Chapter 128. Nitrous Oxide Anesthesia

Nitrous oxide (N2O) has been used for more than 150 years in medical practice for its anesthetic, analgesic, and anxiolytic properties. It is easy to administer, inexpensive, and has a rapid effect, as well as a rapid elimination. Nitrous oxide is suitable for patients of all ages and can be combined with other medications and local anesthetics. Joseph Priestley synthesized nitrous oxide in 1772, shortly after his discovery of oxygen. Humphry Davy was the first to identify the analgesic and anesthetic effects of nitrous oxide in 1799. However, it remained a recreational drug known as “laughing gas” until Horace Wells used it as an anesthetic during dental extractions at Massachusetts General Hospital in 1845. Andrews added oxygen to the nitrous oxide mixture in 1868 in order to prevent hypoxia that was commonly seen with the use of nitrous oxide. The first detailed analysis of nitrous oxide–oxygen mixtures as they apply to pain relief of angina without sedation or hypoxia was published by Stanislav Klikovich in 1881. In 1934, Minnitt introduced a self-administered apparatus of nitrous oxide with air to facilitate childbirth.1 In 1949, Seward improved on the self-administered apparatus by adding oxygen instead of air to the nitrous oxide for a more prolonged analgesia and sedation during childbirth without the possibility of inducing hypoxia.2 Ruben completed a study in 1969 of more than three million patients receiving nitrous oxide without a mishap.3 Since then, nitrous oxide has gained widespread acceptance and is the most frequently used inhalational anesthetic agent. It is used in conjunction with a volatile anesthetic gas since it only posses weak anesthetic properties. Recently, nitrous oxide has been used experimentally in animal models postresuscitation. It has been show to offer global neuroprotection due to its blockade of the N-methyl-D-aspartate (NMDA) receptor in the brain.4

Nitrous oxide–oxygen mixtures were first applied in an ambulatory setting in 1955; dentists in Denmark used them for office-based procedures. A 50:50 mixture of nitrous oxide with oxygen (Entonox, Linde Healthcare Inc., Worsley, Manchester, UK) has been used by the British Ambulance Service in a self-administered format since 1970.5 Nitrous oxide–oxygen mixtures became popular in the United States as a sedative and analgesic for use in the Emergency Department during the late 1970s.6

At room temperature, nitrous oxide is a colorless gas with a pleasant, slightly sweet odor and taste. It is heavier than air and nonflammable. When mixed with oxygen, however, it is combustible. Nitrous oxide is poorly soluble with a high minimum alveolar concentration (MAC) value. Nitrous oxide is 34 times more soluble in plasma than nitrogen. It diffuses rapidly across biologic membranes into the bloodstream (lung–blood and blood–CNS), resulting in a rapid onset (30 to 60 seconds) and short duration of action. Maximum effect occurs at approximately 2 minutes. Its duration of action lasts 2 to 5 minutes after discontinuation of the administration. Nitrous oxide does not have significant cardiovascular or respiratory depressant effects. Nitrous oxide, when inhaled at levels below 50%, maintains protective airway reflexes and does not require fasting or postprocedure monitoring.7 However, some do recommend eating a light meal 2 hours prior to the procedure. Cortical function is depressed quickly after the start of administration. There are decreases in all sensations including hearing, smell, taste, touch, pain, and temperature.

Nitrous oxide displaces nitrogen and increases the volume of gas in body cavities, such as the middle ear, sinuses, pleural spaces, and gastrointestinal tract. It will result in an increased pressure within these confined spaces. Nitrous oxide is lipid insoluble resulting in minimal uptake by fat, muscle, and solid organs. It has no excretion products and is eliminated unchanged through the lungs. This makes it useful in patients with liver or kidney disorders.

Nitrous oxide acts supraspinally to induce analgesia by activation of opioidergic neurons in the periaqueductal gray matter and nonadrenergic neurons in the locus ceruleus of the brainstem.8–10 This leads to disinhibition or activation of the descending noradrenergic inhibitory pathways via inhibition of γ-aminobutyric acid-mediated interneurons. This results in a negative modulation of the nociceptive processes at the spinal cord level.11 The predominant theory of the molecular mechanism to account for nitrous oxide's anesthetic action is a noncompetitive inhibition of the NMDA subtype of excitatory glutamate receptors.12

