Treatment for beta-blocker poisoning: a systematic review.

Introduction: Beta-adrenoreceptor antagonist (beta-blocker) poisoning is a common overdose which can lead to significant morbidity and mortality.Objective: To evaluate the effects of treatments for beta-adrenoreceptor antagonist poisoning.Methods: Searches were conducted across MEDLINE (1946-26 November 2019, Ovid); Embase (1974-26 November 2019, Ovid); and the Cochrane Central Register of Controlled Trials (CENTRAL, to 26 November 2019) utilising a combination of subject headings and free text. The search strategy identified 15, 553 citations. Two reviewers screened titles and abstracts prior to selecting 141 articles (Kappa on articles included = 0.982, 95% CI 0.980-0.985). Primary outcomes included mortality and improvement in haemodynamic parameters (e.g., heart rate, blood pressure or a composite measure able to quantitate a haemodynamic response).Results: The risk of bias was high for all interventions.Gastric decontamination: Fifteen case reports described the administration of activated charcoal and five detailed the use of gastric lavage. As there was concurrent utilisation of multiple interventions, it was difficult to draw definitive conclusions regarding the relative contribution of these interventions to mortality or survival.Catecholamines, inotropes and vasopressors: The use of catecholamines in treating beta-blocker toxicity was reported in 16 case reports, 3 case series and 2 animal studies. These agents most likely provided a survival benefit and improved haemodynamics.Atropine: Multiple intravenous boluses of atropine were associated with improvement in heart rate and blood pressure in one case report.Calcium: Intravenous calcium was associated with an improvement in haemodynamics in three out of six case reports but in association with multiple other therapies as well as in two animal studies.High-dose insulin euglycaemic therapy: The use of this therapy was associated with mortality benefit in 10 case series. Two case reports showed clear haemodynamic improvement in a timeframe consistent with insulin administration (bolus then continuous infusion). Maintenance dosing ranged from 1 to 10 units/kg/h of insulin. However, it is unclear whether high-dose insulin euglycaemic therapy improved haemodynamic response above catecholamines and other inotropic agents in humans. Hypoglycaemia and hypokalemia were commonly observed adverse effects.Glucagon: Glucagon was associated with minor improvements in haemodynamics through an increase in heart rate in two cases series, nine case reports and five animal studies.Methylthioninium chloride (methylene blue): Four case reports reported an association with improvement in haemodynamics following administration of methylene blue but in the setting of co-ingestion with amlodipine.Intravenous lipid emulsion therapy: There was variable response to intravenous lipid emulsion therapy reported in 10 case series, 5 animal studies and 21 case reports.Lignocaine: There were four case reports showing variable response to lignocaine in arrhythmias secondary to beta-blocker toxicity.Other treatments: Fructose diphosphate, levosimendan and amrinone did not provide a mortality or significant haemodynamic benefit in three animal studies and nine case reports. .Veno-arterial extracorporeal membrane oxygenation: Veno-arterial extracorporeal membrane oxygenation was associated with improved survival in patients with severe cardiogenic shock or cardiac arrest in an observational study and four cases series.Dialysis: The evidence of four case reports suggest haemodialysis may assist in the management of massive overdose of specific water-soluble beta-blockers (e.g., atenolol) by improving elimination; however, a survival or haemodynamic benefit was not established.Pacing: One case series and a single case report showed the utility of temporary overdrive cardiac pacing to prevent arrhythmias in sotalol toxicity.Conclusions: Catecholamines, vasopressors, high-dose insulin euglycaemic therapy and veno-arterial extracorporeal membrane oxygenation were associated with reduced mortality. However, it must be acknowledged that multiple treatments were often given simultaneously. Haemodynamic improvements in blood pressure and cardiac output were seen with the use of catecholamines, vasopressin and high-dose insulin euglycaemic therapy. Evidence for treatment recommendations is almost entirely drawn from very low- to low-quality studies and subject to bias. However, it is reasonable to have a graduated response to cardiovascular instability beginning with intravenous fluids, commencement of a single or a combination of catecholamine inotropes and vasopressors depending upon the type of haemodynamic compromise (bradycardia, left ventricular dysfunction, vasodilation). High-dose insulin euglycaemic therapy can be introduced as an adjunctive inotrope and lastly, more invasive methods such as veno-arterial extracorporeal membrane oxygenation should be considered in cases unresponsive to other therapies.

Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies.

Management of cardiovascular instability resulting from calcium channel antagonist (CCB) or beta-adrenergic receptor antagonist (BB) poisoning follows similar principles. Significant myocardial depression, bradycardia and hypotension result in both cases. CCBs can also produce vasodilatory shock. Additionally, CCBs, such as verapamil and diltiazem, are commonly ingested in sustained-release formulations. This can also be the case for some BBs. Peak toxicity can be delayed by several hours. Provision of early gastrointestinal decontamination with activated charcoal and whole-bowel irrigation might mitigate this. Treatment of shock requires a multimodal approach to inotropic therapy that can be guided by echocardiographic or invasive haemodynamic assessment of myocardial function. High-dose insulin euglycaemia is commonly recommended as a first-line treatment in these poisonings, to improve myocardial contractility, and should be instituted early when myocardial dysfunction is suspected. Catecholamine infusions are complementary to this therapy for both inotropic and chronotropic support. Catecholamine vasopressors and vasopressin are used in the treatment of vasodilatory shock. Optimizing serum calcium concentration can confer some benefit to improving myocardial function and vascular tone after CCB poisoning. High-dose glucagon infusions have provided moderate chronotropic and inotropic benefits in BB poisoning. Phosphodiesterase inhibitors and levosimendan have positive inotropic effects but also produce peripheral vasodilation, which can limit blood pressure improvement. In cases of severe cardiogenic shock and/or cardiac arrest post-poisoning, extracorporeal cardiac assist devices have resulted in successful recovery. Other treatments used in refractory hypotension include intravenous lipid emulsion for lipophilic CCB and BB poisoning and methylene blue for refractory vasodilatory shock.

Characteristics of paediatric frequent presenters to an Australian emergency medicine network.

AIM: The study aims to describe the characteristics of paediatric emergency department (ED) patients defined as frequent presenters (FP) presenting to an Australian ED health service and compare these with a cohort of non-frequent presenters (NFP). METHOD: A retrospective chart review utilising an electronic emergency medicine patient medical record database was performed on paediatric patients (18 years or younger) presenting to Monash Health EDs from March 2009 to March 2010. NFPs were defined as patients presenting five or less times and FPs as presenting eight or more times in the study period. Characteristics of both groups were described and compared. RESULTS: During the 12-month study period, there were 130 paediatric FP patients with 839 admissions and 34,262 paediatric NFP patients with 46,043 admissions. FPs to the ED were more likely to be female, utilise the ambulance service to arrive at the hospital and more likely to be admitted to hospital. In particular, FPs were more likely to require admission for a mental health-related problem. They were also more likely to have a discharge diagnosis related to oncology, neurology, respiratory, endocrinology and psychiatric complaints, compared with NFP who were more likely to present with a diagnosis related to injury or trauma. CONCLUSIONS: Paediatric FPs are a vulnerable population with complex multidisciplinary care needs. A holistic approach towards their needs is essential to understanding the reasons for their higher frequency of attendance. By considering all the elements of the child's well-being, the child and family need support to assist in integration with other non-ED service providers. By focusing on wellness and self-management, there is a potential to reduce the reliance on acute emergency care for ongoing chronic health problems.

Cloning and activity of a novel α-latrotoxin from red-back spider venom.

The venom of the European black widow spider Latrodectus tredecimguttatus (Theridiidae) contains several high molecular mass (110-140 kDa) neurotoxins that induce neurotransmitter exocytosis. These include a vertebrate-specific α-latrotoxin (α-LTX-Lt1a) responsible for the clinical symptoms of latrodectism and numerous insect-specific latroinsectoxins (LITs). In contrast, little is known about the expression of these toxins in other Latrodectus species despite the fact that envenomation by these spiders induces a similar clinical syndrome. Here we report highly conserved α-LTX, α-LIT and δ-LIT sequence tags in Latrodectus mactans, Latrodectus hesperus and Latrodectus hasselti venoms using tandem mass spectrometry, following bioassay-guided separation of venoms by liquid chromatography. Despite this sequence similarity, we show that the anti-α-LTX monoclonal antibody 4C4.1, raised against α-LTX-Lt1a, fails to neutralize the neurotoxicity of all other Latrodectus venoms tested in an isolated chick biventer cervicis nerve-muscle bioassay. This suggests that there are important structural differences between α-LTXs in theridiid spider venoms. We therefore cloned and sequenced the α-LTX from the Australian red-back spider L. hasselti (α-LTX-Lh1a). The deduced amino acid sequence of the mature α-LTX-Lh1a comprises 1180 residues (∼132kDa) with ∼93% sequence identity with α-LTX-Lt1a. α-LTX-Lh1a is composed of an N-terminal domain and a central region containing 22 ankyrin-like repeats. The presence of two furin cleavage sites, conserved with α-LTX-Lt1a, indicates that α-LTX-Lh1a is derived from the proteolytic cleavage of an N-terminal signal peptide and C-terminal propeptide region. However, we show that α-LTX-Lh1a has key substitutions in the 4C4.1 epitope that explains the lack of binding of the monoclonal antibody.

