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Hi-Yield Poisonings and Envenomations

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Board Review #4: Digitalis (Digoxin)

This is a classic. While it isn’t as common these days, the mechanism is still interesting. Take a look!

What is the on Digitalis toxicity?

The usual suspects: Digoxin, foxglove, lily of the valley, and oleander (both yellow and white), bufo toads. #dangerouslyseductive #lookscandeceive


Cardiac glycosides are steroid molecules with a carbohydrate side chain. #bigbadmolecule #lookatthesizeofthatthing #structures

Calcium-Induced Calcium Release (CICR): Cellular depolarizationopens voltage gated calcium channels causing calcium influxwhich induces calcium release by the SR. #tellMEsomethingIdontkno

Digoxin inhibits the Na/K ATPase causing more calcium in, more SR calcium, and ultimately, better SQUEEZE. #moarSQUEEZEplz


Digoxin increases automaticity, shortens the QT interval, and ultimately, can predispose one to arrhythmia. GET AN EKG! The most common arrhythmia is PVC’s, the most characteristic is bidirectional ventricular tachycardia,. #itgoesbothways

Because digoxin makes the AV node refractory to conduction via vagal parasympathetic stimulation, it is almost impossible to have SVT in digoxin toxicity #anythingbutSVT


Normal digoxin levels are from .5-2.0ng/mL and the therapeutic window is narrow. Get a level at 6 hours post ingestion. #TrenchRun

Give DigiFab if: K>5mEq/L in acute poisoning, unstable dysrhythmia, chronic elevation with symptoms, Dig level >15 or >10 after 6 hrs, acute ingestion of 10mg (child, 4mg), or intake of nondigoxin cardioactive steroid #DisIsImportant #GivingIsCaring

Digoxin levels will generally cross-react with other cardiac glycosides. A dig level can still be positive in cardiac glycosides such as foxglove or oleander, but don’t use the level itself to guide care. #qualitativeNOTquantitative

Symptoms of chronic cardiac glycoside poisoning include both neurologic and GI manifestations: yellow vision, weakness, confusion, lethargy, with nausea/vomiting, abdominal pain. #IseeFUNNYwithGASTRO

Typically in acute overdoses,  bradycardia is seen, which could be atropine-responsive as it is vagally mediated. #AtropinePlz #DontForgetDigiFab


In acute toxicity, hyperkalemia can develop due to Na/K ATPase inhibition, K>5.0 is an independent indicator of poor prognosis. #alltheKontheoutside

Calcium administration is controversial, although newer data suggests safety, but older animal data suggests risk of cardiac tetany #stoneheart


-Give DigiFab! This is the antidote of digitalis poisoning. Can adjust dosing for weight or ingested dose, but if sick, give 10 vials up front. #SlugEmWithVials

When to suspect?

Toxicity from cardiac glycosides, such as digoxin, can present as acute and chronic poisoning. Although falling out of favor due to safer alternatives and no reduction in mortality, digoxin is still being utilized for heart failure as well as atrial fibrillation. However, exposure to natural forms of cardiac glycosides have occurred, in particular from flowering plants such as foxglove, lily of the valley, or oleander. Also, bufo toads can also possess cardioactive steroids in their skin, and in their salivary/venom glands and toxicity generally occurs with ingestion of the dried toads instead of its topical application.

 


Chronic toxicity is usually due to digoxin accumulation, from causes like P-glycoprotein inhibition or renal insufficiency. P-glycoprotein is an efflux pump that normally excretes digoxin, however, with introduction of verapamil or amiodarone, digoxin clearance can decrease, inducing toxicity.

-Facts of Digoxin: Onset: 1.5-6hrs PO 5-30minutes IV, max effect in 4-6 hrs PO, 1.5-3 hrs IV, 40-90% absorption. Volume of distribution is 5-7 L/kg, Half life is 1.6 days. 60-80% elimination via kidneys, 7% enterohepatic circulation.

 

Mechanism of Action
Digoxin works by blocking the sodium channel ATPase. Normally this pumps out sodium, and brings in potassium. Instead, sodium continues to accumulate, and a sodium/calcium exchanger (normally sodium in, calcium out) reverses because it is dependent on the concentration gradient (where the cell now is high in sodium ) and spits out sodium and brings in more calcium. More calcium in, more sarcoplasmic calcium through calcium-induced calcium release, more actin-myosin cross-bridging, and ultimately better squeeze (increased inotropy).

