Transcript File

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