Toxicology cases

Dr James Dear
Edinburgh University
 Consultant posts coming up in Edinburgh!

1or even 2 in Clinical Pharmacology

1 in Toxicology
Edinburgh Sri Lanka -
Clinical Clinical and public
health intervention
Toxicology Clinical trials of
studies on pesticide &
NAC for PCM
poisoning plant self-poisoning
Research ME
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Biomarker studies
Antidote - exosomes,
RESEAR microRNAs
development
(human, pig, fish) CH (human, pig, fish)
thiamine, cyanide, 3 PIs, JD
NAC 12 staff &
ME
students MINIPIG ICU
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ME
Case 1.

59 M Hospital in North of England

Patient presented at 11 am in morning.

Came to HDU at 3 pm.

Claims to have taken an overdose but will not disclose what taken other than co-codamol.

Estimated 50+ tablets. Paracetamol 49 mg/L at an unknown time. Salicylate undetectable.

Other meds include statin, adcal, amlodipine, thiamine, salbutamol, alendronic acid, frusemide, omeprazole.

BP low but responding to fluid, systolic 105.

Liver Function Tests AST 60, raised but lower than normal (normally ast and alt in 90s)

Urea, Electrolytes + Creatinine Creat 186 on admission, now 124 with fluids (normally 64)

Arterial Blood Gases (ABG's) H+ 90, pH 7.01, bicarb 5, serum lactate 25.

Question : What is the cause of acidosis?

Case 1.

59 M Hospital in North of England

Denies taking methanol or ethylene glycol but smiled when he denied it and has access to toxic
alcohols through work.

Measured osmolality 370, calculated 310

Ethanol 207

OSMOLAL GAP = [MEASURED OSMOLALITY- CALCULATED OSMOLALITY]

Calculated osmolality = (2x[sodium]) + [potassium] + [urea] + [glucose]

(All should be measured in mmol/L)
The normal osmolal gap is about 10 mOsm/kg H20
A significant osmolal gap is > 10-15 mOsm/kg H20
Case 1.

59 M Hospital in North of England

Indications for treatment with fomepizole (or ethanol)

high anion gap metabolic acidosis

OR

osmolal gap greater than 10 mosmols/kg without there

being another likely cause (e.g. ethanol intoxication)
Case 1.

59 M Hospital in North of England

Indications for haemodialysis are any one of the following:

Ethylene glycol concentration greater than 500 mg/L (0.5 g/L; 8 mmol/L)
Severe metabolic acidosis
Renal failure
Deteriorating condition despite supportive measures
Severe electrolyte imbalance
A desire to shorten the duration of the poisoning

Dialysis should be continued until:

Plasma ethylene glycol concentration is undetectable

AND

Acidosis and signs of systemic toxicity have resolved

Case 2. Vietnamese Male Age unknown. Hospital in midlands.

Patient was involved in a house fire in a house containing cannabis plants.

He was GCS 3/15 at the scene but at the time of the call was GCS 15/15.

He is currently receiving airway resuscitation due to inhalation injury and has

been intubated for this.

Arterial blood gas sample- pH 7.28, pCO2 5.2, CO = 30%, lactate 12, base
excess = -7.5.

Initial carboxyhaemoglobin was 38% but now 30% and has been receiving
100% oxygen for the last hour.

Question is this cyanide toxicity?

 Case 2. Vietnamese Male Age unknown.
Hospital in midlands.

Cyanide has a high affinity for mitochondrial cytochrome oxidase

and inhibition leads to anaerobic metabolism and lactic acidosis.

The degree of lactic acidosis correlates with the severity of

poisoning

The cytochrome oxidase-cyanide complex dissociates through an

enzymatic reaction that transfers sulphur (from endogenous
thiosulphate) to cyanide with the formation of thiocyanate, which is
subsequently excreted by the kidneys.

Other endogenous methods of cyanide detoxification include binding

to methaemoglobin, reaction with cysteine and incorporation into
choline and methionine.
 Case 2. Vietnamese Male Age unknown.
Hospital in midlands.

