SODIUM NITROPRUSSIDE AND CYANIDE RELEASE

792

BRITISH JOURNAL OF ANAESTHESIA

For these reasons we do not believe that the paper of Bisset and colleagues presents a valid alternative explanation for the many independent reports of increased concentrations of cyanide and its products in blood following infusions of SNP. We would therefore urge that maximum dosage recommendations be strictly adhered to. CYRIL J. VESEY PETER COLE

London PETER SIMPSON

Bristol REFERENCES

Bisset, W. I. K., Butler, A. R , GlideweU.C, and Reglinski, J. (1981). Sodium nitroprusside and cyanide release: reasons for re-appraisal. Br. J. Anaath., 53, 1015 Rock, P. A., and Swinehart, J. H (1966). The kinetics of aqueous hydrogen sulphide-nitroprusside system. Inorg. Chem , 5, 1078 Vesey, C. J., and Batistoni, G A. (1977). The determination and stability of sodium nitroprusside in aqueous solutions. / . Chn. Pharm., 2, 105. Cole, P., and Simpson, P. (1976a). Cyanide and thiocyanate concentrations following sodium nitroprusside infusion in man. Br. J. Anaesth., 4&,(>5\. (1976b). Changes in cyanide concentrations induced by sodium nitroprusside. Br. J. Anaesth., 48, 268. Krapez, J. R. (1980). The effects of sodium nitroprusside and cyanide on haemoglobin function. / . Pharm. Pharmacol., 32,256. Simpson, P. J., Adams, L , and Cole, P. V. (1979). Metabolism of sodium nitroprusside and cyanide in the dog. Br./. Anaesth., 51, S9

Sir,—Dr Vesey and his colleagues criticize our conclusion that cyanide is released from nitroprusside, not by reaction with blood, but via the photoproduct aquapentacyanoferrate(TII), [Fe(CN)5H2O]2 ~. When we started this research we were looking for a mechanism for the blood-induced breakdown of nitroprustide and it was only after several years' work, during which we were unable to observe this reaction, that we began to question

the suitability of the analytical procedure used by previous workers. We now believe that the previously accepted hypothesis that cyanide isreleasedby reaction of nitroprusside with haemoglobin (Smith and Kurszyna, 1974) is inconsistent with the known properties of the nitroprusside ion, is inconsistent vith the laws of thermodynamics, and has been specifically disproved (Bisset et al., 1981). Since the chemistry has plainly not been understood by our critics we summarize it here; full chemical details are discussed in the last reference. The nitroprusside ion [Fe(CN)5NO]2~ (pace Vesey and coworkers, it is not a molecule or a radical) has hi jh thermodynamic stability (formation constant 0j= 1030) and contains low-spin Fe(II), d* and is, therefore, inert to hgand substitution. Indeed, at one time the recommended antidote for cyanide poisoning was the administration of Fe(II) salts because of the formation of a very stable and inert cyanoferrate(II). Of the hundreds of papers in the chemical literature on nitroprusside known to us, none contains an unambiguous example of cyanide release under nonphotochemical or non-redox conditions; the example cited (Rock and Swinehart, 1966) is speculative. Photolysis of nitroprusside, independent of pH and wavelength, results m formation of the aqua ion [Fe^CNO^O] 2 " (Lodzinska and Gogolin, 1973; Wolfe and Swinehart, 1975). This ion is also of high thermodynamic stability, ps - 1036, but contains low-spin Fe(III), d5, and is, therefore, readily susceptible to hgand substitution. This means that the cyanide ligands of the aqua ion can be displaced by other ligands The conditions of the analytical procedure of Vesey and coworkers are ideally constructed to do just that The solution is acidified and aerated. Any cyanide released by hgand exchange with water is protonated to give volatile HCN and swept out of the solution. This is a non-equilibrium, entropy-driven process. It is essential always to be clear whether reactions are proceeding under equilibrium or non-equilibrium conditions, as this is crucial to the yield of HCN observed From the analytical point of view it means that, if the nitroprusside solution is at any time exposed to light, before infusion or mi-ringj during incubation, or during analysis, it is inevitable that cyanide will be detected. The absence or presence of blood is irrelevant. The amount of cyanide will depend upon the radiant power to which the solution is exposed, but we hope our critics will concede that this particular analytical procedure is peculiarly ill-suited for the detection of cyanide in the presence of nitroprusside. We have never suggested that cyanide is directly generated by the action of light on nitroprusside. In our hands the use of a more selective analytical technique, as ion-sensitive electrode, provided no evidence for cyanide release on mining, and incubating, nitroprusside with different blood fractions as well as whole blood; we note that Vesey and colleagues ignore our clear statement that we obtained the same results using the more sensitive colorimetric assay. Vesey and colleagues are seriously in error when they state that hydroxide is necessary for the formation of the ion [F^CNOsHjO]2" The action of hydroxide on nitroprusside produces a totally different ion, [ F ^ C N ) ^ ^ ] 3 " , — a n Fe(II) species which is entirely irrelevant to the present discussion. An appreciation of metal oxidation states is crucial to an understanding of these iron complexes. Most non-redox reactions of nitroprusside involve attack on the nitrosyl group and the Fe(CN)s moiety remains intact. The complete breakdown of nitroprusside to give cyanide, under ambient, equilibrium conditions is, because of its high 0s value, an astonishing reaction; the laws of thermodynamics are not suspended, even in vwo. From well-founded chemical considerations we have criticized

