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.
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.124 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.43
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: inattention, apathy, and impaired memory and visuospatial skills with relative preservation of language.43 Autopsy studies reveal white matter degeneration including cerebral and cerebellar atrophy and thinning of the corpus callosum.72,106 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.43 This targeting of myelin, which is 70% lipid, may be explained by toluene's lipophilicity.43 As myelination 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.42 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.43 It is postulated that reactive oxygen species generated either by toluene or its metabolite benzaldehyde induce lipid peroxidation in the brain.82,104 Genetic polymorphisms and host susceptibility among chronic abusers are also hypothesized to play a role.54
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.9 It is thought that the inhalant "sensitizes the myocardium" by blocking the potassium current (IKR), thereby prolonging repolarization.95 This produces a substrate for dysrhythmia propagation; the activity or stress then causes a catecholamine surge that initiates the dysrhythmia (Chap. 23).95 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.44,125
More typically, the clinical presentation of a patient with hydrocarbon cardiotoxicity may include palpitations, shortness of breath, syncope, and electrocardiographic (ECG) abnormalities, 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,56,137 Freon (Dupont trade name for fluorinated hydrocarbons), and Glade Air Freshener (SC Johnson), which contains a mixture of short-chain aliphatic hydrocarbons.77 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.2 Although cardiotoxic effects of inhalant abuse are generally acute, dilated cardiomyopathy is reported with chronic abuse of toluene and with trichloroethylene.86,139 Microscopy reveals evidence of chronic myocarditis with fibrosis.139
The primary respiratory toxicity complication of inhalational abuse is hypoxia, which is either caused by rebreathing of exhaled air, as occurs with bagging, or displacement of inspired oxygen with the inhalant, reducing the fraction of inspired oxygen (FIO2). Direct pulmonary toxicity associated with inhalants is most often a result of inadvertent aspiration of a liquid hydrocarbon (Chap. 106). Aspiration injury is associated with acute lung injury and 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.132 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.9,29,131
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. Rebreathing of exhaled air, as occurs with bagging, may lead to hypercapnia and hypoxia. Acute eosinophilic pneumonia following abuse of a fabric protector containing 1,1,1-trichloroethane is also reported.69 Barotrauma presents as pneumothorax, pneumomediastinum, or subcutaneous emphysema.109
Hepatoxicity is associated with exposure to halogenated hydrocarbons, particularly carbon tetrachloride, but also chloroform, trichloroethane, trichloroethylene, and toluene.81 Intentional inhalation of carbon tetrachloride 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.103 The resultant depletion of glutathione and the potentially fatal centrilobular necrosis mimic acetaminophen toxicity and have led to a postulated role for N-acetylcysteine (NAC) and its use is suggested. Animal studies on the efficacy of NAC in preventing carbon tetrachloride–induced hepatoxicity have yielded mixed results.33,36 There are no clinical trials in humans, but case series suggest a protective role for NAC.107 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 liver cirrhosis.47 Inhalation of either toluene or one of the many halogenated hydrocarbons is associated with elevated liver enzymes and hepatomegaly that generally return to baseline within 2 weeks of abstinence.5,61,66,76,94,97
Most reported renal toxicity is associated with toluene inhalation. Traditionally, prolonged toluene inhalation was said to cause a distal renal tubular acidosis (RTA), resulting in hypokalemia. However, distal RTA is associated classically 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.30 Hippurate excretion, usually expressed as a ratio to creatinine, rises dramatically with toluene inhalation.87 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 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.30 Through unclear mechanisms, other renal abnormalities occur 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.14,128,143
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. The mean serum potassium concentration was 1.7 mEq/L and six of these patients also had manifestations of rhabdomyolysis. Four patients were quadriplegic on presentation and of these, two were initially diagnosed erroneously with Guillain-Barr syndrome. The patients had inhaled toluene 6 to 7 hours per day for 4 to 14 days prior to presentation.120
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 difluoroethane from a computer cleaner.90 Pyrolysis of difluoroethane may yield hydrofluoric acid burns.45 Vesicular lesions resembling frostbite and massive, potentially life-threatening edema of the oropharyngeal, glottic, epiglottic, and paratracheal structures are also reported.1,73,84 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.87
Bone mineral density was significantly lower in 25 adolescent chronic glue sniffers compared with that of healthy controls.39 In a mouse model, chronic exposure to toluene significantly reduced bone mineral density.4
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.98 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).8,121 Methanol toxicity is reported following intentional inhalation of methanol-containing carburetor cleaners.46,78,83 Significant findings may include hyperemic discs on funduscopic examination, metabolic acidosis, and CNS and respiratory depression (Chap. 107). 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, that interferes with glyceraldehyde-3-phosphate dehydrogenase–dependent axonal transport, resulting in axonal death.38 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.31 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.74 Nerve conduction studies show marked conduction slowing and conduction block (Chap. 18).31,74
Reports of polyneuropathy associated with chronic gasoline inhalation date to the 1960s and describe a symmetric, progressive, sensorimotor neuropathy with occasional superimposed mononeuropathies.27,67 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.27,110 n-Hexane is present in gasoline in concentrations of up to 3% and is thought to be the likely mediator of gasoline neuropathy.134
Fetal solvent syndrome (FSS) was first reported in 1979.127 The authors described a 20-year-old primigravida 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 a number of cases and case series have been reported.3,60,108,136 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.3,136 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.108 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.127 Hypoplasia of the philtrum and nose are more characteristic of FAS.100 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.3,136 Follow-up studies of these infants show developmental delay when compared with children matched for age, race, sex, and socioeconomic status.3,60 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.53 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.21,65 In another rat model of maternal inhalant abuse, toluene levels in fetal brain tissue, the placenta, and amniotic fluid increased in a concentration-dependent manner.22
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.41,135 Additionally, 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.55 Withdrawal symptoms, including irritability, insomnia, craving, nausea, tremor, and dry mouth lasting 2 to 5 days after last use, are described.112
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 to direct toxicity.123,131 Investigations following deaths associated with N2O have found many of the dead were discovered with plastic bags over their heads, in an apparent attempt to both prolong the duration of effect and increase the concentration to heighten the effect.131 Autopsy findings in these cases were consistent with asphyxiation: acute lung injury, cardiac petechiae, and generalized visceral congestion.123,131 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 N2O displaces oxygen in a closed space.131 Additionally, N2O concentrations in this simulation were greater than 60%; at concentrations of nitrous oxide greater than 50%, the normal hypoxic response is diminished.131 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. Additionally, 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. 67).101 Case reports and small case series in humans following self-reported chronic, heavy abuse of N2O found development of myeloneuropathy resembling the subacute combined degeneration of the dorsal columns of the spinal cord of classic vitamin B12 deficiency.16,75,130 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.28,101 Among reported patients with N2O-associated neurotoxicity who had documented levels of vitamin B12, approximately 50% had low serum vitamin B12 concentrations.16,28,75,117,130 In the few patients who underwent Schilling tests, results were normal.75,130 Nerve conduction studies and electromyography typically revealed a distal, axonal sensorimotor polyneuropathy.28,75,130