Hi-Yield Poisonings and Envenomations

Category: Board Review

Board Review #7: Spiders

There are about 40,000 different species of spiders worldwide, with only a handful of species being medically relevant causing significant bites and stings. We’ll cover our two most common players: the brown recluse and black widow spiders. Here we go!

Brown Recluse Spider-Loxosceles reclusa

What is the with Brown Recluse Spider envenomations?

In the south and the lower Midwest. Look for the fiddle! It has six eyes! #6EyeGuy #FiddlerSpider
Painless bite, with necrosis. Hyaluronidase (tissue penetration) and sphingomyelinase D (necrosis/thrombosis/ischemia), but no systemic symptoms #VitalSignsStable #HyaluronidaseFirst #SphingoWUTDoesEverything
Erythema, poss scar heals in weeks. Bad ones can cause ulceration, vesiculation, violaceous necrosis, blanching. Eschar in weeks. N/V/F/C, arthralgias, low platelets, rhabdo, DIC, and renal failure can occur (Get CBC/CMP/Coags). Hemolysis can happen at 24-72 hours. Pain control and supportive care .
 #RedWhite&BlueSign #ItsABigDeal #GetLabs #SupportiveCareFTW

When to suspect?
Brown recluse spiders are generally localized within the Midwest and the south. Texas, Oklahoma, Kansas, Missouri, southern Illinois and Indiana, Kentucky, Alabama, Mississippi, Arkansas and Louisiana are home to the brown recluse.

Distribution of the Brown Recluse Spider in the US

Anecdotally, brown recluse spiders have been found in California among other states, although never confirmed. Literature suggests that encounters with spiders beyond endemic regions are rare.
These spiders will measure up to 2 cm long, colored gray, orange, or brown. The brown recluse spider is characterized with a pigmented fiddle-like shape on their thorax. That said, other species of spiders can possess this as well, therefore it is not specific. However, unique to the loxosceles species, are their 6 eyes (one anterior with two lateral pairs), versus the average spider possessing 8. The spider is generally nocturnal and shy—it generally bites when threatened. It lives within dark, and dry areas including basements, wood piles, and closets. It usually bites in the morning, between the spring and fall. It is a very resilient in that it can survive up to 6 months without food or water, while tolerating temperatures between 45-110F. Females, like the black widow, are more dangerous than the males. 

How it hurts:
The brown recluse spider causes a necrotic presentation, because its venom contains hyaluronidase and sphingomyelinase D among other enzymes. Hyaluronidase allows for venom penetration into tissues, while sphingomyelinase causes necrosis of tissue through a chain reaction that produces inflammatory mediators that causes vessel thrombosis, ischemia to tissue, and skin injury.  In comparison to the black widow spider (the other clinically significant spider in North America), it generally does not have any systemic symptoms.

The bite of a brown recluse is generally painless, which creates a diagnostic challenge in terms of the patient knowing when he/she got bitten and identification of the spider.  Patients may present to the ED with skin lesions they attribute to a spider bite, although it often has another etiology. In one study, of 182 patients who complained of spider bite only 3% were confirmed while 84% had a skin and soft tissue infection.

Bites commonly manifests as a mild erythematous lesion/papule with possible scar, but ultimately heals in a week or two. More severe bites or reaction to bite can result in substantial pain, erythema and pruritis with associated swelling. Ulceration can occur in 2-8 hours. This will evolve in 1-3 days where there is ecchymosis. There is usually central hemorrhagic vesiculation, ulceration, then violaceous necrosis surrounded by ischemic blanching of skin and outer erythema and induration. This is often dubbed as the “red, white and, blue sign.” By a week, an eschar can form.

While systemic symptoms of a brown recluse spider bite are rare, a sign of systemic brown recluse envenomation is hemolysis, which generally occurs 24-72 hours after the bite. They may also develop nausea, vomiting, fever, chills, arthralgias, thrombocytopenia, rhabdomyolysis, DIC, hemoglobinuria, and renal failure. Systemic loxoscelism typically affects children and severity cannot be predicted by the extent of the cutaneous lesion.

