84: Inhalants

Inhalant abuse is defined as the deliberate inhalation of vapors for the purpose of changing consciousness or becoming “high.” It is also referred to as volatile substance abuse and was first described in medical literature in 1951.³⁷ Inhalants are appealing to adolescents because they are inexpensive, readily available, and sold legally. Initially, inhalant abuse was viewed as physically harmless, but reports of “sudden sniffing death” began to appear in the 1960s.¹¹ Shortly thereafter, evidence surfaced of other significant morbidities, including organic brain syndromes, peripheral neuropathy, and withdrawal.

The demographics of inhalant abuse differ markedly from those of other traditional substances of abuse. According to the 2011 National Survey on Drug Use and Health, inhalants continued to be the most frequently reported illicit xenobiotics used by 12 and 13 year-olds. The age at initiation of illicit drug use is youngest for those choosing inhalants, and the reported usage of inhalants peaked at age 14.¹⁴⁰ A worrisome trend reported by the 2011 Monitoring the Future study is that although the perceived risk of even one-time use of an inhalant has fallen steadily since 2001, and a study of 279 youths who were lifetime inhalant users found 37% perceived experimental inhalant use of slight or no risk.^100,116

In the United States, the problem is greatest among children of lower socioeconomic groups. Non-Hispanic white adolescents are the most likely and black adolescents the least likely to use inhalants.^14,96 Although inhalant use is a problem in both urban and rural communities, it is more prevalent in rural settings.^96,134 This may relate to the easier access that teens in urban areas have to other drugs of abuse.

Inhalant abuse includes the practices of sniffing, huffing, and bagging. Sniffing entails the inhalation of a volatile substance directly from a container, as occurs with modeling glue or rubber cement. Huffing involves pouring a volatile liquid onto fabric, such as a rag or sock, and placing it over the mouth, nose, or both while inhaling and is the method used by more than 60% of volatile-substance abusers.⁹⁶ Bagging refers to instilling a solvent into a plastic or paper bag and rebreathing from the bag several times; spray paint is among the xenobiotics commonly used with this method.

There are myriad xenobiotics abused as inhalants (Table 84–1), most of which are volatile hydrocarbons. Hydrocarbons are organic compounds comprised of carbon and hydrogen atoms and are divided into two basic categories: aliphatic (straight, branched, or cyclic chains) and aromatic. Most of the commercially available hydrocarbon products are mixtures of hydrocarbons; for example, gasoline is a mixture of aliphatic and aromatic hydrocarbons that may consist of more than 1500 compounds. Substituted hydrocarbons contain halogens or other functional groups such as hydroxyl or nitrite that are substituted for hydrogen atoms in the parent structure. Solvents are themselves a heterogeneous group of xenobiotics that are used to dissolve other chemical compounds or provide a vehicle for their delivery.

The most commonly inhaled volatile hydrocarbons are fuels, such as gasoline, and solvents, such as toluene.¹³⁴ Other commonly inhaled hydrocarbon-containing products include spray paints, lighter fluid, air fresheners, and glue. In most reported cases of inhalant use, the inhalant is identified not by its chemical name (eg, butane and toluene) but rather by its intended use (eg, lighter fluid and paint thinner). Because exact components may vary between products, identification by the intended commercial use of the product is inaccurate and imprecise. The choice of xenobiotic used likely reflects their availability: cases from the 1970s frequently reported abuse of antiperspirants and typewriter correction fluid; computer and electronics cleaners have replaced these products. Dusting refers to the inhalation of compressed air cleaners containing halogenated hydrocarbons (eg, CRC Dust Off), marketed for cleaning computer keyboards and electronics equipment. Reports of exposures to these products, including death and ventricular dysrhythmias, doubled in 2005 and tripled in 2006.⁹⁵ Of the 30 deaths attributed to recreational inhalant use in North Carolina between 2000 and 2008, one-third involved compressed-air products; yet, dusting is not perceived to be harmful by users and, surprisingly, many users do not consider it a form of inhalant abuse.^64,95

Although volatile alkyl nitrites are technically substituted hydrocarbons, they have pharmacologic and behavioral effects, as well as patterns of abuse, distinct from the other volatile hydrocarbons. For this reason, researchers usually classify them as a separate category among abused inhalants. Amyl nitrite is the prototypical volatile alkyl nitrite.⁹ Amyl nitrite became popular in the 1960s with the appearance of “poppers,” small glass capsules containing the chemical in a plastic sheath or gauze. When crushed, the ampules release the amyl nitrite. When nonprescription sales of amyl nitrite were restricted in 1968, sex and drug paraphernalia shops began ­selling small vials of butyl and isobutyl nitrites marketed as room deodorizers or liquid incense.^9,91 Because of further restrictions on sales of alkyl nitrites, most of these products now contain chemicals not technically alkyl nitrites, such as cyclohexyl nitrite.⁹

The most commonly used non–hydrocarbon inhalant is nitrous oxide. Nitrous oxide, or “laughing gas,” is used medicinally as an inhalational anesthetic (Chap. 68). It is the propellant in supermarket-bought whipped cream canisters, and cartridges of the compressed gas are sold for home use in whipped cream dispensers. These battery-sized metal containers of compressed gas may be used as “whippits,” in which the container is punctured using a device known as a “cracker,” and the escaping gas is either inhaled directly or collected in a balloon and then rebreathed.

