Morbidity and mortality from childhood poisoning have decreased
in the last few decades. This decrease can be credited to the development
of poison control centers with a sophisticated poison management
database, new governmental regulations, widespread use of child-resistant
enclosures for medications, safer packaging for consumer products,
public education and anticipatory guidance, and a growing understanding
of the environmental and pharmacologic foundations of toxicology.
In particular, poison control centers provide immediate and expert
advice from trained specialists in poison information to aid the
practitioner in the management of poisoned patients. In the United
States, 1-800-222-1222 is the nationwide toll-free number connecting
any caller to an American Association of Poison Control Center regional poison
center. A clinical toxicologist is available on request to provide
consultation regarding decontamination, antidotes or other medical
treatment, selection of appropriate laboratory tests, and enhanced
The goal of poison prevention programs is to prevent pediatric
poisoning through legislation and educational strategies such as
parental anticipatory guidance during well-child visits (Table 120-1). Brochures and other poison
prevention materials can be obtained from local poison centers or
the American Academy of Pediatrics. Legislative initiatives such as
the Poison Prevention Packaging Act have been instrumental in decreasing
the impact of childhood poisoning.
120-1. Poison Prevention Strategies ||Download (.pdf)
120-1. Poison Prevention Strategies
|Install child-proof locks on cabinets and drawers
that contain dangerous materials.|
|Keep all medicines in child-proof containers and
placed in a locked cabinet.|
|Discard old medications.|
|Keep all medications and chemicals in labeled
|Keep alcohol and cigarettes away from the reach
|Remove poisonous plants from the home and yard.|
|Ask visitors and relatives to place medications
where the child cannot reach them and not in a purse or suitcase. |
|Keep the numbers of the local poison control
center and emergency department by the telephone.|
Young children usually have little difficulty finding toxic substances.
Personal-care products and cleaning substances are the most common
agents involved in household intoxications, though pharmaceutical
products are responsible for the majority of fatalities. Analgesics
are the most common pharmaceutical exposure.
There are fewer adolescent exposures reported to poison centers
compared with younger children. Most adolescent poisonings are intentional,
and involve greater amounts of toxin, as well as exposure to multiple
agents. Exposures in the younger child are usually unintentional. Delayed
presentation for medical attention can also complicate medical care.
As a consequence, adolescent poisonings often result in more serious
the Poisoned Patient
Determining the type of toxin involved guides therapy. The presumptive
diagnosis can often be made using information from the history, vital
signs, and physical examination before extensive laboratory results
The type of toxin, timing, amount, and route of exposure are
ascertained by asking the patient, family members, or other sources.
The circumstances of the exposure and history of psychiatric illness
help determine the risk for intentional harm. Potentially toxic
household products such as automotive and cleaning products should
not be overlooked. Paramedics provide important information about
the scene of exposure and progression of the patient’s
signs and symptoms. The poison center can aid in the identification
of unknown pills.
Toxidromes or “toxic syndromes” are characteristic
vital signs and physical findings that indicate the presence of
a specific category of toxins (Table 120-2).
Toxidromes are especially helpful when the patient
has been exposed to a single toxin. Exposure to multiple substances can
obscure the clinical diagnosis, whereas other disease processes
may mimic the toxidromes. Stimulation or inhibition of specific
receptors in the autonomic and somatic nervous systems results in
the classic toxidromes (eFig. 120.1).
The opioid toxidrome results from stimulation of opiate receptors
in the central nervous system. Withdrawal syndromes are associated
with sudden abstinence after chronic use of sedative-hypnotic drugs
120-2. Common Toxidromes ||Download (.pdf)
120-2. Common Toxidromes
|Anticholinergic (antidepressants, anti-parkinsonism, antihistamines, antipsychotics, atropine)||Sympathomimetic (cocaine, amphetamines, etc) Flight-or-Fight Response|
|Delirium (mad as a hatter)||Agitation|
|Dry skin (dry as a bone)||Diaphoresis|
|Flushed skin (red as a beet)||Hypertension|
|Hyperthermia (hot as a hare)||Hyperthermia|
|Mydriasis (blind as a bat)||Seizures|
|Urinary retention||Sedative-Hypnotic Withdrawal (from ethanol, benzodiazepines, barbiturates)|
|Cholinergic—Muscarinic (organophosphates, carbamates, pilocarpines)||Anxiety||Cardiovascular collapse|
|Mnemonic: DUMBELLS||Hypertension →||Delirium|
|Miosis||Opioid Withdrawal |
|Bradycardia, bronchorrhea, bronchoconstriction||Psychologic||Physical|
|Cholinergic—Nicotinic (organophosphates, carbamates, nicotine, coniine)||Hallucinations||Increased bowel motility|
|Mnemonic: Days of the Week||Paranoia||Piloerection|
|Thursday: Tremors, hypertension||Vomiting|
Stimulation or inhibition of specific receptors in the
autonomic and somatic nervous systems results in the classic toxidromes,
manifested by specific symptoms. (Abbreviations: Ach, acetylcholine; nAChR,
nicotinic acetylcholine receptor; mAChR, muscarinic acetylecholine
receptor; NE, norepinephrine; Epi, epinephrine; α,
alpha-adrenergic receptor; β, beta-adrenergic receptor.)
Basic laboratory evaluation provides valuable information for
the diagnosis and management of the poisoned patient. An arterial
blood gas demonstrating an acid–base disturbance can narrow
the differential diagnosis. The electrolyte values will determine
if there is an elevated anion gap metabolic acidosis suggesting
the presence of a specific type of toxin (Table
120-3). The anion gap is estimated using serum mEq/L
Table 120-3. Causes
of High Anion Gap Metabolic Acidosis ||Download (.pdf)
Table 120-3. Causes
of High Anion Gap Metabolic Acidosis
|Lactic Acidosis||Non–Lactic Acid Metabolic Acidosis|
|Acetaminophen (levels > 600 mg/dL)||Exogenous organic and mineral acids|
|Beta-adrenergic receptor agonists||Formaldehyde (formic acid)|
|Biguanides (metformin/phenformin)||Ibuprofen (propionic acid)|
|Carbon monoxide||Ketoacidosis (alcoholic, diabetic, starvation)|
|HAART (highly active antiretroviral therapy)||Metaldehyde|
|Salicylates (salicylic acid)|
|Hypoxia||Toxic alcohols (methanol/ethylene
|Methylxanthines (caffeine, theophylline)||Valproic acid|
[Na+] – ([Cl–] + [HCO3–])
where the bracketed symbols represent the serum concentrations
of sodium, chloride and bicarbonate. An anion gap of 8 to 12 mEq/L
is considered normal. An elevated anion gap suggests the presence
of an unidentified negatively charged molecule in the serum, which may
represent a toxin or a byproduct of the intoxication, such as lactate.
If there is an unexplained metabolic acidosis, obtaining serum
osmolarity, electrolytes, blood urea nitrogen (BUN), and glucose
and then calculating the osmolar gap can aid in diagnosis. An elevated
anion gap metabolic acidosis accompanied by an elevated osmolar
gap suggests toxic alcohol poisoning. The osmolar gap is calculated
Measured serum osmolality – Calculated serum osmolality
The measured serum osmolality is determined on a sample sent
to the laboratory. The calculated osmolality can be estimated by
the following formula:
2[Na] + [Glucose]/18 + [BUN]/2.8
An osmolar gap of 10 is considered normal. An elevated osmolar
gap indicates the presence of a low-molecular-weight and osmotically
active substance such as methanol or ethylene glycol in the blood.
A normal osmolar gap does not eliminate the possibility of toxic
alcohol poisoning if the alcohol has already been converted into
Quantitative blood tests are ordered for specific drugs or toxins whose serum concentration can
guide therapy or predict toxicity. In cases of unknown ingestions,
serum acetaminophen and salicylate levels are obtained because these
poisonings are common and early diagnostic clues may be absent.
Toxicology screens should only be ordered when the result is
expected to influence patient management. Urine drug-of-abuse screens
detect several common illicit drugs, but are usually not necessary
in the initial management of the intoxicated patient. The history
and clinical toxidrome are usually adequate to narrow the differential
diagnosis and guide management decisions. Comprehensive blood or
urine toxicology screens have a longer turnaround time and qualitatively
detect only 40 to 100 specific drugs. They will not affect emergency
management, but may be helpful to the admitting physicians when
the patient’s diagnosis remains unclear and the clinical
course is complicated.
Abdominal radiographs aid in the visualization of certain substances
such as bezoars, radio-opaque medications, metals, and drug-filled packets.
Serial abdominal radiographs are useful to assess gastrointestinal
decontamination in such patients.
Initial treatment follows the same principles applied to other
life-threatening conditions. Decreased respiratory effort, airway
obstruction, and severe respiratory distress are indications for endotracheal
intubation and mechanical ventilation. Judicious use of an opioid
antagonist may restore normal breathing, precluding the need for
endotracheal intubation. Intravenous access should be obtained promptly,
and cardiovascular dysfunction corrected with intravenous fluids and
pharmacologic support. Appropriate monitoring includes measurement
of temperature, respiratory rate, oxygen saturation, heart rate, blood
pressure, and electrocardiogram.
The goals of decontamination are to prevent the absorption of
a toxin from the gastrointestinal tract and to remove a toxic substance from
the skin or eyes. Decontamination is most effective immediately
after exposure and the benefit decreases with passage of time.
Ocular and Dermal Decontamination
Immediate and thorough irrigation with tap water or normal saline
may ameliorate injury following ocular and dermal exposures. Contact
lenses are removed and irrigation of the eyes performed rapidly
to prevent ocular damage. The patient’s clothing, jewelry,
and other items should be removed for dermal decontamination and
care is required to protect health-care staff from secondary toxin
Syrup of ipecac is a potent emetic that is no longer recommended
as a home remedy for ingestions. The efficacy of syrup of ipecac
in improving clinical outcomes remains unproved, and its use may
delay the use of other decontamination techniques such as activated
Activated charcoal administered into the gastrointestinal tract
binds most toxins, decreasing systemic absorption. It is ineffective
for iron and other metals, lithium and other small ions, cyanide,
alcohols, and most caustics. The dose of activated charcoal is 1
g/kg by mouth or via nasogastric tube for children and
50 to 100 g for adolescents and adults. A potential complication
of charcoal administration is pulmonary aspiration. If a nasogastric
tube is necessary, consideration must be given as to whether the expected
benefit exceeds the risk. Patients with protracted vomiting are
not candidates for activated charcoal, and those with decreased
consciousness or undergoing sedation should not receive charcoal
unless the airway has been protected with an endotracheal tube.
Orogastric lavage should be considered in patients who present
to medical attention within one to two hours after ingestion of
a potentially lethal toxin. It is not routinely recommended for
all overdose patients due to the risk of complications, including
visceral perforation, tracheal placement of the orogastric lavage
tube, and aspiration of vomit. Contraindications include a patient
with depressed mental status and an unprotected airway and ingestion
of a caustic or hydrocarbon. A large bore lavage tube (pediatrics,
16–28 Fr; adults, 36–40 Fr) is placed orogastrically
with the patient in the left lateral decubitus position to optimize
gastric decontamination and reduce the risk of aspiration. The stomach
is lavaged with 50 to 250 mL aliquots of water or saline until clear
of residual toxin.
Whole bowel irrigation reduces the absorption of ingested toxins
by decreasing gastrointestinal transit time. Polyethylene glycol
electrolyte solution is administered via nasogastric tube at rates
of 25 to 40 mL/kg/hour for children and 1.5 to
2 L/hour for adults until rectal effluent is clear. Whole
bowel irrigation should be stopped if no rectal effluent occurs after
several hours. Indications include ingestion of delayed-release
medications, substances not adsorbed by charcoal, or drug-filled packages
in drug smugglers (“body packers”).
Enhanced elimination procedures hasten the excretion of toxins
from the systemic circulation at a rate greater than endogenous
clearance. Interventions include urinary alkalization, multiple-dose
activated charcoal, hemodialysis, and hemoperfusion.
