Salicylates Tca Toxicity

Dr Hicham Al Mawla
2016
Objectives
Discuss the toxicological effects
of salicylate overdose
Identify key management issues
Discuss the limitations of the
Done nomogram and how to avoid
pitfalls of management
History
and Demographics
Hippocrates 5th century B.C.

Powder from the willow bark
1800s sodium salicylate for
arthritis
Abdominal pain
Felix Hoffmann
Acetylsalicylic acid (ASA)
Introduced 100 years ago
Antipyretic, analgesic, antiinflammatory
History
and Demographics
Decline in use, but

Prophylactic for migraine, colon ca
Antiplatelet agent
Decline in incidence of Reyes
Childproof caps 1970s
legislature
OTC meds
Combined with antihistamines,

caffeine, barbs, and opioids
Salicylate
formulations
Oil of wintergreen: 98% methyl
salicylate
1400 mg/mL
Bismuth subsalicylate
Aggrenox
Therapeutic
doses
Pediatric 10-20 mg/kg

Adults 650-1000 mg q 4-6 hrs
Produce a serum level of 5-10 mg/dL
Potential
Toxic Acute dose >
150 mg/kg
Serious toxicity: 300-500 mg/kg
Chronic toxicity: >100
mg/kg/day
Peak
levels
Therapeutic 1-2 hours

Therapeutic EC 4-6 hours
OD 10-60 hours
Reason for delay ? Concretions,
contraction of the pylorus or
combination of drugs that delay
gastric emptying (opioids and
anticholinergics)
Liquids absorbed in 1 hr
Distribution
is facilitated by
pH
Elimination dependent on dose
First order kinetic to zero order
From 4 hours to 15-29 hours
A 24-year-old male presented to the

ED with nausea, vomiting, tinnitus,
and tachypnea after ingesting 100
aspirin tablets. His 4-hour
salicylate level was 78 mg/dL; Chem8 revealed Na 143, Cl 105, K 4.2,
HCO3 17; the ABGs showed pH 7.38, pO2
107, and pCO2 27 on room air. He was
initially treated with reasonable
volume and admitted to the ward.
Orders
for sodium bicarbonate

were given to alkalinize the
urine, but this was ineffective
in raising urine pH.
Approximately 6 hours later the
attending was notified that the
patient had become confused.
He was transferred to the ICU
where he was sedated and
intubated.
Approximately
20 minutes
after
intubation,
the patient
rapidly
deteriorated
and died.
ASA is hydrolyzed to salicylic acid

Responsible for therapeutic and toxic
effects
Direct stimulation of respiratory

center
Medulla
Uncouples oxidative phosphorylation

Increase in O2 consumption and CO2
production
Increase respiration
Respiratory alkalosis
Renal
and K
excretion of bicarb, Na
Metabolic acidosis
Inhibition
of mitochondrial
respiration
Increase pyruvate and lactic acid

Metabolic acidosis
Disruption
of Krebs cycle
metabolism and glycolysis
Hyperglycemia, ketonemia
Dehydration
Hyperpnea
Diaphoresis
Vomiting
Fever (increased muscle metabolism)
Vasoconstriction of auditory
microvasculature
Enhance insulin secretion =>
hypoglycemia
Decrease peripheral glucose
utilization => hyperglycemia
Increase
permeability of
pulmonary vasculature
Increase the production of
leukotrienes
Stimulate medullary
chemoreceptor trigger zone
Hematologic effects
ASPIRIN Mnemonic
Altered mental status (lethargy coma)
Sweating/diaphoresis
Pulmonary edema
Increased vital signs (HTN, inc RR, inc
T, tachycardia)
Ringing in the ears
Irritable
Nausea and vomiting
Early
Nausea, vomiting, diaphoresis,
tinnitus, deafness
Level 25-30 mg/dL
Hyperventilation
Later
Hypotension, NCPE, oliguria,
acidemia, cerebral edema,

delirium, seizure, coma
Classic
acid-base disturbance
AGMA
Respiratory alkalosis with
metabolic acidosis
Acidemia
Increases tissue distribution

Brain, heart, lung
Severe
hypokalemia
NCPE
Older patients
Smokers
Levels >100 mg/dL
Acidemia
CNS involvement (hallucinations,
sz)
Chronic toxicity
Features
Acute
Chronic
Age
Young
adult
Overdose
Older
adult/infants
RX misuse
Coingestions
Frequent
Rare
Mental
status
Normal
Altered
Presentation
Early
Late
Mortality
Low w/ Rx
High
Serum levels
40 to >120 30 to >80
Etiology
Salicylate
level
Peak 4-6 hr
EC and SR preparations late rise
Every 2-4 hours until clearly
decreasing
Then q 4-6 until <30 mg/dL
Always confirm units!