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be expected to yield significant amounts of HCN on immediate analysis, particularly if measured with the relatively insensitive cyanide specific electrode. The statement that there are no in vitro reactions, a pan from photolysis, that result in the release of HCN from SNP (Bisset et al., 1981) is incorrect Rock and Swinehan (1966) suggest, that following reaction of SNP with sulphides, cyanide can be released under certain conditions. Indeed we have found the HCN is obtained after incubation with cysteine at pH 7 4 (Vesey, Cole and Simpson, 1976b). (iv) A recent patient infused with SNP 1.3 g over the course of 108.5 h for ergot poisoning, showed an increase of plasma thiocyanate (SCN; a detoxication product of HCN) from 79 umol litre"' to 8 50 umol litre"' (unpublished data). Any effect of light on the SNP was eliminated since both the infusion solution and the giving set were foil-wrapped. This confirms that SNP breaks down to release HCN m vivo (and not during the assay), not only because we are able to measure increased concentrations of HCN in the blood of patients and animals infused with SNP, but also because plasma SCN concentrations increase as a result of the detoxication of endogenously produced cyanide.

CORRESPONDENCE

793

the analytical procedure used by previous workers for the assay of cyanide in the presence of nitroprusiide. Until these criticisms are answered satisfactorily all in vwo or in vitro experiments purporting to confirm cyanide release by reaction with blood must, we believe, receive the old Scottish legal verdict of not proven. If cyanide is indeed liberated as readily in vwo as Vesey and co-workers have repeatedly asserted, we question whether its use in clinical practice should continue. A. R. BUTLER C.GLIDEWELL

St Andrews Dundee REFERENCES

Bisset, W. I K., Burdon, M. G., Butler, A R., GudeweU, C , and Reglinski, J (1981) Photochemistry of the nitroprusside ion and the consequences for the detection of cyanide in mixtures of nitroprusaide and blood: use of nitroprusside as a hypotensive agent. / . Chem. Res. (S), 299, 3501 Lodzinska, A., and Gogohn, R. (1973) Effect of pH on photolysit of sodium pentacyanonitrosylferrate in aqueous solutions. Rocz. Chem., AT, 1101.

Rock, P. A., and Swinehart, J H (1966). The kinetics of the aqueous hydrogen sulphide-nitroprusside system. Inorg. Chem., 5,1078. Smith, R P., and Kruszyna, H. (1974). Nitroprusside produces cyanide poisoning via a reaction with haemoglobin. / . Pharmacol. Exp. Ther., 191, 557 Wolfe, S. K., and Swinehart, J. H. (1975) Photochemistry of pentacyanonitrosylferrate(2-), nitroprusside. Inorg. Chem. ,14, 1049.