Presentation

When patients present with digoxin poisoning, they generally have three particular organ systems to pay attention to: heart, brain, and the gut. Starting with the heart, the most common arrhythmia observed is PVCs due to increased automaticity. Given its ability to slow cardiac conduction and increase vagal tone (increases ACh release from vagal nerves), all forms of AV nodal blockade (except Mobitz type II) Given earlier repolarization and increased ectopy, many other dysrhythmias can occur such as ventricular tachycardia and ventricular fibrillation.

Besides arrhythmias, digitalis can be observed from the classical features on EKG dubbed as the digitalis effect: T wave peaking or inversion, shortening of the QT segment, scooping of the ST segment or ST depression, and U wave amplitude increase. That all said, these EKG findings are not indicative of prognosis: they simply imply presence of digitalis.

However, what ARE associated with a poor prognosis are hyperkalemia and ventricular dysrhythmias. In one study, K of 5.0 to 5.5 associated with 50% mortality, and K>5.5 associated with 100% mortality in acute toxicity!

Beyond the heart, digitalis can increase vagal parasympathetic tone, which is likely to contribute to its GI symptoms—many patients with digitalis toxicity will present with nausea, vomiting, diarrhea, and abdominal pain. Generally, GI symptoms will occur earliest in setting of toxicity.

From the top, CNS disturbances include the classical vision changes of yellow vision (xanthopsia), scotomata, confusion, headache, fatigue, and paresthesias.  That said, these neurological or gastrointestinal symptoms are generally reversible and attention should generally be placed towards the cardiac presentation/symptoms.

A digoxin level is generally therapeutic between 0.5-2.0 ng/mL, . For healthy adults, a single dose less than 5mg rarely causes toxicity—the average digoxin dose generally is <0.75mg.

Chronic toxicity generally occurs within the elderly, for only a 2-3 fold increase in their therapeutic dose can induce toxicity.

The benefit of a digoxin level is that it can pick up other digitalis substances such as Bufo toxins or oleander given the cross-reactivity given molecular similarity. That said, the disadvantage is that the cross-reactivity is not close to 100% nor can it differentiate between digoxin and other digitalis, therefore the level itself is not useful.

Management

Ultimately, symptomatic life-threatening digitalis toxicity is quickly managed with digoxin-specific Fab fragments, which both bind to and inactivate the digoxin. While symptomatic bradycardia, tachyarrhythmias, or significant hyperkalemia can occur in digitalis toxicity, treat all of these abnormalities with administration of the antidote first and foremost.

-EKG, first and foremost. Put the patient on the monitor!

-Get a digoxin level: .5-2.0ng/mL is therapeutic and get it at 6 hours given the high volume of distribution for the drug.

-Indications for DigiFab:

  1. Any digoxin related life-threatening dysrhythmias regardless of level.
  2. Potassium >5mEq/L in acute poisoning.
  3. Chronic elevation with significant GI sx or AMS.
  4. SDC>15ng/mL or 10ng/ml 6 hrs post-ingestion regardless of presentation.
  5. Acute ingestion of 10mg of digoxin in adult, or 4mg in a child
  6. nondigoxin cardioactive steroid (such as oleander). (Goldfrank recommends 10-20 vials in acute poisoning, and 3-6 or 1-2 vials for adults and children, respectively)

-If there’s significant bradycardia, and/or there is no antidote available, administration of atropine may help.  0.5mg IV, every 5 minutes as necessary. Pacing has been reported to temporize, but fab fragments are definitive.

-Cardiovert unstable rhythms (v-tach or v-fib) but leave other stable dysrhythmias alone. You can risk worsening the rhythm with cardioversion!

-If potassium is >5mEq/L, DigFab is indicated! Correct HYPOkalemia before giving Digifab in settings of dysrhythmias.

-Generally, the antidote dosing is 0.6mg/vial if the amount ingested is known. Technically, 1 vial DigiBind and DigiFab will bind to: .5mg and .6mg of digoxin, respectively.

-The fab fragments are generally benign and well-tolerated, except for patients having a papaya or sheep allergy-DO NOT ADMINISTER unless directed by a toxicologist!

