1) Nitrous oxide has been used as an anesthetic since the 1800s. It is commonly used today in combination with other anesthetic agents to reduce their required doses and decrease cardiovascular depression. 2) Nitrous oxide also has analgesic properties and is used for procedural sedation and pain management, though repeated or long-term use is discouraged due to health risks. 3) While nitrous oxide provides faster induction and recovery from anesthesia, its use may increase postoperative nausea and vomiting. Prolonged exposure can also cause vitamin B12 deficiency and neurological effects in some cases. Therefore, the risks and benefits must be considered when deciding whether to use nitrous oxide.

1. MODERATOR- Dr. NEELKAMAL
PRESENTER- Dr. RICHA

2. NITROUS OXIDE

3. Prepared first by JOSEPH PRIESTLY in 1772

4. Anesthetic properties first demonstrated by
HUMPHERY DAVY in 1800

5. Used for painless tooth extraction first by HORACE WELLS

6. PRODUCTION AND STORAGE
 Nitrous oxide is produced commercially by heating
ammonium nitrate to 240C.
 Water vapour and impurities, including higher oxides of
nitrogen, ammonia and nitric acid, are subsequently removed
by passage through a series of washers and scrubbers.
 Nitrous oxide is stored in French-blue cylinders (pin-index 3,
5) pressurized to 4400kPa at room temperature.
 Nitrous oxide is usually stored below its critical temperature,
and thus exists simultaneously in liquid and vapour phases.

7. PHYSICAL PROPERTIES
 Only Non Organic Gas In Use Regularly Today
 Non Irritating, Sweet Smelling And Colourless
 NON-inflammable/ NON-explosive but supports combustion of
other agents as it dissociates to N2 and O2 above 450°C
 Gas at room temperature and ambient pressure
 Can be kept as a liquid under pressure as its critical temperature
lies above room temperature

8. Molecular Weight - 44.01
Specific Gravity - 1.527
Boiling Point - - 89°C
Blood/Gas Solubility Coefficient - 0.47
Vapour Pressure At 20°C - 800psi
Maximum Safe Concentration - 80%
MAC - 105

9. PHARMACOKINETICS
 Rapidly absorbed from the alveoli because nitrous oxide diffuses
more rapidly across alveolar basement membranes than does nitrogen
(s 30 times more water soluble)
 100 ml of blood will carry 45 ml of nitrous oxide in its plasma
 Elimination is as fast as the absorption because it does not combine
with hemoglobin or undergo any chemical combination in the body
 POOR BLOOD SOLUBILITY permits rapid achievement of an
alveolar and brain partial pressure
 Analgesic effect is prominent but short livedinhibitory action at N-
methyl-D-aspartate (NMDA) glutamate receptors & stimulatory
activity at dopaminergic, a1 and a2 adrenergic and opioid receptors.

10. The concentration effect:
A high PI delivered from anesthetic machine is required during
initial administration of the anesthetic.
A high initial input offsets the impact of uptake  accelaration
of induction of anaesthesia reflected by rate of rise in PA &
PBRAIN
The impact of PI on rate of rise in PA of inhaled anesthetic is
known as concentration effect.
Thus it states that higher the PI more rapidly PA approaches PI
by offsetting uptake

11. The concentrating effect results from:
A) a concentrating effect
B) augmentation of tracheal flow
 Concentrating effect reflects concentration of inhaled
anesthetic in smaller lung volume due to uptake of all gases in
lung
 At the same time , anesthetic input is increased to fill the void
produced by uptake of gases in blood.

12. The second gas effect
 The second gas effect is a direct result of the concentration
effect.
 It reflects ability of high volume of one gas to accelerate
increase in PA of concurrently administered “second gas”

13. 2
100
2
65
65
35
2.7
100
(augmentation of
tracheal inflow)
Second gas effect
Due to conc.
Effect of N2O
35
65
=53.8%

14.  The reverse may occur at the end of anaesthesia, when the
administration of nitrous oxide ceases.
 Nitrous oxide enters the alveoli far more rapidly than nitrogen
leaves, causing dilution of the gaseous contents of the alveolus.
 This results in the dilution of oxygen within the alveoli of
patients breathing air and may cause ‘diffusion hypoxia’.
 The dilution of the alveolar content may also dilute the
concentration of volatile agents, enhancing their elimination,
and speeding wakening.

