DESCRIPTION

Nitrous oxide (dinitrogen monoxide or N₂O) can be found in dental offices and operating suites where it is used extensively for its anesthetic properties after being mixed with oxygen (usually 50:50) and titrated to effect.

FORMS AND USES

• It is commonly encountered in prepackaged whipped cream containers and in metallic "chargers" or "whippets" for making whipped cream.
• It is also used as a drug of abuse.
  • Inhalation produces euphoria.
  • It is sold in balloons or other containers at rock concerts, etc.
• Nitrous oxide is used in metallurgy, to freeze foods, and in rocket fuel formulations.
• Synonyms include laughing gas and "nitrous."

TOXIC DOSE

• Acute toxicity is primarily related to hypoxia and thus may develop abruptly.
• Chronic toxicity may be produced by daily abuse for several weeks.

PATHOPHYSIOLOGY

• The majority of acute toxicity cases are due to the asphyxiant action of nitrous oxide (replacing oxygen in the inhaled gas), resulting in hypoxia.
• Long-term exposure may produce vitamin B₁₂ deficiency states.
  • In animal studies, nitrous oxide inactivates vitamin B₁₂.
  • This impairs synthesis of DNA and myelin by interfering with methionine synthetase and folate metabolism.
  • Subacute combined degeneration may develop.
• Nitrous oxide is a partial opioid agonist at the µ, kappa-, and sigma- opioid receptors.
• Daily occupational exposure has been associated with increased risk of cervical cancer in one study.

EPIDEMIOLOGY

• Toxicity most commonly occurs in health-care settings, where 25 million patients and 200,000 workers are exposed to the gas annually.
• Intentional abuse is also common.
• Toxicity is usually mild, and death occurs rarely.

CAUSES

Toxicity is usually due to long-term exposure, either in the workplace or from abuse.

PREGNANCY AND LACTATION

• Acute, severe hypoxia to the mother may result in fetal hypoxia and distress.
• Long-term exposure may increase the risk of abortion or teratogenesis.

WORKPLACE STANDARDS

• OSHA. PEL has not been defined for nitrous oxide.
• ACGIH. TLV TWA is 50 ppm.
• NIOSH. REL TWA is 25 ppm.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• PREGNANCY AND LACTATION
• WORKPLACE STANDARDS

DIFFERENTIAL DIAGNOSIS

• Toxic causes of acute hypoxia and CNS depression include other simple asphyxiants (methane, CO₂, inert gases), carbon monoxide, hydrocarbons, hydrogen sulfide, opiates, barbiturates, alcohol, and benzodiazepines.
• Nontoxic causes include pulmonary embolus, pneumonia, and hypoglycemia.

SIGNS AND SYMPTOMS

• Acute symptoms are those of inebriation and euphoria followed by symptoms of hypoxia with increasing exposure.
• Chronic symptoms are of sensory and motor neuropathy.

Vital Signs

Tachypnea and tachycardia are common initially, followed by bradycardia, respiratory depression, and hypotension.

HEENT

• Freezing injuries to the lips and mouth may occur if the gas is inhaled directly from a cylinder.
• Air spaces will tend to expand with nitrous administration, resulting in damage to the middle ear, obstucted sinuses, etc.

Dermatologic

Diaphoresis and cyanosis may occur with hypoxia.

Pulmonary

• Air hunger, tachypnea, and hyperpnea occur early; as hypoxia worsens, respiratory depression will develop.
• Inhaling the gas directly from whipped cream containers has caused interstitial emphysema and pneumomediastinum.

Cardiovascular

Hypotension has been reported.

Neurologic

• Acute delirium and euphoria are followed by lethargy and coma as hypoxia develops.
• Long-term abuse (>2 months) may result in subacute combined degeneration of the spinal cord, resulting in numbness, paresthesia, and ataxia.
• Further exposure may result in abnormal gait, weakness, impotence, and incontinence.
• Onset may begin months after a period of intense exposure.
• Chronic abusers also may develop depression, memory disturbances, and confusion.

Reproductive

• Long-term exposure (e.g., dental office workers) has been correlated with higher rates of infertility (in men and women), spontaneous abortions, and congenital abnormalities.
• Deranged spermatogenesis has been noted.