Although chemically heterogeneous, inhalants are generally highly lipophilic and gain rapid entrance into the central nervous system (CNS). Little is known about the cellular basis of the effects of inhalants. Evidence to date shows that the most commonly abused hydrocarbons have molecular mechanisms similar to those of other classic CNS depressants, frequently with common cellular sites of action. Their effects are probably best represented by the model for ethanol in which multiple different cellular mechanisms explain diverse pharmacologic and toxicologic effects.⁹

Volatile Hydrocarbons

The clinical effects of the volatile hydrocarbons are likely mediated through stimulation of inhibitory neurotransmission and antagonism of excitatory neurotransmission within the CNS. Like ethanol, toluene, trichloroethane (TCE), and trichloroethylene enhance γ-aminobutyric acid type A (GABA_A) receptor–mediated synaptic currents as well as glycine-receptor–activated ion function. Stimulation of these receptors acts to increase chloride permeability, hyperpolarizing the neuronal cell membrane and inhibiting excitability.^16,70,136 Like inhaled anesthetics, these abused inhalants appear to act presynaptically on the GABA_A nerve terminals. Toluene-induced increase in inhibitory synaptic current is blocked by dantrolene and ryanodine, suggesting toluene effects release of calcium from intracellular nerve terminal stores.⁹⁰ Despite very different molecular structures, ethanol, enflurane, chloroform, toluene, and TCE compete for binding sites at α₁ glycine receptors.¹⁵ Like ethanol and subanesthetic concentrations of isoflurane, toluene, TCE, and benzene all interfere with glutamate-mediated excitatory neurotransmission by inhibiting N-methyl-d-aspartate (NMDA) receptor–mediated currents in a concentration dependent manner.^8,39,118,129 Furthermore, repeated toluene exposure increases NMDA receptors, suggesting that chronic exposure can lead to upregulation of excitatory neurotransmission as occurs with ethanol.^8,157

Toluene is the prototypical volatile hydrocarbon and the best studied. In animal models, differences in pharmacologic action are demonstrated between toluene and other alkylbenzenes, and halogenated hydrocarbons such as TCE, and acetone.^{22,39,85,130,144} These differences may represent evidence that specific cellular sites for their actions exist. In addition, these differences may explain the variation in their abuse potential or their clinical effects.^9,85 Despite these distinctions, there are marked similarities in the behavioral and pharmacologic effects of the volatile hydrocarbons. Moreover, the clinical effect profile shared by the volatile hydrocarbons, subanesthetic concentrations of general anesthetics, ethanol, and benzodiazepines suggests that they share cellular mechanisms. Shared clinical effects include anxiolysis,²⁷ anticonvulsant effects,¹⁵⁹ impaired motor coordination,¹⁰³ and evidence of physical dependence on withdrawal.^47,48

Most research on inhalants has focused on the neural basis of their effects, yet it is the cardiotoxicity that is responsible for the majority of their lethal effects. In vivo, toluene reversibly inhibits myocardial voltage-activated sodium channels.⁴⁰ Similarly, it inhibits muscle sodium channels but with less potency.⁵⁵ Ethanol and toluene have opposite effects on potassium channels in vivo; ethanol potentiates the large conductance, calcium-activated potassium channels as well as certain G protein-coupled inwardly rectifying potassium channels, while toluene inhibits them.⁴² The combined inhibition of the sodium channels and the inwardly rectifying potassium channels is postulated to play a role in cardiac dysrhythmias and sudden sniffing death associated with the aromatic and halogenated hydrocarbons. Animal studies show toluene and 1,1,1-trichloroethane produce biphasic dose–response curves for motor activity: low concentrations yield motor excitation, while high concentrations produce sedation, motor impairment, and anesthesia.^23,152 Molecular mechanisms underlying both the neural and cardiac effects may maximize the risk effects and explain the observed clinical phenomenon described in sudden sniffing deaths (see below).