Nitrous oxide has the five actions of mild sedation, anxiolysis, mild to moderate analgesia, weak anesthesia, and mild dissociative effects.13 Nitrous oxide has been shown to be effective in 85% of cases involving mild to moderate pain.14 Nitrous oxide does not require intravenous access, a feature highly desirable by most patients. The agent is a more potent anxiolytic than an analgesic. Anxiolysis is obtained by inducing a state of euphoria with a concurrent mild sedating effect. The analgesic effect is a result of an increase in the pain threshold. Inhalation of a 50:50 nitrous oxide–oxygen mixture has been reported to produce analgesia equivalent to 10 to 20 mg of morphine; however, it is highly variable in patients.6,15 Because of this variable response, combination therapy with an analgesic is often required due to its relatively weak analgesic effects, especially for painful procedures. For example, the infiltration of a local anesthetic solution for laceration repair is made more tolerable following the use of nitrous oxide. Nitrous oxide may be used as a means to decrease the dose of local anesthetic required for the procedure.

Nitrous oxide used in an ambulatory care setting (e.g., Emergency Department) is usually mixed with oxygen in a 50:50 mixture. Nitrous oxide becomes a more effective general anesthetic when concentrations exceed this level. Hypoxemia is a concern at general anesthetic doses. The nitrous oxide–oxygen ratio must be adjusted for altitude due to the effects of a lower atmospheric pressure as well as a lower partial pressure of the gas. A 70:30 ratio of nitrous oxide to oxygen was effective in Denver, for example, with an elevation of 5000 feet.16 The sex of the patient does not influence the response to nitrous oxide administration.16

Nitrous oxide is an attractive agent for procedural sedation due to its rapid onset and offset of sedation.17 Nitrous oxide has been used by many types of medical and dental practices. Nitrous oxide-oxygen mixtures have been shown effective in both the Emergency Department and the prehospital setting to alleviate anxiety as well control mild to moderate pain states. The indications for nitrous oxide use are reserved for patients with mild to moderate pain states, who are anxious, or who will undergo a painful procedure. It has been useful in laceration repairs, fracture reduction, dental procedures, urethral catheterization, foreign body removal, abscess drainage, wound debridement, lumbar puncture, migraine pain, angina pain, and vascular access.15,17–22 A more detailed list of the uses of nitrous oxide is shown in Table 128-1.

There are contraindications to the use of nitrous oxide anesthesia (Table 128-2). Given that the gas is self-administered, normal cognitive function is required for its safe and effective use. Patients with altered consciousness, head injuries, or the inability to understand instructions for administration should all be excluded. Children who are younger than 4 years of age cannot properly follow the instructions for the use of the system. Hysterical patients, somnolent patients, and those with altered mental status also cannot comprehend and follow the instructions for the proper use of the system. Patients with significant heart failure require higher oxygen levels and should not be given nitrous oxide. It is important to restate that nitrous oxide is a relatively weak analgesic and commonly requires supplemental analgesic use (e.g., local anesthetic infiltration or intravenous analgesic administration).

Nitrous oxide has the ability to rapidly cross membranes and exchange with nitrogen. Patients with risks for a closed nitrogen-containing space injury are not eligible candidates. This includes patients with a pneumothorax, a pneumoperitoneum, bowel obstruction, middle ear surgery, pneumocephalus, air embolism, or emphysema. Rapid diffusion of nitrous oxide into a closed gas-containing space, in combination with its inability to leave the space quickly, results in an increased volume of the space and an increased pressure within the space. Patients may have intraocular gas bubbles placed in their eye by an Ophthalmologist in the management of retinal diseases. These gas bubbles may persist for several months in the eye. Exposure to nitrous oxide can cause rapid expansion of these gas bubbles and may lead to blindness.23 Patients with decompression sickness or undergoing hyperbaric oxygen therapy should also be excluded.

Nitrous oxide oxidizes cobalamin and thereby inactivates vitamin B12, a cofactor of methionine synthetase that is an instrumental enzyme in folate and methionine metabolism.24 Patients with methionine synthetase deficiency will have bad outcomes with nitrous oxide exposure. In addition, inactivation of methionine synthetase is associated with increased plasma homocysteine concentrations, which may increase the risk of postprocedural cardiovascular complications.25 Nitrous oxide irreversibly inhibits deoxyribonucleic acid (DNA) synthesis.26 Other inborn errors of metabolism that can result in serious outcomes when nitrous oxide is administered include homocystinuria and methylmalonic academia.27 Patients with a B12 deficiency or an acquired B12 deficiency (e.g., resection of the terminal ileum or pernicious anemia) can develop myeloneuropathy, leukopenia, or megaloblastic anemia after receiving nitrous oxide.28 Relative contraindication to the use of nitrous oxide may include pulmonary hypertension, prolonged anesthesia (>6 hours), first trimester pregnancy, and myocardial ischemia.29

