This document discusses the debate around the safety of nitrous oxide. It summarizes the findings of several major studies on this topic, including the ENIGMA trials which found mixed results about nitrous oxide's effects. While some studies suggested nitrous oxide may increase complications, others found no difference or even potential benefits. The document concludes that the evidence is still unclear and more research is needed, as abandoning nitrous oxide based on the current evidence may be premature.

1. Dr. Wesam Mousa
Assisstant Professor Anesthesia& Surgical ICU
Dammam Hospital of theUniversity
KSA12/11/15 1
Nitrous Oxide:
Is the Debate Closed?

2. Nitrous
oxide
 Simple linear compound
Colorless, odorless, tasteless,
and does not burn
Inert nature with minimal
metabolism
 Only anesthetic agent that is

3.  Prepared by Priestly in 1776
 Anesthetic properties described by Davy in 1799
 Used by Horace Wells- 1845

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In the last few yeas, prolonged dispute took place
regarding N2O safety
supporters say:
In view of the large number of patients exposed worldwide
every year for many years, good proof for its safety and
beneficial effects is accumulated.

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Non supporters say:
We have also, increasingly, seen wave after wave of scandals:
hypoxic events, neurological complications, foetal loss…
especially now as new, more glamorous pretenders to the
throne try to unseat it.

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Nitrous oxide as seen by supporters:
 Powerful analgesic. It reduces anesthetic and opioid
requirements intraoperatively and improves acute pain
outcome postoperatively
 Minimal effects on heart rate and blood pressure
 Little effect on respiration
 Low blood solubility (quick recovery)

7. BLOOD GAS PARTITION
COEFFICIENT
Agents with low solubility inAgents with low solubility in
blood quickly saturate theblood quickly saturate the
blood. The additionalblood. The additional
anesthetic molecules areanesthetic molecules are
then readily transferred to thethen readily transferred to the
brain.brain.
Blood: gas partition co-efficient:

8.  At beginning: second gas effect
 At end: diffusion hypoxia
 During maintenance: weak
 Inhibits methionine synthetase, precursor to DNA synthesis
 Inhibits vitamin B-12 metabolism
 Teratogenic
Nitrous oxide as seen by non-supporters:

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The point at which nitrous oxide is most
hit is that it inhibits methionine synthetase,
which increases plasma homocysteine after
surgery

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Pathophysiologically,
hyperhomocysteinemia have been found to:
 Cause endothelial dysfunction
 Impair myocardial substrate utilization
 Enhance platelet aggregation

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In nonsurgical settings, it is well
recognized that long-term increases of
plasma levels of homocysteine are an
independent risk factor for coronary
artery and cerebral vascular disease.

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Cardiovascular events can plausibly be predicted to
be increased with acutely elevated homocystinemia
induced by nitrous oxide.
Such increases have been reported by Badner et al.,
in moderate-risk patients having carotid
endarterectomy

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However, preoperative administration of folate and B
vitamins was shown to inhibit the nitrous oxide–
induced increase in homocysteine.

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These data -in part- led to the conduct of
the trial “Evaluation of Nitrous Oxide In the
Gas Mixture for Anaesthesia”: ENIGMA-I
It was a Randomised Controlled Trial which
was published in Anesthesiolog 2007.
Entitled:
“Avoidance of Nitrous Oxide for Patients
Undergoing Major Surgery”

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This trial was taken by many to be the
death knell for nitrous oxide: a view
endorsed by the accompanying editorial

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This trial recruited 2050 patients, randomly assigning them
to either a nitrous oxide-free (80% oxygen, 20% nitrogen)
group or a nitrous oxide-based (70% nitrous oxide, 30%
oxygen) group. All patients were scheduled to undergo
major surgery of at least 2 hours duration.

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The primary endpoint was duration of hospital stay.
Secondary endpoints included duration of ICU stay, PONV,
pneumonia, pneumothorax, pulmonary embolism, wound
infection, myocardial infarction, venous thromboembolism,
stroke, awareness, and death within 30 days

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The results showed that there was no difference between the
two groups with regard to the primary endpoint (duration of
hospital stay)
Analysis of the secondary endpoints, however, appeared to
show a lower rate of complications in the nitrous oxide–free
group : wound infection, atelectasis, pneumonia and PONV
No significant difference in major adverse cardiac events
or death was reported.

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Conclusions of ENIGMA 1 trial:
Avoidance of nitrous oxide and the concomitant
increase in inspired oxygen concentration
decreases the incidence of complications after
major surgery, but does not significantly affect
the duration of hospital stay. The routine use of
nitrous oxide in patients undergoing major
surgery should be questioned.

