Introduction

Many toxicologic syndromes can present with a wide range of overlapping presentations, however then vary in their respective treatments. This vast spectrum of presentations can make deciphering what substance you’re dealing with difficult. Another complicating factor to the care of these patients is that almost all require prompt treatment. This urgent care may include key reversal agents or antidotes that make huge differences in the patient’s overall clinical outcome. Knowing key differentiators in signs and symptoms is necessary for management of these patients. I wanted to go over some commonly encountered board-question syndromes that have a crucial antidote as well as a few of those that do not. Hopefully this article will help elucidate on key pathophysiology, clinical presentations, and specific remedies among a few of the toxicology disorders. 

Editors Note: A lot of us default to “magnesium” and “sodium bicarbonate” as our treatments for the crashing patient who ingested a substance. Instead of focusing on toxidromes treated with some mag and bicarb, we’re focusing on ones that CAN’T be treated with those meds.

Acetaminophen – N-acetylcysteine

We’ll start with acetaminophen (APAP) which in normal doses is mostly conjugated with glucuronic acid or sulfate to then be excreted by the kidneys. A small amount is acted on by the cytochrome P450 enzyme activating it to a reactive metabolite, N-acetyl-p-benzoqinone imine (NAPQI). At therapeutic doses, this small amount of reactive metabolite is detoxified by glutathione to revert to a stable form. When a toxic dose, which is about 12 g or more, is ingested, the total amount of glutathione stored within the liver is depleted. When glutathione is depleted, NAPQI binds to cysteine groups on protein forming APAP-protein adducts. Current first line treatment of APAP overdose is N-acetylcysteine (NAC) which acts to maintain glutathione stores.¹

APAP toxicity typically lacks characteristic exam findings however there are four classic stages of toxicity.

• Stage 1 occurs within the first 24 hrs and is asymptomatic or subtle malaise with nausea and vomiting.
• Stage 2 starts approximately 16 to 24 hrs after ingestion and is when liver injury becomes evident. The predominant lab abnormalities will be those of hepatocellular toxicity, AST/ALT, PT/PTT, however cholestatic features including hyperbilirubinemia may occur.
• Stage 3 typically transaminases will peak and decline, typically peaking at 10,000 to 20,000. Other manifestations of hepatic failure including, metabolic acidosis, hypoglycemia, hyperammonemia may occur. Renal failure can co-occur secondary to hepatorenal syndrome.
• Stage 4 is where the patient’s liver recovers or death occurs. In the ED the mainstay of management is NAC which is given in the acute phase if the patient has a level above the treatment threshold on the Rumack-Matthew nomogram. However if a patient who ingested APAP toxic dose comes in with an elevated acetaminophen concentration with unknown time of ingestion or elevated transaminases NAC can be given regardless of unknown ingestion time. Lastly, in cases where obtaining an APAP level would take beyond 8 hrs since ingestion, starting NAC empirically is indicated given it is most beneficial when started within 8 hrs of post-ingestion.

Typically given IV, NAC can also be given orally. NAC can be given in a 3-bag protocol or a 1-bag protocol. The 3-bag protocol is more classically used where Bag 1 is 150 mg/kg added to 200 mL of D5W and infused at 150 mg/kg/hr over 1 hr, Bag 2 is 50 mg/kg added to 500 cc of D5W and infused at 12.5 mg/kg/hr over 4 hrs, and Bag 3 is 100 mg/kg added to 1000 mL of D5W and infused at 6.25 mg/kg/hr over 16 hrs. The 1-bag protocol is 30 g in 1 L of D5W initially bolused at 150 mg/kg over 1 hr and then infused at 12.5 mg/kg/hr over the next 20 hrs. There is also evidence that a single dose of Activated Charcoal administration within 2 hrs of ingestion may decrease measured plasma concentrations. ²

Link to MD Calc for NAC Dosage Calculations

Opioids – Naloxone

Opioid toxicity is not an uncommon toxidrome seen by emergency physicians. Opioids include both opiates and semisynthetic or fully synthetic derivatives and potency varies considerably between some opioids. There are three opioid receptor types; mu, delta, and kappa, however mu is responsible for the majority of clinical effects we care about including analgesia, euphoria, and respiratory depression. 

