Toxicology

1
Toxicology

• Management of the Poisoned Patient

2
Background

• DSP is a big problem
• Intentional self harm or suicide, was ranked 15th
  of all deaths registered in Australia in 2007
• Poisoning accounted for 25 of these deaths
• The primary aim in the treatment of poisoned
  patients is to reduce mortality and early and
  late morbidity
• The first priority in the assessment of patients
  is the adequacy of ABC
• Simultaneous investigation and treatment

3
So many drugs but so little time...

• Paracetamol
• Salicylates
• TCAs
• Lithium
• Other...
• But first some general principles

4
General Principles

• The first priority in the assessment of patients
  is to ascertain the adequacy of their
• Airway
• Ventilation
• Circulation
• Subsequent management determined by the risk to
  the patient from the poisoning.
• Need to know information regarding the toxin, the
  exposure, and the patient.

5
General Principles

• History
• Examination
• Investigations
• Differential Diagnosis
• General and Supportive Management
• Specific Interventions

6
Core Info

• History
• What drug, how much, when
• Sources of info?
• Prev DSPs what, when, where, treatment
• Targeted Examination
• Identify Toxidromes / life threatening
  abnormalities
• Investigations
• Routine bloods inc ABG
• Drug levels
• UDS
• ECG

7
Treatment

• GI decontamination
• AC single vs multidose
• Gastric lavage
• WBI
• Enhanced elimination
• Ion trapping
• Dialysis
• MDAC

• Supportive care
• ICU admission for ABCs
• Who needs intubation?

8
Paracetamol
9
Paracetamol

• Common
• Really common
• Primarily an ED managed thing
• Mostly wont need ICU involvement if single agent
  but may be involved in polysubstance ingestions
• Guideline changed in 2008

10
Paracetamol 2

• What changed?
• Acute ingestion
• One line nomogram
• Above the line treat
• Below the line dont treat
• Chronic ingestion
• Based on dose per 24hr period and duration since
  commencement of ingestion
• NAC infusion regime

11
Salicylates
12
Salicylate Poisoning

• PK Review
• Aspirin is a weak acid (pKa 3.5).
• ASA dependent protein binding and metabolism
• Acidosis
• Increased Vd
• Increased CNS penetration
• Hepatic clearance
• Zero Order Kinetics / capacity limited
  elimination
• Normal T(1/2) 2-4.5h Overdose 18-36h
• Renal excretion more important in overdose

13
Salicylates Effects

• Respiratory alkalosis
• Salicylates directly stimulate the respiratory
  centre leading to hyperventilation and a
  respiratory alkalosis
• Major feature is a Metabolic acidosis.
• Raised AGMA (acronyms anyone?)
• This triggers
• An increase in metabolic rate
• Increased oxygen consumption
• Increased CO2 formation
• Increased heat production
• Increased glucose utilisation

14
Salicylates Effects

• Other effects
• CNS effects mild / mod / severe
• Electrolyte imbalances
• Potassium depletion
• Dehydration
• Hepatic effects
• Glucose metabolism
• GIT disturbance

15
Salicylates Investigations

• FBC, EUC, Coags, Calcium, Glucose
• Arterial blood gas
• Urinalysis and urine pH
• Plasma salicylate concentration and repeat Q2-4H
• Q2H ABGs for acidaemia, electrolytes and glucose

16
Salicylates Treatment 1

• Patients should be admitted to ICU if they
  fulfill any of the following criteria
• An acute ingestion gt 300 mg/kg
• Moderate or severe clinical severity
• Acid-base disturbances where pH lt 7.4
• Salicylate concentration gt 4 mmol/L
• Treatment consists of monitoring and correction
  of
• Hydration
• Metabolic acidosis
• Hypokalaemia
• Hypoglycaemia

17
Salicylates Treatment 2

• Correct acidaemia, potassium deficit and
  dehydration.
• Urinary alkalinisation
• The patient should be commenced on 1 mEq/kg/hour
  of bicarbonate added to the IV fluid. Bolus doses
  may be required in severe acidosis.
• Causes ion trapping and increases excretion
• Haemodialysis

18
Ion Trapping
19
Salicylates Dialysis

• Indications for haemodialysis
• Pre-existing cardiac or renal failure
• Pulmonary oedema
• Intractable acidosis or severe electrolyte
  imbalance
• Salicylate concentrations
• gt9.4 mmol/L in ACUTE ingestions (when the
  concentration has been taken within 6 hours of
  ingestion)
• gt4.5 mmol/L in CHRONIC intoxication
• Clinically serious toxicity regardless of
  concentration

20
Tricyclic Antidepressants
21
TCAs

• In Australia they are the number one cause of
  fatality from drug ingestion and 90 of
  successful TCA suicides do not reach hospital but
  die at home (Buckley et al, 1995).
• The ingestion of 15-20mg/kg of tricyclics is
  potentially fatal.

