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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