Bienvenidos Amigos! (para espanol, click on this)

This is my first post! Rock!

I hope this site provides a forum to review and de-mystify all things toxicologic...please check in and comment often, this is your website as much as it is mine...

The first installments will consist mainly of my review notes for emergency providers. After these are up, I'll branch out into interesting cases, clinical pearls, trivia and tidbits and a few of my favorite tox-related MTV moments! Let the banter begin!

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I was going to do my review notes in alphabetical order but (due to longstanding personal bias against acetaminophen which i will explain in a future post) I decided to skip ahead to a more exciting overdose... salicylates.

Enjoy!

Salicylates in a Nutshell

Here are review notes for Salicylates/ Aspirin toxicity. Got questions, just holler.

Salicylates
Sources: ASA, Pepto-Bismol, pain-relief creams, OIL of WINTERGREEN (7.5 grams per tsp!!)
Salicylic acid is a weak acid (pKa = 3.4)
i. Ionized form cannot cross membranes, favored at basic pH
ii. UNIONIZED form crosses cell membranes, favored in acidic pH
iii. Therefore, distribution of the compound is pH dependent—acidemia favors tissue penetration into brain, heart, muscles, etc
Pharmacokinetics: hepatic metabolism is overwhelmed at high concentrations, and renal excretion becomes an important pathway for elimination
Toxic Mechanisms and Clinical Effects
i. Depletes ATP productivity by uncoupling oxidative phosphorylation (destroys proton gradient by acting as a proton shuttle between mitochondrial matrix and inner membrane). This is the primary cause of the METABOLIC ACIDOSIS and HYPERTHERMIA
ii. Central stimulation of respiratory centre in the medulla oblongata. This is the primary cause of the RESPIRATORY ALKALOSIS
iii. Enhanced lipolysis and ketone formation.
iv. Gastric irritation. Causes vomiting and dehydration.
v. Liver toxin and direct inactivator of coagulation factors.
vi. Increases capillary permeability in lungs, CNSà pulmonary and cerebral edema
vii. Central nervous system disfunction and neuroglycopenia (decreased brain glucose) results in seizures

Clinical Effects
i. Neurogenic hyperventilation (esp in adults) with primary resp alkalosis
ii. Metabolic acidosis of the high-gap variety
iii. Pure metabolic acidosis more common in children and mixed acid-base disorder in adults
iv. Hyperthermia and diaphoresis (by the way, “hyperthermia” is not the same as “fever”)
v. Nausea, vomiting, dehydration which may contribute to contraction alkalosis
vi. Ototoxicity: Tinnitus and deafness, voices can sound “muffled”
vii. In severe toxicity, altered mental status and seizures are OMINOUS developments
viii. Coagulopathy, transaminitis due to liver toxicity and hyperthermia
ix. Noncardiogenic pulmonary edema (also contributes to hyperventilation)
x. Cerebral edema, low CSF glucose, seizures
xi. Hemorrhagic gastritis and pylorospasm
xii. Rhabdomyolysis and ARF
xiii. Chronic Toxicity mimics many other diseases, such as sepsis, PE, pneumonia, DKA and is often diagnosed late. Be vigilant when patients take daily aspirin and have unexplained AMS with acidosis
Diagnostic Considerations
i. Expect death/severe effects when levels are above or approaching 100 mg/dL in acute overdose
ii. In chronic overdose, the serum salicylate level may be lower but the BODY BURDEN is HIGHER so severe toxicity occurs at or above 50-75 mg/dL
iii. A single low level is NOT ENOUGH! Levels will rise over many hours in acute overdose, esp if there are concretions in GI tract…must get ASA level every 2-3 hrs until a peak and/or plateau is established.
iv. CAUTION: Some labs will report the units as mg/L (so multiply the above numbers by ten)
v. Urine tests are largely of historical interest
1. Ferric Chloride – 2 drops in a urine sample will turn purple
2. Trinder’s Reagent: also turns a urine sample purple
3. These should not be used if the urine sample has been “dipsticked” because the dipstick chemicals can cause false positives