R. S J. CLARKE R K MFRAKHUR

Btlfast

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W. I. K. BISSET

to an increase in heart rate (Eger, 1962; Mirakhur, Jones and Dundee, 1981. Morerecentreportssuggest that a dose of atropine in the region of 1.2mg administered before or with neostigmine was safe provided ventilation was maintained (Riding and Robinson, 1961; Kemp and Morton, 1962; Baraka 1968a,b) They showed that, even in a mixture, the effect of atxopine in increasing the heart rate appeared before the negative chronotropic effect of neostigmine Pooler (1957) reported a patient having frightening tachycardia when given atropine before neostigminereversaland he believed that atropine may have been responsible for unexplained deaths during reversal. When atropine is routinely administered before neostigmine the degree of tachycardia is invariably much more than when the two drugs are given together (Baraka, 1968a, b; Ovassapian, 1969; Rosner, Kepes and Foldes, 1971 ; Mirakhur etal., 1981). It is even more important in ill patients with poor cardiac function not to increase their heart rates and rate—pressure products unduly—situations which are avoided by administering atropine and neostigmine together or perhaps using glycopyrrolate instead of atropine in the mixture (Cozanius et al , 1980; Mirakhur et al., 1981). Better understanding of the need to maintain proper ventilation during reversal has resulted in thereversalof neuromuscular block being a safe procedure. In conclusion, we believe that atropine and neostigmine are better administered together unless there is pre-existing bradycardia of sufficient severity to warrant prior administration of the anncholinergic drug This appears to be the current practice of the majority of anaesthetists in this country (Mirakhur etal., 1978).

ANTAGONISM OF NEUROMUSCULAR BLOCK

REFERENCES

Sir,—The recent discussion between Foldes (1981) and Payne and Hughes (1981) regarding the way atropine and neostigmine should be administered to antagonize neuromuscular block has prompted us to write this letter Macintosh (1949) and Clutton-Brock (1949) described patients in whom cardiac arrests occurred when atropine and neostigmine were given together. These and the comments by Bain and Broadbent (1949) are given as reasons by Drs Payne and Hughes for advocating administration of atropine before neostigmine. However, closer scrutiny of these reports showi administration of reversal mixtures containing only 1/100 gr (0.65 mg) of atropine with neosogmine 2 - 2 5mg during a cyclopropane anaesthetic, with apparently unassisted respiration during reversal It was pointed out by Hunter (1953) and Edwards and his colleagues (1956) that 1/100 gr (0 65 mg) of atropine was inadequate and the former showed that atropine 1 3mg was required with each 2.5 mg of neostigmine A recent study (Mirakhuretal., 1981)has actually showed that even atropine 20 fig kg~ l (1.2 mg in a 60-kg patient) might be inadequate whether given before orini mixture with neostigmine 50figkg~ ' (3.0 mg in a 60-kg patient). Bain and Broadbent (1949) also reason that, since atropine given s.c. can produce initial slowing of heart rate, the same may happen on i.v. administration. In addition, according to Bain and Broadbent the peripheral effects of atropine may commence after 20—30min. No anaesthetist believes that i.v. atropine takes 20-3Omin to produce an effect on the heart rate. Whereas initial slowing results after s.c. or i.m. administration of small to moderate doses, i.v. administration in anaesthetized patients always leads

Bain, W. A , and Broadbent, J L. (1949) Death following neostigmine. Br. Med. J., 1, 1137. Baraka, A. (1968a). Safe reversal- Atropine followed by neostigmine, an electrocardiographic study. Br. J. Anaesth., 40, 27. (1968b) Safe reversal: Atropine-neostigmine mixtures; an electrocardiographic study Br. J. Anaesth.,40, 30. Clutton-Brock, J (1949). Death following neostigmine. Br. Med. 7,1,1007. Cozanius, D. A , Dundee, J. W , Merrett, J. D., Jones, C. J., and Mirakhur, R. J. (1980). Evaluation of glycopyrrolate and atropine as adjuncts to reversal of non-depolarizing neuromuscular blocking agents in a "true-to-life" situation. Br J. Anaesth , 52, 85 Edwards, G., Morton, H. J V., Pask, E. A., and Wylie, W. D. (1956). Deaths associated with anaesthesia. Anaesthesia, 11, 194. Eger, E. I. (1962). Atropine, scopolamine and related compounds. Anesthesiology, 23, 365. Foldes, F. F. (1981). Atracurium in anaesthetized man. Br. J. Anaesth., 53,1366. Hunter, A. R (1953) The anucurare agents. Br.Med.J., 1,640. Kemp, W. W., and Morton, H. J. V. (1962) The effect of atropine and neostigmine on the pulse rates of anaesthetised patients. Anaesthesia, 17,170. Macintosh, R R. (1949) Death following injection of neostigmine Br Med. J., 1,852 Mirakhur, R. K., Clarke, R. S. J., Dundee, J. W., and MacDonald, J. R. (1978). Anticholinergic drugs in anaesthesia: a