MicroRNA from a 12-h versus 20-h acetylcysteine infusion for paracetamol overdose.

Paracetamol overdose is common and microRNA (miR)-122 expression is increased with liver injury. We aimed to measure miR-122 in the setting of an abbreviated paracetamol overdose treatment regimen. We compared miRNA expression in patients treated for paracetamol poisoning with an abbreviated 12-h intravenous acetylcysteine regimen (200 mg/kg over 4 h, 50 mg/kg over 8 h) or a 20-h regimen (200 mg/kg over 4 h, 100 mg/kg over 16 h) (NACSTOP trial). miR-122 expression is increased (decreased cycle threshold (Ct) values) with paracetamol liver injury. We assessed miR-122 expression in patients receiving the two acetylcysteine regimens and in a separate group with acute liver injury (ALI). We examined 121 blood samples in 38 patients. After 20 h of acetylcysteine, median alanine transaminase (ALT) was 12 U/L (18, 14) versus 16 U/L (11, 21) ( p = 0.17) and median miR-122 Ct was 30.1 (interquartile range (IQR): 28.9, 33.3) versus 31.4 (28.9, 33.9) ( p = 0.7) in the NACSTOP abbreviated and control groups, respectively. Median normalized miR-122 Ct after 20 h of acetylcysteine was 2.2 (IQR 1.9, 6.4), 1.1 (0.7, 2.9), 63.9 (2.5, 168), 123.2 (40.9, 207.8) in the NACSTOP-abbreviated, NACSTOP-control, ALI and hepatotoxicity groups, respectively. There was no significant difference in ALT or miRNA between NACSTOP treatment groups and no signal of increased liver injury from an abbreviated 12-h acetylcysteine regimen. These findings suggest that an abbreviated acetylcysteine regimen in low-risk patients who have overdosed on paracetamol is safe. Further study is required to validate this finding utilizing miRNA as a comparative biomarker.

Methodology for AACT evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning

Intravenous lipid emulsion (ILE) therapy is a novel treatment that was discovered in the last decade. Despite unclear understanding of its mechanisms of action, numerous and diverse publications attested to its clinical use. However, current evidence supporting its use is unclear and recommendations are inconsistent. To assist clinicians in decision-making, the American Academy of Clinical Toxicology created a workgroup composed of international experts from various clinical specialties, which includes representatives of major clinical toxicology associations. Rigorous methodology using the Appraisal of Guidelines for Research and Evaluation or AGREE II instrument was developed to provide a framework for the systematic reviews for this project and to formulate evidence-based recommendations on the use of ILE in poisoning. Systematic reviews on the efficacy of ILE in local anesthetic toxicity and non-local anesthetic poisonings as well as adverse effects of ILE are planned. A comprehensive review of lipid analytical interferences and a survey of ILE costs will be developed. The evidence will be appraised using the GRADE system. A thorough and transparent process for consensus statements will be performed to provide recommendations, using a modified Delphi method with two rounds of voting. This process will allow for the production of useful practice recommendations for this therapy.(AU)

Methylene blue used in the treatment of refractory shock resulting from drug poisoning.

BACKGROUND: Methylene blue inhibits the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, decreasing vasodilation and increasing responsiveness to vasopressors. It is reported to improve haemodynamics in distributive shock from various causes including septicaemia and post-cardiac surgery. Reports of use in overdose are limited. We describe the use of methylene blue to treat a case of refractory distributive shock following a mixed drug poisoning. CASE DETAILS: A 41-year-old male presented following reported ingestion of 18 g extended-release quetiapine, 10 g controlled-release carbamazepine, 240 mg fluoxetine, 35 g enteric-coated sodium valproate and 375 mg oxazepam. He was comatose and intubated on presentation. Progressive hypotension developed. Echocardiogram revealed a hyperdynamic left ventricle, suggesting distributive shock. The patient remained hypotensive despite intravenous fluid boluses, escalating vasopressor infusions. Arterial blood gas revealed metabolic acidaemia and high lactate. Methylene blue was administered as loading-dose of 1.5 mg/kg and continuous infusion (1.5 mg/kg/h for 12 h, then 0.75 mg/kg/h for 12 h) resulting in rapid improvement in haemodynamic parameters and weaning of vasopressors. Serum quetiapine concentration was 18600 ng/mL (30-160 ng/mL), collected at the time of peak toxicity. CONCLUSION: Severe quetiapine poisoning produces hypotension primarily from alpha-adrenoreceptor antagonism. Methylene blue may have utility in the treatment of distributive shock resulting from poisoning refractory to standard vasopressor therapy.

