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Goldfrank's Manual of Toxicologic Emergencies

Goldfrank's Manual of Toxicologic Emergencies


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Published by Kang Kyu Choi
Goldfrank's Manual of Toxicologic Emergencies
Goldfrank's Manual of Toxicologic Emergencies

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Published by: Kang Kyu Choi on Jul 10, 2011
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Inhalant abuse is defined as the deliberate inhalation of vapors for the pur-
pose of changing one’s consciousness or becoming “high.” It is also referred
to as volatile substance abuse and was first described in 1951. Inhalants are
appealing to adolescents because they are inexpensive and readily and legally

The demographics of inhalant abuse differ markedly from those of other tra-
ditional substances of abuse. Estimates in the United States suggest that more
than 2 million youths 12–17 years of age used inhalants at least once in their
lifetime. Between 1994 and 2000 the number of new inhalant users increased
more than 50%, and the median age of first use was 13 years. In the United
States, the problem is greatest among children of lower socioeconomic groups;
non-Hispanic white adolescents are the most likely to use inhalants.
Inhalant abuse includes the practices of sniffing, huffing, and bagging.
Sniffing entails the inhalation of a volatile substance directly from a con-
tainer, as occurs with airplane glue or rubber cement. Huffing, the most com-
mon method, involves pouring a volatile liquid onto fabric, such as a rag or
sock, and placing it over the mouth and/or nose while inhaling. Bagging re-
fers to placing a solvent into a plastic or paper bag and rebreathing from the
bag several times; spray paint is among the agents commonly used with this


Most of the xenobiotics involved are commercially available volatile hydro-
carbons that are mixtures of aliphatic and aromatic hydrocarbons. For exam-
ple, gasoline is a mixture of more than 1500 compounds. Substituted hydro-
carbons contain halogens or other functional groups (eg, hydroxyl or nitrite).
The most commonly inhaled volatile hydrocarbons are fuels, such as gaso-
line, and solvents, such as toluene. Other commonly inhaled hydrocarbon-
containing products include spray paints, lighter fluid, air fresheners, and
glue. Although volatile alkyl nitrites are technically substituted hydrocar-
bons, they have pharmacologic and behavioral effects, as well as patterns of
abuse that are distinct from the other volatile hydrocarbons. Amyl nitrite, the
prototypical volatile alkyl nitrite, became popular in the 1960s with the ap-
pearance of “poppers,” small glass capsules containing the chemical in a
plastic sheath or gauze. The most commonly used nonhydrocarbon inhalant is
nitrous oxide. Nitrous oxide is the propellant in supermarket-bought whipped
cream canisters, and cartridges of the compressed gas are sold for use in
whipped cream dispensers.


Although chemically heterogeneous, inhalants are generally highly lipophilic
compounds that gain rapid entrance into the central nervous system (CNS).
Little is known about the cellular basis of the effects of inhalants and it is un-
clear whether these actually represent a single pharmacologic group. The

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clinical effects of the volatile hydrocarbons are likely mediated through stim-
ulation of γ-aminobutyric acid (GABA), although affects on the N-methyl-D-
aspartate (NMDA) receptor are also described.
There are scant data on the pharmacokinetics of the inhalants. Factors de-
termining pharmacokinetic and pharmacodynamic effects include concentra-
tion in inspired air; its partition coefficient; interaction with other inhaled
substances, alcohol, and drugs; the patient’s respiratory rate and blood flow;
the patient’s percent body fat; and individual variation in drug metabolism.
The higher the blood-to-gas coefficient, the more soluble the substance is in
blood. Substances with a low blood-to-gas partial coefficient, like nitrous ox-
ide, are rapidly taken up by the brain and, conversely, are rapidly eliminated
from the brain once exposure is ended (Table 79–1).
Inhalants are eliminated unchanged via respiration, undergo hepatic metabo-
lism or both. Nitrous oxide and the aliphatic hydrocarbons are frequently elim-
inated unchanged in the expired air. The aromatic hydrocarbons are usually
metabolized extensively via the cytochrome P450 (CYP) system, particularly
CYP2E1, which has a substrate spectrum that includes a number of aliphatic,
aromatic, and halogenated hydrocarbons.

Volatile Alkyl Nitrites

Unlike other volatile hydrocarbons, the volatile alkyl nitrites are not thought
to have any direct effects on the CNS. Their effects are mediated through
smooth muscle relaxation and they share a common cellular pathway with
other nitric oxide (NO) donors, like nitroglycerin and sodium nitroprusside.
Anesthetic uptake or induction, as well as emergence with N

2O, is rapid be-
cause of its low solubility in blood, muscle, and fat. There is no appreciable
metabolism of N

2O in human tissue. An animal study found that N

2O signifi-
cantly inhibited excitatory NMDA-activated currents and had no effect on
GABA-activated currents.