• Nitrous oxide tank
• Oxygen tank
• Mixing valve
• Scavenging device
• Demand valve apparatus
• Nasal mask
• Face mask
• Sensor to measure ambient levels of nitrous oxide
• Pulse oximeter
• Cardiac monitor
• Supplemental oxygen source
• Intravenous catheters, tubing, and fluid
• Analgesic agents
• Anxiolytic/sedative agents
• Resuscitation equipment

A typical hospital-based device applicable for Emergency Department use is shown in Figure 128-1. The mixing valve ensures that a 50:50 mixture of both gases, oxygen and nitrous oxide, is delivered to the patient. The sources for the nitrous oxide–oxygen mixture can be from premixed cylinders, individual cylinders, or wall units. The device has a fail-safe mechanism that automatically stops gas flow when either tank becomes empty. In addition, through special reference pressures, the unit provides automatic oxygen enrichment at very shallow breathing rates.

It is required, in accordance with the National Institute of Occupational Safety and Health (NIOSH), to have a sensor to monitor ambient levels of nitrous oxide within the treatment area. The scavenging device reduces the ambient levels of nitrous oxide within the treatment area. Elevated levels of nitrous oxide have been associated with a decreased fertility rate, an increased rate of spontaneous abortion, and neurologic disturbances among dental assistants.30 Ambient levels of nitrous oxide were measured and noted to be 500 ppm following 8 minutes of patient administration.31 The ambient levels in a similarly sized room were 0 ppm when a scavenging device was added.32

Portable, handheld units were previously available for use in clinics and ambulances (Figure 128-2). Many of these units are still being used. The original manufacturer has recently sold this division of their company and the new manufacturer has temporarily discontinued this product line. Several companies are in the process of developing and testing portable units. These may be available in the near future. The nitrous oxide levels will vary in an ambulance with the airflow within the patient compartment. Trace levels of the gas are reduced to safe levels, even without the use of a scavenging device, if the air-conditioning or fans are operating and the ambulance is in motion.33

Entonox (Linde Healthcare Inc., Worsley, Manchester, UK) is a pre-prepared 50:50 mixture of nitrous oxide and oxygen. It is supplied in blue cylinders so it is not mistaken for another gas. It is quite popular with prehospital care providers due to its compact size and being lightweight. The main drawback is that only a fixed concentration of nitrous oxide can be administered. Oxygen is heavier than nitrous oxide. The tank, if sitting in cold weather, should be inverted several times prior to use to mix the contents as the gasses can separate. If not inverted, the patient can receive a higher concentration of oxygen at the start of using the tank and a higher concentration of nitrous oxide toward using the end of the tank. This formulation of nitrous oxide is not currently approved for use in the United States by the Food and Drug Administration (FDA).

A face mask or nasal mask (suited for pediatric patients) connected to a demand valve will help minimize the unwanted release of nitrous oxide into the treatment area. The demand valve allows for the self-administration of the gaseous mixture. A negative inspiratory flow (–1 to –5 cm H2O) must be generated in order to activate the gas flow. An airtight seal is required between the patient's face and the mask in order to achieve a negative inspiratory flow. The demand valve provides for a safe administration of nitrous oxide, minimizes the risk of oversedation, guards against human error, and protects against equipment failure. This demand valve system makes overdose almost impossible. As the patient's level of conscious declines, they will be unable to hold the mask in position and will therefore inhale room air.

Currently, most commercially available nitrous oxide administration devices do not have a demand valve and allow the nitrous oxide concentration to be adjusted from 0% to 70%. The advantages of these devices are the ability to control the percentage of nitrous oxide delivered and make adjustments based on the clinical situation. Unfortunately, these devices have numerous disadvantages. The Emergency Physician must monitor the patient much more closely for the effects of sedation, oversedation, hypoxemia, and adjust the settings during the procedure for which the nitrous oxide is being used. The lack of a demand valve can result in oversedation. The free flow of the nitrous oxide through the mask when the patient releases it results in increased concentrations in the procedure room, which can affect the healthcare personnel.

Inform the patient and/or their representative of the risks, benefits, potential complications, and alternatives to nitrous oxide anesthesia. Obtain a signed informed consent for the nitrous oxide anesthesia in addition to the consent for the procedure for which nitrous oxide is administered. Establishing intravenous access is not required but recommended. It can be obtained after beginning the nitrous oxide administration to make the pain of catheter insertion much more tolerable. Apply noninvasive cardiac monitoring leads, a noninvasive blood pressure cuff, and pulse oximetry to the patient. Place the patient supine on a gurney or sitting in a procedure (dental) chair that reclines. Preoxygenate the patient for 2 to 3 minutes with 100% oxygen. Encourage the patient to remain calm and breathe in a controlled manner, with special emphasis not to breathe too deeply or rapidly.

