Nitrous oxide medical messer

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT NITROUS OXIDE MEDICAL MESSER (DINITROGENOXIDE MEDICINAL MESSER)

Composition:

Active substance: dinitrogen oxide with a minimum content of 98.0% by volume N2O.

Dosage form. Compressed medical gas.

Main physicochemical properties: colorless, odorless gas; cylinder appearance: white body, dark blue shoulder.

Pharmacotherapeutic group.

General anesthetics. Other agents for general anesthesia. Nitrous oxide.

ATC Code: N01AX13.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Available data indicate that nitric oxide exerts both direct and indirect effects on the transmission of several neurotransmitters in the brain and spinal cord. Its influence on the endorphin system in the central nervous system is likely one of the most central mechanisms underlying its analgesic effect. Results also showed that nitrous oxide affects inhibition and noradrenaline activity in the posterior horn of the spinal cord, contributing in a specific manner to its analgesic action.

Pharmacodynamic effects

Nitrous oxide is a gas with strong analgesic and weak anesthetic properties. Nitrous oxide has a dose-dependent effect on sensory and cognitive functions, starting at a concentration of 15%. Concentrations above 60–70% lead to loss of consciousness. Nitrous oxide has dose-dependent analgesic properties, clinically evident at end-expiratory concentrations of approximately 20%. Other pharmacodynamic effects are mostly dependent on the concomitant agent.

Pharmacokinetics.

Distribution

Distribution in various body tissues depends on the solubility of nitrous oxide in these tissues. Low blood and tissue solubility promotes rapid equilibrium between inspired and expired nitrous oxide concentrations. Nitrous oxide rapidly saturates the blood and reaches equilibrium faster than other currently available inhalation anesthetics.

Biotransformation and elimination

Nitrous oxide is not metabolized and is exhaled unchanged; its elimination depends on pulmonary blood flow and alveolar ventilation. After discontinuation of nitrous oxide, elimination time corresponds to the uptake time. Due to low solubility in blood and other tissues, nitrous oxide undergoes rapid absorption and elimination.

Small amounts of nitrous oxide are excreted through the skin and intestine.

Clinical characteristics.

Indications.

Administer:

• for induction and maintenance of general anesthesia in combination with other anesthetics;
• for short-term analgesia and/or sedation in mild to moderate pain syndromes when rapid onset of analgesia and rapid recovery after sedation are required.

Contraindications.

During nitrous oxide inhalation, gas bubbles (gas emboli) and closed gas-filled cavities may expand due to increased diffusion of nitrous oxide. Therefore, the use of nitrous oxide is contraindicated under the following conditions:

• in patients with symptoms of pneumothorax or gas embolism;
• immediately after diving (due to the associated risk of decompression sickness);
• after connection to extracorporeal circulation using a heart-lung machine;
• in severe head trauma;
• after intravitreal injection of gas (e.g., SF6, C3F8), due to the risk of increased intraocular pressure, which may lead to ocular damage.

Additionally, nitrous oxide must not be administered to patients with the following diseases/symptoms/conditions:

• presence of signs of intestinal obstruction (ileus) — due to the risk of further bowel distension;
• severe confusion, loss of consciousness, or other signs indicating increased intracranial pressure — since nitrous oxide may further exacerbate this condition;
• depressed level of consciousness and/or reduced ability to cooperate during the use of nitrous oxide for analgesia — due to the risk of impaired natural protective reflexes;
• diagnosed but untreated vitamin B12 deficiency.

Special precautions.

Nitrous oxide should be used with particular caution in patients with severe pulmonary dysfunction, heart failure, or cardiac dysfunction (e.g., after cardiac surgery). During treatment of such patients, pulmonary and cardiovascular functions must be closely monitored. Even mild myocardial depression may lead to further deterioration of cardiac function.

Special caution is also required when treating patients with ear problems, as middle ear pressure increases during nitrous oxide administration.

Due to the potential risk of impaired vitamin B12 absorption, nitrous oxide should not be used for prolonged periods, e.g., for sedation in intensive care units.

Nitrous oxide causes inactivation of vitamin B12, a cofactor of methionine synthase. Therefore, prolonged administration of the drug 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 be administered only under careful clinical and hematological monitoring. In such cases, consultation with a hematologist is necessary.

