Nitrous oxide

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT NITROUS OXIDE (DINITROGEN OXIDE)

Composition:

Active substance: dinitrogen oxide with a content of the main substance of not less than 98%.

Pharmaceutical form. Compressed gas.

Main physicochemical properties: colourless gas, heavier than air, without noticeable odour. Non-flammable, supports combustion.

Pharmacotherapeutic group. General anaesthetics. Other agents for general anaesthesia. Nitrous oxide. ATC code N01AX13.

Pharmacological Properties.

Pharmacodynamics.

The precise pharmacological mechanism of analgesia/anesthesia with nitrous oxide is not fully understood, but it is known to involve modulation of several central nervous system (CNS) neurotransmitter systems, including endogenous opioids and noradrenergic transmission in the spinal cord. Nitrous oxide also affects GABA- and NMDA-receptors.

The intensity of the analgesic effect depends on the patient's psychological state. The action of nitrous oxide is dose-dependent.

When inhaled at concentrations up to 50–60%, nitrous oxide produces enhanced analgesia and effects on cognitive function. This results in analgesia and sedation: the patient is relaxed and displays detachment.

At concentrations of 60–70%, nitrous oxide induces light anesthesia, characterized by loss of consciousness, lack of response to verbal stimuli, and reduced response to light tactile stimulation.

In combination with other anesthetics/analgesics, nitrous oxide provides deeper anesthesia.

Pharmacokinetics.

Absorption

Nitrous oxide is administered by inhalation; absorption depends on the pressure gradient between the inhaled air and the blood passing through ventilated alveoli.

Distribution

Distribution in body tissues depends on tissue perfusion and blood saturation with nitrous oxide. Equilibration in other tissues depends on solubility, defined by the partition coefficient for individual tissues. Nitrous oxide has low solubility in blood and other tissues, resulting in rapid equilibration of the inhaled and end-expired gas concentrations; thus, nitrous oxide is quickly "washed out" and reaches equilibrium faster than other inhaled anesthetics.

Elimination

Nitrous oxide is inert and not metabolized; it is eliminated via alveolar ventilation and exhaled. Elimination from the body depends solely on alveolar excretion and ventilation. The time required for nitrous oxide elimination after discontinuation is similar to the time required for tissue saturation with the gas.

Clinical Characteristics

Indications.

• As an anaesthetic agent for use in combination with any other intravenous or inhalational anaesthetic agent.
• For the treatment of short-term pain of mild to moderate intensity when rapid analgesia is required.

Contraindications.

During nitrous oxide inhalation, gas bubbles (gas emboli) and closed spaces may fill with gas due to the enhanced diffusibility of nitrous oxide. Therefore, the use of Nitrous Oxide medicinal gas is contraindicated:

• In patients with pneumothorax, pneumopericardium, severe bullous emphysema, gas embolism, or severe head injury.
• Immediately after diving (risk of decompression sickness).
• After recent cardiopulmonary bypass with heart–lung machine.
• In patients who have recently undergone intraocular gas injection (e.g., SF6, C3F8) until complete gas resorption has occurred, due to the risk of further expansion of the gas bubble which may lead to blindness.
• In patients with severe abdominal distension.

Nitrous oxide is also contraindicated:

• In patients with heart failure or serious cardiac dysfunction (e.g., following cardiac surgery), as its weak myocardial depressant effect may further impair cardiac function.
• In patients with existing signs of confusion, altered cognitive function, or other symptoms that may be related to increased intracranial pressure, since nitrous oxide may further increase intracranial pressure.
• In patients with reduced level of consciousness and/or reduced functional capacity when used for anaesthesia, due to the risk of loss of protective reflexes.
• In patients with vitamin B12 deficiency, folate deficiency, or genetic disorders affecting this system.

Special precautions for use.