Scant data exist on the pharmacokinetics of the inhalants. Most data are derived from studies on occupational and environmental exposures and have limited applicability to intentional inhalation. More relevant to the understanding of inhalants are the similarities with the inhalational anesthetics, many of which are also halogenated hydrocarbons. Factors determining pharmacokinetic and pharmacodynamic effects of a given inhalational anesthetic include its concentration in inspired air; partition coefficient; interaction with other inhaled substances, ethanol, and drugs; the patient’s respiratory rate and blood flow; percent body fat; and individual variation in drug metabolism (Chap. 68).⁵⁹

Partition coefficients measure the relative affinity of a gas for two different substances at equilibrium and are used to predict the rate and extent of uptake of an inhaled substance. The blood:gas partition coefficient is most commonly referenced. The higher the number, the more soluble the substance is in blood. Substances with a low blood:gas partition coefficient, like nitrous oxide, are rapidly taken up by the brain and, conversely, are ­rapidly eliminated from the brain once exposure is ended (Table 84–2).

In a rodent model of inhalation abuse of toluene and acetone, the rapidity of onset and the extent of CNS depression were dependent on the concentration of the solvent inhaled.³⁰ There was a parallel relationship between brain concentration and pharmacologic effect during induction (inhalation) and postexposure. Brain and liver concentrations dropped rapidly after exposure; concentration in blood decreased at the slowest rate. Elimination was biphasic: rapid elimination during the first step was a result of tissue redistribution, alveolar ventilation, and metabolic clearance. During the second phase, there was a slow decrease in tissue concentrations as a result of the gradual mobilization from adipose tissue with subsequent exhalation or metabolism. Acetone, which is more water soluble than toluene, is less potent and slower acting than toluene, but is eliminated much more slowly than toluene and has a much longer duration of action.³⁰ Positron emission tomography (PET) studies using (¹¹ C) radiolabeled toluene, butane, and acetone in nonhuman primates showed rapid uptake of radioactivity in striatal and frontal regions of the cortex followed by rapid clearance from the brain.⁵⁶ Whole-body PET scans in mice showed excretion through the kidneys and liver.⁵⁷

The inhalants are eliminated unchanged by the lungs, they undergo hepatic metabolism, or both (Table 84–2). For some, the percentage that is metabolized versus eliminated unchanged varies with the exposure dose. Nitrous oxide and the aliphatic hydrocarbons are frequently eliminated unchanged in the expired air. The aromatic and halogenated hydrocarbons are 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.^20,65,66,160 Extrahepatic expression of CYP2E1 occurs to a lesser extent but may be of toxicologic significance, particularly in the kidneys and the dopaminergic cells of the substantia nigra.^21,71,148 In humans, there appears to be no significant gender difference in CYP2E1 activity; however, it is polymorphic and, as such, allelic distributions vary among different human populations.^21,132 Moreover, this polymorphism may explain the varying degrees of toxicity exhibited following inhalant abuse.

Reward and reinforcement effects of inhalants are readily demonstrated. While the mechanisms underlying their reinforcement behavior remain poorly studied, activation of the mesolimbic dopamine system is thought to play an important role in solvent abuse, similar to more commonly studied drugs of abuse.^57,121 Interestingly, the reward and reinforcement effects of ­toluene appear to vary with age of exposure, suggesting that physiologic as well as psychosocial factors play a role in the prevalence of inhalant abuse among adolescents compared with adults.^12,25,109 Furthermore, age at exposure differentially affects dendritic growth in the brain suggesting that the adolescent brain is more at risk for cognitive impairment following inhalant use.¹¹¹

Volatile Alkyl Nitrites

Unlike other volatile hydrocarbons, the volatile alkyl nitrites do not have any demonstrable direct effects on the CNS. Their effects are mediated through smooth muscle relaxation in the central and peripheral vasculature, and they share a common cellular pathway with other nitric oxide (NO) donors similar to nitroglycerin and sodium nitroprusside.⁷⁹ A rat model of inhalation of isobutyl nitrite found a half-life of 1.4 minutes with almost 100% biotransformation to isobutyl alcohol. Bioavailability following inhalation was estimated to be 43%.⁷⁸

Nitrous Oxide

The pharmacokinetics and pharmacodynamics of nitrous oxide (N₂O) abuse are derived from its use as an inhalational anesthetic. Anesthetic uptake or induction, as well as emergence with N₂O, is rapid because of its low solubility in blood, muscle, and fat.¹³⁷ No appreciable metabolism of N₂O is present in human tissue. An animal study found N₂O significantly inhibited excitatory NMDA-activated currents and had no effect on GABA-activated currents.⁷² N₂O also stimulates dopaminergic neurons, but the significance of this in mediating its anesthetic effects remains unclear.^76,104

Animal studies suggest the analgesic effects (or more accurately the antinociceptive effects because it refers to animals) of N₂O appear to be mediated through opioid peptide release in the midbrain. These antinociceptive effects can be reversed by the opioid antagonist naloxone.¹⁸ However, in humans the anesthetic effects are not attenuated by naloxone, and the subjective and psychomotor effects of N₂O are not extinguished by even high doses of naloxone.^133,161

Signs and symptoms of inhalant use may be subtle, tend to vary widely among individuals, and generally resolve within several hours of exposure. Following acute exposure, there may be a distinct odor of the abused inhalant on the patient’s breath or clothing. Depending on the inhalant used and the method, there may be discoloration of skin around the nose and mouth. Mucous membrane irritation may cause sneezing, coughing, and tearing. Patients may complain of dyspnea and palpitations. Gastrointestinal complaints include nausea, vomiting, and abdominal pain. After an initial period of euphoria, patients may have residual headache and dizziness.