An assessment of the in vivo effects of intravenous lipid emulsion on blood drug concentration and haemodynamics following oro-gastric amitriptyline overdose.

BACKGROUND: Overdose with lipophilic drugs, such as amitriptyline, may cause cardiotoxicity in overdose. Severe poisoning can be resistant to traditional treatments. Intravenous lipid emulsion (ILE) has been recommended as a novel therapy for the treatment of such overdoses; however, a little is known about the effects of ILE-infusion on drug concentration and haemodynamics in the early/absorptive phase after oral poisoning. METHOD: Thirty minutes after oro-gastric administration of amitriptyline (70 mg/kg), either 20% intravenous lipid emulsion (ILE), 8.4% sodium bicarbonate or Hartmann's solution was infused to anaesthetized and ventilated rodents (n = 10 per group). Heart rate, blood pressure, cutaneous ECG - QRS interval duration (QRS-d), and survival were serially recorded over 120 min. Blood drug concentrations were also collected during this period. Continuous variables were compared using one-way ANOVA. RESULTS: ILE infusion significantly decreased the survival compared to other treatments (10% ILE vs 70% bicarbonate vs 70% Hartmann's solution, p = 0.005). There was a gradual prolongation of QRS-d and fall in blood pressure over time compared to baseline (T0) measurement for both ILE and Hartmann's solution treatments. This was associated with significantly increased blood AMI concentration with ILE treatment at T60, T90 and T120 min to the other treatments (p < 0.02). CONCLUSION: Administration of ILE early after oral amitriptyline overdose resulted in worse survival and no improvement in haemodynamics. In addition, blood amitriptyline concentrations were higher in the ILE-treated group. This suggests that either drug absorption from the gastrointestinal-tract was facilitated or drug redistribution was retarded when ILE was given early after oral poisoning.

Levosimendan infusion improves cardiac output but not blood pressure in a rodent model of severe metoprolol toxicity.

UNLABELLED: Levosimendan (Levo) is an inodilator improving cardiac output (CO) and reducing afterload in heart failure. Previously, we reported that Levo improved CO but not blood pressure (BP) in a rodent model of verapamil poisoning. We theorised that Levo-induced vasodilation should not influence BP to a similar degree in metoprolol poisoning. AIM: To assess the effect of Levo on haemodynamics in a rodent model of metoprolol poisoning. METHOD: Anaesthetized male Wistar rats were infused metoprolol continuously. When the BP dropped to 50% of baseline (time 0) rats received 1 of the 4 treatments: (a) control (0.9% saline bolus + infusion); (b) Levo-l (Levo 36 µm/kg loading dose followed by 0.6 µm/kg/min); (c) Levo-I (Levo infusion only at 0.6 µm/kg/min); and (d) Epi (epinephrine 0.5 µm/kg/min). All groups received comparable fluid volumes. Haemodynamics were recorded every 10 min for 70 min. CO, mean arterial pressure (MAP) and heart rate (HR) of each group were compared to the control. RESULTS: All groups had comparable baseline and time 0 HR, MAP and CO. Levo-L and Levo-I rats showed significantly greater CO at t = 10 min (p > 0.02 and p > 0.04, respectively). CO was higher at all other time points for both Levo groups. This was not statistically significant. Levo did not improve MAP compared to control. Adrenaline increased MAP but not CO compared to control and Levo groups. CONCLUSION: Levo did not improve MAP but moderately improved CO compared to control in this model of metoprolol poisoning. The response was similar to that reported previously in verapamil-poisoned rats. The improvement in MAP seen with epinephrine was most likely vasoconstriction mediated.

Overdose with modified-release paracetamol results in delayed and prolonged absorption of paracetamol.

