Monograph: |
Nitrous Oxide
Laughing Gas: Nitrogen Monoxide:
A colourless gas. heavier than air. odourless or almost odour-
less and tasteless; it supports combustion. One vol. measured
at a pressure of 101 kPa dissolves, at 20", in about 1.5 vol. of
water; freely soluble in alcohol: soluble in ether and in oils.
It is supplied compressed in metal cylinders. National stand-
ards are usually in operation for the labeling and marking of
such cylinders.
Storage. Cylinders containing 50% nitrous oxide and 50%
oxygen should be protected from the cold to prevent separa-
tion of the gases. Cylinders exposed to temperatures lower
than -7Β° should be rolled at room temperature lo ensure mix-
ing or alternatively stored horizontally for 24 hours at a tem
perature of not less than 10Β°.
Adverse Effects
The main complications following the use of nitrous
oxide are those due to varying degrees of hypoxia.
Prolonged administration has been followed by
megaloblastic anaemia and peripheral neuropathy.
Depression of white cell formation may also occur.
There is a risk of increased pressure and volume
from the diffusion of nitrous oxide into air-contain-
ing cavities. Malignant hyperthermia has been re-
ported rarely. Nitrous oxide has been subject to
abuse.
See also Adverse Effects of General Anaesthetics.
Effects on the blood. Nitrous oxide interacts with vitamin
B 12. This blocks the transmethylation reaction for which vita-
min Bi; is a coenzyme and results in depletion of methionine
and tetrahydrofolate. Metabolic consequences have been at-
tributed to depletion of either or both. Interference by nitrous
oxide with DNA synthesis prevents production of both leuco-
cytes and red blood cells by the bone marrow. Megaloblaslic
changes in bone marrow and impaired granulocyte produc-
tion are found in patients exposed to anaesthetic concentra-
tions of nitrous oxide for 24 hours. In patients with normal
bone marrow, stores of mature granulocytes will normally be
adequate to prevent leucopenia during exposure for up to 3
days; in patients exposed to nitrous oxide for longer periods
of time, leucopenia will develop and exposure for 4 days or
longer can result in agranulocytosis. In general, healthy sur-
gical patients can be given nitrous oxide for upto 24 hrs.
without harm. In situations where nitrous oxide is used for
more than 24 hours, folinic acid 30 mg twice daily has been
given lo protect the haematopoietic system. Repeat exposure
la nitrous oxide at intervals of less than 3 days will have a
cumulative effect on DNA synthesis and megaloblastic mar
row changes have been reported following multiple short-
term exposure.' Depletion of methionine has been implicated
in the neurological deficit (see below) seen mainly after
chronic use of nitrous oxide. It may also account for the feto-
toxicitv observed in rats. see below.
Effects on the nervous system. Neurological disorders
(mainly myeloneuropathies and neuropathies) have occurred
in persons who chronically abuse nitrous oxide. Similar ef-
fects have been noted after repeated administration of nitrous
oxide in hospitalized patients. These neurological effects arc
considered to be due to nitrous oxide-induced methionine de-
ficicncy (see Effects on the Blood, above.
In patients with undiagnosed subclinical deficiency of vita-
min B-12 (a coenzyme involved in methionine synthesis) neu-
rological manifestations, including those consistent with
subacule combined degeneration of the spinal cord. have oc-
curred following a single exposure to nitrous oxide for anaes-
thesia.
Malignant hyperthermia. An 11 -year-old girl whose la-
ther had died from malignant hyperthermia alter anaesthesia
developed hyperthermia after anaesthesia with nitrous oxide
and oxygen.
Precautions
Hypoxic anaesthesia is dangerous and nitrous oxide
should always be administered with at least 20 to
30'%. oxygen. Nitrous oxide diffuses into gas-filled
6ody cavities and care is essential when using it in
patients at risk from such diffusion such as those
with abdominal distension, occlusion of the middle
ear. pneumothorax, or similar cavities in the pericar-
dium or peritoneum. Care is also required in patients
during or after air encephalography. Oxygen should
be administered during emergence from prolonged
anaesthesia with nitrous oxide lo prevent diffusion
hypoxia where the alveolar oxygen concentration is
diminished. See also Precautions for General An-
aesthetics. In addition to the above precau-
tions. mixtures of equal parts of nitrous oxide and
oxygen should not be employed for analgesia in pa-
tients with head injuries with impairment of con-
sciousness, maxillo facial injuries, decompression
sickness, or those heavily sedated.