Volatile Hydrocarbons

The CNS is the intended target of the inhalants and is most susceptible to its adverse effects. Initial CNS effects include euphoria and hallucinations, both visual and auditory, as well as headache and dizziness. As toxicity progresses, CNS depression worsens and patients may develop slurred speech, confusion, tremor, and weakness. Transient cranial nerve palsies are reported.¹⁴² Further CNS depression is marked by ataxia, lethargy, seizures, coma, and respiratory depression. These acute encephalopathic effects ­generally resolve spontaneously and associated neuroimaging abnormalities are not reported.⁵⁰

As can be expected, given the high lipophilicity of most inhalants, toxicity from chronic use is manifested most strikingly in the CNS. Toluene leukoencephalopathy, characterized by dementia, ataxia, eye movement disorders, and anosmia, is the prototypical manifestation of chronic inhalant neurotoxicity. Patients with toluene leukoencephalopathy display characteristic neurobehavioral deficits reflecting white matter involvement, including inattention, apathy, impaired memory, and visuospatial skills, with relative preservation of language.⁵⁰ Autopsy studies reveal white-matter degeneration including cerebral and cerebellar atrophy and thinning of the corpus callosum.^2,80,122 On microscopy, there is diffuse demyelination with relative sparing of the axons. Abundant perivascular macrophages containing coarse or laminar myelin debris found in areas of the greatest myelin loss is a characteristic pathologic feature.^2,50 This targeting of myelin, which is 70% lipid, may be explained by the lipophilicity of toluene.⁵⁰ As myelinization continues at least through the second decade of life, the typical toluene abuser who begins inhaling during adolescence may be particularly susceptible to its toxic CNS effects.⁴⁹ Advances in magnetic resonance imaging (MRI) with gadolinium, which allow enhanced visualization of the cerebral white matter, demonstrate that the extent of white matter injury in the brain directly corresponds to the clinical severity of toluene leukoencephalopathy.⁵⁰ It is postulated that reactive oxygen species generated either by toluene or its metabolite benzaldehyde induce lipid peroxidation in the brain.^93,120 Genetic polymorphisms and host susceptibility among chronic abusers are also hypothesized to play a role.⁶¹

Acute cardiotoxicity associated with hydrocarbon inhalation is manifested most dramatically in “sudden sniffing death.” In witnessed cases, sudden death frequently occurred when sniffing was followed by some physical activity. Examples include running or wrestling or a stressful situation like being caught sniffing by parents or police.¹¹ It is thought that the inhalant “sensitizes the myocardium” by blocking the potassium current (I_KR), thereby prolonging repolarization.¹⁰⁶ This produces a substrate for dysrhythmia propagation; the activity or stress then causes a catecholamine surge that initiates the dysrhythmia (Chap.16).¹⁰⁶ Cardiac dysrhythmias following the inhalation of hydrocarbons were documented with the halogenated inhalational anesthetics in the early 1900s, and this association was subsequently confirmed in both animal and human studies.^51,143

More typically, the clinical presentation of a patient with hydrocarbon cardiotoxicity may include palpitations, shortness of breath, syncope, and abnormalities on electrocardiography, including atrial fibrillation, premature ventricular contractions, QT interval prolongation, and U waves.

Multiple case reports of ventricular fibrillation follow intentional inhalation of other hydrocarbons such as butane fuel,^63,156 fluorinated hydrocarbons, and Glade Air Freshener (SC Johnson), which contains a mixture of short-chain aliphatic hydrocarbons.⁸⁷ Among 44 patients with a history of inhalant abuse, specifically toluene exposure, the QT interval and corrected QT dispersion were significantly greater than in healthy controls. Furthermore, the QT interval and corrected QT dispersion were significantly greater in the 20 toluene abusers with a history of unexplained syncope than in asymptomatic abusers and controls.³ Although cardiotoxic effects of inhalant abuse are generally acute, dilated cardiomyopathy is reported with chronic abuse of toluene and trichloroethylene.^97,158 Microscopy reveals evidence of chronic myocarditis with fibrosis.¹⁵⁸