If your suspicion is high, obtain CBC, CMP, and coagulation studies.

Clean the wound site, given tetanus prophylaxis as indicated. Elevate the bitten extremity and apply cool compresses.

Supportive care (including pain) will be paramount in management of a brown recluse spider bite. If the site appears infected, then antibiotics are warranted. Serial wound evaluations are warranted such that if the wound worsens, surgical debridement may be warranted after adequate tissue demarcation has occurred, typically several weeks after the initial bite. Early excision of the bite site has not been shown to be helpful.

There are other experimental interventions, however these have not been proven to be beneficial: dapsone, colchicine, antivenom, HBO.

Black widow spider—Latrodectus

What is the with Black Widow Spider envenomations?

Look for the hourglass #ButDatHourglassDoe
Where? Everywhere, but west coast (California), the south, and the east coast are common places #ItsEverywhere #NobodyIsSafe

Toxin binds to presynaptic neurexin I-a (Ca2+ dependent), and Ca2+ independent receptor, called latrophilin. Causes a calcium pore to form, with exocytosis of vesicles (NE, dopa, neuropeptides, ACh, glutamate, and GABA. G-protein receptors and PLP) #LeakingCalcium #ItsAllCalciumBaby #NeurotransmitterShotgun
Pinprick bites, spreads up the extremity. Erythema, with a target-like lesion or halo #LymeMimic
Erythema, and neuromuscular cramps/rigidity as early as 15 min. Chest, Abd, face. #latrodectismSUCKS #cramps #rigidityNOTtetanus #MyBellyHurtsEverywhere #ImGonnaDie #PavorMortis
Abx are not routine. Give IV opioids and benzos for pain and spasm control. #BenzosBenzosBenzos #SeeAPatternYet

Antivenom puts at risk for anaphylaxis and serum sickness (HORSE SERUM), and usually reserved for pregnant women.  #GiveWhenWarranted #Horsey

When to suspect?
Latrodectus spiders, or widow spiders are found worldwide. There are 5 species in the US, however the black widow is only three of these (mactans, variolus, hesperus). Many of the latrodectus species, both US and worldwide, have a distinct design on their abdomen, whether it be . The classical hourglass is on the mactans species. Males are small, and they cannot bite. Females however, measure up to 1cm in body width with leg spans up to 4-5cm and their bite can be very toxic. The females lay their eggs in the warmer months, and will defend her eggs aggressively, thus most black widow bites occur between April and October usually on the hands and forearms. Latrodectus spiders are found in similar places as the brown recluse, such as woodpiles, garages, sheds, basements, stone walls, crevices, woodpiles, outhouses, barns, stables, rubbish piles. Geographically, most of the latrodectus live in temperate conditions, on the west coast (California predominantly), the south, or the east coast.

How it hurts:
The venom of the black widow deserves respect. It is more potent than on a volume per volume basis versus a pit viper. There are 6 components to the venom, a-latrotoxin and 5 latroinsectotoxins/latrocurstatoxin. These toxins bind to presynaptic neurexin I-a (Ca2+ dependent) and a Ca2+ independent receptor for a-latrotoxin, known as latrophilin. When it binds, it causes conformational change, which then forms a pore, with a calcium ionophore, with exocytosis of vesicles that contain norepinephrine, dopamine, neuropeptides, Ach, glutamate, and GABA. The mechanism is mediated through G-protein receptors and phospholipase C.

Unlike the brown recluse bite (where it is often unnoticed), most latrodectus bites are felt as a pinprick. Pain starts at the bite site and spreads quickly up the extremity. Erythema arises within an hour of the bite. A small macule may emerge from the bite site, that evolves into a target lesion (blanched center) or a halo presentation.

