Use of nitrous oxide in anaesthesia

L. Dimpel1 and M. Enlund2

1 Plymouth, UK 2 Västerås, Sweden

Editor—Enlund and colleagues1 reported stopping the routine use of N2O in their department. Some of their theoretical considerations and their rhetorical question ‘has the value of N2O been overestimated?’ are begging for comment.

In 1990, Eger and colleagues2 found in an empirical study, that omission of N2O increased isoflurane requirements only marginally—from an average of 0.64% with N2O 60% to 0.85% without.

The value of N2O, added to a halogenated vapour, is usually thought of in terms of 'MAC reduction' of that vapour. Therefore, Enlund and colleagues anticipated that for every 10% N2O, the concentration of vapour could be reduced by 0.1 MAC.1 Based on reported MAC values, this would amount to isoflurane 0.7% for N2O 60%. This fallacy has plagued the anaesthetic community ever since the introduction of the MAC concept.3

Not that anything is wrong with MAC in itself—it measures what it purports to measure: the potency of an inhaled anaesthetic to cause absence of a motor response following a noxious stimulus. The fallacy is in equating this with 'anaesthetic potency', since anaesthesia is not a single entity. Anaesthesia is a spectrum of effects on many different neuronal, functional and anatomical substrates. The most important of these effects are, for practical purposes, ‘unconsciousness’ and amnesia, both probably a spectrum of physiological effects. (Immobility, whilst useful, can be achieved by ancillary drugs.) Each of these effects has its own dose–response curve, with its own shape, slope, and EC50. MAC only represents the EC50 for the endpoint of immobility after noxious stimulation. There is nothing to suggest that the ratio between potency to cause immobility and potency to cause unconsciousness is the same for all agents—but this has been assumed for decades, despite evidence to the contrary. A study from the department where MAC originated clearly demonstrated that N2O is less potent in causing unconsciousness and amnesia than isoflurane at equal MAC fractions. At 0.45 MAC isoflurane, less than 10% of volunteers responded to verbal command, whilst at 0.45 MAC N2O all volunteers responded. Conscious memory was prevented by 0.45 MAC isoflurane, but not completely prevented by even 0.6 MAC N2O (the highest concentration tested). A modelled EC50 for prevention of conscious memory was 0.2 MAC for isoflurane (95% confidence interval 0.15–0.25), and 0.5 MAC for N2O (0.43–0.55).4 In effect, N2O is less than half as potent an amnesic and hypnotic than was implicitly extrapolated from its potency as an immobilizer. To a lesser degree, this is also true for other agents. For example, halothane is a less potent hypnotic than isoflurane at equal MAC fractions. According to Eger, MACawake of halothane is 0.65 MAC, and that of isoflurane is 0.34 MAC.5

It should come as no surprise that the EC50 for one effect does not allow extrapolation to other effects, since different phenomena are mediated by different neuroanatomical and functional substrates. Movement in response to a noxious stimulus is largely mediated by the spinal cord.6 7 Hypnosis and amnesia are largely not. It is well known that any given anaesthetic agent produces a heterogeneous pattern of depression of various areas of the central nervous system, and that these patterns vary between agents.8 9

A further possible fallacy is the tacit assumption that the hypnotic effect of N2O (small as it is) would be additive to that of a co-administered halogenated vapour. A volunteer study suggested a subadditive effect/partial antagonism on memory suppression.10 Using the EEG median frequency as an endpoint, however, Röpcke and Schwilden claimed additivity, with each 10% of N2O replacing 0.04% of isoflurane (i.e. approximately a third of its effect on MAC).11 My interpretation of their data is that they support linearity, but allow no conclusion of additivity. Other authors12 have found EEG activation with N2O, which would suggest a (partially) antagonistic action.

In summary, the ‘vapour sparing’ effect of N2O for the endpoints of unconsciousness and amnesia is small, at best in the region of isoflurane 0.3% for N2O 70%, based on findings of the above quoted studies. Whether this reduction in vapour requirement represents any benefit for the patient, has never been substantiated. I suspect such belief is an atavism from times when anaesthetists worked with chloroform, trichloroethylene, and halothane.

