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APAP and Salicylate Poisoning. Corinne M. Hohl R5, EM Training Program McGill University September 2003. Acetaminophen. APAP – Question 1. What is the therapeutic mechanism of action of APAP?. Q1: mechanism of action. Central prostaglandin synthetase inhibitor

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apap and salicylate poisoning

APAP and SalicylatePoisoning

Corinne M. Hohl

R5, EM Training Program

McGill University

September 2003

apap question 1
APAP – Question 1
  • What is the therapeutic mechanism of action of APAP?
slide4

Q1: mechanism of action

  • Central prostaglandin synthetase inhibitor

 analgesic, antipyretic with weak anti-inflammatory properties.

apap question 2
APAP – Question 2
  • Name 4 metabolic pathways of APAP and the proportion of APAP metabolized by each pathway in a normal adult host with a therapeutic ingestion.
q2 met pathways of apap
Q2: met pathways of APAP
  • Hepatic glucuronide conjugation(40-65%) 90%
  • Hepatic sulfate conjugation(20-45%)

 inactive metabolites excreted in the urine.

  • Excretion of unchanged APAP in the urine (5%).
  • Oxidation by P450 cytochromes (CYP 2E1, 1A2, and 3A4) to NAPQI(5-15%)

 GSH combines with NAPQI

 nontoxic cysteine/mercaptate conjugates

 excreted in urine.

q2 metabolic pathways of apap
Q2: metabolic pathways of APAP
  • The safety of acetaminophen depends on the availability of electron donors such as reduced glutathione (GSH) and other thiol-containing substances required to detoxify NAPQI.
apap question 3
APAP – Question 3
  • What happens to APAP metabolism in an OD situation?
q3 apap metabolism in od
Q3: APAP metabolism in OD
  • Saturation of glucuronidation and sulfation pathways
  • Amount of APAP metabolized by p450 cytochromes to NAPQIincreases.
  • Normally NAPQI is detoxified by reduced GSH (glutathione) and thiol-containing substances.
  • In OD: rate and quantity of NAPQI formation overwhelms GSH supply and regeneration:

 elimination of NAPQI prolonged

 free NAPQI binds critical cell proteins with sulfhydryl groups

 cellular dysfunction and cell death.

  • Animal models: hepatotoxicity when GSH stores fall <30% of baseline  large margin of safety where therapeutic dose 10-15mg/kg to toxic dose of 150mg/kg for single acute ingestion.
apap question 4
APAP – Question 4
  • Name 3 factors which adversely affect APAP metabolism.
q4 apap metabolism
Q4: APAP metabolism
  • Upregulation (i.e. induction) of CYP 2E1 enzyme activity:
    • smoking, barbituates, rifampin, carbamazepine, phenytoin, INH, + ethanol
    • use of APAP by alcoholics has not been associated with higher risk of liver injury in prospective trials
  • Decreased glutathione stores.
  • Frequent dosing interval of APAP.
  • Prolonged duration of excessive dosing.

(Kuffner et al. 2001)

apap question 5
APAP – Question 5
  • Name 3 factors which decrease GSH stores.
  • Name 2 ways in which GSH stores can be replaced.
q5 gsh stores
Q5: GSH stores
  • Glutathione stores are determined by:
    • age
    • diet
    • liver disease
    • fasting prior ingestion
    • chronic malnutrition (anorexia)
    • gastroenteritis
    • chronic alcoholism
    • HIV
  • Glutathione replacement by sulfhydryl compounds:
    • eating
    • NAC
  • Whitcomb DC, Block GD: Association ofacetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845
q5 toxicity in children
Q5: toxicity in children
  • Most APAP ODs in children occur in the scenario of acute febrile illness.
  • It is unclear whether short-term fasting in acute febrile illness in children prediposes them to oxidant stress which depletes GSH leading to APAP toxicity, or whether this is simply the most common setting in which children most commonly receive multiple excessive dosing.
  • Given the large therapeutic index children are unlikely to become toxic from ingestion on one or two tablets.
  • Whitcomb DC, Block GD: Association ofacetaminophen hepatotoxicity with fasting and ethanol use. JAMA 1994; 272:1845
apap question 6
APAP – Question 6
  • Why is APAP toxic to the kidney as well? (Name 2 mechanisms).
q6 renal toxicity
Q6: renal toxicity
  • Organ dysfunction results everywhere where local oxidative metabolism (via p450) creates NAPQI that cannot be detoxified  direct toxicity:
    • cytochrome P-450 enzymes produce NAPQI in the renal tubules  NAPQI binds cellular macromolecules  acute tubular necrosis.

