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Salicylate Toxicity

A Clinical Case Presentation
by

Dayne Laskey

on 11 July 2012

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Transcript of Salicylate Toxicity

Salicylate Toxicity
Objectives:
(cc) image by jantik on Flickr
Patient case
Hippocrates reports the antipyretic, antiinflamatory, and analgesic properties of willow bark. Willow enters the materia medica.
(cc) image by jantik on Flickr
Ancient Empires
1800s
1900s
1826
German chemist Johann Andreas Buchner isolates and names salicin from the bark of the white willow (salix alba)
400 BC
2000 BC
Sumerian medical text lists willow amongst other natural remidies.
1. Explain the mechanism of salicylate toxicity and rationale for treatments.

2. Identify the physiological effects of mild, moderate, and severe salicylate overdose.

3. Discuss indications and contraindications for specific elimination and/or decontamination measures.

4. Describe specific treatment for salicylate overdose.

(cc) image by nuonsolarteam on Flickr
History of Salicylate Poisoning
1838
Italian chemist Raffaele Piria splits salicin into two components - a sugar and an acid that is more potent than the salicin extract. He names this new component salicylic acid.
2000s
A 32-year-old African-American female:
"I took a whole bottle of pills for my toothache last night and now I have ringing in my ears."
Complains of nausea, diaphoresis, and has been experiencing generalized weakness
1899
Bayer receives a patent on ASA and releases it under the trade name "Aspirin"
1913
Hanzlik, PJ. "A study of the toxicity of salicylates based on clinical statistics." JAMA. 60(13):957-962. 1913.

A retrospective study of 400 patients treated with a common regimen of 10-20 grains (650-1200 mg) hourly finds that mean toxic dose is 165 grains (10 g). Report is largely ignored.
1917
July, 1918
May, 1918
Bayer loses patent on Aspirin. Many other manufacturers jump into the market
1918 H1N1 Pandemic
Influenza pandemic breaks out in Spain
Increased influenza mortality is noted in London. 5-10% of patients develop a strange, unexplained bronchopneumonia
August, 1918
H1N1 hits the US.
2000 sailors fall ill in Boston
October 5, 1918
JAMA recommends Aspirin for relief of flu
"The acetylsalicylic acid may be given in a dosage of 15 grains (1000 mg) every three hours...or a smaller dose combined with 2 grains (100 mg) acetophenetin, until symptomatic relief is secured."
Bayer loses patent on Aspirin
No warnings or instructions on bottles
Toxic doses and kinetics are unknown
Frequencies are unspecified
Daily doses range from 8-31.2 grams daily
One London doctor's report for the British Ministry of Health details "drenching" his patient with Aspirin, giving "20 grains (1300 mg) hourly for 12 hours nonstop"
A Perfect Storm for ASA Toxicity
Reports of the pandemic note some peculiar findings
As many as 10% of patients develop pulmonary edema with no accompanying leukocytosis
Autopsies show thin, bloody liquid in lungs
Brain weight is increased by ~100-200 g in 50% of deaths
Swollen kidneys, liver
1940s
The ability to measure ASA blood levels is developed
1948
Graham and Parker first correlate blood level with toxicity
1960s
Levy first demonstrates non-linear kinetics of ASA
When total drug in serum reaches ~360 mg, kinetics become 0 order, T1/2 increases dramatically
Pharmacology
Salicylate Products in the USA
Bismuth Subsalicylate
Pepto-Bismol
May contain up to 525 mg/15 mL
Acetylsalicylic Acid
Bayer, Goody's Powder, BC Powder, Excedrin, many combinations
Tablets come in 81, 325, 500, 650 mg
Salicylic Acid
Wart remover, acne medication, "natural" willow
Methylsalicylate
1 g = 1.4 g ASA equivalents
Bengay, IcyHot: ~20-37% by weight
Oil of Wintergreen: 98% by weight
In a 10-kg child, 1 mL of Oil of Wintergreen equates to 140 mg/kg of salicylates. This puts it on the "mouthful can kill" list.
Therapeutic Mechanism
At recommended doses:
At Therapeutic Dose
In Overdose
Peak
Vd
Pharmacokinetics vs Toxicokinetics
Protein Binding
Metabolism
T 1/2
Kinetics
~1 h
0.2 L/kg
90%
Renal Excretion
2-4 h
1st Order
~4 h
70%
Renal Excretion
>20 h
Zero Order
0.5 L/kg
4 Steps to Toxic Exposure Management:
Stabilization and
Supportive Care
Decontamination and Enhanced Elimination
Antidote:
Alkalinization
Alkalinization:
Rationale
Alkalinization:
Procedure
Expert Opinion
CAB
Rehydration
Seizure control
Activated Charcoal
Dialysis
Whole-bowel Irrigation
Management
Monitoring
Dayne Laskey, PharmD
PGY-1 Toxicology Fellow
Grady Health System
Mechanisms of Toxicity
Gastrointestinal
Direct irritation to GI mucosa
Hemorrhagic gastritis
Decreased gastric motility
Pylorospasm
Centrally-mediated nausea
Vomiting
Electrolyte losses
Hypokalemia
Central Nervous System