As part of hematological evaluation, megaloblastic changes in erythrocytes and hypersegmentation of neutrophilic granulocytes should be assessed. Neurotoxicity may occur without concomitant anemia or macrocytosis and with vitamin B12 concentrations within the normal range. Neurotoxicity has been observed in patients with undiagnosed subclinical vitamin B12 deficiency after a single administration of nitrous oxide for anesthesia.

Animal studies have also shown effects on DNA synthesis, leading to fetal damage.

In patients at risk of vitamin B12 deficiency, vitamin B12 levels should be checked before using nitrous oxide for anesthesia. Risk groups include elderly individuals, patients with eating disorders, vegetarians, and patients with a history of anemia. These patients require additional vitamin B12 therapy before nitrous oxide administration.

High concentrations of nitrous oxide (> 50%) may impair protective reflexes and consciousness. Concentrations above 60–70% often cause loss of consciousness, increasing the risk of impaired protective reflexes.

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

After general anesthesia using high concentrations of nitrous oxide, there is a well-known risk of hypoxia (diffusion hypoxia), caused not only by alveolar gas mixture but also by reflex response to hypoxia, hypercapnia, and hypoventilation. Administration of supplemental oxygen after general anesthesia is recommended until the patient regains consciousness, and oxygen saturation should be monitored using pulse oximetry.

Patients should be advised not to consume alcohol before nitrous oxide administration, as alcohol potentiates the effects of anesthetic agents.

There is a general risk of dependence associated with the use of nitrous oxide. Repeated administration or exposure to nitrous oxide may lead to dependence. Caution should be exercised in patients with a history of substance abuse, as well as in healthcare workers exposed to nitrous oxide during work.

Chronic exposure to low levels of nitrous oxide is potentially hazardous to health. Reduced fertility has been reported in medical and paramedical personnel after repeated exposure to nitrous oxide in poorly ventilated areas. At present, it is not established whether there is a causal relationship between chronic exposure to low concentrations of nitrous oxide and the development of diseases. A link between such chronic exposure and the risk of tumor development or other chronic diseases, fertility disorders, spontaneous abortion, and/or fetal malformations cannot be completely ruled out. There are hygiene threshold values below which (even in case of chronic exposure) health risks are not expected. An average value for an 8-hour work cycle below 25–100 ppm (threshold limit value below 25–100 ppm = 0.0025–0.01%) is considered the threshold for a harmless environment regarding nitrous oxide. Rooms where nitrous oxide is used must be adequately ventilated and/or equipped with purification/ventilation devices. The goal should be a suitable working environment with the lowest possible concentration of nitrous oxide, in accordance with local regulations.

In animal studies, simultaneous administration of nitrous oxide and ketamine resulted in enhanced neurotoxicity compared to individual administration of these agents. However, the relevance of these experimental data to medical use in humans is unknown.

Interaction with other medicinal products and other forms of interaction.

Combination with anesthetics/sedatives and analgesics

When nitrous oxide is used in combination with other inhalational anesthetics, an enhanced effect should be expected. Interactions with intravenous anesthetics and/or other centrally acting agents (e.g., opioids, benzodiazepines, and other psychomimetics) are also possible.

When nitrous oxide is combined with other inhalational anesthetics, enhanced uptake of other gases occurs (second gas effect). These interactions have clear clinical effects and reduce the requirement for other agents when combined with nitrous oxide. The combination usually results in less cardiovascular and respiratory depression and improved/accelerated recovery.

High-dose administration of opioids, such as fentanyl, in combination with nitrous oxide may lead to decreased heart rate and cardiac output.

Nitrous oxide potentiates the effect of methotrexate on folate metabolism.

In animal studies, simultaneous administration of nitrous oxide and ketamine resulted in enhanced neurotoxicity compared to individual administration of these agents. However, the relevance of these experimental data to medical use in humans is unknown.

Special precautions for use.

Use during pregnancy or breastfeeding

Pregnancy

Extensive experience with use in pregnant women during the first trimester (more than 1000 pregnancy outcomes) does not indicate a risk of developmental abnormalities. Furthermore, no fetal or neonatal toxicity has been specifically attributed to nitrous oxide exposure during pregnancy. Therefore, if clinically indicated, nitrous oxide may be used during pregnancy. In rare cases, nitrous oxide may cause respiratory depression in the newborn. When administered shortly before delivery, the newborn should be monitored for possible respiratory depression.

