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Acetominophen NSAID and Salicylate poisoning

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					Acetaminophen, NSAID and
    Salicylate poisoning



      Presented by Dr. Hellman
Slides prepared by Brian A Romito, DO
            IM/EM PGY-5
             Feb 8th 2007
   Acetaminophen (APAP) Overdose
Most absorption 2º, even after OD

Peak concentration 4º then hepatic metabolism

90% elimination 3 routes; conjugation w/ gluconroide
(40-67%) or sulphate (20-46%), or oxidation via
CP450 or similar enzyme then conjugation

Oxidation by CP450 or subfamily CYP2E1--> very
reactive electrophile; NAPQI (aka N-acetyl-p-
benzoquinoeimine)
Glutathione oxidation
Glutathione; it’s about moving electrons via Sulfur
Most common cause of liver failure
        APAP Toxicity MOA
NAPQI normally combines w/ glutathione & other thio-
compounds forming non-toxic conjugates in urine

NAPQI exceeds glutathione supply, Free NAPI
binds hepatocyte intracellular proteins--> toxicity

CYP450 inducers (EtOH, Isoniazid, anticonvulsants),
& Inhibitors (cimetidine) affect NAPQI formation

Renal injury may occur w/ or w/o Hepatic Injury!!!
Activation Prostaglandin syntheses in Kidneys
Liver Failure- how much Tylenol has he
      taken in the past 40 years???
           Liver Pathology

Most oxidative metabolism in Liver Zone III,
affected most by acetaminophen toxicity!

Sever toxicity also affects Liver Zones I & II
& can destroy the entire Liver!

Fulminate Liver Failure 2º to toxicity rather
than direct APAP effects
hepatocytes closest to the arterioles (zone 1 below) are the best
  oxygenated, are the first to "see" and potentially absorb blood-
 borne toxins absorbed into portal blood from the small intestine
while those farthest from the arterioles have the poorest supply of
                               oxygen.
Tx for Acetaminophen Toxicity
N-acetylcysteine (NAC) serves as both glutathione
precursor & substitute

NAC may ↓ NAPQI formation & ↑ non-toxic sulfation

NAC improves survival in pts w/ acetaminophen-induced
fulminant liver failure, even long after initial metabolism

Possible MOA for survival benefit; ↑ oxygen
delivery/uptake by tissues, change in microcirculation,
scavenging ROS & ↓ cerebral edema
NAC as a Liver Damage Snack
4 stages APAP-induced Hepatic Injury post
ingestion

Stage 1: pre-injury; 1st 24º, no specific Sx; N/V,
anorexia, diaphoresis, malaise... common in 1st 8º

Stage 2: onset Liver injury 24º (12 to 36º after OD).
If sever may be 8º; N/V, RUQ/mid-epigastric pain

Stage 3; Max liver injury; 3-4 days. Sx vary; fulminant
hepatic failure; encephalopathy, coma, coagulopathy,
hypoglycemia, metab acidosis, haemorrhage, ARDS

Risk renal injury ↑ 25% w/ severe toxicity vs.
2% w/o hepatotoxicity
4 stages APAP-induced Hepatic Injury post
ingestion
Stage 4; Recovery Liver Enzymes to baseline 5-7
days, longer w/ severe injury. Histologicly- months

Regeneration of liver is complete w/o chronic dys-fxn
        Diagnostic strategies
ID risk for Hepatotoxicity & initiate timely Tx w/ NAC!

H&P establish risk, but early Sx are unreliable, and
late Sx occur long after ideal NAC start time...

Lab evaluation is essential

Once APAP toxicity risk determined, START NAC

Acute OD is a single ingestion w/in a 4º period

Liver failure/death can be completely prevented if
NAC is started early after ingestion
        Diagnostic Consideration
Factors that complicate eval & Management; inability
to est time of ingestion, presents > 24 hours post
ingestion, age < 5yrs, pregnancy

Management of Chronic excessive APAP dosing
controversial
   Assess/Tx Acute APAP Ingestion
Lab eval; serum APAP level 4º & ASAP

AST; Pt has Sx of hepatic injury, APAP on or above
nomogram line, time of ingestion unknown

PT, Lytes, Glu, BUN, creatine kinase if AST greatly ↑

NAC Tx if; APAP is on or above nomogram tx line,
AST ↑, APAP > 10ug/mL, or unknown ingestion time
  Assess/Tx Chronic APAP ingestion
Sx hepatic injury

