Nitrous oxide – a routinely used carrier gas

Since 1860 nitrous oxide was as extensively used in clinical anaesthesia (1,2), that every current anaesthetic machine features all the tools to routinely add nitrous oxide to the anaesthetic gas. Up to now, with no thought given to its true value or disadvantages, in most of European anaesthetic departments a mixture of oxygen and nitrous oxide is used as carrier gas to deliver inhalational agents. Even total intravenous anaesthesia, where the concurrent use of any gaseous anaesthetic should be unnecessary, is frequently carried out with the additive use of nitrous oxide.
 

Nitrous oxide – still arguments for its further use?

For a great number of anaesthetists the following arguments support the continuing use of nitrous oxide (3-5): According to the concept of “balanced anaesthesia” nitrous oxide is assumed to exert a quite powerful analgesic and along with the other inhalation anaesthetics a modest, but nevertheless significant hypnotic effect. By using nitrous oxide the doses of supplementary opioids and other anaesthetics can be considerably reduced. The rapid wash-out of this gas, together with its dose reducing effect, favourably accelerates recovery from anaesthesia. During mask induction in paediatric anaesthesia the second gas effect accelerates the wash-in of inhalation anaesthetics, thus, shortening the induction time. Its mild sympathetic effect counteracts the depressive effects of the volatile agents on the cardiovascular system. Nitrous oxide is widely assumed to be an essential factor in the prevention of intraoperative awareness and in suppressing spinal reflex movements caused by intense surgical stimulation.
 

Nitrous oxide – its anaesthetic and analgesic potency

Nitrous oxide seems to reduce significantly the concentration of volatile anaesthetics needed for sufficient anaesthesia: The MAC50 declines in a linear relationship with increasing nitruos oxide concentration. This measure of anaesthetic depth, however, is defined by the incidence of motor response to the initial skin incision. In this context it must be emphasized that nitrous oxide excerts its power by activating descending inhibitory neuronal pathways resulting in modulation of the nociceptive process in the spinal cord and supressing spinal reflex movements (6). Current knowledge shows that, with respect to its anaesthetic potency, the assumption of an additive MAC-effect of nitrous oxide is wrong. Refering to clinical findings and EEG-analysis, the anaesthetic effect of 60% nitrous oxide sufficiently can be replaced by a moderate increase of only 20-30% of the MAC-value of the respective anaesthetic (3,7). Thus, the anaesthetic potency of nitrous oxide is significantly lower than it could be estimated from the MAC50 reduction. Nitrous oxide is only a weak anaesthetic which cannot be used as a monoanaesthetic as, furthrermore, a safe loss of  consciouness will not be gained (8).
 

Nitrous oxide – an inert anaesthetic gas?

The common opinion, that nitrous oxide is a near inert, albeit anaesthetic, gas which can be used without any problem is no longer sustainable in the light of current knowledge (9). Nitrous oxide interacts with the vitamin B12, folate, methionine and homocysteine  metabolism, mainly by an irreversible oxidation of the B12 coenzym, resulting in essential reduction of the activity of  Co B12-dependent enzymes like methionine synthetase and methylmalonyl-CoA-mutase. Impaired methionine metabolism will lead to impaired neurotransmitter, choline, phopholipid, DNA and RNA synthesis. Not only diseases like chronic gastritis, gastrectomia, Crohn´s disease, ileum resection, alcohol abuse or malnutrition syndromes, but also strict vegetarian lifestyle may lead to vitamin B12 deficiency. Thus, one must be aware, that a lot of conditions exist leading to increased toxicity of nitrous oxide. Long term exposition to nitrous oxide results in bone marrow depression with megaloblastic anaemia, leucopenia and thrombocytopenia (10,11). However, even short term exposure to this gas ( < 1h ! ) can lead to toxic effects in patients suffering from chronic vitamin B12 or folate deficiency with a myeloneuropathic disorder, characterized by progressive demyelination and axonal lesions of the peripheral nerves and cervicothoracic spinal cord and resembling funicular myelosis. Furthermore, in cases suffering from congenital neutropenia nitrous oxide may cause agranulocytosis. Due to its proven harmful effect on DNA synthesis, nitrous oxide may be considered to be contraindicated in pregnant women during the first two trimesters, during preparations for in-vitro fertilisation, or in immunosuppressed patients with impaired function of lymphocytes and reduced neutrophil responsiveness.