In the absence of a cyanide concentration the following features suggest cyanide poisoning:

Lactate > 7 mmol/L

Elevated anion gap acidosis

Reduced arterio-venous oxygen gradient

MILD POISONING

Features: nausea, dizziness, drowsiness, hyperventilation, anxiety.

Lactate concentration < 10mmol/L.Cyanide concentration < 1 mg/L (38 micromol/L)

MODERATE POISONING

Features: reduced conscious level, vomiting, convulsions, hypotension.

Lactate concentration 10 15 mmol/L Cyanide concentration 1-3 mg/L (38-114 micromol/L).

SEVERE POISONING

Features: coma, fixed dilated pupils, cardiovascular collapse, respiratory failure, cyanosis.
Lactate concentration >15mmol/L Cyanide concentration > 3 mg/L (114 micromol/L).
Case 2. Vietnamese Male Age unknown.
Hospital in midlands.

MILD POISONING

Give 25 mL of 50% sodium thiosulphate (12.5 g) intravenously

MODERATE POISONING

Give 20 mL of 1.5% dicobalt edetate solution (300 mg) IV over 1 minute followed immediately by 50 mL of 50%
dextrose in adults.

OR

If dicobalt edetate is not available, give 25 mL of 50% sodium thiosulphate (12.5 g) intravenously over 10 minutes
for an adult.

SEVERE POISONING

In an adult give 20 mL of 1.5% dicobalt edetate solution (300 mg) IV over 1 minute followed immediately by 50 mL
of 50% dextrose.

OR

If dicobalt edetate is not available, give 10 mL of 3% sodium nitrite solution (300 mg) IV over 5-20 minutes. The
dose in children is 0.12-0.33 mL/kg or 4-10 mg/kg (maximum 10 mL or 300 mg).
AND
25 mL of 50% sodium thiosulphate (12.5 g) IV over 10 minutes. The paediatric dose of sodium thiosulphate is 400
mg/kg (0.8 mL/kg of 50% solution) intravenously (Note that the paediatric dose is higher than the equivalent adult
dose).
Case 2. Vietnamese Male Age unknown.
Hospital in midlands.

Dr James Dear spoke to caller directly. He later called me back and confirmed
that he was GCS 4/15 at the scene and was brought into department GCS
15/15.He said that the patient's condition was unlikely to be due to cyanide
toxicity and more related to carbon monoxide poisoning-which was also
confirmed by Professor Nick Bateman with whom Dr Dear spoke with. Dr Dear
said the raised lactate was due to the hypoxia. He also confirmed the patient
was stable with respect to the patient's cardiovascular status. Advised
symptomatic and supportive care from this point onwards.
Case 3. Male Age unknown. Hospital in North-West of England

Patient has taken 1 month worth of all his medications

Presented at 4am - and was thought to be asymptomatic at the time since
then his BP has dropped markedly and his lactate has increased to 9.6

Agent 1 Metformin 20.50 Grams

Agent 2 Carbamazepine 16.80 Grams
Agent 3 Diltiazem 5.60 Grams
Agent 4 Felodipine 70.00 Milligrams
Agent 5 Tamsulosin 11.20 Milligrams
Agent 6 Doxazosin 36.00 Milligrams
Agent 7 Mirtazapine 840.00 Milligrams
Agent 8 Lansoprazole 420.00 Milligrams
Agent 9 Perindopril 224.00 Milligrams
Agent 10 Atorvastatin 560.00 Milligrams
Agent 11 Aspirin 2.10 Grams

Question: Which of these are bad and how are they

managed?
Case 3. Male Age unknown. Hospital in
North-West of England

Advised to give IV calcium and transfer to HDU/ITU where they can begin on high
dose insulin dextrose. They can be given vasopressors as needed and IV bicarb
for acidosis as well as MDAC for the carbamazepine. If acidosis and hypotension
were to continue could try haemodialysis. Have intralipid ready in case need to
use it and also can give metraminol if required.
 What is the evidence
HDI works?