A modified-release formulation of paracetamol is currently available in Australasia and marketed under a number of different trade names. These include: Panadol Osteo, Panadol Extend Tablets, and Duatrol SR. We report four cases of intentional overdose with this formulation resulting in delay to peak plasma paracetamol concentrations and prolonged paracetamol absorption. Physicians must be aware that a single plasma paracetamol estimation four or more hours post-ingestion may not be adequate in the risk assessment of patients requiring treatment with N-acetylcysteine (NAC). Current Australasian guidelines for the management of modified-release paracetamol overdose advise empiric commencement of NAC if the suspected ingested dose is greater than 10 grams or 200 mg/kg (whichever is the least), an initial plasma paracetamol concentration should be assayed four or more hours post-ingestion and a second assay should be estimated four hours after the first. Treatment with NAC should continue if either concentration falls above the paracetamol treatment nomogram line. With massive ingestions of this paracetamol formulation (>50 grams) plasma concentrations may be elevated for several days and prolonged treatment with NAC is recommended. When modified-release paracetamol overdose is suspected a clinical toxicologist or Poisons Information Centre should be consulted to help guide management decisions.

"Punk" rock can be bad for you: a case of surgical emphysema from a "punk" rocker's leather jacket.

Stab wounds to the thorax are seen in the emergency department (ED) and can be caused by a variety of mechanisms. This case highlights an unusual cause of injury: a leather jacket with spikes on the back of it. This type of jacket is often worn by "punks" as a fashion statement. We report that falling onto such a jacket may result in accidental thoracic injury leading to subcutaneous emphysema. A thorough clinical assessment is mandatory to exclude underlying lung injury or pneumothorax. In patients with subcutaneous emphysema and an otherwise normal chest radiograph, an in hospital observation period of 24 hours to check for any delayed complications is adequate if the patient remains clinically stable.

Cross-reactivity of Sydney funnel-web spider antivenom: neutralization of the in vitro toxicity of other Australian funnel-web (Atrax and Hadronyche) spider venoms.

Australian funnel-web spiders are recognized as one of the most venomous spiders to humans world-wide. Funnel-web spider antivenom (FWS AV) reverses clinical effects of envenomation from the bite of Atrax robustus and a small number of related Hadronyche species. This study assessed the in vitro efficacy of FWS AV in neutralization of the effects of funnel-web spider venoms, collected from various locations along the eastern seaboard of Australia, in an isolated chick biventer cervicis nerve-muscle preparation. Venoms were separated by SDS-PAGE electrophoresis to compare protein composition and transblotted for Western blotting and incubation with FWS AV.SDS-PAGE of venoms revealed similar low and high molecular weight protein bands. Western blotting with FWS AV showed similar antivenom binding with protein bands in all the venoms tested. Male funnel-web spider venoms (7/7) and female venoms (5/10) produced muscle contracture and fasciculation when applied to the nerve-muscle preparation. Venom effects were reversed by subsequent application of FWS AV or prevented by pretreatment of the preparation with antivenom.FWS AV appears to reverse the in vitro toxicity of a number of funnel-web spider venoms from the eastern seaboard of Australia. FWS AV should be effective in the treatment of envenomation from most, if not all, species of Australian funnel-web spiders.

Red-back spider (Latrodectus hasselti) antivenom prevents the toxicity of widow spider venoms.

STUDY OBJECTIVES: Widow spiders of the genus Latrodectus are found worldwide and produce similar clinical envenomation syndromes. In Australia, red-back spider antivenom (RBS-AV) is effective therapy for Latrodectus hasselti envenomation and it has been reported to reverse envenomation by other widow spiders. This study assessed the efficacy of RBS-AV in preventing in vitro and in vivo toxicity of widow spider venoms of North America and Europe. METHODS: The binding of RBS-AV to alpha-latrotoxin and Latrodectus venoms (Latrodectus spp mactans, hesperus, lugubris, tredecimguttatus, hasselti) was assayed using Western blotting. Prevention of in vitro toxicity to alpha-latrotoxin and the same venoms was tested by pretreating an isolated chick biventer cervicis nerve-muscle preparation with RBS-AV. Prevention of in vivo toxicity was determined by a lethality study in male Balb/c mice (2.5 to 5x median lethal dose [LD50]) or alpha-latrotoxin (10x LD50) preincubated with antivenom or without RBS-AV (control). RESULTS: In Western blots, RBS-AV bound to alpha-latrotoxin and similar widow spider proteins in all venoms tested, indicating antigenic similarity with proteins found in RBS venom. Antivenom prevented the typical in vitro muscle contracture and loss of twitch tension seen with alpha-latrotoxin and the venoms tested. Control mice rapidly developed signs of envenomation, but mice treated with RBS-AV remained free of signs of envenomation. CONCLUSION: RBS-AV prevented both in vitro and in vivo toxicity from Latrodectus venoms and alpha-latrotoxin in mice. These data suggest that RBS-AV may be clinically effective in the treatment of envenomation resulting from the bite of other widow spiders.