Naloxone is the antidote of choice when opioid toxicity is suspected in a patient with significant respiratory depression. Naloxone (aka Narcan) is a competitive opioid antagonist thus reversing the effects of the opioid.

Clinical presentation consists of the classic triad of CNS depression, respiratory depression, and miosis. Management in the ED consists of supplemental oxygen, assisted ventilation, and expeditious use of opioid antagonist Narcan. Suction for emesis that may occur after reversal. Initial dose of IV Narcan is dependent on if opioid dependence is suspected in the patient. If dependence is suspected, an initial dose of Naloxone 0.04 mg IV is used so as not to put patients in withdrawal. If no dependence is suspected then the technical “standard dose” is 0.4 mg IV. Onset of action is typically less than 2 minutes. If IV access cannot be obtained, can be given IM, subcutaneously, intranasally. Patients with recurrent respiratory depression who have received additional narcan doses and responded can be started on an infusion. Two-thirds of the bolus dose initially needed to reverse respiratory depression is the hourly maintenance dose.

Organophosphates – Atropine/Pralidoxime

Organophosphates (OPs) and carbamates (CMs) work by preventing the breakdown of acetylcholine (ACh) via antagonism of acetylcholinesterase (AChE) inhibitors. This generally follows pesticide poisoning or chemical weapons. Acetylcholine binds to and activates nicotinic and muscarinic receptors. In OP and CM toxicity acetylcholine continuously stimulates these receptors. Muscarinic receptors are found in visceral smooth muscle, cardiac muscle, and secretory glands. Nicotinic receptors are located at autonomic ganglia and at skeletal muscle motor end plates. OPs differ from CMs in that they form a covalent bond with AChE permanently inactivating the enzyme however it takes time for this specific covalent bond to be formed. The antidote to this toxicity is atropine which works by competitively binding postsynaptic muscarinic receptors allowing for the removal of acetylcholine from these receptors. It is typically administered with pralidoxime (an oxime) which reactivates AChE by removing OP and allowing for metabolization of ACh. 

Presentation consists of cholinergic overactivation symptoms – DUMBELS: Diarrhea, Urination, Muscle weakness/Miosis, Bradycardia/Bronchospasm, Emesis, Lacrimation, Salivation. Management starts with atropine and pralidroxime. Atropinization in the severely symptomatic patient should be achieved by doubling the previous dose every 5 minutes until adequate cardiorespiratory function, up to 40 mg or more in 24 hrs. Mildly or moderately symptomatic adults should receive 2 mg every 5 minutes. Pralidoxime is given concurrently with atropine doses with initial IV doses being 1.0 g for adults. The remaining management is supportive care of cholinergic clinical manifestations. 

Methanol & Ethylene Glycol – Fomepizole

These toxic alcohols can be found in antifreeze (methanol metabolizes to formic acid) and windshield washer fluid/moonshine (ethylene glycol metabolizes glycolic and oxalic acid). These toxic alcohols are metabolized via alcohol dehydrogenase and aldehyde dehydrogenase to form toxic metabolites that then cause end organ damage. Formic acid is produced from methanol metabolism and exerts its toxicity on mitochondria. Oxalic acid is formed from the degradation of ethylene glycol and it binds with calcium which accumulates within renal tubules resulting in acute kidney injury. The antidote is fomepizole to stop metabolites from being made by inhibiting alcohol dehydrogenase. 

Presentation typically consists of intoxication with an elevated anion gap metabolic acidosis and elevated osmolar gap. The patient will need dialysis if the patient has evidence of end organ damage, pH is < 7.3, and ethylene glycol lvl >50 or methanol lvl >50. Fomepizole is given as a loading dose of 15 mg/kg IV over 30 min followed by 10 mg/kg IV q12 hr for 4 doses. If the patient is started on dialysis, doses will need to be adjusted. In addition to fomepizole, we can also give magnesium, thiamine, pyridoxine for patients who likely consumed ethylene glycol and folic acid for patients who likely consumed methanol to shunt alcohol towards their non toxic metabolites. Ethanol can be used in place of fomepizole however, fomepizole binds stronger with alcohol dehydrogenase and it does not contribute to inebriation, which can complicate assessment of the patient.