Direct stimulation of respiratory center
Moderate/High Toxicity
Tachypnea
Hyperpnea
Respiratory alkalosis
Initial neuronal excitation
Latent CNS depression
Moderate Toxicity
Confusion
Agitation
High Toxicity
Respiratory Center
Neuronal Activity
Delirium
Psychosis
Seizure
Stupor
Coma
Pulmonary
Increase in capillary permeability
Pulmonary edema
More likely in chronic toxicity
2009 AAPCC Statistics
Analgesics were the most common exposure among humans
20,227 Pure salicylate exposures
5,714 Required treatment at a healthcare facility
37 Deaths had a salicylate listed as the first ingredient
Chemistry
Acidic - pKa 3.5
Ionized at higher pH
Unionized at lower pH
Absorbtion can be affected by:
pH of GI
Salicylate-induced pylorospasm
Pyloric stenosis
Dosage form (ex. effervescent, enteric coated)
Bezoar formation
Non-selective COX inhibition
Inhibits prostaglandin formation
Anti-inflammatory
Analgesic
Anti-pyretic
Platelet inhibition
[Acidosis is usually more profound]
Concurrent CNS depressants, intubation, fatigue, and worsening toxicity can slow respiration
Metabolic
Metabolic Acidosis
Uncoupling of oxidative phosphorylation
Inhibition of Kreb's cycle
Induction of lipolysis
Increased Glucose Consumption
Early hyperglycemia
Latent hypoglycemia
Clinical Presentation
Gastrointestinal
Metabolic
CNS
Respiratory
Nausea, vomiting, abdominal pain
Acidosis, hypoglycemia, hyperthermia, electrolyte loss
Tachypnea
Respiratory alkalosis
Altered mental status, seizure, lethargy, tinnitus
Recap:
Serum ASA level
Decrease in PG formation results in decreased cochlear blood flow
Tinnitus
Alterations in sound perception
Reversible hearing loss
Otolaryngologic
Serum ASA level (mg/dL)
Therapeutic
Mild toxicity
Moderate toxicity
Severe toxicity
10-28
30-60
60-80
> 80
Notable labs
Urine drug screen
Urinalysis
APAP, EtOH levels
Abdominal X-ray
Ketones
Adult
Children/elderly
20-45
45-70
> 70
< 20
PMH
Allergies
Social History
EtOH/tobacco /drugs
Asthma, seizure disorder (last sz 10 months ago), schizophrenia, left ear deafness.
NKDA
Single, college educated, currently unemployed.
Denies all ETOH and illicit drug use. Tobacco use x 20 years, quantity unknown.
Heart Rate
Resp Rate
(cc) image by anemoneprojectors on Flickr
Temperature
O2 Sat
135/73
93
25
37.5
BP
98%
Must be monitored every 2-4 hours
Continue to draw levels until peak is reached
Stabilize airway, maintain adequate PO2
Monitor vitals
Be wary of using sedation medications without mechanical ventilation
Patients will be notably hypovolemic
Sources of fluid loss:
Kidneys increase fluid excretion
Vomiting
Tachypnea
Diaphoresis/fever
Rationale:
Restoration of euvolemia
No evidence for use of "forced" diuresis
Procedure:
IV fluids
PO fluids
Urine output goal 3-5 mL/kg/hr
In severe toxicity
Benzodiazepines
If patient presents soon after ingestion
• Surface area: 1000-3000 m2/gram
• Not systemically absorbed
• ADR: Constipation, vomiting, diarrhea (when given with sorbitol)
Activated Carbon
GI obstruction
Need for endoscopy
Risk of aspiration
Contraindications
Dosing
1 g AC can adsorb ~550 mg ASA
Ideal AC:ASA ratio is 10:1
If ASA dose is unknown, use 1 g/kg
Adding sorbitol is generally discouraged
Efficacy
The sooner after ingestion, the more effective
Must be < 2 hours post-ingestion
Reduces therapeutic ASA absorbtion 50-80%
Acceptable to use in EC or IR formulations
Reserved for severe toxicity
Indications
Indicators of poor prognosis: Severe AMS, hyperthermia, pulmonary edema
ASA > 100 mg/dL in acute ingestion
ASA > 60 mg/dL in chronic ingestion
Ingestion > 500 mg/kg at any ASA serum level
Severe fluid/electrolyte disturbances
Renal insufficiency - acute or chronic
Gastric Lavage
Salicylates exist in unionized form in acidic environments
Acidemia promotes transfer of ASA into tissue (CNS)
Ionized form is unable to cross membranes
ASA becomes "trapped" in less acidic environments
Plasma alkalinization shifts equilibrium out of tissue
100-150 mEq in 1 liter D5W at 150-200 mL/h
Consider adding 20-40 mEq potassium
Goal urine pH 7.5-8.0
Monitor serum pH, do not exceed 7.55
1897
Bayer chemists derive acetylsalicylic acid with significantly less GI upset than traditional salicylic acid
The Done Nomogram:
Outdated and limited applicability (4, 5)
Published 1960
Based on pediatric population
Only for non-enteric coated ingestions
Criteria are "sx" or "no sx"
Blood pH must be >7.4
Risk of incorrectly classifying severity
Do Not Use
Weigh risk vs. benefit
Only useful in very recent ingestions (<1 h)
Removes ~30% of ingested drug
Airway must be protected
Very traumatic, many complications
Only indicated for life-threatening ingestions