Multiple-dose activated charcoal enhances elimination and decontaminates
the gastrointestinal tract by: (1) disrupting enterohepatic recirculation
of the toxin; (2) utilizing the intestinal mucosa as a dialysis
membrane (“gut dialysis”) to draw the toxin from
the bloodstream into the intestinal lumen; and (3) binding any toxin
present in the gut. It enhances elimination of phenobarbital, salicylate,
quinidine, theophylline, carbamazepine, and dapsone. The dose of
activated charcoal without cathartic administration is 0.5 to 1
g/kg by mouth or via nasogastric tube every 4 hours. It
should be discontinued if ileus develops. Complications include
charcoal aspiration, formation of charcoal bezoars, and intestinal obstruction.
Urinary alkalinization enhances elimination of drugs that are
weak acids by trapping the ionized drug in the renal tubule, where
it is subsequently excreted in the urine (eFig.
120.2). Salicylate poisoning is the
most common indication for urinary alkalinization. Sodium bicarbonate
is administered in a dose of 1 to 2 mEq/kg intravenously
followed by a continuous infusion titrated to a urinary pH of 7.0
to 8.0. Hypokalemia must be corrected because it impedes urinary
alkalinization as potassium is reabsorbed in exchange for hydrogen
Urinary alkalinization (ion trapping). Urinary alkalinization
is used to enhance the urinary excretion of weak acids, especially
salicylates. Most drugs are partially dissociated at physiologic
pH in a proportion that is determined by the drug’s dissociation
constant (pKa) and the pH of the medium in which the drug is dissolved.
Cell membranes are more permeable to substances that are in the
nonionized form. The ionization of a weak acid (HA) is increased
in an alkaline environment. An increase in urine pH increases the
proportion of drug in the ionized form, thereby reducing the drug’s
rate of diffusion from the renal tubule lumen back into the blood.
This causes the weak acid to be trapped in the urine and excreted
from the body.
Hemodialysis can be utilized to correct fluid, electrolyte, and
acid–base imbalances and to hasten the removal of some
toxic substances from the blood. It is effective for toxins with small
volumes of distribution (< 1.0 L/kg), low molecular
weight, and low protein binding (Table 120-4).
Additional indications include a blood level of
the toxin associated with severe toxicity or death, impairment of
the natural mechanism of elimination, deteriorating clinical condition
despite maximal supportive care, and toxins with severe delayed
120-4. Agents Removed by Hemodialysis ||Download (.pdf)
120-4. Agents Removed by Hemodialysis
|Mnemonic: I STUMBLE|
Hemoperfusion is similar to hemodialysis except for substitution
of the dialysis membrane by a cartridge containing an adsorbent material
such as charcoal. Hemoperfusion often achieves greater clearance
rates than hemodialysis and is more effective for larger molecules
because there is no ultrafiltration.
An antidote is an agent that prevents or reverses the effects
of poisoning. Most are dispositional antidotes that decrease toxicity
by altering absorption, distribution, metabolism, or elimination.
Competitive antagonists interfere with the toxin binding to receptor
sites. Physiologic antagonists alter the physiologic effect of the
toxin. Antidotes are available for a very limited number of poisonings
and do not replace meticulous supportive care and good clinical
judgment. The risks and benefits of each antidote must be carefully
Asymptomatic patients with a potential toxic exposure are observed
4 to 8 hours from the time of exposure. If symptoms develop, the
patient is admitted to the hospital for further management. Any
patient with severe toxicity will require admission to an intensive
care unit. A longer observation period is required for toxins with
delayed onset of action such as sustained-release products, agents
that are converted into toxic metabolites, and drugs with delayed
distribution into the tissue compartment. Cellular injury may begin
early with delayed onset of overt symptoms, such as with acetaminophen.
All poisonings in children require social evaluation to determine
home safety and provide poison prevention education. Patients may have
been intentionally poisoned as a form of physical abuse or for purposes
of sexual exploitation. Any intentional overdose warrants psychiatric
evaluation to evaluate suicidal intent. Patients with chemical dependency
are referred to an appropriate treatment program.
or APAP), a widely used analgesic and antipyretic agent, is responsible
for 10% of all calls to poison control centers. After therapeutic
dosing, acetaminophen undergoes glucuronidation and sulfation in
the liver prior to urinary and bile excretion (see Fig.
120-1). A small percentage is oxidized in the hepatocytes by
the cytochrome P450 system of CYP oxidases to produce N-acetyl-p-benzoquinoneimine
(NAPQI), a highly reactive two-electron species that can act as
an oxidant and thus is highly cytotoxic. NAPQI is eliminated by
conjugation to the reduced form of glutathione (GSH), and the resulting
APAP-GSH conjugate is eliminated as mercapturic and cysteine conjugates.
After an overdose, however, the amount of NAPQI generated can exceed
the capacity of this detoxification mechanism. NAPQI then accumulates
in the hepatocytes and toxicity ensues (Fig. 120-1).
Acute ingestion of more than 150 to 200 mg/kg in children
or 7.5 g in adults is potentially hepatotoxic. Chronic or subacute
overdose also results in liver injury.
Mechanism of acetaminophen (N-acetyl-p-aminophenol
or APAP) toxicity. See text for details.
The clinical presentation of acute acetaminophen toxicity is
described in 4 phases. Phase I occurs during the
first few hours after ingestion, and is characterized by gastrointestinal
symptoms of nausea, vomiting, and abdominal pain, but some patients
are asymptomatic. Phase II occurs within 24 hours
as the acute gastrointestinal symptoms subside. The onset of hepatotoxicity
is manifested by upper-right quadrant abdominal tenderness and elevation
of laboratory markers of liver injury such as transaminases and
prothrombin time (PT). Phase III is the period
of maximal hepatotoxicity, usually occurring within 72 to 96 hours.
In mild cases, spontaneous recovery occurs. In severe cases, fulminant
hepatic failure is manifested by coagulopathy, encephalopathy, and
coma. Fatalities typically occur between 3 and 5 days because of
multiorgan failure, hemorrhage, respiratory failure, sepsis, and
cerebral edema. Phase IV is the period of hepatic
recovery, which may take a week or longer, depending on the severity
of the liver injury.
Treatment decisions are guided by plotting the serum acetaminophen
concentration on the Rumack-Matthew nomogram (Fig.
120-2) at 4 hours or later after an acute ingestion. In the United
States, the usual recommendation is to initiate antidotal therapy
if the acetaminophen level is above the lower (possible hepatotoxicity)
line on the nomogram because this is the safer course of action.
Antidotal therapy with N-acetylcystine (NAC) should
be started within 8 hours of drug ingestion because its efficacy
for preventing fulminant hepatic failure diminishes thereafter.
Rumack-Matthews nomogram showing the risk of hepatotoxicity
based on the relationship between plasma acetaminophen concentration
and time after ingestion. The range between the red lines represents
a 25% chance of clinically significant disease.
NAC functions both as a glutathione precursor to replenish depleted
glutathione stores and as a glutathione substitute that directly
binds to NAPQI. In addition, NAC facilitates the sulfation pathway
of acetaminophen metabolism. The oral NAC protocol consists of a
loading dose of 140 mg/kg followed by 17 subsequent doses
of 70 mg/kg administered every 4 hours over a 72-hour period.
Treatment may be discontinued at 24 hours if there has been no elevation
of liver transaminases and acetaminophen is no longer detectable
in the serum. There are several intravenous N-acetylcysteine regimens
that have been utilized, including 21-, 36-, and 48-hour protocols.
The commonly used 21-hour protocol consists of a loading dose of
150 mg/kg administered over 1 hour, followed by an additional
50 mg/kg over the next 4 hours, and a subsequent 100 mg/kg over
the next 16 hours.1
Laboratory monitoring includes measuring the serum acetaminophen
level, liver transaminases, electrolytes, blood urea nitrogen, creatinine,
and prothrombin time. Patients with severe hepatotoxicity require
early evaluation for liver transplantation.
Warfarin (Coumadin) was initially used as a rodenticide before
its therapeutic applications were recognized. Rats and mice quickly
became resistant, prompting the development of more potent second-generation
superwarfarins. Rodenticides are typically marketed in very low
concentration pellets, requiring multiple exposures to exterminate
the rodent. These compounds inhibit vitamin K, a cofactor required
for the synthesis of coagulation factors II, VII, IX, and X.
The typical clinical scenario for warfarin ingestion would be
a toddler who has ingested a small amount of rodenticide. In this
situation, no significant anticoagulation is expected, and no interventions
are required.2 In contrast, larger ingestions with
suicidal intent or chronic exposures may result in poisoning. The anticoagulant
effect will not be seen until the circulating clotting factors have
been degraded, which may take 1 to 2 days. Excessive anticoagulation
results in ecchymoses, bleeding gums, subconjunctival hemorrhage,
hematemesis, melena, or hematuria. In severe cases, intracranial
hemorrhage or gastrointestinal bleeding is life threatening. The
duration of effect after a single dose of warfarin is 2 to 7 days, whereas
coagulopathy from superwarfarin poisoning often persists for months
due to an extremely long elimination half-life.
Laboratory monitoring includes evaluation of the prothrombin
time (PT) and International Normalized Ratio (INR). A normal PT
48 hours after ingestion rules out poisoning. With more significant
exposures, a complete blood count, blood type, and crossmatch are
obtained. Severe hemorrhage is treated with fresh-frozen plasma, packed
red blood cells, and other blood products as needed. Administration
of vitamin K1 (phytonadione) allows regeneration of clotting
factors, but peak effect may take 24 hours or longer. Prolonged
coagulopathy may require repeated administration of vitamin K1 and
fresh-frozen plasma. Vitamin K1 is recommended for documented
coagulopathy, but should not be administered prophylactically because
it will mask the development of toxicity and make the end point
of treatment difficult to assess.
The anticonvulsants are a diverse group of medications with different
mechanisms of action and toxicities in overdose. They are used for
seizure control and other conditions such as mood disorders and
refractory pain syndromes. Carbamazepine, phenobarbital, phenytoin,
and valproic acid are most commonly responsible for acute intoxications.
Carbamazepine’s primary therapeutic mechanism of action
is sodium channel inhibition in the central nervous system. Toxic
manifestations after an overdose are similar to those produced by
tricyclic antidepressants, with which carbamazepine has structural
analogies, resulting in central nervous system depression, anticholinergic
effects, and myocardial sodium channel inhibition. Induction of
vasopressin secretion may result in the syndrome of inappropriate
secretion of antidiuretic hormone.
Elevated serum carbamazepine levels are associated with neurologic
abnormalities including nystagmus, ataxia, dysarthria, myoclonus, and
dystonia. Levels above 40 mg/dL are associated with severe
toxicity, including coma, respiratory depression, and seizures.
Cardiovascular disturbances include tachycardia, hypotension, myocardial
depression, and cardiac conduction abnormalities such as prolongation of
the QRS complex and QT interval. Mydriasis, hyperthermia, ileus,
and other signs of cholinergic inhibition may occur.
Monitoring after an ingestion should include obtaining serum
carbamazepine level every 4 to 6 hours until a downward trend is
established. Serum electrolytes should be checked for hyponatremia
and electrocardiogram monitoring helps detect cardiotoxicity. Treatment
is supportive. Enhanced elimination procedures may be considered
in patients with severe toxicity that is not responsive to standard
Barbiturates depress central nervous system function by enhancing
the neuronal inhibition mediated by gamma-aminobutyric acid (GABA).
Supratherapeutic serum phenobarbital levels are associated with
progressive ataxia, dysarthria, nystagmus, sedation, coma, hypothermia,
and respiratory depression. Decreased sympathetic tone results in
bradycardia and hypotension. A serum phenobarbital level should
be obtained serially until it is documented to be decreasing. Treatment
is supportive. Enhanced elimination may benefit patients with severe
toxicity refractory to supportive care.
Phenytoin and fosphenytoin are nonsedating at therapeutic doses.
Phenytoin decreases the activity of neuronal voltage-dependent sodium channels,
resulting in suppression of seizure activity. Excessive doses result
in ataxia, nystagmus, diplopia, dysarthria, confusion, coma, and respiratory
depression. Cardiotoxicity has not been reported following oral
overdoses of phenytoin, although rapid intravenous administration
may cause bradycardia and hypotension.
