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125. Toxicology – Antidote: Hyperbaric Oxygen Therapy (HBOT)

Indications

Hyperbaric oxygen therapy may be considered for selected severe poisonings involving asphyxiant toxins, particularly carbon monoxide poisoning. It has also been discussed as an adjunct in severe hydrogen sulfide or cyanide toxicity, although evidence is much less established for these exposures.

Asphyxiant Toxins

Asphyxiants interfere with normal aerobic metabolism and oxygen utilization.

They can be divided broadly into:

• Simple asphyxiants: Reduce the amount of available oxygen in the surrounding environment.
• Systemic asphyxiants: Interfere with oxygen transport or prevent cells from using oxygen normally.

Examples include:

• Carbon monoxide: Forms carboxyhemoglobin and interferes with oxygen delivery
• Cyanide: Inhibits mitochondrial cytochrome oxidase
• Methemoglobin-forming agents: Oxidize hemoglobin so it cannot effectively carry oxygen
• Hydrogen sulfide: Can inhibit mitochondrial respiration in a manner similar to cyanide

Mechanism of Action

HBOT exposes the patient to 100% oxygen at pressures greater than normal atmospheric pressure, usually in a specialized hyperbaric chamber.

This greatly increases the amount of oxygen dissolved directly in the plasma, allowing oxygen delivery to tissues even when hemoglobin-dependent transport is impaired.

In carbon monoxide poisoning, HBOT also:

• Accelerates removal of carbon monoxide from hemoglobin
• Improves tissue oxygenation
• May reduce ongoing neurologic injury in selected severe cases

Clinical Use

For carbon monoxide poisoning, HBOT may be considered when significant features are present, such as:

• Loss of consciousness
• Persistent neurologic abnormalities
• Myocardial ischemia or serious cardiac involvement
• Severe metabolic acidosis
• Pregnancy with significant exposure
• Other evidence of severe poisoning

Exact indications vary, so consultation with a hyperbaric medicine specialist, poison center, or medical toxicologist is recommended.

Risks and Contraindications

Potential complications include:

• Ear or sinus barotrauma
• Oxygen toxicity
• Pulmonary barotrauma
• Claustrophobia

An untreated pneumothorax is the major absolute contraindication because increased chamber pressure can worsen trapped pleural air.

Key Points

• HBOT increases the amount of dissolved oxygen in plasma.
• Its best-established toxicologic role is in selected cases of severe carbon monoxide poisoning.
• Its role in cyanide and hydrogen sulfide poisoning is much less certain and should not delay established antidotal and supportive treatment.
• Hyperbaric treatment requires specialist consultation and access to an appropriate facility.

Toxicology – Antidotes: Atropine & Pralidoxime (2-PAM)

Indications

Atropine and pralidoxime are used for cholinergic poisoning, especially from:

• Organophosphate insecticides
• Nerve agents
• Selected carbamate insecticides

These poisonings result from excessive acetylcholine activity caused by inhibition of acetylcholinesterase.

Mechanism of Action – Atropine

Atropine is a competitive muscarinic acetylcholine receptor antagonist.

It blocks the effects of excess acetylcholine at muscarinic receptors and is especially important for treating:

• Excess bronchial secretions
• Bronchospasm
• Bradycardia
• Other muscarinic manifestations

Atropine does not reverse the underlying acetylcholinesterase inhibition and has limited effect on skeletal muscle weakness.

Mechanism of Action – Pralidoxime (2-PAM)

Organophosphates bind to and inhibit acetylcholinesterase, causing acetylcholine to accumulate.

Pralidoxime can reactivate the inhibited enzyme by removing the organophosphate from acetylcholinesterase, provided this is given before the enzyme-toxin complex undergoes “aging.”

Aging refers to a chemical change that makes the organophosphate–acetylcholinesterase bond effectively irreversible.

Pralidoxime is particularly helpful for nicotinic and neuromuscular effects, including:

• Muscle weakness
• Fasciculations
• Respiratory muscle paralysis

Management

Treatment priorities include:

• Airway and respiratory support
• Rapid atropine administration for significant secretions and respiratory compromise
• Pralidoxime for suspected organophosphate toxicity
• Benzodiazepines for seizures, marked agitation, or severe muscle activity
• Appropriate decontamination while protecting healthcare personnel from secondary exposure

Atropine may need to be repeatedly administered and titrated to improvement in airway secretions and ventilation, rather than to a fixed total dose.