It remains a matter of scientific discussion, whether chronic exposure to trace gas concentrations of nitrous oxide really endangers  theatre personnel, although embryotoxic and teratogenic effects were found in animal experiments. Most countries stipulate a maximum workplace concentration for nitrous oxide (12).

Nitrous oxide is also not inert in respect to ecology, as it is known to have a significant green house gas effect and is a potent destroyer of the stratospheric ozone layer. Although the emission of anaesthetic nitrous oxide, comprising not more than about 1 % of the total global output, seems to be negligible if compared with the vast amount generated by bacterial metabolism in fertilized soil, anaesthetists should be obliged to fully utilize currently available technology to minimize unneccessary wastage of this gas (13).
 

Nitrous oxide - contraindications and shortcomings

Due to its tendency to much more rapidly diffuse into gas filled spaces than nitrogen is taken up by the blood, generally accepted contraindications to the use of nitrous oxide include all cases where there is confinement of air in tissues or hollow spaces of the body such as ileus, pneumencephalon, pneumothorax or occlusion of the Eustachian tube. If there is the danger of air embolism resulting from surgical procedures needing a sitting position of the patient, the use of nitruos oxide shall be avoided. In abdominal operations of long duration the diffusion of nitrous oxide into gas-containing spaces will cause bowel distension with consequent impairment of operative conditions and delays in the recovery of bowel function  (14). Although the results of meta-analyses of scientific publications on this topic were somewhat ambiguous, nitrous oxide seems to play a role in postoperative vomiting and probably nausea also (15,16). In all patients, who have on previous occasions suffered from severe PONV, the use of nitrous oxide should be avoided.

Nitrous oxide causes increased cerebral blood flow and so is contraindicated in patients with head injuries and raised intracranial pressure (17). In patients with compromised coronary perfusion the administration of nitrous oxide results in a significant decrease in myocardial contractility with a secondary increase in the left ventricular end-diastolic pressure. For this reason nitrous oxide should be avoided in all patients with severe cardiac disease and latent myocardial insufficiency (18).

Nitrous oxide is taken up rapidly, thus, especially during the initial wash-in-phase, an increase of the concentration of additively administered volatile anaesthetics may result. This second gas effect was assumend to accelerate the onset of inhalation anaesthesia, especially useful in inhalation induction in pediatric anaesthesia. This, assumption, however, was disproved (19). There are, contrarily, strong arguments just against the use of nitrous oxide in inhalation induction in small infants, as the FRC, serving as oxigen reservoir in any case of difficulties to secure the airway, is especially small. Thus, in some academic centres it is the stringent rule, during inhalation induction just to omit the use of nitruos oxide. During emergence in case of apnea or hypoventilation the rapid increase of the alveolar concentration of nitrous oxide may result in diffusion hypoxia theatening the patient.
 

Nitrous oxide - are there any definite indications?

Four reviews on nitrous oxide shall be cited synoptically, as doubts seem to be justified in respect to the question, whether actually a legitimate indication can be defined for the use of nitrous oxide in modern inhalation anaesthesia. In his conclusions concerning the use of nitrous oxide Schirmer (4) states: „Generally, nowadays general anaesthesia could be performed satisfactorily, although renouncing the use of nitrous oxide, with the available modern anaesthetics“. The following recommendations for the use of nitrous oxide only list syndromes and surgical interventions in which favourably this gas should not be used, a clear indication is, however, missing. Similarly to James (5) Dale and Husum (11) conclude in their editorial: "Nitrous oxide should not automatically be included as the basis of any anaesthetic but, like other anaesthetic agents, should be administered after careful consideration of the needs of the individual patients in relation to the planned surgical procedure“. Again this statement is followed by a list of contraindications whereas a clear definition of any indication for this gas is not given. Eger et al. (3), judging the results of their comprehensive clinical investigation, conclude: "In summary, we found that the addition of N2O to isoflurane for maintenance of anesthesia only subtle, if at all, altered the course of anesthesia and the development of untoward outcomes". Whether this résumé justifies the further use of nitrous oxide remains the question. Brodsky and Cohen (10), however, refer to an editorial in Lancet from 1978 „Nitrous oxide and the bone marrow“:  „In fact, N2O would probably not be released if it were a new drug being considered for introduction into clinical practice today“.
 