General Treatment Concerns
i. Volume repletion to correct dehydration (limited in cases of pulmonary edema, renal failure, or CHF) and hypotension
ii. When mechanical ventilation is required, it is IMPERATIVE to maintain hyperventilation once the patient is sedated and intubated. Hypoventilation causes acidosis, which increases the tissue distribution of salicylates. Many cases of death from salicylates occur because this principle is neglected.
iii. Get nephrology involved as soon as the diagnosis of severe toxicity is made, because it may take several hours to get the HD equipment/personnel ready
iv. Treat hyperthermia with cooling mists and other measures, not antipyretics.
v. Coagulopathy may not respond to vitamin K, use FFP if INR> 6.
vi. Maintain euglycemia and even a moderate hyperglycemia in children who are more prone to neuroglycopenia and have low glycogen stores.
Specific Treatments
i. Decontamination: Activated charcoal in the awake and compliant patient. Use multiple doses of AC to bind the large quantitiy of aspirin (up to 100 grams) as it is slowly released from concretions
ii. Whole bowel irrigation with Go-Lytely solution is also appropriate in large ingestions.
iii. Enhanced Elimination: Salicyclic acid is renally excreted and seems to undergo tubular reabsorption as an unionized compound (proton is bound to acid). The unionized form can not be reabsorbed, so depleting protons (H+) from the urine will favor urinary elimination. This is the basis for alkalinization of the urine.
1. Bolus 2 Amps IV (or 2 mEQ/kg) and then use a bicarbonate infusion (d5W + 3 amps NaHCo3 makes an alkaline, isotonic solution) and infuse adults with 200 cc/hr if tolerated (Infuse less if there is pulm edema).
2. Aim for a serum pH for 7.45 to 7.5. Do NOT overshoot!
3. Do not need to measure urinary pH. Most older texts recommend this but urine pH is titrated so much beyond the proximal tubule (where the crucial biochemistry is happening) that it makes no sense to follow this value.
4. Even if the patient has a normal pH but severely toxic, I bolus 2 amps and start an infusion. This provides volume and helps decrease any work of breathing due to blowing off acids. However, this approach requires very close monitoring of serum pH (e.g. every 2 hours) to avoid alkalemia.
iv. Hemodialysis
1. Levels above 100 mg/dL or 60-70 in chronic toxicity are considered indications for emergent hemodialysis. However, it is important to note that these levels are MERELY GUIDELINES and other clinical considerations must also weigh in the decision.
2. Lethargy, seizures, volume overload, renal failure, multiple comorbid conditions, and severe acidosis and electrolyte problems are also important factors to consider even when the levels are “too low to dialyze.” One session is usually enough, but check a post-HD level before pulling the catheter.

Lithium (click on this)

1. Lithium is an elemental substance used commonly for manic depression/bipolar disorder. Its mechanisms of action are not well-undersood; it may affect second messenger signalling in neurl pathways controlling behavior and mood. 
2. In the past, lithium salts were used as a therapy for neutropenia because they do induce a leukocytosis. Until 1950, lithium was used as a salt substitute in 7-Up soft drinks (in fact, perhaps coincidentally, lithium's molecular weight is 6.9). 
3. Lithium,like sodium, has almost total renal elimination; renal insufficiency or dehydration causes and complicates lithium toxicity.
4. Because brain and muscle tissues act as a "sponge" for lithium, chronic toxicity in a lithium user is worse (and harder to treat) than acute toxicity in a nonuser. Chronic toxicity is also associated with LOWER numerical levels of lithium (see below) because the "lithium level" only reflects the amount of toxin in the bloodstream, not in the tissues. 
5. Clinical effects: nausea, vomiting, lethargy, hyperreflexia; tremors; ECG changes (flat or inverted T waves; bradycardia); nephrogenic DI with hypernatremia and free water wasting (manifests after IVFs are started). Rare: hypercalcemia (hyperparathyroid); hypothyroidism; neurologic disfunction which may me irreversible; serotonin syndrome;  
6. Treatment: Maintain Euvolemia and maximize urine output.
7. Hemodialysis may be needed if level is greater than 4 in patients with severe symptoms. Usually requires multiple sessions or prolonged HD because CNS is a lithium “sink” and hard to detoxify.
8. NSAIDS, ACE-inhibitors, dehydration are frequent triggers for toxicity because they decrease GFR and promote lithium retention.
9. Kayexalate not useful in humans although animal data indicates this enhances GI elimination if given in massive doses

iron (click on this)