Perhaps useful for enteric coated or extended-release ingestion
Non-obstructive bezoar
Polyethylene glycol electrolyte solution
Given PO or through NG tube
Continue until clear excrement
Multi-Dose Activated Charcoal (MDAC)
May enhance elimination over single dose regimen
Unclear whether MDAC increases clearance of absorbed salicylate (no known GI dialysis effect)
AACT position states "insufficient data" to support routine use
May be considered to inhibit absorbtion, not to increase clearance
Doses vary, but 0.5 g/kg q 2 to 4 h for 12 h is average
Increasing urine pH from 5 to 8 increases renal salicylate clearance from 1.3 mL/min to 100 mL/min
Increasing urine pH from 5 to 8 decreases serum T1/2 from 48 h to 6 h
September 13, 1918
US Surgeon General Rupert Blue states that aspirin has been used in foreign countries "apparently with much success in the relief of symptoms."
Stimulation of chemoreceptor trigger zone
Hyperthermia
From uncoupling of electron transport chain
Marker of poor prognosis
ASA
HEENT:
CV:
Respiratory:
GI:
Extremities:
Neuro:

Urinalysis:
Normocephalic and atraumatic head. PERRLA.
S1, S2. Regular rate and rhythm. No murmurs, rubs, or gallops.
Bibasilar expiratory wheezing throughout.
Soft. Obese. Nontender. Nondistended. Bowel sounds heard.
No pedal edema. No cyanosis.
Cranial nerves II-XII intact. No focal deficit. Normal gait. Motor strength 5/5 throughout. Normal sensation. Patient mildly agitated.
139
3.7
12
0.9
147
108
19
13.2
38
6.2
230
Anion Gap
18
Ca+
8.7 (9.2 adjusted)
Albumin
3.4
Yellow, hazy. Specific gravity 1.033, pH 5.5, protein 1+, hemoglobin 2+, negative lymphocyte esterase
Aspirin dosing is based largely on case reports
Parmacobezoar
An mass of undigested tablets or capsules
More likely with EC, XR, DR formulations
Less likely in children
If intubating, remember:
Set the vent to the patient's respiratory rate
It is not recommended to attempt to alkalinize by managing respiratory rate
current
1.
2.
3.
4.
Stabilize patient
Discontinue exposure
Decontamination measures
Antidotal therapy
image by Ricardo Liberato via Wikimedia commons
Michaelis-Menten Kinetics
Dose ingested
Serum [ASA]
Theoretical benefits
Indications
Procedure
Adults
Initial rate 250-500 mL/hr
Goal rate 1-2 L/hr
Children 6-12 y.o.
Goal rate 500-1000 mL/hr
Children < 6 y.o.
Goal rate 500mL/hr
Sodium Bicarbonate IV solution
Indications:
Indications (Georgia Poison Center protocol):
Bicarbonate administration at ASA >[40 mg/dL]
Clinical features should be taken into account
Salicylate Toxicity
Recap:
Clinical Presentation
Gastrointestinal
Metabolic
CNS
Respiratory
Nausea, vomiting, abdominal pain
Acidosis, hypoglycemia, hyperthermia, electrolyte loss
Tachypnea
Respiratory alkalosis
Altered mental status, seizure, lethargy, tinnitus
Monitoring
If serum ASA > 40
If serum ASA > 100