Nitrous oxide - further medical aguments to omitting this anaesthetic gas

There are absolutely no contraindications for the use of a carrier gas mixture only consisting of oxygen and nitrogen, and the gas mixture circulating within the breathing system can be adapted to any needs. Omission of nitrous oxide enables anaesthetists to freely choose any oxigen concentration being favourable for the individual patient´s needs. Perioperative high oxygen concentrations significantly reduce the incidence of postoperative wound infections, seem to play a favourable role in preventing postoperative nausea and vomiting, and increase the patient´s safety in all phases where the patient is kept apnoic by intention, for instance during induction of emergence, but also intraoperatively to facilitate short lasting operative procedures at the larynx or the upper airways. Intraoperative high oxygen concentrations, increasing the pulmonary oxygen reserve, also will enhance patient´s safety in all cases of accidental apnea, due to failure of the anaesthetic machine or disconnetion between ventilator and patient. The reaction time, needed for identification and adequate correction of the underlying fault, is significantly augmented by the high oxygen reservoire of the lung (20).
 

Nitrous oxide - technical aguments to omitting this anaesthetic gas

The technical infrastructure for nitrous oxide supply, like gas manifolds, the central piping system and wall outlets would completely become dispensable with consistent omission of the use of nitrous oxide. The same holds for the measurement of nitrous oxide workplace concentration which is stipulated bindingly, at least in Germany, whenever there is any suspicion that the given work place concentration limits may be exceeded. This argument for consistently omitting the use of nitrous oxide holds the more for all working conditions where central gas scavenging systems are not available.

Considerable costs result from routine technical maintenance and checks of the whole central gas piping system, possibly from the required regular measurement of work place contamination by a certified company and also from the purchase and transportation of nitrous oxide. All in all, there is considerable potential for savings (21).

According to the current technical regulations, gas control systems including elements for dosing nitrous oxide have to be equipped with anti-hypoxic devices, like the Oxygen-Ratio-Controller or the Link 25, guaranteeing an oxygen content of at least 21 to 25% in the fresh gas. Although this devices can not safely exclude the development of any hypoxic gas mixture in rebreathing systems, from legal aspects every anaesthetist would be obliged not to use any older anaesthetic machine lacking in such anti-hypoxic tools any more. If, however, any nitrous oxide supply would be abandoned completely, even older anaesthetic machines still could be used (22).
 

Nitrous oxide - its consistent omission increases efficiency of inhalation anaesthesia

Consistent omission of nitrous oxide enables anaesthetists to extensively make use of the rebreathing technique (21). If the carrier gas does not contain any nitrous oxide, the patient only takes up oxygen and a comparatively small amount vaporized anaesthetic agent. Thus, compared with low flow anaesthesia using nitrous oxide, a higher excess gas volume is available in nitrous oxide-free low flow anaesthesia, resulting in an improved gas filling of the breathing system and, hence, a significant decrease in the risk of accidental gas volume deficiency. This facilitates considerably the performance of low flow and minimal flow anaesthesia in routine clinical practice. Without nitrous oxide even the performance of closed system anaesthesia becomes possible with conventional anaesthetic machines. After establishing the required anaesthetic concentration within the breathing system any admixture of air can be stopped completely and the oxygen flow can be reduced to just that volume equalling the individual oxygen uptake calculated by applying Brody’s formula, i.e. about 250 ml/min in average adults. Thus, the amount of carrier gas delivered into the system meets approximately the respective total gas uptake of the patient, and no further excess gas is discharged. As the oxygen consumption can be assumed to be nearly stable, the oxygen flow can be maintained unchanged during the whole course of anaesthesia, unless increased gas loss due to leaks necessitates the replenishment of the gas volume. Performing this technique a maximum in efficiency of applying inhalation anaesthetics can be gained. This is the more advantageous when the newer anaesthetic agents are used characterised by low solubility and comparatively low anaesthetic potency like desflurane or sevoflurane.

The advantages gained by the consistent omission of nitrous oxide by far outweigh the small additive analgesic and anaesthetic effects gained by ist use. This holds the more as new anaesthetics with favourable phamacokinetic properties are readily available today.
 