A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning.

STUDY OBJECTIVE: To compare the efficacy and safety of physostigmine with benzodiazepines for the treatment of agitation and delirium associated with anticholinergic poisoning. METHODS: We conducted a retrospective study of 52 consecutive patients referred to a university hospital toxicology consultation service who were treated with physostigmine, benzo-diazepines, or both for anticholinergic agitation and delirium. Patients treated with physostigmine were compared with those treated with benzodiazepines with respect to demographics, severity of poisoning, response to treatment, side effects of treatment, and complications. RESULTS: Physostigmine controlled agitation and reversed delirium in 96% and 87% of patients, respectively. Benzodiazepines controlled agitation in 24% of patients but were ineffective in reversing delirium. Initial treatment with physostigmine (n=30) resulted in a significant decrease in the incidence of agitation (P <.001) and level of central nervous system stimulation (P <.001), whereas initial treatment with benzodiazepines (n=22) did not (P =.03 and P =.05, respectively). Patients treated initially with physostigmine had a significantly lower incidence of complications (7% versus 46%; P <. 002) and a shorter time to recovery (median, 12 versus 24 hours; P =. 004) than those treated initially with benzodiazepines. There were no significant differences between these groups in the incidence of side effects (7% versus 14%; P =0.6) and length of stay (median, 32 versus 39 hours; P =.15). CONCLUSION: Results suggest that physostigmine is more effective and safer than benzodiazepines for the treatment of anticholinergic agitation and delirium. A prospective controlled study is necessary to confirm such findings.

Triethylene glycol poisoning treated with intravenous ethanol infusion.

INTRODUCTION: Poisoning with triethylene glycol has been rarely reported in humans. Triethylene glycol is thought to be metabolized by alcohol dehydrogenase to acidic products resulting in the production of a metabolic acidemia. Triethylene glycol metabolism has previously been shown to be inhibited by fomepizole (4-methyl pyrazole) administration. We report a case of triethylene glycol ingestion, presenting with a metabolic acidemia, treated with intravenous ethanol administration. CASE REPORT: A 23-year-old female presented to the emergency department approximately 1-1.5 hours following ingestion of a gulp of triethylene glycol (99%) brake fluid with coma (GCS-3) and metabolic acidemia (pH 7.03, PCO2 44 mm Hg, Bicarbonate 11 mmol/L, anion gap 30 mmol/L, serum creatinine 90 mumol/L). She was intubated and given 100 mmol of intravenous sodium bicarbonate. An ethanol loading dose was administered followed by an infusion to maintain serum ethanol at 100 mg/dL. Acidemia gradually resolved over the next 8 hours and she was extubated 12 hours later. The ethanol infusion was continued for a total of 22 hours. There was no recurrence of acidemia. Serum ethanol, ethylene glycol, and methanol levels were nondetectable on presentation, as was serum salicylate. Urine drug of abuse screen and thin-layer chromatography revealed no other coingested substances. The patient was discharged to a psychiatric ward 36 hours postingestion. CONCLUSION: Pure triethylene glycol poisoning results in coma and metabolic acidemia and may be treated with alcohol dehydrogenase inhibitors such as ethanol.

Serotonin syndrome resulting from drug interactions.

We describe six patients diagnosed with serotonin syndrome after exposure to drugs with serotonergic activity. Drug interactions occurred as a result of a combination of tricyclic antidepressants, selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors or monoamine oxidase inhibitors. Management included supportive care and the use of non-specific serotonin antagonists (cyproheptadine, benzodiazepines and chlorpromazine). All patients made uneventful recoveries.

