Miscellaneous agent toxicity

Arsenic

• Mostly arsenic trioxide (inorganic) form in commercially-available form
• Acute ingestion – Severe GI with sequential MODS
• Subacute exposures from industrial accidents, food contamination and herbal medicines
• Chronic intoxication usually from contaminated artesian water (>10 years)
• Organic arsenoids in seafood are non-toxic
• Risk assessment
  • Ingestion >1mg/kg is potentially lethal
  • Ingestion <0.05mg/kg may be mild and self-limiting GI upset

• Toxic mechanism
  • Interferes with cellular respiration and inhibits DNA replication/repair
  • Produces reactive oxygen intermediates leading to lipid peroxidation
  • Binds to sulfhydryl groups and substitutes for phosphate in ATP
• Toxicokinetics
  • Absorbed via dermal, respiratory and GI routes

• Clinical features
  • Acute intoxication
    • Rice water diarrhoea, vomiting, abdominal pain
    • Encephalopathy, seizures, coma within hours
    • Hypersalivation and garlic odour are characteristic
    • Prolonged QT and dysrhythmias
    • ARDS, renal injury and hepatic injury follow
    • Bone marrow suppression within 24-72 hours, nadir at 2-3 weeks
    • Peripheral neuropathy within 1-3 weeks mimicking GBS
  • Subacute toxicity
    • GI symptoms, leukopaenia, LFT derangement and haematuria
    • Peripheral neuropathy over weeks
  • Chronic toxicity
    • Constitutional symptoms, hyperkeratosis palms/soles, hyperpigmentation, Mees’ lines on nails, painful peripheral neuropathy (glove-stocking) and malignancy of skin/bladder
• Ix
  • Spot urinary arsenic confirms ingestion
  • 24 hour urinary arsenic reflects total burden

• Management
  • Resus and fluid replacement given GI losses
• Decontamination 
  • AC does not bind arsenic
  • WBI if inorganic arsenic confirmed on  AXR
• Enhanced elimination n/a
• Antidotes
  • Succimer PO
  • Dimercaprol IM

Baclofen

• Risk assessment
  • Ingestions >200mg in adults cause significant CNS depression, delirium, respiratory depression, coma and seizures
• Toxic mechanism
  • Synthetic GABA derivative
  • Acts mainly on spinal GABA-B receptors to inhibit release of excitatory amino acids (Glutamate and aspartate)
  • In overdose, brain GABA receptors are stimulated leading to sedation/coma
  • Also mediates pre- and post-synaptic inhibition, causing seizures in overdose
• Toxicokinetics
  • Rapidly and completely absorbed
  • Peak serum levels at 2 hours
  • Readily cross BBB
  • Vd 0.7L/kg
  • 15% metabolised by liver and renally excreted with half-life 3.5 hours

Baclofen

• CNS: Delirium, respiratory depression, profound coma, seizures (may resemble brain death)
• CVS: Sinus bradycardia or tachy, hypertension or hypo, 1^st degree heart block and rarely QT prolongation
• May have absent brainstem reflexes
• Duration of coma 24-48 hours
• Management
  • Usual supportive care, treat seizures with benzos, fluids for hypotension
  • AC not indicated unless intubated
  • Enhanced elimination n/a
  • Antidotes n/a

• Disposition
  • Monitor for at least 4 hours
• Handy tips
  • Consider in any patient presenting with coma
  • Intrathecal pumps can deliver small bolus resulting in profound coma
  • Withdrawal syndrome is seen 24-48 hours after cessation with seizures, hallucinations, dyskinesia and visual disturbances
• Pitfall
  • Failure to reinstitute therapeutic baclofen following recovery from overdose with subsequent withdrawal syndrome and seizures (may be mistaken for ongoing toxicity)
• Management of intrathecal overdose
  • All above + remove any from reservoir and perform LP removing 30-50mL of CSF

Benztropine

• Used for patients on antipsychotics to ameliorate dyskinaesias
• Potent anticholinergic in overdose
• Sometimes used recreationally for this purpose
• Risk assessment
  • Any overdose is likely to cause anticholinergic syndrome
• Synthetic drug containing tropine component of atropine and diphenylmethyl component of diphenhydramine (antihistamine)
• Anticholinergic, antihistaminergic and dopamine reuptake inhibitor
• Management is supportive + AC if within 2 hours +- physostigmine
• Delirium may persist for days
• Insert IDC as soon as possible as retention is almost universal in anticholinergic delirium
• Pitfalls
  • Missed urinary retention
  • Failure to differentiate from underlying psychosis or antisocial personality disorder

Button batteries

• Majority pass through without complication
• Larger batteries may lodge in oesophagus with potential fatality
• Risk assessment
  • <20mm diameter unlikely to lodge in oesophagus
  • >20mm are likely to and then cause severe corrosive damage within 2 hours
  • Local corrosion can also occur with smaller batteries in aural and nasal cavities
  • Most severe injuries occur in under 4 yo
  • Heavy metal contents not enough to cause toxicity
  • New battery worse than spent battery but even a spent one may carry enough charge to cause corrosive injury

• MOI:
  • Hydroxide ion formation at negative pole caused by current in adjacent tissue
  • Localised alkaline injury with liquefactive necrosis
  • Potential complications include oesophageal perforation, tracheo-oesophageal fistula, aorto-oesophageal fistula and stricture formation
• Consider in any child with airway obstruction, cough, fever, dysphagia, sore throat, chest discomfort, reduced oral intake, or coughing/choking with eating or drinking
• Management
  • If lodged in oesophagus – Endoscopic removal, ideally within 2 hours of ingestion
  • Beyond pylorus in asymptomatic child – can pass naturally
  • If still in stomach
    • Repeat X-rays at 4 days if 15-20mm with endoscopic retrieval if not passed in that time frame
    • Smaller batteries can be managed expectantly at home without repeat X-rays
  • Magnet co-ingestion prompts immediate endoscopy no matter where the battery is

• Pitfalls
  • Failure to perform X-rays in non-specific presentations
  • Mistaking a button battery for a coin on X-ray (distinctive appearance)
    • Lateral X-ray may help
  • Delayed referral to endoscopist

Carbon monoxide

• Common cause of poisoning death
• Risk assessment attempts to identify those at risk of myocardial injury and long-term neuropsychiatric sequelae
• Acute deliberate poisoning usually involves high partial pressures of CO for short period of time – less risk of long-term sequelae in survivors
• Accidental occupational or domestic poisoning involves low partial pressures for prolonged duration – high risk of long-term sequelae in survivors

• High-risk features for long-term issues
  • Significant LOC or coma
  • Persistent neurological dysfunction (e.g. confusion)
  • Abnormal cerebellar examination
  • Metabolic acidosis
  • Myocardial ischaemia
  • Age >55
• Outcome is poorly correlated with COHb level

• Pregnancy: Fetus Hb binds CO more avidly and so is more at risk
• Toxic mechanism
  • 210x affinity for Hb than O2 with resultant tissue hypoxia
  • CO also binds to intracellular cytochromes
  • CO also initiates endothelial oxidative injury, lipid peroxidation and inflammation
• Toxicokinetics
  • Elimination half-life depends on PaO2
    • Room air: 240min
    • 100% O2: 90 min
    • 100% O2 at three atm: 23 min

• Clinical features
  • Usually headache, nausea and altered mentation that rapidly improve with O2
  • CNS: Headache, nausea, dizziness, confusion, poor concentration, ataxia, seizures, coma
  • CVS: Tachy, hypertension, ischaemic ECG, hypotension, dysrhythmias, acute MI
  • Resp: Non-cardiogenic pulmonary oedema
  • Metabolic: Lactic acidosis, rhabdo, hyperglycaemia
  • Other: DIC, bullae, alopecia, sweat gland necrosis, cherry red skin (severe toxicity)

• Persistent neurological sequelae
  • Evident from time of poisoning and seen in 30% of survivors at 1 month
• Neuropsychiatric sequelae
  • 6-10% at 12 months
  • Personality changes, poor concentration, dementia, psychosis, parkinsonism, ataxia, peripheral neuropathy and hearing loss