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The editorial of the Anesthesiology journal was
“pleased” of the results of ENIGMA and their
comment was:

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Harriet W. Hopf, M.D., Department of Anesthesiology, University of Utah wrote:
“This study is not the last word on nitrous oxide, but it is an important
one that is likely to have a major impact on clinical practice in
anesthesia. I personally stopped using nitrous oxide nearly a decade
ago because of previous trials demonstrating the importance of high
tissue oxygen in preventing wound complications. I am pleased to
have added justification for residents who challenge me to
provide evidence to support my clinical practice”

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The validity of ENIGMA results, particularly with regard to the
secondary endpoints, has generated a flurry of controversy. The
opponents of nitrous oxide use have enthusiastically endorsed these
results as definitive evidence to abandon its use.
This view is inappropriate for a number of
:reasons
K de Vasconcellos University of KWAZULU-NATAL

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It was presented as a pragmatic not
explanatory study with no attempts done
to control possible confounding variables and
the anesthetist had the option to cross
over from one group to the other

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The chief reason, however, is that the primary endpoint of the study
showed no difference between the two groups. Presumably this
endpoint was chosen as a composite endpoint to reflect any
significant adverse postoperative events, and was adequately
powered to detect any significant differences.
The fact that it showed no difference can thus be taken, “as an
additional evidence of the remarkable safety of nitrous oxide
over the past 150 yr”
K de Vasconcellos University of KWAZULU-NATAL

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In addition, results of the secondary endpoints must be viewed with
suspicion. As even the authors of ENIGMA noted:
“We undertookmultiple comparisons, which
increases the chance of a type I error; the
secondary, exploratory, and subgroup analyses
should be treated cautiously.”
K de Vasconcellos University of KWAZULU-NATAL

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Other criticisms of ENIGMA include the choice of 80% O2/20% N2
as a control group. The question which has been raised frequently is
thus, is any difference between the groups due to a nitrous oxide effect
or an oxygen effect?
Although academically interesting, It is not thought to discredit the
study. It simply means that if we believe there is a difference between
the groups, it could be due to avoidance of N2O or due to use of a
high inspired concentration of oxygen. It is useful to know which of
these it is, but, as a high FiO2 would be impossible to achieve with the
use of nitrous oxide, for our purposes, it makes little practical
difference. K de Vasconcellos University of KWAZULU-NATAL

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Another criticism is that the depth of anaesthesia between the two
groups was not equivalent. The median end-tidal agent concentration
in the nitrous oxide-free group was 0.87 MAC while in the nitrous
oxide group the total was 1.31 MAC.
Monk, et al showed that cumulative deep hypnotic time was an
independent predictor of postoperative mortality
K de Vasconcellos University of KWAZULU-NATAL

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In addition, due to the pragmatic nature of the study other
confounding variables may not have been adequately
accounted/controlled for. As an example, the nitrous oxide-free group
received significantly more propofol. It’s not possible to say whether
this affected the PONV results, or any other outcomes.
K de Vasconcellos University of KWAZULU-NATAL

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The authors of ENIGMA have also been accused of bias against N2O.
They appear to have highlighted the adverse secondary outcomes
over the neutral primary outcome.
In addition, the study was not blinded.
K de Vasconcellos University of KWAZULU-NATAL

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It should also be highlighted that ENIGMA included only patients
undergoing major surgery predicted to last longer than 2 hours. This
represents only a group of patients at particular risk of adverse
perioperative outcomes
K de Vasconcellos University of KWAZULU-NATAL

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As a final word on ENIGMA, clinical practice should generally not be
altered on the basis of a single study. This is especially true when
based on secondary outcomes of doubtful validity.
K de Vasconcellos University of KWAZULU-NATAL

36. 12/11/15 36
wow giving up nitrous in a practice is a profound effect
from a blog article

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An incredible amount of additional data will be needed to
'out' nitrous oxide. Count on the pharmaceutical
industry to lead the search for excuses to supplant N20
with a more expensive, proprietary "solution".

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No single article, speech, research report or opinion should
change a decades-long practice of safe, readily-available,
reliable and cost-effective medicine (in any specialty).

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Hmmm……..
as mentioned in the previous post, this is another example
of throwing out the known for the more expensive
unknown. Correct me if I'm wrong but its more of a
comparison of oxygen versus nitrous!!!

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Again in Anesthesiology 2011, Leslie et al. have
published the longer-term results of the original
ENIGMA-I trial. They found that patients exposed to
nitrous oxide had an increased incidence of myocardial
infarction, in a mean follow-up period of 3.5 years
after a nitrous oxide–based general anesthetic with no
difference in mortality

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Another editorial of Anesthesiolgy journal stated that:
“The results provided by Leslie et al. are a valuable addition to our
knowledge about the effects of intraoperative nitrous oxide. The
article is undoubtedly intriguing; however, it still does not answer
several important safety aspects. There is clearly a need for more
information on this subject. We hope that the ENIGMA-II trial, a
prospective study of intermediate- or high-risk patients randomized to
the use of nitrous oxide that is currently enrolling patients, will help
provide some additional answers”.

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Another large analysis was carried out to verify long term safety
of the use of nitrous oxide depending on the POISE Trial

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BACKGROUND: In this analysis of the Perioperative
Ischemic Evaluation (POISE)trial, we wanted to
determine whether nitrous oxide was associated with
the primary composite outcome of:
cardiovascular death,
nonfatal myocardial infarction
nonfatal cardiac arrest within 30 days of randomization.