Digoxin – DigiFab

Digoxin is an older cardiac glycoside antiarrhythmic drug that increases vagal tone on the heart. This drug has a narrow therapeutic range and toxicity can be acute or chronic. Digoxin inhibits sodium potassium ATPase causing intracellular sodium and extracellular potassium to increase. This change in cellular sodium is what leads to intracellular calcium increasing promoting cardiac contractility. Digoxin also increases vagal tone and shortens refractory period of the myocardium leading to bradycardia and increased automaticity, respectively. Antidote of Digoxin toxicity is digoxin-Fab (digifab) which is prepared from sheep antibodies and it possesses greater affinity for digoxin than Na-K ATPase does thereby decreasing free unbound Digoxin. As extracellular digifab binds digoxin, it equilibrates in extracellular fluid, and also promotes release of the digoxin from the receptor sites.³

Acute toxicity typically presents in younger individuals while chronic toxicity, and typically presents in older individuals usually secondary to drug-drug interactions or renal compromise. Acute toxicity in younger adults is usually due to intentional ingestion and presents with nausea, vomiting, abdominal pain, hyperkalemia, bradycardia or tachycardia, confusion, weakness, fatigue, headache, scotomata, and color vision disturbances, classically xanthopsia (yellow vision). Chronic toxicity is more gradual symptom onset with predominance of malaise and generalized weakness and can also present with hypokalemia. Both toxicities can present with dysrhythmias, the three most commonly described include paroxysmal atrial tachycardia with block, junctional AV nodal tachycardia, and ventricular tachycardia. Management is supportive care including correcting any fluid and electrolyte imbalances. It is important that hypokalemia be corrected before or during administration of digoxin-fab as it can further lower potassium. After an overdose of digoxin one should administer fab for hyperkalemia >5, hemodynamic instability, any life threatening dysrhythmia, and or cardiac arrest. For acute overdose of unknown amount give 5 to 10 vials of fab, and for chronic overdose 1 to 3 vials of fab. Fab fragment vials are given over 30 mins, unless the patient is in cardiac arrest, then it is bolused. Resolution of dysrhythmias and hyperkalemia is usually noted within 30 – 60 mins of administration however it can take several hours.

Cyanide – Hydroxocobalamin

Cyanide (CN) poisoning can result from smoke inhalation, ingestion of CN salts and cyanogenic compounds, and occupational exposures. At the cellular level, CN produces hypoxia by forming a complex with the ferric iron of cytochrome oxidase a3 within the mitochondria. This causes blockade of oxidative phosphorylation and thus aerobic respiration. Metabolic acidosis occurs due to increased ATP hydrolysis and anaerobic metabolism. Endogenous rhodanese typically helps to detoxify small amounts of cyanide in the body ( it does not have adequate sulfur donors to detoxify large amounts). The antidote to this toxicity is hydroxocobalamin which binds with CN to form cyanocobalamin (Vitamin B12).⁴

Patients will typically present with a history of occupational or environmental exposure with rapid cardiovascular collapse. Patients will have significantly elevated lactate >8-10. Management consists of administering hydroxocobalamin in anyone with suspected CN poisoning. Adult dose is 5 g via IV over 15 minutes however if you can’t obtain IV access expeditiously, it can give intraosseously as cyanide is a fast acting toxin. If hydroxocobalamin is not readily available, a Cyanide antidote kit with sodium thiosulfate and sodium nitrite can be used. However sodium nitrites (or amyl nitrite) cannot be given if there is concurrent CO poisoning as well as they can cause methemoglobinemia and impair oxygen delivery.