Carbamate Poisoning

Carbamates generally inhibit acetylcholinesterase reversibly and for a shorter duration than organophosphates.

• Atropine remains important
• The benefit of pralidoxime is less certain, but it may be considered in severe or unclear cholinergic poisoning when organophosphate exposure cannot be excluded

Key Points

• Atropine treats muscarinic symptoms, especially excessive secretions and bronchospasm.
• Pralidoxime reactivates acetylcholinesterase before aging occurs.
• Early pralidoxime is most important in significant organophosphate poisoning.
• Severe cases may require unusually large cumulative amounts of atropine.
• Benzodiazepines are used when seizures or severe CNS manifestations occur.

Toxicology – Ipecac

Indication

No routine indication. Syrup of ipecac was historically kept in homes to induce vomiting after accidental poison ingestion, especially in children. It is no longer recommended for routine prehospital management of poisoning.

Mechanism of Action

Ipecac is derived from the roots and rhizomes of the Cephaelis ipecacuanha plant.

It causes vomiting through two main effects:

• Direct irritation of the stomach and intestinal lining
• Stimulation of the central chemoreceptor trigger zone

Why It Is No Longer Recommended

Inducing vomiting has not been shown to reliably improve outcomes after poisoning and can create additional problems, including:

• Aspiration
• Delayed administration of more effective treatments
• Prolonged vomiting
• Difficulty giving activated charcoal or other therapies

Adverse Effects

Repeated or chronic use can cause significant toxicity, including:

• Persistent vomiting
• Electrolyte disturbances
• Muscle weakness
• Cardiomyopathy

Key Points

• Ipecac should not be used routinely after toxic ingestion.
• It has largely been replaced by supportive care and more selective decontamination strategies.
• Chronic misuse can cause serious cardiac toxicity.
• Poisoning exposures should be discussed with a poison control center or medical professional rather than treated by inducing vomiting at home.

Toxicology – GI Decontamination: Whole Bowel Irrigation

Indications

Whole bowel irrigation (WBI) may be considered for selected poisonings in which a substance is expected to remain in the gastrointestinal tract for a prolonged period.

Examples include:

• Large ingestions of sustained-release or enteric-coated medications
• Certain slowly absorbed toxic substances
• Some iron or lead ingestions
• Ingestion of multiple transdermal patches
• Selected sustained-release drugs such as calcium channel blockers, theophylline, venlafaxine, or bupropion

Because evidence and indications vary, WBI should generally be discussed with a medical toxicologist or poison control center.

Mechanism of Action

WBI uses a polyethylene glycol–electrolyte lavage solution (PEG-ELS) to rapidly move gastrointestinal contents through the bowel.

PEG-ELS is designed to be essentially iso-osmotic, allowing large volumes to pass through the intestine with relatively little net fluid or electrolyte absorption.

The goal is to:

• Shorten gastrointestinal transit time
• Reduce continued absorption of substances still present in the bowel
• Promote elimination of intact tablets, drug packets, or poorly absorbed toxic material

Administration

PEG-ELS is given orally or through a nasogastric tube in a monitored setting and continued until bowel output is adequately cleared.

The exact rate and duration depend on factors such as:

• Patient size and age
• Substance involved
• Clinical condition
• Tolerance of the lavage

Important Limitations

WBI is not appropriate for every overdose and may be unsafe in patients with:

• Bowel obstruction or ileus
• Gastrointestinal perforation
• Significant GI bleeding
• Hemodynamic instability
• An unprotected airway or high aspiration risk

Key Points

• WBI is most useful when the toxic substance may remain in the gut for a long time.
• It is conceptually similar to bowel preparation used before colonoscopy, but in toxicology it is used for decontamination.
• Polyethylene glycol (PEG) is completely different from ethylene glycol, the toxic alcohol found in antifreeze.
• WBI should be used selectively and usually with toxicology guidance.

Toxicology – Antidote: Octreotide for Sulfonylurea Poisoning

Indication

Octreotide is used for sulfonylurea or meglitinide overdose, especially when recurrent or persistent hypoglycemia is occurring.