Latrodectism is a constellation of signs associated with a bite from a widow spider. Like the erythema, severe neuromuscular symptoms can occur within the hour. Time to symptoms is correlated to the severity of the bite. Severe muscle cramps can occur within an hour, as early as 15 minutes. Rigidity can spread to other muscles throughout the body, particularly in the chest, abdomen, and face. It can in fact, mimic a surgical abdomen, but this is secondary to severe muscle spasms. These will resolve in a few hours but can recur over days. In addition, sweating, contorted/grimaced face, with blepharitis, conjunctivitis, rhinitis, and masseter trismus can all occur. Patients will describe a fear of death, known as pavor morits. Symptoms such as nausea, vomiting, sweating, tachycardia, hypertension, restlessness can occur. Severe complications such as malignant hypertension, respiratory distress, and cardiovascular instability, and gangrene can ensue that can cause death. That said, in a span of 20 years, only 2 deaths have been reported, which in part, is due to the development of antivenom.

In all things emergency medicine, ensuring airway, breathing, and circulation is paramount. Evaluate the wound, provide tetanus prophylaxis, and like brown recluse bites, antibiotics are not warranted unless an obvious infection is present. If the envenomation causes muscular pain with migration to the trunk or even worse, with abnormal vital signs with systemic symptoms, give IV opioids and benzodiazepines to manage pain and muscle spasm.

The antivenom of latrodectus is effective, but has been known to cause anaphylaxis and serum sickness given that it is a crude hyperimmune horse serum. Because of this risk, the antivenom is usually reserved for the most severe envenomations, ones that are producing systemic symptoms with vital sign abnormalities, especially pregnant women. The dose is generally 1-2 vials of antivenom diluted in 50-100ml of D5W or NS, infused over an hour. At this time there is no evidence supporting or rejecting use of antihistamines in setting of antivenom administration.


Schneir A, Clark RF. Chapter 311: Bites and Stings-Spiders. In Tintinalli JE, editors. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8th edition.  

Hahn I. Chapter 118: Arthopods. Goldfrank’s Toxicologic Emergencies. 10th edition.

Text written: Alexander Huh, MD
Reviewed by: Anthony Scoccimaro, MD

Board Review #6: Snakebites

In the US: thousands of snake bites annually, with very few (if any) deaths per year.

Worldwide: 5 million snake bites with 125,000 deaths globally.

There are five families of venomous snakes which include: viperidae, elapidae, hydrophiidae, atractaspididae, colubridae. In the US, the only two families of venomous snakes are the viperidae and elapidae. The Viperidae include rattlesnakes and vipers, whereas the elapidae include the coral snakes. The two families have different presentations and characteristics of envenomations thus we will address them separately.


Crotalinae, also known as pit vipers, or crotalids, are snakes with a triangular shaped head, elliptical pupils, and equipped with heat sensing pits. They are generally found throughout the US except Maine and Hawaii. for which most envenomations occurring between May and October (hibernate in the winter) in the afternoon hours

The striking distance of a crotalid is half of its length, and typically makes a subcutaneous envenomation. . Thus, the venom of crotalids spreads through the lymphatic system—they will rarely be intravenous envenomations. Most bites are from rattlesnakes, with the remaining bites from cottonmouths, water moccasins, and other species. Cottonmouths and water moccasins have generally less severe envenomations than rattlesnakes. A quarter of the bites from crotalids will be dry bites. However, those with real envenomation will experience severe pain and swelling within minutes, followed by ecchymosis and blistering between minutes to hours. Anaphylaxis can occur, albeit rare. Occasionally the severity of the envenomation can produce rhabdomyolysis. Systemic symptoms may include weakness, malaise, abdominal pain, anxiety, nausea, vomiting, and diarrhea with possible hypotension. Patients commonly develop coagulopathy and/or may develop neurotoxicity. Generally, if one doesn’t have symptoms within 6-8 hours, it is a dry bite (leg bites are the exception, may have delayed onset of symptoms), thus observation between 8-12 hours is reasonable.