(25% of hepatotoxic cases).

  • Hepatorenal Syndrome
  • Volume depletion
apap question 7
APAP – Question 7
  • How could one distinguish with a simple lab test between hepatorenal syndrome and ATN?
q7 hrs vs direct toxicity
Q7: HRS vs. direct toxicity
  • Fractional excretion of sodium (FeNa) :

FeNa: >1 in primary renal injury

FeNa: <1 hepatorenal syndrome

apap question 8
APAP – Question 8
  • What other 2 organs are most commonly (although overall rarely) damaged in an APAP overdose?
slide22

Q8:other organs damaged

  • Heart  myocarditis
  • Pancreas  pancreatitis

It is controversial whether these entities are part of multisystem organ failure (MSOF) from fulminant hepatic failure (FHF) or from the local accumulation of toxic metabolites.

apap question 9
APAP – Question 9
  • What percent of pts whose APAP level falls above the upper line of the Rumack-Matthew normogram will develop hepatotoxicity?

(defined as elevation of the plasma transaminases above 1,000 U/L)

apap question 10
APAP – Question 10
  • By how many hrs after ingestion do you expect the transaminases to rise if an APAP ingestion was hepatotoxic? In which clinical stage would this be?
q10 time of ast alt rise
Q10: time of AST/ALT rise
  • I 0.5-24h n/v, anorexia, asymptomatic.
  • II 24-48 h resolution of stage I sxs
  • RUQ pain, elevation of PTT, INR, bili + enzymes (at the latest by36h)
  • III 48-96h coagulopathy, peaking of enzymes, acidosis, hypoglycemia, bleeding diathesis, jaundice, anuria, cerebral edema, coma. ARF in 25% of pts with hepatotoxicity
  • IV 4-14d resolution
apap question 11
APAP – Question 11
  • Which lab test is the most sensitive for early detection of hepatotoxicity.?
apap question 12
APAP – Question 12
  • Your resident saw a patient 90min post APAP ingestion of unknown quantity: He tells you the APAP is <10 and AST 40. How would you dispo and manage this pt.
q12 1h level
Q12: 1h level
  • This patient needs a 4-hr APAP level – there is no point in doing an APAP level in an acute single ingestion before 4h post ingestion unless it is a chronic ingestion or the history is unreliable.
  • There is no point in doing LFTs either unless the 4hr APAP is on or near the treatment line, the pt has symptoms suggestive of liver injury or pt looks unwell (i.e. prior liver disease).
apap question 13
APAP – Question 13
  • Another resident tells you another patient has a 4 hr APAP of 70mg/mL with an AST of 50. As you pursue the story you find out that your patient is from Europe and may have ingested an extended release form of paracetamol. What is your management?
q12 xr tablets
Q12: XR tablets
  • Check 6h and 8h APAP levels.
  • Tx with NAC if:
    • 4, 6 or 8h level above the R-M tx line  full course NAC.
    • If all levels are below the tx line and the 8h APAP level is less than 50% of tx line  D/C home (NYPC).
    • If the 8h APAP line is btw 50% of tx line and tx line  NAC. for 24-36h and D/C once APAP <10 or transaminases normal (NYPC).
    • If the 6-hour level is greater than the 4-hour level, begin NAC therapy.

* More prolonged monitoring of levels may be necessary if the patient has food in the stomach or co-ingestants that delay gastric emptying.

q12 xr tablets34
Q12: XR tablets
  • Several studies show that elimination of extended and immediate-release acetaminophen are nearly identical after 4 hours.
  • However, some case reports have documented APAP levels falling above the treatment normogram line as late as 11-14 hours post ingestion of the extended-release preparation.
q12 xr tablets35
Q12: XR tablets

Healthy 17yo girl after ingestion of 13g of ER tylenol.