-Although designed for digoxin, in non-digoxin cardiac glycoside toxicity, empiric administration of a larger dose (10-20 vials) is warranted given the digoxin level does not have 100% cross-reactivity for an accurate level, and cross-reactivity of the Fab fragments is not 100% to other digitalis. Bottom line: Generally, 5-10 vials of Digifab does the trick (more if not digoxin), and run it over 30 minutes (unless in arrest, just bolus it).

-Like with many poisonings, activated charcoal is not recommended routinely for PO digitalis toxicity unless within 1-2 hours of ingestion, no active vomiting and their airway is secured. Goldfrank’s suggests that there is significant enterohepatic circulation and thus can be beneficial to administer even late (1g/kg of body weight ever 2-4 hrs up to 4 doses).

-Electrolyte abnormalities can occur with digoxin toxicity. Hyperkalemia (hypokalemia in chronic digitalis toxicity) and hypomagnesia can both occur. Our general gut instinct is to give calcium, when potassium can be greater than 5.5, and with EKG changes. There is a historical account of calcium bolus producing cardiac tetany, or “stone heart.” Newer evidence says calcium may be safe in digoxin toxicity, however, the evidence still does not support the administration of IV calcium. Continue to pursue administering the antidote. You can still give IV insulin, dextrose, bicarbonate, and kayexalate. Hypomagnesemia worsens the inward calcium current, thus reversing this can be beneficial. Increasing magnesium can counter calcium binding, counter ventricular irritability, and blocks potassium from leaking out of the cell. With low magnesium, you can give magnesium sulfate (2-3 g over a minute) (Goldfrank’s: 2g over 20 minutes, with drip of 1-2g/H). Do not give magnesium in bradycardia, AV block, or renal insufficiency.

-Arrythmias can also be managed with other adjuncts such as IV phenytoin of 25mg/min (total 15mg/kg) (Goldfrank’s: 50mg/min or 100mg boluses every 5 minutes [max 1000mg in adults), lidocaine (1mg/kg), or magnesium sulfate (2-3g over a minute). Reduce your power settings if you need to defibrillate.

References

Digitalis (cardiac glycoside) poisoning. In: UpToDate, Grayzel J (Ed.), UpToDate, Waltham, MA, 2017.

Kashani JS. 2015. Chapter 325: Cardiac Glycosides. In: Ling L , Wolfson AB, editors.  Harwood-Nuss’ Clinical Practice Of Emergency Medicine. 6th ed. Philadelphia (PA): Wolters Kluwer. p. 1409-1412.

Nelson L., et al. Goldfrank’s Toxicologic Emergencies

Text written by: Alex Huh, MD
Podcast by: Joshua Shulman, MD
Reviewed by: Joshua Shulman, MD

 

Board Review #3: Tricyclic Antidepressants (TCAs)

Tricyclic antidepressants are a great place to start in terms of understanding physiology behind toxicology. If you understand the 7 different mechanisms behind TCA toxicity, not only will you understand how to manage a TCA overdose, you will know how to manage many other toxidromes given that they share many mechanisms with TCAs.

What is the on TCA toxicity?

Seven different mechanisms! #7in1 #7fer #AAAKING #PIMPable


Names are commonly -triptylines or -amines, but not all. But, structures help! See a resemblance? #TRIcyclic #structures #MolecularMimicry


Besides your ABCs and H&P, the EKG shall be your friend. Get one early, and be very scared if you see either of these rhythms (wide QRS/vtach or long QT/torsades), but you know what to do: Bicarb or Mag. #JustGotInteresting #keepcalm #GETdaPADZ #NaHCO3 #bicarb #Mg


Earliest changes on EKG are the 40ms right axis shift, basically prominent R wave in aVR, and S wave in I and aVL. See the QRS widen! #whats40ms #prominence #hiQRS


Use 2-3 amps of bicarbonate to bolus, every 3-5 minutes, with pH goal of 7.5 to 7.55. Can do a drip with 3 amps of bicarbonate in 1L D5W at 2X maintenance. #bicarbISyourFWEND #choices #beaggressive

If dysarrhythmia occurs or refractory to bicarb, 2nd line interventions include: lidocaine (1mg/kg), hyperventilation (alkalosis), hypertonic saline, and magnesium sulfate. #YesIsaidLidocaine #breathefaster #hypertonic&Mag


Give 1-2mg ativan IV or 5-10mg valium IV for seizures. Intubate and use propofol if refractory to benzos. #Good4Agitation


Hypotensive? Fluid resuscitate with crystalloid boluses, continue bicarb, and use norepinephrine if needed. #bolusbolusbolus


Once stabilized, give charcoal. Anticholinergic effects of TCAs will slow gastric emptying, higher likelihood of therapeutic benefit. #charcoalsponge


If all that doesn’t work, intralipid therapy and/or ECMO have been utilized. #lastditch #heregoesnothing

When to suspect?

