Transcript Approach to Self poisoning: common pharmaceuticals Risk

General Approach to the
Toxicology Patient
Risk/Benefit + Evidence =Practice
Andrew Dawson
NSW Poisons Information Centre
Royal Prince Alfred Hospital
SACTRC
Case 1…Late one 1992 night

The phone rings.

A doctor informs us that they have just ceased
resuscitating a 14 year old girl who presented
following a chloroquine overdose. He asks, " if
there was anything I could of done".

We reply, "##@/etc there is little you can do
now, because she is dead”
South Asian Clinical Toxicology Research Collaboration
Take home messages
• Poisons are simple
• Patients are complicated
• Toxicology Care is mostly supportive
• When you don’t know…….phone a
friend
Understand the Mechanism
Overview
• Epidemiology
• Clinical Approach
– Important Poisonings
• Red Flag messages
What do the patients look like?
• 300 presentations /per year/ 100,000
– 10% ICU
– 20% repeat within a year
• Previous sexual assault
• 70% women
• 30% men
• Drug and alcohol
• Psychiatric
• Social issues
Drug Deaths?
• Death is Rare < 0.5%
• Psychiatric drugs are now designed for overdose
• Cardiovascular drugs are not designed for overdose
• Verapamil, diltiazem,beta blockers, digoxin, antiarrythmics
• Cellular Poisons (colchicine, cyanide, paracetamol,
metals)
• Medical complications
• Pulmonary Embolus, aspiration
• Cardiac and CNS Toxicity
pharmaceutical toxicity
Extension of its therapeutic effect
– + Additional toxic effects
– Variation within a pharmaceutical class
Rapid onset is the rule
– EXCEPT
Controlled Release Drugs
Cellular poisons eg paracetamol
•
•
Risk Assessment Overdose
• Patient
–
–
–
–
Dose
Time
Pre-existing illness
Signs of toxicity
• Vital signs
• Examination
• Simple tests
• Doctor
– Is this toxicity
• Prior knowledge
• Authoritative information
• 131126
Effect
Concentration
Where on the curve are we?
• Assess risk
• Resuscitate
• ? Specific Treatment
• ? Decontaminate
Time
Clinical Risk Assessment
• Cardiovasular
– Pulse & BP
• Airway and Oxygenation
• Neurological
– Level of consciousness
– Reflexes
• Investigations
– ECG
– Blood gases
– Glucose
– Specific assays
Time
Effect
Concentration
Volume, Pressor or Inotrope ?

Many agents have myocardial depressant and
peripheral vasodilatory effects

In severe poisoning:
EARLY assessment of myocardial function
important
ECG – is there QRS widening? Na+ channel toxicity
Bed-side ECHO
Cardiac output assessment – PICO
QRS prolongation – Bicarb and Hypertonic Saline
 LOW CO = inotropes
 LOW SVR = pressors

South Asian Clinical Toxicology Research Collaboration
Normal Repolarization
Na
Ca K
K
+30 mV
Ventricular Myocyte /
Purkinje Cell
Action Potential
-40 mV
Absolute
Refractory
Period
-70 mV
-90 mV
Corresponding ECG
Waves
Relative
Refractory
Period
P
PR
QRS
T
ST
Segments
QT
What do gases tell us?
• ? CO2
• ? O2
• Acid Base
• Lactate: explain
?anion gap (in mmol/L) = (Na+ K) - (HCO3 + Cl)
MUDPILES
methanol,
uremia,
diabetic ketoacidosis,
propylene glycol,
isoniazid,
lactic acidosis,
ethylene glycol,
salicylates
Benzyl alcohol
Beta-adrenergic agents
Caffeine
Carbon monoxide
Cyanide
Ethanol
Ethylene glycol
Hydrogen sulfide
Ibuprofen
Iron
Isoniazid (INH)
Lithium
Metformin
Methanol
Paracetamol
Paraldehyde
Phenformin
Salicylates
Strychnine
Sympathomimetic amines
Toluene
Psychiatry Pre 1950
•
•
•
•
•
•
•
•
•
Opium
Bromides
Barbiturates
Hysocine
Paraldehyde
Antihistamines
Benzedrine
Amphetamine
Thyroxine
Psychotic patient
1932 Promethazine
1950 Chlorpromazine
1954 Imipramine
1971 Clozapine
1980 Olanzapine
1972 Fluoxetine
1990 Quetiapine
1993 Venlafaxine
If the ECG is important…..
Is man smarter than a
machine?
Is it NormalMachine
? reading QTc 430ms
Hand-measurement and QTc by
Bazett formula 640ms
The Next Minute - Tdp
• Measure manually
• 3 limb leads
• (I, II, and one other)
• 3 Chest leads
• V2, V4, and V6
• Use QT not QTc
"not all QT prolongation is equal"
Acquired long QT
Important List (5A + CLAM)
• Antiarrhythmia
• Antidepressants
• Antipsychotic
• Antihistamine
• Antimicrobial
• Macrolides, Antifungal
• Others (CLAM)
• Cisapride / Cesium, Li, Arsenic Trioxide, Methadone
Extensive List : www.qtdrugs.org
What?
If the QRS>100msec
suspect Na Channel block
I
S in I, aVL
aVR
Sinus
Tachycardia
Response to NaHCO3
QRS 190ms
TCA: pH = 7.1
TCA: pH= 7.3
• 200 mEq
bicarbona
te
TCA: pH =7.4
• 200 mEq
bicarbonat
e
Altering Ionization
HA
+
H
+A
Equilibrium influenced by external pH
 The balance of the equilibrium can be
expressed by pKa
 The pKa is the pH where [ionized] =
[unionized]