• Specific investigations
  • COHb
    • Confirms diagnosis and loosely correlates to symptoms shortly after exposure
    • If already received oxygen therapy, poor correlation
    • <10% – Background level in smoker
    • 10% – Asymptomatic, slight headache
    • 20% – Dizziness, nausea, dyspnoea, throbbing headache
    • 30% – Vertigo, ataxia, visual disturbance
    • 40% – Confusion, coma, seizures, syncope
    • 50% – Cardiovascular and respiratory failure, dysrhythmia, seizures

• Investigations
  • ABG
  • FBC
  • EUC
  • Troponin
  • Beta-hCG
  • MMSE
  • CT brain – Cerebral oedema/atrophy, basal ganglia injury or cortical demyelination

• Supportive care
• High-flow O2 until all symptoms resolved and for at least 8 hours
• Pregnant patients remain on for 24 hours while fetal wellbeing assessed
• Hyperbaric oxygen
  • For patients with one or more high risk factors and all pregnant patients (consider)
• Need follow-up in 1-2 months for neuropsychiatric testing
• Pitfalls
  • Failure to chase source and other potential victims in accidental exposure
  • Failure to diagnose accidental exposure in those with headache or non-specific symptoms
  • Failure to perform detailed neurological examination and MMSE

• Hyperbaric O2
  • Accelerates COHb dissociation, increases dissolved O2, may reverse effects on cytochrome c, reduces cerebral oedema through vasoconstrictive effect
  • May decrease neuropsychiatric sequelae in mild-moderate poisoning
  • Indications
    • Within 6 hours of poisoning most benefit
    • ALOC of no other cause
    • COHb >20% in adults (>15% in pregnant or children/elderly)
    • Unexplained metabolic acidosis (BE >-2)
    • ECG evidence of myocardial toxicity

• Alfred study
  • Randomised control trial – no benefit compared to 48 hours 100% O2 on neuropsychiatric sequelae
  • Criticisms
    • 50% loss of follow-up however
    • Severely poisoned only
    • Very high incidence of cognitive impairment cf other studies
    • Practical limitations on 48 hours of continuous 100% O2

• The Salt Lake City trial
  • Methodologically vigorous with sham HBO2, 150 patients over 7 years
  • Very high level of follow-up
  • Trial stopped early by safety committee due to significant benefit
  • Halved cognitive impairment at 6 weeks and 6 months
  • Criticisms
    • Higher level of cerebellar dysfunction in control group at randomization
    • 1/3 suicide attempts vs. 2/3 accidental from heaters (quite different to Australian population)

Chloroquine/hydroxychloroquine

• Quinolone-related antimalarials
• Most toxic antimalarials in overdose
• Rapid hypotension, CNS depression, cardiac conduction defects and hypokalaemia
• Risk assessment
  • >10mg/kg of chloroquine is potentially lethal
  • >30mg/kg predicts serious toxicity and increasing mortality
  • >5g chloroquine is usually fatal without intervention
  • Children: One tablet may be lethal

• Toxic mechanism
  • CNS voltage-gated Na channel blockade + cerebral hypoperfusion from systemic hypotension
  • Multiple inward and outward membrane currents blocked in heart
  • Hypotension and cardiogenic shock due to direct cardiodepressant effect
• Clinical features
  • Rapid onset within 1-2 hours of hypotension, QRS/QT prolonging, cardiac arrest, reduced conscious state, seizures and hypokalaemia (intracellular shift)
• Management
  • Treat broad-complex tachycardias as for TCA
  • Treat seizures with benzodiazepines
  • High-dose diazepam 0.5mg/kg IV bolus then 1mg/kg IV over 24 hours post-intubation has potential protective effect
  • Activated charcoal after intubated

• Handy tips
  • Predict catastrophic deterioration in all patients who present early
    Intubate and hyperventilate at the first sign of clinical deterioration or cardiac toxicity
  • Avoid over-enthusiastic replacement of K as whole body K is not depleted
    • Target 3.0
  • Level of hypokalaemia strongly correlates with toxicity

Chloral hydrate

• Used as a sedative for children undergoing procedures
• Very narrow therapeutic window
• Causes CNS depression and cardiac dysrhythmias in overdose
• Appears to sensitise myocardium to catecholamines
• Treatment
  • Immediate I&V
  • Beta-blockers metoprolol 5mg IV (0.1mg/kg) by slow IV injection q5min for cardiac tachydysrhythmias
  • Esmolol infusion can be used and titrated to response
  • Catecholamines are contraindicated in hypotension as highly dysrhythmogenic in this setting. Fluids are key
  • Upper GI endoscopy in large oral overdoses to assess for mucosal damage

• TdeP rarely responds to Mg or overdrive pacing. Needs beta-blockers
• Consider haemodialysis if refractory dysrhythmias and instability
• Pitfalls
  • Catecholamine use for hypotension
  • Failure to use beta-blockers for ventricular dysrhythmias

Colchicine

• Severe GI upset followed by MODS
• Aggressive decontamination and supportive care required to prevent death
• Risk assessment
  • <0.5mg/kg – GI symptoms
  • 0.5-0.8mg/kg – Systemic toxicity including bone marrow suppression. 10% mortality
  • >0.8mg/kg – Severe cardiovascular collapse, coagulopathy, renal failure. Near 100% mortality
  • Children – any symptomatic child needs assessment. One or two tabs okay.

• Toxic mechanism
  • Found in autumn crocus and glory lily
  • Binds tubulin and prevents microtubule formation to inhibit mitosis
  • Tissues with high cellular turnover are preferentially targeted in OD
• Toxicokinetics
  • Rapidly absorbed, peak levels at 1.5-2 hours. BA 45% due to extensive first-pass metabolism
  • Extensively tissue bound. Vd 2L/kg
  • Hepatic metabolism
  • Half-life up to 30 hours in overdose

• Phases
  • 2-24 hours: Nausea, vomiting, abdo pain, severe GI losses, peripheral leukocytosis
  • 2-7 days: Pancytopaenia, rhabdo, AKI, progressive metabolic acidosis, respiratory insufficiency, ARDS, cardiac dysrhythmias and risk of sudden cardiac death
  • >7 days: Rebound leukocytosis, transient alopecia. Complete recovery expected if survived to this point
• Management
  • Aggressive supportive care
• Decontamination
  • AC as soon as possible to any patient who has ingested >0.5mg/kg
  • Prevention of even small amount of absorption may be lifesaving
• Enhanced elimination
  • MAC not shown to affect outcome and not routinely recommended

• Disposition
  • If no GI symptoms at 24 hours, can be discharged
• Handy tip
  • Admit ALL colchicine overdoses and early transfer to ICU if >0.5mg/kg ingested or any symptoms
• Pitfalls
  • Failure to identify ingestion at presentation
  • Failure to anticipate severity

Corrosives

• Alkalis: Ammonia, potassium hydroxide, sodium hydroxide, sodium hypochlorite
• Acids: Hydrochloric acid, sulfuric acid
• Other: Paraquat, glyphosate, phenols, potassium permanganate, mercuric chloride, zinc chloride
• Upper airway and GI tract injury with upper airway involvement a life-threatening emergency
• Endoscopy and CT used to stratify risk for delayed sequelae

• Risk assessment
  • Ingestion of concentrated sulfuric acid, sodium hydroxide and solid preparations are associated with severe corrosive injuries to pharynx, upper airway, oesophagus and stomach but NOT associated with systemic toxicity
  • Stridor, dyspnoea, dysphonia or throat pain indicate airway injury and immediate life threat
  • Significant gastro-oesophageal injury indicated by any two of: Stridor, drooling, vomiting
  • Ingestion of >60mL of hydrochloric acid leads to severe stomach and duodenal injury with necrosis, perforation, severe MODS and is usually fatal
  • <150mL of household bleach with dilute sodium hypochlorite does not usually cause significant corrosive injury
  • Absence of lip or oral burns does not rule out significant injury
    • 10-15% of oesophageal burns have no oral burns
    • If oral burns are present, 1/3 have oesophageal burns
  • Alkalis cause more oesophageal burns vs. acids gastric burns
  • Severe systemic toxicity expected for: Paraquat, Glyphosate, mercuric chloride, potassium permanganate and zinc