References

1. Smith WDA. Under the influence: A history of nitrous oxide and oxygen anaesthesia. The crucial experiment, its eclipse and its revival. The Wood Library-Museum of Anesthesiology, Park Ridge, Ill. 1982; 53-66

2. Duncum B. Nitrous Oxide. In: The Development of Inhalation Anaesthesia. Royal Society of Medicine Press Ltd, London 1994; 273-310

3. Eger EI, Lampe GH, Wauk LZ, Whitendale P, Cahalan MK, Donegan JH. Clinical pharmacology of nitrous oxide: an argument for its continued use. Anesth Analg 1990; 71: 575-585

4. Schirmer U. Lachgas - Entwicklung und heutiger Stellenwert. Anaesthesist 1998; 47: 245-255

5. James MFM. Nitrous oxide: still useful in the year 2000? Curr Opin Anaesthesiol 1999; 12: 461-466

6. Maze M, Fujinaga M. Pharmacology of nitrous oxide. In: Tonner PH, Scholz J (eds.) Use of Nitrous Oxide in Anaesthesia. Baillière´s Best Practice & Research. Clinical Anaesthesiology 2001; Vol. 15, No. 3: 339-348

7. Röpcke H, Schwilden H. Interaction of Isoflurane and Nitrous Oxide Combinations Similar for Median Electroencephalographic Frequency and Clinical anesthesia. Anesthesiology 1996; 84: 782-788

8. Ghonheim MM. Nitrous oxide effects on EEG and awareness. In: Tonner PH, Scholz J (eds.) Use of Nitrous Oxide in Anaesthesia. Baillière´s Best Practice & Research. Clinical Anaesthesiology 2001; Vol. 15, No. 3: 397-407

9. Takács J. Toxicology of nitrous oxide. In: Tonner PH, Scholz J (eds.) Use of Nitrous Oxide in Anaesthesia. Baillière´s Best Practice & Research. Clinical Anaesthesiology 2001, Vol. 15, No. 3: 349-362

10. Brodsky JB, Cohen EN. Adverse effects of nitrous oxide. Med Toxicol 1986; 1: 362-374

11. Dale O, Husum B. Nitrous oxide: from frolics to a global concern in 150 years. Acta Anaesth Scand 1994; 38: 749-750

12. Hoerauf KH. Nitrous oxide: workplace concentrations / ecology. In: Tonner PH, Scholz J (eds.) Use of Nitrous Oxide in Anaesthesia. Baillière´s Best Practice & Research. Clinical Anaesthesiology 2001; Vol. 15, No. 3: 389-396

13. Logan M, Farmer JG.  Anaesthesia and the ozone layer: Br J Anaesth 1989; 53: 645-646

14. Scheinin B, Lindgren L, Scheinin T M. Perioperative nitrous oxide delays bowel function after colonic surgery. Br J Anaesth 1990; 64: 154-158

5 Hartung J. Twenty-four of twenty-seven studies show a greater incidence of emesis associated with nitrous oxide than with alternative anesthetics. Anesth Analg 1996; 83: 114-116

16. Tramer M, Moore A, McQuay H. Omitting nitrous oxide in general anaesthesia: meta-analysis of intraoperative awareness and postoperative emesis in randomized controlled trials. Br J Anaesth 1996; 76: 186-193

17. Watts A, Luney SR, Lee D, Gelb AW.  Effect of nitrous oxide on cerebral blood flow velocity after induction of hypocapnia. J Neurosurg Anesthesiol 1998; 10: 142-145

18. Neidecker J. Nitrous oxide: use in cardiovascular risk patients. In: Tonner PH, Scholz J (eds.) Use of Nitrous Oxide in Anaesthesia. Baillière´s Best Practice & Research. Clinical Anaesthesiology 2001; Vol. 15, No. 3: 429-435

19. Sun X, Su F, Shi Y, Lee C. The "second gas effect" is not a valid concept. Anesth Analg 1999; 88: 188-192

20. Baum J, von Bormann B, Meyer J, van Aken H. Sauerstoff als Trägergas in der klinischen Anästhesie (Oxygen as carrier gas in clinical anaesthesia). Anästhesiologie & Intensivmedizin 2004; accepted for publication

21. Baum JA. Nitrous oxide: use in low-flow systems / economics. In: Tonner PH, Scholz J (eds.) Use of Nitrous Oxide in Anaesthesia. Baillière´s Best Practice & Research. Clinical Anaesthesiology 2001; Vol. 15, No. 3: 377-388

22. Fielden JM. Anaesthetic machines and anti-hypoxia devices. Interim solution is to remove nitrous oxide cylinders and pipelines and cap their connections. BMJ 2002; 324:169-170
 
 

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