15. PHARMACODYNAMICS
 Nitrous oxide has effects on many physiological systems
RESPIRATORY SYSTEM:
 decrease in TV
 increase in RR (by CNS + and possibly activation of pulmonary
stretch receptors )
 MV is maintained.
 reduction in the ventilatory response to hypoxia and
hypercapnia.
 Depresses tracheal mucociliary flow and neutrophil
chemotaxis  increase incidence of post-operative respiratory
complications.
 At low concentrations nitrous oxide has a negligible effect on
HPV; however, at higher concentrations it may be impaired

16.  CARDIOVASCULAR:
 direct myocardial depression,
 Increases central sympathetic outflow.
 In general :arterial pressure is little affected by nitrous oxide.
 Pulmonary vascular resistance is increased due to constriction
of the pulmonary vascular smooth muscle  increase in RA
pressure best avoided in pulmonary HTN
 Other vascular beds are also altered decrease in renal and
hepatic blood flow due to an increase in vascular resistance of
these beds

17. CENTRAL NERVOUS SYSTEM
 Increases CBF, cerebral metabolism & ICP
 increase in cerebral metabolism increase in cerebral blood
flow.
 These changes are particularly marked when there is disruption
of normal cerebral autoregulation  may result in a significant
(and potentially detrimental) decrease in cerebral perfusion.
 Important in patients undergoing neurosurgical procedures,
but must also be considered in those with cerebral or
cerebrovascular pathology (e.g. head injury or cerebrovascular
disease) for extracranial surgery.

18. NEUROMUSCULAR
 Most volatile anaesthetic agents depress the neuromuscular
junction and augment the effects of non-depolarizing
neuromuscular blockers
 In contrast, nitrous oxide has the potential to increase skeletal
muscle activity and has less depressant activity at the
neuromuscular junction.
 It does not potentiate the action of non-depolarizing
neuromuscular blocking agents.

19. ANALGESIC ACTIONS
 mediated by activation of opioid receptors in the
periaqueductal grey of midbrain
 modulation of nociceptive pathways through the release of
norepinephrine and activation of a2 adrenoceptors in the
dorsal horn of the spinal cord.
 This may explain tolerance to nitrous oxide that may be seen
as a consequence of depletion of central opioid peptides

20. CLINICAL APPLICATION
1.General anaesthesia
 Although nitrous oxide has anaesthetic properties, it is not suitable as
a sole anaesthetic agent under standard atmospheric conditions.
 Its minimum alveolar concentration (MAC) is 105% at 1 atmosphere
pressure.
 However, it is used extensively in combination with other volatile
anaesthetic agents :
1. This reduces the required dose of volatile agent
2. reduces the cardiovascular depression that occurs with most volatile
agents.
3. Reduces cost

21. 2. Obstetrics
 Nitrous oxide was first used as an analgesic during labour in
1881
 Although not a potent analgesic during labour, it appears safe
for pregnant women, their babies and healthcare workers who
are in attendance.
 For many women, it provides adequate labour analgesia but co-
ordination of administration with contractions can be difficult.
 Maternal side effects include nausea, dizziness, paraesthesia
and dry mouth.

22. 3. Pain management
 Excellent analgesia for acutely painful procedures such as
fracture reduction and changes of burns dressings.
 In the emergency department setting has a role in the
management of the pain of ureteric colic and sickle cell crises
and positioning for radiological procedures.
 Repeated or long-term use is discouraged because of its risks
 useful in the theatre for supplementation of regional
techniques

23. ADVERSE EFFECTS OF NITROUS OXIDE
 POSTOPERATIVE NAUSEA AND VOMITING
 PONV is a major cause of anaesthetic morbidity and nitrous oxide
has been implicated in its aetiology.
 The mechanism for the emetogenic potential of nitrous oxide is not
fully understood but changes in middle ear pressure, bowel
distension and activation of dopaminergic neurones may all be
involved.
 Omission of nitrous oxide reduces PONV by nearly 30%, maximally
seen in female patients.

 When considering the potential benefits of nitrous oxide omission,
the incidence of adverse outcomes (such as awareness) must also be
considered

24.  AIR-FILLED SPACES
 The relative solubilities of nitrous oxide and nitrogen cause
rapid expansion of nitrogen-containing spaces when nitrous
oxide is commenced.
 Pressure or volume changes or both depending upon the nature
of the space (e.g. pneumothorax, bowel, middle ear).
 These changes can have deleterious consequences.
 There are several clinical situations where nitrous oxide should
be avoided owing to the potentially dangerous effects of space
expansion

26.  Cuff pressures of endotracheal tubes and laryngeal masks can
increase significantly during prolonged administration of
nitrous oxide.
 This may lead to local ischaemia and mucosal damage.
 Regular checks of cuff pressure should be made using a
pressure gauge during prolonged surgery.