Both a 3 and 5hr level were below the treatment line.

NAC was started after the 11hr level was above the treatment line.

She did not develop hepatotoxicity.

Vasallo et al. Ann Intern Med. 1996; 125 (11) 940.

apap question 1336
APAP – Question 13
  • Name four indications (lab criteria) for treating a patient for repeated excessive APAP dosing.
q13 chronic od
Q13: chronic OD
  • If the APAP level is above the treatment line (plot earliest possible dose to have high sensitivity).
  • Symptomatic pt with AST >normal.
  • Any asymptomatic patient with a hx of chronic excessive APAP ingestion and an AST > 2x normal.
  • AST >normal with APAP >10.
  • If the APAP level is greater than expected for the appropriate dose.
apap question 14
APAP – Question 14
  • A 3rd ingestion comes in:18 yr old pregnant girl ingested 20g of Tylenol in a suicidal gesture 36h ago because she found out it is too late for her to have an abortion. Her APAP is <10 and her AST is 90.
  • How will you manage her medically?
  • She asks you whether her baby will have any defects.
q14 apap in pregnancy
Q14: APAP in pregnancy
  • APAP crosses the placenta.
  • She needs a full course of NAC.
  • There is no point in giving her AC at this point, although AC would probably be safe in an acute OD.
  • Birth defects: poorly studied in OD, some evidence for birth defects.
q14 pregnancy and apap
Q14: Pregnancy and APAP
  • AC: Class C
    • Safety for use during pregnancy has not been established.
  • NAC: Class A
    • Safe in pregnancy
apap question 15
APAP – Question 15
  • Name 4 mechanisms by which NAC works.
q15 4 mech of action of nac
Q15: 4 mech of action of NAC
  • Early  Prevents binding of NAPQI to hepatocytes.
    • GSH precursor  increases GSH stores
    • Increases sulfation metabolism of APAP  less NAPQI formed
    • Reduces NAPQI back to APAP (at least in animal models).
    • Sulfur group of NAC binds and detoxifies NAPQI to cysteine and mercaptate conjugate (= GSH substitute).
  • Late (12-24h)  Modulates the inflammatory response.
    • Antioxidant, free radical scavenger.
    • Reservoir for thiol groups (i.e. GSH).
    • Impairs WBC migration and function  antiinflammatory.
    • Positive inotropic and vasodilating effects (NO)  improves microcirculatory blood flow and O2 delivery to tissues.
    •  Decreases cerebral edema formation, prevents progression of hepatic encephalopathy and improves survival.
apap question 16
APAP – Question 16
  • Name 4 indications for NAC therapy.
q16 4 indications for nac
Q16: 4 indications for NAC
  • APAP level above the treatment line.
  • Hx of significant APAP ingestion presenting close to 8h (give while waiting for level).
  • All APAP ingestions who present late (>24h with either detectable APAP or elevated transaminases.
  • Chronic lg ingestions (>4g/day in adult, >120mg/d in child) with elevated transaminases.
  • Hx of exposure and FHF.
iv nac
IV NAC
  • 3 situations in which IV NAC is undoubtedly preferable to oral:
    • Fulminant hepatic failure
    • Pregnancy
    • Inability to tolerate oral NAC.
apap question 17
APAP – Question 17
  • Name 4 poor prognostic indicators:
q17 poor prognostic indicators
Q17: poor prognostic indicators
  • pH <7.3 (2 days after OD, after fluids)
  • Hepatic encephalopathy
  • PT >1.8 times normal.
  • Serum creatinine >300mmol/L
  • Coagulation factor VIII/V ratio of >30

Note: Transaminase levels do NOT predict the clinical course. They can decline during hepatic recovery or with FHF.