Phenytoin is poorly water soluble, and the intravenous preparation
requires a solution of 40% propylene glycol and 10% ethanol
at a pH of 12. Rapid infusion (> 50 mg/min phenytoin) results
in myocardial depression and decreased peripheral vascular resistance
largely owing to propylene glycol. Local irritation and tissue damage
may be caused by the propylene glycol and the alkaline pH of the
intravenous formulation. Fosphenytoin is a water-soluble product that
is converted into phenytoin following intravenous administration.
It is buffered to a pH of 8 to 9 and does not contain propylene
glycol, allowing rapid intravenous administration (up to 150 mg/min
of phenytoin equivalents). However, excessive doses of fosphenytoin
have been reported to cause myocardial depression.
A serum phenytoin level should be obtained serially until a downward
trend is documented. Management is supportive. Multiple-dose activated
charcoal may enhance the elimination of phenytoin, but is usually
not necessary because of the success of supportive care alone.
Valproic acid inhibits voltage-gated sodium channels and increases
GABA levels in the central nervous system, resulting in central nervous
system depression. In addition, valproic acid interferes with fatty
acid metabolism by causing carnitine deficiency, impaired mitochondrial
beta-oxidation, and disruption of the urea cycle.
Patients with valproic acid toxicity present with confusion and
lethargy, which may progress to coma, cerebral edema, and respiratory
failure. Severe toxicity includes hypotension, metabolic acidosis,
hypernatremia, hypocalcemia, pancreatitis, hepatic injury, hyperammonemia,
renal insufficiency, and bone marrow suppression. Elevated ammonia
levels result in valproate-induced hyperammonemic encephalopathy, characterized
by altered mental status, focal neurologic abnormalities, and seizures.3
A serum valproic acid level is obtained serially until a downward
trend is established. Other useful laboratory studies include blood gas analysis,
complete blood count, serum electrolytes, glucose, blood urea nitrogen,
creatinine, calcium, liver transaminases, bilirubin, prothrombin
time, lipase, amylase, lactate, ammonia, and carnitine. Treatment
with carnitine is recommended if hyperammonemia, hepatotoxicity,
or carnitine deficiency is present. Enhanced elimination techniques
may be considered in patients with severe toxicity.
The antipsychotic medications are classified as typical or atypical
(Table 120-5). The typical antipsychotics
were introduced in the 1950s. Soon they were associated with serious adverse
effects including extrapyramidal syndromes (particularly dyskinesia
in children), tardive dyskinesia, and neuroleptic malignant syndrome. Noncompliance
and treatment failures were common. Some of these medications are
nowadays prescribed because of their non-psychoactive properties,
such as the antiemetic effect of promethazine.
Table 120-5. Classification
of Selected Antipsychotic Agents ||Download (.pdf)
Table 120-5. Classification
of Selected Antipsychotic Agents
The atypical antipsychotics were developed to overcome the shortcomings
of the traditional antipsychotic medications, and were first marketed
in the 1980s. They are less likely to cause extrapyramidal syndromes
or tardive dyskinesia and they are less toxic following acute overdose.
The therapeutic mechanism of typical antipsychotic agents is
antagonism of D2-dopaminergic receptors in the mesolimbic system.
However, nonselective antagonism of D2 receptors in other
dopaminergic pathways may result in extrapyramidal side effects,
including acute dystonia, akathisia, parkinsonism, neuroleptic malignant
syndrome, and tardive dyskinesia. Adverse cardiovascular effects
include alpha-adrenergic receptor antagonism, blockade of myocardial
sodium channels, and inhibition of the delayed rectifier current.
Typical antipsychotics can have anticholinergic activity and cause
lowered seizure threshold and impaired temperature regulation.
Atypical antipsychotics are more selective antagonists of mesolimbic
D2 receptors with a lower binding potency, resulting in
fewer extrapyramidal side effects. Therapeutic benefit also results
from blockade of serotonergic 5-HT1A and 5-HT2A receptors.
Adverse effects are due to inhibition of α-adrenergic,
H1 histamine, and M1 muscarinic receptors.4
The clinical presentation of mild intoxication includes confusion,
sedation, vagolysis, and orthostatic hypotension with reflex tachycardia. Severe
overdoses result in coma, seizures, respiratory arrest, and hypothermia
or hyperthermia. Hypotension occurs secondary to impaired myocardial
contractility and peripheral vasodilation. Conduction abnormalities
owing to impaired sodium and potassium channel activity include
widened QRS and QTc interval prolongation. Ventricular tachycardia
including torsade de pointes may result.
Extrapyramidal dystonic reactions include tremor, rigidity, bradykinesia,
and spasms of the muscles of the eyes (oculogyric crisis), face,
tongue, lips, jaw, neck (torticollis), abdomen (tortipelvis), and
spine (opisthotonus). Neuroleptic malignant syndrome (NMS) is a life-threatening
condition characterized by altered mental status, muscular rigidity,
hyperthermia, and autonomic dysfunction.
Diagnosis is based on the clinical presentation. Quantitative
blood levels are not routinely available. Comprehensive urine toxicology screens
may detect only phenothiazines. Continuous electrocardiogram monitoring
is essential to detect cardiac conduction abnormalities and dysrhythmias.
Management is primarily supportive. Specific interventions include
sodium bicarbonate for treatment of myocardial sodium channel blockade
and QRS interval prolongation and magnesium infusion or overdrive
pacing for treatment of torsade de pointes. Dystonic reactions are treated
with diphenhydramine or benztropine. Management of neuroleptic malignant
syndrome requires aggressive cooling measures, intravenous hydration,
advanced airway management as indicated, and intravenous benzodiazepines
for sedation and muscle relaxation. Dantrolene (a muscle relaxant)
and bromocriptine (a dopamine agonist) may be of benefit in the
treatment of neuromalignant syndrome.
and Calcium Channel Blockers
Beta-adrenergic blocker (BB) and calcium channel blocker (CCB)
medications are discussed together because of similarities in clinical
presentation and management after overdose. Many of these similarities
are owing to their common effect of inhibiting the influx of calcium
into myocardial cells, where it participates in physiologic signaling
and other critical processes. Severe poisoning is difficult to treat
and is associated with significant morbidity and mortality.
Beta-blockers inhibit the binding of catecholamines to β-adrenergic
receptors. Normally, myocardial β1-adrenergic
receptor stimulation results in activation of adenyl cyclase, which
catalyzes the formation of cyclic adenosine monophosphate (cAMP),
which in turn promotes phosphorylation and opening of calcium channels.
Blockade of cardiac β1-adrenergic receptors
results in decreased chronotropy and inotropy. Blockade of noncardiac β2-adrenergic receptors
antagonizes bronchial and smooth muscle relaxation, and also causes
hypoglycemia by inhibition of glycogenolysis and gluconeogenesis.
Calcium channel blockers bind to and inhibit the influx of calcium
through the L-type calcium channels of myocardial cells, resulting
in decreased chronotropy and inotropy. Antagonism of similar vascular
smooth muscle calcium channels results in coronary and peripheral
vasodilation. Calcium-mediated insulin release from pancreatic β-islet
cells is inhibited. This prevents myocardial cells from utilizing
glucose as an energy source, resulting in further myocardial dysfunction.
The resulting shock state resembles diabetic ketoacidosis, with
hyperglycemia and acidemia.
The hallmark of beta-blocker and calcium channel blocker poisoning
is cardiovascular depression manifested by bradycardia, heart block,
impaired cardiac contractility, hypotension, and profound shock.
A widened QRS duration may be caused by beta-blockers such as propranolol
that also inhibit sodium channels. Altered mental status is usually
caused by cerebral hypoperfusion, but in the case of beta-blockers
may also be caused by hypoglycemia. Beta-blockers such as propranolol
that cross the blood-brain barrier and have membrane-depressant
effects may cause coma, convulsions, and respiratory arrest. Noncardiac
effects of calcium channel blockers include nausea, vomiting, and
hyperglycemia. Global hypoperfusion may result in angina or myocardial infarction,
cerebral ischemia, hepatic dysfunction, renal failure, and metabolic
Diagnosis of beta-blocker and calcium channel blocker poisoning
is based on the history and clinical presentation, especially bradycardia
and hypotension. Beta-blocker poisoning may cause hypoglycemia, whereas
calcium channel blocker poisoning typically results in hyperglycemia.
Studies that are helpful in assessment and management include electrolytes, glucose,
blood urea nitrogen, creatinine, blood gas analysis, and electrocardiogram
monitoring. A rapid bedside cardiac ultrasound is useful to assess
myocardial function. Patients with severe poisoning may require
invasive monitoring to guide management.
Gastric lavage and administration of activated charcoal may be
helpful early in patients with large recent ingestions. If the patient
already has significant bradycardia, hypotension, or altered mental
status, resuscitative procedures take precedence. Whole bowel irrigation
and multiple-dose activated charcoal should be considered in patients
with ingestion of sustained-release preparations. General supportive
measures include atropine for bradycardia and intravenous fluids for
hypotension. Calcium and catecholamines should be used initially
but may be ineffective after calcium channels and β-adrenergic
receptors are inhibited. Glucagon is a specific antidote for beta-blocker
poisoning and has been used with some success in calcium channel
blocker overdose as well. Glucagon produces positive inotropic and
chronotropic effects by stimulating adenyl cyclase and opening calcium
channels independent of the β-adrenergic receptor
activation. Amrinone increases intracellular cAMP and calcium influx
to improve myocardial contractility, but may exacerbate hypotension
by causing peripheral vasodilation. Vasopressin improves blood pressure
and increases the response to catecholamines. Hyperinsulinemia/euglycemia
therapy improves myocardial contractility in calcium channel blocker
overdose, often when other pharmacologic therapy has failed. It
is postulated that this therapy corrects the impaired myocardial
substrate utilization caused by calcium channel blocker–induced hypoinsulinemia,
resulting in improved carbohydrate metabolism and increased myocardial contractility.5 Other
extraordinary measures have been used to maintain perfusion while waiting
for cardiac drug toxicity to abate. When pharmacologic therapy has
failed, cardiopulmonary bypass or extracorporeal membrane oxygenation
may be life-saving.
Clonidine is a centrally acting antihypertensive agent that is
also prescribed for conditions such as attention deficit hyperactivity disorder
and drug withdrawal. Clonidine binds to inhibitory presynaptic α2-adrenergic receptors
in the medulla, resulting in decreased sympathetic outflow from
the central nervous system.
The hallmark of intoxication is generalized sympathetic depression.
Neurologic manifestations are similar to the opioid toxidrome, including
pinpoint pupils, hypotonia, sedation, coma, hypothermia, respiratory
depression, and apnea. Cardiovascular toxicity is manifested by bradycardia,
decreased cardiac output, and hypotension.
Although clonidine poisoning mimics the opioid toxidrome, it
does not respond to naloxone. Sinus bradycardia does not require
treatment unless it is associated with hypotension and poor perfusion.
Atropine will often improve heart rate and cardiac output. Persistent
hypotension is treated with intravenous fluids and catecholamine
infusion. Coma and respiratory depression may require advanced airway
management. Gastrointestinal decontamination is usually not indicated
because of rapid onset of symptoms and good outcome with supportive
Tricyclic antidepressants (TCAs) were first drugs used to treat
depression in the 1950s, but tricyclic antidepressant overdoses
caused severe toxicity, resulting in many poisoning deaths. The
selective serotonin reuptake inhibitors (SSRIs) were introduced
in the 1980s and have a better safety profile than the tricyclic antidepressants.
The therapeutic mechanism of tricyclic antidepressants is inhibition
of reuptake of biogenic amine neurotransmitters in the central nervous system,
including norepinephrine, dopamine, and serotonin. In overdose,
other mechanisms result in toxicity, including antagonism of muscarinic
cholinergic receptors, α1-adrenergic receptors,
serotonin receptors, histaminic H1 and H2 receptors,
GABAA receptors, and myocardial fast sodium channels.