Human data around 70 people

Case reports and case series

Does HDI work in humans calcium channel blocker
 Why does HDI work?

Is it just an inotrope or is there something

special about calcium channel blockers?
 How does HDI work metabolic view

Blockade of L-type calcium channels impairs insulin release by

the pancreatic -islet cells and impairs glucose uptake by tissues
by altering sensitivity to insulin

Serum glucose concentrations correlate directly with the

severity of CCB poisoning. Levine et al. 2007.

Under stress the myocardium utilizes glucose as main energy

store

Calcium channel blockers produce a state of energy starvation

 Metabolic effects of HDI
Insulin increases glucose and lactate
uptake by myocardial cells and improves
function

Induces pyruvate dehydrogenase which

increases myocardial lactate oxidation and
breaks down glycolytic byproducts that
impair calcium handling
Does HDI work in humans beta blocker
Is there clinical evidence that HDI work in
non CCB/BB poisonings?
 Case 4

A 27 year old man is found unconscious surrounded by

packets of amitriptyline and venlafaxine (slow release).
On arrival in ED his pulse is 110 bpm, BP 109/67mmHg,
GCS 12/15.
An ECG is performed:
What does this ECG demonstrate?

A) Atrial fibrillation
B) Broad-complex tachycardia
C) Narrow complex tachycardia
D) Normal sinus rhythm
What does this ECG demonstrate?

A) Atrial fibrillation
B) Broad-complex tachycardia
C) Narrow complex tachycardia
D) Normal sinus rhythm
 Given the clinical history of amitriptyline and
venlafaxine overdose, what is the
pathophysiological basis of this abnormal cardiac
rhythm?

A) Beta blockade
B) Calcium channel blockade
C) Potassium channel blockade
D) Sodium channel blockade
 Given the clinical history of amitriptyline and
venlafaxine overdose, what is the
pathophysiological basis of this abnormal cardiac
rhythm?

A) Beta blockade
B) Calcium channel blockade
C) Potassium channel blockade
D) Sodium channel blockade leading to
prolongation of the cardiac action
potential with resultant QRS widening
and potential for ventricular arrhythmias
Given the ECG findings what is the
first line of management?

A) Amiodarone
B) Calcium
C) Magnesium
D) Sodium bicarbonate
Given the ECG findings what is the
first line of management?

A) Amiodarone
B) Calcium
C) Magnesium
D) Sodium bicarbonate
 From Toxbase
Even in the absence of an acidosis, consider
alkalinisation with IV sodium bicarbonate in patients
with:

QRS duration greater than 120msec

Arrhytmias
Hypotension resistant to fluid resuscitation
 The patient is started on intravenous sodium
bicarbonate and the ECG QRS duration is reduced.
Then the patient has a 3 seizures despite treatment with
a benzodiazepine. What anti-epileptic drug should be
used to terminate these drug-induced seizures?

A) Carbemazepine
B) Phenobarbital
C) Phenytoin
D) Sodium valproate
 The patient is started on intravenous sodium
bicarbonate and the ECG QRS duration is reduced.
Then the patient has a 3 seizures despite treatment with
a benzodiazepine. What anti-epileptic drug should be
used to terminate these drug-induced seizures?

A) Carbemazepine
B) Phenobarbital
C) Phenytoin CONTRAINDICATED
D) Sodium valproate
 A few hours later the patients seizures have
settled and a repeat ECG is performed:

What does this ECG demonstrate?

 At risk

Low risk

If the nomogram indicates a risk of torsade de pointes, particularly in the presence of other risk factors
(e.g. frequent ectopics, underlying structural heart disease), consider administration of magnesium
sulphate IV over 10-15 minutes: adults 2 g (8 mmol Mg2+), children 25-50mg/kg (max 2g) (repeated once
if necessary).