q17 other rules of thumb
Q17: other rules of thumb
  • If PT in seconds > number of hours since ingestion.
  • If INR is abnormal and still increasing on 4th day post ingestion.
q17 indicators for need for transplant
Q17: indicators for need for transplant:
  • Arterial pH <7.3 at any time after FHF develops that fails to correct with colloid loading

OR

  • In patients with a normal arterial pH all 3 of the following:  
    • PT >100 sec (without FFP or Vit K)
    • Creatinine >300 μmol/L
    • Grade III or grade IV hepatic encephalopathy

Makin AJ, Williams R: Acetaminophen-induced hepatotoxicity: Predisposing factors and treatments. Adv Intern Med 1997; 42:453

Lee WM: Acute liver failure. N Engl J Med 1993; 329:1862

q17 indicators for transfer to transplant center
Q17: indicators for transfer to transplant center
  • INR > 5

OR

  • any of the following complications:
    • ARF: creatinine >200 μmol/L
    • metabolic acidosis: pH <7.35 or bicarb <18 mEq/L
    • Hypotension
    • Encephalopathy
    • Hypoglycemia
  • A rising PT on the fourth day after overdose is the single best marker of a poor prognosis(39)
apap question 18
APAP – Question 18
  • Why is the coagulation factor VIII/V ratio abnormal in APAP poisoning?
q18 factor viii v ratio
Q18: factor VIII/V ratio
  • Factor VIII is produced by endothelial cells and its production is not impaired by APAP
  • Factor V is produced by hepatocytes and its production diminishes with hepatocellular necrosis.
apap question 19
APAP – Question 19
  • Name 3 mechanisms by which you can develop a metabolic acidosis in APAP poisoning?
q19 metabolic acidosis
Q19: metabolic acidosis
  • Intravascular volume depletion and lactic acidosis from dehydration/hypoperfusion.
  • ARF
  • Lactic acidosis without evidence of FHF from a direct effect of acetaminophen inhibition of hepatic lactic acid uptake and metabolism.
  • FHF
slide58

ASA – Question 1

  • Name 3 factors which may delay salicylate absorption in an OD situation.
slide59

Q1: delayed absorption

  • Enteric coating
  • Bezoar formation
  • Salicylate-induced pylorospasm
  • Gastric outlet obstruction
  • Concomitant ingestion of sustance which decreases gastric motility
slide60

ASA – Question 2

  • What is the highest therapeutic dose of ASA that should be prescribed?
slide61

Q2: ASA dosing

  • Adult (usually for RA) acc. to the FDA:
    • 650mg po q4h for 10d
    • Initial dose can be 1000mg.

 max: 3900mg/day for adults

    • Child: no more than 15mg/kg q4
slide62

ASA – Question 3

  • Name 3 patient factors which enhance the toxicity of topical salicylates (i.e. oil of wintergreen)?
slide63

Q3: toxicity topical SA

  • heat
  • occlusive dressings
  • young age (high BSA to weight ratio)
  • inflammation
  • psoriasis/break of the skin
  • long application

** real danger is through oral ingestion of topical ingestion.

slide64

ASA – Question 4

  • What is the approximate daily dose of ASA beyond which we worry about toxicity in repeated daily ingestions?
slide65

Q4: chronic OD toxic dose

  • 100mg/kg (vs. 200-300mg/kg in a single acute ingestion)
  • Especially predisposed are the elderly and infants.
slide66

ASA – Question 5

  • Contrast acute vs. chronic salicylism with respect to (4 out of 6):
    • patient age
    • Comorbidities
    • serum concentration
    • mental status
    • hydration status
    • mortality.
slide67

Q5: acute vs. chronic

MORE DANGEROUS!