Signs and symptoms of inhalant use may be subtle, vary widely among individ-
uals, and generally resolve within 2 hours of exposure. There may be a distinct
odor on the patient’s breath or clothing, as well as discoloration of skin around
the nose and mouth. Mucous membrane irritation may cause sneezing, cough-
ing, and tearing. Patients may complain of dyspnea and palpitations. Gas-
trointestinal complaints include nausea, vomiting, and abdominal pain. After an
initial period of euphoria, patients may have residual headache and dizziness.

Volatile Hydrocarbons

Initial CNS effects include euphoria and hallucinations (both visual and audi-
tory), as well as headache and dizziness. As toxicity progresses, CNS depres-
sion worsens and patients may develop slurred speech, confusion, tremor, and
weakness. Transient cranial nerve palsies are reported. Further CNS depres-
sion is marked by ataxia, lethargy, seizures, coma, and respiratory depression.
These acute effects generally resolve spontaneously.
Toxicity from chronic use is manifested most strikingly in the central ner-
vous system. Leukoencephalopathy, characterized by dementia, ataxia, eye
movement disorders, and anosmia, is the prototypical manifestation of
chronic inhalant neurotoxicity. Neurobehavioral deficits include inattention,


TABLE 79–1.Blood:Gas Partition Coefficients, Routes of Elimination, and Important Metabolites of Selected Inhalants


Blood:Gas Partition
Coefficient (98.6°F/37°C)

Routes of Elimination

Important Metabolites



Largely unchanged via exhalation
95% and urine 5%




Largely unchanged via exhalation


Carbon tetrachloride


50% unchanged via exhalation;
50% hepatic metabolism and uri-
nary excretion

CYP2E1 to trichloromethyl radical, trichloromethyl peroxy
radical, phosgene



10–20% exhaled unchanged;
hepatic metabolism and urinary

CYP2E1 to 2-hexanol, 2,5-hexanedione, γ-valerolactone

Methylene chloride


92% exhaled unchanged; hepatic
metabolism and urinary excretion

(1) CYP2E1 to CO and CO


(2) Glutathione transferase to CO

2, formaldehyde, and for-

mic acid

Nitrous oxide


>99% exhaled unchanged




<20% exhaled unchanged;

CYP2E1 to benzoic acid, then

>80% hepatic metabolism and uri-
nary excretion

(1) glycine conjugation to form hippuric acid (68%)
(2) glucuronic acid conjugation to benzoyl glucuronide (insig-
nificant pathway except following large exposure to toluene)



91% exhaled unchanged; hepatic
metabolism and urinary excretion

CYP2E1 to trichloroethanol, then
(1) conjugated wih glucuronic acid (urochloralic acid) or
(2) further oxidized to trichloracetic acid



16% exhaled unchanged; 84%
hepatic metabolism and urinary

CYP2E1 to epoxide intermediate (transient); chloral hydrate
(transient); trichloroethanol (45%), trichloroacetic acid (32%)



apathy, and impaired memory and visuospatial skills with relative preserva-
tion of language.

Acute cardiotoxicity associated with hydrocarbon inhalation is manifested
most dramatically in “sudden sniffer’s death.” The inhalant “sensitizes the myo-
cardium” by blocking the potassium current (I

Kr), thereby prolonging repolariza-
tion. This produces a substrate for dysrhythmia propagation. Activity or stress
then causes a catecholamine surge that initiates the dysrhythmia. Although car-
diotoxic effects of inhalant abuse are generally acute, dilated cardiomyopathy is
reported with chronic abuse of toluene and with trichloroethylene.
The primary respiratory complication of inhalational substance abuse is
hypoxia, which is either a result of rebreathing of exhaled air, as occurs with
bagging, or displacement of inspired oxygen with the inhalant, reducing the

2. Direct pulmonary toxicity associated with inhalants is most often a re-
sult of inadvertent aspiration of a liquid hydrocarbon, producing acute lung
injury. Irritant effects on the respiratory system are frequently transient, but
patients may develop chemical pneumonitis, characterized by tachypnea, fe-
ver,tachycardia, rales/rhonchi, leukocytosis, and radiographic abnormalities.
Barotrauma presents as pneumomediastinum or subcutaneous emphysema.
Hepatoxicity is associated with exposure to halogenated hydrocarbons,
particularly carbon tetrachloride, as well as chloroform, trichloroethane, tri-
chloroethylene, and toluene. Renal toxicity is most frequently described follow-
ing inhalation of toluene. Production of hippuric acid, a toluene metabolite, is the
most likely etiology for the nephrotoxicity. The excretion of abundant hippurate
in the urine unmatched by ammonium mandates an enhanced rate of excretion of
sodium and potassium cations. Continued loss of potassium in the urine leads to
hypokalemia. Toluene is rapidly metabolized to hippuric acid, and the hippurate
anion is swiftly cleared by the kidneys, leaving the hydrogen ion behind. This
prevents the rise in anion gap that would normally occur with an acid anion other
than chloride, generating a normal anion gap. Thus toluene abusing patients may
present with profound hypokalemic muscle weakness.
Vesicular lesions resembling frostbite and massive, potentially life-threat-
ening edema of the oropharyngeal, glottic, epiglottic and paratracheal struc-
tures are caused by the cooling of the gas associated with its rapid expansion
once released from its pressurized container.
Methylene chloride, (dichloromethane), most commonly found in paint re-
movers and degreasers, is unique among the halogenated hydrocarbons in
that it undergoes metabolism in the liver by CYP2E1 to carbon monoxide. In
addition to acute CNS and cardiac manifestations, inhalation of methylene
chloride is associated with delayed onset and prolonged duration of signs and
symptoms of carbon monoxide poisoning.
Methanol toxicity is reported following intentional inhalation of methanol-
containing carburetor cleaners. Significant findings may include metabolic
acidosis, CNS and respiratory depression, and blindness.
Chronic inhalation of the solvent n-hexane, a simple aliphatic hydrocarbon
found in rubber cement among other places, may cause a sensorimotor pe-
ripheral neuropathy. Numbness and tingling of the fingers and toes is the
most common initial complaint; progressive, ascending loss of motor func-
tion with quadriparesis may ensue.