Lactation

Although data on the excretion of nitrous oxide into breast milk are lacking, due to its rapid elimination from the bloodstream via gas exchange in the lungs and its low solubility in blood and tissues, transfer to infants through breast milk is unlikely. Breastfeeding need not be interrupted following short-term use.

Fertility

Animal studies have shown adverse effects on the reproductive system and fertility in both males and females.

A potential risk associated with chronic occupational exposure cannot be ruled out.

Ability to affect reaction speed when driving vehicles or operating machinery.

Nitrous oxide has a significant effect on the ability to drive or operate machinery, as it affects both cognitive and psychomotor functions. It is rapidly eliminated after administration. However, as an additional safety precaution, driving, operating machinery, and other activities requiring high psychomotor performance should be avoided for an appropriate period after administration. The physician should assess whether the patient's cognitive and psychomotor abilities have fully recovered before allowing the patient to drive or operate machinery.

Method of Administration and Dosage

General Anesthesia

Using nitrous oxide alone as the sole anesthetic agent is generally insufficient for anesthesia during surgical procedures; therefore, it should be combined with other anesthetics used for general anesthesia.

Nitrous oxide is typically used in concentrations of 35–70% in a mixture with oxygen, and, if necessary, with other anesthetics. The inspired oxygen concentration must not be less than 30%. In patients with impaired alveolar oxygen uptake, the inspired oxygen fraction should be increased.

Nitrous oxide must not be administered in concentrations exceeding 70% to ensure a safe oxygen fraction.

In combination with most other anesthetics, nitrous oxide has an additive effect. When used alone as an anesthetic, its effect is independent of patient age, but when used in combination with other anesthetics, the mixture is usually more effective in elderly patients than in younger ones.

After general anesthesia with nitrous oxide, there is a well-known risk of hypoxia (diffusion hypoxia). Therefore, administration of supplemental oxygen and monitoring of saturation are recommended until the patient has recovered from anesthesia.

Analgesia, Sedation with Consciousness

At concentrations up to 50–60%, nitrous oxide relieves pain, produces calming effects, and reduces agitation, but usually does not affect the level of consciousness or patient responsiveness. At these concentrations, breathing, circulation, and protective reflexes are normally maintained safely.

Nitrous oxide produces dose-dependent analgesic and sedative effects and also has dose-dependent effects on cognitive functions.

Children and Adolescents

The dosage of nitrous oxide as a sole anesthetic does not depend on age. The same doses as for adults are used. There is insufficient data on the use of nitrous oxide in newborns to confirm its safety and efficacy in this patient group.

Route of Administration

Nitrous oxide is administered by inhalation, either during spontaneous breathing or controlled ventilation.

Nitrous oxide is administered in combination with oxygen using a specialized device capable of delivering a mixture of nitrous oxide and oxygen. This device must provide monitoring of oxygen concentration and be equipped with an alarm function to prevent the use of a hypoxic gas mixture (FiO2 < 30%).

Nitrous oxide should not be administered for more than 12 consecutive hours or for repeated periods without monitoring hematological effects.

The following instructions for handling cylinders filled with medical gases must be strictly observed

Medical gases should be used only for therapeutic purposes and according to indications.

Only trained personnel are permitted to handle cylinders.

Inhalation accessories (e.g., nasal cannula, breathing mask, tubing) must be suitable for the intended use.

Only technical equipment appropriate for the specific product, pressure, and temperature should be used. In case of doubt, consult the gas supplier.

Containers must not be painted, and all stamping must remain undamaged; identification labels must not be removed.

Modification or repair of cylinders, equipment, or other components of technical devices may be performed only by qualified specialists.

It is prohibited to use cylinders or refill them for purposes other than intended by the consumer or third parties.

Cylinders must be protected from falling (e.g., by using a cylinder trolley) and from mechanical damage.

Only cylinders necessary for uninterrupted gas withdrawal may be present at the site of use (storage is not permitted).

Cylinders must be protected from excessive heating (typically above 40°C).

Before connecting a cylinder, ensure that backflow into the cylinder is impossible.

If pressure reduction is required, connect an appropriate device for removing medical nitrous oxide from the cylinder. Follow the operating instructions for the pressure device. Avoid contamination of the connection.