Coagulopathy is a common, as victims will have low fibrinogen and platelet counts, and PT/PTT times being considerably prolonged. It is not unusual for the coagulation studies to be abnormal despite significant clinical improvement.

The immediately most concerning issues such as airway issues (analyphylaxis) are very rare, and the Mojave is the only North American crotalid that is neurotoxic (producing lethargy, cranial nerve deficits and respiratory failure through a neurotoxin that inhibits neurotransmitter release presynaptically). Bleeding from DIC is rare, and so is compartment syndrome, which is important to monitor for.  While incredibly rare, documented cases do exist of anaphylaxis occurring to those who have been sensitized to crotalids. It is mediated through IgE like any other anaphylaxis case, but it may be difficult to distinguish from severe envenomation.

For crotalid envenomation, NEVER USE a tourniquet, ice, compression bandage, incision/suction, or venom extractors. None of these help. Like any sick patient, do the ABCs: manage their airway, give IV fluids, and pressors if hypotensive. Epinephrine is a popular choice for pressor. Elevate the extremity, fentanyl for pain control, and benzos for anxiety. Continue neurovascular checks, update tetanus status, and monitor the circumference of an extremity and indicate the extent of swelling on the extremity by time and date. Keep the extremity in extension, and place into a splint. Prophylactic antibiotics are unnecessary in these envenomations. There is significant swelling, and often many providers are concerned for compartment syndrome. As mentioned earlier, the envenomation is subcutaneous, although patients will complain of paresthesias, tense swelling, pain, and weakness, which is obviously concerning for compartment syndrome. The question of dermotomy or fasciotomy comes up, and when in doubt, check compartment pressures, however it is rarely needed. It was found that fasiotomies and subcutaneous decompression doesn’t prevent myonecrosis in animals receiving venom injections. They have even found that envenomations will increase arterial blood flow distal to the swelling, which is contrary to what we would expect in compartment syndrome.  Once the swelling subsides, wound debridement occurs with surgery, usually in 3-6 days.

The most important labs include platelets, PTT and fibrinogen level. Blood products are not indicated in the absence of bleeding, and anything given for low platelets or coagulation factors will be consumed immediately after being given (since active venom is present), such that it is futile to administer blood products without concurrent administration of antivenom also. Trend coagulation studies after each antivenom bolus dose and prior to hospital discharge. Just remember that normalization of coagulation studies is not an endpoint, as coagulation studies may not completely normalize.

One can imagine, when do you give antivenom?!?! Consider the three possibilities:
1. Rapid progression of swelling
2. Significant coagulopathy or thrombocytopenia
3. Systemic symptoms (neurotoxicity, shock, etc)

The antivenom of choice is CroFab. It is a polyvalent immune Fab, where the Fc fragment is removed, leaving only the Fab component that binds to the venom. It is derived from sheep that were immunized with Mojave, western and eastern and cottonmouth snake venom. Studies have shown that Crofab stops progression of swelling, reverses hematologic toxicity, and likely reverses systemic symptoms,but there is still no evidence that prevents tissue loss.

Give 4-6 vials of CroFab, with normal saline over 1 hour Once the first 4-6 vials are done, repeat the 4-6 vials until clear improvement is appreciated in swelling, coagulopathy and platelet counts. Maintenance CroFab is then given with 2 vials every 6 hours for three total maintenance doses.

CroFab is not without its own limitations. A recurrence phenomena can occur where once the envenomation resolves with treatment, swelling or hematologic abnormalities (coagulopathy, thrombocytopenia) recur. The timeframe usually is several days after treatment, and if the patient is rebleeding, retreat with CroFab, however otherwise observe the patient. Beyond recurrence, CroFab is expensive, results in longer hospital stays, and outpatient follow-up required.