Fetal solvent syndrome (FSS) was first reported in 1979 and is characterized
by facial dysmorphia, growth retardation, and microcephaly, a constellation



of findings that resembles fetal alcohol syndrome. Compared to matched con-
trols, infants born to mothers who report inhalant abuse are more likely to be
premature, to be low birth weight, to have smaller birth length, and to have
small head circumference. Followup studies of these infants show develop-
mental delay compared to children matched for age, race, sex, and socioeco-
nomic status.


Observed similarities in the acute effects of inhalants compared with other
CNS depressants have suggested similar patterns of tolerance and with-
drawal. Symptoms include sleep disturbances, nausea, tremor, and irritability
lasting 2–5 days after last use. Whether this represents a true withdrawal syn-
drome or residual effects of the inhalant is unclear.

Volatile Alkyl Nitrites

Methemoglobinemia caused by inhalation of amyl, butyl, and isobutyl ni-
trites is well reported. Patients may present with signs and symptoms of
methemoglobinemia, including shortness of breath, cyanosis, tachycardia,
and tachypnea.

Nitrous Oxide

Reported deaths associated with abuse of nitrous oxide (N

2O) appear to be a

consequence of secondary effects of N

2O, including asphyxiation and motor
vehicle collisions while under the influence, and not a consequence of direct
toxicity. Chronic abuse of nitrous oxide is associated with neurologic toxicity
mediated via irreversible oxidation of the cobalt ion of cobalamin (vitamin

12). Myeloneuropathy resembles the subacute combined degeneration of the
dorsal columns of the spinal cord of classic vitamin B

12deficiency. Presenting
signs and symptoms reflect varying involvement of the posterior columns, the
corticospinal tracts, and the peripheral nerves. Numbness and tingling of the
distal extremities is the most common presenting complaint. Physical examina-
tion may reveal diminished sensation to pinprick and light touch, vibratory sen-
sation and proprioception, gait disturbances, the Lhermitte sign (electric shock
sensation with neck flexion), hyperreflexia, spasticity, urinary and fecal inconti-
nence, and extensor plantar response.


Routine urine toxicology screens are not capable of detecting inhalants or their
metabolites. Most volatile agents are detectable using gas chromatography after
exposure; the likelihood of detection is limited by the dose, time to sampling, and
storage of the specimen. Blood is the preferred specimen, but urinalysis for me-
tabolites such as hippuric acid (for toluene) may extend the time until the limit of
detection is reached. Depending on the patient’s signs and symptoms additional
diagnostic testing may be indicated, including an electrocardiogram, chest radio-
graph, serum electrolytes, liver enzymes, and serum pH. The patient’s presenting
complaint(s) should guide decisions regarding further diagnostic testing.


Management begins with assessment and stabilization of the patient’s airway,
breathing, and circulation. The patient should be connected to a pulse oxime-



ter and cardiac monitor. Oxygen should be administered and the patient
should be treated with nebulized albuterol if wheezing is present. Early con-
sultation with a regional poison control center may assist with identification
of the toxin and patient management.
Cardiac dysrhythmias associated with inhalant abuse carry a poor prognosis.
Life-threatening electrolyte abnormalities must be considered early and corrected
in the patient presenting with dysrhythmias. Patients with nonperfusing rhythms
should receive standard management with defibrillation. There are no evidence-
based treatment guidelines for the management of inhalant-induced cardiac dys-
rhythmias, but agents with β-adrenergic antagonist activity are thought to offer
some cardioprotective effects to the sensitized myocardium.
Other complications, including methemoglobinemia, elevated carboxyhe-
moglobin, and methanol toxicity, should be managed with the appropriate an-
tidotal therapy. Patients with respiratory symptoms that persist beyond the
initial complaints of gagging and choking should be evaluated for hydrocar-
bon pneumonitis and treated supportively. Agitation, either from acute effects
of the inhalant or from withdrawal, is safely managed with a benzodiazepine.
In the vast majority of patients, symptoms resolve quickly and hospitalization
is not required.


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