1. Formulations (in order of elemental iron content): Fumarate /Sulfate/ Gluconate /childrens Flintstones vitamins/carbonyl iron.
2. Elemental iron is different in each formulation: F(0.3) /S (0.2)/ G (0.1); Flintstones and carbonyl do not have enough bioavailable in OD to cause problems, but childrens vitamins have sorbitol sweetener, which causes diarrhea, dehydration
3. Severe iron toxicity occurs when ingestion is greater than 60 mg/kg; Vomiting with 30 mg/kg.
4. Mechanisms: iron is a potent oxidant and interferes with many enzyme systems (mitochondria, coagulation factors); usually bound to proteins (transferring and ferritin) which controls toxic effects but these storage systems are overwhelmed in toxicity and free iron wreaks havoc on multiple organ systems, esp liver and cardiovascular.
5. MUST KNOW-- the 4 stages of iron toxicity:

                                               i.     Local irritation w/ vomiting (hemorrhagic) and diarrhea—looks like AGE

                                             ii.     “Quiescent” stage—GI symptoms stop but tachycardia may persist—DO NOT DISCHARGE PATIENT

                                            iii.     Systemic toxicity: vasomotor collapse, myocardial depression, lethargy, cerebral edema, liver failure (periportal necrosis), coagulopathy, ARDS, renal failure

                                            iv.     Late complications—GI strictures, gastric outlet obstruction

6. Diagnosis: KUB for tablets; serum iron levels 4-6 hrs after ingestion (> 350-500 is toxic; > 700 fatal). TIBC, serum ferritin and transferrin are not useful; surrogate markers such as glucose and WBC reflect stress response and are generally nonspecific.
7. Treatment:

                                               i.     IVFs (aggressive volume repletion may be limited by ARDS). Cannot dialyze or use charcoal for iron!

                                             ii.     Deferoxamine (fungal molecule from Streptomyces pilosus) is an iron chelator, but not a great antidote. 100 mg DFO will bind only 8.5 mg of iron! (Example: a potentially fatal ingestion of 50 mg/kg in a 50 kg adult will be a dose of 2500 mg; this will take 25 GRAMS of DFO). DFO can only be given at 15-30 mg/kg/hr because higher doses result in hypotension.  Thus it would take 16 HOURS to infuse all the DFO in a critically ill patient.

                                            iii.     Yersinia enterolitica sepsis is associated with DFO used in iron toxicity; possible reason is that this organism grows well in iron-rich environments when a siderophore (iron carrier ) is available. 

antihypertensive overdoses: how to TURN AROUND a total eclipse of the heart (click on this)

Uploaded by hushhush112

1. Beta-Blockers.
1. Most will cause both bradycardia and hypotension. Keep in mind that some BBs with intrinsic sympathetic activity (ISA ) can cause transient tachycardia or hypertension (ex: pindolol).
2. Propanolol can cause widened QRS (due to sodium channel blockade)  and coma/seizures (lipophilic; crosses into brain easily). Atenolol  is renally cleared and can be dialyzed in overdose.
3. Treatment of B toxicity: Glucagon. Use higher doses than typical: 5-10 mg and begin a drip if needed (use the dose required to improve BP/HR per hour).
4. If glucagon fails, use pressors (epinephrine) or intraaortic balloon pump. Pacers may improve HR but not BP.
5. Use sodium bicarbonate for wide QRS due to propanolol.
6. Use whole-bowel irrigation for extended release products.
2. Calcium channel blockers
1. Similar to BB in that patients usually develop bradycardia and hypotension. CCBs tend to cause less sedation, more hyperglycemia (pancreatic ca channel blockade of insulin release).
2. Some CCBs are more dangerous than others; peripherally acting cmpds (dihydropyridines e.g. nifedipine) are less cardiotoxic and cardiac output is maintained so these are less fatal than phenylalkylamines (verapamil) which is more centrally toxic.
3. Sustained release products: Start whole bowel irrigation.
4. Treatment: Glucagon should be tried but it may not work.
5. Calcium is considered first line—use calcium chloride in a central line if available (about 12 mEq per amp); otherwise calcium gluconate (3.5 mEq per amp) in a peripheral line. Goal is to keep calcium level at or above 15.
6. Pressors and IV fluids are also important supportive measures.
7. New therapeutic approach: Insulin. This improves carbohydrate metabolism by the myocardium. (remember, CCBs block insulin release from the pancreas). Use high doses (1 unit/kg loading dose then 0.5-1 units/kg/hour) and maintain normoglycemia with D5 or D10 drips.
8. Pacers, atropine, intraortic balloon pumps may also used adjunctively.
3. Clonidine and Related Compounds
1. Imidazolines and Tetrahydrazolines. (Ex: oxymetazoline aka afrin)
2. Mechanism: These agents act as both imidazoline receptor agonists and central alpha-2 agonists. Imidazoline receptors have a complex interaction with opioid and catecholamine pathways centrally, which may explain the symptoms overlapping with classic "opioid" overdoses (see d and e below). 
3. Initial hypertension, very brief! May need nipride in some rare cases to combat hypotension, but expect to have late and prolonged hypotension.
4. A longer period of hypotension, bradycardia, sedation, small pupils, hypothermia.
5. Resemble opioid overdose, and in some cases naloxone can reverse effects.
6. Supportive care with fluids. Pressors rarely required, but if needed use direct alpha agonist.
4. ACE-inhibitors. Generally benign in isolated overdoses; treat symptoms with fluids, pressors. Narcan (naloxone)  is sometimes cited as a possible antidote but lacks any credible evidence (not to mention pharmacologic explanation) supporting its use as a standard treatment.  Check and correct any potassium/magnesium abnormalities; patients on chronic ACE-inhibitor therapy are prone to multifactorial renal dysfunction. Although angioedema is an incompletely understood but well-known adverse effect of ACE-inhibitor therapy, acute overdose does not confer a higher risk of developing angioedema.     

