Observations were made during both spontaneous and artificial respiration on 12 fit patients anesthetized for routine surgical procedures. Above a tidal volume of 350 ml (BTPS), the anatomical dead space was close to the predicted normal value for the subject. Below 350 ml, it was reduced in proportion to the tidal volume. The physiological dead space (below the carina) approximated to 0.3 times the tidal volume for tidal volumes between 163 and 652 ml (BTPS). Throughout the range the physiological dead space was considerably in excess of the anatomical dead space measured simultaneously. The difference (alveolar dead space) varied from 15 to 231 ml, being roughly proportional to the tidal volume. The mean arterial to end-tidal CO2 tension difference was 4.6 (S.D. ±2.5) mm Hg and not related to tidal volume or arterial CO2 tension. None of the findings appeared to depend on whether the respiration was spontaneous or artificial. Submitted on September 25, 1959

Conventional lateral radiography was used in 18 elderly male patients to investigate the changes induced by general anaesthesia in the upper airway. The effect of tongue traction under anaesthesia was studied similarly in another 11 patients. Following induction of anaesthesia, there were highly significant approximations to the posterior pharyngeal wall of the soft palate (median change 1.3 mm, 95% confidence interval (Cl) 0.3-2.6 mm; P = 0.006), tongue base (mean change 6.5 mm, 95% Cl 5.3-7.7 mm; P less than 0.001) and epiglottis (mean change 3.8 mm, 95% Cl 3.1-4.5 mm; P less than 0.001). Apparent radiographic occlusion of the airway occurred most consistently at the level of the soft palate (17 of 18 patients), sometimes at the level of the epiglottis (four patients), but the tongue base did not touch the posterior pharyngeal wall in any patient. Traction on the tongue failed to clear the nasopharyngeal obstruction. Attempted inspiration under anaesthesia caused major secondary collapse of the pharynx, with multiple sites of obstruction, similar to that found in obstructive sleep apnoea.

Vitamin B M is a bound coenzyme of methionine synthase and has a tetrapyrrole ring with monovalent cobalt at the centre. The cobalt functions as a methyl carrier in the transmethylation reaction shown in figure 1. In 1968, Banks, Henderson and Pratt reported that nitrous oxide reacted in vitro with vitamin B 12 , converting the cobalt from the monovalent form (Cob(I)alamin) to the bivalent form (Cob(II)alamin), which can no longer function as a methyl carrier. Their paper, in a journal not perused by many in the biomedical field, remained unnoticed by both haematologists and anaesthetists for 10 years. In a seminal study, Amess and his colleagues (1978) showed that 24 h of administration of nitrous oxide to patients caused interference with deoxyribonucleic acid (DNA) synthesis, and they correctly inferred that nitrous oxide had interfered with the function of vitamin B,,. A few months later, Deacon and her colleagues (1978) showed that nitrous oxide did in fact cause rapid inhibition of the activity of methionine synthase in the rat. Also in the same journal and the same year, Layzer (1978) reported a condition resembling sub-acute combined degeneration of the cord in 15 patients who had been chronically exposed to high concentrations of nitrous oxide. There was thus a parallel with megaloblastic anaemia and a working hypothesis for the agranulocytosis and the teratogenesis which had previously been observed as toxic effects of nitrous oxide. Metabolic changes So far as is known, nitrous oxide interacts in the body only with vitamin B,j. This is the coenzyme for both methionine synthase and methylmalonyl CoA mutase. Vitamin B lt does not function as a

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