Characteristics:

FeaturesAcute Chronic

Age Young adult Older adult/infants

Etiology OD Therapeutic misuse

Co-ingest. Frequent Rare

Past history OD or psych Comorbidities/pain/RF

Presentation Early Late

Dehydration Moderate Severe

Mental status Normal(initially) Altered

Serum [conc] 40 - ≥120 mg/dL 30 to ≥80 mg/dL

Mortality Low w/ treatment High

slide68

ASA – Question 6

  • Name 3 reasons why the serum concentration of SA rises dis-proportionately to the dose ingested in toxic doses.
slide69

Q6: metabolism in OD

  • Metabolizing enzymes get saturated: switch from first  zero order kinetics.
  • Decrease in albumin binding at toxic levels.
  • Urinary excretion is fixed.
  • SA = weak acid:
    • at physiologic pH most SA is ionized  does not penetrate tissues well.
    • acidosis  more unionized SA  greater tissue penetration.
slide70

methylsalicylate

Hydrolysis

in GI tract, liver, RBC’s

2.5% excreted unchanged in urine (pH independent)

slide71

methylsalicylate

Free tissue SA

90% of free SA binds albumin at conc < 10mg/dL

2.5% excreted unchanged in urine (pH independent)

slide72

methylsalicylate

Free tissue SA increases

Hydrolysis

in GI tract, liver, RBC’s

% of free SA bound to albumin decreases as the [serum] increases: 75% bound @ 40mgdL 50% bound @ 75mg/dL

2.5% excreted unchanged in urine (pH independent)

First order kinetics

zero order kinetics once saturated

zero order kinetics once saturated

slide73

ASA – Question 7:

  • Name 4 mechanisms by which ASA can cause a metabolic acidosis.
slide74

Q7: met acidosis in ASA

  • Salicylate ion = weak acid which contributes to the acidosis.
  • Dehydration from hyperpnea, vomiting, diaphoresis and hyper-thermia contributes to lactic acidosis.
  • Uncoupling of mitochondrial oxidative phosphorylation  anaerobic metabolism  lactate and pyruvate production.
  • Increased fatty acid metabolism (as a consequence of uncoupling of oxydative phosphorylation)  lipolysis  ketone formation.
  • In compensation for the initial respiratory alkalosis the kidneys excrete bicarbonate which later contributes to the metabolic acidosis.
  • Increased sodium and potassium accompany the initial renal bicarbonate diuresis  hypokalemia  hydrogen ion shift out of cell to maintain electrical neutrality.
  • Inhibition of liver lactate elimination.
  • Renal dysfunction  accumulation of SA metabolites which are acids: sulfuric and phosphoric acids.
slide75

ASA – Question 8

  • What is Reye’s syndrome?
slide76

Q8:

  • ASA associated hepatitis in children:
    • Nausea, vomiting, hypoglycemia
    • Elevated liver enzymes
    • Fatty infiltration of liver
    • Coma
    • Following viral illness, usually influenza or varicella
    • 555 cases in US in 1980  steady decline since with declining use of ASA.
slide77

ASA – Question 9

  • An adult presents with a respiratory acidosis post ASA ingestion. What 3 entities need to be ruled out quickly? (Trauma and prior lung disease have been ruled out.)
slide78

Q9:

  • Respiratory decompensation from fatigue.
  • Co-ingestants which blunt the respiratory drive.
  • SA induced acute lung injury.
slide79

ASA – Question 10

  • Name 2 risk factors for developing pulmonary edema after ASA intoxication.
slide80

Q10: ALI

  • Age > 30
  • Smoking
  • Chronic salicylate ingestion
  • Presence of neurologic symptoms on presentation.
  • Hypoxia (increase in pulmonary vasomotor tone)
  • Degree of acidosis independent of serum [SA] is associated with ALI: it is unclear whether this is a causative factor or a consequence of ALI.
slide81

ASA – Question 11

  • List 15 clinical manifestations (signs or symptoms) or laboratory abnormalities of SA poisoning excluding acid/base abnormalities.
slide82

Q11: clinical manifestations

  • CNS:tinnitus, decreased hearing, vertigo, hallucinations, agitation, hyperactivity, delirium, stupor, coma, lethargy, seizures, cerebral edema, SIADH
  • Hem:hypoprothrombinemia, platelet dysfunction and bleeding
  • GI:n/v, hemorrhagic gastritis, decreased GI motility, pylorospasm, abnormal LFTs
  • Met:fever, hypoglycemia, hyperglycemia, ketosis, ketonuria, rhabdomyolysis
  • Pulm:tachypnea, ALI
  • Renal:proteinuria, Na and water retention
  • Volume:diaphoresis and dehydration.
slide83