Digoxin and Cardiac Glycosides (click this, but don't lick this)

1. Cardiac Glycosides
1. Sources: Digitalis purpurea (foxglove; digitalis); Oleander (oleandrin); Yellow Oleander (Thevetin); Red Squill (urginea matitimea, scillaren); Cerebra Manghans (sea mango); Bufo toads (Bufo alvarius and marinus; Colorado river and cane toads; bufodienolides)
2. Mechanisms of action: Block Na/K ATPase, leading to increased intracellular calcium; leads to  vagal activation and cardiac irritability
3. Clinical Effects: Vomiting, Bradycardia, multiple PVCs; hyperkalemia; xanthopsia (seeing yellow halos) 
4. Classic dig toxicity rhythm is BIVENTRICULAR Ventricular TACHYCARDIA (see figure).






5. Patients taking digoxin: dehydration and renal insufficiency leads to toxicity
6. Potassium: K above 5.5 after acute overdose heralds poor prognosis—give digibind, don’t wait for dig level; K may be normal to low in chronic toxicity.
7. AVOID CALCIUM—it can exacerbate intracellular hypercalcemia and lead to cardiac tetany. However, this caveat remains quite controversial in the toxicology literature, with very little real evidence in the peer-reviewed literature. In truth, one suspects that calcium is given inadvertently to dig-toxic patients more often than is recognized-- the use of calcium occurs so frequently as a “reflex” for hyperkalemia.
8. Phenytoin or lidocaine for digoxin-related dysrhythmias—no evidence to support effectiveness.
9. Pacers, atropine, pressurs—may be needed as adjuncts if no digibind available
10. Decontamination/GI elimination with Cholestyramine (esp useful for digitoxin); MDAC
11. Digibind indications: Severe bradycardia, VF/VT; Potassium level >5.5; Serum level at steady state above 10-15 ng/mL; ingestion of >10 mg (adults) or >4 mg (kids)
12. Therapy: Digibind/digifab,

a.     Sheep-derived partial antibody.

b.     Digibind Dose can be calculated :

[Steady state dig level] x weight (in kgs)/ 100

c.     If the digoxin level is unknown, 5 – 10 vials can also be given empirically ( but this typically overestimates the actual dose needed).