Mechanism of Action

Octreotide is a long-acting somatostatin analog that suppresses insulin release from the pancreas.

In sulfonylurea poisoning, giving dextrose raises the blood glucose but can also stimulate additional insulin secretion, causing another episode of hypoglycemia. Octreotide helps break this cycle by reducing pancreatic insulin release.

It is usually used together with dextrose to:

• Correct low blood glucose
• Reduce recurrent hypoglycemia
• Decrease the need for repeated dextrose administration

Administration

Octreotide is typically given by subcutaneous or IV dosing at repeated intervals, with the exact regimen adjusted for age, severity, and clinical response.

Treatment should be accompanied by close glucose monitoring, particularly because recurrent hypoglycemia can occur after the initial correction.

Monitoring

Important monitoring includes:

• Frequent bedside blood glucose checks
• Mental status
• Oral intake when appropriate
• Recurrence of hypoglycemia after dextrose is reduced or stopped

Key Points

• Octreotide helps prevent the cycle of repeatedly “chasing the glucose” with dextrose.
• It works by inhibiting insulin secretion, rather than simply raising blood glucose.
• Children with suspected sulfonylurea ingestion require particularly cautious observation because even small exposures can cause prolonged hypoglycemia.
• Recurrent hypoglycemia may occur for many hours, so observation is often necessary even after the glucose initially normalizes.

Toxicology – Antidote: Digoxin Immune Fab

Indications

Digoxin immune Fab is the specific antidote for severe or life-threatening cardiac glycoside toxicity. It may be considered when poisoning produces findings such as:

• Hemodynamic instability or significant hypotension
• Severe symptomatic bradycardia or advanced conduction abnormalities
• Dangerous ventricular dysrhythmias
• Significant hyperkalemia in acute poisoning
• Rapidly worsening toxicity after a major exposure

It can also bind several naturally occurring cardiac glycosides found in plants such as foxglove, oleander, dogbane, milkweed, and lily of the valley.

Mechanism of Action

Digoxin immune Fab consists of antibody fragments that bind circulating digoxin and related cardiac glycosides.

Once bound:

• Free digoxin concentrations fall
• Digoxin dissociates from its tissue receptors
• Inhibition of the Na⁺/K⁺-ATPase decreases
• The digoxin–Fab complexes are subsequently cleared from the body

This can rapidly reverse serious cardiac and systemic toxicity.

Digoxin Toxicity Mechanism

Normally, digoxin inhibits the Na⁺/K⁺-ATPase pump, increasing intracellular sodium.

This reduces the activity of the Na⁺/Ca²⁺ exchanger, causing intracellular calcium to rise. More calcium becomes available for release from the sarcoplasmic reticulum, producing digoxin’s positive inotropic effect.

At toxic concentrations, however, excessive intracellular calcium promotes abnormal automaticity and dysrhythmias. Digoxin also increases vagal activity, which slows the sinus rate and conduction through the AV node.

Administration

The amount of digoxin immune Fab required depends on factors such as:

• Whether toxicity is acute or chronic
• The estimated amount of digoxin involved
• Serum digoxin concentration when appropriately timed
• Severity of the patient’s clinical findings

In severe emergencies, empiric treatment may be given without waiting for laboratory confirmation. Dosing should follow current toxicology or poison-center guidance.

Monitoring After Fab

Monitor:

• ECG and cardiac rhythm
• Potassium
• Renal function
• Blood pressure and clinical response

Potassium may decrease rapidly as toxicity reverses, so hypokalemia can develop after treatment.

Important Laboratory Point

After an acute ingestion, a digoxin concentration obtained too early—before tissue distribution is complete—can be difficult to interpret; levels are generally most useful several hours after ingestion.

After digoxin immune Fab is administered, routine digoxin assays can measure both bound and unbound drug and may therefore show a markedly elevated total digoxin concentration that does not represent ongoing toxicity.

Key Points

• Digoxin immune Fab directly binds and neutralizes circulating cardiac glycosides.
• Severe dysrhythmias, cardiovascular instability, and significant hyperkalemia are important warning signs of serious toxicity.
• Digoxin’s increased contractility comes from increased intracellular Ca²⁺, while its slowing of heart rate and AV conduction is largely related to enhanced vagal effects.
• Do not interpret routine serum digoxin levels normally after Fab has been administered.