Special precautions for use

In patients with normal cardiovascular function, the effect of nitrous oxide on the cardiovascular system is minimal. Nitrous oxide has been shown to have a slight depressant effect on myocardial contractility, but this is compensated by a slight increase in sympathetic cardiac stimulation. Therefore, significant overall circulatory effects are usually absent. However, due to the potential for myocardial depression, nitrous oxide should be used with caution in patients with mild to moderate cardiac dysfunction. Nitrous oxide is contraindicated in patients with severe cardiac dysfunction or overt heart failure.

The use of nitrous oxide at high concentrations (> 50%) as the sole agent for procedural sedation may lead to loss of laryngeal reflexes and impaired consciousness. Concentrations above 60–70% frequently result in loss of consciousness and increase the risk of impaired laryngeal reflexes.

Nitrous oxide should only be administered where supplemental oxygen can be provided, and in the presence of personnel trained in emergency resuscitation procedures.

Nitrous oxide can diffuse into air-filled spaces. Thus, nitrous oxide may increase pressure in the middle ear and in other gas-filled cavities. Administration of nitrous oxide may also increase pressure in balloon catheters, for example during tracheal intubation.

Nitrous oxide must not be used during laser surgery of the airways due to the risk of ignition and explosion.

After general anaesthesia with a high percentage of nitrous oxide, the risk of hypoxaemia (diffusion hypoxia) is a well-recognized clinical issue, depending not only on alveolar gas composition but also on compromised responses to hypoxia, hypercapnia, and hypoventilation. After general anaesthesia, administration of supplemental oxygen and monitoring of saturation by pulse oximetry are recommended.

Occupational exposure, environmental pollution

Efforts should be made to keep nitrous oxide concentrations in the workplace as low as possible and in compliance with local regulations.

A clear causal relationship between exposure to trace concentrations of nitrous oxide and any adverse health effects cannot currently be established. However, the risk of impaired fertility, as reported by medical or paramedical staff, due to prolonged exposure in inadequately ventilated areas cannot be completely ruled out.

Rooms where nitrous oxide is frequently used should be equipped with adequate ventilation or scavenging systems to maintain ambient nitrous oxide concentrations below established national recommendations.

Abuse and risk of dependence

The potential for abuse should be acknowledged. Repeated administration or exposure to nitrous oxide may lead to dependence. Caution is advised in patients with a known history of substance abuse and in healthcare workers subject to occupational exposure to nitrous oxide.

Nitrous oxide causes inactivation of vitamin B12, a cofactor of methionine synthase. Prolonged administration of nitrous oxide disrupts folate metabolism and DNA synthesis. Prolonged or frequent use of nitrous oxide may lead to megaloblastic changes in the bone marrow, myeloneuropathy, and subacute combined degeneration of the spinal cord. Nitrous oxide should not be used without careful clinical monitoring and haematological surveillance. Haematological consultation should be sought if necessary.

Haematological evaluation should include assessment for megaloblastic changes in erythrocytes and hypersegmentation of neutrophils. Neurological toxicity may occur in the absence of anaemia or macrocytosis and with normal vitamin B12 levels. Neurological toxicity has occurred in patients with undiagnosed subclinical vitamin B12 deficiency after a single administration of nitrous oxide for anaesthesia.

Nitrous oxide interferes with vitamin B12/folate metabolism. It should be used with caution in patients at risk of vitamin B12 or folate deficiency, i.e., in cases of inadequate intake or absorption of vitamin B12/folate or genetic disorders of this system, as well as in immunodeficiency. Replacement therapy with vitamin B12/folic acid should be considered.

Children

Special warnings and precautions for use in children are the same as for adults.

Interaction with other medicinal products and other forms of interaction.

Combination with anaesthetics, sedatives and analgesics

When nitrous oxide is used in combination with other inhalational anaesthetics or agents with central nervous system depressant effects (e.g., opioids, benzodiazepines and other psychotropic drugs), additive effects occur. These interactions have a clear clinical effect, reducing the dose required for other agents when combined with nitrous oxide, decreasing cardiovascular and respiratory depression, and increasing the speed of recovery.