Hydrocarbons

1. Hydrocarbons
1. Sniffing (from container) vs huffing (from a rag) vs bagging (breathing vapors in bags)
2. All hydrocarbons can cause sedation and inebriation; popular among underage teens who can buy these from department or hardware stores. There are thousands of hydrocarbon compounds, and many are mixtures (e.g. gasoline). Here are a few highlights and points of interest. 
3. Silver spraypaint allegedly gives the best high—picture a cachectic patient with silver hands and mouth.
4. Chlorinated hydrocarbons (chloral hydrate, trichloroethylene, methylene chloride, halothane) can cause SUDDEN SNIFFING DEATH. SSD occurs because myocardium becomes more sensitized to catecholaminesà sudden VF results when patient is suddenly excited. The key to treating this condition is to use beta-blockers to block the effects of adrenergic stimulation, even in cases of VF/Vtach/torsades.
5. Toluene: acutely converted to hippuric acid (wide anion gap acidosis) but chronic abuse causes renal tubular acidosis (a nongap acidosis) with low potassium. Weakness in a "glue-sniffer"/inhalant abuser is RTA-associated hypokalemia until proven otherwise. Chronic toluene abuse can also cause cerebellar atrophy and cerebral leukoencephalopathy (white matter degeneration) which are permanent.
6. Aspiration of hydrocarbons into the lung causes breakdown of surfactant and alveolar collapse (HYDROCARBON PNEUMONITIS). Lowgrade fevers, infiltrates and hypoxia expected to occur as early as the first few hours (this is not an infection). Compunds with low viscosity (not thick like maple syrup) and high volatility (easily vaporized) are most likely to cause pneumonitis.
7.  In kids with hydrocarbon accidental ingestion, the recommendation is to observe for 6 hrs and get a 6-hr film and oxygen saturation to r/o aspiration pneumonitis. Coughing and gagging immediately upon ingestion heralds a poor prognosis.
8. Organic nitrites are volatiles that include cyclohexyl, butyl, and amyl nitrites, commonly known as “poppers.” Amyl nitrite is still used in certain diagnostic medical procedures. When marketed for illicit use, they are often sold in small brown bottles labeled as “video head cleaner,” “room odorizer,” “leather cleaner,” or “liquid aroma.” Nitrites can cause methemoglobinemia, weakness, hypotension/syncope.
   
   
9. Chloral hydrate—a highly sedating hydrocarbon. It classically smells like pears. Used in pediatrics for procedures. Inhibits metabolism of ethanol, and ethanol inhibits chloral hydrate metabolism (this combination is the notorious "Mickey Finn"). Sudden cardiac death can occur (see part d above) due to catecholamine sensitization. Torsades de pointes is  also possible via the same mechanism. Chloral hydrate is also radioopaque—KUB xray can show an air-on-fluid-on- fluid level. Also very irritating to the GI tract—burns the mucosal membranes.
10. Methylene Chloride (CH2Cl2) is found in in paint strippers. Liver will convert this compound into carbon monoxide within 8-12 hrs. Watch for delayed CO toxicity.

Toxic Alcohols

Key Points: 
1. ALL alcohols are more or less intoxicating based on number of carbon atoms (most: isopropyl alcohol and ethylene glycol; least is methanol)

2. Toxic Alcohols are toxic because of their TOXIC Metabolites

In general, the parent compound (alcohol) is not directly tissue toxic; the metabolites (aldehydes and especially the acids) made from the actions of alcholol and acetaldehyde dehyrdogenase are the major problem. For example, in ethylene glycol poisoning, the metabolites glycolate, glycoxylate, and oxalate cause acidosis and multiple organ failure. This process, as with all metabolic reactions, takes time and PATIENTS DO NOT BECOME ILL RIGHT AWAY. In many cases, it can take 12-24 hours for acidosis and organ failure to occur.


3. Therefore, the key to management of toxic alcohols is PREVENTION of metabolite formation until the parent compounds can be excreted or dialyzed.





4. Diagnostic Testing and the 2 Gaps: The extent of exposure to the PARENT compounds can be approximated by the osmolar gap; extent of acidosis due to the METABOLITES can be calculated by the anion gap. 

Gaps “cross over” one another (see diagram)below. This means that the osmolar gap is usually normal by the time a WIDE ANION GAP is notable.

Here is the OSMolar Gap formula: 

2 (Na) + (glucose/18) + (BUN/2.8) + (toxic alcohol level x 10 /molecular weight of the alcohol).


You can factor in the contribution of ethanol and other alcohols by using the following values for the molecular weight of the alcohols: EtOH: 46; MeOH: 32; EG: 64; Isopropyl Alcohol: 56

Example: An ethanol level of 46 gives you 10 osms; an EG level of 64 also gives you 10 osms. 

The OSM GAP is not that helpful for several reasons:

A. The measurement of osmolarity must be done at the same time as the initial electrolytes-- in other words, as soon as the ingestion is suspected. By the time the acidosis is manifest, the osm gap will be closed (see above).