If patients are asymptomatic, observe for 6-8 hours for those suspected to be bitten by a pit viper. Be vigilant for subtle signs of envenomation

The other family of venomous snakes are the elapidae, which include coral snakes, cobras, mambas, tiger snakes, and taipan. Coral snakes are the elapidae encountered in the US. These are notorious for neurotoxicity, with minimal local findings, in contrast to the crotalids. The US is home to 3 coral snake species: The Eastern, Texas, and Sonoran coral snakes. They are often confused with king snakes which are nonvenomous. Coral snakes have black snouts. Additionally, many remember the color bands on the bodies of the snakes: “black on yellow, kill a fellow, red on black, venom lack.” Overall compared to the Crotalids, they are much more docile.

Elapidae envenomations can appear deceptively benign given that the pain is often minor. In comparison to crotalids where their fangs puncture deeper, coral snakes have shallower fangs with a ‘gnawing’ bite (and may not immediately let go), where removing the snake is akin to peeling off Velcro. Less than 40% of elapidae envenomations are clinically significant. In decreasing prevalence, local swelling, paresthesias, nausea, vomiting, euphoria, weakness, dizziness, diplopia, diaphoresis, and muscle tenderness occur. Severe envenomations have been reported with long asymptomatic periods >12 hours, and when they deteriorate, respiratory distress/failure and neurologic abnormalities occur with the major cause of immediate death is respiratory failure secondary to neuromuscular weakness. That said, ventilation and supportive care is effective as the weakness/paralysis is reversible over the course of couple days. Close observation for a day will be paramount for these patients.


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

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

Board Review #5: Carbon Monoxide

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What is the on Carbon Monoxide?

Carbon monoxide is produced from incomplete complete combustion instead of CO2, CO is produced.

It is commonly associated with fires, car exhaust, natural disasters, broken furnaces. Or the, “I’m symptomatic but my pet died!”

Symptoms include nausea, vomiting, headache, syncope, dyspnea, altered mental status, and can precipitate shock, seizures, coma, and death.

CO has multiple mechanisms of effect: Displace O2 from Hgb, Left shift of Bohr effect, and inhibition of the electron transport chain @Complex IV.

Symptoms can start at a HbCO level of 10-15, but 25 is the level to consider hyperbaric oxygen.

Initial intervention (in the field through ED course): OXYGEN. Get a non-rebreather!

Goal is to reduce the half-life of CO-Hgb using supplemental oxygen! Get your CO level <5%!

Indications for hyperbaric oxygen: COHgb level >25%, AMS, Coma, Seizure, cerebellar dysfunction, >35 years old, end-organ ischemia/significant acidosis/myocardia infarction, loss of consciousness, pregnant with COHgb>20%.

Greatest concern is neurologic sequelae; CO damages the basal ganglia! Consider a CT/MRI if the patient looks bad!

When to suspect?

Carbon monoxide (CO) poisoning can occur in a variety of circumstances. Given that it is most commonly due to incomplete combustion, fires are a common cause of CO poisoning. Additionally, incomplete combustion from cars, or broken furnaces cause be a cause as well. There are instances where intentional poisoning occurs with the car running in the garage, but also unintentional from wanting to ‘warm the car up’ before going to work. Natural disasters, surprisingly, account for a significant amount of carbon monoxide poisoning as makeshift charcoal stoves or grills, or gas stoves when people are displaced from their homes. It is also very important to ask who else was around the patient as, “my dog died!” or, “other people in the house have been sick too!” may be the only tip-offs that this is CO poisoning.

Mechanism of Action?

Bear in mind that carbon monoxide’s affinity to hemoglobin is 250X greater than oxygen! This plays an important role in the mechanism of action. Oxygen binds to hemoglobin through an effect called cooperativity. Each oxygen bound increases hemoglobin’s affinity for an additional oxygen, from allosteric protein conformation changes. That is why the oxygen saturation curse has an exponential slope near the beginning, however tapers off at an inevitable ceiling since hemoglobin can only bind up to 4 oxygen molecules. With carbon monoxide, it does not induce the allosteric protein changes and does not cause cooperativity to occur. Therefore, the carrying capacity of each hemoglobin molecule is diminished.