The therapeutic mechanism of serotonin reuptake inhibitors is
serotonin reuptake inhibition. These medications do not usually
cause severe toxicity except in large overdose. However, excessive
serotonergic activity may result in the life-threatening serotonin
syndrome (see later in this section). Some serotonin reuptake inhibitors
cause additional toxicity via inhibition of dopamine and norepinephrine
reuptake and antagonism of α1-adrenergic
receptors. Some agents also have sodium and potassium channel inhibition
causing QRS and QTc prolongation.
Patients with significant tricyclic antidepressants ingestions
usually manifest symptoms within 30 to 60 minutes, and life-threatening toxicity
within 6 hours. The most common cause of death is cardiovascular
toxicity. Inhibition of myocardial fast sodium channels causes slowed
phase 0 depolarization, decreased contractility, widened QRS and
QT intervals, and ventricular tachycardia including torsades
de pointes. Severe hypotension is caused by norepinephrine
depletion, α1-adrenergic receptor blockade,
myocardial depression, and dysrhythmias. Muscarinic cholinergic
receptor blockade results in sedation, delirium, coma, myoclonus, and
seizures. Other anticholinergic effects include tachycardia, hyperthermia,
mydriasis, ileus, urinary retention, diminished sweating, and dry
mucus membranes. Seizures are also caused by inhibition of GABAA receptors.
Significant SSRI overdose results in nausea, ataxia, and sedation.
Coma and respiratory depression may occur, particularly when alcohol
or other sedating drugs are also involved. Some agents, such as
buproprion, may cause tremor, agitation, and seizures. Cardiovascular
effects include sinus tachycardia, hypotension, and cardiac conduction disturbances,
but are usually not life threatening.
The most common severe toxicity associated with SSRIs is the
serotonin syndrome, caused by excessive stimulation of serotonin
5-HT2A and possibly 5-HT1A receptors. The serotonin syndrome
often occurs when an SSRI is combined with another drug with serotonergic
activity, but it has been reported in patients taking single or
multiple SSRIs. Its manifestations include agitation, altered mental
status, coma, incoordination, myoclonus, hyperreflexia, tremor, muscle
rigidity, diarrhea, diaphoresis, and hyperthermia. Patients may
only exhibit a few of the symptoms, making the diagnosis challenging.
Deaths are caused by hyperthermia, rhabdomyolysis, lactic acidosis,
disseminated intravascular coagulation, and multiorgan failure.
The diagnosis of cyclic antidepressant poisoning is based on
the history and clinical presentation. In the patient with an unknown ingestion,
the combination of anticholinergic signs, coma, seizures, hypotension,
and a widened QRS interval strongly suggests tricyclic antidepressant
Because of the potential lethality of tricyclic antidepressant
poisoning, gastrointestinal decontamination procedures such as orogastric
lavage and activated charcoal are considered for patients who present
early after an overdose. Patients presenting later with severe symptoms are
unlikely to benefit from gastrointestinal decontamination.
The management of cyclic antidepressant poisoning is mainly supportive.
Intravenous access and cardiac monitoring should be immediately
established. Endotracheal intubation is indicated if significant
central nervous system depression is present. Hypotension should
be treated with rapid crystalloid infusion and pharmacologic support.
Norepinephrine is recommended because of its predominant α1-mediated
Seizures are treated aggressively because the resultant hypoxia
and acidosis potentiate tricyclic antidepressant-induced cardiotoxicity.
Anticonvulsants that enhance gamma-aminobutyric acid such as benzodiazepines
or barbiturates are usually effective.
It is important to monitor the electrocardiogram and QRS interval.
A QRS duration of greater than 100 msec is associated with seizures
and a duration of greater than 160 msec is associated with ventricular
dysrhythmias. Ventricular dysrhythmias and hypotension are treated
with serum alkalinization and sodium loading.6 Increasing
the extracellular sodium concentration helps overcome the sodium channel
blockade caused by tricyclic antidepressants, and serum alkalinization
diminishes drug binding to the fast sodium channel. A QRS interval
greater than 100 msec, ventricular dysrhythmias, or intractable
hypotension should be treated with intravenous sodium bicarbonate
in a dose of 1 to 2 mEq/kg, repeated as necessary to maintain
a serum pH between 7.45 and 7.55. Use of hypertonic saline (3% NaCl)
to increase the extracellular sodium concentration or hyperventilation
to induce a respiratory alkalosis may also be considered in difficult
cases. Ventricular dysrhythmias that fail to respond to sodium bicarbonate
may be treated with lidocaine, a class IB antidysrhythmic agent.
Although lidocaine theoretically can worsen ventricular dysrhythmias,
it has been used safely in tricyclic antidepressants poisoning.
However, phenytoin (another class IB antidysrhythmic agent) is not recommended
because it has not been well studied and may worsen ventricular
dysrhythmias. Class IA and IC antidysrhythmic agents are contraindicated
because they exacerbate tricyclic antidepressant–induced
Patients with cardiogenic shock who fail to respond to maximal
therapeutic interventions are candidates for extracorporeal life support
such as cardiopulmonary bypass or extracorporeal membrane oxygenation. Case
reports indicate that these measures favor survival as the tricyclic
antidepressant is eliminated from the body and the cardiotoxicity
Serotonin syndrome is diagnosed when consistent symptoms occur
in the setting of serotonergic medication use and other etiologies
are excluded. Treatment consists of immediate withdrawal of any
offending drugs and supportive care that focuses on decreasing hyperthermia
and muscular rigidity. Effective measures include external cooling,
intravenous hydration, and benzodiazepines or neuromuscular blockade
to achieve muscle relaxation. Case reports support cyproheptadine to
treat serotonin syndrome owing to its inhibitory effects at 5-HT1A and
5-HT2A serotonin receptors.
Digoxin and related cardiac glycosides are used to treat congestive
heart failure and control ventricular rate in supraventricular tachydysrhythmias.
The narrow therapeutic index of digoxin increases the risk of toxicity
during therapeutic administration and with medication errors. Other sources
of exposure include unintentional and intentional overdose, as well
as ingestion of plants and other natural sources of cardiac glycosides.
Cardiac glycosides inhibit the sodium-potassium-adenosine-triphosphatase
This mechanism is used to treat congestive heart failure because
it increases the intracellular calcium in myocardial cells, resulting
in improved contractility. During normal repolarization, the Na+/K+-ATPase
restores the resting membrane potential by pumping potassium ions into
the myocardial cell in exchange for sodium ions out of the cell.
When this pump is inhibited by cardiac glycosides, the result is
an increase in intracellular sodium and an increase in extracellular
potassium. The increased intracellular sodium inhibits efflux of
calcium through the Na+/Ca2+ antiporter
at the cell membrane. The result is an increase in intracellular
calcium that results in improved inotropy.
In addition, digoxin enhances vagal tone, decreasing the rate
of depolarization and conduction through the sinoatrial (SA) and
atrioventricular (AV) nodes, and increasing the refractory period.
During digoxin poisoning, excessive increases in intracellular calcium
results in oscillatory disturbances of membrane potential, resulting
in ectopy and tachydysrhythmias.
The clinical presentation of acute digoxin poisoning includes
cardiac and noncardiac features. The noncardiac effects include
gastrointestinal manifestations such as nausea, vomiting, and diarrhea;
neurologic manifestations such as confusion, headaches, weakness,
and seizures; and visual manifestations such as blurred vision,
scotoma, and xanthopsia.
The cardiac effects of digoxin poisoning are the primary life-threatening
concern. Bradycardia is an early manifestation. Reduced conduction
velocity through the atrial conducting tissue and atrioventricular
node causes a prolonged PR interval and varying degrees of atrioventricular
block. This is often followed by increased myocardial automaticity
and excitability, resulting in atrial, junctional, and ventricular
ectopy, and tachydysrhythmias. Death occurs due to intractable dysrhythmias,
hypotension, and ventricular fibrillation.
Diagnosis is based on the history of exposure and the characteristic
cardiac and noncardiac effects of digoxin poisoning. The combination
of bradycardia, increased automaticity, and hyperkalemia is characteristic.
The serum digoxin level must be interpreted with caution. The
correlation between clinical effects and serum digoxin level is
based on the steady state concentration. It is therefore more helpful
in predicting toxicity in the patient with chronic overdose. Although
the therapeutic range for serum digoxin is usually between 0.5 and
2 ng/mL, up to 10% of patients in this range may
demonstrate toxicity. Digoxin demonstrates a biphasic distribution
pattern following acute overdose. Serum levels will initially be
elevated without clinical toxicity because distribution into the
tissues occurs over many hours. Digoxin levels 10 times greater
than the therapeutic serum concentration can be seen in patients
during the first few hours after acute overdose without apparent
toxicity. Similar concentrations in a patient with chronic toxicity
would be fatal. Serum digoxin concentrations then decline as the
drug is distributed into the tissues and eliminated by the kidneys,
and it is during this phase that toxicity may begin.
Management of digoxin poisoning begins with standard supportive
care and continuous electrocardiogram monitoring. Intravenous access
is obtained, and blood analyzed for serum digoxin, electrolyte,
creatinine, calcium, and magnesium concentrations.
The treatment of choice for serious digoxin (or other cardioactive
steroids) poisoning is intravenous administration of digoxin-specific
Fab antibody fragments.7 Indications include life-threatening
dysrhythmia, conduction delay, hyperkalemia (> 5 mEq/L),
cardiogenic shock, or cardiac arrest due to digoxin overdose. Other
indications include a high likelihood of progression to life-threatening
digoxin toxicity, such as ingestion of more than 4 mg or 0.1 mg/kg
in a child, ingestion of more than 10 mg in an adult, serum digoxin
level greater than or equal to 15 ng/mL at any time or
greater than or equal to 10 ng/mL 6 hours after ingestion,
or rapidly progressive signs and symptoms of digoxin poisoning.
Formulas are available to calculate the dose of digoxin-specific
Fab based on the serum digoxin concentration or the known amount
of digoxin that was ingested. However, the history of the amount
ingested is notoriously inaccurate and after an acute exposure,
the serum digoxin concentration does not reflect steady-state distribution.
It is more practical to administer an empiric dose of 10 to 20 vials
of digoxin-specific Fab for acute overdose, repeating as needed
to reverse life-threatening toxicity. A lower dose is recommended
for chronic digoxin poisoning to reduce the toxic effects by neutralizing
a fraction of the digoxin while maintaining therapeutic benefits in
the patient with underlying cardiac disease. Empiric dosing of digoxin-specific
Fab for chronic poisoning is 1 to 2 vials for children and 3 to
6 vials for adults, titrated to clinical effect.
Following administration of digoxin-specific Fab, total serum
digoxin levels increase dramatically because digoxin is pulled from
the tissue compartment into the intravascular space, where it is
bound by the Fab fragments and inactivated. The complex is subsequently excreted
by the kidneys. Most laboratory assays measure total digoxin including
the digoxin-Fab complex, which is not generally useful after administration
of digoxin-specific Fab. However, measurement of free serum digoxin
levels may be helpful in guiding further therapy.
A crucial aspect in the treatment of digoxin poisoning is the
management of potassium, magnesium, and calcium homeostasis. Hyperkalemia
is a consequence of digoxin poisoning and may be treated with sodium
bicarbonate or glucose and insulin to shift potassium into the cells.
Administration of calcium is contraindicated because digoxin has
already caused an excessive influx of calcium into myocardial cells. Administration
of additional calcium increases the incidence of dysrhythmias. Although
digoxin initially causes an elevated extracellular potassium concentration,
increased renal elimination leads to depleted total body stores.
Serum potassium concentrations often fall precipitously following
digoxin-specific Fab and must be checked frequently.
Hypokalemia is especially dangerous in digoxin poisoning because
it exacerbates cardiotoxicity. A fall in serum potassium concentration
from 3.5 mEq/L to 3 mEq/L increases cardiac sensitivity
to digoxin by approximately 50%. Patients with chronic
digoxin toxicity are often hypokalemic because of concomitant treatment
with diuretics. Significant hypokalemia should be corrected cautiously,
especially in the patient with renal insufficiency.
