APAP and Salicylate Poisoning

1
APAP and SalicylatePoisoning

• Corinne M. Hohl
• R5, EM Training Program
• McGill University
• September 2003

2
Acetaminophen
3
APAP Question 1

• What is the therapeutic mechanism of action of
  APAP?

4
Q1 mechanism of action

• Central prostaglandin synthetase inhibitor
• ? analgesic, antipyretic with weak
  anti-inflammatory properties.

5
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.

6
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.

7
(No Transcript)
8
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.

9
APAP Question 3

• What happens to APAP metabolism in an OD
  situation?

10
Q3 APAP metabolism in OD

• Saturation of glucuronidation and sulfation
  pathways
• Amount of APAP metabolized by p450 cytochromes to
  NAPQI increases.
• 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 lt30 of baseline ? large margin of safety
  where therapeutic dose 10-15mg/kg to toxic dose
  of 150mg/kg for single acute ingestion.

11
(No Transcript)
12
APAP Question 4

• Name 3 factors which adversely affect APAP
  metabolism.

13
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)

14
APAP Question 5

• Name 3 factors which decrease GSH stores.
• Name 2 ways in which GSH stores can be replaced.

15
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 of
acetaminophen hepatotoxicity with fasting and
ethanol use. JAMA 1994 2721845
16
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 of
acetaminophen hepatotoxicity with fasting and
ethanol use. JAMA 1994 2721845
17
APAP Question 6

• Why is APAP toxic to the kidney as well? (Name 2
  mechanisms).

18
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

19
APAP Question 7

• How could one distinguish with a simple lab test
  between hepatorenal syndrome and ATN?

20
Q7 HRS vs. direct toxicity

• Fractional excretion of sodium (FeNa)
• FeNa gt1 in primary renal injury
• FeNa lt1 hepatorenal syndrome

21
APAP Question 8

• What other 2 organs are most commonly (although
  overall rarely) damaged in an APAP overdose?

22
Q8other 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.

23
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)

24
Q9 pts w/ hepatotoxicity

• 60

25
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?

26
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 by 36h)
• 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

27
APAP Question 11

• Which lab test is the most sensitive for early
  detection of hepatotoxicity.?

28
Q11 lab test

• AST

29
APAP Question 12

• Your resident saw a patient 90min post APAP
  ingestion of unknown quantity He tells you the
  APAP is lt10 and AST 40. How would you dispo and
  manage this pt.

30
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).

31
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?

32
(No Transcript)
33
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 lt10 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.

34
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.

35
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.
36
APAP Question 13

• Name four indications (lab criteria) for treating
  a patient for repeated excessive APAP dosing.

37
Q13 chronic OD

• If the APAP level is above the treatment line
  (plot earliest possible dose to have high
  sensitivity).
• Symptomatic pt with AST gtnormal.
• Any asymptomatic patient with a hx of chronic
  excessive APAP ingestion and an AST gt 2x normal.
• AST gtnormal with APAP gt10.
• If the APAP level is greater than expected for
  the appropriate dose.

38
(No Transcript)
39
APAP Question 14

• A 3rd ingestion comes in18 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 lt10 and her AST
  is 90.
• How will you manage her medically?
• She asks you whether her baby will have any
  defects.

40
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.

41
Q14 Pregnancy and APAP

• AC Class C
• Safety for use during pregnancy has not been
  established.
• NAC Class A
• Safe in pregnancy

42
APAP Question 15

• Name 4 mechanisms by which NAC works.

43
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.

44
(No Transcript)
45
APAP Question 16

• Name 4 indications for NAC therapy.

46
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 (gt24h with
  either detectable APAP or elevated transaminases.
• Chronic lg ingestions (gt4g/day in adult, gt120mg/d
  in child) with elevated transaminases.
• Hx of exposure and FHF.

47
IV NAC

• 3 situations in which IV NAC is undoubtedly
  preferable to oral
• Fulminant hepatic failure
• Pregnancy
• Inability to tolerate oral NAC.

48
APAP Question 17

• Name 4 poor prognostic indicators

49
Q17 poor prognostic indicators

• pH lt7.3 (2 days after OD, after fluids)
• Hepatic encephalopathy
• PT gt1.8 times normal.
• Serum creatinine gt300mmol/L
• Coagulation factor VIII/V ratio of gt30

Note Transaminase levels do NOT predict the
clinical course. They can decline during hepatic
recovery or with FHF.
50
Q17 other rules of thumb

• If PT in seconds gt number of hours since
  ingestion.
• If INR is abnormal and still increasing on 4th
  day post ingestion.

