Aspirin and Acetaminophen

Michael Hodgman MD

I have no disclosures

• 52 yo female brought by EMS early am with SOB. Onset earlier the prior day, not response to use MDI. Reports 1 d cough and sweats. No fever/chills/CP/leg swelling. Epigastric pain, no other GI complaints.

• PH: Lung Ca, Ovarian Ca, HTN, anxiety/depression, learning disability (childhood meningitis), chronic back pain. (Cancer free lung x 8 yrs, ovarian x 12 yrs.)

• SH: 0.3 ppd smoker

• Meds: lisinopril, atorvastatin, MDI, clonidine, amphetmine/d-amphetamine, gabapentin, tizanidine, tramadol, EC aspirin.

• Exam: Alert and tachypneic, P 118 bpm, RR 36/min, BP 114/81, T 36.4º C orally, pulse ox 98% on 2 L n/c

• Scattered wheezes on auscultation, abdominal exam unimpressive, extremities without edema/ cords/ tenderness

02:20 iSTAT VBG 7.47 pCO2 < 20 mm Hg, pO2 102, BE -8

03:26 144 124 28 3.1 15 1.0 100

Ca 8.7 Mg 1.8 AST 49, ALT 72, T bili 0.8 lactate 0.7 mmol/L blood acetone negative ethanol negative d-dimer 210 ng/mL

WBC 28.6 K 13.1/38.3% 269 K plt.

measured osmol 332 osmol gap 29

U/A spec grav 1.039 ketones 80 1-2 wbc, 1-2 rbc, few granular casts

EKG: sinus tachycardia, QRS and QT intervals normal, no ischemic changes

• ~ 9 am: confused, restless, increased respiratory difficulty

• transfer to ICU

• 15:20 endotracheal intubation for progressive respiratory difficulty, vent 450 mL TV x 25, 8 cm PEEP

• NE infusion for hypotension

• 18:00 INR = 4.6, 4 U FFP and vitamin K

• ~ 9 am: confused, restless, increased respiratory difficulty

• transfer to ICU

• 15:20 endotracheal intubation for progressive respiratory difficulty, vent 450 mL TV x 25, 8 cm PEEP

• NE infusion for hypotension

• 18:00 INR = 4.6, 4 U FFP and vitamin K

• mother arrives late afternoon and reports patient using aspirin frequently for back pain due to inability to get opioids

• specimen from 03:26 that am: salicylate 99 mg/dL

• Salicylate

• chronic toxicity = SIRS

• acid base disturbance: mixed primary respiratory alkalosis and metabolic acidosis

• beware hyper-chloremia and lack anion gap

• risks intubation: at least match minute ventilation, by providence in this case the intensivist did this

• what about the INR?

Case 2• 32 yo female with acute aspirin overdose

• lavage, charcoal, initial salicylate 197 mg/L (= 19.7 mg/dL)

• 6 hr later salicylate 97.5 mg/dL

• HD recommended (she is in a small rural hospital)

• air transportation delayed due to poor weather, another 5 h delay before land transport initiated

• shortly after transport brady/asystolic cardiac arrest, return to hospital, T > 107º F

aspirin

• brief review pertinent pharmacokinetics

• manifestations of toxicity

• management and pitfalls

bad player

Salicylic Acid

Salicyalte anion

pharmacokinetics• therapeutic doses: rapid and complete absorption

• large overdoses: erratic, maybe delayed, concretions may form, delayed gastric emptying due to pylorospasm

• saturable metabolic pathways: Michaelis-Menton kinetics

• t 1/2 therapeutic dose: 2-3 h

• at toxic levels: 20+ hours

• decreased protein binding at increasing concentrations

Salicylate toxicity

• Central respiratory center stimulation

• primary respiratory alkalosis

• renal bicarbonate wasting early on

• insensible fluid losses from increased RR

Salicylate toxicity• metabolic effects

• uncoupling oxidative phosphorylation

• inhibition TCA cycle

• accumulation pyruvate, lactate

• increased metabolic rate: lipolysis, glycolysis, protein catabolism

• ketonemia

• hyperthermia

• neuroglycopenia

• In rats lethality correlates with brain salicylate concentration

• The preferred energy substrate of the brain is glucose

• In mice given a lethal dose salicylate (IP) a 65% decrease in brain glucose seen with normoglycemia