Magnesium plays an important role in digoxin toxicity because
it is a cofactor for the Na+/K+-ATPase
pump. Hypomagnesemia potentiates digoxin-induced cardiotoxicity
and inhibits correction of hypokalemia. Patients who are on chronic
digoxin therapy may be hypomagnesemic because of concurrent diuretic use.
Intracellular magnesium depletion may be present despite a normal
serum magnesium concentration. Magnesium replacement is indicated
for patients with digoxin-related cardiotoxicity, hypokalemia, and
documented hypomagnesemia. Caution is again advised in the patient
with renal insufficiency.
Gastrointestinal decontamination will not benefit the patient
with chronic digoxin toxicity, but may be considered for recent
acute ingestions. Activated charcoal binds to digoxin, decreasing
gastrointestinal absorption. Digoxin poisoning results in conduction
delays and increased vagal tone, and therefore induced emesis and
gastric lavage are avoided because vagal stimulation may induce
Iron is found in many commonly available preparations (eTable 120.1) and remains an important cause
of severe childhood poisoning. Its toxic effects are mediated primarily
by free-radical production, resulting in multiorgan injury.
120.1. Iron Preparations ||Download (.pdf)
120.1. Iron Preparations
|Ferrous Salt||Elemental Iron Concentration (%)|
The first stage of iron poisoning results from
direct gastrointestinal toxicity and is characterized by nausea,
vomiting, diarrhea, and abdominal pain. Hematemesis and hematochezia
may also occur. The second stage is the latent
stage, which usually occurs 6 to 24 hours after ingestion following
resolution of gastrointestinal symptoms and preceding the onset
of systemic toxicity. Patients may have persistent lethargy, tachycardia,
and metabolic acidosis. The third stage is shock
and systemic toxicity, which can occur very rapidly after a massive
ingestion or up to 24 hours after a moderate ingestion. Hypoperfusion
and metabolic acidosis result from decreased myocardial contractility,
vasodilation, and hypovolemia secondary to gastrointestinal bleeding
and fluid shifts from the vascular to extravascular space. Central
nervous system involvement includes lethargy, seizures, or coma.
The fourth stage is hepatic failure, which can
occur 2 to 3 days after ingestion. This stage is characterized by coagulopathy,
hypoglycemia, elevated transaminase levels, hyperbilirubinemia,
hyperammonemia, coma, and renal failure. The fifth stage is
the late complications resulting from the initial corrosive gastrointestinal
injury, such as gastric outlet obstruction and small intestinal strictures.
These may manifest 2 to 8 weeks following ingestion.
Diagnosis is based on a history of iron ingestion and the presence
of consistent signs and symptoms, especially gastrointestinal distress
or shock. The absence of symptoms within the first 6 hours excludes
serious iron toxicity. The amount of elemental iron ingested correlates
with toxicity (Table 120-6). A peak serum
iron concentration obtained 4 hours after ingestion predicts the
severity of toxicity. Peak iron concentrations less than 300 μg/dL
are usually nontoxic, whereas levels of 300 to 500 μg/dL
often result in mild to moderate toxicity. Peak iron concentrations greater
than 500 μg/dL are associated with severe
toxicity, and those greater than 1000 μg/dL
may be lethal.
120-6. Estimation of Iron-Poisoning Severity ||Download (.pdf)
120-6. Estimation of Iron-Poisoning Severity
|Elemental Iron Ingested (mg/kg)||Severity of Iron Poisoning|
|< 20||Asymptomatic to mild|
|20–60||Mild to moderate|
|> 60||Severe to lethal|
Other helpful laboratory studies include a complete blood count,
blood gas analysis, electrolytes, glucose, blood urea nitrogen,
creatinine, liver function tests, lactate and coagulation studies
to evaluate for anemia, metabolic acidosis, liver failure, renal
insufficiency, and coagulopathy. Abdominal radiographs may identify
iron tablets, concretions, or free air in the abdomen.
Treatment of the patient with serious iron overdose starts with
stabilization and supportive measures. Intravenous chelation with
deferoxamine should be considered for any patient with a serum iron
level greater than 500 μg/dL or signs
of significant toxicity such as metabolic acidosis and hypoperfusion.
Deferoxamine binds iron with high affinity, forming ferrioxamine
(deferoxamine-iron) that is eliminated by the kidneys. The classic vin
rosé coloration of the urine does not always occur
even in the presence of significant iron toxicity. Therapy may be
discontinued when systemic toxicity resolves and serum iron levels
return to normal. Rapid infusion of deferoxamine may result in hypotension,
and prolonged deferoxamine therapy has been associated with lung
injury and Yersinia enterocolitica sepsis.
Whole bowel irrigation is recommended when iron tablets are seen
on radiographs of the gastrointestinal tract. Serial abdominal radiographs
are obtained to document elimination of the iron tablets. Gastric
lavage is ineffective because iron tablets are too large and adherent
to be removed. Activated charcoal does not bind iron. Surgery may
be required to excise adherent iron concretions that cannot be removed
with whole bowel irrigation. Although hemodialysis does not enhance elimination
of iron, it may be necessary to remove the ferrioxamine complex
in patients with renal failure.
Isoniazid (INH) is a first-line antituberculous medication and
is a hydrazide derivative of isonicotinic acid. Acute INH toxicity
causes deficiency of gamma-aminobutyric acid (GABA) in the central
nervous system, resulting in seizures and coma (Fig.
120-3). Metabolites of INH deplete pyridoxine (vitamin B6) and
prevent conversion to pyridoxal 5′-phosphate,
which is an essential cofactor for the conversion of glutamate (excitatory
neurotransmitter) to GABA (inhibitory neurotransmitter). INH also
inhibits the conversion of lactate to pyruvate, exacerbating the
lactic acidosis resulting from seizures.
Actions of isoniazid and pyridoxine on gamma-aminobutyric
acid (GABA) formation. Isoniazid inhibits pyridoxyl phosphokinase
that converts pyridoxine to pyridoxyl 5′ phosphate.
Pyridoxyl 5′ phosphate is a cofactor for
glutamate decarboxylase that converts the excitatory neurotransmitter
glutamate into the inhibitory neurotransmitter GABA.
Vomiting, ataxia, respiratory depression, coma, and seizures
occur within 2 hours of acute isoniazid overdose. Severe anion gap
metabolic acidosis develops after seizures, but does not typically
occur in their absence. Rhabdomyolysis often results from prolonged
seizures. Elevated liver enzymes may occur within several days.
Isoniazid poisoning should be suspected in an unknown overdose
with the characteristic presentation of coma, unexplained seizures
(especially if they are refractory to standard therapy), and profound
metabolic acidosis. Arterial blood gas analysis, electrolytes, blood
urea nitrogen, creatinine, calcium, lactate, and glucose are needed
to evaluate for other etiologies of seizures and elevated anion
gap metabolic acidosis.
Initial management consists of standard supportive care for seizures,
coma, and metabolic acidosis. Benzodiazepines alone may be ineffective
in terminating isoniazid-induced seizures. The specific antidote
is pyridoxine (vitamin B6), which restores the ability
to synthesize gamma-aminobutyric acid (GABA). Pyridoxine and benzodiazepines
act synergistically because pyridoxine reverses the GABA deficiency,
while benzodiazepines sensitize postsynaptic receptors to GABA.
The dose of pyridoxine is 70 mg/kg intravenously in children
up to a maximum of 5 g in adults, infused at a rate of 1 g per minute
until seizures are controlled. If seizures are terminated before
the full dose of pyridoxine is administered, the remainder may be
infused over the next 4 hours while the isoniazid is gradually cleared.
If seizures recur, the dose of pyridoxine may be repeated.
Opioids are agents capable of recreating opium-like effects by
binding to opiate receptors and are categorized as natural opiates
derived from the Papaver somniferum poppy (ie,
morphine, codeine), semisynthetic opioids (ie, heroin, hydrocodone),
and synthetic opioids (ie, fentanyl, merperidine). Opioids are often prescribed
for analgesia (see Chapter 113), cough suppression,
and diarrhea control.
Opiate receptor activation is responsible for opioid effects
such as analgesia, euphoria, sedation, respiratory depression, miosis,
gastrointestinal dysmotility, and pruritus. Opiates with long half-lives
such as methadone are of particular concern in overdose because
of relapse of symptoms after antidote therapy.
The classic opioid toxidrome consists of coma, respiratory depression,
and miosis. Other effects include bradycardia, hypotension, hypothermia,
ileus, decreased muscle tone, and hyporeflexia leading to apnea,
cardiovascular collapse, and death. Noncardiogenic pulmonary edema
occurs, especially with heroin overdoses. Seizures are associated
with certain opioids such as meperidine, propoxyphene, and tramadol.
Opioid withdrawal syndrome occurs in dependent individuals after
opioid use has been discontinued, and is characterized by dysphoria,
anxiety, piloerection, diaphoresis, vomiting, diarrhea, abdominal
cramps, insomnia, tachycardia, and hypertension.
Diagnosis is not difficult when the opioid toxidrome is present
and improvement occurs with administration of the opioid antagonistnaloxone. Urine toxicology screens can confirm recent use of certain
opioids. Serum acetaminophen and salicylate levels should be obtained
because many prescription opioids are combined with these analgesics.
Initial management is focused on support of the airway and ventilation.
Early administration of naloxone may obviate the need for definitive airway
management. The primary goal is reversal of respiratory depression,
which usually improves rapidly after naloxone. High-potency opioids
such as fentanyl may require higher doses. Altered mental status
and respiratory depression will not be effectively reversed if other sedative-hypnotic
drugs are also contributing to toxicity.
A useful starting dose of naloxone for the opioid-dependent patient
is 0.1 mg intravenously followed by escalating doses every 1 to 2
minutes as needed to a maximum of 10 mg. The objective is to achieve
reversal of respiratory depression without inducing withdrawal symptoms.
Isolated opioid toxicity is unlikely if there is no improvement
after 10 mg of naloxone. Larger starting doses may be administered to
the patient who is not opioid dependent.
Patients who initially respond to naloxone must be closely monitored
for several hours because naloxone’s duration of action
is shorter than that of many opioids. Return of respiratory depression
requires additional doses or continuous infusion of naloxone and
hospital admission. Other indications for hospitalization include
noncardiogenic pulmonary edema, aspiration pneumonia, hypoxic-ischemic injury,
or other complications.
The primary therapeutic mechanism of action of salicylates is
decreased biosynthesis of prostaglandins via inhibition of cyclooxygenase,
which results in their analgesic, antipyretic, and anti-inflammatory
properties. The pathophysiology of salicylate poisoning is complex
because of the multiple mechanisms of toxicity (eTable
eTable 120.2. Pathophysiology
of Salicylate Poisoning ||Download (.pdf)
eTable 120.2. Pathophysiology
of Salicylate Poisoning
|Vasoconstriction of auditory microvasculature||Tinnitus|
|Stimulation of medullary respiratory center||Hyperpnea|
|Stimulation of medullary chemoreceptor trigger zone||Vomiting|
|Fluid and electrolyte loss|
|Local gastric irritation||Gastritis|
|Fluid and electrolyte loss|
|Uncoupling of oxidative phosphorylation||Decreased adenosine 5'-triphosphate production |
|Increased CO2 production |
|Increased O2 consumption |
|Increased glucose demand|
|Increased insensible fluid loss|
|Inhibition of Krebs cycle enzymes||Metabolic acidosis (increased lactate, pyruvate)|
|Inhibition of amino acid metabolism||Metabolic acidosis|
|Altered glucose metabolism||Increased glycolysis and gluconeogenesis |
|Hyperglycemia or hypoglycemia|
|Decreased cerebrospinal fluid glucose concentration|
|Altered fatty acid metabolism||Ketoacidosis (increased beta-hydroxybutyrate, acetoacetate,
|Inhibition of platelet cyclooxygenase ||Decreased platelet function|
|Decreased prothrombin formation||Thrombocytopenia|
|Increased capillary fragility||Hypoprothrombinemia|
|Increased prothrombin time and prolonged bleeding time|
|Increased permeability of pulmonary vasculature||Noncardiogenic pulmonary edema|
Acid–base disturbances are characteristic of salicylate
toxicity. Stimulation of the medullary respiratory center results
in hyperpnea and primary respiratory alkalosis. An elevated anion gap
metabolic acidosis also begins early and worsens as the poisoning
progresses. Blood gas analysis demonstrates early respiratory alkalosis,
followed by mixed respiratory alkalosis and metabolic acidosis.