Draw salicylate levels every 2-4 hours until they begin to trend down
Treatment
Alkalinization:
Sodium Bicarbonate
100-150 mEq/hr IV
Renal consult
Dialysis
Stabilize patient

Decontamination (if appropriate)


Antidote:
Stabilize ABCs, rehydrate, control seizures
Activated charcoal, gastric lavage, whole bowel irrigation
References
Salicylate level:
27.4 mcg/mL
What treatment do you recommend?
Patient was given 1 amp (50 mL) bicarbonate bolus
Received IV hydration
3-hour [ASA] was 23.8 mcg/mL
Patient was discharged from the ED within 6 hours
Rupert Blue
Image: US Deptartment of Health and Human Services
http://1918.pandemicflu.gov/biographies/01.htm
Bartlett D. The ABCs of Gastric Decontamination. Journal of Emergency Nursing. 2003 Dec;29(6):576-7.
Outcome:
What if the second level had been 30 mcg/mL?
What if it had stayed the same (27.4 mcg/mL)?
Detection
May or may not be visible on abdominal x-ray
Consider contrast
Levels that continue to increase despite treatment
Levels that fail to decrease
Case: Delayed Salicylate Toxicity with Undetectable Initial Levels after Large-dose Aspirin Ingestion
Herres J. Ryan D. The American Journal of Emergency Medicine (2009) 27, 1173.e1-1173.e3
53 y.o. male presents to the ED ~45 minutes after ingesting two hundred 325 mg ASA tablets
Initial [ASA] level undetectable, no clinical s/sx of overdose
Given 50 g activated charcoal and saline rehydration
3-hour [ASA] was 33 mg/dL
7-hour [ASA] was 35 mg/dL
After 8 hours, patient was discharged to psychiatric care
Seventeen hours after admission,
The patient returns to the ED
Found to be diaphoretic, tachypneic, unresponsive to questions
Within 20 minutes, he seizes, becomes bradycardic, and dies
Serum [ASA] is found to be 128 mg/dL, serum pH 7.08
Chronic Toxicity
Hearing abnormalities, nausea, vomiting, delirium, agitation, hyperactivity, slurred speech, seizures
Most common in elderly population
Slower onset, less severe manifestations than acute overdose
Keep in mind for elderly patients with recent unexplained deterioration of mental status
Dugandzic RM, Tierney MG, Dickinson GE, Dolan MC, McKnight DR.
Annals of Emergency Medicine. 1989 Nov;18(11):1186-90.
Evaluation of the Validity of the Done Nomogram in the Management of Acute Salicylate Intoxication
Retrospective review of 55 salicylate overdoses
3 emergency physicians reviewed and ranked severity
Physician scores were compared against Done nomogram scores
Overall predictive index of Done nomogram was 0.42 (32 of the 55 cases were discordant with physicians)
Nomogram overpredicts mild and moderate toxicity
10 of 13 cases categorized as "severe" by the nomogram were categorized as "mild" or "moderate" by physicians
1. Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Griffin SL. 2009 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 27th Annual Report. Clinical Toxicology 2010 Dec;48(10):979-1178.