Beta Blocker and Calcium channel Blockers

Both of these medications are used in management of hypertension and tachydysrhythmias among other uses (and are thus commonly unintentionally or intentionally ingested at toxic doses). Beta blockers mechanism of action consist of antagonizing the beta adrenergic receptors of the sympathetic nervous system. This ultimately results in decreased chronotropy and inotropy (B1) and impaired bronchial and peripheral smooth muscle relaxation (B2). Calcium channel blockers are broken into two groups: dihydropyridines which act as peripheral vasodilators and non-dihydropyridines which reduce cardiac inotropy and chronotropy. Furthermore, CCBs impair calcium dependent insulin release (more on that later). In toxicity these therapeutic effects described are exacerbated.  ⁵

Signs of overdose of both BBs and CCBs are refractory hypotension and bradycardia. Primary hyperglycemia can support CCB toxicity diagnosis (remember calcium dependent insulin release is decreased) whereas hypoglycemia may be seen with BB toxicity. 

Primary management includes resuscitation with fluids and vasopressors if needed. Glucagon is recommended in the management of significant overdose of beta blocker toxicity as it directly activates cAMP second messenger system. This allows for another way to allow influx of extracellular calcium to intracellular cells to allow for muscle contraction. Use Glucagon 5-10 mg IV over 5 minutes to aid in reversal of hypotension and bradycardia. If no effect, repeat the dose or start infusion at rate of 5- 10 mg/hr.

Calcium infusion helps flood receptors and stabilize the cardiac membrane. You can infuse 3 g IV of calcium gluconate via slow push or 1 g of calcium chloride slow push. High dose insulin euglycemia therapy (HIET) is recommended in the management of CCB toxicity.⁶ It works by increasing glucose and lactate uptake by myocardial cells and increasing activity of Ca-dependent ATPase in sarcoplasmic reticulum. Ultimately this allows for myocardial contraction due to greater glucose availability and concentration of calcium in the cytoplasm. In HIET an initial IV bolus of 1 u/kg of regular insulin is given and followed by infusion of 1 to 10 u/kg/hr titrated to systolic bp >90 and HR >50. Obviously, starting patients on insulin necessitates tight glycemic control to make sure they don’t end up hypoglycemia.

Carbon Monoxide Toxicity (CO)

CO is absorbed from the lungs and binds to hemoglobin with much greater affinity than that of oxygen and it shifts the oxygen-hemglobin dissociation curve to the left thereby decreasing the reduced remaining oxygen there is. CO also binds to intracellular proteins and triggers immune and inflammatory mediated ischemic reperfusion injury to the brain due to generation of reactive oxygen species, lipid peroxidation, and apoptosis. 

These patients present with variable and nonspecific symptoms however primarily the brain and heart will be most symptomatic. These presentations can be more common in winter and following large power outages (people running gas or wood heaters indoors). Other key history clues are after house fires, household members with similar symptoms, patients in cars with engines running in enclosed space, hookah pipes, generators and space heaters, and beds of pickup trucks. Management of these patients includes oxygen as the first line. Hyperbaric oxygen should be strongly considered if the patient had syncope, exposure >6 hrs, age >36 yo, abnormal cerebellar function, seizure, coma, altered mental status. A COHgb level >25% requires hyperbaric oxygen.

Aspirin (ASA)/Salicylate overdose

Aspirin acts by irreversibly inhibiting cyclooxygenase which converts arachidonic acid to prostaglandins and thromboxanes. This inhibition of prostacyclin synthesis and resulting accumulation of lipoxygenase causes increased alveolar membrane permeability and pulmonary edema. Aspirin is absorbed in the small intestine where it is quickly hydrolyzed into salicylic acid. It is primarily eliminated by liver metabolism. However when hepatic metabolism is saturated it is excreted via kidneys. When salicylate concentrations continue to rise, direct stimulation of medullary chemoreceptors and respiratory center cause vomiting and hyperventilation leading to a respiratory alkalosis. As toxicity progresses, mitochondrial oxidative phosphorylation uncoupling occurs and gluconeogenesis, glycolysis, and lipid metabolism result. This leads to increased serum amino acid, carbon dioxide, and ketoacid, lactic acid, and pyruvic acid production.