51
Q17 indicators for need for transplant

• Arterial pH lt7.3 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 gt100 sec (without FFP or Vit K)
• Creatinine gt300 µmol/L
• Grade III or grade IV hepatic encephalopathy
• Makin AJ, Williams R Acetaminophen-induced
  hepatotoxicity Predisposing factors and
  treatments. Adv Intern Med 1997 42453
• Lee WM Acute liver failure. N Engl J Med 1993
  3291862

52
Q17 indicators for transfer to transplant center

• INR gt 5
• OR
• any of the following complications
• ARF creatinine gt200 µmol/L
• metabolic acidosis pH lt7.35 or bicarb lt18 mEq/L
• Hypotension
• Encephalopathy
• Hypoglycemia
• A rising PT on the fourth day after overdose is
  the single best marker of a poor prognosis(39)

53
APAP Question 18

• Why is the coagulation factor VIII/V ratio
  abnormal in APAP poisoning?

54
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.

55
APAP Question 19

• Name 3 mechanisms by which you can develop a
  metabolic acidosis in APAP poisoning?

56
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

57
Salicylates
58
ASA Question 1

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

59
Q1 delayed absorption

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

60
ASA Question 2

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

61
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

62
ASA Question 3

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

63
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.

64
ASA Question 4

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

65
Q4 chronic OD toxic dose

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

66
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.

67
Q5 acute vs. chronic
MORE DANGEROUS!
Characteristics Features Acute Chronic Age
Young adult Older adult/infants Etiology OD Th
erapeutic misuse Co-ingest. Frequent Rare Past
history OD or psych Comorbidities/pain/RF Present
ation Early Late Dehydration Moderate Severe Me
ntal status Normal(initially) Altered Serum
conc 40 - 120 mg/dL 30 to 80
mg/dL Mortality Low w/ treatment High
68
ASA Question 6

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

69
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.

70
methylsalicylate
Hydrolysis in GI tract, liver, RBCs
2.5 excreted unchanged in urine (pH independent)
71
methylsalicylate
Free tissue SA
90 of free SA binds albumin at conc lt 10mg/dL
2.5 excreted unchanged in urine (pH independent)
72
methylsalicylate
Free tissue SA increases
Hydrolysis in GI tract, liver, RBCs
of free SA bound to albumin decreases as the
serum increases 75 bound _at_ 40mgdL 50 bound _at_
75mg/dL
2.5 excreted unchanged in urine (pH independent)
First order kinetics
zero order kinetics once saturated
zero order kinetics once saturated
73
ASA Question 7

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

74
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.

75
ASA Question 8

• What is Reyes syndrome?

76
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.

77
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.)

78
Q9

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

79
ASA Question 10

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

80
Q10 ALI

• Age gt 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.

81
ASA Question 11

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

82
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.

83
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
  gt100mg/dL or co-ingestions)
• Severe hyperthermia from uncoupling of oxidative
  phosphorylation is a preterminal event.

84
ASA Question 12

• Name 8 presenting manifestations of chronic
  salicylism.

85
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.

86
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?

87
Q13

• Urine dip ketones
• CBGM hypoglycemia

88
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 gt7.4. It is notoriously
  unreliable.
• What is a better way of following the severity of
  your pts acute or chronic ASA poisoning? Which
  lab tests, at what frequency?

89
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.

90
ASA Question 16

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

91
Q15 decontamination

• Aim for a 101 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.

92
ASA Question 16

• Explain the concept of ion trapping.

93
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.

94
Q16 ion trapping
Tissue pH 6.8 Plasma pH 7.1 Urine pH
6.5 HA HA HA H A- HA- HA-
Pee it out.
HA-
Prior alkalinization.
After alkalinization.
Tissue pH 6.8 Plasma pH 7.5 Urine pH
8.0 HA HA HA H A- HA- HA-
Pee it out
95
ASA Question 17

• Beyond what serum SA should you consider urine
  alkalinization?

96
ASA Question 17

• gt40mg/dL in an acute OD
• gt30mg/dL in a chronic OD

97
ASA Question 18

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

98
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 gt100mg/dL
• Liver failure with coagulopathy