patient given FFP developed transfusion-related acute lung injury. Three deaths occurred in low-dose antivenom/FFP patients, including one intracranial hemorrhage. There was no difference in recovery rates of INR or fibrinogen, but there was more rapid initial recovery of factor V and FX in FFP patients. Conclusion FFP after antivenom administration in patients with Russell's viper bites did not hasten recovery of coagulopathy. Low-dose antivenom/FFP did not worsen VICC, suggesting that low-dose antivenom is sufficient.

Collett's snake (Pseudechis colletti) envenoming in snake handlers.

BACKGROUND: Collett's snake (Pseudechis colletti) is a member of the black snake genus and occurs in a warm temperate to sub-tropical region of central Queensland, Australia. There are no reports of bites occurring in the wild, and bites were previously thought to cause only minor effects. They are a popular snake among zoos and exotic snake keepers. AIM: To investigate the clinical effects of severe envenoming by Collett's snake, and possible treatment options. DESIGN: Case series. METHODS: Clinical and laboratory features are described for six bites, all in snake handlers. RESULTS: All six bites were from captive snakes, resulting in severe envenoming in four. Two patients were treated early with black snake antivenom, and only developed an anticoagulant coagulopathy and mild myolysis. Two developed anticoagulant coagulopathy and severe rhabdomyolysis associated with acute renal failure, requiring haemodialysis; both received antivenom >10 h after the bite, and initially received minimal fluid replacement. Other effects included thrombocytopenia, non-immune haemolytic anaemia and a marked leukocytosis. DISCUSSION: Collett's snake envenoming is characterized by early generalized systemic effects (nausea, vomiting, abdominal pain, diarrhoea and headache) and an anticoagulant coagulopathy, followed in some cases by rhabdomyolysis and acute renal failure in untreated patients within 24 h. Early initiation of fluid therapy and treatment with black snake antivenom should be undertaken in all envenomed patients.

Hyperbaric oxygen for carbon monoxide poisoning.

BACKGROUND: Poisoning with carbon monoxide (CO) remains an important cause of accidental and intentional injury worldwide. Several unblinded non-randomized trials have suggested that the use of hyperbaric oxygen (HBO) prevents the development of neurological sequelae. This has led to the widespread use of HBO in the management of patients with carbon monoxide poisoning. OBJECTIVES: To examine randomized trials of the effectiveness of hyperbaric oxygen (HBO) compared to normobaric oxygen (NBO) for the prevention of neurologic sequelae in patients with acute carbon monoxide poisoning. SEARCH STRATEGY: We searched MEDLINE (1966-present), EMBASE (1980-present), and the Controlled Trials Register of the Cochrane Collaboration, supplemented by a manual review of bibliographies of identified articles and discussion with recognized content experts. SELECTION CRITERIA: All randomized controlled trials involving non-pregnant adults acutely poisoned with carbon monoxide (regardless of severity), with adequate or unclear allocation concealment. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted from each trial information on: the number of randomized patients, types of participants, the dose and duration of the intervention, and the prevalence of neurologic symptoms at follow-up. MAIN RESULTS: Seven randomized controlled trials of varying quality were identified; one was excluded because it did not evaluate clinical outcomes. Of the six remaining trials, two represent incomplete publications (one interim analysis, one abstract). Of these six trials, four found no benefit of HBO for the reduction of neurologic sequelae, while two others did. Although pooled analysis does not suggest a benefit from HBOT (OR for neurological deficits 0.78, 95%CI 0.54 to 1.12, p=0.18), significant methodologic and statistical heterogeneity was apparent among the trials, and this result should be interpreted cautiously. Moreover, design or analysis flaws were evident in all trials. Importantly, the conclusions of one positive trial may have been influenced by failure to adjust for multiple hypothesis testing, while interpretation of the other positive trial is hampered by apparent changes in the primary outcome during the course of the trial. AUTHORS' CONCLUSIONS: Existing randomized trials do not establish whether the administration of HBO to patients with carbon monoxide poisoning reduces the incidence of adverse neurologic outcomes. Additional research is needed to better define the role, if any, of HBO in the treatment of patients with carbon monoxide poisoning. This research question is ideally suited to a multi-center randomized controlled trial.

A prospective study of 750 definite spider bites, with expert spider identification.