Typical presenting symptoms include nausea, vomiting, abdominal pain, headache, tinnitus, tachypnea, dizziness, and lethargy. Dehydration is also usually present. Moderate poisoning will have metabolic acidosis with respiratory alkalosis, in typically 6-18 hrs. Severe poisoning includes significant anion gap metabolic acidosis coma, seizures, cerebral edema, papilledema, respiratory depression, profound dehydration. A chest x-ray may show noncardiogenic pulmonary edema. Management includes aggressive fluid resuscitation as the degree of dehydration is often underestimated. Dextrose should be given to those with altered mental status even if normal blood glucose as CNS hypoglycemia can still be present. In those with renal dysfunction and concomitant cerebral or pulmonary edema, hemodialysis is indicated. Sodium bicarbonate can also be used to alkalinize the urine, thereby trapping ASA in the renal tubules and promoting excretion.

Iron Overdose

The body cannot excrete excess iron so it is absorbed via the GI tract. Free unbound iron is toxic to tissues so normally the body keeps it bound. Excessive iron is corrosive to the GI tract which can lead to potential for hemorrhage. Iron in toxic doses accumulates mostly in the liver however, it can affect any other organ. It has a preference for accumulating in the mitochondria where it disrupts oxidative phosphorylation. It can also lead to venodilation and increased permeability and thus the acidosis seen in iron poisoning is usually due to hypovolemia and hypoperfusion causing shift to anaerobic metabolism. The ingestion of more than 20 mg of elemental iron/kg of body weight produces gastrointestinal upset. Doses of 40-60 mg/kg can be fatal.

Clinical presentation is typically in stages, first stage a few hours after ingestion is due to corrosive effects of iron on GI tract, characterized by abdominal pain, nausea, vomiting, and diarrhea. In the second stage GI issues resolve and patients may show improvement. Third stage is when systemic poisoning becomes apparent with hypovolemia, metabolic acidosis, and hepatic dysfunction. Fourth stage can occur several weeks after acute toxicity has resolved and is due to the scarring produced by irons corrosive effects. These patients typically present with SBO or gastric outlet obstruction. Management is based on patient symptom severity and amount ingested. This can include whole bowel irrigation and chelation therapy with deferoxamine.

Lead poisoning

Lead is a cation that binds strongly to sulfhydryl groups on proteins of organs throughout the body. It distorts enzymes and structural proteins. It also competes with calcium for binding sites on cerebellar phosphokinase, inhibiting flow of calcium intracellularly. It also accumulates within the mitochondria producing swelling and distortion of protein architecture thus leading to uncoupled energy metabolism, inhibition of cellular respiration. ⁷

Patients present with many nonspecific symptoms however adults tend to present with motor neuropathy, hypertension, anemia, and colicky abdominal pain. Dark blue discoloration of gingiva at dental border may be present. In the subacute presentation, neuropsychiatric manifestations also present including irritability, fatigue, and difficulty concentration. Lead poisoning in adults is classically related to occupational exposure in home restoration via inhalation or ingestion of dust or paint. Management is largely supportive however in patients with acute encephalopathy with high suspicion for lead poisoning, chelation therapy should be initiated, typically dimercaprol. If severe, EDTA can be co-administered with dimercaprol. 

Summary

This article provides an overview of several common toxicological syndromes encountered in the emergency department, focusing on those with specific antidotes or treatment options. It details the mechanism of action, clinical presentation, and management of toxicity caused by substances such as acetaminophen, opioids, organophosphates, methanol, ethylene glycol, digoxin, cyanide, beta-blockers, calcium channel blockers, carbon monoxide, aspirin, iron, and lead. The article emphasizes the importance of early recognition and prompt administration of antidotes like N-acetylcysteine for acetaminophen overdose, naloxone for opioid toxicity, and fomepizole for methanol and ethylene glycol poisoning, among others. It also highlights supportive care measures crucial for managing these toxidromes, including fluid resuscitation, electrolyte correction, and respiratory support. Keep this page favorited so you can easily find it when you have a patient you suspect had ingested or was exposed to one of the above substances.

Cite this post: Mariaelena Uceda, MD, Arman Hussain, MD. “When Bicarb and Mag Aren’t Enough – Toxicology Deep Dive”. GW EM Blog. 1/8/2025. Available at: https://gwemblog.com/tox-overview-1/

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