Q11: temporal sequence

  • Early: tinnitus, n/v, diaphoresis + hearing loss (a bit later)
  • Vertigo, hyperventilation, hyperactivity, agitation, delirium, hallucinations, Sz, lethargy and stupor.
  • Late: coma (after massive ingestions  levels >100mg/dL or co-ingestions)
  • Severe hyperthermia from uncoupling of oxidative phosphorylation is a preterminal event.
slide84

ASA – Question 12

  • Name 8 presenting manifestations of chronic salicylism.
slide85

Q12: chronic clinical toxicity

  • tinnitus, hearing loss, vertigo, n/v, dyspnea, hyperventilation, tachycardia, hyperthermia, confusion, hallucinations, seizures, coma
  • Slower onset of symptoms than in acute OD and less severe manifestations.
  • nonspecific presentation  maintain high index of suspicion in elderly on ASA.
  • Delayed diagnosis common  mortality is higher when diagnosis is delayed.
slide86

ASA – Question 13

  • What 2 rapid pint-of-care bedside tests that we have available in our EDs can confirm your suspicion for an ASA poisoning?
slide87

Q13:

  • Urine dip: ketones
  • CBGM: hypoglycemia
slide88

ASA – Question 14

  • The Done normogram was derived from predominantly pediatric data for a level 6hrs post ingestion from a single, acute ingestion of non-enteric coated tablets. Also, it is only applicable for levels from a blood pH >7.4. It is notoriously unreliable.
  • What is a better way of following the severity of your pt’s acute or chronic ASA poisoning? Which lab tests, at what frequency?
slide89

Q14: lab monitoring

  • ASA levels a 2-4 hourly intervals, looking for the direction of change.
    • Careful in interpreting a decreasing level: this can indicate increased clearance with decreasing toxicity OR increased tissue distribution with lower pH and increased toxicity.
    • Even a lowering [ASA] with a decreasing pH may be ominous.
  • Serial ABG monitoring.
  • Monitor the mental status.
slide90

ASA – Question 16

  • How would you decontaminate a 16yo boy who ingested 100 tablets of 325mg ASA 2 hrs ago?
slide91

Q15: decontamination

  • Aim for a 10:1 ration of AC: drug. So, 300g of AC in multiple doses.
  • Controversial:
    • Benefit of MDAC– may decrease GI absorption.
    • WBI/PEG may diminish desorption of SA bound to AC for enteric coated tablets, unknown whether this is superior to MDAC.
slide92

ASA – Question 16

  • Explain the concept of “ion trapping”.
slide93

Q16: ion trapping

  •  the more acidotic the compartment the more SA will be NONionized because SA is a weak acid (the stronger acids will dissociate and give off their H+ first.)
  • the more basic a compartment the more IONIZED SA will be because there is a relative lack of H+  so because SA is an acid it will give off its H+ and be ionized, i.e. “trapped” in that milieu.
slide94

Q16: ion trapping

Tissue pH 6.8 Plasma pH 7.1 Urine pH 6.5

HA HA HA

H+ A-H+A-H+A-

Pee it out….

H+A-

Prior alkalinization.

After alkalinization.

Tissue pH 6.8 Plasma pH 7.5 Urine pH 8.0

HA HAHA

H+ A-H+A-H+A-

Pee it out…

slide95

ASA – Question 17

  • Beyond what serum [SA] should you consider urine alkalinization?
slide96

ASA – Question 17

  • >40mg/dL in an acute OD
  • >30mg/dL in a chronic OD
slide97

ASA – Question 18

  • Name 5 indications for hemodialysis indications in SA poisoned patients.
slide98

Q18 - HD

  • Renal failure
  • CHF
  • Pulmonary edema or acute lung injury
  • Refractory acidosis or electrolyte imbalance despite maximal therapy
  • Persistent CNS symptoms
  • Progressive vital sign deterioration
  • Acute OD with level >100mg/dL
  • Liver failure with coagulopathy