• In mice given a lethal dose salicylate survive if given glucose simultaneously (both IP)

Hill NEJM 1973;288:1110-1113

Thurston,J Clin Invest 1970;49:2139-2145

• 10 month old female with lethargy, 3 days aspirin dosing for fever/URI • serum salicylate 32 mg/dL, blood glucose 0 mg/dL, CSF glucose

0 mg/dL • full recovery day 7

• 2 yo male, acute OD aspirin in coma appx 24 h post ingestion • salicylate 46 mg/dL, blood glucose 5 mg/dL, arousal with dextrose

Am J Dis Child 1964;108:171-173

Toxicity

• Acid/base disturbances

• 1º respiratory alkalosis, 1º metabolic acidosis

• acidosis is mixed: lactate, ketoacids, other organic acids and salicylate

• essentially any acid/base disturbance

• acidemia = 5 alarm fire

• free salicylate fraction doubles with pH change 7.4 to 7.2

• 7.40: 0.004% unionized

• 7.20: 0.008% unionized

• acidosis decreases protein binding to albumin

• alkalosis impedes movement salicylate into brain

Toxicity

• abdominal pain, N/V

• dehydration: hyperventilation, hyperthermia, nausea, (early osmotic diuresis)

• CNS: tinnitus/ hearing loss, confusion, delirium, coma, seizure

• Non-cardiogenic pulmonary edema

Management• GI decontamination

• MDAC may be beneficial with large overdoses

• more for adsorption aspirin still in gut

• Fluid resuscitation

• Alkalinization

• keep it out of the brain, facilitate ion trapping in urine

• D5W (1 L minus 150 mL) with 3 amps 8.4% NaHCO3

• (pay attention to K+, Mg+2)

Minute ventilation

• hyperpnea ≠ respiratory failure

• primary CNS response to salicylate

• compensatory response to organic acids

• inadequate ventilation, respiratory failure are grave findings

The path to disaster

2 deaths and 1 bad neurologic outcome in 7 mechanically ventilated patients, both deaths occurred within hours of intubation

Neuroglycopenia?

• If altered mental status, consider dose dextrose

• 43 yo female with chronic salicylism and confusion, agitation, GSC deteriorates to 10. FSG 133 mg/dL. One amp D50 with improvement GCS to 14 within 2 minutes. Recurrent deterioration 90 minutes later again responds to dextrose.

• A second similar case also reported in this paper.

ClinToxicol 2007;45:526-529

Hemodialysis• CNS toxicity: coma, seizure, progressive lethargy

despite other measures • pulmonary edema • renal disease • persistent metabolic acidosis • acute overdose and [>100 mg/dL] or chronic and

[>40-60 mg/dL]See also: Ann Emerg Med 2015. doi 10.1016/j.annemergmed.2015.03.031, [epub ahead of print] or extrip-workgroup.org

Pitfalls

Am J Emerg Med 2013;31:1536.e3-.e4

• salicylate interference with chloride electrode

• in case presented today

• at their clinical lab:

• a salicylate of 20 mg/dL increases a chloride of 103 meq/L by 4% (107 meq/L)

• a salicylate of 60 mg/dL increases a chloride of 103 meq/L by 15% (118 meq/L)

False positive assay• Fluorescence polarization immunoassay

• Diflusinal

• Calorimetric assay

• elevated bilirubin levels

• elevated beta-hydroxybutyrate and other ketone bodies

What about the INR?• salicylate interferes with Vit K

epoxide reductase cycle

• clinically evident only at toxic concentrations

• elevated INR suggests chronic, or at least delayed presentation after acute overdose

• In rabbits serum salicylate of 35.5 mg/dL results in potent suppression Vit. K dependent factors

J Pharm Pharmacol 1981;33:25-28

Other routes exposure• Topical salicylate

• methyl salicylate liniment or rubefacient

• Oil of Wintergreen

• 98% methyl salicylate (1.4 g salicylate/mL)

• Bismuth subsalicylate

• ~ 38% salicylate

• Why should we have a low threshold to measure salicylate concentration in someone sick?