27.  POTENTIAL ADMINISTRATION OF A
HYPOXIC MIXTURE
 It is possible to deliver a hypoxic mixture of gases to a patient
from anaesthetic machines where no hypoxic guard is fitted.
 To prevent this catastrophe the Medical Device Agency has
stated that all anaesthetic machines in use must be fitted with
either a hypoxic-guard or an oxygen analyser

29.  HEMATOLOGICAL
 Prolonged administration of nitrous oxide causes inhibition of
methionine synthetase  interference with DNA synthesis in
both leukocytes and erythrocytes.
 Vitamin B12 is required as a coenzyme for methionine
synthetase.
 However, vitamin B12 is oxidized by nitrous oxide and so is
unable to interact with methionine synthetase.
 In addition, nitrous oxide reduces the motility and
chemotactic response of leucocytes.
 Oxidation of the cobalt atom in B12 by nitrous oxide can
precipitate megaloblastic changes in the bone marrow and a
neuropathy in experimental animals.

30. INCREASED HOMOCYSTEINE
Causes endothelial dysfunction
Induce oxidative stress
Destabilize coronary artery plaques
Impair myocardial substrate utilization
Enhances platelet aggregation

31.  It is well recognized that long term increase of plasma
concentration of homocysteine are an independent risk factor of
Coronary artery disease and cerebrovascular disease
 Such changes may also be observed in humans and are of
particular concern where there is clinical or subclinical B12 or
folate deficiency
 Mild megaloblastic changes are seen in healthy people after 12
h of anaesthesia and these changes become marked after 24 h.
 The neurological alteration can range from transient mild
paraesthesia through to a picture that resembles subacute
combined degeneration of the cord.

32.  Some studies support that Vitamin B12 and folate
supplementation preoperatively can help to prevent these
unwanted actions.
 On other hand some suggest treatment with vitamin
B12 did not alleviate the symptoms or enhance
recovery; thus, it occurs in those who abuse N2O on a
long-term basis.

33.  OCCUPATIONAL EXPOSURE
 In the pre-scavenging era, there were concerns that nitrous
oxide might contribute to the increased relative risk of
miscarriage and reduced fertility seen in female theatre workers.
 Provided that anaesthetic gases are scavenged and the levels of
ambient nitrous oxide are maintained below 100 p.p.m., it
appears that the safety of those who have long-term
occupational exposure is not compromised.

34.  TERATOGENICITY
 The mechanism of the teratogenicity is thought to be
multifactorial and not simply a consequence of impaired DNA
synthesis.
 Stimulation of a1 adrenergic neurones leads to decreased
ciliary activity which may cause disordered organogenesis and
explain why situs inversus has been observed.

35.  Human studies have generally focused on the long-term behavioral
effects of maternal obstetric medication.
 Claims have been made that the medication given at delivery to the
mother produces depressed motor skills and impaired language
ability in the infant and child for several years. Such claims,
however, are controversial.
 Behavioral abnormalities in offspring whose mothers received
inhaled anesthetics at any time during delivery have not been well
studied
 Furthermore, studies have not been done to assess the
neurobehavioral function of children of operating room personnel
who have been exposed to waste anesthetic gases.
 Firm conclusions await further investigation as there is no
evidence that the modern fluorinated inhaled anesthetics are
mutagenic or carcinogenic.

36.  ENVIRONMENTAL CONCERNS
 Nitrous oxide, like carbon dioxide, methane and perflurocarbons, is
a greenhouse gas.
 Most environmental nitrous oxide is produced via the use of
nitrogen-based fertilizers in agriculture, burning of fossil fuels and
sewage management programmes.
 It is 200–300 times more effective at trapping heat than is carbon
dioxide, and contributes to global warming.
 However, nitrous oxide only constitutes 5% of greenhouse gases.
 Concerns about the environmental impact of anaesthetic use of
nitrous oxide are probably unfounded; anaesthesia accounts for <1%
of total nitrous oxide emissions.
 The contribution of anaesthetic gases may be even lower with the
increasing use of low-flow systems.

37. ENIGMA - I TRIAL
EVALUATION OF NITROUS OXIDE IN GAS MIXTURE FOR ANESTHESIA
 It was a randomized controlled trial-2007
 Entitled “ AVOIDANCE OF NIROUS OXIDE FOR PATIENTS
UNDERGOING MAJOR SURGERIES”
 Recruited 2050 patients randomly assigned to either nitrous
oxide free group ( 80% oxygen 20% nitrogen) or nitrous oxide
based group ( 70% nitrous oxide , 30% oxygen)
 All patients were scheduled to undergo major surgery of atleast
2 hours duration.

