APAP Li Fe Toxicity

Heather Patterson PGY-4

Dr. Ingrid VicasOctober 8, 2008

Learning Outcomes

• By the end of the session learners will be able to:– Identify clinical presentations, appropriate

diagnostic and therapeutic management for acetaminophen, lithium, and iron toxicity

Acetaminophen

• Accounts for more deaths than any other pharmaceutical agent• Most common ingestion in all age groups

• One of the most common causes of acute hepatic failure

• Mainstays of Rx – GI decontamination/A.C. – NAC

Acetaminophen - Pharm

• Absorption:• Within 2 h

• Distribution• Peak plasma levels

within 4h

• Metabolism• 90% hepatic

• Excretion• Renal

• Dosing:• Therapeutic 4g/d or

75mg/kg/d• Toxic 7.5g/d or

>150mg/kg

Acetaminophen - Metabolism

Acetaminophen

• General approach:• ABC’s–

• rarely an issue in acute OD • subacute presentation may be an issue with coma/encephalopathy

• Decontaminate• AC – If early yes, otherwise not much benefit

• In large OD definitely

• Enhance Elimination - none• Antidote

•NAC

Acetaminophen - Levels

• When should we get the first APAP level?• No added benefit of getting a level <4h

• Peak levels at 4h• 1st point on the RM nomogram

APAP – Labs in acute ingestion

• AST/ALT:• APAP level above Rx line on RM nomogram• Time of ingestion is unknown or >24h• Suspicion for multiple ingestion

• INR/lytes/glucose/BUN/Cr:• AST/ALT elevated >1000

APAP: R-M Nomogram

APAP: R-M Nomogram

• When can we NOT use the Nomogram to guide our therapy?• Chronic OD• 24h since time of ingestion• >Unknown time of ingestion ???• Extended release preps???

APAP: NAC

• When should we initiate therapy?

• Smilkstein et al 1988

Time to NAC (h) 72 hour PO 20 hour IV

0-4 5/97 (5.2%) 0/92 (0)

4-8 13/417 (3.1%) 8/812 (1.0%) *

8-12 60/612 (9.8%) 22/461 (4.8%)*

12-16 93/422(22.0%) 45/244 (18.4%)

16-20 84/295(28.5%) 33/129 (25.6%)

20-24 56/179(31.2%) 24/70 (34.2%)

Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985)

APAP – NAC

• What is NAC and what is the MOA?1. Glutathione precursor2. Glutathione substitute3. Enhances sulfate conjugation of APAP4. Anti-inflammatory and anti-oxidant effects5. Inotropic and vasodilatory properties that

improve microcirculation

APAP – NAC

• What are 5 indications for NAC?1. Level above “possible hepatic toxicity” line

on nomogram2. Hx of ingestions & level not available

before 8h3. Hx APAP ingestion + evidence of hepatic

toxicity4. Multiple APAP doses, RFs for hepatotoxicity

+ >66mcg/mL 5. Unknown time of ingestion and level

>66mcg/mL??

APAP – NAC

• How is NAC administered? • Initial: 150mg/kg in 250-500cc D5W over

30-60min

• 2nd infusion: 50mg/kg in 500-1000cc D5W over 4 h

• 3rd infusion: 100mg/kg in 1000cc D5W over 16h

• Better way of doing this is CPS: There is a chart that looks at dosing and mixing of NAC in a user friendly format.

Extended release preps

• Tabs have ½ immediate release acetaminophen and ½ as extended release

• Study by Cetaruk et al showed that ordering only a 4h level would have missed 3/14 pts when treatment was indicated by a second level• Suggests that ongoing absorption occurs

beyond the 2-4h absorption seen with non-ER tabs

Extended release preps

• How should we manage these overdoses?• Cetaruk et al – repeat APAP level 4-8h post

first level (if first level within 8h)

• Manufacturer – • Undetectable @4h – no Rx, no repeat level• Above Rx line – treat• Detectable but below line@4h – repeat level 4-6h

later

• Rosen’s – single level at 4h and treat based on that level

Case 2:

•75M. Hx of RA & EtOH abuse.• Presents to ED with FOOSH injury and distal

radius #.• d/c’d with a script of Percocets – which he

took faithfully, but did not stop his regular Rx

• Returns to ED two days later c/o of abdominal pain – especially RUQ

•MEDS:• tylenol daily ( 2-3gm/day), dilantin.

