Approach to the Toxicology patient Peter Llewellin Anaesthetics 2005 Revised ED 2010, EMC 2015

Objectives Understand how substances may develop a toxicity profile Develop and approach to the assessment of the toxicology patient Understand priorities of treatment and techniques of managing the toxicology patient Learn how to manage paracetamol toxicity in the acute overdose situation

Epidemiology 90% poisonings accidental 60% children under 5 60% managed at home In ED - 1% of workload ; much higher rate of intentional overdose in ED population. Mortality - 90% pre-hospital deaths; 50% suicides; paediatric deaths rare.

Epidemiology Most common agents in adults – Ethanol Paracetamol Benzodiazepines Opioids Antidepressants Antihistamines Phenothiazines Most common agents in children – Paracetamol Antihistamines Rodenticides Eucalyptus/essential oils Bleach + detergents Benzodiazepines

Toxicokinetics Absorption - may be altered in large doses eg injurious to GIT/gastric stasis Bioavailability - drugs with saturable 1st pass effect may have higher amount of drug released to circulation i.e relatively low ER Volume of distribution - Important when considering elimination of drug. Large Vd suggests sequestration outside plasma  not amenable to dialysis Clearance - volume of plasma cleared of drug per unit time. Is the sum of clearances by liver/kidney/sweat/faeces/lung Primary elimination pathway of a toxin important in order to enhance elimination Most drugs are eliminated by first- order kinetics at therapeutic dose, but display zero-order kinetics in toxic doses as enzyme systems are overloaded eg paracetamol, phenytoin

Toxicodynamics Toxicity may result from extension of the therapeutic effect - ability to become toxic depends upon efficacy and dose response curve e.g benzo’s vs barbiturates Toxicity may stem from alternate pharmacodynamic activity of drug becoming prominent eg Na-channel blockading activity of TCA Toxicity may result not from pharmacodynamic effect but from toxic metabolites due to normal or saturated metabolism eg ethylene glycol, paracetamol

Resuscitation Most deaths from poisoning due to failure of basic cardiopulmonary function. Airway Breathing Circulation D – Control seizures/correct hypoglycaemia E – Correct hyperthermia Consider antidotes

Risk Assessment - History Agent(s) ingested Dose (mg/kg) Assume ‘worst case scenario’ – esp. children Time course since ingestion Correlate clinical features and progress since ingestion Patient co-morbidities and weight Consult specialist service if required for predicted course based upon above information

Clinical features Look for particular toxidromes to assist diagnosis and assessment of severity Opioid Anticholinergic (anti-muscarinic) Sympathomimetic Cholinergic - Muscarinic/Nicotinic Other features - odour/colour/nystagmus/respiratory pattern

Supportive care + Monitoring Observe in appropriate environment for time course as dictated from risk assessment Ensuring ABC secure will be sufficient for most toxicology cases Monitoring may be PR/BP/BSL’s/GCS. Electrical monitoring occasionally required. Change in pt condition = Resuscitation and repeat Risk Assessment

Investigations 12 lead ECG + Paracetamol level + BSL only mandatory investigations in self harm ingestions Other tests frequently over-ordered for no benefit. Should be ordered specific to expected toxicity as based on risk assessment. Majority of drug levels of no use in acute ingestions. Urinary drug screens rarely influence toxicology management. Levels that may be useful if indicated by risk assessment are Salicylate; Digoxin; Iron; Li; Anticonvulsants; Theophylline Acid-base determinations may also be useful in selected poisonings.

Gastric decontamination Traditional initial treatments aimed at reducing absorption of ingested agents Little or no evidence of benefit for general ingestions More recent recognition of harm from routine use Initiation of a gastric decontamination technique requires assessment of risk vs. benefit For most ingestions, likely to be NO effect from ANY technique outside of 2 hr from ingestion

Gastric Decontamination X - Induced emesis – Ipecac - X X - Gastric lavage –40Fr OGT and washout - X Labour intensive, risky and no benefit over charcoal alone Activated Charcoal Not proven to be clinically effective in a RCT; should not be regarded as routine Rx. Theoretical use in co-operative pt ingestion <1hr Major risk =aspiration; avoid in drowsy patients. Whole Bowel Irrigation Bowel cleansing with 2L/hr of PEG via NGT. Reserved for high lethality ingestions with likely slow release of toxin not amenable to charcoal. Not performed in the ED.

Enhanced Elimination Aimed at increasing rate of removal of drug from body to reduce toxicity Toxin needs to be high lethality agent AND Poor outcome from supportive care alone AND Slow endogenous elimination AND Have suitable toxicokinetics

Enhanced Elimination Multi-dose activated charcoal (‘Gut dialysis’) Interrupts entero-hepatic circulation Binds soluble drug travelling down concentration gradient across gut membranes May be indicated carbamazepine toxicities Urinary alkinalisation ‘Traps’ ionised drug in renal tubules by altering pH relative to pKa May be suitable for salicylates – generally not utilised however in favour of dialysis Haemodialysis/Haemoperfusion Clearly not ED intervention. Suitable for easily dialysed compounds with high lethality Examples – toxic alcohols; Li; salicylates; massive anticonvulsant ingestion

Antidotes Required in <2% of poisonings Paracetamol -N-acetylcysteine - glutathione group donator Opioids - Naloxone - competitive antagonist Digoxin - Digibind - antibody complex with drug Organophosphates - Atropine/pralidoxime - Atropine competively antagonises in massive doses. Pralidoxime prevents inactivation of cholinesterase if given early Risk benefit analysis still applies to utilisation of antidotes Antidotes not necessarily stocked at your hospital

Paracetamol toxicity Common overdose Both intentional and unintentional Toxicity – overloading of normal metabolic pathway (sulphation/glucoronidation) Minor pathway becomes prominent – production of NAPQI; requires glutathione to remove. Glutathione rapidly depleted in body in overdose, and NAPQI then damages hepatocytes

Clinical features Minimal symptoms first 24 hrs – anorexia/malaise/nausea Hypokalaemia may be seen Resolves after 12-24 hrs, but replaced by RUQ tenderness/transaminitis Nausea/malaise returns followed by hepatic failure/coagulopathy/renal failure day 3-4 Presence of acidosis day 4 – 95% mortality

Risk assessment – How much is too much

Management Gastric decontamination Assess toxicity potential N-acetylcysteine

Gastric decontamination Activated charcoal recommended for alert co-operative individuals <2 hrs from ingestion time Increased time frame to 4 hrs for massive ingestion >30g, or SR formulations Dose 50g adult, or 1g/kg for children >6 yrs age Not appropriate to forcibly administer

Assess toxic potential Where ingestion >200mg/kg or 10g suspected, serum paracetamol level required. NB no other blood tests routinely required or recommended as don’t alter management Children <6 yrs with liquid formulation ingestion ; 2hr level acceptable – if <1500mcmol/L no treatment required All others, 4 hr level required –plot result to treatment nomogram -

N-Acetylcysteine therapy NAC metabolized to cysteine then glutathione in body ‘Mops-up’ NAPQI Virtually eliminates risk of hepatotoxicity if given within 8 hrs Anaphylactoid reactions possible (10%)

Questions?

Summary Effective attention to ABC’s sufficient for majority presentations Risk assess each case – allows prediction of clinical course Become familiar with recognising toxidromes to assist in assessment Consider gastric decontamination and enhanced elimination when appropriate Risk assess paracetamol toxicity by ingested dose/timeframe and serum level Institute NAC as dictated by Australasian guidelines