Patients in the past were on TCAs as a first line agent for their depression, however it is used these days for refractory forms of depression. Identified as “-triptyline’s” and “-amines,” (however not all are named like this!) people have been prescribing less given the advent of safer drugs. That said, you will see TCA toxicity present itself in overdose from time to time, and its good to know about their mechanisms!

Mechanisms of Action/Presentation/Treatment:

I use the mnemonic AAA-KING. There are 7 different mechanisms of action–the king of mechanisms in toxicology! (The AAA looks like a king’s crown if you squint).

It represents:

Anticholingeric: Presents as hot as a hare (fever), blind as a bat (mydriasis), dry as a bone (dry), red as a beet (flushing), mad as a hatter (delirium), full as a flask (urinary retention). Treat them with benzos and supportive care. Sometimes the agitation is from urinary retention and can be fixed with a foley catheter!

Antihistaminic: Causes sedation. At toxic doses, this can be overwhelmed by the other effects, depending on the drug. If severe, protecting the airway via intubation may be necessary.

Alpha-1 blockade: Hypotension from vasodilation- treat them fluids first and a pressor if that doesn’t work (not dopamine!)

K+ (potassium) blockade: QTc prolongation–watch out for torsades! Give 4-8g mag sulfate.

Inhibition of Reuptake (of norepinephrine, serotonin, and other biogenic amine neurotransmitters): Can cause tachycardia, hypertension, and serotonin syndrome. Treat with sedation… maybe a benzo?

Na+ (sodium) blockade: QRS prolongation, hypotension from bradycardia, and decreased cardiac contractility, leading to ventricular dysrhythmias. Treat with sodium bicarbonate boluses and a drip- you may need to give a lot to keep the QRS from getting too wide.

GABA blockade: Lowers the threshold for seizures and adds to the many reasons these patients get agitated. The treatment? You guessed it, more benzos.

 

“Stealth” TCAs

Several drugs which are not classified as antidepressants are very similar to TCAs in terms of their chemical structures. The clinical importance of this similarity becomes clear when overdoses of these drugs present similarly to a TCA overdose, and can be treated the same way. They can also trip a urine drug screen for TCAs! Important “stealth” TCAs include:

First generation antihistamines (diphenhydramine, chlorpheniramine and others)
Carbamazepine/Oxcarbazepine
Cyclobenzaprine
Quetiapine