Treatment of the serotonin syndrome with cyproheptadine.

The serotonin syndrome is the result of excess stimulation of central nervous 5-hydroxytryptamine (5HT)-1a and 5HT-2 receptors. The diagnosis requires a history of exposure to agents active at serotonin receptors and the presence of alterations in mental status, autonomic instability, and neuromuscular abnormalities such as tremor, hyperreflexia, or myoclonus. In this descriptive case series, five cases of serotonin syndrome are reported. All patients gave a history of recent exposure to one or more serotonergic medications, including moclobemide, paroxetine, sertraline, and venlafaxine, with clinical evidence of serotonin syndrome. All patients were administered cyproheptadine (4-8 mg orally) for serotonergic signs. Three had complete resolution of signs within 2 h of administration. Another two had a residual tremor or hyperreflexia following the first dose, which resolved following a repeat dose. There were no adverse outcomes from cyproheptadine use. The role of specific serotonin receptor antagonists such as cyproheptadine in the treatment of the serotonin syndrome remains to be delineated. Its use should be considered an adjunct to supportive care. Currently, it is unknown whether cyproheptadine modifies patient outcome.

Treatment of methanol poisoning with intravenous 4-methylpyrazole.

Treatment of human methanol poisoning with the alcohol dehydrogenase inhibitor, 4-methylpyrazole (fomepizole), has not been previously described. We report the clinical and toxicokinetic data of a patient with methanol poisoning who was treated with fomepizole. Formic acid levels remained undetectable during fomepizole treatment, the toxic effects of methanol were prevented, and the patient made a full recovery.

Regional intravenous infusion of calcium gluconate for hydrofluoric acid burns of the upper extremity.

STUDY OBJECTIVE: To describe regional intravenous infusion of calcium gluconate as a therapy for hydrofluoric acid (HF) burns of the forearm, hand, or digits. METHODS: This study describes seven patients with HF burns. Calcium gluconate, 10 mL of 10% solution with 30 to 40 mL normal saline solution, was injected intravenously into the affected limb using a Bier block technique. Ischemia was maintained for 20 to 25 minutes. Therapy was considered successful if significant reduction of pain and tenderness was noted after tourniquet release. RESULTS: Seven patients were treated. HF concentration varied from 5% to 49%. Exposure sites included the forearm (two cases), thenar eminence and digits (two cases), or digits only (three cases). Complete pain resolution occurred on tourniquet release in four patients (two with burns to the forearm, two with burns to digits only). One patient had partial relief (thenar but not digital exposure site), and two had no relief of symptoms. Intraarterial calcium gluconate perfusion was subsequently administered to the three patients with persistent subungual and pulp, or thenar pain. Recovery was complete in all cases. No adverse effects were noted. CONCLUSION: Regional intravenous infusion of calcium gluconate should be considered a therapeutic option in HF burns of the forearm, hand, or digits when topical therapy fails.

Fluoxetine-induced cardiotoxicity with response to bicarbonate therapy.

This report describes a patient with an acute intentional fluoxetine exposure who developed unique cardiovascular and neurovascular toxicity. The patient presented with lethargy and cardiac conduction delays (QRS 110 msec, QTc 458 msec) and developed a delayed seizure. On admission, therapy with intravenous sodium bicarbonate promptly narrowed the QRS to 90 msec. A comprehensive toxicology screen demonstrated only a serum fluoxetine concentration of 901 ng/mL (therapeutic range, 37-301), a serum norfluoxetine concentration of 451 ng/mL (29-329) and a serum acetaminophen concentration of 174 mg/L. Tricyclic antidepresants were specifically noted to be absent. A self-limiting generalized seizure was witnessed 16 hours after ingestion. At this time the bicarbonate infusion had been ceased and the QRS interval was not prolonged. The patient improved over time and no other apparent causes for the observed clinical effects could be discovered. Emergency physicians need to be aware of the uncommon occurrence of fluoxetine-induced cardiotoxicity and the potential benefit of sodium bicarbonate therapy.