Toxicology – Antidote: Glucagon for Beta-Blocker Poisoning

Indication

Glucagon may be used in beta-blocker overdose, particularly when significant bradycardia, hypotension, or reduced cardiac contractility is present.

Mechanism of Action

Normally, stimulation of cardiac beta receptors activates a G protein, which stimulates adenylyl cyclase. This increases cAMP, activates protein kinase A, increases calcium entry into cardiac cells, and improves heart rate and contractility.

In beta-blocker poisoning, this pathway is blocked at the beta receptor. Glucagon can bypass the blocked receptor by activating its own receptor and stimulating adenylyl cyclase through a separate pathway.

This leads to:

• Increased cAMP
• Increased intracellular calcium
• Improved cardiac contractility
• Increased heart rate

A useful way to remember this is that glucagon activates adenylyl cyclase through a “backdoor” pathway that does not depend on beta receptors.

Administration

Glucagon is given intravenously, often as an initial bolus followed by a continuous infusion if the patient responds.

Because relatively large doses may be required in toxicologic emergencies, treatment should be directed by a poison center or medical toxicologist.

Adverse Effects

The most common adverse effect is:

• Nausea and vomiting

Antiemetic therapy may therefore be useful. Hyperglycemia can also occur.

Key Points

• Glucagon can bypass beta-receptor blockade and increase intracellular cAMP.
• It may improve bradycardia and myocardial contractility in beta-blocker poisoning.
• Vomiting is common after administration.
• In severe beta-blocker toxicity, glucagon is usually one part of a broader resuscitation strategy that may also include vasopressors and hyperinsulinemic euglycemia therapy.

Toxicology – Antidote: Hyperinsulinemic Euglycemia (HIE) Therapy

Indications

Hyperinsulinemic euglycemia therapy is used for severe calcium channel blocker (CCB) and beta-blocker poisoning, especially when there is significant myocardial depression, hypotension, or shock.

Mechanism of Action

In severe CCB and beta-blocker toxicity, the heart becomes less able to use its usual fatty-acid energy pathway and relies more heavily on glucose.

High-dose insulin helps by:

• Increasing myocardial glucose uptake
• Improving cellular energy production
• Producing a positive inotropic effect
• Improving cardiac contractility and circulation

In calcium channel blocker overdose, pancreatic insulin release may also be suppressed, producing hyperglycemia with relative hypoinsulinemia.

Administration

HIE therapy uses high-dose IV insulin together with glucose supplementation as needed to maintain normal blood glucose.

Treatment typically involves:

• An initial IV insulin dose
• A continuous high-dose insulin infusion
• Dextrose supplementation when necessary
• Gradual adjustment based on blood pressure, cardiac function, and metabolic response

Because this therapy uses insulin doses far above those used routinely for diabetes, it should be managed in a closely monitored critical-care setting.

Monitoring

Frequent laboratory and bedside monitoring is essential, especially:

• Blood glucose
• Potassium
• Other electrolytes
• Blood pressure
• Heart rate and rhythm
• Cardiac perfusion and overall hemodynamic response

Major Risks

The most important complications are:

• Hypoglycemia
• Hypokalemia

Both require active monitoring and correction during therapy.

Key Points

• HIE is an important treatment for severe CCB and beta-blocker toxicity.
• Its main benefit is improved myocardial energy utilization and contractility.
• CCB poisoning often causes hyperglycemia because calcium-channel blockade reduces pancreatic insulin secretion.
• A useful memory aid is that the poisoned myocardium is energy-starved and benefits from increased glucose utilization.
• HIE should be performed with intensive glucose, electrolyte, and cardiovascular monitoring.

Toxicology – Antidotes: Chelating Agents

Overview

Chelators bind specific toxic metals and form complexes that can be eliminated from the body, usually through the urine. The appropriate agent depends on the metal involved and the severity of poisoning.

Succimer (DMSA)

Binds: Lead, arsenic, and mercury.

Mechanism of Action

• Water-soluble compound related to dimercaprol (BAL)
• Contains sulfhydryl groups that bind toxic metals
• The resulting complexes are primarily excreted in urine
• Has only limited effectiveness for cadmium removal

Succimer is commonly used as an oral chelator, particularly for selected cases of lead poisoning.