The respiratory alkalosis may be blunted if the patient also has
salicylate-induced pulmonary edema, severe central nervous system
toxicity, or coingestion of another agent that results in respiratory
Fluid and electrolyte abnormalities are always present with significant
salicylate poisoning. Dehydration results from vomiting, hyperventilation,
hyperthermia, diaphoresis, and diuresis associated with obligatory
excretion of Na+, K+, and HCO3– as
a response to the respiratory alkalosis. The serum potassium concentration
may be normal early, but often decreases later in the course, complicating
management. Hyperglycemia is often present early as increased energy
demand promotes glycolysis and gluconeogenesis. Later, increased
metabolic demands exceeding the supply of glucose result in hypoglycemia. Neuroglycopenia
may occur even in the presence of a normal serum glucose concentration.
Central nervous system toxicity is manifested by lethargy, delirium,
seizures, coma, and respiratory depression. Acidemia contributes
to central nervous system toxicity because it decreases salicylate
dissociation and promotes the ingress of salicylate into the brain.
Combined respiratory and metabolic acidosis results in severe acidemia,
which is often a preterminal finding. Hyperthermia, cerebral edema,
respiratory failure, and cardiovascular collapse ultimately result in
Diagnosis is based on the history of salicylate exposure as well
as characteristic laboratory and clinical findings. Blood gas analysis, serum
electrolytes, and glucose concentrations are crucial to diagnosis
and management because of the frequent acid–base abnormalities,
dehydration, hypoglycemia, and electrolyte disturbances. Renal function
tests are important because of the renal elimination of salicylates
and the frequent occurrence of dehydration. Measurement of urine
pH helps monitor the progress of urinary alkalinization.
Measurement of the serum salicylate concentration confirms the
diagnosis and helps predict severity of toxicity but must be evaluated
in the context of the patient’s clinical examination and laboratory
results as well as other factors such as time elapsed since ingestion,
formulation of the salicylate, and adequacy of decontamination. Serial
salicylate levels are needed because of the possibility of delayed
absorption from sustained-release products or tablet concretions
in the gastrointestinal tract.
Treatment of salicylate poisoning begins with meticulous correction
of fluid, electrolyte, and acid–base disturbances. Dehydration
requires fluid resuscitation to restore adequate circulating volume,
tissue perfusion, and urine output. Excessive hydration should be
avoided as it increases the risk of pulmonary and cerebral edema.
Potassium is added to maintenance fluids to replace ongoing losses.
Dextrose is provided even if the patient is normoglycemic, because
increased metabolic demands often result in neuroglycopenia.
Sodium bicarbonate is a specific treatment for salicylate poisoning
for two main reasons. First, sodium bicarbonate increases the serum pH
and favors movement of salicylate from the central nervous system
and other organs into the serum compartment. Second, alkalinization
of the urine favors excretion and enhanced elimination of salicylate.
Intravenous sodium bicarbonate is indicated when the patient is
symptomatic and the serum salicylate level is greater than 40 mg/dL.
Alkalinization is initiated with a 1 to 2 mEq/kg sodium
bicarbonate intravenous bolus followed by a continuous infusion
that is prepared by adding 132 mEq (3 ampules) of sodium bicarbonate
to 1 L of 5% dextrose water (D5W) with 20 to 40
mEq potassium chloride per liter. This solution is infused at a
rate 1.5 to 2 times that of normal maintenance fluid requirements
to achieve urinary alkalinization and to replace fluid and electrolyte deficits.
Hypokalemia must be corrected to achieve urinary alkalinization.
The goal of sodium bicarbonate therapy is a urinary pH of 7.5 to 8
and a serum pH of 7.4 to 7.5. Frequent salicylate, blood gas, electrolyte,
and urine pH determinations guide therapy.8
Hemodialysis eliminates salicylate and corrects fluid, electrolyte,
and acid–base disturbances. Indications for hemodialysis
include inability to eliminate salicylate (renal failure), severe
intoxication, extremely high serum salicylate levels (> 100 mg/dL),
severe acid–base or electrolyte abnormalities despite adequate treatment,
and progressive deterioration in vital signs.
Gastrointestinal decontamination with activated charcoal binds
salicylate, preventing systemic absorption. Multiple-dose activated charcoal
is recommended salicylate poisoning because of delayed absorption
from sustained-release preparations or salicylate concretions.
The end points of therapy are resolution of symptoms, normalization
of electrolyte and acid–base disturbances, and serial salicylate levels
that remain less than 25 mg/dL after sodium bicarbonate
therapy has been discontinued.
Oral hypoglycemic agents are used for the treatment of type II
diabetes mellitus. Sulfonylureas are the most likely to cause severe hypoglycemia
following an acute overdose. The sulfonylureas include acetohexamide, chlorpropamide,
glimepiride, glipizide, glyburide, tolazimide, and tolbutamide.
Sulfonylureas bind to receptors on pancreatic β cells,
stimulating release of insulin. They also enhance peripheral insulin
sensitivity and reduce gluconeogenesis. The principal feature of
sulfonylurea overdose is hypoglycemia, which can be severe and prolonged.
Early signs and symptoms of hypoglycemia caused by catecholamine
release include anxiety, tremor, diaphoresis, tachycardia, and vomiting.
Neuroglycopenia results in confusion, lethargy, coma, and seizures.
Permanent brain injury or death is the consequence of severe and prolonged
The diagnosis of sulfonylurea poisoning is based on history of
ingestion and clinical manifestations of hypoglycemia. Serum sulfonylurea
concentrations are not indicated in acute management because of
lack of rapid availability, but may be helpful in the diagnosis
of difficult cases.
Supportive care, immediate treatment with intravenous dextrose,
and hospitalization are indicated for significant hypoglycemia.
The agent of choice for treating sulfonylurea overdose is octreotide,
a semisynthetic long-acting analog of somatostatin. Octreotide inhibits
release of insulin from the pancreas, reduces dextrose requirements,
and prevents rebound hypoglycemia in patients with sulfonylurea poisoning.
The starting dose is 4 to 5 mcg/kg/day divided
every 6 hours intravenously or subcutaneously in children and up
to 50 to 100 μg every 6 hours in adults. Persistent
hypoglycemia may necessitate more frequent dosing or continuous
infusion. Most significant sulfonylurea poisonings will require
24 hours of octreotide therapy and another 24 hours of observation
after therapy is discontinued to monitor for recurrent hypoglycemia.
Blood glucose should be monitored frequently in asymptomatic
patients who may have ingested a sulfonylurea. The patient should
be allowed normal access to food and liquids. Patients who do not
develop hypoglycemia within 8 hours of ingestion are probably safe
to discharge home, although some experts recommend 24-hour hospital
observation for all patients.9 Intravenous dextrose
is not indicated in euglycemic patients because it masks the onset of
hypoglycemia, makes it difficult to ascertain whether the patient
is dependent on intravenous dextrose, and prolongs the observation
period. Excessive dextrose stimulates release of insulin, which
results in rebound hypoglycemia.
Carbon monoxide (CO) is an odorless gas produced by incomplete
combustion of carbon-containing material. Common sources of exposure include
house fires, automobile exhaust, and improperly ventilated water
heaters, stoves, furnaces, fireplaces, and space heaters. Inhalation
of CO is the leading cause of poisoning death in the United States.
Carbon monoxide causes cellular hypoxia via several mechanisms.
First, CO binds to hemoglobin with an affinity 250 times greater than
that of oxygen, forming carboxyhemoglobin (COHb). This results in
decreased oxyhemoglobin saturation and oxygen delivery to the tissues.
Second, the formation of COHb shifts the oxyhemoglobin dissociation
curve to the left, further diminishing release of oxygen to the
tissues. Third, CO binds to cytochrome oxidase, impairing cellular
respiration and oxidative metabolism. In addition, CO binds to myoglobin,
resulting in myocardial depression, hypotension, dysrhythmias, and
The diagnosis of carbon monoxide poisoning is readily suspected
in the patient found unconscious in a house fire or running automobile.
However, the diagnosis is difficult when the patient presents with
nonspecific symptoms after an unrecognized exposure. Mild to moderate
exposures present with malaise, nausea, vomiting, dyspnea, headache, dizziness,
and confusion. Such patients are often misdiagnosed with influenza
or gastroenteritis. Severe poisoning is characterized by syncope,
seizures, coma, cardiorespiratory depression, and death.
A high level of suspicion and detailed history of possible carbon
monoxide (CO) exposure is essential when the diagnosis is not obvious.
Once suspected, the exposure can be confirmed by determining the
carboxyhemoglobin (COHb) level from a blood gas sample using co-oximetry.
There is a correlation between COHb levels and clinical presentation (Table 120-7). However, if significant time
has elapsed since exposure, the COHb level will underestimate the
initial severity of the poisoning. Metabolic acidosis is an indicator
of the severity of cellular hypoxia and ischemia. The arterial blood
gas oxygen saturation should be measured with a co-oximeter, which
specifically detects COHb. With CO poisoning, the arterial PO2 is normal
because dissolved oxygen is unaffected by COHb. Routine blood gas
measures the PO2 and calculates the oxygen saturation from that value, reporting
false normal oxygen saturation in the setting of CO poisoning. Likewise,
transcutaneous pulse oximeters give false normal readings because
they do not distinguish between oxyhemoglobin and COHb.
Table 120-7. Symptoms
and Signsof Carbon Monoxide Poisoning ||Download (.pdf)
Table 120-7. Symptoms
and Signsof Carbon Monoxide Poisoning
|Carboxyhemoglobin (%)||Symptoms and Signs|
|20–40||Increasing headache, nausea, vomiting, dyspnea, fatigue,
lightheadedness, impaired judgment|
|40–60||Tachypnea, tachycardia, confusion, syncope, seizure, coma|
|60–70||Hypotension, dysrhythmias, coma, death|
|> 70||Rapidly fatal|
In addition to general supportive measures, the treatment of
carbon monoxide (CO) poisoning is aimed at reducing the amount of
CO bound to hemoglobin, cytochrome oxidase, and myoglobin by administering
the highest possible oxygen concentration to the patient. The half-life
of carboxyhemoglobin (COHb) decreases from approximately 4 hours
when the patient is breathing room air (21% oxygen) to
1 hour when the patient is on 100% oxygen. Hyperbaric oxygen
treatment at 2 to 3 atm pressure can further decrease the COHb half-life
to 20 to 30 minutes. Although the utility of hyperbaric oxygen therapy
remains controversial because of conflicting research design and
results, it should be considered for patients with significant CO
poisoning if practical (eTable 120.3) .10 The
decision to initiate HBO must be individualized depending on severity
of poisoning, the patient’s stability and suitability for transport,
and distance to the nearest hyperbaric chamber. The regional poison
control center and hyperbaric chamber should be contacted for advice.
eTable 120.3. Indications
for Hyperbaric Oxygen Therapy for Carbon Monoxide Poisoning* ||Download (.pdf)
eTable 120.3. Indications
for Hyperbaric Oxygen Therapy for Carbon Monoxide Poisoning*
|Acute neurologic symptoms such as altered mental status and
|Carboxyhemoglobin > 25%|
|Metabolic acidosis pH < 7.2|
|Pregnant patients with carboxyhemoglobin > 20% or
with any maternal or fetal symptoms|
Caustic agents are found in household products such as drain
cleaners, oven cleaners, rust removers, toilet bowl cleaners, tile
cleaners, and hair straighteners. They are capable of causing serious
injury on contact with the skin, eyes, and gastrointestinal tract.
The most commonly encountered caustic agents are acids and alkalies.
Acids denature proteins (coagulation necrosis), producing a firm
coagulum that may limit tissue penetration. Acids often have a strong
odor and cause immediate pain, which can limit the amount ingested.