Management:
  • Get the usual set of labs and be sure to check for coingestants, but get an EKG ASAP.
  • A relatively sensitive marker for TCA toxicity (and cardiotoxicity), would be to look for a “terminal 40ms change (120-270 deg)” on the EKG. In layman’s terms, look for an prominent R wave on lead aVR and a prominent S wave on leads I and aVL. Remember, on a normal EKG, you shouldn’t be seeing a large R wave on aVR and the S wave on I and aVL. And of course, look out for the widened QRS!
  • As far as the threshold goes for treating with bicarbonate, QRS >100ms is the accepted threshold to start sodium bicarbonate. Use 2-3 amps of bicarbonate to bolus, do this every 3-5 minutes, with pH goal of 7.5 to 7.55. After the initial bolus, can also consider giving a drip with 3 amps of bicarbonate in 1L D5W at 2X maintenance.
  • While bicarbonate will help counter arrythmias both from the sodium load and alkalinization, if you encounter dysrhythmias, consider lidocaine (which is paradoxical because it is also a IB sodium channel blocker) but behaves through altering the conformation to reduce TCA binding to cause sodium channel blockade. Give 1mg/kg as a slow bolus, then continuously at 20-50ug/kg/min.  Other adjuncts to consider are hypertonic saline (sodium load to counter sodium channel blockade), hyperventilation (to induce alkalosis), and magnesium sulfate (max 2 g).
  • With alkalinization, may have to continue for 12-24 hrs given redistribution within adipose tissue.
  • Seizure likelihood increases past a QRS of 120, get IV access so you can administer Valium 5-10 mg or Ativan 1-2mg. If this doesn’t work, you can consider using phenobarbital, or propofol (if not hypotensive). Propofol might be preferred given its easy “on and off” pharmacodynamics. Bolus with .5mg/kg, then titrate between 20-80ug/kg/hr.
  • With hypotension, give fluid boluses, and then norepinephrine is the ideal vasopressor if refractory. Start at .04 and titrate up as needed.
  • Countering anticholinergic effects is challenging, currently physostigmine is not recommended for this purpose especially for those with arrythmias or are hemodynamically unstable.
  • Give early charcoal. TCAs do delay gastric emptying, therefore there is more hope that your TCA will be adsorbed by the charcoal.
  • Last ditch effort (if nothing works): Consider doing intralipid emulsion (1.5ml/kg bolus of 20% emulsion, every 5 min). By this point, you will have likely consulted a toxicologist. Also, ECMO is a good consideration with managing hemodynamics.
References: 
Anthony Foianini, Timothy Joseph Wiegand & Neal Benowitz (2010) What is the role of lidocaine or phenytoin in tricyclic antidepressant-induced cardiotoxicity?, Clinical Toxicology, 48:4, 325-330.
Cole Jon B. 2015. Chapter 339: Cyclic Antidepressants. In: Ling L , Wolfson AB, editors.  Harwood-Nuss’ Clinical Practice Of Emergency Medicine. 6th ed. Philadelphia (PA): Wolters Kluwer. p. 1448-1451.
Liebelt EL. 2015. Chapter 71: Cyclic Antidepressants. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, editors. Goldfrank’s Toxicologic Emergencies. New York (NY): McGraw-Hill Education. p. 972-982.
Sahalnick S. Tricyclic antidepressant poisoning. In: UpToDate, Grayzel J (Ed.), UpToDate, Waltham, MA, 2017.
Weingart S. Podcast 98-Cyclic (Tricyclic) Antidepressant Overdose. Emcrit.org. 4 May 2013.
Text written by: Alex Huh, MD
Reviewed by: Andrew Farkas, MD and Anthony Pizon, MD

Board Review #2: Acetaminophen

Disclaimer: Like salicylates, we DO realize that with acetaminophen there are plenty of well-made FOAMed resources out there that have been made and reviewed by our toxicology peers. That said, it would be a shame for us to not cover these quickly in HYPE-style! We are integrating these resources, and will appropriately cite them as well. Cheers!

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What is the on acetaminophen (APAP) toxicity?

Many different medications, especially OTC formulations have acetaminophen.


APAP (paracetamol here) forms toxic NAPQI when sulfation and glucuronidation pathways are oversaturated in the liver.


N-acetylcysteine (NAC) serves as an antidote by helping replenish glutathione (GSH) which neutralizes NAPQI through “GSH conjugation” (two pics above)

Acetaminophen toxicity exists in four stages.


The half-life of acetaminophen is 2-4 hrs, with peak con’c achieved within 1-2 hours.

 
Use the M-R nomogram to determine if NAC is indicated!


“The Rule of 150”-How much is toxic, and how much NAC to give!

When to suspect?

Intentional overdoses, elevated LFTs without an explanation, management for chronic pain, overdose on medications that do not solely have acetaminophen  (Excedrin, OTC cold medications for example). With all causes of acute liver failure, almost half of the causes were caused by acetaminophen. It does not happen often however, as it has been noted that only ~5% of patients develop hepatotoxicity making APAP the most common cause of acute liver failure in the USA. Consider the medications that the patient is taking: many OTC medications as well as narcotic pain medications have acetaminophen incorporated into it.

How it works:

Acetaminophen has a half life between 2-4 hours with peak serum concentrations achieved within 1-2 hours of ingestion. When acetaminophen is ingested, most of it is metabolized through sulfonation and glucuronidation. In setting of overdose where sulfonation and glucuronidation are occurring at capacity, additional acetaminophen is metabolized through cytochrome P450 (Largely CYP2E1). When this occurs, a reactive toxic intermediate called N-acetyl-p-benzoquinoneimine (NAPQI) is formed. NAPQI will generally be rapidly conjugated with glutathione, where its products are renally cleared. However, in setting of overdose, where the conjugation pathways for sulfonation/glucuronidation are completely overwhelmed, excess NAPQI is formed through the CYP enzyme pathways and glutathione stores are depleated, where it then begins to react with hepatocytes. It has been reported that once glutathione stores are depleted to 70-80%, hepatocellular enjury ensues. Centrilolobular necrosis (zone III) occurs because the cytochrome P450 enzymes have the greatest concentration in that location.