Driving. A slight but quantified impairment in driving ability
was found up to 30 minutes following 15 minutes' inhalation
of nitrous oxide/oxygen mixtures.'
Epidural anaesthesia* Nitrous oxide diffuses into gas-
filled body cavities and can increase the size of any air bub-
bles injected into the epidural space to determine placement
of the needle in epidural anaesthesia. ' This could result in un-
even spread of the local anaesthetic and produce inadequate
analgesia. The volume of air injected should be limited or an-
other technique used to determine placement of the needle if
nitrous oxide is lo be given subsequently.
Hazard to user. A scavenging system and effective ventila-
tion may be necessary to control the nitrous oxide pollution
that can occur when this gas is used for analgesia or anaesthe-
sia. Risk areas include, in addition to operating theatres, de-
livery rooms and dental surgeries. Occupational exposure
can lead to serious toxicity with bone-marrow and neurologi-
cal impairment. It Reduced fertility has been reported in fe-
male dental workers exposed to high concentrations of
nitrous oxide. such women also appear to have a higher rate
of spontaneous abonion.5 It has been suggested that nitrous
oxide can also affect male fertility: in one study a dose-relat-
ed increase in the incidence of spontaneous abortion was
found in the wives of men with occupational exposure to ni-
trous oxide.
Pregnancy. Nitrous oxide is fetotoxic in rats. However, ret-
rospective reviews' and individual case reports' have not
shown nitrous oxide anaesthesia to be fetotoxic in man. See
also under Hazard to User, above.
Vitamin B-12 deficiency. For reports of neurological dys-
function associated with the use of nitrous oxide in patients
with undiagnosed sub clinical vitamin B-12 deficiency, see effects on nervous system above.
Interactions
The concurrent administration of nitrous oxide with
an inhalational anaesthetic accelerates the uptake of
the latter from the lungs. This phenomenon is
known as the second gas effect. It is due to the dis-
proportionate absorption of nitrous oxide into the
blood resulting in an increased alveolar concentra-
tion of the second gas.
The use of high doses of opioids such as fentanyl
with nitrous oxide may result in a drop in heart rate
and cardiac output.
See also Interactions for General Anaesthetics
Methotrexate. Combined use of nitrous oxide and meth-
otrexate may increase the side-effects of methotrexate thera
py.
Pharmacokinetics
Nitrous oxide is rapidly absorbed on inhalation. The
blood/gas partition coefficient is low and most of the
inhaled nitrous oxide is rapidly eliminated un-
changed through the lungs though small amount
diffuse through the skin.
Uses and Administration
Nitrous oxide is an anaesthetic administered by in
halation. It is a weak anaesthetic with a minimum
alveolar concentration (MAC) value of
110%. It has strong analgesic properties, but pro
duces little muscle relaxation. Nitrous oxide must be
administered with air or oxygen, otherwise hypoxia
will occur although mixtures with air are rarely used
now, oxygen being preferred.
Nitrous oxide with oxygen may be used in the in
duction and maintenance of anaesthesia .
However, it is now mainly employed as an adjuvant
to other inhalational anaesthetics, permitting them
to be used at significantly lower concentrations. It is
also used, with oxygen, in subanaesthetic concentration
for analgesia in obstetrics and other painful
procedures.
Induction of anaesthesia may be carried out with
about 20 to 30% v/v of oxygen and maintenance
with up to 50% v/v of oxygen. Recovery is usual.'
rapid from nitrous oxide anaesthesia.
Nitrous oxide 25 to 50% v/v with oxygen is used for
analgesia: cylinders containing premixed nitrous
oxide 50% v/v and oxygen 50% v/v are available in
some countries.
Alcohol withdrawal syndrome: The symptoms of acute alcohol withdrawal are usually managed with benzodiazepines but nitrous oxide has been reported to reduce symptoms when tried in alcohol withdrawal. In mold to moderate cases a single administration of up to 20 mts duration of a nitrous oxide-oxygen mixture in analgesic doses has been employed.
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