• Risk assessment
  • Children: Household drain/oven cleaner or automatic dishwasher powder can cause severe corrosive injury
    • Household bleach usually okay
  • Keep all symptomatic children NBM
• Clinical features
  • 30% of Grade IIB or III injury develop oesophageal stricture
  • Grade II and III injuries are associated with oesophageal carcinoma 40-50years later
  • Look for signs of upper GI, upper airway injury and peritonism

• Persistent vomiting, oral burns, drooling or abdominal pain
  • Need endoscopy or CT to risk stratify immediate risk of perforation and later risk of stricture
  • Endoscopic grading
    • 0 – Normal
    • I – Mucosal oedema and hyperaemia
    • IIA – Superficial ulcers, bleeding and exudates
    • IIB – Deep focal or circumferential ulcers
    • Grade IIIA – Focal necrosis
    • Grade IIIB – Extensive necrosis

• CT grading
  • O – Normal appearance
  • I – Oedematous wall thickening
  • II – Grade I + soft tissue infiltration
  • III – II + air bubbles in organ wall, free mediastinal or peritoneal air or fluid collection
• Management
  • Early intubation if evidence of injury
  • Avoid use of agents to neutralise the corrosive substance
  • Do not insert an NG until after endoscopy
  • Supportive measures, analgesia, NBM until imaging/endoscopy
  • Broad-spectrum antibiotics only if perforated
  • Urgent surgical intervention if full thickness necrosis or perforation
  • Can rinse mouth as immediate first-aid measure. Do not drink.
  • VBG as can get systemic acidaemia/alkalaemia

• Disposition
  • If asymptomatic and tolerating fluids at 4 hours can be discharged
  • Symptomatic patients remain NBM and are monitored for 24 hours with endoscopy performed as inpatient
    • 14% of acid ingestions had high-grade injuries
    • 2.9% of alkaline ingestions had high-grade injuries
    • Intentional ingestions have higher rates of high-grade injuries
    • Drooling, dysphagia, vomiting and pain are all markers of high-grade injury
    • 65% of those with high-grade lesions have oral lesions
      • PPV 0.71; NPV 0.81; sensitivity 0.43; specificity 0.93
    • If no symptoms, NPV of 1 for severe oesophageal injury (Lamireau et al.)
  • Bonnici advise to avoid endoscopy in asymptomatic adults with no clinical signs and to be more cautious in children with extended period of observation if decision made to avoid endoscopy initially
  • If no symptoms or signs after ingestion of commercial agent and able to eat/drink can be discharged

• PPI/H2-receptor antagonists
  • No controlled studies
  • Advise high-dose PPI based on case series of 13 adult patients
• Handy tips
  • Symptoms and signs correlate poorly with extent of injury
  • Stridor, dysphonia or dysphagia warrant urgent intubation
• Pitfall
  • Delaying endoscopy or CT beyond 24 hours of injury

• Endoscopy vs. CT
  • Endoscopy was gold standard and often performed 12-24 hours post-ingestion for injury to ‘mature’
  • Guidelines suggest waiting until day 5-15 risks perforation given maximal weakness in tensile strength occurs at this stage
  • Ryu et al. retrospectively studied ability of CT to predict longer-term complications of corrosives including likelihood of stricture formation
    • CT better than endoscopy in predicting stricture formation
  • Lurie et al. examined shorter-term value in predicting mortality and emergency laparotomy
    • CT less sensitive than endoscopy in predicting mortality or need for surgery
    • Only 23 patients covered
  • CT underestimates injury in early phase
  • CT has lower sensitivity and higher specificity for major outcome prediction
  • CT may be safer
  • Endoscopy should remain procedure of choice (Bonnici et al. 2014) given lack of evidence and insensitivity in predicting mortality / emergency laparotomy

Cyanide

• Rare but lethal
• Risk assessment
  • Ingestion of cyanide salts or inhalation of hydrogen cyanide. Death is likely before hospital arrival
  • Lethal dose 50mg hydrogen cyanide or 200mg potassium cyanide
  • Ingestion of acetonitrile can lead to delayed (up to 24 hours) life-threatening cyanide toxicity
  • Amygdalin (cyanogenic-containing plant material e.g. apricot seeds) is rarely ingested in sufficient doses for serious poisoning to occur
  • Chronic occupational intoxication leads to headache and fatigue

• Toxic mechanism
  • Binds to ferric ions (Fe3+) of cytochrome oxidase to inhibit oxidative metabolism, leading to lactic acidosis
  • Stimulates release of biogenic amines leading to pulmonary and coronary vasoconstriction
  • In CNS triggers neurotransmitter release (NMDA) leading to seizures
• Toxicokinetics
  • Absorption – Rapidly absorbed and taken up into cells
  • Distribution – Highly protein bound 1.5L/kg Vd
  • Metabolism – Hepatic transfer of sulfane sulfur to cyanide forming thiocyanate (non-toxic and excreted in urine)
  • Elimination – Cyanide elimination half-life 2-3 hours
  • **Acetonitrile undergoes hepatic metabolism in vivo to cyanide slowly with conversion half-life >30 hours

• Clinical features
  • Acute inhalation of hydrogen cyanide produces LOC within seconds
  • Acute ingestion of cyanide salts leads to symptoms in minutes
  • Nausea, vomiting, headache, dyspnoea, tachypnoea, hypertension, tachycardia, agitation, collapse and seizures
  • Progressive hypotension, bradycardia, confusion, tetany, drowsiness, respiratory depression and coma
  • Delayed parkinsonism seen months after survival
• Ix
  • ABG: Serum lactate strongly correlates with severity of intoxication
  • In smoke inhalation victims without severe burns, lactate >10 confers sensitivity of 87%, specificity of 94% and PPV of 95% for cyanide level >40micromol/L
  • Cyanide levels just confirm diagnosis in retrospect. Take samples into heparinised tubes before antidotes provided

• Management
  • Immediate intubation and ventilation 100% O2 in severe poisoning
  • Decontamination
    • Removal from source of hydrogen cyanide gas is crucial
    • Remove clothes and wash with soap and water (bag clothes)
    • Resuscitation takes priority and AC only after intubation
• Antidotes
  • Hydroxocobalamin is preferred agent
  • Thiosulfate
  • Dicobalt edetate (most common in Australia)

• Hydroxocobalamin
  • Vitamin B12 precursor that chelates cyanide in high-doses
  • Cobalt ion bound by hydroxyl group at centre with high affinity for cyanide
  • Forms cyanocobalamin, which is non-toxic and excreted in urine
  • Reconstitute 2.5g (1 ampoule) in 100mL N/S IV over 15 minutes
  • Repeat with second kit
  • Should bind 100mg cyanide (need more if initial dose larger than this)
  • If no improvement within 15 minutes, repeat or administer sodium thiosulfate
  • End-points: Improvement in conscious state, haemodynamic stability, improved metabolic acidosis

• Hydroxocobalamin
  • Adverse reactions: Minor hypertension, bradycardia, tachycardia, orange-red discolouration of the skin/mucous membranes/urine/plasma for 12-48 hours
  • Handy tips
    • Failure to improve after first dose should prompt reconsideration of diagnosis

• Sodium thiosulfate
  • Enhances endogenous cyanide detoxification
  • Can use alone for mild to moderate cyanide toxicity but should be used with hydroxocobalamin in severe cases
  • Acts as a sulfur donor to rhodanese enzyme in order to enhance conversion of cyanide to thiocyanate
  • 12.5g (50mL 25% solution) IV over 10 minutes repeated after 30 minutes if toxicity continues
  • Minor adverse effects only
  • Valuable in doubtful cases (e.g. smoke inhalation) as has both therapeutic and diagnostic value

• Dicobalt edetate
  • Severe toxic effects if NOT cyanide poisoning limits use
  • Inorganic cobalt salt that forms cobalt-cyanides that are far less toxic
  • 300mg IV over 1 minutes followed by 50mL 50% dextrose IV to protect against toxicity
  • Can repeat up to 2x if immediate response not observed
  • Cobalt toxicity if no cyanide present results in seizures, facial/neck oedema, chest pain, dyspnoea, hypotension, vomiting and urticaria