Torsade de pointes and VT/VF preceded by prolonged QT should be treated with magnesium sulphate 8
mmol (2 g, or 4 mL of 2 mmol/mL solution) in adults and 25-50mg/kg (max 2g) in children intravenously
over 30-120 seconds, repeated twice at intervals of 5-15 minutes if necessary. Torsade de pointes may
respond to increasing the underlying heart rate through atrial or ventricular pacing or by isoprenaline
(isoproterenol) infusion to achieve a heart rate of 90-110 beats/minute.

Drugs that prolong the QT interval (e.g. amiodarone, quinidine) should be avoided in the presence of QT
prolongation and after torsade de pointes.
 The patients condition has deteriorated significantly
with his blood pressure being barely recordable and his
cardiac monitor demonstrating runs of VT.
His ECG now:
The patients condition has deteriorated significantly with
his blood pressure being barely recordable and his
cardiac monitor demonstrating runs of VT.
What treatment should be considered?

A) Calcium
B) Haemodialysis
C) Insulin/Dextrose
D) Intralipid
The patients condition has deteriorated significantly with
his blood pressure being barely recordable and his
cardiac monitor demonstrating runs of VT.
What treatment should be considered?

A) Calcium
B) Haemodialysis
C) Insulin/Dextrose
D) Intralipid
Intralipid
 Do you believe Intralipid works?

A) Yes
B) No
C) Depends
D) Dont know
 Do you believe Intralipid works?

A) Yes
B) No
C) Depends if you said depends on
what?
D) Dont know I dont know!
Intralipid
 Intralipid fact or fiction
1. Most patients with TCA poisoning who reach
hospital survive

In single centre study only 1 out of 302

patients died despite significant toxicity
 Intralipid fact or fiction
2. Lipid sink theory creating a pool of lipid for drug

500ml intralipid contains 100g fat

Average human body contains 10,000g

Is it likely that sink theory can make big difference?

 Intralipid fact or fiction
3. Could intralipid increase drug absorbtion?

ORAL DOSING
 Is it too late now for intralipid?
45 Directors of US poisons centers - all felt intralipid had a role in
poisoning

in setting of cardiac arrest:

intralipid administered always or often
bupivacaine (43 out of 45), verapamil (36 out of 45),
amitriptyline (31 out of 45).

in setting of shock;
intralipid administered always or often
bupivacaine (40 out of 45), verapamil (28 out of 45),
amitriptyline (25 out of 45)
Key messages

QRS complex broadening reflects sodium channel

blockade
Treatment should be with sodium bicarbonate

QT interval prolongation reflects potassium channel

activity
Treatment is with magnesium

Seizures in the context of sodium channel blocking

drugs should not be treated with phenytoin

Intralipid is an option for severe cardiotoxicity but the

jury is out regarding efficacy
Case 5 Male unknown age. Boxing Day. Hospital in North-west England.

Presented to A&E 4am. Went into cardiac arrest at a nightclub approx 3.45am,
resuscitated by paramedics on scene. Two further cardiac arrests in A&E,
given adrenaline, spontaneous circulation since

Temp 40.

GCS 9

Agitated +++

BP 105/60, HR 77.

Arterial Blood Gases (ABG's) pH 7.127, pCO2 5.06, pO2 13, Bi 12.1, BE -15

Urea, Electrolytes + Creatinine U 9.2, Cr 219, K 8.5, Na 131 CK 38000

What is the likely poison/syndrome?

 3,4-methylenedioxymethamfetamine
(MDMA - ecstasy)

MDMA causes release of serotonin, and to a lesser extent

dopamine, in the brain.

Central and peripheral catecholamine release also occurs.

Severe toxicity include cardiac arrhythmias,

hyponatraemia., convulsions, delirium, coma, hypotension
and cardiovascular collapse.

MAY LEAD TO SEROTONIN SYNDROME

SEROTONIN SYNDROME
SEROTONIN SYNDROME
 SEROTONIN SYNDROME

MANAGEMENT

Stop the causal drugs

Cooling

Benzodiazepines

Specific 5HT2 receptor antagonists

Milder cases: Cyproheptadine Severe

cases: Chlorpromazine
 Case 6
19 year old female
Attends A&E having taken 25g of paracetamol and 1g of
amitriptyline 30 minutes previously. Toxbase recommends
immediate charcoal therapy for this life threatening overdose.

