287

HYPOTENSION IN HEPATIC FAILURE SIR,-Gazzard et al.l observed that arterial hypotension often developed at the start of charcoal haemoperfusion in patients with fulminant hepatic failure. This hypotension could usually be reversed by infusion of blood or plasma. Data on blood-volume were not presented; however, the reported fall in central venous pressure could have indicated hypovolsemia. There could also have been loss of vasopressor or an increase in vasodepressor substances within the circulation. Assuming that the renin/angiotensin system helps to regulate blood-pressure by direct vasoconstriction in low-output states 2,3and is important in severe liver failure, charcoal haemoperfusion might remove circulating angiotensins. Free angiotensins are very rapidly bound by charcoal in radioimmunoassay systems.4 However, renin-substrate deficiency is not uncommon in liver diseases5 and could limit angiotensin release.6 Liver damage induced by a single dose ofD-galactosamine reduced plasma-renin-substrate concentration (bioassayed) in fourteen guineapigs from 852291 (s.D.) to 41:30 ng. per ml. 72 hours after poisoning, and mean blood-pressure had dropped from 80 ±9 (S.D.) to 40 11 mm. Hg. The pronounced increase in plasma-renin concentration (radioimmunoassayed) was inversely related to bloodpressure (r= - 0-932, P < 0-001, n=16). Renin-substrateenriched plasma infusions rapidly returned blood-pressure to normal by generating angiotensin, whereas volume expansion by ’Hæmaccel’ did not correct arterial hypotension. Renin concentration fell after substrate infusions

(P< 00005, n=14). It has been postulated that reduced hepatic synthesis of renin substrate, leading to an intrarenal angiotensin deficiency, might contribute to the hepatorenal syndrome.7 We conclude that angiotensin-n concentration at the vascular receptor sites is an important determinant of blood-pressure regulation in hepatic failure, but further studies are needed to confirm this hypothesis. Medizinische Universitätsklinik, Josef-Schneider-Strasse 2, 8700 Würzburg, Germany.

H. WERNZE D. BRACHTEL.

STANDARDISATION OF HEPARIN FOR CLINICAL USE SIR,-A significant development in the treatment of venous thromboembolism is prophylactic low-dose sub-

heparin. However, this development increases importance of standardisation of heparin. The inter-

cutaneous

the

national collaborative study of the assay of heparin 9 demonstrated the unreliability of the usual standardisation of heparin based on coagulation tests and showed that this was due to variation in relative potency of different heparin preparations with changes in the coagulation substrate used. Further, attention was earlier drawn to the fact that the results of such coagulation tests did not necessarily reflect the ability of the heparin preparations to prevent venous thrombosis, since a commercial heparin preparation was found to be 2½ times as effective as international heparin standard in preventing experimental jugular-vein 1.

2.

3.

Gazzard, G., Portmann, B., Weston, M. J., Langley, P. G., Murray-Lyon, I. M., Dunlop, E. H., Flax, H., Mellon, P. J., Record, C. O., Ward, M. B., Williams, R. Lancet, 1974, i, 1301. Guyton, A. C., Cowley, A. W., Coleman, T. G. Am. J. Med. 1972, 52, 584. Johnson, J. A., Davis, J. O. Circulation Res. 1973, 22/23, suppl. 1, B.

159.

Ochi, Y., Shiomi, K., Hachiya, T., Yoshimura, M., Miyazaki, T., Endocrinol. Japon. 1973, 20, 1. 5. Ayers, C. R. Circulation Res. 1967, 20, 594. 6. Brachtel, D., Wernze, H. Verh. dt. Ges. inn. Med. 1974, 80, 207. 7. Berkowitz, H. D., Galvin, C., Miller, L. D. Surg. Forum, 1972, 23,

4.

342. 8. 9.

Kakkar, V. V. Lancet, 1972, ii, 101. Bangham, D. R., Woodward, P. M. Wld Hlth Org. Bull. 1970, 42, 129.

thrombosis in rats. 10 Variation in clinical potency of commercial heparin has had little significance up to now, since heparin has been given in large doses (excess dosage) in the presence of an established thrombus, and in repeated doses, so that when the clinician observed that the first dose appeared ineffective, he could increase the dosage with successive

injections.

For this, it

was not

necessary

consider whether the observed lack of effect was due to resistance of the patient or to lower activity of the heparin preparation. It is evident from this that with low-dosage heparin used prophylactically, it is much more important to have accurate standardisation of heparin for clinical use. Otherwise, considerable variation in clinical efficacy can be expected with consequent confusion from clinical failures of the treatment in some instances. Fortunately, recent studies have provided information on the chemical nature of heparin which explain the controversies in the past and offer hope that more direct procedures of standardisation are possible. The sulphated polysaccharide structure of heparin has been identified by the application of proton magnetic resonance, gel electrophoresis, and specific enzymes of Flavobacterium heparinum.11-16 Commercial heparins have been shown to consist of a spectrum of 21 heparins with molecular weights from 3000 to 37,500 with only a portion of these showing anticoagulant activity by the U.S.P. assay.16 Hence, in the future, with the establishment of which heparins are effective clinically, it will be possible to standardise heparin using physicochemical parameters. I suggest clinical investigations of heparin fractions are urgently needed to determine the physicochemical parameters responsible for clinical efficacy. to



College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan.

L. B.

JAQUES.

RADIOIMMUNOASSAY FOR CARCINOEMBRYONIC ANTIGEN

SIR,—Although radioimmunoassay for carcinoembryonic antigen (C.E.A.) has not proved to be a specific test for colorectal cancer it may be a useful guide to the presence of and it of the disease.

metastases

can

be used

to

monitor the clinical

course

radioimmunoassays are available through the supraregional assay service, but the ability to continue to provide such a service and to develop the C.E.A. test further depends on having an adequate supply of raw material for extraction of the antigen. The most suitable source material is the medium-to-large hepatic metastasis obtained at necropsy within 24 hours, and preferably within 12 hours, of death from colorectal or pancreatic carcinoma. Despite the efforts of pathologists at this hospital and some others who have kindly cooperated with us, supplies are inadequate and we would welcome the help of any pathologist in the United Kingdom who could provide such tissue. Livers or part-livers containing metastases should be placed in a plastic bag with a label stating the primary site, and stored at —20°C as soon as possible. C.E.A.

Arrangements for collection phoning

me or

Mrs

can

Joan Dent

on

Charing Cross Hospital (Fulham), Fulham Palace Road, London W6 8RF.

be made from here by tele01-748 2050, ext. 2087.

K. D. BAGSHAWE.

Jaques, L. B. Thromb. Diath. Hœmorrh. 1963, suppl. 11, p. 27. Jaques, L. B., Kavanagh, L. W., Mazurek, M., Perlin, A. S. Biochem. Biophys. Commun. 1966, 24, 447. 12. Dietrich, C. P. Biochem. J. 1968, 108, 647. 13. Perlin, A. S., Mackie, D. M., Dietrich, C. P. Carbohyd. Res. 1971, 18, 185. 14. Dietrich, C. P., Silva, M., Michelacci, Y. J. biol. Chem. 1973, 248, 6408. 15. Silva, M., Dietrich, C. P. Biochem. Biophys. Res. Commun. 1974, 56, 965. 16. Nader, H. B., McDuffie, N. M., Dietrich, C. P. ibid. 1974, 57, 488.

10. 11.

Letter: Standardisation of heparin for clinical use.

287 HYPOTENSION IN HEPATIC FAILURE SIR,-Gazzard et al.l observed that arterial hypotension often developed at the start of charcoal haemoperfusion in...
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