Hematologic

• Prolonged exposure may produce megaloblastic anemia, leukopenia, and thrombocytopenia, similar to the findings in pernicious anemia.
• Methemoglobinemia has resulted from contaminants in nitrous oxide canisters.

PROCEDURES AND LABORATORY TESTS

Essential Tests

No tests may be needed for asymptomatic patients.

Recommended Tests

Acute Exposure

• Arterial blood gases or pulse oximetry in symptomatic patients to evaluate hypoxia
• Methemoglobin level if the patient is cyanotic
• Serum electrolytes, BUN, creatinine, and glucose to assess altered mental status
• Head CT, lumbar puncture, bacterial cultures, and toxicology studies as needed to evaluate other causes of altered mental status that does not improve promptly

Chronic Abuse

• Complete blood count (CBC) and vitamin B₁₂ level in symptomatic patients, especially with history of chronic use
• Nerve conduction studies (e.g., sensory and visual evoked potentials) in symptomatic patients with chronic exposure

Not Recommended Tests

Nitrous oxide levels can be performed on plasma or urine but are not clinically useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Pulmonary
  • Cardiovascular
  • Neurologic
  • Reproductive
  • Hematologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Oxygen therapy should be initiated while continuing supportive care and appropriate airway management.
• The dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Patient does not improve with oxygen therapy or other serious effects are present (acute exposure).
• Toxic effects are not consistent with nitrous oxide.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Patient should be referred to a health-care facility when:

• Patient or caregiver seems unreliable.
• Toxic effects develop.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management is warranted for patients with persistent symptoms, hypoxia, severe anemia, or disabling neuropathy.

DECONTAMINATION

The patient should be removed from exposure immediately, and oxygen therapy should be initiated.

ANTIDOTES

• There is no specific antidote for nitrous oxide poisoning.
• Methylene blue should be considered for methemoglobinemia greater than 30% (see SECTION II, Methemoglobinemia chapter)

ADJUNCTIVE THERAPIES

Administration of cyanocobalamin (vitamin B₁₂) is recommended by some authors for chronic toxicity.

Hypotension

• Patient is placed in the Trendelenburg position and administered 10 to 20 ml/kg 0.9% saline.
• Further fluid therapy is guided by central pressure monitoring to avoid volume overload.
• A vasopressor is added, if needed.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
• ANTIDOTES
• ADJUNCTIVE THERAPIES
  • Hypotension

PATIENT MONITORING

Acute Exposure

Cardiac and respiratory function should be continuously monitored in symptomatic patients.

Chronic Exposure

• Serial CBCs should follow resolution of anemia.
• Neurology follow-up should be obtained for all patients with neuropathic findings.

PATIENT EDUCATION

• Nitrous oxide should be used in well-ventilated areas, and a nitrous scrubber should be considered for work settings where nitrous oxide is used.
• Patients who present with nitrous abuse should be referred to a substance abuse treatment center.

EXPECTED COURSE AND PROGNOSIS

• Acute effects develop rapidly and resolve over minutes to hours unless sequelae of hypoxia intercede.
• Chronic nitrous oxide poisoning should improve if exposure to the gas is strictly avoided.
• The neuropathic symptoms may not reverse completely.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department
  • Asymptomatic patients may be discharged following a brief observation period.
  • Patients should be referred for substance abuse counseling, if appropriate.
• From hospital
  • Patient may be discharged when toxic effects resolve or stabilize.
  • Patients should be referred for substance abuse counseling, if appropriate.

Section Outline:

• PATIENT MONITORING
  • Acute Exposure
  • Chronic Exposure
• PATIENT EDUCATION
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

• It is important to recognize other toxicities, including other asphyxiants, nitrous cylinder contaminants such as N₂ or NO₂, or drugs of abuse.
• It is vital to note potential methemoglobinemia.

Poisoning by other central nervous system depressants and anesthetics: other gaseous anesthetics.

See Also: SECTION II, Hypotension chapter; and SECTION III, Methylene Blue chapter.

RECOMMENDED READING

Brodsky JB, Cohen EN. Adverse effects of nitrous oxide. Med Toxicol 1986;1:362-374.

Author: John P. Marshall

Reviewer: Kennon Heard