The most significant respiratory complication of inhalational abuse is hypoxia, which is either caused by displacement of inspired oxygen with the inhalant, reducing the fraction of inspired oxygen (FiO₂), or by rebreathing of exhaled air, as occurs with bagging. Direct pulmonary toxicity associated with inhalants is most often a result of inadvertent aspiration of a liquid hydrocarbon (Chap. 108). Aspiration injury is associated with the acute respiratory distress syndrome, a continuum of lung injury characterized by increased permeability of the alveolar–capillary barrier and the resulting influx of edema into the alveoli, neutrophilic inflammation, and an imbalance of cytokines and other inflammatory mediators.¹⁵¹ Reports of asphyxiation initially ascribed to inhalant abuse were later found caused by suffocation by a plastic bag, mask, or container pressed firmly to the face, and not specifically by toxicity of the inhaled vapor.^11,34,150

Irritant effects on the respiratory system are frequently transient, but patients may develop chemical pneumonitis. This syndrome is characterized by tachypnea, fever, tachycardia, crackles, rhonchi, leukocytosis, and radiographic abnormalities, including perihilar densities, bronchovascular markings, increased interstitial markings, infiltrates, and consolidation. Acute eosinophilic pneumonia following abuse of a fabric protector containing 1,1,1-trichloroethane is also reported.⁷⁷ Barotrauma, from deep inhalation or breath holding, presents as pneumothorax, pneumomediastinum, or subcutaneous emphysema.¹²⁵

Hepatoxicity is associated with exposure to halogenated hydrocarbons, particularly carbon tetrachloride (CCl₄), as well as chloroform, trichloroethane, trichloroethylene, and toluene.⁹² Intentional inhalation of CCl₄ is rarely reported, but its toxic metabolite, the trichloromethyl radical, created by the cytochrome CYP2E1, can covalently bind to hepatocyte macromolecules and cause lipid peroxidation.¹¹⁹ This has led to a postulated antidotal role for hyperoxia and hyperbaric oxygen supported by some rat studies and human case reports.^32,146 Histologically, the potentially fatal centrilobular necrosis that occurs with CCl₄ mimics acetaminophen toxicity and antidotal N-acetylcysteine (NAC) therapy has been explored. Animal studies on the efficacy of NAC in preventing CCl₄–induced hepatoxicity have yielded mixed results.^38,41 There are no clinical trials in humans, but a case series suggest a protective role for NAC.¹²³ Two cases of centrilobular hepatic necrosis following inhalation of trichloroethylene are reported. In a case series of 34 serum-confirmed inhalant deaths, two of the three who died from trichloroethane and trichloroethylene inhalation had cirrhosis of the liver at autopsy. None of the victims of other inhalants had cirrhosis.⁵⁴ Inhalation of either toluene or one of the many halogenated hydrocarbons is associated with elevated liver enzymes and hepatomegaly that generally return to pre-exposure condition within 2 weeks of abstinence.^{7,69,74,86,105,108}

Most reported kidney toxicity is associated with toluene inhalation. Prolonged toluene inhalation was said to cause a distal renal tubular acidosis (RTA), resulting in hypokalemia. However, distal RTA is typically associated with a hyperchloremic metabolic acidosis and a normal anion gap, whereas toluene abuse may be associated with an increased anion gap. Production of hippuric acid, a toluene metabolite, plays an important role in the genesis of the metabolic acidosis.³⁵ Hippurate excretion, usually expressed as a ratio to creatinine, rises dramatically with toluene inhalation.⁹⁸ 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, thus leaving the hydrogen ion behind. This prevents the rise in the anion gap that would normally occur with an acid anion other than chloride, resulting in a normal anion gap. In some cases, the loss of sodium causes extracellular fluid volume contraction and a fall in the glomerular filtration rate, which may transform the metabolic acidosis with a normal anion gap into one with a high anion gap caused by the accumulation of hippurate and other anions.³⁵ Other renal abnormalities of uncertain etiology are associated with toluene inhalation, including hematuria, albuminuria, and pyuria. Glomerulonephritis associated with hydrocarbon inhalation is also reported and is a result of antiglomerular basement membrane antibody-mediated immune complex deposition.^17,147,162

Toluene-abusing patients may present with profound hypokalemic muscle weakness. In a study of 25 patients admitted to the hospital following inhalant abuse, nine presented with muscle weakness.¹³⁸ The mean serum potassium concentration was 1.7 mEq/L, and six of these patients also had rhabdomyolysis. Four patients were quadriplegic on presentation; of these, two were initially diagnosed erroneously with Guillain-Barré syndrome. The patients had inhaled toluene 6 to 7 hours per day for 4 to 14 days prior to presentation.¹³⁸