B. Even when done on time, the osm gap is a poor test to begin with. That's because, unlike an anion gap, there is a wide variability of normal values.  The "Normal" Osm Gap in a population can vary from -5 to 14. So if you get an osm gap of 10, this could be normal, or it could represent an EG level correlating with 64mg/dL-- this is high enough to be toxic!!  

Bottom line: The osm gap helps to rule in a toxic alcohol ingestion when it is VERY positive, but it doesn't necessarily rule OUT toxic exposure when it is negative. 

Ethanol ingestion in children results in HYPOGLYCEMIA (low hepatic glycogen reserves, gluconeogenesis stops when there is a lot of NADH/NAD+ due to activity of alcohol dehydrogenase)




All toxic alcohols can cause intoxication, sedation and hypotension. Acidosis (except isopropanol) can be severe, but delayed up to 30 hours after ingestion. This is especially true if ethanol is coingested because it prevents formation of the acidic metabolites.




Methanol: winshield wiper fluids; industrial solvents; formalin (=methanol and formaldehyde); causes optic nerve toxicity due to FORMIC ACID toxicity; hemorrhagic infarcts of the basal ganglia; hemorrhagic pancreatitis is also a well-described complication. See images below of optic nerve edema and basal ganglia infarcts following methanol poisoning (from www.nature.com)

Ethylene glycol: antifreeze ingestions; severe multiorgan failure and edema due to deposition of OXALIC ACID crystals (calcium-oxalate crystals); can see these in the urine as needles or envelope-shaped crystals); fluorescent urine and oral cavity due to the presence of fluorescein in the antifreeze; cerebral edema with CN 6 palsy, pericarditis, rhabdomyolysis.Below is a picture of calcium oxalate crystals in the urine, which are highly specific for ethylene glycol poisoning and sometimes the first clue to the diagnosis.

Isopropanyl alcohol: rubbing alcohols. Converted to acetone and exhaled; no acidosis, only KETOSIS. Acetone breath. Very intoxicating and causes hemorrhagic pancreatitis.

Propylene glycol: newer antifreezes (safer than EG, see below). Converted to lactate in the liver, with resulting lactic acidosis and, occasionally, renal failure. Also used as a diluent in IV meds like phenytoin, lorazepam...may cause lactic acidosis in prolonged infusions (ICU patients on drips for more than 36 hrs).

Diethylene glycol: Severe renal failure and multiorgan failure when used as a diluent in medications. Epidemics in Haiti, India, lots of other places. In 1937, epidemic poisoning due from DEG in a sulfanilimide antibiotic solution in the USA (aka the "Sulfanilimide Disaster") led to the formation of FDA.

Treatment Considerations

General Treatment: Support Airway and BP; Multivitamins to help shunt metabolism away from toxic compounds (use folate for methanol; thiamine, magnesium, and pyridoxine for ethylene glycol). Rule out AKA with serum ketoacid levels. Use bicarb to maintain physiologic pH.

Specific therapy: BLOCK conversion to toxic compounds via Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase enzymes.
i. This was traditionally done with IV or PO ethanol—a competitive inhibitor of ADH. Titrate to keep a BAL of 100 mg/dL, which is sometimes challenging in the hemodynamically unstable (and withdrawing) alcoholic....these infusions invariably require ICU admission. Watch for hypotension and hypoglycemia, esp in kids.

ii. The New Antidote: Fomepizole—a direct inhibitor of ADH. This is more expensive, but easy to dose and does not require titration; causes no hypotension, transaminitis, or hypoglycemia. Use a loading dose of 20 mg/kg then BID dose of 10 mg/kg for 4 doses, then BID dose of 15 mg/kg until toxic alcohol level is below 20 mg/dL. Redose immediately after dialysis. Many published reports of low to no toxic sympoms when fomepizole is

Tox in Sri Lanka

When I was a fellow, I had an amazing opportunity to visit Sri Lanka and write about my toxicology experience during my month there. This was the article, originally published in the Kaiser Permanente Journal. Click on the title to jump to the article.

Bonus: Here is the best video ever made in Sri Lanka. (Apologies to M.I.A. fans!)
I went to the cafe featured here, in downtown Colombo, and the waiter said he knew "Simon and the boys" from back in the day. Totally, Awesomely, Radical.

acute acetaminophen toxicity, general overview

This week I got called about a woman with severe toxicity presumably from an acute overdose of extra-strength tylenol. She was prescribed 240 tablets of vicodin ES (which has 750 mg/tablet) two weeks prior, and the bottle was empty at the time she was brought in by medics. I'm not sure how many of these she took on the day of the overdose, but her liver functions were already out, her creatinine was up, and, most surprisingly, her bicarb was 6 (pH 6.98 initially). She was transferred to another center for possible emergency liver transplant...i am not sure what the outcome was as of yet. More about this case later, below is a general discussion of tylenol and related products, which in the tox world remain the most common overdose overall and the number one toxicologic killer in industrialized countries.