The women has been brought to A&E by a friend. The patient has
no history of deliberate self-harm, is not intoxicated and is fully
alert. She states her friend convinced her to come and she still
wishes to die.

The patient refuses any investigations or treatment despite

repeated requests from staff and her friend. No other family
members are available

How would you manage this patient?

Options

1. A psychiatrist deems the woman to be mentally competent

and fully aware of her situation, but you would forcibly
detain her under common law

2. You would first assess the patients capacity for

consent/refusal of treatment before applying common law

3. You would investigate the patient against her will, but in her
best interests, by measuring her paracetamol levels at 4
hours

4. Your would, against her will, but in her best interests, treat
her by, sedation, passing an NG tube and giving charcoal
A competent adult can refuse treatment even when doing so may result in
permanent physical injury or death

All people aged 16 and over are presumed, in law, to have capacity to consent
to treatment unless there is evidence to the contrary

A patient with a mental illness does not, necessarily, lack competence to

consent to treatment

The fact that a decision is irrational or unjustified should not be taken as

evidence that the individual lacks capacity
To demonstrate capacity individuals should:

Understand in simple language what the treatment is, its purpose

and nature and why it is being proposed

Understand its principal benefits, risks and alternatives

Understand what the consequences of not receiving treatment are

Believe the information

Retain the information for long enough to use it and weigh it in the
balance in order to arrive at a decision

Communicate the decision

 Patient presents to A&E refusing treatment

Doctor must assess capacity and record assessment

understands, believes and is able to weigh up

Psychiatrist must assess patient if mental illness is possible as

may be affecting capacity

Competent - cannot treat Not competent

Explain that can change decision, Essential treatment only
Try to persuade Capacity may change
Use family
 Case 7

44 year old male

Found collapsed at home by his wife. He is brought to A&E drowsy, smelling of
alcohol having been found surrounded by empty packets of diazepam and
paracetamol
When his wife found him there was a note that she confirms is from the patient:
Date : Today
Please do not treat me at all
Signed : patient

His wife has now gone and you cannot contact her
How would you manage this patient?
 Case 8
67 year old male
Found collapsed at home by his wife. He is brought to A&E GCS 5 with
a compromised airway having been found surrounded by empty
packets of diazepam.

The patient has a long history of crippling rheumatoid arthritis.

The patients wife gives you an advance directive completed five years
ago. The patient had seen family die in ITU and did not want that for
himself. The advance directive stated that if the patient were to
deteriorate he did not want life-sustaining treatment. The advanced
directive was agreed and signed by the patients GP. His wife does
not want to make the decision.

How would you manage this patient?

 What makes an advanced directive valid?

SCOTLAND DIFFERENT TO ENGLAND AND WALES

In England and Wales the Mental Capacity Act enshrined in law the right of an
adult with capacity to make an advance directive to refuse a specific treatment at a
future time when they lack capacity.

In Scotland no statute law but common law supports advance directives and we
need to take them into account.
Key points from England and Wales

1. Patient must be a competent adult at time of completion of AD

2. If referring to life-saving treatment the AD MUST be in writing,

signed and witnessed and include a specific statement that it
applies to a specific treatment even if life at risk.

3. Must be valid at time. If evidence that patient has changed mind

over time, for example done something against the AD, then
invalid. Withdrawal of AD does not need to be in writing

4. Must be applicable to the current situation

If doubt exists it is acceptable to provide life saving treatment until

courts decide.
In overdose setting

1. Was the patient competent at time of writing AD? Was there significant
mental illness?

2. Does the AD specifically apply to overdose? Often quickly reversible if

intubated and ventilated

3. Has the person changed since writing AD? Five years ago may not have
been depressed, but now significant depression?
Friday 6th September 2013