• Disposition
  • If well at 4 hours – discharge
  • If acetonitrile ingestion need 24 hour observation
• Handy tips
  • Consider in sustained lactic acidosis in patient presenting following collapse
• Pitfalls
  • Failure to recognise cyanide intoxication
  • Inability to access antidotes
  • Failure to provide antidotes early while awaiting cyanide levels

Glyphosate

• Widely used herbicide
• Severe toxicity in intentional ingestion of concentrated formulations
• GI corrosive damage and severe metabolic acidosis, hyperkalaemia and cardiovascular collapse
• Dose-related symptoms
  • <50mL 100% concentrate – Asymptomatic or minor GI
  • 50-150mL 100% concentrate – GI symptoms only
  • >150mL 100% concentrate – Severe GI, risk of early upper airway swelling, metabolic acidosis, hyperkalaemia, hypotension
  • >300mL 100% concentrate – Potentially fatal with refractory shock

• Risk assessment
  • Acute corrosive injury to upper airway is the imminent threat to life
  • Risk factors for poor outcome
    • Abnormal CXR
    • Older age
    • Tachycardia
    • Metabolic acidosis
    • Hyperkalaemia
    • Acute renal impairment
  • Dilute ingestions post minimal risk and cutaneous exposures only cause local irritation
  • Children: Minor ingestions do not need hospital assessment unless symptomatic

• Toxic mechanism
  • Surfactant effect and effects of co-formulants
  • Does NOT inhibit cholinesterase enzymes
  • May involve cellular membrane disruption and uncoupling of mitochondrial oxidative phosphorylation
  • Direct corrosive injury when ingested
• Toxicokinetics
  • Poorly but rapidly absorbed with peak levels at 4-6 hours
  • Not metabolised
  • Excreted unchanged by kidneys half-life 4-6 hours

• GI – Corrosive, nausea, vomiting, diarrhoea, abdo pain. Grade III injuries NOT reported
• CVS – Myocardial depression, hypotension, cardiovascular collapse
• Respiratory – Upper tract irritation and drooling, aspiration pneumonitis, non-cardiogenic pulmonary oedema
• Metabolic – Hyperkalaemia, metabolic acidosis
• Investigations
  • Bloods, ABG, CXR
  • Endoscopy/CT chest not routine as severe injury unusual

• Supportive resuscitation
• If unresponsive to fluid boluses, may require vasopressors
• Decontamination not indicated
• Enhanced elimination – Useful if complicated by severe metabolic acidosis/AKI
• Antidotes n/a
• Disposition
  • If well at 4 hours, discharge
  • If >150mL 100% concentrate, admit to ICU pending MODS
• Handy tip
  • Intubate early if stridor develops
• Pitfalls
  • Failure to appreciate potential for cardiovascular collapse
  • Confusion with organophosphate poisoning

Hydrocarbons

• Aliphatic: Essential oils (eucalyptus oil), kerosene, petrol, turpentine
• Aromatic: Benzene, toluene, xylene
• Halogenated: Carbon tetrachloride, methylene chloride, tetrachloroethylene, trichloroethylene
• Can be ingested or inhaled leading to rapid CNS depression, seizures and rarely cardiac dysrhythmias
• Aspiration can lead to chemical pneumonitis
• Long-term occupational exposure can cause other end-organ damage

• 1-2mL/kg of petroleum distillates causes systemic toxicity
• As little as 10mL of eucalyptus oil or other essential oils can lead to seizures and CNS depression, always within 1-2 hours
• Aspiration pneumonitis can develop over hours
• Large or prolonged inhalational exposure can result in asphyxia
• High-viscosity compounds e.g. vaseline or motor oil have very low risk of systemic toxicity
• Children
  • 5mL of essential oil can cause rapid onset of coma

Hydrocarbons

• Toxic mechanism
  • Disruption of lung surfactant leads to aspiration pneumonitis
  • CNS depression of unclear cause
  • Dysrhythmias are due to increased catecholamine sensitisation of myocardium
  • Negative inotropic effects of unclear cause
  • Chlorinated hydrocarbons are metabolised to a hepatotoxic metabolite
• Toxicokinetics
  • Absorption following inhalation is determined by concentration, duration of exposure and minute ventilation
  • Absorption following ingestion is inversely related to the MW of the hydrocarbon
  • Minimal absorption from dermal exposure
  • Mostly eliminated unchanged in expired air

• Clinical features
  • Respiratory
    • Wheeze, tachypnoea, hypoxia, haemoptysis and pulmonary oedema herald pneumonitis
    • Typically worsens over 24-72 hours and resolves over 5-7 days
  • CVS – Dysrhythmias pre-hospital
  • Neuro 
    • Profound CNS depression, coma and seizures within 2 hours
    • Chronic toluene exposure causes ataxia, dementia and peripheral neuropathy
  • GI: Nausea and vomiting
  • Other:
    • Hepatic and renal injury in carbon tetrachloride poisoning
    • Toluene is nephrotoxic
    • Benzene can cause haemolysis and leukaemia

• Resus and supportive care
• If VT/VF:
  • ACLS
  • Metoprolol 5mg IV, correct K and Mg and withold catecholamines if possible
• Manage seizures with benzos
• Supportive care of pneumonitis
• Withhold antibiotics until objective evidence of pulmonary sepsis vs. pneumonitis
• Decontamination
  • Remove patient from exposure, remove clothing and wash
  • Activated charcoal does NOT bind hydrocarbons
• Enhanced elimination n/a
• Antidote n/a

• Disposition
  • Children suspected of ingestion can be observed at home. Any respiratory symptoms warrant hospital presentation
  • Clinically well at 6 hours can be discharged
  • High-pressure injection injuries need surgical referral for debridement
• Handy tip
  • Coughing or gagging after ingestion suggests aspiration
• Pitfall
  • Failure to recognise dry cough as a symptom of pneumonitis

Hydrofluoric acid

• Risk assessment
  • Life-threatening if:
    • Dermal exposure > 2.5% BSA of 100% HF
    • 8% BSA with 70% HF solution
    • 11% BSA with 23% HF solution
    • Ingestion >100mL of 6% HF solution
    • Ingestion of any volume of higher concentration HF solution
  • Children: Any ingestion of any concentration is potentially lethal
• Toxic mechanism
  • Fluoride ions bind calcium and Mg directly + interfere with K channels
  • Systemic toxicity and ventricular dysrhythmias due to hypocalcaemia, hyperkalaemia, hypomagnesaemia and acidosis

• Clinical features
  • Dermal exposure
    • If <50% concentration, not immediately painful and may be unnoticed for hours
    • Then severe, deep unremitting pain without obvious erythema or blistering
    • Pallor and blanching after hours
    • Blistering and tissue loss over days
    • Pain 24-36 hours duration
  • Inhalational exposure
    • Immediate mucosa irritation with delayed wheeze, dyspnoea and cough
    • Non-cardiac pulmonary oedema in severe cases
  • Ingestion
    • <20% concentration minimally corrosive
    • Vomiting, mild throat pain dysphagia and abdominal pain
    • Cardiac arrest from 30 minutes to 6 hours if systemic fluorosis
  • Fluorosis
    • Tetany and prolonged QT (hypoCa and hypoMg)
    • Ventricular dysrhythmias and cardiac arrest

• Ix
  • Q2h ECG’s
  • Q4h iCa/Mg
  • Endoscopy if ingestion but only once stable
• If ventricular dysrhythmias
  • ACLS, intubate and ventilate
  • 60mL calcium gluconate (0.6mL/kg) or 20mL calcium chloride (0.2mL/kg) IV every 5 minutes until ROSC
  • Sodium bicarbonate 100mmol IV (3mmol/kg IV) – not in the same line as calcium as precipitates
  • MgSO4 10mmol (0.05mmol/kg) iV

• Antidotes
  • Calcium gluconate gel to topical burns (10mL calcium gluconate in 30mL lubricant)
  • Calcium gluconate subcutaneously, Bier’s or intra-arterial infusion (NOT CALCIUM CHLORIDE)
    • 0.5mL/cm3 SC (not on fingers)
    • 10mL in 40mL N/S as Bier’s block and release cuff after 20 minutes
    • 10mL in 40mL N/S intra-arterial infusion over 4 hours
  • Nebulised 2.5% calcium gluconate solution for inhalational injury
• Follow-up in Burns clinic