Changes to the Oxygen saturation curve (the opposite Bohr Effect)
Remember the days of biochemistry in medical school? For some of you, this was a dreadful experience. However, the Bohr effect and understanding carbon monoxide’s effect on the saturation curve makes a significant difference in the delivery of oxygen. To review, the oxygen saturation curve is shown below.
As this graph shows, some things can cause the saturation curve to shift to the left, and to the right. The Bohr effect, describes a rightward shift as blood carrying oxygen moves to end organs and delivers oxygen. Why does the shift occur? Because metabolism occurs at the muscle, converting ATP to ADP + PO4 + H+. Such acidosis (or presence of H+) induces oxygen to unload, and therefore will unload more at a given partial pressure of oxygen. Same is seen with the presence of carbon dioxide as well, which is a product of cellular respiration. Therefore at the top-right area of the curve, oxygen saturation is at 100%. This is where you sit on the curve when blood is at the lungs, where maximum oxygenation is occurring (at highest partial pressure of oxygen). And on this next curve, changes in pH cause more oxygen to fall off (as saturation decreases) which occurs where there is low partial pressure of oxygen (muscle/end organs).

You may ask, what does carbon monoxide do then? Well, it is similar to myoglobin (above), in that it binds much more tightly to oxygen, and has a curve that is shifted to the left. Therefore, instead of unloading more oxygen at a given partial pressure of oxygen, it in fact unloads LESS. You will sit higher on the oxygen saturation curve for a given partial pressure of oxygen, which means your organs are not receiving enough oxygen.

Electron transport chain
No classic toxidrome would not have an effect on the electron transport chain! Carbon monoxide binds to complex IV (cytochrome c oxidase). A quick reminder: protons are being pumped out of the matrix into the intermembrane space in mitochondria from each complex in the ETC to induce a proton gradient, harnessed by the ATP synthetase to power production of ATP. Carbon monoxide binds to complex IV tightly as a competitive inhibitor as oxygen normally binds to complex IV to receive electrons to reduce it to water (H2O). Cytochromes all have heme molecules, and this is no exception: CO’s affinity to heme over oxygen again causes oxygen to be competitively inhibited by CO’s presence. Since carbon monoxide unlike O2 cannot be reduced, electrons do not flow from cytochrome C and the ETC is put to a halt. Given that it is affecting complex IV (which is further downstream) versus complex I, a greater metabolic effect is appreciated since the pathway converges to this point. As ATP production stops, the paucity in energy causes injury in organs, akin to ischemia. Damage to the brain, especially in the basal ganglia occurs as this is an area of the brain that is similar to a watershed zone in that organ perfusion is limited at baseline. Additionally, once CO poisoning is treated with supplemental oxygen, there is increased risk for reperfusion injury, which is proposed to be the real mechanism for damage to the basal ganglia, with lipid peroxidation producing free radicals causing neuronal damage.

Also, given predominance of ADP from ATP hydrolysis, an abundance of protons is produced, causing acidosis. Remember, a lactate level is a surrogate marker for poor organ perfusion and is inevitably produced in anaerobic metabolism, but it is NOT the cause of the acidosis. Acidosis is due to the fact that all remaining ATP is depleted into ADP which results in a proton (ACID!). This is a reason why rigor mortis occurs rapdily, because all of the ATP is all used up! (Remember, ATP is used for the relaxation phase, and after ATP is hydrolyzed to ADP, it contracts!)

Signs and Symptoms

Any situation where something is burning, is good enough to raise suspicion for carbon monoxide poisoning. Symptoms at a lower level of CO poisoning include headache, nausea, vomiting, and fatigue. As the HbCO level rises, patients develop dyspnea, syncope, altered level of consciousness, chest pain, and confusion. At levels of 50 or higher, it is concerning for shock, cardiac dysrhythmias, seizures, coma, and/or death.

Something to keep in mind: Carboxyhemoglobin and oxyhemoglobin absorb light at the same frequency, therefore the color is similar. Thus, when measured on a pulse oximeter, the O2 saturation is falsely normal!