Acute dermatologic and upper airway toxicity is associated with the inhalation of fluorinated hydrocarbons. First- and second-degree burns of the face, neck, shoulder, and chest are reported in a 12 year-old girl inhaling a computer cleaner containing difluoroethane.¹⁰¹ Pyrolysis of difluoroethane may yield hydrofluoric acid burns.⁵² Vesicular lesions resembling frostbite and massive, potentially life-threatening edema of the oropharyngeal, glottic, epiglottic, and paratracheal structures are also reported.^1,81,95 This is caused by the cooling of the gas associated with its rapid expansion once it is released from its pressurized container. With chronic abuse of volatile hydrocarbons, patients may develop severe drying and cracking around the mouth and nose as a consequence of a defatting dermatitis known as “huffer’s eczema.” Other manifestations of chronic irritation include recurrent epistaxis, chronic rhinitis, conjunctivitis, halitosis, and ulceration of the nasal and oral mucosa.⁹⁸

Bone mineral density was significantly lower in 25 adolescent chronic glue sniffers compared with that of healthy controls.⁴⁵ In a mouse model, chronic exposure to toluene significantly reduced bone mineral density.⁵ Methylene chloride (dichloromethane), most commonly found in paint removers and degreasers, is unique among the halogenated hydrocarbons in that it undergoes metabolism in the liver by CYP2E1 to carbon monoxide.¹¹⁰ 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 (CO) poisoning. The CO metabolite is generated 4 to 8 hours after exposure and its apparent half-life is 13 hours, significantly longer than that of CO following inhalation (Chap. 125).^10,139 Methanol toxicity is reported following intentional inhalation of methanol-containing carburetor cleaners.^53,88,94 Significant findings may include hyperemic optic discs on funduscopic examination, metabolic acidosis, and CNS and respiratory depression (Chap. 109). Methanol-containing carburetor cleaners may also contain significant amounts of toluene (43.8%), methylene chloride (20.5%), and propane (12.5%). These xenobiotics may potentiate CNS depression and contribute to the ­toxicity associated with these products.

Chronic inhalation of the solvent n-hexane, a petroleum distillate and a simple aliphatic hydrocarbon found, for example, in rubber cement, can cause a sensorimotor peripheral neuropathy. Toxicity is mediated via a metabolite, 2,5-hexanedione, which interferes with glyceraldehyde-3-phosphate dehydrogenase–dependent axonal transport, resulting in axonal death.⁴⁴ Numbness and tingling of the fingers and toes is the most common initial complaint; progressive, ascending loss of motor function with frank quadriparesis may ensue.³⁶ Sural nerve biopsy shows axonal swelling and axonal loss, with secondary loss of myelin, probably as a result of retraction by axonal swelling, and accumulation of neurofilaments.⁸² Nerve conduction studies show marked slowing and blockade (Chap. 24).^36,82

Reports of polyneuropathy associated with chronic gasoline inhalation date to the 1960s and describe a symmetric, progressive, sensorimotor neuropathy with occasional superimposed mononeuropathies.^31,75 Initially, these deficits were attributed to the presence of tetraethyl lead as an “antiknocking” agent in gasoline, but cases following abuse of unleaded gasoline are also reported.^31,126 n-Hexane is present in gasoline in concentrations of up to 3% and is thought to be the likely mediator of gasoline neuropathy.¹⁵³

Teratogenicity.

Fetal solvent syndrome (FSS) was first reported in 1979.¹⁴⁵ The authors described a 20 year-old primigravida woman with a 14 year history of solvent abuse defined as “daily” and “heavy” who gave birth to an infant exhibiting facial dysmorphia, growth retardation, and microcephaly, a constellation of findings that resembles fetal alcohol syndrome (FAS). Since then, many cases and case series have been reported.^4,68,124,155 A general limitation of these case series is their reliance on self-reporting of substance abuse. In a number of cases included for analysis of teratogenic effects, mothers admit to use during pregnancy of other potential teratogens, including ethanol, cocaine, heroin, and phenobarbital.^4,155 Cases purported to represent inhalant abuse in the absence of other drug abuse, particularly ethanol, are not verified by laboratory testing. A small study of infants born to mothers with a self-reported history of chronic solvent abuse found 16% had major anomalies, 12.5% had facial features resembling FAS, and 3.6% had cleft palate.¹²⁴ Craniofacial abnormalities common to both FAS and FSS include small palpebral fissures, thin upper lip, and midfacial hypoplasia. Features of FSS that distinguish it from FAS include micrognathia, low-set ears, abnormal scalp hair pattern, large anterior fontanelle, and downturned corners of the mouth.¹⁴⁵ Hypoplasia of the philtrum and nose are more characteristic of FAS.¹¹³ Compared with matched controls, infants born to mothers who report inhalant abuse are more likely to be premature, have low birth weight, have smaller birth length, and have small head circumference.^4,155 Follow-up studies of these infants show developmental delay when compared with children matched for age, race, sex, and socioeconomic status.^4,68 A rat model of toluene abuse embryopathy found a significant reduction in the number of neurons within each cortical layer, as well as abnormal neural migration.⁶⁰ In animal models of inhalant abuse, exposure to brief, repeated, high concentrations of toluene significantly increases rates of growth restriction, minor malformations, and impaired motor development.^24,73 In another rat model of maternal inhalant abuse, toluene concentrations in fetal brain tissue, the placenta, and amniotic fluid increased in a concentration-dependent manner.²⁶

Withdrawal.