• Handy tips
  • The less concentrated the product, the longer the delay in symptoms
  • Pain out of proportion to local signs
  • Parenteral opioids effective until calcium organised
  • LA techniques contraindicated as pain is used as a surrogate marker for adequate calcium delivery
  • Do not use calcium gluconate to irrigate eyes (just use water or saline)

Hydrogen peroxide

• Risk assessment
  • <30mL of 3% H2O2 causes mild GI upset only
  • Larger volumes risk corrosive injury and gas embolism
  • >10% concentration risks significant life-threatening corrosive injury and gas embolism
  • >10% solution to eye risks permanent corneal damage
  • >10% solution to skin causes dermal corrosive injury
  • Children: Any solution >10% concentration or where symptomatic warrants hospital assessment

• Toxic mechanism
  • Direct corrosion
  • Oxygen gas formation: Metabolism liberates O2 and once this exceeds maximal solubility in blood, gas bubbles form leading to embolism
  • Direct cytotoxic lipid peroxidation
• Toxicokinetics
  • Following ingestion, H2O2 readily absorbed into portal venous system where it is rapidly metabolised by catalases in red cells to yield O2 and water. 30mL of 35% H2O2 liberates 3.5L of O2

• Clinical features
  • Ingestion
    • Corrosive injury and foaming at mouth
    • Blistering, stridor, laryngospasm and respiratory arrest
    • Tachycardia, lethargy, confusion, coma, seizures and cardiac arrest can occur within minutes of >10% concentration
    • Painful gastric distension and belching
    • Progressive neurological deterioration in the event cerebral oxygen gas embolism
  • Inhalation – Cough and dyspnoea
  • Dermal – Corrosive injury
  • Ocular – Corneal ulceration and perforation with concentrated solutions

• Investigations
  • Chest and AXR can show gas embolism
  • CT brain to show gas embolism
  • Upper GI endoscopy if significant corrosive injury suspected and >10% solution ingested
• Management
  • Early aggressive airway management if ingested >10% solution
  • High-flow oxygen to all patients
  • Hyperbaric oxygen for cerebral air embolism
  • Water for decontamination of any affected area

• Pitfall
  • Premature discharge with vague neurological signs

Iron

• Risk assessment
  • <20mg/kg elemental iron – Asymptomatic
  • 20-60mg/kg – GI symptoms
  • >60-120mg/kg – Systemic toxicity anticipated
  • >120mg/kg – Potentially lethal
• Classic stages
  • 0-6 hours: Vomiting, diarrhoea and abdo pain due to corrosive effect. Fluid losses can lead to shock
  • 6-12 hours: Some resolution of symptoms with absorption
  • 12-48 hours: Disruption of cellular metabolism leading to vasodilatation, third-spacing, HAGMA and hepatorenal failure
  • 2-5 days: Acute hepatic failure (high mortality)
  • 2-6 weeks: Delayed cirrhotic liver disease and GI fibrosis/strictures

• Refinement of initial risk assessment can be done by AXR to confirm and quantify ingestion + iron level at 4-6 hours
• If established iron toxicity, prognosis is poor
• Children: >60mg/kg can cause systemic toxicity
• Toxic mechanism
  • Local: Direct corrosive effect can be severe
  • Systemic: Direct cellular toxin (CVS and liver mostly). Severe lactic HAGMA + liberation of hydrogen ions from hydration of free ferric ions in plasma
  • Coagulopathy frequently observed due to interference in coagulation pathway by iron directly (rather than just liver failure)
• Toxicokinetics
  • Regulatory mechanisms of iron absorption overwhelmed in OD leading to greatly enhanced bioavailability. Absorbed iron shifts intracellularly within hours. Elimination is minimal under normal conditions

• Investigations
  • Screening ECG, BSL, para
  • Serum iron
    • Peaks at 4-6 hours
    • Peak levels >90micromol/L are predictive of systemic toxicity
  • Blood gas – HAGMA is useful marker of systemic toxicity
  • AXR – Shows pills
  • Hyperglycaemia and leukocytosis are often seen but do not correlate with systemic toxicity

• Management
  • Resus with fluid boluses (due to third spacing in GI toxicity)
  • Decontamination
    • AC not effective
    • WBI recommended for >60mg/kg ingestions confirmed on X-ray
    • Surgical or endoscopic removal can be considered if deemed potentially lethal if WBI is impractical or fails
  • Antidotes
    • Desferrioxamine if systemic toxicity ensues or predicted (serum iron >90 at 4-6 hours)
      • Binds ferric ion to form ferrioxamine, which is excreted in urine
      • Cannot bind iron outside the vascular compartment
      • 15mg/kg/hr up to 40mg/kg if life-threatening provided hypotension does not supervene
      • Continue until clinically stable and serum iron <60

• Desferrioxamine continued
  • Must have cardiac monitoring (esp. BP)
  • Reduce rate if hypotension ensues
  • Adverse reactions
    • Hypersensitivity
    • Hypotension (esp. rapid or high-dose IV)
    • ARDS if >24 hours duration
    • Toxic retinopathy
    • Acts as siderophore to promote growth of Yersinia and mucormycosis
  • Ideally provided before iron moves intracellularly (within hours)
  • 6 hours of therapy is usually sufficient
  • Urine changes colour to vin rose but THIS IS NOT a good indicator of successful chelation

• Disposition
  • If asymptomatic at 6 hours and abdominal X-ray negative – can discharge
  • Do not get systemic toxicity without GI toxicity
• Handy tips
  • Care of pregnant patients is unchanged
  • Fetus is relatively protected until cardiovascular disruption occurs in mother
• Pitfalls
  • Overtreatment of trivial ingestions
  • Failure to perform initial risk assessment and missed window for chelation
  • Failure to recognise systemic iron toxicity in patient who presents late with minimal elevation in serum iron (as already moved intracellularly)

Isoniazid

• Risk assessment
  • Rare but potentially fatal
  • Rapid onset toxicity
  • >1.5g (>20mg/kg): May develop symptoms
  • >3g (>40mg/kg): Seizures, metabolic acidosis and coma
  • >10g (130mg/kg): Uniformly fatal without intervention
• Toxic mechanism
  • Toxicity due to pyridoxine-5-phosphate deficiency as isoniazid inhibits conversion of pyridoxine to this
  • Pyridoxine-5-phosphate is required for glultamic acid to GABA conversion in CNS and thus leads to acute GABA deficiency manifesting as seizures

• Clinical features
  • Lightheaded, blurred vision, photophobia, nausea, vomiting +- tachycardia, dilated pupils, slurred speech, ataxia and hyperreflexia
  • Rapidly develop confusion, ALOC, seizures, severe lactic acidosis and death
• Aggressive resuscitation
• Manage seizures with benzos while pyridoxine obtained
• AC once airway controlled
• Enhanced elimination
  • Haemodialysis effectively removes isoniazid but timecourse of toxicity makes it not useful
• Antidote
  • IV Pyridoxine (1g for each gram of pyridoxine or 5g if dose unknown)

• Handy tips
  • Consider isoniazid overdose in differential of status epilepticus, particularly if any TB in family

Lead

• Risk assessment
  • Acute or subacute severe lead intoxication is usually due to ingestion or inhalational occupational exposure.
    • Associated with encephalopathy, cerebral oedema and death
  • Chronic exposure leads to vague multisystem disorder and potential for permanent neuropsychological sequelae
  • Risk of long-term sequelae loosely correlates with blood lead levels
    • <10mcg/dL: Minor dose-dependent reduction in IQ in young children
    • >10mcg/dL: Subtle learning difficulties
    • >30mcg/dL: Non-specific abdo pain, malaise, headaches, insomnia. Subclinical peripheral neuropathy, radial nerve wrist drop, chronic interstitial nephritis, Fanconi’s syndrome, decreased fertility
    • >100mcg/dL: Severe GI symptoms, encephalopathy, coma, death