Mg/dL vs. mg/L
Done
Nomogram (Pediatrics 1960)
NOT USEFUL for

Chronic
ingestions
Liquid
preparations
EC or SR
Acidemia
Renal failure
Unknown time of
ingestion
Methylsalicylate
Severity of ingestion
Serum levels
Acid-base status
Acuteness of ingestion
Mental status
Bedside Tests
Trinders reagent 10%
ferric chloride
Ames phenistix
Chemistry
Panel
Q 4-6 h
LFTs
Coagulation studies
ABGs
APAP
Consider: CT, Serum
osm,
ketones, LP, CO, serum Fe,
blood cultures
Gastric lavage / WBI

Activated charcoal - MDAC
Hydration and electrolyte replacement
Correct hypokalemia aggressively
Urine alkalinization
Increase salicylate excretion

1-2 mEq/kg NaHCO3 bolus IV
Then 150 mL in 850 ml D5W run 1.5-2 times
maintenance
Caution in elderly and chronic
Monitor UO
Dialysis
Serum levels > 100 in acute

Levels > 60 in chronic
Pulmonary edema
Renal failure
CHF
Poor response to standard Rx
AMS and acidemia
Enteric
Coated aspirin
Can cause delayed symptom onset
Don't
wait for clinical

deterioration.
Alert you nephrology team early
and call the poison center even

earlier.
Serial
salicylate levels are

imperative.
One teaspoon of methyl salicylate

contains 7,000 mg of salicylate which
is equivalent to approximately 21
regular strength aspirin tablets!
The presence of fever is a poor
prognostic sign in adults!
Cerebrospinal fluid salicylate levels
correlate with symptoms better than
blood levels
The
Done nomogram, has limited

usefulness
Be aware of the proper unit of
measure
(mg/dL not mg/L or g/L or
mmol/L)!
Start
potassium supplementation
early (in the absence of renal
insufficiency) because
hypokalemia makes urinary
alkalization impossible!
Multiple-dose activated
charcoal and alkalinization are
currently the most popular
methods of treatment.
Be
aggressive. Dialyze early if

signs of toxicity are evident.
ASA
and elderly
Impaired renal function

Decreased elimination
Impaired hepatic function
The risk of salicylate
nephrotoxicity is increased with

age,
Upper gastrointestinal bleed is
associated with increased mortality
in older age groups.
Mortality
and Epidemiology
From 15% to 1.7% in 1977

Second leading cause of death from
overdose in US (Analgesics first).

Approximately 500,000 overdoses
annually
Female, age 20-29, single,
employed, no history of drug abuse
Approximately 70% die pre-hospital
Indications
Depression
Chronic pain syndromes
OCD
Panic and Phobic disorders
Migraine prophylaxis
Peripheral neuropathies
Acute
Toxic Doses
Fatal ingestions range 10-210
mg/kg
2-4 mg/kg is therapeutic, 20 mg/kg
is potentially fatal
Variable response
Absorption
Rapidly and completely absorbed
Massive OD delays absorption
Enterohepatic re-circulation secretes
30%
Distribution
Wide range in Vd (15-40 L/kg)
Genetic variation
Lipophilic
Elderly has higher Vd
Distribution
(contd)
Tissue levels usually 10 times
plasma levels
Protein binding usually exceeds 90%
with some variations
pH dependent
Elimination
Genetic component
Metabolism influenced by other
drugs
Therapeutic
effects
Not completely understood

Blocks serotonin and NE uptake
Anticholinergic effects
Cardiac
Effects
Sinus tachycardia, dysrhythmias

Na channel blockade quinidine effect
Hypotension
Alpha adrenergic blockade and NE
depletion
Conduction delays / blocks
CNS
Anticholinergic
Excitation, confusion, hallucination,
ataxia
Seizures
Coma
Respiratory
Pulmonary edema
ARDS
Aspiration pneumonia
Gastrointestinal
Delayed gastric emptying

Decreased motility
Prolonged transit time
Case #1
25 year-old man ingested 60 tablets
of Elavil 50 mg each. He presented to
the ED about 45 minutes post
ingestion agitated and confused.
Possibly hallucinating. BP 145/94, P
112, R22, T99.6. He became more
agitated and combative and was
intubated, lavaged and given AC.
EKG revealed QRS 108 with rate 114
What are the critical ECG changes?
Prolongation of the QRS complex:

Blockage of fast sodium channels slows
phase 0 depolarization of the action
potential.
Ventricular depolarization is delayed,
leading to a prolonged QRS interval.
Patients with QRS intervals >100 ms are
at risk for seizures and patient with
QRS intervals >160 ms are at risk for
arrhythmias.
QRS interval is evaluated best using
the limb leads.
R wave in aVR >3 mm:

greater selectivity and toxicity to the distal
conduction system of the right side of the
heart.
effect can be observed as an exaggerated height
of the R wave aVR.
may be more predictive of seizure and arrhythmia
than prolongation of the QRS complex.
R/S ratio >0.7 in aVR

QT interval prolongation
Arrhythmias
How do you treat this?
ABCs
Activated Charcoal: 30-50 gm
Sodium
Bicarbonate
Dose
Endpoint
What
is the mechanism?
Alkalinization
appears to uncouple TCA from
myocardial sodium channels.

Alkalinization may increase
protein binding
Increases
the extracellular
sodium concentration
improves the gradient across the
channel.
The initial bolus of 1-2 mEq/kg

A constant infusion of sodium
bicarbonate
commonly accepted clinical practice
without any controlled studies

validating the optimum administration
100 to 150 mEq of sodium bicarbonate
to each liter of 5% dextrose,
the resulting solution is hypotonic or
nearly isotonic.
What
if NaHCO3 doesnt work?
may require treatment with
lidocaine and/or magnesium

sulfate.
Class Ia and Ic agents
contraindicated
Beta blockers and CCB
Worsen or potentiate hypotension
Hypotension, Persistent
Direct acting alpha agonists, such as
norepinephrine and phenylephrine

Dopamine may not be as effective
Require release of endogenous catecholamines
that may be depleted during TCA toxicity.
Dopamine or dobutamine alone may result
in unopposed beta-adrenergic activity

due to TCA induced alpha blockade and,
therefore, may worsen hypotension.
Vasopressin (ADH)
What about Seizures from TCA

Usually
brief (<1 min)

self-limiting
acidosis increase cardiovascular toxicity.
Benzodiazepines
Phenytoin is no longer recommended
limited efficacy and possible
prodysrhythmic.
Phenobarbital may be used as a long-acting
anticonvulsant.
Agitation from TCA

Anticholinergic effects
Benzodiazepines are also the treatment of
choice
Physostigmine is contraindicated in TCA
overdoses
May cause bradycardia and asystole in the
setting of TCA cardiotoxicity.
Flumazenil is contraindicated even in the
presence of a benzodiazepine coingestion.

Several case reports - seizures
Emergency
department discharge
criteria
At least 6 hour observation period
No significant sign of toxicity during
observation period, including normal

follow-up ECG prior to discharge
Accidental ingestion
Appropriate follow-up measures in place
Adequately supervised home environment

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Dr Hicham Al Mawla

Hippocrates 5th century B.C.

Decline in use, but

Combined with antihistamines,

Oil of wintergreen: 98% methyl

Pediatric 10-20 mg/kg

Toxic Acute dose >

Therapeutic 1-2 hours

A 24-year-old male presented to the

for sodium bicarbonate

ASA is hydrolyzed to salicylic acid

Direct stimulation of respiratory

Uncouples oxidative phosphorylation

Increase pyruvate and lactic acid

acidemia, cerebral edema,

Increases tissue distribution

Always confirm units!

Nomogram (Pediatrics 1960)

NOT USEFUL for

Gastric lavage / WBI

Increase salicylate excretion

Serum levels > 100 in acute

Can cause delayed symptom onset

wait for clinical

Alert you nephrology team early

and call the poison center even

salicylate levels are

One teaspoon of methyl salicylate

Done nomogram, has limited

aggressive. Dialyze early if

Impaired renal function

nephrotoxicity is increased with

From 15% to 1.7% in 1977

overdose in US (Analgesics first).

Fatal ingestions range 10-210

Tissue levels usually 10 times

Not completely understood

Sinus tachycardia, dysrhythmias

Delayed gastric emptying

Prolongation of the QRS complex:

R wave in aVR >3 mm:

R/S ratio >0.7 in aVR

myocardial sodium channels.

The initial bolus of 1-2 mEq/kg

without any controlled studies

if NaHCO3 doesnt work?

may require treatment with

lidocaine and/or magnesium

norepinephrine and phenylephrine

Dopamine or dobutamine alone may result

in unopposed beta-adrenergic activity

What about Seizures from TCA

brief (<1 min)

Agitation from TCA

Flumazenil is contraindicated even in the

presence of a benzodiazepine coingestion.

observation period, including normal

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