The nitrous oxide–oxygen gas mixture must be administered by appropriately licensed individuals, or under the direct supervision thereof, according to state law. The Emergency Physician responsible for the treatment of the patient and/or the administration of the nitrous oxide–oxygen gas mixture must be trained in the use of such agents and techniques and the appropriate emergency response in the rare case of respiratory compromise.

Prepare the machine. A flow rate of 4 to 6 L/min of nitrous oxide is generally appropriate for most patients. Begin with 2 minutes of 100% oxygen followed by a 40% nitrous oxide mixture (4 L/min of nitrous oxide and 6 L/min of oxygen). Increase the nitrous oxide in 10% intervals until to achieve the desired clinical effect and a maximum of 70% nitrous oxide (7 L/min of nitrous oxide and 3 L/min of oxygen). Most systems do not allow over 70% nitrous oxide to be administered. The concentration of nitrous oxide should not routinely exceed 50% during the administration. Titrate the nitrous oxide concentration to the clinical situation. It may be decreased during less painful procedures and increased during more painful procedures. It is important to continuously monitor the patient's respiratory rate and level of consciousness during the procedure.

The nitrous oxide–oxygen gas mixture can be administered via a nasal mask or a face mask. The nasal mask is used primarily by Dentists. It has been shown to be more effective in pediatric patients and patients undergoing procedures around the mouth and chin. The size and positioning of the nasal mask are important for ensuring a snug fit. Encourage the patient to breathe through their nose as opposed to their mouth in a controlled manner (i.e., not too fast or too deep).

With the face mask system, the demand valve prevents gas flow unless a negative inspiratory pressure is applied with a self-administered face mask. The gas flows constantly if a demand valve is not used. The patient applies the face mask ensuring an airtight seal that covers both the mouth and nose (Figure 128-3). Do not remove the face mask between breaths unless adverse effects are noted (e.g., dysphoria, headache, nausea, vomiting, lightheadedness, or vertigo). In these circumstances, remove the mask and administer 100% oxygen via a non-rebreather mask for 5 minutes or until the adverse symptoms resolve. The analgesic effects of nitrous oxide are commonly noted within 90 to 120 seconds of the onset of administration.34 Once the patient becomes mildly sedated (3 to 5 minutes), supplemental analgesics (e.g., wound infiltration of a local anesthetic) may be administered as needed or the procedure can be performed.

The patient cannot overdose on nitrous oxide if the mask is not attached to their face with tape or a strap. The patient will often remove the hand and the mask from their face as a state of analgesia and euphoria develops. The mask will fall off or loosen if the seal is not maintained. The demand valve will not be triggered if the mask falls off the patient's face. If not using a demand valve, the gas flows into the room and not directly into the patient. It is extremely important not to secure the mask to the patient's head with straps or tape so that nitrous oxide delivery will cease as the patient falls asleep. The patient may reapply the mask and self-administer additional nitrous oxide upon awakening or the experience of pain.

Remove the face mask upon completion of the procedure. Administer 100% oxygen for 5 minutes. This increases the rate of elimination of nitrous oxide and minimizes the side effects such as dizziness, lightheadedness, nausea, vomiting, headache, or dysphoria.35 Record the amount of gas and the duration of time used in the patient's chart. Record this information in the log maintained with the nitrous oxide device. Clean the demand valve apparatus, if used, prior to and after each administration.

The previously described preparation and technique applies to the pediatric patient with a few differences. Explain how the gas works to the patient. Show the child the equipment and let them handle it to realize it is not scary. Demonstrate the use of the mask on yourself and the parent before demonstrating it on the child. A face mask is preferred over the nasal mask for young children as it is difficult for them to cooperate with not mouth breathing. Unfortunately, the young child may have difficulty following instructions or using the face mask. Apply a flavored scent or flavored lip balm to the inside of the mask to make it more inviting for the child to use. A trained healthcare provider other than the Emergency Physician (e.g., another Emergency Physician, Nurse, Nurse Practitioner, Respiratory Therapist, or Physician Assistant) may be required to administer the nitrous oxide. This second provider can help hold the mask over the child's face and monitor the level of sedation to prevent oversedation.