• Pregnancy: Major teratogen
• Children: Impaired intellectual development with no threshold below which lead is not deleterious
• Toxic mechanism
  • Interferes with intracellular function, haem synthesis, neurotransmitter systems and steroid production
• Toxicokinetics
  • Absorption from ingestion, inhalation, topical and lead foreign bodies
  • BA 50% in children vs. 20% in adults
  • Lead is absorbed and bound by red cells for distribution around body
  • Bony skeleton acts as a reservoir
  • Crosses placenta easily

• Clinical features
  • Acute ingestion: Abdo pain, nausea, vomiting, haemolytic anaemia, hepatitis
  • Cerebral oedema, encephalopathy, coma are pre-terminal conditions
• Management
  • Supportive care
  • Lead foreign body ingestion – Endoscopic retrieval if above GOJ, otherwise high fibre diet and PEG
  • Remove lead foreign bodies
  • Chelation therapy if symptomatic
    • EDTA (IV chelator)
    • Succimer (oral chelator)

Methotrexate

• Toxicity following acute ingestion is unlikely due to saturable gastrointestinal absorption and rapid renal elimination (requires active transport via folate carrier-1 protein)
• Folinic acid competes with MTX for absorption via this transporter
• Acute ingestion <1000mg results in <1g/m2 bioavailable dose and thus does not warrant folinic acid rescue therapy
• Folinic acid rescue therapy advised for patient with renal failure or >1000mg (>5mg/kg)
• Oral folinic acid can be given for 24 hours to reduce absorption and acting as a supply of reduced folate for metabolic functions (bypassing DHFR)
• Levels can prove useful
• Supratherapeutic dosing does result in toxicity
  • Lethal bone marrow suppression
  • Can occur if weekly dose is taken daily for only 3 days
• Competitive inhibitor of DHFR and thymidylate synthetase resulting in reduced DNA/RNA synthesis and reduced cell replication
• Presentation of supratherapeutic dosing
  • GI, bone marrow, hepatic and renal injury

• Management
  • <1000mg (<5mg/kg) – Ensure adequate hydration, check renal fx and MTX level at 6 hours
  • >1000mg (>5mg/kg) 
    • Activated charcoal if within 2 hours, ensure adequate hydration, commence folinic acid and check renal fx and MTX level at 6 hours
• After acute single ingestion threshold level for toxicity
  • 6 hour level – 5micromol/L
  • 12 hour level – 1
  • 24 hour level – 0.1
• If level above this, level not obtainable within 24 hours of ingestion, patient is symptomatic or renal function is abnormal – Administer folinic acid

• Disposition
  • If renal fx normal and MTX level below threshold – medically cleared
• Folinic acid
  • 15mg PO, IM or IV q6h
  • Can cease after acute ingestion once level below threshold otherwise it is continued until serum level <0.05micromol/L
  • With chronic toxicity, continue for at least 3 days, until MTX is <0.05micromol/L and evidence of bone marrow recovery
• Pitfalls
  • Administration of folic acid instead of folinic acid as antidote

NSAID’s

• Usually benign unless massive OD
• Ibuprofen >2/3 of cases
• Risk assessment
  • Ibuprofen
    • <100mg/kg: Asymptomatic
    • 100-300mg/kg: Mild GI and CNS symptoms
    • >300mg/kg: MODS
  • Overdose with any amount of mefenamic acid is commonly associated with self-limiting seizures
• Children: Significant symptoms rare if <300mg/kg ingested. Any amount of mefenamic acid needs hospital assessment due to risk of seizures

• Toxic mechanism
  • Competitive COX-1/2 inhibition
  • Direct GI irritation
  • Prostaglandin synthesis inhibition results in glomerular vasoconstriction and mild reversible renal dysfunction
  • Bleeding time prolonged due to inhibition of thromboxane A2 synthesis
• Clinical features
  • Minor GI upset usually
  • Minor lethargy sometimes seen
  • Massive OD can lead to MODS
  • Chronic ibuprofen use associated with renal tubular acidosis and life-threatening hypokalaemia

• Ix
  • Screening ECG, BSL, para
  • EUC, LFT, FBC in symptomatic patients
  • HAGMA often seen but not of clinical consequence
• Management
  • Treat seizures with benzos
  • Supportive care
  • AC not clinically useful and CI in mefenamic acid due to seizure risk
• Disposition
  • If well at 4 hours, discharge home
• Handy tip
  • Predict seizures in mefenamic acid
• Pitfalls
  • Failure to appreciate risk of MODS in massive OD

Organophosphates/carbamates

• Organophosphates
  • Chlorpyrifos, coumaphos, diazinon, dichlorvos, dimethoate, fenthion, malathion, parathion, trichlorfon
• Carbamates
  • Aldicarb, carbendazim, carbendazole, carbazine, propoxur
• Chemical nerve agents
  • Sarin (GB), Soman (GD), Tabun (GA), VX
• Deliberate poisoning responsible for >100 000 deaths per year
• Generally cause death by respiratory failure

• Risk assessment
  • Deliberate self-poisoning almost always life threatening
  • Carbamate ingestion produces similar toxicity but of shorter duration and less likely to be fatal
  • Can have delayed onset up to 12 hours
  • Accidental exposure can be serious but usually not life-threatening
  • Significant secondary poisoning to healthcare workers does not occur

• Toxic mechanism
  • Inhibits acetylcholinesterase leading to increased muscarinic and nicotonic activity
  • Effects at CNS, PSNS, SNS and skeletal muscle synapses
  • Irreversible loss of alkyl side chains and permanent binding of the agent (ageing) to AChE prevents reactivation of AChE by pralidoxime
  • Time to ageing depends on agent
  • Ageing does not occur with carbamates
  • Frequently formulated with volatile hydrocarbon solvents with resultant inhalation of fumes causing headache and dizziness (agents themselves have very low vapour pressures and have to be aerosolised for inhalation)

• Toxicokinetics
  • Well absorbed after ingestion
  • Dermal and inhalational exposures occur occupationally
  • Large Vd and accumulate in lipids
  • Carbamates are distributed less to the CNS
• Clinical features
  • Symptoms within minutes to hours depending on agent
  • Muscarinic or nicotinic symptoms can predominate
  • Dimethoate is typically early onset coma, CVS collapse and death within 24 hours
  • Chlorpyrifos has early cholinergic symptoms
  • Fenthion has delayed onset paralysis (2 days) with minimal early symptoms

• Muscarinic
  • Diarrhoea, urination, miosis, bronchorrhoea, bronchospasm, emesis, lacrimation, salivation (DUMBELS)
  • Bradycardia and hypotension
• Nicotinic
  • Fasciculation, tremor, weakness, respiratory muscle weakness
  • Tachycardia, hypertension
  • Fasciculation best seen in small muscles e.g. tongue
• CNS
  • Agitation, coma, seizures
• Respiratory
  • Chemical pneumonitis if hydrocarbon solvent aspirated

• Intermediate syndrome
  • Delayed onset paralysis at 2-4 days after apparent recovery
  • Seen following fenthion, diazinon, malathion poisoning
• Delayed neurotoxicity
  • 1-5 weeks post-exposure to fenthion, chlorpyrifos, parathion
  • Ascending sensorimotor polyneuropathy due to ageing of axonal neuropathy target esterase (NTE)
• Chronic neuropsychiatric disorder
  • Long-term neuropsychiatric disorder can occur

• Investigations
  • Screening BSL, ECG, para
  • Red cell and plasma (butyryl-, pseudo-) cholinesterase activity 
    • Can be helpful in making definitive diagnosis and monitoring therapy
    • Significant clinical features seen at <25% usual activity
    • Difficult to get result and not validated
• Management
  • Supportive care
  • Resuscitation must no be delayed by external decontamination. Normal PPE enough
  • If muscarinic symptoms, start atropine 1.2mg doubled every 5 minutes until dry secretions, resolution of bradycardia and good air entry
    • Atropine has no effect on NMJ
  • Control agitation with benzos

• Pralidoxime
  • May reverse NM blockade by reactivating inhibited Acetylcholinesterase before ageing occurs
  • Clinical utility is unclear
  • 2g IV then 0.5g/hr infusion for at least 24 hours
  • Not necessary in carbamate intoxication
• Disposition
  • Monitor for at least 12 hours
• Pitfalls
  • Failure to appreciate life threat
  • Failure to recognise cholinergic syndrome
  • Excessive concern re: nosocomial poisoning