A thought: Acute alcohol ingestion is not a risk factor for hepatotoxicity and may be protective as it can compete with acetaminophen for the CYP substrate. However, chronic alcoholics may be at greater risk because alcohol can induce CYP2E1, combined with associated malnutrition common in alcoholics with likely low glutathione stores.

Signs and Symptoms:

Like aspirin, there are 4 stages that are associated with acetaminophen toxicity.

In phase I, patients generally have nonspecific symptoms, such as nausea, vomiting, diarphesis, pallor, lethargy, and malaise. Also, their symptoms may be driven by coingestants as some patients may remain asymptomatic. Lab results are normal in this phase. However, APAP levels are elevlated.

Nausea, vomiting, diaphoresis, pallor, lethargy, and malaise. (Phase I: .5-24hrs)

After the first day, in phase II, the abovementioned symptoms abate, while lab abnormalities occur, such as transaminitis, and patients develop RUQ pain with possible liver enlargement and tenderness on exam.

Mild transaminitis, resolution of systemic symptoms, possible nephrotoxicity (Phase II: 24-72hrs)

It is thought that from 72-96 hours, the transamitis will peak, in phase III. The systemic symptoms that disappeared in phase II return, with jaundice, encephalopathy/AMS, elevated ammonia, with coagulopathy, lactic acidosis, and hyperbilirubinemia. LFTs can easily be over 1000, and can jump to 10000+ in severe poisonings. Renal failure may also occur as well, with the AKI from ATN.

Systemic symptoms return, peak transaminitis, renal failure, encephalopathy, coagulopathy, lactic acidosis, hyperammonemia, and hyperbilirubinemia. (Phase III: 72-96hrs)

In phase IV (after 96 hrs), traditional teaching suggests the patient will die, or recover. However, there are many variations to these phases. Complete recovery, if it will occur, usually completes in a week, with full recovery extending to several weeks. Renal failure will likely resolve, however patients may require dialysis in the interim.

Death, or recovery (Phase IV: 96+ hrs)

Management:
  • Get a 4-hour acetaminophen level! The acetaminophen antidote, N-acetylcysteine (NAC or acetadote) needs to be administered within 8 hours of ingestion for the best outcome, and immediately if presenting later than 8 hours.
  • Use the Matthew-Rumack diagram to guide your evaluation for toxicity. The simple rule: at 4 hours, if it is >150, give NAC.
  • If less than 2 hour upon presentation, give activated charcoal. (there is a study showing less likely to be above MR diagram line if charcoal given within 2 hrs of ingestion)
  • How to give NAC? Dr. Michelle Lin has a wonderful ALIEM PV-Card for acetaminophen toxicity, for which she calls the ‘RULE OF 150’: Toxic dose of acetaminophen is 150mcg/kg (10.5g in a 70kg person), give NAC if APAP>150 at 4 hours, give starting loading bolus of NAC at 150mg/kg.
  • After the starting bolus, give NAC at 50mg/kg for 4 hours, followed by 100mg/kg for 16 hours (average 300mg/kg over 20 hours), continue until LFTs downtrend.
  • My shop only has oral NAC: 140mg/kg first dose, then 70mg/kg every 4 hours. Be warned: oral NAC is very unpalatable.
  • The big question: What if I don’t know when they ingested? Give NAC if serum APAP level >10mcg/ml or AST/ALT is elevated.
  • For chronic APAP toxicity, start NAC if LFTs are elevated.
  • What if they start to look REALLY sick? You may consider giving liver transplant a ring, and see if your patient qualifies under the King’s College Criteria: Arterial pH 6.5, SCr>3.4, grade III or IV encephalopathy. (Either marked confusion, incoherent speech, sleeping or comatose, unresponsive, decorticate/decerebrate positioning-Check out the West Haven Criteria: stages of hepatic encephalopathy [AASLD paper] ).

