Nitrous oxide the venerable old gentleman of the anaesthetic world

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وقل رب زدنى اآلية علما طه (114 )سورة

Dr. Wesam MousaAssisstant Professor Anesthesia& Surgical ICU

Dammam Hospital of theUniversity04/15/23 1

Nitrous Oxide: the venerable old gentleman of the anaesthetic world

Nitrous oxide N=N=O Simple linear compound

Colorless, odorless, tasteless, and does not burn

Inert nature with minimal metabolism

Only anesthetic agent that is inorganic

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Dark controversy still going on regarding N2O safety

Proponents 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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Repellents 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.

Proponents and repellents only agree for:

Prepared by Priestly in 1776

Anesthetic properties described by Davy in 1799

Used by Horace Wells- 1845

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Nitrous oxide as seen by supporters:

Weak anesthetic, powerful analgesic (MAC 105%). It

reduces anesthetic and opioid requirements

intraoperatively and improve acute and chronic pain

outcomes postoperatively

Minimal effects on heart rate and blood pressure

But may cause myocardial depression in sick patients

Little effect on respiration

Low blood solubility (quick recovery)

Blood: gas partition co-efficient:

BLOOD GAS PARTITION COEFFICIENT

Agents with low solubility in Agents with low solubility in blood quickly saturate the blood quickly saturate the blood. The additional blood. The additional anesthetic molecules are anesthetic molecules are then readily transferred to then readily transferred to the brain.the brain.

Blood: gas partition co-efficient:

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:

OIL GAS PARTITION CO-EFFICIENT

The higher Oil: Gas Partition Co-efficient, the lower the MAC . E.g., Halothane

1.4 220

0.8

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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

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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Pathophysiologically, hyperhomocysteinemia have been

found to:

cause endothelial dysfunction impair myocardial substrate

utilization enhance platelet aggregation

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Cardiovascular events can plausibly be predicted to be

increased with acutely elevated homocystinemia; such increases

have been reported by Badner et al., in moderate-risk patients

having carotid endarterectomy

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 ENIGMA-I trial which was published in Anesthesiolog 2007. Entitled “Avoidance of Nitrous Oxide for Patients Undergoing Major Surgery”, 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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The primary endpoint was duration of hospital stay.

Secondary endpoints included duration of ICU stay, severe

PONV, pneumonia, pneumothorax, pulmonary embolism,

wound infection, myocardial infarction, venous

thromboembolism, stroke, awareness, and death within 30

days

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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. It was presented as a pragmatic

study, with no attempt to control for possible confounding

variables and the anaesthetist had the option to cross over

from one group to the other

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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 major

complications (wound infection, atelectasis, and

pneumonia) and severe PONV. No significant difference in

major adverse cardiac events or death was reported.

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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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The chief reason 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 one

correspondent to Anesthesiology put it, “as additional evidence of the

remarkable safety of nitrous oxide over the past 150 yr”


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In addition, results of the secondary endpoints must be viewed with

suspicion. As even the authors of ENIGMA noted “We undertook

multiple comparisons, which increases the chance of a type I error; the

secondary, exploratory, and subgroup analyses should be treated

cautiously.”


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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, I don’t think

it discredits 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.


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A more important factor 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


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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.


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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.


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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 proportion of surgical procedures, and a group of

patients at particular risk of adverse perioperative outcomes


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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.


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In response to these concerns regarding ENIGMA, ENIGMA II

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) 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 and we eagerly await

the results of this study.


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wow giving up nitrous in a practice is a profound effect

from a blog article

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your original post on this matter a few months back caused me to give up nitrous after 28 years; your blog changed a practice 8 thousand miles away!(give or take a few) Thanks!

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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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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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The results provided by Leslie et al.15 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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BACKGROUND: In this post hoc subanalysis of the

Perioperative Ischemic Evaluation (POISE)trial,

we sought 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 blockade or peripheral nerve

blockade. Logistic regression, with inverse probability

weighting using estimated propensity scores, was used to

determine the association of nitrous oxide 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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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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This review considers the current position of nitrous oxide in anaestheticpractice 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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Conclusion

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 heterogenouspatient population.

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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.


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NITROUS OXIDE Who will have the last laugh?

Nitrous oxide the venerable old gentleman of the anaesthetic world

Health & Medicine

nitrous oxide n

gas partition co efficient

avoidance of nitrous

oil gas partition coefficient

gas effect

blood pressure

weak anesthetic

nitrous oxideinduced