Paraquat

• Widely used herbicide that is potentially lethal in a mouthful
• Risk assessment
  • GI corrosive injury universal after ingestion
  • Deliberate self-poisoning >20% concentration is almost universally fatal
    • MODS and pulmonary fibrosis
  • Inhalational injury does not cause significant toxicity
  • Dermal toxicity only if prolonged or broken skin
• Toxic mechanism
  • Caustic agent specifically transported to pneumocytes causing superoxide production and depletion of superoxide dismutase and NADPH
  • Oxygen free radicals cause lipid peroxidation, free radical release and cell membrane disruption
  • Activates NF-kB -> Inflammatory cascade

• Toxicokinetics
  • Rapidly but not completely absorbed
  • Rapidly distributed to lung, liver, kidney and muscle
  • Vd 1.2-1.6L/kg
  • Within 12-24 hours, 90% of absorbed paraquat is excreted unchanged in urine
  • After a few hours, renal clearance declines rapidly in severe poisoning
  • Actively taken up against marked concentration gradient into type II pneumocytes with extremely slow elimination from this compartment

• Clinical features
  • Central tongue ulceration (paraquat tongue) in first few days and GI symptoms are universal
  • MODS within hours
  • Renal PCT necrosis
  • Hepatic congestion and hepatocellular injury
  • Moderate ingestions can have no systemic features until 48 hours acute renal failure, progressive pulmonary injury and death within days to weeks
  • >50-100mL of 20% w/w results in fulminant organ failure with hypoxia, shock and metabolic acidosis at presentation
  • Smaller ingestions lead to toxicity over 2-6 days in target organs (lungs, kidneys) – Mortality >50%
  • Creatinine concentrations can help predict toxicity in the first 24 hours
  • Lung injury
    • Two phases: Acute alveolitis over 1-3 days followed by secondary fibrosis over 3-7 days with rapidly progressive fibrosis over next 5 weeks
  • No long-term ramifications known for liver or kidney injury

• Investigations
  • Screening ECG, BSL, para
  • SpO2 monitoring
  • Serial PFT’s
  • VBG, FBC, EUC, LFT – Lactate >4.4 is associate with fatal outcome
  • CXR – Fibrosis and aspiration
  • Urinary paraquat dithionite test to confirm diagnosis semi-quantitative)
    • If urine paraquat concentration is >1mg/L then turns reagent blue -> Indicates very poor prognosis
  • Serum paraquat – Not available within clinically useful time but serum levels define prognosis
  • Can consider endoscopy for corrosive GI lesions as risk of perforation/stenosis/mediastinitis and pneumomediastinum

• Management
  • The only poisoning in which decontamination takes priority over resuscitation (ideally at scene)
  • If acutely unwell after deliberate ingestion of large dose managed palliatively
  • In moderate or accidental ingestions, aim is to reduce load to lungs
  • Supplemental O2 only if <90% and targeted to 90%
• Decontamination
  • At scene administer food or soil to prevent/slow absorption
  • 50g AC immediately on hospital arrival
  • Fuller’s earth of no benefit over AC

• Enhanced elimination
  • Haemodialysis of greatest urgency in patients taking near fatal dose (mouthful upwards) but will not prevent death in large doses
  • Maximal benefit if within 2 hours (not helpful beyond this in dog study) but can consider up to 4 hours unless severe toxicity ensues
• Antidotes
  • Commence all patients on NAC but no proven benefit

• Immunosuppression
  • Theory is that inflammatory alveolitis can be ameliorated
• Antioxidants
  • Vitamin E: No evidence
  • Vitamin C: No evidence
  • NAC: Good evidence of effect but not widely studied
  • DFO: No human studies. Theoretically inhibits role of iron in Fenton reaction generation of oxygen free radicals
  • Salicylic acid: No human studies

Potassium chloride

• Primary concern is slow-release K available in bottles up to 100 without prescription
• Rare but potentially fatal hyperkalaemia
• Risk assessment
  • >2.5mmol/kg of potassium theoretically overwhelms kidney capacity
  • >40 x 600mg tablets prompts early planning for haemodialysis in case conservative measures fail
  • AXR assists risk assessment as slow release tablets are radio-opaque
  • Children: 3x 600mg tabs can cause significant hyperkalaemia in 10kg toddler
• Toxic mechanism
  • Direct irritant plus effects of hyperkalaemia
• Toxicokinetics
  • Absorption – Rapid
  • Distribution – To intracellular compartment
  • Excretion – Urine 90%

• Clinical features
  • Abdo pain, nausea, vomiting
  • Ileus and mucosal perforation can occur
• Management
  • CaCl 10mL 10% IV
  • Neb salbutamol 10-20mg 
  • 10U actrapid + 50mL 50% dextrose
  • Sodium bicarb 50-100mmol IV slow
  • Arrange dialysis if suspected to be necessary

• Decontamination
  • AC not binding
  • WBI: Must never delay haemodialysis if required. Primary value is in completing decontamination once hyperkalaemia has been controlled by haemodialysis
• Haemodialysis
  • Indications
    • >40 x 600mg tabs confirmed on AXR
    • Renal impairment
    • CV instability
    • Serum K >8
    • Rapidly rising serum K
  • Continues until decontamination performed by WBI
• Resonium A binds only 1mmol K per gram and is not useful following massive slow-release K ingestion

Quinine

• Cinchonism – Nausea, vomiting, tinnitus, vertigo and deafness
• Larger overdoses can cause cardiotoxicity and visual disturbance
• Risk assessment
  • Consider all cases potentially life-threatening
  • >1g usually causes cinchonism
  • >5g risks more severe toxicity and universal if >10g
  • Children: 2 tabs (600mg) has potential for life-threatening toxicity
• Toxic mechanism
  • Class 1A anti-dysrhythmic + potassium rectifier channel blocking activity with prolongation of QRS and QT
  • Directly toxic to retina 
  • Stimulates pancreatic insulin release like sulfonylureas

• Clinical features
  • Cinchonism occurs early
  • CVS: Hypotension, sinus tachy, broad QRS, prolonged QT, TdeP (within 8 hours)
  • CNS: Drowsiness and confusion in larger ingestions. Seizures and coma are rare
  • Eyes; Visual disturbance delayed > 8hours. Blurring, disturbed colour vision, dilated pupils and visual field constriction. Recovery (if it does occur) takes weeks. Permanent deficits more likely if complete blindness in acute phase
• Quinine blood levels
  • >10mg/L at 6 hours is associated with CVS and retinal toxicity but results never obtainable within clinically relevant time

• Management
  • Wide complex dysrhythmias – As for TCA overdose
  • TdeP – MgSO4 10mmol over 15 min, overdrive pace (isoprenaline, adrenaline, electrical)
  • Control seizures with benzos
• Decontamination
  • AC to all patients who can drink it themselves or after intubation
• Enhanced elimination
  • MDAC indicated if >5g ingested or any degree of visual disturbance
    • 50g then 25g q2h
• Handy tips
  • Consider in any intentional overdose with visual disturbance
• Pitfalls
  • Failure to assess for delayed visual disturbance beyond 6-8 hours

Salicylates

• Aspirin and methyl salicylate (NOT any other NSAID’s)
• Acute intoxication – Vomiting, tinnitus, hyperventilation, respiratory alkalosis and metabolic acidosis. Severe cases seizures and coma
• Chronic intoxication – Non-specific and often missed. Morbidity and mortality higher
• Risk assessment
  • Acute aspirin OD
    • <150mg/kg: Asymptomatic
    • 150-300mg/kg: Mild-moderate hyperpnoea, tinnitus, vomiting (salicylism)
    • >300mg/kg: Severe metabolic acidosis, altered mental status and seizures
    • >500mg/kg: Potentially lethal
  • In children, rarely take enough aspirin to cause concern but as little as 5mL of methylsalicylate (e.g. oil of wintergreen) can cause death
  • Chronic salicylism has been reported with regular use of choline salicylate-containing teething gels