Alkalies dissolve proteins and saponify fats (liquefaction necrosis),
resulting in deeper tissue penetration. Alkalies are often odorless
and do not cause immediate pain on contact, which may allow ingestion
of larger volumes. Strong acids (very low pH) and strong alkalies
(very high pH) cause the greatest damage, but the severity of tissue
injury is also determined by other factors such as duration of contact,
volume of exposure, and physical state of the caustic substance.
Ingestion is the most common route of exposure. The complete
absence of signs and symptoms after several hours usually indicates
that significant injury has not occurred. However, the absence of
oropharyngeal burns on physical examination does not completely
rule out the possibility of esophageal or gastric injury. Patients
with caustic burns usually report pain of the mouth, throat, chest,
or abdomen. Young children manifest pain by crying, drooling, and refusing
to swallow. Esophageal perforation usually causes severe mediastinitis.
Gastric injury may result in hematemesis and epigastric or upper-left
quadrant abdominal pain. Peritonitis and metabolic acidosis are
ominous signs, correlating with severity of tissue necrosis, esophageal
or gastrointestinal perforation, and sepsis.
Respiratory tract injury may occur via direct extension of esophageal
burns or secondary to aspiration of the caustic while swallowing
or vomiting. Upper airway edema may result in hoarseness, stridor,
and catastrophic upper airway obstruction. Pulmonary involvement
includes bronchospasm and pneumonitis.
Ocular exposure to caustic agents, especially strong alkalies,
often results in severe damage. Initial findings include eye pain,
blepharospasm, lacrimation, conjunctival injection, and edema. Necrosis
and opacification of the cornea, lens, and anterior chamber lead
to blindness. Dermal contact results in localized pain, erythema,
blistering, and deeper necrosis when the exposure is severe.
The caustic substance should be identified with respect to pH,
concentration, amount, and time of exposure. Immediate decontamination
is of the utmost importance. Patients should be undressed, inspected
for dermal exposures, and washed thoroughly with tepid water. In
the case of ocular exposures, the eyes should be immediately irrigated.
Tap water is usually readily available, and the eyes should be flushed
under running water for a minimum of 15 minutes. In the emergency
department, local anesthetic drops may be applied and each eye irrigated
with a liter of saline. After thorough ocular decontamination, the
pH of the tears is checked with litmus paper or a urine dipstick.
Further irrigation is indicated if the pH has not returned to approximately
7.4. Following irrigation, a Wood’s lamp and fluorescein
dye are used to evaluate for corneal and conjunctival injuries.
Ophthalmologic consultation should be obtained for all ocular caustic
injuries. Following ingestion of a caustic substance, gastrointestinal
decontamination is of limited utility. The mouth should be rinsed
thoroughly in patients with oral burns. Some experts recommend diluting
the gastric contents by having the patient drink small volumes of
water or milk. The placement of a small nasogastric tube to suction
the stomach may be considered in recent and large intentional ingestions.
Activated charcoal does not bind caustics and obscures endoscopy.
Imaging for serious caustic ingestions may include lateral neck,
chest, and abdominal radiographs. Patients with respiratory distress
require laryngoscopy to assess for airway burns. Immediate surgical
consultation is required if esophageal or gastrointestinal perforation
is suspected based on hypotension, mediastinitis, abdominal rigidity,
sepsis, metabolic acidosis, and radiographic or endoscopic evidence.
Gastroenterology consultation is required for all caustic ingestions
with signs and symptoms of injury. If the patient is stable, endoscopy
is performed 8 to 12 hours after ingestion to evaluate full progression
of the burn. Endoscopic grading of the severity of esophageal injuries
helps to guide subsequent management (Table 120-8).11 Antibiotics
should not be administered prophylactically for mild injuries, but
are indicated for patients with gastrointestinal perforation or
signs of infection.
120-8. Grading of Esophageal Burns ||Download (.pdf)
120-8. Grading of Esophageal Burns
|Esophageal Burns Grade||Endoscopic Description||Complications||Management|
|Grade I||Superficial erythema and edema||None||Resume normal diet as tolerated|
|Steroids not indicated|
|Grade II||Partial thickness injuries with ulceration extending into
the submucosa||Grade IIb burns are at greater risk for acute perforation
and subsequent stricture formation after healing||Grade II burns usually require total parenteral nutrition
until healing occurs|
|Grade IIa burns are noncircumferential||Grade II burns are at increased risk of carcinoma
development after decades||It is controversial whether steroids are of benefit
for grade IIb burns to decrease stricture formation|
|Grade IIb burns are near or fully circumferential|
|Grade III||Full thickness injuries with necrosis extending
to periesophageal tissues||Greatest risk for acute perforation, subsequent
stricture formation and carcinoma development||Surgical intervention for perforation|
|Total parenteral nutrition until healing occurs|
|Steroids do not decrease stricture formation|
Hydrocarbons are found in many common household and automotive
products. They are derived from petroleum distillation and other sources
including coal tar, plant oils, and animal fats. Hydrocarbon exposures
are a frequent cause of pediatric morbidity and mortality. Common
clinical scenarios include toddlers who aspirate a liquid hydrocarbon
and recreational inhalation of volatile hydrocarbons by adolescents.
Most hydrocarbons are poorly absorbed from the gastrointestinal
tract after ingestion and lack systemic toxicity. The chief concern is
pulmonary aspiration resulting in chemical pneumonitis. The risk
for aspiration is determined by the hydrocarbon’s physical
properties of viscosity and surface tension. Viscosity is the tendency
to resist flow and is the best predictor of aspiration. Hydrocarbons
with low viscosity have the highest risk for aspiration, while those
with high viscosity are less likely to be aspirated. Surface tension
is the cohesive force between molecules and defines the ability
of the liquid to move along a surface. Hydrocarbons with low surface
tension have a higher risk for aspiration. Volatility is the ability
of a liquid to vaporize into a gas. Volatile hydrocarbons can displace
alveolar oxygen, resulting in hypoxia. These compounds are easily
absorbed across the alveolar-capillary membrane, resulting in systemic
effects such as central nervous system depression.
The respiratory injuries caused by hydrocarbon aspiration are
multifactorial. Irritation of the larynx and trachea results in
coughing, choking, and laryngospasm. Spread of the hydrocarbon to
the lower airways results in bronchospasm, bronchial inflammation,
and necrosis. When the hydrocarbon reaches the alveoli, changes
in pulmonary dynamics occur due to lipid solubilization and disruption
of the surfactant layer, resulting in alveolar collapse and decreased
compliance. Direct injury to lung parenchyma results in alveolar
edema, exudates, and hemorrhage, with interstitial inflammation
and necrosis leading to a further ventilation-perfusion mismatch
and decreased compliance.
Cardiovascular toxicity is unusual after hydrocarbon ingestion
or aspiration, but is well described with inhalational abuse of
halogenated or aromatic hydrocarbons. Sensitization of the myocardium
to endogenous catecholamines results in ectopy, tachydysrhythmias, ventricular
fibrillation, and sudden death. The term sudden sniffing
death syndrome has been used to describe this phenomenon
associated with inhalational solvent abuse.
Central nervous system depression following hydrocarbon aspiration
is most commonly caused by hypoxia secondary to pulmonary injury.
Systemic absorption of volatile hydrocarbons following inhalation
or ingestion can result in central nervous system depression because
of disruption of neuronal membranes. It is this alteration of mental
status that is sought by the inhalant abuser. Chronic inhalational
abuse of volatile hydrocarbons can result in irreversible white
matter degeneration and dementia. Certain hydrocarbons, including
camphor, halogenated hydrocarbons, aromatic hydrocarbons and hydrocarbons
containing metals or pesticides, have systemic toxicities that may
require consultation with a poison control center (eTable 120.4).
eTable 120.4. Hydrocarbons
with Systemic Toxicities ||Download (.pdf)
eTable 120.4. Hydrocarbons
with Systemic Toxicities
|H: Halogenated Hydrocarbons|
|A: Aromatic Hydrocarbons|
|M: Hydrocarbons containing metals|
|P: Hydrocarbons containing pesticides|
Most patients with hydrocarbon aspiration will have immediate
symptoms of coughing, gagging, and choking. In mild cases, these symptoms
may be transient, but patients with significant aspiration will
have persistent coughing and tachypnea. Patients with severe aspiration
present with severe respiratory distress including coughing, grunting, bronchospasm, tachypnea, intercostal retractions,
use of accessory muscles, cyanosis, agitation, and somnolence. Other
patients may have more gradual development of respiratory distress.
Patients who remain asymptomatic for 6 hours after ingestion
are unlikely to have pulmonary aspiration and may be safely discharged
home with careful follow-up instructions. Symptomatic patients are
admitted to the hospital for further observation and management.
Persistent cough or tachypnea should be evaluated with a chest radiograph,
which usually demonstrates pneumonitis. Pneumatoceles are a late
finding, appearing on radiographs a week or two after the initial
necrotizing pneumonitis. In patients with more significant respiratory
distress, blood gas analysis may demonstrate hypoxemia and hypercarbia
with a combined respiratory and metabolic acidosis. The complete
blood count often shows a leukocytosis with a left shift, and many
patients will also manifest a fever in the first day or two due to
inflammatory mediators from the chemical pneumonitis. Empiric antibiotics
are usually not recommended unless the fever and leukocytosis develop
later, suggesting bacterial superinfection. Corticosteroids are
not helpful in limiting the pulmonary injury.
Patients with severe respiratory distress require immediate endotracheal
intubation with mechanical ventilation and oxygenation. Decreased
lung compliance necessitates increased positive end-expiratory pressures.
Patients who fail these interventions may be candidates for extracorporeal
membrane oxygenation to allow time for the lungs to heal.
The use of gastrointestinal decontamination following hydrocarbon
ingestion is controversial because the primary risk is pulmonary aspiration.
For these agents, gastric decontamination is not indicated because
of the increased risk of aspiration. Some experts recommend gastric
emptying for hydrocarbons with serious systemic toxicity, especially
large intentional ingestions. However, the benefit of gastric emptying
must be weighed against the risk of aspiration pneumonitis. Most
ingestions occur in young children and are unintentional, resulting
in smaller volumes ingested, reducing the need for gastric decontamination.
Activated charcoal has poor adsorptive capacity for most hydrocarbons.
Methanol and Ethylene
Methanol and ethylene glycol are found in many consumer products.
Ingestion of these toxic alcohols results in significant morbidity and
mortality, but outcomes can be improved with early diagnosis and
Both alcohols derive their toxicity from the fact that they are
metabolized by alcohol and aldehyde dehydrogenases into more toxic
metabolites (eFig. 120.3). The parent alcohol initially
causes an elevated osmolar gap, followed by the gradual development
of an elevated anion gap metabolic acidosis as toxic metabolites
are formed. Later, the osmolar gap normalizes and severe anion gap
metabolic acidosis predominates.
Mechanism of action of fomepizol and ethanol in ethylene
glycol and methanol poisoning. Both antidotes compete for the alcohol
dehydrogenase, limiting the metabolism of both alcohols to more
The toxic metabolite of methanol is formic acid, which causes
metabolic acidosis as well as optic nerve and brain injury. The
principal toxic metabolites of ethylene glycol are glycolic and oxalic
acid. Glycolic acid is primarily responsible for the metabolic acidosis.
Oxalic acid causes calcium oxalate precipitation in the kidney leading to
renal failure, and in the brain resulting in altered mental status,
coma, seizures, and cerebral edema. Widespread calcium oxalate precipitation may
lead to severe hypocalcemia with seizures, prolonged QT interval
on electrocardiogram, and ventricular dysrhythmias.
Suspected methanol and ethylene glycol ingestions must be taken
with extreme caution because the lethal dose is very low. Initial
symptoms include ataxia, altered mental status, and vomiting. Patients
will subsequently exhibit Kussmaul respirations as metabolic acidosis
develops. Both poisonings can result in coma, seizures, myocardial
depression, and hypotension. Visual disturbances and blindness are
specific for methanol, whereas renal failure, calcium oxalate formation,
and hypocalcemia are specific for ethylene glycol poisoning.