• nearly any acid base disturbance may be seen

• lack of anion gap may be factitious

• chronic salicylism looks like sepsis

Salicylates• consider in anyone sick • usually volume depleted • alkalinization protects the brain, and enhances renal

clearance • consider dextrose if altered • high minute ventilation if intubation • trend salicylate concentration, absorption can be

prolonged and erratic • amenable to hemodialysis

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/ucm071471.htm

http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/ucm071471.htm

Acetaminophen

• What is the toxic target?

• What is the toxic metabolite?

• What is the primary enzyme that produces toxic metabolite?

NEJM 2008;359:285-92

• A 16 yo female presents to ED following a reported overdose of 100 tablets of Tylenol

• What do want to know?

• What do we use to risk assess, decide if antidotal treatment indicated?

• When can we use the Rumack-Matthew nomogram?

untreated:above 200 line: risk hepatotoxicity 60%, death 5%above 300 line: 90%, 11%(hepatotoxicity = ALT or AST > 1000 IU/L)

• A 16 yo female presents to ED following a reported overdose of 100 tablets of Tylenol

• Ingestion time was 4 hours ago

• What interventions now?

• A 16 yo female presents to ED following a reported overdose of 100 tablets of Tylenol PM

• Ingestion time was 8 hours earlier

• Does this change our initial approach v. ingestion 4 h earlier?

Buckley NA, Clin Tox 1999;37:759-767hepatotoxicity = ALT or AST > 1000 IU/L

≥ 200 mcg/mL line

• A 22 yo male presents with nausea and tooth ache.

• He has been taking 2 Extra Strength Tylenol every 2 hours around the clock past 2 days without significant relief of his dental pain.

• How do we approach chronic over ingestion, or a chronic overdose?

• and, what about an unknown time of ingestion overdose/ unknown overdose (positive APAP assay)?

• Acute overdose

• time ingestion known

• consider decontamination

• if < 8 h, plot on nomogram

• if ≥ 8 h, start NAC, send [APAP]

• if presentation near 8 h start NAC pending [APAP]

• Chronic overuse, time unknown acute overdose

• if either detectable [APAP] or abnormal AST/ALT not explained otherwise start NAC

When do the transaminases begin to rise after APAP OD?• usually within with 24 h of an acute OD

• most 12-24 h post

• worrisome sign: rapid doubling time of transaminase

• delayed rise in transaminase, > 24 h usually associated with a more benign course, less likely progression to severe hepatotoxicity

Ann Emerg Med 1995;26:49-53 Clin Toxicol 2010;48:787-792

Acidosis with APAP• Early lactic acidosis

• co-ingestion, shock

• or, this is a very large overdose (typically > 600+ mg/L)

• at very high [APAP] mitochondrial toxin

• Early acidosis, not lactic acid

• 5-oxoproline (pyroglutamic acid)

• Late presentation lactic acidosis

• bad prognostic sign, risk death from liver failure

N-acetylcysteine• Standard IV course

• 300 mg/kg over 21 h

• Standard po course

• 1330 mg/kg over 72 h

• Non-traditional

• shorter oral courses

• combined oral/ IV with massive ingestions

• If increasing transaminases/ hepatic injury; continue NAC beyond defined course

• With shorter courses ensure that [APAP] not detected and transaminases not increasing prior to d/c NAC

• beware of with very large ingestions and co-ingested anti-muscarinic or opioid

• we recommend repeat [APAP] at completion shorter course NAC regimens

Camelus bactrianus Bactrian camel

wikipedia

J Med Toxicol 2010;6:337-344

Why do we give NAC after the APAP is gone?