Stages of Acetaminophen Toxicity

• Stage 1: <24h• Historical features• N/V/anorexia, malaise, diaphoresis

• Stage 2: 24-72h• P/E features• Stage 1 plus RUQ/epigastric pain

Stages of Acetaminophen Toxicity

• Stage 3: 2-7d• Lab features: AST/ALT >1000• Fulminant hepatic failure,

hypoglycemia, coagulopathy, encephalopathy/coma

• Stage 4: >7d• Recovery• Enzymes return to N within 5-7d

Acute vs. Chronic Ingestions

• Acute:• Entire ingestion within 4h

• Chronic• All other repeated supratherapeutic

ingestions

• Factors that complicate acute ingestions:• Unknown time of ingestion• >24h after ingestion• ?peds

Risk Factors for Chronic Toxicity

• Chronic EtOH abusers in subacute/chronic OD

• Medications that induce P450 system• Malnourished

• Depleted glutathione stores• Less NAPQI binding with glutathione• More hepatotoxicity

• Febrile illness in peds <5y

Indications for Labs in Chronic

1. S+S of hepatotoxicity2. Peds:

• >75mg/kg in 24h with risk factors• >150mg/kg in 24h with risk factors

3. Adults:• >4g/24h with risk factors• >7.5g/24h without risk factors

Indications for NAC in Chronic

1. Signs or symptoms of hepatic dysfunction

2. Laboratory indications (if labs were indicated):• APAP of any level• ALT elevation >1000• INR >2

Chronic Ingestion S/Sx of Hepatic Injury

Yes Tx w/NAC

NoRisk Factors*

*Risk Factors include chronic EtOH use, febrile infants, ?malnourished

Yes

No

Order labs (ALT,coags) if >4gm/24H Or >75mg/kg

Order labs if >7.5gm/24HOr >150mg/kg

If either are APAPOr ALT are , Tx with NAC

Chronic Ingestion: Goldfranks

Case 3

• 18F suicide attempt a few days ago. Told friend but swore her to secrecy.

• Nausea and vomiting x 1 day. Improved for a day. Now returns with N/V and RUQ pain. Feeling ++ unwell.

NAC and Fulminant Liver Failure

• Keays et al (late 80s)• Population: 50pts with liver failure

secondary to APAP toxicity without NAC treatment

• Intervention: IV NAC or standard therapy

Outcomes

NAC and Fulminant Liver Failure

• Conclusion:• IV NAC is indicated in fulminant hepatic

failure• If late presentation:

• Empiric Rx if APAP +/or AST elevated• Rx endpoint:

• INR<2• Encephalopathy resolves• Death

DDx AST/ALT >1000

• Acute viral hepatitis• Shock liver• Drugs/Toxins

• APAP, antiretrovirals, mushrooms• Rare: HELLP, Budd-Chiari,

Transplant Criteria

• pH <7.3 despite adequate fluid resuscitation

OR

• Grade III/IV encephalopathy AND

INR>5AND

Cr >300

Transplant

• Consider if:• INR>5• Metabolic acidosis (pH <7.35 or CO2

<18)• Hypoglycemia• Renal failure, Cr>300• Encephalopathy

Case 4

• Unknown time of ingestion

Indications for NAC

• Unknown time of ingestion• APAP detectable regardless of

level???• Repeat levels/half life

• AST elevated regardless of APAP level

• NO Rx if APAP –ve and AST is normal

Anaphylactoid reactions to NAC

• Can look like anaphylaxis• <20% of IV NAC infusions

• Management:• Prevent if possible use ideal body wt• Temporarily stop infusion, wait 10-15min• Give benadryl IV• Restart at a 1/2 rate and over next hour

increase to original rate

Iron

• MC of death due to poisoning in children– Traditionally iron OD’s where in children < 6

yo taking excess multi-vits

• Less of an issue now because of the packaging of iron and the different formulations of children multi-vits

Iron: Absorption

• Non-heme bound iron is absorbed (<10%) in the ferrous state (Fe2+) at the duod/jejunum

• Bound by ferritin at intestinal mucosa

• Transported by transferrin to cells

Iron: Pathophysiology

• Free Iron uncouples oxidative phosphorylation which results in cell dysfunction and death– This leads to impaired ATP fxn

and free radical production which cause the systemic manifestations

Iron Toxicity

• Toxicity of Fe compounds depends on amount of elemental iron

• (% elemental iron x mg tabs) x number of tabs= amt of elemental iron

* ie. 100 tabs of Ferrous sulphate (325mg each)

=20% x 325 x 100

=6500mg of elemental iron

Ferrous Salt Elemental Iron (%)Tablet Size

(mg)Elemental Iron

Content/Tablet (mg)

Sulfate 20 300 60

    325 65

Fumarate 33 200 66

Gluconate 12 300 36

Multivitamins with iron:

 Children’s chewable

    4–18

 Adult     6–50

 Prenatal     36–65

Iron: Elemental Iron %

Iron Toxicity

• Elemental Fe Peak [ ] Toxicity– < 20 mg/kg < 30 umol/L none– 20 - 40 mg/kg 30 - 60 mild– 40 - 60 mg/kg 60 - 90 mod– > 60 mg/kg > 90 umol/L severe

• LD50 is 200-250mg/kg but there have been reported deaths with as little as 130 mg/kg

Iron: Local toxicity

• Dose: 10-20mg/kg lower doses than systemic toxicity

• Mech: Direct GI corrosive/irritant– N, V, abdominal pain, – diarrhea, – hematemasis, melena, hematochezia

• Must consider on ddx of gastroenteritis/ GI bleed in peds

Iron: Systemic Toxicity

• Dose: >40mg/kg higher dosing than local

• Mech: Caused by impaired intra-cellular metabolism– Coagulopathy – Liver toxicity (periportal necrosis)– Coma - 2 to acidosis, encephalopathy,

hypotension

• CONSIDER Fe OD in AGMA/SHOCK NYD

Iron: Stages of Toxicity

• STAGE I (< 6hrs): GI signs symptoms

• STAGE II (6 - 24hrs): Latent period (subclinical hypoperfusion & AGMA)

• STAGE III (variable): Systemic toxicity

• STAGE IV (2-3 days): Hepatic Necrosis

• STAGE V (weeks): Bowel obstruction

Iron: Stage 1

• Gastrointestinal (0.5–6.0 hr) – Abdominal Pain– Vomiting– Diarrhea– Hematemesis– Hematochezia

Iron: Stage 2

• Latent Stage/Relative Stability (4-12H)– Aka “CALM BEFORE THE STORM”– May not have obvious signs or symptoms but

they are getting sick– GI Sx usually resolve during this stage– Evidence of subclinical hypoperfusion and

AGMA

Iron: Stage 3

• Systemic toxicity- Shock and Acidosis (6-72H)– Hypoperfusion– Metabolic acidosis– Coma– Coagulopathy– MODS

Iron: Stage 4

• Hepatic Necrosis (12-96H)– Coma – Coagulopathy– Hypoglycemia– Jaundice– +/- Fulminant Hepatic Failure

Iron: Stage 5

• Bowel Obstruction (2-4 wks)– Abdominal pain– Vomiting– Dehydration

Iron: Investigations

• Name 3 ways to directly assess for Iron?

– Serum Iron levels (4-6h post ingestion)

– Deferoxamine Challenge• What is this?

– AXR

Iron: Fe Levels

• Measure at 4-6H (5hrs reasonable)• Levels can help risk stratify severity of

toxicity– Mild/moderate/severe

• Falsely low– With deferoxamine :. must do before

administration– Late measurement b/c Fe is rapidly transported

intracellularly and deposited in the liver

Iron: Deferoxamine Challenge

• 10mg/kg per hour x 4h and see if urine color changes

• +ve = urine color change -----------> tx• -ve = no urine color change --------->no tx• Problems

– UNRELIABLE – do a specific gravity– Need urine from a dehydrated patient– Qualitative colour change– DO NOT use as sole determinant for basis of

treatment

Iron: AXR

• Which toxins are visible on AXR?– Chloral hydrate, crack vials, Ca carbonate– Heavy metals– Iron, iodides– Psychotropics, phosphates– Enteric –coated preps– Slow-release preparations

Iron: AXR

• Absence on AXR does NOT r/o ingestion

• How can one have a –ve AXR?– Pt did not take Iron– Iron solutions (liquid) are not radiopaque– Chewables formulations are not

radiopaque– Iron tabs have already dissolved

Iron: Investigations

• Which labs are you going to order?– CH6, serum iron, LFTs, coags– ABG– +/-APAP/ASA

• 3 Abnormalities on CH6– Increased WBC– AG– Hypoglycemia

Iron: Decontamination

• Charcoal does not bind Fe• Gastric Lavage

– tabs are large therefore may not work– Use tap water or saline

• Whole Bowel Irrigation– Indicated if iron tabs visible past stomach on

AXR – PEG- 1.5-2L/H (20-40mL/kg/H) until clear PR

effluent & no iron tabs seen on AXR• OR 10L then stop

Decontamination

• What substances will NOT bind with AC?• C - caustics• H – heavy metals, hydrocarbons• I - Iron• L - Lithium• E – ethanol, methanol, EG

Iron: Elimination

• INDICATION FOR DEFEROXAMINE?1. hypotension/shock/coma2. refractory met acidosis3. levels (>90)4. severe GI sx

• Endpts of Tx– Urine returns to normal colour & – Resolution of AGMA &– Clinically well

Iron: Elimination

• Administration of Deferoxamine– IV dosing– Goal is 15 mg/kg/hr– Replete intra-vascular volume

prior to deferoxamine

Iron: Elimination

• Adverse Effects of Deferoxamine– Hypotension with rapid administration– ARDS – usually if deferoxamine therapy for

>24• Stop infusion at 12h

– Increased risk of yersinia infections

Iron: Shock

• What are the causes of shock in Fe OD?