Combination with methotrexate

Nitrous oxide exhibits a synergistic effect on folate metabolism when used concomitantly with methotrexate. The chemotherapeutic effects of methotrexate, as well as its toxicity, are likely to be enhanced, as demonstrated in animal models. However, there is very little clinical evidence of this effect in human use.

Other interactions

Nitrous oxide affects folate metabolism.

Children

There is no information on other interactions beyond those observed in adults.

Use during pregnancy or breastfeeding

Pregnancy

Nitrous oxide affects folate metabolism.

Animal studies have shown teratogenic effects following high and/or prolonged administration of nitrous oxide during early pregnancy.

Teratogenic effects have not been observed in humans. There are insufficient epidemiological data on the use of the drug during the first two trimesters of pregnancy. Therefore, the use of nitrous oxide during the first two trimesters of pregnancy is not recommended. However, it may be used during labour. Epidemiological data are insufficient to assess potential adverse effects on embryonic/fetal development. If nitrous oxide is administered to a pregnant woman before delivery, newborns should be monitored for possible adverse effects.

No risk of adverse effects on the fetus has been observed in women who are occupationally exposed to prolonged inhalation of nitrous oxide during pregnancy, provided that the room is equipped with an appropriate scavenging or ventilation system. In the absence of such a system, increased rates of spontaneous abortions and fetal malformations have been reported. These findings are questionable due to methodological biases and exposure conditions, and no risk has been observed in subsequent studies when appropriate scavenging or ventilation systems were implemented.

Breastfeeding

Nitrous oxide may be used in women who are breastfeeding, but should not be administered directly during breastfeeding.

Fertility

No data are available. The potential impact of clinical doses of nitrous oxide on fertility is unknown. A potential risk associated with continuous occupational exposure cannot be excluded.

Ability to affect reaction speed when driving or operating machinery.

Nitrous oxide affects cognitive and psychomotor functions. Nitrous oxide is rapidly eliminated from the body after short-term inhalation, and adverse psychometric effects rarely persist beyond 20 minutes after discontinuation, whereas its effect on cognitive abilities may persist for several hours.

When used as the sole agent, driving and operating complex machinery are not recommended for at least 30 minutes after discontinuation of nitrous oxide and until the patient has returned to their baseline mental state, as assessed by a physician.

Method of Administration and Dosage

Nitric oxide is administered by medical personnel who have appropriate education and knowledge regarding the use of this medicinal gas.

Nitrous oxide, compressed gas, should only be administered when immediate access to equipment for airway management and resuscitation is available.

Dosage

Nitrous oxide exhibits dose-dependent analgesic, sedative, and effects on cognitive functions.

Analgesia/Sedation

When inhaled at concentrations up to 50%, nitrous oxide produces analgesic, sedative, and anxiolytic effects, usually without impairing consciousness or response to verbal commands.

A concentration of 30% has been documented for analgesia; in some cases, 50% may be required (higher concentrations, such as 70%, are used for anesthesia, e.g., in dentistry).

Respiration, circulation, and protective reflexes are generally safely maintained when these concentrations are used.

Anesthesia

When used for general anesthesia, nitrous oxide is typically administered in concentrations ranging from 35% to 75% in combination with oxygen.

• Nitrous oxide alone is usually insufficient to achieve adequate anesthetic effect; therefore, it should be used in combination with an appropriate dose of another anesthetic agent used for general anesthesia. Nitrous oxide has an additive interaction with most other anesthetics.
• Typically, nitrous oxide in combination with oxygen is used in a ratio of one part oxygen to two parts nitrous oxide. This creates a mixture of approximately 33% oxygen and 66% nitrous oxide, providing an equivalent of about 63% of one MAC (minimum alveolar concentration).

The effects of nitrous oxide do not depend on patient age; however, its interaction with other anesthetics changes with patient age. A more pronounced effect is observed in older age groups, and the relative effect of MAC reduction increases after 40–45 years of age.