Here are the basics of acetaminophen overdose...if you haven't seen at least one in the last month, consider yourself due for one on your next shift...  

1. The “Rule of 150.” Toxic dose is generally 150 mg/kg ( or at least 7.5 gms per day in adults); toxic level is (depending on the reference) 150-200 mg/L at 4 hrs, and declining from there with a 4-hr half life. NAC loading dose is also 150 mg/kg.
2. The Rumack-Mattew nomogram (reproduced below) is useful in ACUTE,  SINGLE IMMEDIATE-RELEASE OVERDOSES (not for chronic or multiple ingestions). Opioids and benadryl—don’t seem to affect nomogram utility! See the nomogram below, it demonstrates that the toxic level decreases with time. It begins at 4 hrs after ingestion, so levels done prior to this time are not useful for determining whether to treat with the antidote, NAC. (However, if the level is zero and the clinical suspicion is low, then a stat level rules out toxicity).
3. For extended release product overdoses, the manufacturer recommends 2 levels, 4-6 hrs apart; if either one crosses the line then treat as a toxic ingestion and give NAC.
4. Major clinical effects: vomiting (but remember, many severely overdosed patients can be virtually asymptomatic for 2-3 days); fulminant hepatic failure; pancreatitis, acute renal failure; metabolic acidosis and sedation characterize MASSIVE ACUTE OVERDOSE (for example 50-100 gram ingestions)
5. Liver toxicity is centrilobular necrosis (maybe some apoptosis) due to a compound called NAPQI (this is a free radical quickly eliminated by glutathione reductase until glutathione stores are depleted); renal toxicity is due to free radicals from tubular prostaglandin synthetase or p450-mediated NAPQI; pancreatitis is rare, not due to NAPQI, and thus not helped by NAC.
   
6. N-acetylcysteine, or NAC is the antidote for acetaminophen. NAC effects: regenerates glutathione by donating sulfhydryl groups, which allow NAPQI detoxification; directly inactivates NAPQI; converts NAPQI back to acetaminophen; acts to increase hepatic microcirculation and attenuate free radical damage.
   
7. NAC DOSE: loading dose is 150 mg/kg PO or IV; PO dose is given as 70 mg/kg every 4 hours; IV dose can be same as PO dose or continuous infusion over 20 hrs (use loading dose over 15 minutes, then 50 mg/kg over 4 hours; then 100 mg/kg over 16hrs). There is also a protocol for continuous infusion when using the newer formulation of NAC (trade name, Acetadote), which uses 3 concentrations in 3 bags given over 20 hours. Contact your pharmacy for the details on preparation. Keep in mind that the "older" formulation of NAC can be used IV if a 22-micron pyrogen filter is used in line of the infusion...a minority of patients experience histaminergic effects such as itching and bronchospasm, which can should be treated with antihistamines/steroids/slowing the infusion. There is no credible evidence that NAC causes anaphylaxis, so do not withhold treatment in someone who needs it!
8. WHEN TO START NAC: level is above the 150 ng/mL line on the nomogram (or 200 depending on clinician’s comfort level and accuracy of history); if late presentation, can start NAC if AST ALT are elevated even if acetaminophen level is nondetectable.
   
9. WHEN TO STOP NAC: Acetaminophen level is nondetectable AND AST/ALT/INR are normal. Some clinician s will discontinue NAC if liver functions are slightly abnormal but show a trend towards normalizing, esp if patient has chronic liver disease. In severe toxicity and liver failure, continue NAC at maintenance doses until transplantation or death.
   
10. In general, oral NAC is the most direct way to the liver via portal circulation; IV NAC risks metabolism before reaching hepatic circulation. However, IV is preferred if patient is vomiting, GI tract is not well perfused (e.g. shock); pregnancy (to ensure placental delivery). PO NAC is foul to taste and smell; if patient vomits within 1 hr of swallowing a dose, then redose with antiemetics or use the IV formulation.