The diagnosis of methanol or ethylene glycol poisoning is based
on a careful history and interpretation of physical examination
and laboratory data. Measurement of blood methanol and ethylene
glycol levels confirms the diagnosis and guides therapy, but results
may not be immediately available. Other helpful laboratory studies include
serum osmolality, blood gas analysis, blood urea nitrogen, creatinine,
electrolytes, calcium, glucose, and lactate. Elevated anion gap metabolic
acidosis not due to lactate suggests toxic alcohol poisoning. Urinalysis
may reveal calcium oxalate crystals due to ethylene glycol poisoning.
The treatment of methanol and ethylene glycol poisoning is aimed
at preventing formation of toxic metabolites by blocking the activity
of alcohol dehydrogenase. Two therapeutic options are available
for the blockade of alcohol dehydrogenase: ethanol and fomepizole.
The newer antidote fomepizole has many advantages over ethanol,
which make it the antidote of choice for toxic alcohol poisoning
(eTable 120.5). The indications for fomepizole
in the setting of suspected methanol or ethylene glycol poisoning
are outlined in Table 120-9. Because the
turnaround time for methanol and ethylene glycol levels may be long,
the decision to start treatment with fomepizole must often be made
based on clinical presentation, an elevated osmolar gap, or an elevated
anion gap metabolic acidosis. The loading dose of fomepizole is
15 mg/kg intravenously (up to 1 g), followed by maintenance doses
of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg
every 12 hours thereafter.12
eTable 120.5. Fomepizole
versus Ethanoal as Antidoes for Methanol and Ethylene Glycol Poisonings ||Download (.pdf)
eTable 120.5. Fomepizole
versus Ethanoal as Antidoes for Methanol and Ethylene Glycol Poisonings
|Dosing||Once every 12 hours||Constant infusion|
|Monitoring of serum concentrations||No||Yes|
|Requirement for ICU setting||No||Yes|
|Need for hemodialysis (ethylene glycol)||No (nonsevere cases)||Yes|
Table 120-9. Treatment of
Suspected Methanol or Ethylene Glycol Poisoning ||Download (.pdf)
Table 120-9. Treatment of
Suspected Methanol or Ethylene Glycol Poisoning
|Indications for Fomepizole Treatment|
|Methanol or ethylene glycol level > 20 mg/dL|
|Osmolar gap > 10 mOsm/L not accounted for by ethanol
or other alcohols|
|Serum bicarbonate < 20 mEq/L|
|Arterial pH < 7.3|
|Oxalate crystals in the urine (ethylene glycol)|
|Indications for Hemodialysis |
|Methanol or ethylene glycol level > 50 mg/dL (or
osmolar gap > 10 mOsm/L not accounted for by ethanol or
other alcohols) and therapy with fomepizole or ethanol
not immediately available to block formation of toxic metabolites|
|Significant metabolic acidosis (pH < 7.25–7.3)|
|Visual disturbances or severe neurologic abnormalities|
Hemodialysis eliminates the toxic alcohol and its metabolites
and corrects fluid, electrolyte, and acid–base disturbances.
The indications for hemodialysis are outlined in Table 120-9.
Early nephrology consultation for hemodialysis is critical for seriously
poisoned patients. Treatment with fomepizole and dialysis should
be continued until serum methanol or ethylene glycol levels are
negligible, the increased osmolar gap and anion gap metabolic acidosis
are resolved, and the patient is clinically improved.
Methemoglobinemia occurs when hemoglobin is oxidized to form
methemoglobin (MetHb) as a result of exposure to oxidizing drugs,
nitrate-contaminated well water, or other oxidative stress. Normally,
99% of the iron in hemoglobin is in the reduced ferrous
state (Fe2+) and 1% is present as MetHb,
the oxidized ferric state (Fe3+). Methemoglobin
is unable to bind and transport oxygen. The oxyhemoglobin dissociation curve
is shifted to the left, further reducing oxygen delivery to the
tissues. These effects are exacerbated when anemia is present. Many
oxidizing agents also cause hemolysis secondary to oxidative effects on
the cell membrane, especially in patients with glucose-6-phosphate
dehydrogenase (G6PD) deficiency.
Two enzyme systems are responsible for reducing MetHb back to
normal hemoglobin (Fig. 120-4). The primary
enzyme is nicotinamide adenine dinucleotide (NADH)-dependent MetHb reductase
that utilizes NADH generated from glycolysis and performs 95% of
this activity. The secondary enzyme is nicotinamide adenine dinucleotide
phosphate (NADPH)-dependent MetHb reductase that relies on the G6PD-dependent
hexose monophosphate shunt. This second enzyme system accounts for
only 5% of normal activity, but can be induced to rapidly
reduce MetHb to hemoglobin. The antidote methylene blue increases
the activity of this second NADPH-dependent pathway.
Formation and reduction of methemoglobin. Methemoglobin
inducers oxidize ferrous hemoglobin (HbFe2+)
to methemoglobin (HbFe3+). NADH from glycolysis aids
the reduction of methemoglobin back to ferrous hemoglobin via the
NAD-dependent cytochrome b5 reductase enzyme system. The antidotemethylene blue reduces methemoglobin via NADP reductase and NADP
from the hexose monophospate shunt.
Infants are at greater risk of methemoglobinemia because of functional
immaturity of the NADH-dependent methemoglobin reductase enzyme
and may develop methemoglobinemia following gastroenteritis or ingestion of
nitrate-containing well water.13 Nitrates do not directly
result in methemoglobinemia, but they are converted to nitrites
by intestinal bacteria. Nitrites are strong oxidizing agents that readily
The signs and symptoms of methemoglobinemia result from cellular
hypoxia. Clinical severity correlates with increasing MetHb levels as
shown in Table 120-10. For a given MetHb level,
the clinical effects will be more severe if the patient has concomitant
anemia. Diagnosis depends on a high index of suspicion and history
of exposure to oxidizing agents. Methemoglobinemia should be suspected
in the cyanotic patient with no obvious cardiac or respiratory disease,
whose cyanosis does not improve with oxygen and is out of proportion
to the degree of respiratory distress. Infants presenting with gastroenteritis
and methemoglobinemia may have severe metabolic acidosis and shock
that is out of proportion to degree of dehydration.
Table 120-10. Symptoms
and Signs of Methemoglobinemia in Patients Without Anermia ||Download (.pdf)
Table 120-10. Symptoms
and Signs of Methemoglobinemia in Patients Without Anermia
|Methemoglobin (%)||Symptoms and Signs |
|20–40 ||Dyspnea, headache, tachypnea, tachycardia|
|40–50||Confusion, lethargy, metabolic acidosis|
|> 50||Coma, dysrhythmias, seizures |
The patient’s blood has a characteristic chocolate brown
color. The diagnosis is confirmed by sending a blood sample to the
laboratory for measurement of the MetHb level and blood gas analysis
on a co-oximeter. Routine blood gas analysis does not detect MetHb,
and also incorrectly calculates normal oxygen saturation based on
the measured PO2 (which is normal with methemoglobinemia).
With significant cellular hypoxia, blood gas analysis demonstrates metabolic
acidosis and serum lactate is elevated secondary to anaerobic metabolism.
The absorption spectrum of MetHb causes transcutaneous pulse oximeters
to measure oxygen saturation incorrectly.
Patients with MetHb levels less than 20% usually improve
simply with supportive care and removal of the oxidizing agent.
More severely affected patients require treatment with methylene
blue. A lower threshold for treatment is indicated in patients with
anemia or cardiopulmonary disease. Methylene blue is a thiazine
dye that increases the reduction of MetHb to hemoglobin. Methylene
blue is first reduced to leukomethylene blue by NADPH-dependent
methemoglobin reductase. Leukomethylene blue in turn reduces methemoglobin
to hemoglobin (Fig. 120-4). This pathway
requires Glucose 6-Phosphate Dehydrogenase (G6PD), and therefore
methylene blue is not effective and may cause hemolysis in patients
with G6PD deficiency. The dose of methylene blue is 1 to 2 mg/kg
intravenously over 5 minutes, repeated in 30 minutes if the response
is inadequate. Methylene blue will transiently cause a false decrease in
oxygen saturation measured by transcutaneous pulse oximetry. Excessive
doses of methylene blue (> 7 mg/kg) may actually cause methemoglobinemia.
If the patient has not responded to a second dose of methylene blue, consider
other problems such as G6PD deficiency or NADPH-dependent methemoglobin
reductase deficiency. Exchange transfusion may be considered in
patients with severe methemoglobinemia if methylene blue has failed
or is contraindicated.
Organophosphorus and carbamate insecticides prevent the breakdown
of acetylcholine in the synaptic cleft by inhibiting the acetylcholinesterase
(AChE) enzyme, resulting in continued stimulation of muscarinic,
nicotinic, and central nervous system receptors. Carbamates form
reversible bonds with AChE that undergo spontaneous hydrolysis with
full return of AChE activity by 24 hours in most cases. Carbamate toxicity
is shorter and less severe compared to organophosphorus compounds,
which can permanently inhibit AChE, resulting in prolonged toxicity.
The “aging” process during which the reversible
bond becomes a stable covalent bond may take 24 to 72 hours. Infants
are at increased risk of toxicity because they have decreased AChE
activity compared to adults.
Inhibition of acetylcholinesterase (AChE) by organophosphorus
and carbamate insecticides results in signs and symptoms of cholinergic
excess, which are summarized in the cholinergic muscarinic and nicotinic
toxidromes. A mixture of muscarinic and nicotinic toxidromes is
usually present. The primary cause of death is respiratory failure.
The pulmonary muscarinic effects include bronchorrhea and bronchospasm,
whereas the nicotinic effects on skeletal muscle result in weakness,
muscular incoordination, and fasciculations. The respiratory compromise
is compounded by central nervous system cholinergic effects of coma
Diagnosis is based on history of exposure and clinical presentation
consistent with cholinergic excess (muscarinic and nicotinic toxidromes). Plasma
cholinesterase and red blood cell (RBC) cholinesterase activity
are both decreased after organophosphorus poisoning. Plasma cholinesterase
activity is a more readily available and sensitive measure of organophosphorus
poisoning. A plasma cholinesterase level 20 to 50% of normal
correlates with mild poisoning, 10 to 20% indicates moderate
poisoning, and less than 10% is severe. Red blood cell
cholinesterase activity is a better indicator of neurosynaptic acetylcholinesterase
activity, and is therefore a more specific test for organophosphorus
poisoning, but is not readily available in most hospitals. Plasma cholinesterase
and RBC cholinesterase levels are not helpful with initial management
and diagnosis of organophosphorus compound toxicity but aid management
of prolonged toxicity. Cholinesterase measurements are not helpful
after carbamate poisoning because the inhibition of cholinesterase
activity is usually mild and transient.
The first priority of treatment is decontamination of the victim
and protection of health-care providers from secondary exposure.
Resuscitation is focused on correcting respiratory dysfunction.
Atropine is the initial antidote for organophosphorus and carbamate
poisoning because it is a competitive antagonist of muscarinic acetylcholine
receptors. The goal of atropinization is the reduction of pulmonary secretions,
reversal of bronchospasm, and improvement in respiratory distress.
The initial dose of atropine is 0.02 mg/kg intravenously up
to 0.5 to 2 mg in adults, doubling the dose every 5 minutes until
adequate oxygenation is achieved. Extremely high doses are required
to overcome the cholinergic excess, and severely poisoned patients
require frequent dosing or continuous intravenous infusion. Atropine
has no effect at nicotinic receptors, and will not reverse nicotinic
The second antidote for organophosphorus poisoning is pralidoxime
chloride (2-PAM), which reactivates acetylcholinesterase (AChE), reverses
both muscarinic and nicotinic effects, and reduces atropine requirements.
Pralidoxime must be administered early for organophosphorus poisoning
because the inhibition of AChE becomes irreversible over time. Pralidoxime
is not necessary for carbamate poisoning because of rapid hydrolysis
of the carbamate–AChE complex. The dose of 2-PAM is 25
to 50 mg/kg intravenously in children up to 1 to 2 g in
adults over 15 to 30 minutes, repeated if there is no improvement
in muscle weakness or fasciculations. Severely poisoned patients
require repeat dosing or continuous infusion, which may be necessary for