Text written by: Alex Huh, MD
Podcast by: Michael Abesamis, MD
Reviewed by: Michael Abesamis, MD and Anthony Pizon, MD

Board Review #1: Salicylates

Disclaimer: We believe salicylates are one of our favorite overdoses to manage, however we DO realize that there are plenty of well-made FOAMed resources out there, that have been made and reviewed by our toxicology peers. That said, it would be a shame for us to not cover these quickly in HYPE-style! We are integrating these resources, and will appropriately cite them as well. Cheers!

Download (right click, “save target as”)

What is the  on Salicylates?


The usual suspects #notjustaspirin


Salicylates stimulate the respiratory centers in the brain, causing a respiatory alkalosis #medullaoblongata


Early respiratory alkalosis followed by metabolic (lactic) acidosis #blue2red


Mitochondrial uncoupling induces lactic acidosis + heat #breakup


Labs: VBG, BMP, CBC, ASA, Lactate, LFTs, Coags, UA, UTox #spamthelab


GIVE FLUIDS: 1L of D5W + 3 Amps of bicarb + 40mEq of KCl at 2X maintenance rate #fluidsfluidsbaby


Aim for Serum pH between 7.5-7.55 and Urine pH between 7.5-8.0 #pHgoals #alkalosisISBAE

Give fluids for a goal of 2-3 mls/kg/hr. Place a foley! #goldenriver


If the salicylate level >90 (acute) or >50 (chronic), worsening clinical condition, or end organ damage, dialyze! #doUevenDIALYZE

If you need to intubate, bolus an amp of bicarb before intubating. Match ventilator settings after intubation! #bolusTUBEmatch

 

When to suspect?

Aspirin, “pain-killer ingestion,” willow bark, oil of wintergreen, “BenGay,” “PeptoBismol,” “AlkaSeltzer” all contain salicylate, some more than others. Not every salicylate toxicity is from aspirin.

Mechanism of Action?

Respiratory alkalosis:

While most of salicylic acid is ionized (salicylate), minute amounts of protonated acid will reach the medulla—the respiratory center. This will increase breathing (hyperventilation), breathing out CO2 causing respiratory alkalosis. The degree of alkalosis can be up to: 7.45-7.50.

Respiratory alkalosis also contributes to acidosis because alkalosis induces bicarbonaturia (part of the ion trapping strategy), which means adequate replacement of bicarbonate is crucial. This, combined with mitochondrial uncoupling  results in metabolic acidosis.

Mitochondrial Uncoupling:

You’ve probably heard of cyanide, azide, carbon monoxide, rotenone, and others that inhibit the electron transport chain (ETC). Aspirin is a little different—it uncouples. Normally, the inner mitochondrial membrane holds a proton gradient where there are lots of protons in the intermembrane space, and much less in the matrix. This is the result of the electron transport chain. Each time electrons move between complexes, more protons get pushed into the intermembrane space, out of the matrix. The proton gradient allows the ATPase to generate ATP, as the force behind the gradient allows phosphorylation of ADP into ATP. However, salicylate can diffuse through into the mitochondria, pick up a proton, then diffuse into the matrix where it drops it off. Oddly enough, it can then translocate back into the intermembrane space, and pick up another proton to repeat the process. This destroys the gradient, not allowing for ATP, and heat is produced as protons diffuse through the gradient. Heat = Fever, and no ATP (in brain) = Seizures!

Salicylic acid has a pKa of 2.97. This means at roughly physiologic pH, the ionized A- (salicylate, not salicylic acid) is in abundance ~104.43:1 over the acid (protonated). How I came up with this: Henderson-Hasselbalch equation states: pH=pKa+log(A-/HA). The reason why we care about this, is that a small change in pH, can make a profound change in the overall concentration of salicylate in the brain, because the equation is LOGARITHMIC.

As long as salicylate stays unprotonated and charged, it won’t cross into the CNS (through a lipid, non-ion friendly membrane). Remember, the toxicity in salicylate poisoning is in the HEAD. Once you’re at seizure, or coma, the patient will be at the precipice of death.

Signs and Symptoms

Like acetaminophen and iron toxicities, salicylates have phases to their toxicities. In brief, respiratory alkalosis with metabolic acidosis.
Initially (Phase I), the pH is elevated from the primary respiratory alkalosis, with associated gastritis (w/pylorospasm).