Open valves slowly, smoothly, and completely; do not use lubricants or tools for this purpose.

The tightness of connections should be checked using appropriate methods (leak detection spray).

During withdrawal of medical nitrous oxide, the cylinder must be kept in an upright position. This also applies to cylinders equipped with a special tube for withdrawal of liquefied nitrous oxide.

After use or if gas withdrawal must be interrupted for a prolonged period, all shut-off devices must be closed.

In case of danger of nitrous oxide leakage, close the corresponding shut-off device on the cylinder.

Avoid contamination of cylinders (e.g., due to moisture or water entering the cylinder).

Returning cylinders with a slight residual pressure prevents the entry of foreign substances into the cylinder.

Smoking and the use of open flames or other ignition sources are prohibited in areas where medical gases are stored or used. There is a risk of fire when in contact with flammable materials. Saturation of ambient air with nitrous oxide must be avoided.

Children

Use in newborns (full-term or premature) is not recommended. Nitrous oxide is indicated for use in children from 1 month of age.

Overdose

Symptoms

Symptoms of nitrous oxide overdose include hypoxia, circulatory depression, excitation, and drowsiness leading to loss of consciousness.

Following extremely prolonged inhalation (over 6 hours), reversible neurological toxicity and megaloblastic changes in the bone marrow have been observed.

Treatment

If hypoxemia occurs due to excessively high nitrous oxide concentration, the concentration should be reduced or administration discontinued. Oxygen levels should be increased and adjusted until adequate oxygen saturation is restored in the patient.

If, during administration of analgesic concentrations of nitrous oxide, the patient shows signs of reduced attention, inadequate response to instructions, or other signs of pronounced sedation, administration should be immediately stopped, and the patient should breathe fresh air and/or receive supplemental oxygen as needed.

Monitoring with pulse oximetry is recommended until the patient regains full consciousness and hypoxia resolves. Administration of nitrous oxide must be discontinued until the patient has fully regained consciousness.

Adverse reactions

Adverse reactions are classified by frequency and by organ systems. Frequency categories are defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), not known (cannot be estimated from the available data).

If vitamin B12 deficiency is suspected or confirmed, or if symptoms associated with methionine synthase inhibition occur, vitamin B12 replacement therapy should be administered to reduce the risk of adverse effects/symptoms related to methionine synthase inhibition, such as leukopenia, megaloblastic anemia, myelopathy, or neuropathy.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is crucial. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Incompatibility.

The oxidizing properties of nitrous oxide should be taken into account, especially when using inhaled nitrous oxide in combination with other oxidizing agents or medicinal products that are easily oxidized.

Shelf life.

2 years.

Medical nitrous oxide must not be used after the expiry date.

Use of medical nitrous oxide from opened containers is permitted until the end of the shelf life.

Empty cylinders or cylinders with residual content should be returned to the distributor for refilling or disposal.

Storage conditions.

When storing containers filled with medical gases, the following rules must be observed:

• Store cylinders only in areas designated and authorized for storage of medical gases.
• Store cylinders in a well-ventilated area or ventilated enclosure, protected from rain and direct sunlight.
• Signs prohibiting smoking and open flames must be clearly visible.
• Storage areas must be clean, dry, well ventilated, and free from combustible materials to ensure cylinders remain clean until needed.
• Emergency services must be informed of the location of the gas storage area.
• Different types of gases must be stored separately.
• Empty and full gas cylinders must be stored separately.
• If the cylinder design includes valve protection, it must be secured during storage and transport (e.g., protective cap).
• When storing and transporting cylinders containing medical nitrous oxide, personnel must consider the information provided in the relevant safety data sheet.
• Store cylinders out of reach of children.
• Inventory management should follow the FIFO principle ("first in, first out").

Packaging.

Cylinders with a volume of 1 L, 3.1 L, 4.5 L, 5 L, 10 L, 50 L.

Prescription status.

Prescription only.

Manufacturer.

Messer Austria GmbH.

Manufacturer's address and location of operations.

Industriestrasse 5, 2352 Gumpoldskirchen, Austria.

[1] When nitrous oxide is used as part of general anesthesia.

[2] When nitrous oxide is used as part of analgesia.

[3] When nitrous oxide is used alone.