Children;
ingest > 75mg/kg in 24º w/ febrile illness, malnutrition,
chronic use CYP450 inducers, or > 150/kg in 24º

Adults;
Ingest >4g in 24º assoc w/ chronic EtOH,
malnutrition, or CYP450 inducers (anticonvulsants), or
ingest > 7.5g in 24º
 Assess/Tx Chronic APAP ingestion
HIGH Risk APAP <10;
 1) AST 2X Norm
 2) AST> Normal; pt ASX

HIGH Risk APAP>10 & as expected for normal dose
  1) AST>10

HIGH Risk APAP concentration > expected for dose

LOW Risk; APAP <10, AST Normal to 2X, pt ASX, or
APAP as expected for normal dose & AST Normal

Minimal risk; APAP <10; AST normal
              Tx based on Risk

Higher risk; admit, Tx w/ NAC

Low Risk; Give return instructions for Sign or SX of
hepatic injury, F/U in 24º... otherwise admit, Tx NAC

Minimal Risk; DC from hospital, provide return
instructions
        APAP potential for toxicity
Assume the pt has ingest the greatest amount & LAB

Ingestions > 7.5g in adult or > 150mg/kg child indicate
risk and Lab eval

Establish Risk, then Get APAP concentration at 4º or
ASAP if after 4º

If PE is consistent w/ hepatic injury or timing of
ingestion can Not be established, AST should be
measured, then Treat
Nomogram
       APAP potential for toxicity
Plot APAP concentration on Tx Nomogram

APAP concentration measured b/t 4º & 24º

US tx line is 25% lower than original line Rumack-
matthew adaptation nomogram (inc sensitivity)

Concentration on or above Tx line should be treated!

Pts who present after 8º post ingestion, start NAC &
adjust according to Nomogram results

NAC not recommended; pts unknown ingestion time,
w/ APAP level below detectable limit, Norm AST
    APAP potential Hepatic toxicity
Pt w/ RUQ or epigastric pain or tenderness w/ Hx of
APAP ingestion suggests hepatic injury

AST as screening test

If ↑ AST but APAP plots below the Tx line, consider
other source of hepatic injury, but still tx w/ NAC

Extended release APAP; immediate releases ½ of
APAP dose, then sustained 2nd ½ over several hours

Extend release; get 4º & 8-10º APAP levels to r/o
delayed elevations... Peak plasma levels usually at 4º
              APAP toxicity eval
Acute exposure < 5yrs; severe hepatotoxicity , death

Lab eval on (febrile or on CP450 inducers) > 90mg/kg
concentration in a child or > 4g in adult in 24º

Pts w/o predisposing risk (ie not febrile, or no CP450
meds); ingestion >150mg/kg in child or >7.5g in
adult

After normal dosing peak APAP level should be <
30ug/mL, 30 to 90 min post dose & < 10 by 4-6º
             APAP management
Goals; limit GI absorption, start NAC w/in 8º of
ingestion, control Sx, provide supportive & F/U care

Gastric Lavage, limited use b/c rapid GI absorption

Activated charcoal may bind NAC, no benefit outcome.
Do NOT give charcoal for at least 2º post NAC, unless
directed otherwise

NAC PO; dilute solution (3-5%)... loading dose
140mg/kg, followed by maintenance 70mg/kg Q4º

N/V common w/ NAC, re-give dose vomited w/in 1º
       APAP toxicity management
IV NAC if pts can not tolerate PO... not widely
available...

Can give PO NAC IV w/ dilution…consult pharmacy

Risks of IV NAC...anaphylactoid RXN's, flushing
urticaria, angioedema, bronchospasm, hypotension

4-14% pts develop transient rash with IV NAC

Dose adjustment to slower rate, antihistamine, fluid
boluses in place of discontinuation
       APAP toxicity management
IV NAC (3% soln); 30g NAC in D5W total 1L

Bolus 140/150mg/Kg for 1º, then 4º 15mg/kg/hr,
then 16º 7.5mg/kg/hr

For chronic ingestion or continuous infusion
15mg/kg/hr for 44º

IV NAC fulminant Hepatic failure.. British study; less
vasopressor use, less Death/cerebral edema

Use IV in Oral intolerance, N/V resolved switch to PO
       APAP toxicity management
APAP crosses placenta, can cause fetal death

2nd Trimester fetal CYP450 enzymes present

Maternal NAC safe/effective, fetal outcome usually
good

Oral NAC may reach fetus, but IV NAC may achieve
higher maternal-fetal NAC gradient!

