Inhaled Nitrous Oxide for the Prevention of Emergence Reaction During Ketamine Administration in Adults, a Pilot Study

Drugs such as fentanyl, midazolam, and propofol are widely used in emergency departments for
procedural sedation and analgesia because they have a rapid onset and short duration of
action. Unfortunately, all of these agents may cause respiratory depression, particularly
when combined with other sedative agents, administered in large doses, or given to patients
with underlying respiratory diseases.

Ketamine hydrochloride is a phencyclidine derivative that causes dissociation between the
cortical and limbic systems preventing the higher centers from perceiving visual, auditory,
or painful stimuli. It possesses a rapid onset and short duration of action and produces
profound sedation and analgesia. Ketamine is also a non-competitive NMDA antagonist, which
complements NO. However, laryngeal reflexes are maintained and respiratory depression is
rare. These properties have made ketamine a very popular agent for procedural sedation and
analgesia in pediatric emergency department patients . Unfortunately, when given to adult
patients, it frequently causes emergence anxiety, nightmares, hallucinations, and delirium.
These emergence reactions have limited the use of ketamine in adults. The incidence of these
reactions is about 7-10% in children. Emergence reactions may be a product of the state in
which the patient becomes disassociated . Therefore, if the patient is more relaxed prior to
ketamine administration through the adjunct use of NO, adverse emergence reactions may be
reduced.

A number of agents including diazepam, lorazepam, fentanyl, droperidol, and others have been
used with varying success to reduce or prevent emergence reactions associated with ketamine
use. Diazepam and lorazepam have been the most successful, but their use may prolong
recovery time, making them less desirable in the emergency department setting. Midazolam has
been shown to lower the rate of emergence reaction when used concurrently with ketamine in
adults. However, like all benzodiazepines, there is a small risk of respiratory depression
and hypoxia with the use of midazolam, which could lead to an adverse respiratory event.

Inhaled nitrous oxide may be an ideal adjunct to the prevention of emergence reaction in
adults being treated with ketamine. Nitrous oxide is a colorless gas that diffuses rapidly
across the pulmonary alveoli providing analgesia and anxiolysis with minimal sedative
effects, rapid induction, and emergence. Nitrous oxide is a weak sedative agent with the
potential for significant analgesic effects. Noncompetitive antagonist activity at the NMDA
receptor along with activation of opioid receptors contributes to its anesthetic mechanism.
There are rare adverse events, most often cited as case reports of chronic or acute toxicity
causing myeloneuropathies and polyneuropathies.

Nitrous oxide has been used in general anesthesia for over 2 centuries, but its use outside
of the operating room began when Tunstall introduced the nitrous oxide/oxygen mixture as an
analgesic agent during labor. Since this inception, the nitrous oxide/oxygen mixture has
been used readily in the fields of dentistry, gastrointestinal procedures, and children's
procedural sedation. Nitrous oxide is often administrated via continuous flow or on-demand
at a concentration of 50-70%.

There is some early data describing a favorable adverse event profile with nitrous oxide as
a single agent in adults. Hennequin et al. demonstrated support for the efficacy of nitrous
oxide with no major adverse cardio respiratory events. Although approximately 10% of
participants received mild gastrointestinal and behavioral side effects (e.g. agitation).
Greater than 90% of the study participants stated they would receive nitrous oxide again. In
a large prospective trial, Babl et al. found there to be only 2 patients out of 655 who
suffered serious adverse events (i.e., chest pain and oxygen desaturation). Both patients
had been administered 70% nitrous oxide compared to the more conservative 50% concentration.
Additionally, there was an increased incidence of minor adverse events (i.e., emesis and
agitation) with the higher concentration of nitrous oxide. Kariman et al. compared nitrous
oxide versus parental fentanyl as an analgesic after long bone fracture and found similar
pain scores and a more rapid decrease in the pain score in the nitrous oxide group when
compared with the opiate group.

Nitrous oxide has been shown to be a safe and effective agent for procedural sedation in
children, including work that has combined opiates and benzodiazepines with nitrous
continuously. Burton et al. conducted a small, randomized controlled trial studying the
effectiveness of nitrous oxide on anxiety scores in children during laceration repairs. They
found a significant decrease in the group that used nitrous oxide compared to the placebo
group. This finding was further validated by Luhmann et al. with 50% continuous flow nitrous
oxide resulting in less distress and anxiety as well as increased patient satisfaction
compared to midazolam or topical anesthetic agents. The study also showed that the main
adverse event associated with nitrous oxide was nausea and vomiting, whereas midazolam group
had significant ataxia and dizziness. There was no demonstrable advantage of the combination
of midazolam and nitrous oxide in regard to patient satisfaction versus nitrous oxide alone,
but there was an increase in adverse events when midazolam was included.

A study performed by Evans et al. demonstrated that the pain and memory of the procedure
between children receiving either nitrous oxide versus children receiving intramuscular
meperidine in combination with promethazine for fracture reduction was similar, but there
was increased satisfaction and decreased length of stay in the nitrous oxide group. Seith et
al. demonstrated that the addition of intranasal fentanyl to nitrous oxide in children
resulted in deeper levels of sedation when compared to nitrous oxide alone; however, there
were no serious adverse events.

Nitrous oxide use during ketamine administration may be an ideal combination for the
prevention of emergence reaction in adults sedated in the ED. Like ketamine, nitrous oxide
has an excellent cardio-respiratory profile as well as some analgesic and anxiolytic
qualities. The anxiety and pain surrounding procedural sedation is not limited to the
procedure itself, but the elapsed time from the time the patient enters the ED to the time
spent in preparation for the procedure can be significant and lead to increased anxiety,
which may exacerbate emergence reactions in adults. Using nitrous oxide before ketamine
administration may mitigate this. While midazolam has shown efficacy in reducing emergence
reactions in adults sedated with ketamine, we believe that inhaled nitrous oxide may be
equivalent to midazolam, with a better cardio-respiratory profile.

Since this is a novel concept, we believe that a pilot study to evaluate the safety and
efficacy of 50/50 nitrous oxide/oxygen administration with adult ketamine administration is
warranted.

Inclusion criteria: All spontaneously breathing subjects, 18 years of age and older, with
an American Society of Anesthesiologists (ASA) Physical Status Classification 1 or 2, who
will be receiving sedation for an ED procedure. Written informed consent will be obtained
from all subjects.

Exclusion criteria: Subjects with underlying conditions that could affect ventilation,
perfusion, or metabolism including intubated subjects, subjects with clinical signs of
cardiopulmonary instability, major trauma, thoracic trauma, shock, sepsis, psychiatric
disorders and ASA class 3, 4, and 5. Also those unable to provide informed consent,
nursing home residents, age less than 18 years, non English speaking, pregnant women,
subjects under police custody, or physician discretion.