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METHODS:
The POISE trial of perioperative β-blockade was undertaken in 8351
patients. Nitrous oxide anesthesia was defined as the coadministration of
nitrous oxide in patients receiving general anesthesia, with or without
additional neuraxial blockadeor peripheral nerveblockade.
Statistical analysiswasused to determinetheassociation of nitrousoxide
with the primary outcome, MI, stroke, death, and clinically significant
hypotension.

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RESULTS: Nitrous oxide was administered to 1489 (29%) of the 5133
patients included in this analysis. Nitrous oxide had no significant effect
on the risk of the primary outcome, death or clinically significant
hypotension

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CONCLUSIONS:
nitrous oxide was not associated with an increased risk of adverse
outcomes in the POISE trial patients.
This analysis was limited by the observational nature of the data and the
lack of information on the concentration and duration of nitrous oxide
administration. Further randomized controlled trial evidence is required.
(Anesth Analg 2013;116:1034–40)

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Editorial of Anestheis Analgesia editor
accompanied the article

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In this issue of the journal, Turan et al. report for the first time that
noncardiac surgery patients receiving general anesthesia with nitrous
oxide (N2O) experience 33% decreased odds of 30-day mortality,
17% decreased odds of in-hospital morbidity and mortality, and 41%
decreased odds of pulmonary morbidity compared with patients
anesthetized without N2O.

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No amply powered investigations have previously concluded that N2O
anesthesia reduces all-cause mortality or respiratory complications.
The pulmonary N-methyl-daspartate receptor antagonist explanation for
reduced lung injury with N2O proposed by Turan et al. is an assumption
at present, in the absence of targeted experiments using N2O at the
bench and in the clinic to test this hypothesis. Nor can we suggest
another mechanism that could explain such “wonder-working” effects.

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After that, the british journal of Anesthesia
commented on this controvery in an Editorial:

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This review considers the current position of nitrous oxide in anaesthetic
practice and balances potential beneficial and disadvantageous effects.
The classic adverse characteristics of nitrous oxide, such as diffusion
hypoxia, expansion of gas filled spaces, and postoperative nausea and
vomiting, are often cited as reasons to avoid this old drug. Recent
concerns regarding neurotoxicity, adverse cardiovascular outcomes, and
wound complications have further hardened many practitioners against
nitrous oxide.
New evidence and underpinning mechanistic data, however, suggest
potential beneficial effects on the central nervous system, cardiovascular
system, and acute and chronic pain. While we await the outcome of large
studies including ENIGMA-II, many clinicians have already decided
against this agent.
The authors argue that this
abandonment may be premature.

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ENIGMA II trial commenced enrolment in 2007. This study aims to
recruit 7000 patients at risk of coronary artery disease, undergoing non-
cardiac surgery, to test the hypothesis that omitting N2O will reduce the
incidence of death and major adverse cardiac events. A key difference
(vs. ENIGMA I) is that the control group will now use a 70% N2/ 30%
O2 mix to avoid the possible confounding effect of the high FiO2 in
ENIGMA
K de Vasconcellos University of KWAZULU-NATAL

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They did an international, randomised, assessor-blinded trial
in patients aged at least 45 years with known or suspected
coronary artery disease having major non-cardiac surgery.
Patients were randomly assigned via automated telephone
service, stratified by site, to receive a general anesthetic with
or without nitrous oxide. Attending anaesthetists were aware
of patients' group assignments, but patients and assessors were
not.

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The primary outcome measure was a composite of
death and cardiovascular complications (non-fatal
myocardial infarction, stroke, pulmonary embolism,
or cardiac arrest) within 30 days of surgery.

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Of 10 102 eligible patients, were enrolled 7112 patients
between May 30, 2008, and Sept 28, 2013. 3543 were
assigned to receive nitrous oxide and 3569 were assigned
not to receive nitrous oxide.

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Interpretation
Our findings support the safety profile of nitrous oxide use
in major non-cardiac surgery. Nitrous oxide did not
increase the risk of death and cardiovascular complications
or surgical-site infection, the emetogenic effect of nitrous
oxide can be controlled with antiemetic prophylaxis, and a
desired effect of reduced volatile agent use was shown.

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Nitrous oxide should remain an option in
contemporary anaesthesia. There are
potential advantages in pain control and
prevention, reduction of awareness with recall,
and use in neurologically and cardiovascularly
‘at risk’ patients. With respect to its side-effect
profile, recent data suggest that nitrous oxide
is safe (and possibly beneficial) in an
unselected heterogenous patient population.
Conclusions

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So, let’s suspend our general bias
against nitrous oxide and grant it the
place it deserves in anaesthetic
practice. We might even find that this
faithful old anaesthetic dog has some
exciting new tricks to show us.

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Nitrous oxide is a unique drug with
many positive attributes and
deserves an important place in
anaesthetic practice. Although
modern anaesthesia would not
collapse with the removal of nitrous
oxide, or any other anaesthetic
agent, it would be much poorer for
its absence.
K de Vasconcellos University of KWAZULU-NATAL

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