Nitrous oxide should not be administered at concentrations exceeding 70–75% to ensure a safe oxygen fraction. Patients with impaired oxygenation may require an oxygen fraction >30%.

Nitrous oxide can be administered for up to 6 hours without hematological monitoring in patients without risk factors.

Children

Dosage recommendations for children do not differ from those for adults. However, increased risk of enhanced sedation and reduced protective reflexes should be considered when treating children with nitrous oxide.

Route of Administration

Nitrous oxide should be administered by inhalation using specialized equipment that ensures spontaneous or controlled ventilation throughout the entire administration period.

Nitrous oxide should be administered in combination with oxygen using specialized equipment that delivers a mixture of nitrous oxide and medicinal oxygen. The equipment must include oxygen concentration monitoring with alarms to prevent oxygen concentrations from falling below 21%.

When used for anesthesia, nitrous oxide is administered via specialized equipment in which exhaled gas circulates and can be re-inhaled (i.e., a closed-circuit breathing system with rebreathing).

Nitrous oxide should only be administered in rooms with adequate ventilation and/or scavenging systems to prevent excessive ambient air concentrations, in accordance with local regulations.

Children

Dosage recommendations for children do not differ from those for adults.

For short-term pain in children unable to understand or follow instructions, nitrous oxide may be administered under the supervision of competent medical personnel who can assist the child in keeping the mask in place and actively monitor the administration.

Overdose

Nitrous oxide should always be used in combination with sufficient oxygen to ensure adequate oxygenation and oxygen saturation. Equipment control systems must not allow oxygen concentrations to fall below 21%.

Excessive inhalation of nitrous oxide may lead to hypoxemia and loss of consciousness.

In case of accidental overdose (i.e., concentrations compromising adequate oxygen delivery), hypoxia and ischemia may develop. In such cases, the concentration of nitrous oxide should be reduced or administration discontinued. The oxygen fraction should be increased and adjusted until the patient's condition meets criteria for adequate oxygenation.

When used for pain relief, administration should be immediately stopped if the patient shows signs of decreased level of consciousness, does not respond at all, or fails to respond appropriately to requests, or otherwise exhibits signs of pronounced sedative effect during drug administration. Administration of nitrous oxide must be discontinued until the patient has fully regained consciousness.

Reversible neurological toxicity and changes in bone marrow megakaryocytes have also been observed after prolonged inhalation.

The risk of overdose in children is the same as in adults.

Side effects.

Summary table of adverse reactions

* Reported only in connection with treatment of pain syndrome.

Reporting of possible adverse reactions

Reporting of possible adverse reactions after marketing authorization of the medicinal product plays an important role. It allows continued monitoring of the benefit/risk balance of this medicinal product.

Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life.

5 years.

Storage conditions.

• Do not smoke or use open flames in areas where medical gases are stored or administered (used).
• Cylinders should be stored in a well-ventilated area designated for storage of medical gases.
• Cylinders must be stored under a cap, kept in a dry and clean place, free from oil and grease, and away from flammable materials.
• Cylinders should be stored at temperatures between –20 °C and +40 °C.
• Precautions should be taken to prevent cylinders from impact and falling.
• Cylinders containing different types of gases must be stored separately.
• Full and empty cylinders should be stored separately.
• Cylinders must be stored and transported with valves closed.
• After delivery from the manufacturer, the cylinder must have an undamaged plastic valve cap.

Packaging.

Compressed gas, 7.5 kg in 10 L cylinders; compressed gas, 30 kg in 40 L cylinders; compressed gas, 37.5 kg in 50 L cylinders.

Prescription category.

Prescription only. For use only in hospital settings.

Manufacturer.

Linde Gas Hungary Co. Ltd.

Linde Gas Hungary Co. Ltd.

Manufacturer's address.

9653 Repcelak, Carl von Linde u. 1, Hungary.

9653 Repcelak, Carl von Linde, 1, Hungary.