– Hypovolemia from vomiting and hemorrhage (onset within 1st 24H)

– Distributive shock from vasodilation (onset 24-48H)

– Cardiogenic Shock 2 to –ve inotropy (onset >2 days)

Iron: AGMA

1. Fe 2+ ----------------> Fe 3+ and Hydrogen2. Anaerobic metabolism ---------> lactate3. Hypovolemia from V/D --------> lactate4. Hypovolemia from leaky membranes----->

lactate5. Hypovolemia from GIB ---------> lactate6. -ve Ionotropy ---------------> lactate7. Vasodilation ----------------> lactate

Iron: Approach to Management

H is to ryP h ys ica l

L ab s

M IL D< 2 0 m g /kg

asym p tom atic

M O D E R A TE2 0 - 6 0 m g /kg

u n kn ow n am ou n t"m ild " G I s /s

S E V E R E> 6 0 m g /kg

"severe" G I s /s A G M A or S h ock

D ete rm in e S everity

Iron: Mild Toxicity

• Ingestion < 20 mg/kg and asymptomatic• Management

– Observe 6-8 hrs– D/C if asymptomatic– Consider iron levels but not necessary if story

is reliable

Iron: Moderate Toxicity

• 20 - 60 mg/kg or unknown + “mild”GI S/Sx• Order AXR and Fe level (4-6hr)• Consider Decontamination• Fe level < 60 or 60 - 90 and asymptomatic

– observe 6 - 8 hours and d/c if well

• Fe level > 90 & Sx or 60 - 90 and symptomatic– treat as severe

Bose et al. Conservative management of patients with moderately elevated serum iron levels. Toxicol Clin Toxicol 1995;33(2):135-40.

Iron: Severe Toxicity

• > 60 mg/kg + severe GI s/s, AGMA, shock• AXR, Fe level, baseline urine• Do everything

– Gastric lavage or WBI based on AXR– Start Deferoxamine: target is 15 mg/kg/hr– Consider gastrotomy if large OD (>240mg/kg),

especially if failing despite maximal Tx (?iron bezoar)

Iron: Disposition

• Asymptomatic after 6 - 8 hrs rules out significant ingestion and d/c home

• Management of moderate to severe ingestions depends on …….– Clinical assessment: hx, physical, labs– Amount ingested: > 60 mg/kg is bad– Iron level: > 90 umol/L is bad

Iron: Pitfalls in Management

• Early levels

• Inaccurate calculation of dose of elemental iron ingested

• Excessive reliance on the serum iron concentration (SIC) in management decisions rather than looking at the whole clinical picture

• Reliance on the abdominal radiograph, or associated laboratory tests (including the deferoxamine challenge test) to predict toxicity

• Failure to recognize patients in the latent phase

Mills KC; Curry SC SOEmerg Med Clin North Am 1994 May;12(2):397-413

Iron: Pitfalls in Management

• Inadequate hydration

• Withholding deferoxamine from pregnant patients

• Inadequate deferoxamine dose

• Intramuscular administration of deferoxamine

• Discontinuation of deferoxamine on the basis of urine color alone

Mills KC; Curry SC SOEmerg Med Clin North Am 1994 May;12(2):397-413

Iron: Summary

• LOCAL and SYSTEMIC toxicity• Risk stratify patients and treat

accordingly• Know the indications for deferoxamine • Don’t wait for iron level if good story

and pt has s/sx of severe intoxication• Treat pregnant patients the same

Lithium

• MC used for Tx bipolar disorders • Treatment and prophylaxis

• Narrow Toxic:Therapeutic Ratio (comparable to that of

Digoxin)

• Therapeutic level• = 0.6-1.5mEq/L

• Toxic level• ≥2.5-4.0 (chronic or acute)