South Asian Clinical Toxicology Research Collaboration
QRS 126 ms
Bicarbonate / Alkalinisation:
pH manipulation
Indications

Should be trialled in any broad complex
rhythm associated with poisoning
South Asian Clinical Toxicology Research Collaboration
Bicarbonate / Alkalinisation

Indications
Tricyclic antidepressants & Phenothiazines
Chloroquine
Antiarrythmics
Cocaine
Calcium Channel Blockers
? Organophosphates

Dose
1-2 meq/kg in repeated bolus doses
Titrated ECG
Target pH 7.5-7.55
South Asian Clinical Toxicology Research Collaboration
Case 2
• 15 year old boy
• Took 80 x 40 mg propranolol at a bus stop
and called ambulance 5 mins later
• On ambulance arrival; he had recurrent
seizures, GCS 3.
• Ensuing bradycardia and lost output enroute
to hospital – CPR commenced
• Broad idioventricular rhythm on arrival
Thoughts/Risk
assessment
• 15 y.o. – assume adult weight
• >40 mg/kg dose – toxic dose?
• Is clinical course described expected for
propanolol toxidrome?
• What immediate adjuncts to ALS can be
offered
Initial measures
• RESUSICTAION
• Secure airway
• Bicarbonate
• Hyperventilate
• 2mmol/kg initally
• Establish further access
• 1-2mmol/kg bolus every 3-5
mins
• Cont PALS algorithm
• Atropine
• 0.5 – 1.5 mg IV
• Titrated to ECG
• Target pH 7.55, Na <160
Healthy Myocardial Metabolism

Myocardial metabolism under normal
conditions
Stores of ATP in myocardium are low
Oxidative metabolism
 Citric
acid cycle
 Primarily FFA (80%) + carbohydrates (15%) = 95%
 FFA 80% at rest – more ATP produced but more O2
needed

ATP production 30 moles per mole of glucose
South Asian Clinical Toxicology Research Collaboration
Hantson P Clinical Toxicology (2012), 50, 166–171
Stressed Myocardial Metabolism

Myocardial depression
Reduced BP, reduced O2 delivery
Increased endogenous CCA release
 Increased
glycogenolysis and hyperglycemia
 Increased lipolysis
 Inhibition of insulin secretion
 Decreased sensitivity of tissues to insulin
Reduced myocardial FFA uptake and oxidation
 Reliance on anaerobic glycolysis for energy

effective ATP production – 2 moles per mole of
glucose
 Less
South Asian Clinical Toxicology Research Collaboration
Anaerobic glycolysis
High-dose Insulin-Euglycaemia - HIE

HIE
Myocardial energy normally derived from FFAs
In shock states energy derived from glucose
CCB poisoning inhibits pancreatic insulin secretion
BBs reduce myocardial FFA uptake and transfer to
mitochondria

Insulin thought to
 Improve
delivery of glucose to myocardium
 Improve coronary blood flow, contractility
 Increase lactate uptake
 Improve Ca flux into myocardial cells
 May have direct inotropic effect in high doses
South Asian Clinical Toxicology Research Collaboration
HIE
Onset of effect delayed by 15 to 60 minutes
Probably should be commenced sooner rather than later with
other inotropic agents
 Insulin dose
No studies to determine optimal dose
Most cases use 0.5-1.0 U/kg loading and 0.5 to 1.0 U/kg/h
Reports of up to 10 U/kg/h
 Glucose
Usually already elevated
Bolus dose 25 g + infusion to maintain BSL 6 -14 mmol/L
 Potassium
Will fall – suggested to replace if < 2.5 mmol/L