22
TCAs PK

• Highly lipid soluble weak bases
• Rapidly absorbed
• Anticholinergic effects may prolong absorption
• High volume of distribution
• Protein binding gt 95
• May saturate increasing free fraction
• pH dependent
• P450 Hepatic metabolism
• Saturated in overdose therefore renal excretion
  vital

23
TCA Toxicity

• 3 features
• Anticholinergic toxidrome
• Red / hot / mad / blind / dry
• CNS toxicity
• CVS toxicity

24
TCAs CNS Toxicity

• Psychosis
• Decreased level of consciousness / coma
• Seizures
• May trigger acute deterioration
• Associated with increased mortality
• Anticholinergic delirium during recovery

25
TCAs CVS Toxicity

• Tachycardia
• Bradycardia
• Hypotension
• Arrhythmia
• Prolonged QRS

26
TCAs from bad to worse

• Predictors of severe toxicity
• QRS gt 100 milliseconds or more in a limb lead
• Ventricular arrhythmia
• Seizures
• R in aVR gt 3 mm

27
ECG in TCA overdose 1
28
ECG in TCA overdose 2
29
TCAs Treatment

• Supportive care airway, aggressive IV Fluids
  resuscitation, continuous ECG monitoring for at
  least 6 hours post ingestion
• GI Decontamination for conscious patients who
  present within 1-2/24. for unconscious patients
  via OGT post intubation.
• Avoid acidaemia.
• Treat seizures promptly and beware of CVS
  collapse post seizure
• Extended Resuscitation until pH corrected
  (alkalaemic) and discussed with Toxicologist

30
TCAs Treatment 2

• Sodium bicarbonate / Systemic Alkalinisation
• Multifactorial
• Shifts pH towards pKa
• In discussion with the Toxicologist
• 1-3 meq/kg bolus (if not in shock)
• 1-3 mls/kg of 8.4 solution (1 minijet of NaHCO3)
• 3-6 meq bolus (if in shock)
• Titrated by ECG
• Monitored ABG target pH 7.55 -7.6

31
Lithium
32
Lithium

• Narrow therapeutic range
• Predominately CNS effects in toxicity
• CVS toxicity is bad sign
• Acute toxicity well tolerated
• Treat those with renal failure or sodium
  depletion
• Chronic toxicity is more severe than acute
  toxicity
• Death and long term disability each occur in 10
  of chronic poisonings

33
Lithium PK review

• A well absorbed orally. Peak Li in 2-3/24
• Beware sustained release preparations!
• D not protein bound therefore body water
• Equilibrium btw serum and tissues takes days to
  weeks
• M / E excreted unchanged in urine
• Filtered, reabsorbed in PCT
• ? Na reabsorption means ? Li reabsorption
• Prolonged half-life in overdose

34
Lithium Effects

• Lithium has dose related toxicity in therapeutic
  use
• Initial symptoms include tremor, polyuria.
• Later symptoms
• Impaired consciousness
• Myoclonus
• Dysarthria and ataxia
• Severe toxicity
• Coma / seizures / ARF / death
• CVS ventricular dysrhythmias, prolonged QT
  common

35
Lithium Treatment

• Admission
• anyone with CNS symptoms or level gt 1.5mEq/L
• ICU for those needing Dialysis or with ECG
  changes
• GI decontamination
• AC ineffective
• WBI in patients who present early following
  large OD
• Enhanced Elimination
• Indications for dialysis
• Seizures or coma
• Renal failure in acute or chronic poisoning
• Li gt 2.5-3.0mEq/L
• Hypotension despite adequate fluid resuscitation

36
Lithium Treatment

• Dialysis - Intermittent VS Continuous
• Intermittent HDx
• Rebound phenomenon
• Need to check levels to see if further HDx needed
• CVVHD
• No rebound
• Useful in haemodynamically compromised where IHDx
  not appropriate
• As ongoing treatment post initial HDx
• Slower clearance than IHDx

37
Toxidromes
38
Summary

• Toxicology is about doing the simple things
• Supportive care most of the time
• Treatment should be commenced in ED
• ABCs
• Dialysis and alkalinisation are important and are
  ICU stuff.
• TCAs are bad.
• Lithium and Aspirin arent great either.

39
References

• Hypertox
• WikiTox online reference
• http//curriculum.toxicology.wikispaces.net
• Ohs Intensive Care Manual
• Katzung, Basic and Clinical Pharmacology
• Beckmann, U. et al (2001) Efficacy of continuous
  venovenous hemodialysis in the treatment of
  severe lithium toxicity. Journal of Toxicology,
  Clinical toxicology 39(4) 393-397.
• The Clinical Toxicology Dept at CMN
• ABS
• Zimmerman, J. (2003) Poisonings and overdoses in
  the intensive care unit General and specific
  management issues. Critical Care Medicine
  31(12) 2794-2801.
• Daly et al. (2008) Consensus Statement
  Guidelines for the management of paracetamol
  poisoning in Australia and New Zealand. Medical
  Journal of Australia 188 296301