• One of the few Rx that can ppt it’s own toxicity– Polyuria (from nephrogenic DI) can lead to

volume depletion and increased renal re-absorption of Li

Lithium

• Mortality • acute OD 25%• chronic OD 9%

• Morbidity:• 10% of the survivors from

chronic OD have permanent neurologic sequelae

Li – Pharmacokinetics

• MOA • Not really

understood

• Absorption• Peak 2-3h• SR 2-6h

• Distribution• Slow• Low Vd • Not protein bound

• Metabolism:• Not metabolized

• Elimination:• Renal 95%• Fecal 5%

• 12-22h • Delayed in elderly

and chronic OD

Lithium & the Kidney

• Li excretion:– dependent on

GFR and tubular re-absn

• Treated like Na at the kidney

Li and the kidney

Li: Clinical features

SNAP MUD• Seizures• N,V,D• Ataxia• Parkinsonian

mvmts

• Myoclonus• UMN signs• Delirium/Decr LOC

System Minor effects

Acute OD

Chronic OD

GI N,V,D, N,V,D N,V,anorexia

CNS Tremor, weakness, fatigue

tremors, rigidity, clonus, fasciculations, hyperreflexia, szLethargy -> coma

Weakness, apathy, ataxia, pseudotumour cerebri, blurred vision, sz

CVS T-wave , u-wave

Hypotension

Sinus dysfx, prolonged QT, T-wave , u-wave, myocarditis

Renal Polyuria, ↑ thirst

DI, AIN, RTA, ARF

Endocrine

↓ thyroid,goiter

↑/↓ thyroid, ↑Ca, ↑glycemia, wt gain,

Li: Acute vs Chronic toxicity

• Acute Toxicity– GI symptoms predominate – Tissues not saturated with Li

• Chronic Toxicity – Neuro symptoms predominate– Less likely to have GI effects– Tissues saturated with Li– Tend to be more severe

Li: Chronic toxicity

• Precipitants of Chronic overdose1. Increase in dosage2. Drug Interaction - :. Look up interactions prior

to adding a new med to pts on Lithium

3. ↓ in Na+ intake (i.e. CHF patients) or ↓ ECV

Common Drug Interactions• Major:

– Haloperidol

• Moderate: – ACEI - Methyldopa– Anorexiants - Metronidazole– Benzodiazepines - NSAIDs– Caffeine - Phenytoin– CCB - Tetracyclines– Carbamazepine - Theophyllines– Clozapine - Thiazide diuretics– Fluoxetine - Urea– Iodide salts - Succinylcholine– Loop diuretics - Nondepolarizing muscle paralytics– Phenothiazines - TCAs

• Minor: – Carbonic anhydrase inhibitors, sympathomimetics

Li: Common Drug Interactions

Li: Labs

• Li levels– The absolute value is less important

• Do not correlate with toxicity• Can be toxic due to intracellular effects even if

serum levels are therapeutic

– The level should be used as:1. marker of exposure 2. monitoring response to treatment

Li: Labs

• CBC– non-specific

↑WBC

• ↑Cr/BUN– Renal failure

(may be the cause of toxicity)

• Na ↑/↓– May see LOW

anion gap (<3)

• ↑Ca – Li can cause

hyperPTH – Get EKG to look

at QT

Li: Decontamination

• Charcoal– Li is not absorbed by charcoal– What other toxins are NOT bound by charcoal?

• Gastric Lavage– Li tabs are large :. May not be helpful unless for co-

ingestant.

• WBI– Indicated in large OD or SR tabs

• SPS (kaexylate)– beneficial in many animal models but in the doses

required can cause ↓↓K+

Li: Enhanced elimination

• Restore intravascular volume– Increases renal perfusion, GFR and thus Li

excretion

• Replete IV volume with NS boluses, then NS at 1.5-2x maintenance rate

• No benefit for forced diuresis or NaHCO3 diuresis

Li: Dialysis

1. Clinical indications1. Severe S/Sx of neurotoxicity2. Renal Failure and S/Sx of toxicity3. Pts that unable to tolerate Na repletion (i.e. CHF,

cirrhotic?, pancreatitis?)

2. Laboratory indications1. Level >2.5 if chronic or >4.0 in anyone

• What if the patient is hemodynamically unstable?

Li: CRRT

• ICU can arrange CRRT which is a safer method to enhance elimination in unstable patients

• Lower elimination rate/hr, but same daily clearance rate since CRRT is continuous and IHD is only done in 4-6H/session– CRRT also has essentially no occurrence or

rebound phenomenom

Li: Endocrine effects

• 4 Common Endocrine disorders – Hypothyroid– Hyperthyroid– Hyperparathyroid– Nephrogenic DI

Li: Summary

• Important to recognize Li overdoses early based on Hx, RF & Physical exam

• Management revolves around decontamination and adequate volume resuscitation

• +/- WBI or hemodialysis in certain situations