NAC Treatment course; PO loading followed by 17
doses, 4º intervals. 20º IV NAC in UK & 48º IV in US

All durations NAC effective when started w/in 8º,
longer treatment duration when liver injury
                  Disposition
Contact poison control center

Fulminant Hepatic failure, need ICU, frequent Neuro
checks, glucose measurements, VS monitoring

Early contact Liver transplant center if Liver failure

Serum PH < 7.3 after resuscitation likely to die w/o
transplant.
          Aspirin & NSAID toxicity
Less Deaths; FDA limits 36 tabs baby ASA per bottle,
child resistant containers

Poisoning underestimated; leads to metabolic
acidosis, seizure, hyperthermia, pulmonary edema,
cerebral edema, renal failure & Death
       ASA Absorption & Elimination
Salicylic Acid salts absorbed rapidly GI tract; serum
concentrations ½ º, 2/3 of dose in 1º & peak 2-4º


Absorption to 12º post large ingestion or coated tabs


ASA hydrolyzed to free Salicylic acid via RBC, Liver,
Intestinal wall & reversibly binds albumin


Free Salicylate & conjugates excretion is Renal
   ASA Absorption, Elimination cont…

Therapeutic dose is 1st order kinetics, but > 30mg/dL
has Zero order Kinetics w/ constant Metabolic Rate

Ph-sensitive urinary excretion of ASA det half-
life…toxic doses may be 15-30º

Salicylate stim medullary respiratory center to PH and
CO2 partial pressure.

 amts ASA depress respiratory center. Loss bicarb,
metabolic acidosis; 2º buffering respiratory alkalosis.
Aspirin
                    ASA Toxicity; Metabolic, Renal
Inhibition of Krebs cycle   amts lactic & pyruvic acid.

Uncoupling ETC;  metabolism &Temp, thus  CO2
  production & O2 use,  glycolysis risk  BS. Less
  common  BS due to adrenaline


K+; Vomiting,  Renal Na+K+HCO3 loss,  Renal Tubercle
  permeability, Intracellular H2O, Na+ retention

Uncoupling ETC also  K+ by inhibiting active transport

    Renal Blood flow; ARF & secretion inappropriate ADH
ETC= electron transport chain, arrows; increase or dec, 3 dots; therefore
     ASA Toxicity; pulmonary Edema

MOA unknown


 Risk Adults; smoking, 30+ y/o, chronic use,
metabolic acidosis, Neuro Sx, Salicylate > 40mg/dL


 Risk Peds; High salicylate level, large anion gap,
K+ level, CO2 concentration
      ASA Toxicity; Chronic Ingestion
Aged;  blood flow to Liver   biotransofmation of
salicylate. Kidneys;  function   clearance

 albumin binding w/ chronic use   free salicylate


Free salicylate enters cells causing signif illness w/
lower serum concentration


Chronic toxicity w/ serum 40mg/dL may be more ill
than pt w/ acute ingestion w/ 80mg/dL
               Clinic ASA Toxicity

Peds aggressive dosing ? more serious than acute
ingestion. Sweating, F, tachycardia may be an
underlying infection


Breast milk, teething gels, skin ointments; all have
higher concentrations



Toxic 200-300mg/kg; 500mg/kg potentially Lethal
              Clinic ASA Toxicity

Sx; Tinnitus, impaired hearing, vomiting, hyperpnea
(may be  respiratory depth w/o  rate), dehydration

Vomiting may be w/in 8º of ingestion, CNS Sx;
associated w/ Acidemia


SOB & altered sensorium; pulmonary & cerebral
edema; fail to recognize pulmonary edema  M&M

Bleeding risk;  hepatic Factor VI & platelet
aggregation
 Diagnostic Approach; serum salicylates
Measure level 6º post ingestion, then 2nd sample in 2º


If 2nd sample > 1st sample; do serial; caution w/
coated preps, or chronic ingestion


Frequently monitor PH


Death by CNS depression & Cardiovascular collapse
          Sx of Salicylate Toxicity
ASX; occasionally none

