nitrous oxide: is the debate closed?

Dr. Wesam MousaAssisstant Professor Anesthesia& Surgical ICU

Dammam Hospital of theUniversityKSA05/01/23 1

Nitrous Oxide:Is the Debate Closed?

Nitrous oxide Simple linear compound

Colorless, odorless, tasteless, and does not burn

Inert nature with minimal metabolism

Only anesthetic agent that is inorganic

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)

BLOOD GAS PARTITION COEFFICIENT

Agents with low solubility Agents with low solubility in blood quickly saturate in blood quickly saturate the blood. The additional the 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:

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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 undertook multiple 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

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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 infarctionnonfatal 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.

Statistical analysis 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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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 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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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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InterpretationOur 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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