Salicylates

• Toxic mechanism
  • COX inhibition with reduced prostaglandin synthesis
  • Direct stimulation of respiratory centre leads to respiratory alkalosis
  • Uncoupling of oxidative phosphorylation leads to lactic metabolic acidosis and potentially neuroglycopaenia
  • Promotion of fatty acid metabolism and ketone production contribute to metabolic acidosis
• Toxicokinetics
  • Absorption – Rapidly absorbed (can be delayed in massive OD or bezoar formation)
  • Distribution – Narrow Vd 0.1-0.3L/kg. Protein binding saturated in OD and free drug levels increase precipitously
  • Metabolism – Hepatic metabolism. First-order to zero-order with saturable kinetics
    • Half-life 2-4 hours increases to 24 hours in massive OD
  • Elimination
    • Urinary pH affects renal elimination. High urinary pH (alkalinisation) promotes salicylate excretion as becomes ionised in tubules

• Clinical features
  • Acute
    • Symptoms gradually worsen and can be only apparent at 6-12 hour with subsequent sudden deterioration
    • Actual acidaemia is a late sign (as prior to this have mixed alkalosis/acidosis) and portends imminent demise without intervention
  • Chronic
    • Mostly elderly patients with vague confusion, delirium, dehydration, fever and unexplained metabolic acidosis
• Investigations
  • Screening BSL, para, ECG
  • Salicylate level: Therapeutic range 1.1-2.2mmol/L (15-30md/dL, 150-300mg/L)
  • Levels correlate poorly with toxicity but q2-4hrly levels can identify ongoing absorption from bezoar or slow-release tabs

• Management
  • Controlled hyperventilation if intubation required as want to maintain alkalaemia to increase ionisation of salicylate in blood to prevent penetration into CNS
  • EM:RAP state should deliver glucose boluses irrespective of glucose level if ALOC (? Neuroglycopaenic)
  • Control seizures with benzos
  • Decontamination
    • AC 50g up to 8 hours following ingestion >150mg/kg with second dose at 4 hours if serum salicylate levels continue to rise
    • As forms bezoars and if level still rising after initial AC need to give repeat dose

• Management
  • Enhanced elimination
    • Urinary alkalinisation for all symptomatic patients
    • Haemodialysis indicated if:
      • Urinary alkalinisation not feasible
      • Serum salicylates >4.4mmol/L despite decontamination and urinary alkalinisation
      • Severe toxicity with ALOC, acidaemia or renal failure
      • Acute poisoning salicylate level >7.2mmol/L (>4.4 in elderly)
      • >4.4mmol/L in chronic toxicity

• Urinary alkalinisation
  • Correct hypokalaemia first
  • 1-2mmol/kg IV sodium bicarb
  • Infusion of 150mmol bicarb in 850mL 5% dextrose at 250mL/hr
  • Will require ongoing potassium supplementation
  • Monitor serum bicarb and K q4h
  • Check urine pH >7.5 with dipstick
  • Continue until toxicity resolving

• Handy tips
  • Urgent HD if intubated
  • Consider salicylate poisoning in any elderly patient with ALOC and metabolic acidosis
  • Classically causes HAGMA but many bedside gas machines measure salicylate as chloride and provide a normal anion gap result
• Pitfalls
  • Failure to appreciate ongoing absorption/bezoar formation
  • Failure to maintain alkalaemia after I&V leading to rapid redistribution of agent to CNS and deterioration
  • Failure to identify oil of wintergreen as methylsalicylate and then converting to aspirin units for risk assessment
  • Failure to diagnose chronic salicylate poisoning

Sodium azide

Colourless, odourless crystalline water-soluble solid (NaN3)

Used industrially as propellant in air bags, preservative in laboratories and as a pesticide

Potential for explosion on exposure to metals

Ingestion of 700mg is likely fatal

Has 100% fatality rate in intentional ingestion

MOA

• Mitochondrial toxin
• Binds the electron transport chain, inhibiting oxidative phosphorylation
• Mechanism is similar to cyanide although causes more profound vasodilation due to conversion to nitric oxide
• Hypotension can occur within 1 minute of exposure
• Presents with shock, asystolic arrest, markedly raised lactate and acidosis
• No specific antidote

Strychnine

• Rodenticide that causes generalised skeletal muscle spasm within 30 minutes and death from respiratory failure
• Paralysis, I&V are lifesaving if instituted before hypoxia ensues
• Competitive glycine antagonist at brainstem and spinal post-synaptic receptors
• Loss of normal descending inhibitory motor tone
• Minor toxicity with minor twitching – IV diazepam

Theophylline

• Extremely narrow therapeutic index
• Acute and chronic toxicity can be life-threatening
• Risk assessment
  • All acute overdoses develop systemic toxicity
  • Dosing
    • 5-10mg/kg: Therapeutic loading dose
    • >10mg/kg: Potential for toxicity
    • >50mg/kg: Life-threatening toxicity
  • Chronic toxicity carries poor prognosis with often missed diagnosis
  • Serum levels further define risk assessment
  • Children: 1x200mg MR tab can produce toxicity in toddler

• Clinical features
  • Early acute intoxication – Anxiety, vomiting, tremor and tachycardia
  • Severe poisoning
    • SVT, AF, VT
    • Refractory hypotension
    • Seizures
    • Severe hypokalaemia, hypophos, hypoMg, hyperglycaemia, metabolic acidosis
    • Cardiac dysrhythmias and seizures occur late and portend poor prognosis
  • Chronic
    • Usually elderly or infants with vomiting and tachycardia. Seizures and dysrhythmias occurs frequently and at lower theophylline concentrations

• Toxic mechanism
  • Competitive antagonism of adenosine, altered intracellular Ca transport and phosphodiesterase inhibition leading to elevated intracellular cAMP levels
• Toxicokinetics
  • Absorption – Well absorbed and delayed with MR preparations (peak levels at 15 hours)
  • Distribution – Rapid but small 0.5L/kg
  • Metabolism – CytP450 to active and inactive metabolites. Saturable. 
  • Elimination – Greatly prolonged in acute OD

• Serum levels
  • Predict risk
  • In acute OD, level correlates well with severity and are repeated q2-4h until falling
  • 55-110micromol/L: Therapeutic
  • 110-220micromol/L: Minor toxicity
  • 220-440: Moderate (severe in elderly and severe if chronic)
  • 440-550: Severe
  • >550: Usually fatal without urgent intervention

• Management
  • Aggressive resuscitation and control of seizures with benzos
  • Supportive care while arranging haemodialysis in severe toxicity
  • Fluids +- Noradrenaline for hypotension
  • SVT controlled with beta-blockade (beware bronchospasm as usually asthmatic)
    • Esmolol preferred for this reason but metoprolol 5mg IV slow push repeated as necessary is more practical
  • Correct severe hypokalaemia/hypoPh/hypoMg

• Decontamination
  • AC even if delayed presentation with aggressive control of emesis to allow intake
• Enhanced elimination
  • Haemodialysis is highly effective in achieving good outcome
  • Indications
    • Serum theo level >550micromol/L in acute OD or >330 in chronic OD
    • Clinical severe toxicity
  • MDAC only while organising HD and should never delay it

• If acute ingestion of IR preparation and well at 6 hours, can clear
• If MR preparation, monitor for 12 hours
• Handy tips
  • Identify high-risk patients and dialyse before deterioration
  • Most agents are MR and clinical deterioration can be delayed many hours
  • Any cardiac instability warrants urgent dialysis
• Pitfalls
  • Failure to identify high-risk cases and arranging HD
  • Failure to closely observe and monitor theophylline levels

Thyroxine

• Rarely significant
• If symptoms do occur they are often mild and delayed up to 2 weeks
• If >10mg, symptoms may be expected
• TFT’s after OD are of no clinical benefit
• Beta-blockers for symptoms if delayed presentation
  • Oral propranolol 10-40mg q6h
  • CCB are alternative
• AC if within 1 hour of >10mg acute OD
• Disposition
  • Discharge with advice to return if symptoms arise
  • Can re-start thyroxine after 1 week
  • Beta-blockers usually only required for around 1 week if at all
• Pitfalls
  • Unnecessary admission for prolonged observation
  • Failure to predict delayed onset of symptoms after large overdoses

Last Updated on September 29, 2021 by Andrew Crofton