Observed similarities in the acute effects of inhalants compared with other CNS depressants have suggested similar patterns of tolerance and withdrawal. Rodent models of inhalant abuse with toluene and TCE show evidence of physical dependence that manifests as an increase in handling-induced seizures on cessation of inhalation.^48,154 In addition, these studies demonstrate cross-tolerance of the benzodiazepine diazepam with the motor-stimulating effects of TCE and, to a lesser degree, with toluene. Inhalant abusers have themselves described tolerance with weekly usage in as little as 3 months.⁶² Withdrawal symptoms, including irritability, insomnia, craving, nausea, tremor, and dry mouth lasting 2 to 5 days after last use, are described.¹²⁸

VOLATILE ALKYL NITRITES

Methemoglobinemia caused by inhalation of amyl, butyl, and isobutyl nitrites is well reported.^28,89 Nitrites are strong oxidants that may induce hemoglobin oxidation from the ferrous (Fe²⁺) to the ferric (Fe³⁺) state. Patients may present with signs and symptoms of methemoglobinemia, including shortness of breath, cyanosis, tachycardia, and tachypnea (Chap. 127). Eye pain, transient increased intraocular pressure, and progressive bilateral visual loss are reported following use of amyl nitrite.^6,112,114

Nitrous Oxide

Reported deaths associated with abuse of nitrous oxide (N₂O) appear to be caused by secondary effects of N₂O, including asphyxiation and motor vehicle collisions while under the influence, and not a direct toxic effect.^141,150 Investigations following deaths associated with N₂O have found that many of the people who died were discovered with plastic bags over their heads, in an apparent attempt to both prolong the duration of effect and increase the concentration of the inhalant.¹⁵⁰ Autopsy findings in these cases were consistent with asphyxiation: acute respiratory distress syndrome, cardiac petechiae, and generalized visceral congestion.^141,150 Laboratory simulation of a reported death in which the victim was found with a plastic bag over his head with a belt fastened loosely around his neck and a spent whipped cream canister within the plastic bag showed that N₂O displaces oxygen in a closed space.¹⁵⁰ In addition, N₂O concentrations in this simulation were above 60%; at concentrations of N₂O above 50%, the normal hypoxic response is diminished.¹⁵⁰ The combined effects of displaced oxygen and a blunted hypoxic drive may increase the risk of asphyxia.

Chronic abuse of N₂O is associated with neurologic toxicity mediated via irreversible oxidation of the cobalt ion of cyanocobalamin (vitamin B₁₂). Oxidation blocks formation of methylcobalamin, a coenzyme in the production of methionine and S-adenosylmethionine, required for methylation of the phospholipids of the myelin sheaths. In addition, cobalamin oxidation inhibits the conversion of methylmalonyl to succinyl coenzyme A. The resultant accumulation of methylmalonate and propionate can result in synthesis of abnormal fatty acids and their subsequent incorporation into the myelin sheath (Chap. 68).¹¹⁵ Case reports and small case series in humans following self-reported chronic, heavy abuse of N₂O describe the development of a myeloneuropathy resembling the subacute combined degeneration of the dorsal columns of the spinal cord of classic vitamin B₁₂ deficiency.^19,84,149 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 examination may reveal diminished sensation to pinprick and light touch, vibratory sensation and proprioception, gait disturbances, the Lhermitte sign (electric shock sensation from the back into the limbs with neck flexion), hyperreflexia, spasticity, urinary and fecal incontinence, and extensor plantar response.^33,115 Among reported patients with N₂O-associated neurotoxicity who had documented concentrations of vitamin B₁₂, approximately 50% were low.^{19,33,84,135,149} In the few patients who underwent Schilling tests to evaluate for potential vitamin B₁₂ deficiency results were normal.^84,149 MRI of the spinal column may reveal enhancement and edema of the central and dorsal aspects of the spinal cord.¹¹⁷ Nerve conduction studies and electromyography typically revealed a distal, axonal sensorimotor polyneuropathy.^33,84,149

Routine urine toxicology screens are unable to detect inhalants or their metabolites. Although most volatile inhalants can be detected using gas chromatography, the likelihood of detection is limited by the dose, time to sampling, and method of specimen storage. Blood is the preferred specimen, but urinalysis for metabolites, including hippuric acid (the toluene metabolite) and methyl hippuric acid (the xylene metabolite), may extend the time until the limit of detection is reached.^29,83 Specimens should be stored at a temperature between 23°F (–5°C) and 39.2°F (4°C).²⁵ Testing is not readily available at most institutions and the need to send the specimen to a reference laboratory limits the clinical utility in most situations. A thorough history and physical examination and careful questioning of the friends and family of the patient are probably more helpful in cases of suspected inhalant abuse.