38.  Primary endpoint (duration of hospital stay): no difference in
two groups
 Secondary endpoints ( ICU stay, PONV, pneumonia,
pneumothorax, pulmonary embolism, wound infection,MI,
venous thromboembolism, stroke , awareness and death
within 30 minutes) : showed lower rates in nitrous free group
 No significant difference in major adverse cardiac events or
death was reported

39. CONCLUSION OF ENIGMA I TRIAL:
 Avoidance of nitrous oxide and concominant increase in
inspired oxygen concentration decreases incidence of
complications after major surgery, but does not significantly
affect duration of hospital stay. Routine use of nitrous oxide
in patients undergoing major surgery should be questioned.
CRITICISM
 The difference results in two groups could be due to high
oxygen concentration in nitrous free group
 The depth of anesthesia was not equivalent in two groups
 There may have been confounding factors like use of more
propofol in nitrous oxide free group.. Therefore less PONV

40. ENIGMA II TRIAL
 NITROUS OXIDE AND SERIOUS LONG TERM MORBIDITY
AND MORTALITy IN EVALUATION OF NITROUS OXIDE IN
THE GAS MIXTURE FOR ANAESTHESIA
 PRIMARY OUTCOME: death and cardiovascular complications
within 30 days of surgery
 CONCLUSION: Nitrous oxide should remain an option in
contemporary anaesthesia. There are potential advantages in
pain control and prevention , reduction in awareness with
recall, as use in neurologically and cardiovascularly “at risk”
patients .

42. (1) What is the place of N2O in today’s perioperative
anaesthesia management?
(2) What is the place of N2O in procedural analgesia and
sedation?
(3) Is administration of N2O associated with a health risk
for patients and/or providers?

43. PLACE IN TODAY’S PRACTICE?
 Provides faster and smoother induction with improved
oxygenation
 During maintenance , allows the concentrations of the other
drugs to be decreased which, in turn, may result in faster
recovery at the end of the procedure
 Induce anxiolysis  facilitating mask acceptance as well as
peripheral venous line insertion especially in children BUT
these goals can also be achieved with adequate child
preparation, parental presence and/or pharmacological
premedication

44.  Though it may increase the incidence of PONV however
this non-desirable side effect can easily be controlled with
antiemetic prophylaxis.
 Moreover the incidence of PONV is insignificant when the
duration of exposure is less than 1 hour

45. PLACE OF N2O IN PROCEDURAL
ANALGESIA AND SEDATION ?
 N2O administered as the sole sedation/analgesic agent can
safely be provided by even non-anaesthesiologists who are
appropriately trained in the administration modalities of the
drug & have thorough basic life support training .
 N2O can be used safely for procedural pain management (in
the emergency room, in the normal ward or in a prehospital
situation), for the management of labour pain, and for
anxiolysis and sedation in dentistry
 N2O continues to be the mainstay for paediatric procedural
sedation in a large variety of clinical setting

46. Is administration of N2O associated with a
health risk for patients and/or for providers ?
 The contraindications to the use of N2O are few:
1. the presence of closed gas containing cavities (e.g.
pneumothorax)
2. abnormalities of the metabolism of vitamin B12 (e.g.
vegetarianism, some rare metabolic disorders)
 The issue of repeated anaesthesia or sedation with N2O is poorly
studied.
 Cases of chronic N2O abuse have shown that both polyneuropathy
and megaloblastic anaemia can occur and some groups therefore
recommend not to use N2O more than twice a week.

47.  Properly operating scavenging systems reduce N2O
concentrations by more than 70%, thereby efficiently
keeping ambient N2O levels well below official limits
 an exposure limit to N2O of 25 parts per million (ppm) as a
time-weighted average (TWA) during the period of
anaesthetic administration is recommended

48.  The potential teratogenic effect of N2O observed in experimental
models cannot be extrapolated to Humans.
 There is a lack of evidence for an association between N2O and
reproductive toxicity.
 The incidence of health hazards and abortion was not shown to be
higher in women exposed to, or spouses of men exposed to N2O than
those who were not so exposed.
 The incidence of congenital malformations was not higher among
women who received N2O for anaesthesia during the first trimester of
pregnancy nor during anaesthesia management for cervical cerclage,
nor for surgery in the first two trimesters of pregnancy
 Though it is suggested to avoid N2O in first trimester of pregnancy

49.  There is currently no clinically relevant evidence for the
withdrawal of N2O from the anaesthesia practice or
procedural sedation.
 In procedural sedation, the use of N2O should be limited to
procedures resulting in moderate pain intensity.
 Finally, there is no evidence indicating that the use of N2O in
a modern clinically relevant setting increases health risk in
patients or providers.