I congratulate Enlund, Edmark, and Revenäs and their whole department on their decision to abandon the routine use of N2O three years ago. They might be bemused to hear that at the same time, their colleagues in the UK spent millions of pounds on upgrading their equipment to prevent the administration of hypoxic mixtures of N2O.

L. Dimpel

Plymouth, UK

Editor—We welcome and appreciate the comments from Dr Dimpel. His comprehensive survey is an elegant summary of the pharmacodynamic shortcomings of N2O. Dr Dimpel has filled the vacuum left by the limited number of references allowed in the Short Communication format. The list of references supporting the relative impotency of N2O could be even longer. For instance, Badner and colleagues13 found the same magnitude of difference in required isoflurane concentration, 0.19%, when used with O2 in air or O2 and N2O.

This reference also serves as a good example of a potentially serious, but surprisingly neglected, side-effect of N2O. It was clearly shown that N2O releases homocysteine into plasma.13 The homocysteine release seems to be more than a surrogate marker for myocardial ischaemia.

As professionals we have to reconsider our interventions regularly. We are experts in risk-benefit calculations, but for some curious reason many anaesthetists do not reflect over the use of N2O. Over all, N2O consumption is going down in western European countries, but the trend differs between countries, and certainly within countries (data from the Euroanaesthesia meeting in Glasgow, May 31–June 2, 2003; EAAS2, Scholz J.). Within a narrow health economic perspective, N2O seems to be cost-efficient (i.e. the drug acquisition cost is low). When considering costs for installation and maintenance of pipes, valves and pressure regulators; the costs of the long list of side-effects; and add its minimal hypnotic sparing effect, then we come to the obvious conclusion: omit the routine use of N2O.

M. Enlund

Västerås, Sweden

References

1 Enlund M, Edmark L, Revenäs B. Ceasing routine use of nitrous oxide—a follow up. Br J Anaesth 2003; 90: 686–8[Abstract/Free Full Text]

2 Eger EI, Lampe GH, Wauk LZ, et al. Clinical pharmacology of nitrous oxide: an argument for its continued use. Anesth Analg 1990; 71: 575–85[Abstract]

3 Eger EI, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965; 26: 756–63[ISI][Medline]

4 Dwyer R, Bennet HL, Eger EI, Heilbron D. Effects of isoflurane and nitrous oxide in subanesthetic concentrations on memory and responsiveness in volunteers. Anesthesiology 1992; 77: 888–98[ISI][Medline]

5 Eger EI II. Age, minimum alveolar anesthetic concentration, and minimum alveolar anesthetic concentration awake. Anesth Analg 2001; 93: 947–53[Abstract/Free Full Text]

6 Rampil IJ. Anesthetic potency is not altered after hypothermic spinal cord transection in rats. Anesthesiology 1994; 80: 606–10[ISI][Medline]

7 Antognini JF, Schwartz K. Exaggerated anesthetic requirements in the preferentially anesthetized brain. Anesthesiology 1993; 79: 1244–9[ISI][Medline]

8 Alkire MT, Haier RJ, Barker SJ. Cerebral metabolism during propofol anesthesia in humans studied with positron emission tomography. Anesthesiology 1995; 82: 393–403[ISI][Medline]

9 Alkire MT, Haier RJ, Shah NK, Anderson CT. Positron emission tomography study of regional cerebral metabolism in humans during isoflurane anesthesia. Anesthesiology 1997; 86: 549–57[ISI][Medline]

10 Chortkoff BS, Bennett HL, Eger EI. Does nitrous oxide antagonize isoflurane-induced suppression of learning? Anesthesiology 1993; 79: 724–32[ISI][Medline]

11 Röpcke H, Schwilden H. Interaction of isoflurane and nitrous oxide combinations similar for median electroencephalographic frequency and clinical anesthesia. Anesthesiology 1996; 84: 782–8[ISI][Medline]

12 Yli-Hankala A, Lindgren L, Porkkala T, Jäntti V. Nitrous oxide-mediated activation of the EEG during isoflurane anaesthesia in patients. Br J Anaesth 1993; 70: 54–7[Abstract]

13 Badner NH, Beattie WS, Freeman D, Spence JD. Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy. Anesth Analg 2000; 91: 1073–9[Abstract/Free Full Text]





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