Depending on the patient’s signs and symptoms, additional diagnostic testing may be indicated, including electrocardiography, chest radiography, and laboratory studies (electrolytes, liver enzymes, and blood pH). Inhalation of some xenobiotics presents unique diagnostic considerations (Table 84–3). Routine laboratory testing, including cerebrospinal fluid analysis, is unremarkable in patients with inhalant-induced leukoencephalopathy. Computed tomography of the head is generally normal until late in the disease when diffuse hypodensity of white matter becomes evident. T2-weighted MRI with its superior resolution of white matter is the diagnostic study of choice. Standard MRI does not detect initial changes caused by toluene leukoencephalopathy; measurement of N-acetyl aspartate (NAA), a marker of CNS axonal damage, with magnetic resonance spectroscopy may assist with earlier detection. A decrease in NAA concentration, usually expressed as the ratio of NAA to creatinine (NAA:Cr), may serve as a marker of axonal damage.⁵⁰

Management begins with assessment and stabilization of the patient’s airway, breathing, and circulation (the “ABCs”). The patient should be attached to a pulse oximeter and cardiac monitor. Oxygen should be administered and the patient should be treated with nebulized β-adrenergic agonists if wheezing is present. Early consultation with a regional poison center or medical toxicologist may assist with identification of the xenobiotic and patient management.

Cardiac dysrhythmias associated with inhalant abuse carry a poor prognosis. Sudden death following use is not limited to novices and there appears to be no premonitory signal to the user.^8,11,105 Life-threatening electrolyte abnormalities must be considered and corrected in the patient presenting with dysrhythmia. Patients with nonperfusing rhythms should be managed following standard management with defibrillation. There are no evidence-based treatment guidelines for the management of inhalant-induced cardiac dysrhythmias, but β-adrenergic antagonists are thought to offer some cardioprotective effects to the sensitized myocardium.¹⁰⁶ Propranolol and esmolol both have been used successfully in treatment of ventricular dysrhythmias following inhalant abuse.^58,102

Fluid and electrolyte abnormalities should be sought and corrected early. In the course of management, other complications, including methemoglobinemia, elevated carboxyhemoglobin, and methanol toxicity, should be managed with the appropriate antidotal therapy. Patients with respiratory symptoms persisting beyond the initial complaints of gagging and choking should be evaluated for hydrocarbon pneumonitis and treated supportively (Chap. 108).

With abstinence, cognitive and neuroimaging changes associated with toluene-induced leukoencephalopathy may initially be partially reversible; beyond a poorly defined period, these changes are irreversible.^43,50 Cessation of abuse is the most important therapeutic intervention in patients with n-hexane–induced neuropathy. In N₂O-induced myeloneuropathy ­limited anecdotal evidence supports the coadministration of vitamin B₁₂ (1000 µg intramuscularly) and methionine (1 g orally).^33,127,135

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. The potential toxicity of inhalants should be reinforced and patients should be referred for counseling. Subsets of users who meet the criteria for inhalant dependence and inhalant-induced psychosis require inpatient psychiatric care. Pharmacotherapy with carbamazepine or the antipsychotics haloperidol, risperidone, and aripiprazole appears beneficial to some patients with an inhalant-induced psychotic disorder.^46,67,99 Case reports describe successful treatment of inhalant dependence with lamotrigine, which inhibits excitatory glutamatergic tone, and with buspirone, an atypical anxiolytic.^107,131 Drug use treatment programs for inhalant abuse are scarce and few providers have special training in this area.¹³

• Inhalants are a heterogeneous group of xenobiotics that include the volatile hydrocarbons, alkyl nitrites, and nitrous oxide.

• The incidence of inhalant abuse is greatest among adolescents.

• The CNS is the intended target for the inhalant users; early effects include euphoria, hallucinations, headache, and dizziness.

• Acute cardiotoxicity is manifested most dramatically in “sudden sniffing death.”

• The diagnosis is largely clinical; further diagnostic testing should be guided by the patient’s presenting complaint.

• Management begins with basic life support and care is generally ­supportive.

• Cessation of use is the only known treatment for many manifestations of chronic toxicity.

References