South Asian Clinical Toxicology Research Collaboration
2hrs later….
• Successful return of output at 30mins
• What about decontamination
• Remains hypotensive
• Ongoing therapies
• Inotropes vs HIET
• Then he has a further seizure
Case 3
• 22 y.o. female (wt 50kg)
• Ingests 90 x 500mg paracetamol (standard release
prep) at 2030
• Empty 2L cask of wine found on the counter
• Presents to hospital at 2330; drowsy and confused
• Initial Vital Signs
HR 110, BP 100/60, RR 18, afebrile
Sats 98% RA, GCS 11
• Further History
• Presented with a paracetamol overdose 5
days prior. Level found to be non-toxic. Did
not receive any further treatment or follow
up.
• No other medications found on premises
Assay
Level
Assay
Level
Paracetamol
Na+
140
ALT
3000
(micromol/L)
57
K+
4.1
AST
60
Creat
59
INR
1.4
BAL
0.08%
paO2
130
pCO2
30
HCO3
18
pH
7.1
Risk Assessment
• Significant toxicity
• Decontamination?
• Airway protection
• Appropriate NAC regimen
• Commence on arrival vs wait for level
Gastrointestinal Decontamination
don’t confuse mess with efficacy
Gastrointestinal Decontamination
•
•
•
•
•
Nothing
Emesis
Efficacy decreases with time
Gastric Lavage
Rarely indicated routinely
Or after 2 hours
Activated Charcoal
UNLESS massive ingestions
Whole bowel irrigation
Other thoughts
• Cause for reduced level of consciousness?
• Alcohol intoxication
• Related to paracetamol alone
• Other co-ingestant
• Cause for early acidosis?
• Liver failure
• Co-ingestants
• Effect of toxic paracetamol level?
Late one 1992 night

The phone rings.

A doctor informs us that they have just ceased
resuscitating a 14 year old girl who presented
following a chloroquine overdose. He asks, " if
there was anything I could of done".

We reply, "##@/etc there is little you can do
now, because she is dead”
South Asian Clinical Toxicology Research Collaboration
Case 1…Late one 1992 night

The phone rings.

A doctor informs us that they have just ceased
resuscitating a 14 year old girl who presented
following a chloroquine overdose. He asks, " if
there was anything I could of done".

We reply, "##@/etc there is little you can do
now, because she is dead”
South Asian Clinical Toxicology Research Collaboration
The question is:
When faced with an unknown toxic
cardiovascular surprise what interventions
would we think of using before we would cease
resuscitation?
 Can we develop a mnemonic?

If we have a mnemonic will we get air tickets to
exotic locations to use it?

We decide to use the alphabet to identify
antidotes
South Asian Clinical Toxicology Research Collaboration
The Toxic CVS mnemonic
A
B
C
D
E
F
G
H
I
J
K
L
M
N
O
P
South Asian Clinical Toxicology Research Collaboration
The Toxic CVS mnemonic
Atropine
Bicarbonate
Calcium
Diazepam
Epinephrine Extracorporal
Fab Antibodies
Glucose Glucagon
Human
Insulin Euglycaemia
Joules
K potassium
Lipids??
Magnesium
N
Oxygen
Phone a friend
South Asian Clinical Toxicology Research Collaboration
A
DRUG
INDICATION
DOSE
Atropine
Vagal
0.6 - 1.2mgs
Organophosphates
50-100mgs
B
Bicarbonate Alkalinsation
Tricyclic, Antipsychotics,
Cocaine, Verapamil
1-2 meq/kg in repeated bolus
doses. Target pH 7.5-7.55
C
Calcium Chloride/ Gluconate
Calcium Channel Blockers
1 gram bolus repeated every 3
minutes. Target calcium double
normal level
D
Diazepam
Chloroquine Cocaine &
Amphetamine
Up to 3 mgs/kg in chloroquine,
unitl sedated in cocaine
E
Epinephrine & Inotropics
Chloroquine
F
Fab Antibodies
Digoxin & Cardiac Glycosides
Dose based on ingestion or
concentration or titrated against
effect
G
Glucagon
Beta Blockers,Calcium
Channel Blockers
5-10 mgs IVI stat then infusion if
response
HI
Human Insulin Euglycaemia
Calcium Channel Blockers,
Beta Blockers
0.5 us/kg plus glucose see
protocol
South Asian Clinical Toxicology Research Collaboration
Red Flags
•
All slow, extended or control release drugs
are TOXIC
•
Delayed onset of action
•
Vital signs are vital
•
Change because of ongoing absorption
•
Man is smarter than the machine
•
Measure the ECG
•
When in doubt…phone a friend