BACKGROUND: Spider bite is a subject of much medical mythology with prevalent fears that spiders cause severe envenoming, with neurotoxic effects or necrotic ulcers. Clinical experience and small studies suggest otherwise, but this has not been confirmed by prospective studies of bites by identified spiders. AIM: To describe the clinical effects of bites by accurately identified spiders, and determine whether early clinical features and circumstances can predict spider type. DESIGN: Prospective follow-up study. METHODS: Patients were recruited from admissions to two emergency departments (n=48) and referrals from three state poison information centres (n=1426), over 27 months. Overall, there were 750 people with definite spider bites where the spiders were immediately collected and expertly identified. RESULTS: Significant effects occurred in 44 bites (6%), including 37 (of 56) redback spider bites (Latrodectus hasselti) with significant pain lasting >24 h. Of these, only 6 (11%) received antivenom. One severe neurotoxic envenoming by an Australian funnelweb spider required antivenom. No definite spider bites resulted in necrotic ulcers (0%, 99%CI 0-0.7%). There were no early allergic reactions and secondary infection occurred in seven cases (0.9%, 95%CI 0.4-1.9%). Circumstances and early clinical effects were strongly associated with taxonomic spider identification, with positive predictive values >0.95 for common groups of spiders. CONCLUSIONS: Australian spider bite caused minor effects in most cases and is unlikely to cause necrotic ulcers, allergic reactions or infection. Redback spider bite (widow spider) caused prolonged pain, and antivenom could have been used more frequently. The circumstances and early clinical features of spider bites may allow early appropriate advice and treatment of spider bite without taxonomic identification.

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.

Paracetamol overdose in a preterm neonate.

The first oral overdose of paracetamol in a neonate is reported. A 55 day old neonate, born 29 weeks premature, was accidentally given 136 mg/kg paracetamol. Treatment was with activated charcoal, supportive care, and N-acetylcysteine. There was no biochemical evidence of hepatotoxicity, and no long term sequelae. After modelling of the data, the following pharmacokinetic variables were calculated: absorption half life (t(abs)), 0.51 hours; volume of distribution (V/F(oral)), 0.80 litres/kg; clearance (CL/F(oral)), 0.22 litres/h; they were consistent with population pharmacokinetic studies. The increased plasma half life (Tbeta) of 5.69 hours thus reflected normal slower metabolism in infants, rather than toxicity. The toxicity of paracetamol in neonates is unclear, but appears to be low because of slow oxidative metabolism and rapid glutathione synthesis. In an overdose, estimates of toxicity can be made from dose and Tbeta in neonates, or from maternal toxicity in transplacental poisoning. Treatment includes N-acetylcysteine and supportive care, with activated charcoal for oral poisoning.

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

Mirtazapine overdose is unlikely to cause major toxicity.

OBJECTIVE: There is limited information on mirtazapine overdose, but cases of severe effects (seizures, serotonin toxicity and coma) have been reported. We aimed to investigate the clinical effects and complications of mirtazapine overdose. METHODS: This was an observational case series of mirtazapine overdoses (> 120 mg) identified from admissions to a toxicology unit between January 1987 and August 2013. Demographic information, details of ingestion, clinical effects, ECG parameters (HR, QT and QRS), and length of stay were extracted from a clinical database. RESULTS: From 267 mirtazapine overdoses, there were 89 single-agent mirtazapine ingestions and 178 cases where mirtazapine was taken with at least one other drug. The median age of the 89 single-agent mirtazapine ingestions was 36 years [interquartile range (IQR): 26-49 years; Range: 15-81 years]; 45 were female (51%). The median ingested dose was 420 mg (IQR: 270-750 mg; Range: 150-1350 mg) and 41 patients (46%) had a Glasgow coma score (GCS) < 15, but the minimum GCS was 10. There were no seizures, serotonin toxicity or delirium. Tachycardia occurred in 29 patients (33%) and hypertension in 32 patients (36%). The median QRS was 80 ms (Range: 80-120 ms) and there were no cases with QT prolongation. There were no arrhythmias and no deaths. The median length of stay was 14 h (IQR: 8.8-18.2 h; Range:2.2-75 h). No single-agent mirtazapine patient was admitted to intensive care. The 178 patients taking co-ingestants had more severe toxicity depending on the co-ingested drug. CONCLUSION: Mirtazapine appears to be relatively benign in overdose, associated with tachycardia, mild hypertension and mild CNS depression not requiring intervention.