Mild; Mild-mod hyperpnea, Tinnitus, may get lethargy

Moderate; Severe Hypernea, marked lethargy or
excitable, NO COMA, NO Convulsions

Severe; Severe Hypernea, COMA, Semi-coma, may
get convulsions
Tx Goals prevent > absorption, correct fluid acid-base
                 deficit &  excretion
   Urine output 2-3mL/kg/hr w/ D5NS or D5LR, but No
   Forced diuresis. D5 w/ 100mEq bicarb/L

   Fix K+ & Monitor pH, avoid systemic alkalosis



   Alkalize Urine; ABG; 1-2meq/kg Bicarb, then as needed
   (50ml Bicarb  pH by 0.1)

   DIALYSIS IF; Coma/Seizure, Hepatic failure, Pulm
   edema, Severe acid-base imbalance, Deteriorating
   Status, level > 100mg/dl & 40mg/dL if chronic
            ASA Tox management
VS; especially respiratory rate, assess minute
Volume, skin temp, ABG

Activated Charcoal reduces absorption; consider if
ingestion w/in 1º NO Evidence of benefit of outcome

IVF; dehydration occurs early, correct K+ use
dextrose, accu check frequently. CNS glu maybe low
even if serum euglycemic

Alkalize urine especially if salicylates > 35mg/dL, urine
pH 7.5-8 necessary to  excretion

Consider exchange transfusion in young or dialysis
               Salicylate toxicity

Pregnancy; greater concentration on fetal side of
placenta, fetal distress, associated w/ fetal demise

Deliver distressed fetus if possible

If acute intoxication; pulmonary edema, acidosis,
electrolyte abnormality, renal insufficiency, CNS Sx
other than Tinnitus; ADMIT

Mortality Rate of chronic toxicity 25% vs 1% for acute

DO a Psych EVAL
                NSAIDS Toxicity
Based on COX selectivity, various activities, analgesia.
13 million Americans use Daily.

COX-1; concentrated in platelets, gastric mucosa,
renal collecting tubules, vascular endothieal cells

COX-2; usually expressed in inflammatory stimuli.

Weak organic acids readily cross and high
concentration in gastric mucosa

Most OD even w/ large amounts are ASX or only
minor CNS or GI disturbances. Elimination half-life in
OD not significantly prolonged!
                   NSAID Toxicity
   OD w/ mefenamic acid, a fenamate, high risk seizure
2-7º Post Ingestion– Tx IV Benzo, rapid recovery

Reversible Renal dys-fxn only after massive OD,
  supportive, do not correlate w/ serum level

Phenylbutazone (pyrazolone) rarely used risk aplastic
  anemia, more toxic than other NSAIDS

-   mild poisoning; N/V, abdominal pain, drowsiness
-   Severe; hematemesis, coma, convulsion, fever,
    respiratory arrest, acidosis, EKG abnormalities,
    cardiac arrest. Long clinical course vs other NSAID
           Phenylbutazone-NSAID
Phenylbutazone (pyrazolone) rarely used risk aplastic
  anemia, more toxic than other NSAIDS

-   mild poisoning; N/V, abdominal pain, drowsiness

-   Severe; hematemesis, coma, convulsion, fever,
    respiratory arrest, acidosis, EKG abnormalities,
    cardiac arrest. Long clinical course vs other NSAID
        Management; mostly supportive

  Screen for APAP, NSAID concentrations NOT useful
Lytes, RFP, Hepatic Fxn Panel, ASA, UA, CXR only help
   w/ significant Sx or ASA or APAP toxicity
Peds <100mg/kg Ibupro no medical eval, > 300mg/kg
  need eval. 100-300, eval if Sx
Adults; 6º obs & psych eval
Pyrazolone & Fenamate ingestions NEED EVAL

Activated charcoal use after massive ingestion
                  Management
Observe 4º

High protein binding & rapid metabolism  urine
alkalinization, hemodialysis, hemoperfusion not
clinically useful.

Multi-dose activated charcoal  elimination half-life
phenylbutazone by 30% & some benefit in severe
intoxication.
                Works cited
Paediatrics 55: 871, 1975

Rosen's Emergency Medicine Chapters 146, 147

Annals of Emergency Medicine; Vol 45, Num 5 5-05

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