Prehospital Pharmacology: Nitrous Oxide

     While it's available in some U.S. emergency departments and EMS systems as an adjunct for pain management, nitrous oxide is not widely used. However, it is described as an effective agent for prehospital analgesia in a National Association of EMS Physicians position paper entitled Prehospital Pain Management, published in 2003. We kick off EMS Magazine's 2007 series on out-of-hospital pharmacology by discussing indications, contraindications, background and provider opinions for this particular agent and its utility on the ambulance. Additional information for this article was gathered from interviews with personnel from Dallas (TX) Fire-Rescue. EMS providers in Dallas and contiguous municipalities receive medical oversight from BioTel, their regional medical advisory mechanism. BioTel's protocol for field use of nitrous oxide is found at Biotel.

History and Pharmacology
     N2O is an ultrashort-acting nonhalogenated inhalation sedative/analgesic agent which was first discovered to have analgesic properties in the late 1700s. A dentist named Horace Wells began using it in his practice for tooth extraction in the mid 1800s. Since then it has been used in the hospital environment in both operating suites and emergency departments. According to an article published in the British Medical Journal, N2O was first used in the prehospital setting in 1970. Most lay persons associate nitrous oxide with the term laughing gas, a substance they may have received for minor procedures in their dentist's office. Nitrous oxide first appeared on the U.S. EMS scene in 1977.

     Nitrous oxide is formed by the decomposition of ammonium nitrate to nitrous oxide and water when it's heated to high temperatures. The resulting gas is sweet-smelling, nonirritating and colorless. It is close to 100% pure when manufactured and can be easily stored in compressed form in cylinders. N2O is the only inorganic gas used as an anesthetic in humans.

     Nitrous oxide is a central nervous system depressant. It dulls the senses, blunts perception of painful stimuli and produces a carefree attitude about one's surroundings. The actual mechanism by which it produces this pain relief is unknown. However, it is thought that it potentiates the release of endogenous endorphins, which react with opioid receptors in the central nervous system to elevate the pain threshold and create a feeling of relaxation and euphoria. It has little to no effect on the cardiovascular system other than mild cutaneous vasodilatation. Both heart rate and blood pressure remain relatively unchanged. There is no direct effect on skeletal muscle.

     N2O has both an onset of action and duration of action of 2-5 minutes. It is both metabolized and excreted by the lungs. This makes it an ideal agent for out-of-hospital use, since the patient receives immediate relief of pain. The equivalent analgesic effect in an adult patient has been estimated to require around 10-15 mg of morphine.

     Nitrous oxide is indicated for the temporary relief of pain in the out-of-hospital environment. It is particularly useful for pain due to isolated extremity injuries, burns, renal colic and cardiac chest pain when morphine or other narcotics are contraindicated. The agent is self-administered by breathing the gas through a demand valve mask. The dose is considered to be sufficient when the patient reports adequate pain relief or the mask drops out of their hand.

     Because nitrous oxide is a self-administered medication, the patient must be alert, able to follow instructions and able to hold the mask on his/her intact face. An inability to perform this action due to altered mental status, facial trauma or age is a contraindication to use. Additionally, nitrogen gas diffuses into spaces containing air 34 times faster than nitrogen can diffuse out. This can lead to potentially dangerous airspace expansion in the setting of pneumothorax, bowel obstruction, etc. Thus, nitrous is contraindicated whenever the possibility of these conditions exists. N2O also crosses the placenta and can cause fetal depression, particularly in the first trimester. It is also contraindicated in persons who have preexisting hypoxia, most notably COPD patients.

     From the incident management or operational standpoint, this agent should never be used in a confined space or when the administration set's scavenging system appears to be nonfunctional, since the gas will accumulate, displace oxygen and overcome rescuers.

Adverse Effects
     Nitrous oxide is considered to have a very good safety profile, and relatively few adverse effects have been reported in medical literature. However, a phenomenon known as diffusion hypoxia can occur once treatment with nitrous oxide is terminated if the patient is allowed to breathe only room air. Rapid diffusion of the gas from the bloodstream back into the lungs causes alveolar hypoxia. Symptoms include nausea, lethargy and dizziness; they have been described as similar to a hangover from heavy alcohol consumption. This phenomenon can be prevented by breathing 100% oxygen for several minutes following the conclusion of N2O therapy.

     As mentioned above, conditions in which air is entrapped in a closed space, such as a pneumothorax or bowel obstruction, will worsen in the presence of nitrous oxide. This agent should also not be given to patients suffering from decompression sickness, which is caused by nitrogen gas bubbles in the bloodstream.

     Currently, N2O is widely available as the brand Nitronox, which is a 50/50 preset blended mixture of nitrogen and oxygen. Neither the patient nor medical personnel are able to adjust the mixture to eliminate the risk of delivering a hypoxic blend to the patient. There are a variety of other safety measures built into these systems as well. The administration device will automatically shut off N2O if the oxygen supply is depleted and will automatically deliver 100% oxygen if the nitrogen supply is depleted. Audible alarms indicate faults in the system, and special connectors prevent the misconnection of gas supply hoses.

     Nitrous oxide systems today are built with scavenging systems to protect against leakage of the gas into the patient compartment of the ambulance, a problem brought to light in the early days of its use in the U.S. One issue that must be monitored, due to the difficulty of preventing it, is potential abuse that can occur if EMS providers inhale the gas themselves for pleasure.

Provider Experiences
     Nitrous oxide has been used successfully in U.S. EMS systems for almost 30 years. Paramedics who use it less often tend to be hesitant in suggesting its use to patients, but those who appreciate its rapid effects and titration through self-administration swear by it. The most obvious utilization would seem to be in the pediatric population with non-life-threatening extremity fractures in which pain relief can be accomplished without having to start an intravenous line, and in adult patients without contraindications in whom IVs, for whatever reason, cannot be established. It also has value during short transports, where starting an IV, unlocking the narcotics and administering them would be too time-consuming. However, EMS providers must remember that the analgesic effect is extremely short-lived. Thus, when the patient arrives at the emergency department and the inhalation is discontinued, the therapeutic effects will dissipate very quickly.

Medication Profile

• Nitrous oxide: An inhalational anesthetic and analgesic agent
• Indications: Temporary relief of pain in the prehospital environment
• Contraindications: Pneumothorax, bowel obstruction, facial trauma, altered mental status
• Adverse drug reactions: "Hangover effect"symptoms, diffusional hypoxia

Summary
     Nitrous oxide is a potent inhalational anesthetic/analgesic that is safe and effective for out-of-hospital use. It is a regulated drug that must be purchased and prescribed by a physician. Thus, its use will be limited to those EMS systems where it is allowed by local, regional or state formulary and approved by the system medical director.

David Jaslow, MD, MPH, EMT-P, FAAEM, is chief of the Division of EMS, Operational Public Health and Disaster Medicine within the Department of Emergency Medicine at Albert Einstein Medical Center. He is an active firefighter/paramedic, assistant chief for EMS and EMS medical director for Bryn Athyn Fire Company. He serves as medical editorial consultant for EMS Magazine.

Dorothy Lemecha, DO, is a fellow in the Governmental Emergency Medical Security Services Program at UT Southwestern Medical Center (Parkland Hospital) in Dallas, TX. She is the assistant medical director for the Irving (TX) Fire Department and a tactical physician with the Irving (TX) Police Department.