Occasionally you may have heard that those with carbon monoxide poisoning are oddly ‘reddish’ in color (also known as cherry red lividity), however this is a sign that is often appreciated in those who have expired, and should never be used as a true prognostic indicator as prognosis is well determine by the time this is observed.

CO poisoning can also cause myocardial infarction as the mitochondria within the heart are most sensitive to the effects of ETC inhibition from carbon monoxide. They can present with both STEMIs and NSTEMIs. Retinal hemorrhage and acute kidney injury have also been described in setting of carbon monoxide poisoning.


When CO poisoning is suspected, EMS providers should be aggressive in providing early supplemental oxygen, in particular, oxygen through a non-rebreather (NRB) at 100% O2. It should be continued throughout the course in the ED. The half life of CO is 4-6 hours at room air, 1-2 hours with an NRB, and 22 minutes under hyperbaric oxygen. Putting the patient on supplemental oxygen reduces their half life and improves CO clearance. Treat the patient until the level is <5% with resolution of symptoms.

Obtaining a carbon monoxide level, lactate, and metabolic panel (evaluate for an anion gap) should be of paramount importance once the patient arrives to the ED, and the emergency physician should not forget that carbon monoxide gives a falsely reassuring pulse oximetry oxygen saturation. Severe poisoning can cause shock, and thus fluids and pressors are indicated in this circumstance. Considering most carbon monoxide poisonings are associated with combustion, treatment for cyanide toxicity should be considered given cyanide is produced in combustion and its exposure affects the ETC the same way carbon monoxide does–therefore, consider giving hydroxycobalamin as necessary. The patient may have a mild acidosis (7.2-7.3) that may be permissible, which causes two beneficial outcomes: 1) CO clearance is a function of minute ventilation, and mild acidosis may cause tachypnea that will help breathe out the CO, and 2) mild acidosis will shift the oxygen saturation curve to the right at the area of tissues, which is essentially a Bohr effect, that is protective. Just be sure to continually monitor the patient to ensure he/she doesn’t decompensate.

If severe, with neurological compromise, consider obtaining a CT of the head (or MRI), however it’s more for prognostic purposes generally.

Hyperbaric oxygen (HBO, also known as “diving”) is a point of contention within circles of toxicologists as it has been demonstrated to reduce the half-life of carbon monoxide. Generally, the indications for HBO have been: older than 35 years old, a CO level greater than 25, pregnancy with a level >15, loss of consciousness, altered mental status, or evidence of end organ injury. However, the literature is not convincing that this is always the case. Randomized control trials have both demonstrated superior and inferior outcomes with HBO, with inferior outcomes being secondary to barotrauma or worse neurological sequelae. HBO appears to have an effect early within exposure, however in circumstances it is indicated, it is often long after exposure that anticipated gains from diving are limited. Instead, HBO is timely to set up, expensive, and without medical risk of barotrauma.


Nelson L., et al. Goldfranks Toxicologic Emergencies

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

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 PVCs, 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 dont 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).


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 symptomsmany 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 toxicitythe 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.


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 theres 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. Goldfranks 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) (Goldfranks: 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) (Goldfranks: 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.


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. Goldfranks 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 doa 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 doesnt 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)

  • Get the usual set of labs and be sure to check for coingestants, butget 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.
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!

Download (right click, save target as)

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 commoncause 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)

  • 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 dont 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 Kings 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 medullathe 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:

Youve probably heard of cyanide, azide, carbon monoxide, rotenone, and others that inhibit the electron transport chain (ETC). Aspirin is a little differentit 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 wont cross into the CNS (through a lipid, non-ion friendly membrane). Remember, the toxicity in salicylate poisoning is in the HEAD. Once youre 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 aPV cardthat Sam Shaikh developed, check it out!



  • 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 bodys 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

ACMT Salicylate Guidelines 2013.

Shaikh S. Acute Salicylate ToxicityPV 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. Goldfranks Toxicologic Emergencies

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


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