Ensure that the patient is experiencing adequate analgesia before performing the procedure for which nitrous oxide is administered. Nitrous oxide analgesia is supposed to be the equivalent of administering 10 to 20 mg of morphine. Real use has shown that patients experience a wide range of pain relief (none, mild, moderate, or marked). Nitrous oxide administration may require supplementation with parenteral analgesics, parenteral sedatives, or other anesthetic techniques.

There is no aftercare related to the administration of nitrous oxide anesthesia other than 5 minutes of supplemental 100% oxygen via a non-rebreather mask. Continue to monitor the patient until they return to their pretreatment level of responsiveness. This often takes less than 10 minutes in almost all patients.

The side effects of a 50:50 nitrous oxide–oxygen mixture are relatively mild. Lightheadedness is most common with the occasional patient complaining of paresthesias or nausea. Donen et al. reported a 19% incidence of dizziness, lightheadedness, or vertigo; 4% of patients had paresthesias, headache, or amnesia; 5% had nausea; and 1% had vomiting.5 Other reported side effects include chest pains, desaturations, agitation, hyperventilation, abdominal pain, pallor, fatigue, irritability, hallucinations, and hiccups.17 There is little to no risk of inducing anesthesia or losing protective reflexes if used in concentrations of 50% or less. There has been no reported cases of laryngospasm or the need for advanced airway support using nitrous oxide concentrations up to 70%.17

The concept of diffusion hypoxia was first described by Fink in 1955.36 He noted the rapid diffusibility of nitrous oxide could displace oxygen from the alveoli after discontinuation of the gas.36 This concept has led practitioners to administer 100% oxygen for 5 minutes following the nitrous oxide administration. There has been evidence to disprove diffusion hypoxia in low-dose nitrous oxide mixtures (e.g., 50:50 nitrous oxide–oxygen). It is only a legitimate concern at higher concentrations such as that used during general anesthesia. Given the safety of a short course of 100% oxygen, its use following the cessation of nitrous oxide is still suggested. Caution is advised in patients with COPD in which the increased oxygen concentration found in the nitrous oxide–oxygen mixture can potentially depress their respiratory drive, necessitating close monitoring of their ventilatory status.

There has been a growing concern regarding the safety of trace levels of nitrous oxide in the Operating Room, Emergency Department, and Dentist office. Always use nitrous oxide in a well ventilated treatment room. There is evidence to show that elevated levels of nitrous oxide are associated with reduced fertility among female dental assistants.30 Scavenging devices help reduce the ambient levels of nitrous oxide within treatment areas. The demand valve system allows for all exhaled gases to escape into the surrounding environment without a scavenging device. A scavenging device will collect the exhaled gas and remove it from the patient care area.32 Scavenging devices can maintain ambient levels of nitrous oxide below 1200 ppm according to the guidelines proposed by the National Institute of Occupational Safety and Health (NIOSH).37 Nitrous oxide levels above 1200 ppm are considered a hazardous condition. Scavenging systems combined with air conditioning are considered the most effective means of lowering ambient nitrous oxide levels.38

There has been concern raised about the experimental use of nitrous oxide gas by medical personnel. Prepare a strict protocol on the use of the gas and its associated demand valve apparatus prior to the implementation of nitrous oxide-based procedural sedation in the Emergency Department. Record the volume of gas administered in the patient's chart as well as in a log kept with the nitrous oxide device following each use of nitrous oxide. The demand valve apparatus can be safely secured in the narcotic cabinet or within a Pixis system until it is required for patient use.

Over the many years of nitrous oxide use, there has been concern about the effects of nitrous oxide on the hematologic, neurologic, cardiac, reproductive, and immunologic systems. Nitrous oxide has been associated with decreased proliferation of mononuclear cells and neutrophil chemotaxis, megaloblastic anemia, anemia, thrombocytopenia, subacute combined neurodegeneration of the spinal cord, polyneuropathy, myocardial ischemia, increased spontaneous abortions, reduced fertility and birth defects, and impaired wound healing.27,39–42 More recently, nitrous oxide-induced neurotoxicity has been implicated in the development of long-lasting cognitive deficits when administered to patients of extremes of age.43

The administration of a nitrous oxide–oxygen mixture has been shown to be safe, effective, and easy to administer in an ambulatory care setting. The gas provides rapid onset of sedation as well as hypnosis, and rapid offset. It is a mild anesthetic that helps to facilitate the performance of mildly to moderately painful procedures. The adverse effects are minimal and, given a self-administered application of the gas, concerns of hemodynamic compromise are negligible. The use of nitrous oxide in a closed-space environment should be accompanied by a scavenging device to minimize ambient levels of the gas.