Hyperventilation, nausea, vomiting, abdominal pain, dizziness. (Phase I)

With increased absorption, mild CNS effects will take place with some development of metabolic acidosis (secondary to uncoupling) in Phase II. Uncoupling causes heat production (low-grade fever), with anaerobic metabolism resulting in lactic acidosis. The mild CNS effects are tinnitus and headache usually. They can also become diaphoretic.

Low-grade fever, tinnitus, headache, diaphoresis (Phase II)

With the anion gap widening as more mitochondrial uncoupling occurs, the pH will fall (Phase III). In the brain, decreases in glucose metabolism results in decreased ATP, causing cerebral edema, and altered mental status. Renal failure results from volume depletion. With further stimulation of the respiratory centers in the medulla, but now with significant acidosis to further drive respiration, ARDS may develop as a complication in worsening salicylate poisoning.

Altered mental status, cerebral edema, renal failure, poss. ARDS (Phase III)

Finally, as acidosis worsens, the body will tire from increased respiratory demand, and result in failure. Here is when the protective respiratory alkalosis will result into respiratory acidosis. Worsening of acidosis from both metabolic and respiratory pathways (w/uncoupling, especially in the CNS) will result in seizure, coma, and death.

Respiratory failure, Seizure, Coma, or Death (Phase IV)

These phases are listed eloquently on ALiEM on a PV card that Sam Shaikh developed, check it out!

Management:

 

  • Remember, the respiratory alkalosis is protective for the patient! Do not ‘correct’ the alkalosis. However, your patient may tire out, therefore you need to watch closely. If you must intubate, bolus bicarb (1mEq/kg) to make up for acidosis in process of intubating, and set your ventilator settings to match the minute ventilation prior to intubation! You want to keep the respiratory alkalosis going even after you establish an airway.
  • Like with any sick patient: Fluids, fluids, fluids! WHY: significant insensible losses from tachypnea and fever. Plus, frequent emesis symptoms. Urine output at 2-3ml/kg/hr is important. Prefer LR or plasmalyte over NS due to K+ content (give 30mEq KCl per liter additionally) and avoiding hyperchloremic NAGMA. Plan for a foley! (It will also help with measuring urine output.)
  • BICARB, BICARB, BICARB! Help the body’s efforts by alkalinizing the serum! Serum goal pH should be 7.5-7.55, to push the equilibrium between A- (ionized salicylate) and HA (protonated acid) to the ionized form which has decreased likelihood of CNS infiltration, and better secretion through the urine as it too will be alkalinized with an ion-trapping effect. Goal urine pH: 7.5-8.0 as it can improve excretion 10-fold. The ALiEM PV card recommends bolusing 1 mEq/kg and start drip at 2x maintenance. The ACMT also suggests mixing 1 L D5W w/3 50ml bicarb ampules at 7.5% or 8.4% (total at 132-150mEq) if you need to prepare the solution.
  • Respiratory alkalosis also contributes to acidosis because alkalosis induces bicarbonaturia (part of the ion trapping strategy), which means adequate replacement of bicarbonate is crucial. This, combined with mitochondrial uncoupling results in metabolic acidosis.
  • LABS: ABG, CBC, BMP, LFTs, Coags, lactate, ASA level, urinalysis, Urine bHCG (those in bold indicated for sick patients)
  • Like any other overdose, check for coingestants!
  • With testing, get blood gases and urine pH to trend efforts in alkalinization.
  • Metabolic panels to evaluate anion gap, q1-2 hr in ED
  • Indications for dialysis: ASA level >90mg/dL if acute, AMS or end-organ damage with any elevated ASA level if chronic. End organ damage such as renal failure, CHF, ARDS, AMS, seizures, liver damage
References

ACMT Salicylate Guidelines 2013.

Shaikh S. Acute Salicylate Toxicity PV Card. ALIEM. 6/15/15.

Berman S., Bucher J, Koyfman A. ed, and Bright J. ed. Pearls and Pitfalls of Salicylate toxicity in the Emergency Department. emdocs.net. 10/13/15

Fontes K. 5 Tips in Managing Acute Salicylate Poisoning. ALiEM. 11/4/13.

Nelson L., et al. Goldfrank’s Toxicologic Emergencies

Text written by: Alex Huh, MD
Podcast by: Anthony Pizon, MD
Reviewed by: Anthony Pizon, MD

 

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