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

2. 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

3. 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.

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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.

12. 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

13. 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.

14. 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

15. 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

16. 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

17. 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

18. Clinical features
Minimal symptoms first 24 hrs – anorexia/malaise/nausea
Hypokalaemia may be seen
Resolves after 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

19. Risk assessment – How much is too much

20. Management Gastric decontamination Assess toxicity potential
N-acetylcysteine

21. 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

22. 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 -

23. 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%)

25. Questions?

26. 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