• Early use of NAC

• sulfur moiety to detoxify NAPQI

• Late use (after all APAP metabolized and no further NAPQI generated)

• improved oxygen delivery and utilization by hepatocytes

• anti-oxidant, scavenging of reactive oxygen. nitrogen species

• improved mitochondrial energetics

Adverse reactions NAC• IV use:

• Anaphylactoid

• hold infusion, resume more slowly

• antihistamines

• angioedema, wheeze, hypotension

• consider switch to oral NAC

• Dosing errors

• Oral NAC:

• N/V

Higher risk populations?

• ethanol

• depends on intoxicated or not

• current guidelines are probably fine

• malnourishment may be a greater risk

non-toxic conjugates

NAPQI

CYP 2E1

APAP

Treatment• decontamination with activated charcoal following

acute OD, early presentation

• NAC, remember the 8-10 h window after an acute OD

• NAC beneficial for late presentation as well

• can we dialyze APAP?, and if so when?

Hemodialysis for APAP poisoning

• consider for massive APAP intoxication

• mitochondrial dysfunction with lactic acidosis. hypoglycemia, hypothermia

• altered mental status not explained otherwise

• levels >> 500 ug/mL

• NAC is dialyzable also, doubling of dose during dialysis has been suggested.

Clin Toxicol 2013;51:855-63

Newer tests for APAP toxicity

• APAP x AT multiplication product

• independent time ingestion

• > 1,500 mg x IU/L2

• about 90% sensitive, although specificity not great, in predicting hepatotoxicity

Clin Toxicol 2010;48:793-799 Clin Toxicol 2014;52:506-511

Newer tests for APAP toxicity

• Acetaminophen adducts

• binding of NAPQI to hepatic proteins

• may be detected days after an overdose

• microRNA-122, HMGB1 (high mobility group box-1)

• early markers of hepatic injuryHepatology 2013;58:777-787

Transplant criteria

• Most patients recover without transplant

• Transplantation = life long immunosuppression

• King’s College Criteria a widely accepted set of criteria

• 20 years ago, < 20% patient’s meeting KCC survive without transplant

King’s College Criteria

• Arterial pH < 7.3 after fluid resuscitation

• or serum lactate > 3.5 mmol/L day 2-3 (modified KCC)

• OR

• INR > 6.5 (PT > 100 sec) and

• serum creatinine ≥ 3.4 mg/dL (300 umol/L) and

• Grade III or IV coma

Gastroenterology 1989;97:439-45 Lancet 2002;359(9306):558-563

Liver Transpl 2000;6:277-286

Other therapies

Ann Surg 2008;247: 238–249

• Compared to other causes of acute liver failure

• APAP related ALF with higher rate of non-transplant survival compared to non-APAP ALF

• but, they are more ill and progress to death more rapidly compared to non-APAP ALF

Liver Transpl 2015 epub ahead of print,DOI: 10.1002/lt.24347

Lab interferences

• APAP has modest impact on INR

• NAC has modest impact on INR

• rarely > 1.5 due to either of these

• Really high total bilirubin (> 10 mg/dL) interferes with colorimetric APAP assay (false positive)

Reflexive APAP testing• common OD, no specific early signs/ symptoms

• should we test all ODs/ possible ODs?

a) 365 suspected or confirmed ODs without history or suspicion APAP: 1/365 with what was felt actionable [APAP]

b) 0/136 ODs with negative history APAP use with actionable [APAP], but 4/155 with altered LOC or collapse with detectable [APAP] and treated

Ann Emerg Med 1989;18:1035-1038 Emerg Med J 2001;18:178-182

APAP summary• no specific early clinical findings

• Rumack-Matthew nomogram useful for acute OD

• NAC has benefit both early and late

• early rapid rate increase transaminases portends more severe hepatic injury

• be familiar with King’s College Criteria and your referral transplant center