DMPS (2,3-Dimercapto-1-Propanesulfonic Acid)

Binds: Mercury and arsenic; it can also bind lead.

Mechanism of Action

• Water-soluble dimercaprol-related chelator
• Sulfur-containing groups bind metal ions
• Metal-chelator complexes are eliminated mainly through the kidneys

Availability and approved indications vary by country.

Penicillamine

Binds: Primarily copper; it has also been used in selected cases involving other metals.

Mechanism of Action

• A penicillin-related compound without antibacterial activity
• Acts as a thiol-containing chelator
• Binds free copper and reduces its ability to participate in damaging oxidation-reduction reactions
• Excreted in urine

It is particularly associated with treatment of copper overload, including Wilson disease.

Calcium Disodium EDTA (CaNa₂EDTA)

Binds: Lead.

Mechanism of Action

• Primarily acts in the extracellular compartment
• Binds circulating lead and promotes its urinary elimination
• As circulating lead decreases, additional lead can redistribute from tissues into the blood and become available for chelation

The calcium disodium form is used for lead poisoning; plain disodium EDTA can cause dangerous hypocalcemia.

Deferoxamine (DFO)

Binds: Iron.

Mechanism of Action

• Chelates free ferric iron
• Forms the water-soluble complex ferrioxamine
• Mainly targets free or loosely bound iron rather than iron incorporated into hemoglobin
• The complex is eliminated through urine

Deferoxamine is an important antidote for significant acute iron poisoning.

Dimercaprol (BAL – British Anti-Lewisite)

Binds: Arsenic, mercury, and lead; historically developed for the arsenical warfare agent Lewisite.

Mechanism of Action

• Contains sulfhydryl (–SH) groups that bind toxic metals
• Prevents metals from interacting with sulfhydryl-containing cellular proteins
• Metal-chelator complexes are eliminated primarily through urine

Key Points

• Lead: Succimer or CaNa₂EDTA; dimercaprol may be added in severe cases.
• Arsenic/Mercury: Dimercaprol, succimer, or other specialist-selected thiol chelators.
• Copper: Penicillamine.
• Iron: Deferoxamine.
• Chelation should be guided by the specific metal, blood concentration, clinical severity, and toxicology consultation.

Toxicology – Antidote: Intravenous Lipid Emulsion (ILE)

Indications

Intravenous lipid emulsion may be considered as a rescue therapy for severe cardiovascular toxicity caused by highly lipophilic drugs, particularly when standard resuscitative measures are failing.

The strongest evidence is for local anesthetic systemic toxicity, especially with agents such as bupivacaine. It has also been used in selected severe poisonings involving drugs such as:

• Tricyclic antidepressants
• Calcium channel blockers
• Beta-blockers
• Bupropion
• Lamotrigine
• Some antipsychotics and other lipophilic toxins

Its use outside local anesthetic toxicity is generally based on case reports and specialist toxicology judgment.

Mechanism of Action

The exact mechanism is not fully established. Proposed effects include:

• Lipid shuttle/sink effect: Lipophilic toxins redistribute from target tissues into the intravascular lipid phase, potentially reducing drug availability at the heart and other organs.
• Metabolic support: Fatty acids may provide an additional energy source for cardiac muscle and improve myocardial performance.

Administration

A 20% lipid emulsion is typically used. Exact dosing depends on the clinical situation and local toxicology protocols, and treatment should ideally be guided by a medical toxicologist or poison center.

Management Considerations

ILE is generally reserved for:

• Severe hypotension
• Malignant dysrhythmias
• Cardiovascular collapse
• Cardiac arrest associated with a suspected lipophilic toxin

It should be used alongside standard airway management, cardiac monitoring, and advanced resuscitative care rather than as a replacement for them.

Risks

Potential complications include:

• Hypertriglyceridemia
• Pancreatitis
• Interference with laboratory testing
• Pulmonary complications
• Thrombosis or impaired microcirculatory flow with very large lipid loads

Key Points

• ILE is best established for severe local anesthetic systemic toxicity.
• Evidence for many other poisonings is limited and often case-based.
• It is generally considered a rescue therapy, not first-line treatment for most overdoses.
• Specialist toxicology consultation is strongly recommended when considering its use.