Spiders of medical importance in the Asia-Pacific: atracotoxin, latrotoxin and related spider neurotoxins.

1. The spiders of medical importance in the Asia-Pacific region include widow (family Theridiidae) and Australian funnel-web spiders (subfamily Atracinae). In addition, cupboard (family Theridiidae) and Australian mouse spiders (family Actinopodidae) may contain neurotoxins responsible for serious systemic envenomation. Fortunately, there appears to be extensive cross-reactivity of species-specific widow spider antivenom within the family Theridiidae. Moreover, Sydney funnel-web antivenom has been shown to be effective in the treatment of mouse spider envenomation. 2. alpha-Latrotoxin (alpha-LTx) appears to be the main neurotoxin responsible for the envenomation syndrome known as "latrodectism" following bites from widow spiders. This 120 kDa protein binds to distinct receptors (latrophilin 1 and neurexins) to induce neurotransmitter vesicle exocytosis via both Ca2+-dependent and -independent mechanisms, resulting in vesicle depletion. This appears to involve disruption to a process that normally inhibits vesicle fusion in the absence of Ca2+. Precise elucidation of the mechanism of action of alpha-LTx will lead to a major advancement in our understanding of vesicle exocytosis. 3. delta-Atracotoxins (delta-ACTX) are responsible for the primate-specific envenomation syndrome seen following funnel-web spider envenomation. These peptides induce spontaneous repetitive firing and prolongation of action potentials in excitable cells. This results from a hyperpolarizing shift of the voltage-dependence of activation and a slowing of voltage-gated Na+ channel inactivation. This action is due to voltage-dependent binding to neurotoxin receptor site-3 on insect and mammalian voltage-gated Na+ channels in a manner similar, but not identical, to scorpion alpha-toxins and sea anemone toxins. delta-Atracotoxins provide us with highly specific tools to study Na+ channel structure and function 4. omega- and Janus-faced ACTX, from funnel-web spider venom, are novel neurotoxins that show selective toxicity to insects. In particular omega-ACTX define a new insecticide target due to a specific action to block insect voltage-gated Ca2+ channels. Both these ACTX show promise for the development of baculoviral recombinant biopesticides expressing these toxins for the control of insecticide-resistant agricultural pests. In addition, they should provide valuable tools for the pharmacological and structural characterization of insecticide targets.

Clinical and in vitro evidence for the efficacy of Australian red-back spider (Latrodectus hasselti) antivenom in the treatment of envenomation by a Cupboard spider (Steatoda grossa).

We report the case of a 22-year-old female who was bitten on the shoulder by a spider subsequently identified as a female Cupboard spider (Steatoda grossa). She developed nausea, vomiting, and severe local and regional pain, similar to that seen in latrodectism. Symptoms were treated successfully with red-back spider antivenom (RBSAV). We also present in vitro data, which supports this clinical observation, and suggests that S. grossa venom is immunogenically reactive with both RBSAV and latrotoxin (LTx)-specific antibodies by Western blotting. Moreover, the effects of S. grossa venom on the isolated chick biventer cervicis nerve-muscle preparation are dose-dependent and similar to those seen with Latrodectus spp. venoms. S. grossa venom produced a sustained muscle contracture which could be prevented by pre-incubation of venom with RBSAV. Venom effects could also be reversed by the addition of antivenom after application of venom to the preparation. Although severe envenomation is uncommon following the bite of Steatoda spp. it may resemble latrodectism. These results indicate that RBSAV is likely to be effective in reversing symptoms of envenomation and should be considered in the treatment of patients with distressing or persisting symptoms.