2. Bartlett D. The ABCs of Gastric Decontamination. Journal of Emergency Nursing. 2003 Dec;29(6):576-7.

3. Dargan PI, Wallace CI, Jones AL. An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose. Emergency Medicine Journal. 2002 May;19(3):206-9.

4. Dugandzic RM, Tierney MG, Dickinson GE, Dolan MC, McKnight DR. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Annals of Emergency Medicine. 1989 Nov;18(11):1186-90.

5. Flomenbaum Neal E, "Chapter 35. Salicylates" . Lewis S. Nelson, Neal A. Lewin, Mary Ann Howland, Robert S. Hoffman, Lewis R. Goldfrank, Neal E. Flomenbaum: Goldfrank's Toxicologic Emergencies 8th Edition. 2006. pp1-16.

6. Glisson JK, Vesa TS, Bowling MR. Current management of salicylate-induced pulmonary edema. Southern Medical Journal. 2011 Mar;104(3):225-32.

7. Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbien M. Does multiple-dose charcoal therapy enhance salicylate excretion? Arch. Internal Med. 1990 Jun;150(6):1281-3.

8. Starko KM. Salicylates and pandemic influenza mortality, 1918-1919 pharmacology, pathology, and historic evidence. Clinical Infectious Disease. 2009 Nov 1;49(9):1405-10.

9. Wax, P. "Antidotes in depth: Sodium Bicarbonate." Goldfrank's Toxicologic Emergencies 8th ed. 2006.
(5)
(5)
Image Source: "Chapter 35. Salicylates" Goldfrank's Toxicologic Emergencies 8th Edition. 2006.
Image source: Penn state Biology 110
https://wikispaces.psu.edu/display/110Master/Energy+III+-+Cellular+Respiration+(Krebs+Cycle+and+Electron+Transport+Chain)
(3, 5, 6)
(3, 5, 6)
Image Source: http://www.ars-informatica.ca/article.php?article=29
Image Source: "Chapter 35. Salicylates" Goldfrank's Toxicologic Emergencies 8th Edition. 2006.
Image Source: http://www.rishtonpharmacy.co.uk/shell/contents/smiles/smiles.html
Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbien M.Arch. Internal Med. 1990 Jun;150(6):1281-3.
Does Multiple-Dose Charcoal Therapy Enhance Salicylate Excretion?
Randomized, two-limbed crossover design (n=10)
Subjects ingested 2880 mg of ASA on two occasions
On one of the occasions, subjects ingested 25 g of activated charcoal at 4, 6, 8, and 18 hours
Serum [ASA] measured at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 h
Results:
Peak and time-to-peak concentrations unchanged
AUC unchanged
Wax, P. "Antidotes in depth: Sodium Bicarbonate." Goldfrank's Toxicologic Emergencies 8th ed. 2006.
Flomenbaum Neal E, "Chapter 35. Salicylates" . Lewis S. Nelson, Neal A. Lewin, Mary Ann Howland, Robert S. Hoffman, Lewis R. Goldfrank, Neal E. Flomenbaum: Goldfrank's Toxicologic Emergencies 8th Edition. 2006. pp1-16.
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