DEXTRAN OR HEPARIN?

1315 would indicate that cimetidine had had on their psoriasis.

no

beneficial influence D. I. MCCALLUM P. W. GRANT

Raigmore Hospital, Inverness IV2 3UJ

DID HIPPOCRATES DESCRIBE LEAD POISONING? SiR,—The idea that Hippocrates was the first person to describe lead poisoning can be traced back to at least 1778 when James Hardy stated that such a case was included in the book VII of the Epidemics.’ This suggestion has little substance, but it has been followed by many authorities on lead

poisoning and occupational medicine. 3-6 Henry Sigerist, in his Wesley C. Carpenter lecture of 19367 gave a reference in the Hippocratic corpus which was considered to allude to lead colic (Epidemics VI, 25). This work has not been published in English, although it does appear in the Littre translation.s The supposed patient with lead poisoning is only one of a number discussed in this section of the book, and the reference

to

him is brief. "The

man

from the mines;

right hypochondrium strained; enlarged spleen; stomach tense and rather hard; difficulties with breathing, discolouration, in him, the illness went to the left knee, recurrence; he was completely examined". It is surely straining at a gnat to see in this the description of a case of lead colic, and I suggest that the retrospective diagnosis which has been made by Sigerist and others rests entirely on the fact that the man was a miner. There is another assumption implicit in the diagnosisnamely, that the man was a lead (or rather silver) miner-but even this is uncertain in the original. Things which are repeated from book to book tend to become regarded as fact. I hope that I have finally scotched the myth that Hippocrates was the father of lead poisoning. Let that honour be accorded (if it must) to Nicander.99 I thank Margaret Dyer for her translation.

not only hungry.

free of pain but also

thirsty

and sometimes

even

biased observations, for epimost difficult cases (e.g., with addicts and those problems) as well as respiratory drug the easiest, such as caesarean section. The mother who suckles her baby immediately after seeing it delivered by section never seems to have postoperative distension. This is probably because there is much less blood lost from the uterine wound. It is

dural

improbable that these

analgesia

are

may be used for the

New Cross

Hospital, Wolverhampton WV10 0QP

ALAN M. SMITH

DEXTRAN OR HEPARIN?

SIR,-In his response to my letter of Sept. 30 Professor Kakkar (Oct. 21, p. 899) incorrectly maintains that the South Wales dextran trial was not double-blind and that the results were not statistically significant. In my report to the International Committee on Thrombosis and Haemostasis in Leuven on July 19, 1978, I mentioned that it was suspected, but never confirmed, that one of the many anaesthetists participating in the trial attempted to distinguish between the dextran and placebo solutions by shaking..The use of a one-tail Fisher exact test for the statistical analysis was justified at the same meeting. It is a valid test when comparing a therapeutic agent with a placebo. Another statistical test-the, binomial distribution-when applied to the same data, confirmed the finding that dextran prevents death from pulmonary embolism. Full information on the comparability of the active and placebo groups in the trial were submitted for publication. Regrettably, because of limitations on space imposed by the editorial staff of the journal involved, many data were omitted. Laborious and expensive exercises of this type, attempting to answer important clinical questions, deserve to be fully

reported. Concerning the other points raised by Kakkar:

London School of Hygiene and

Tropical Medicine, TONY WALDRON

London WC1E 7HT

is

POSTOPERATIVE ILEUS

SiR,—Your editorial of Dec. 2, which discusses modern views of postoperative abdominal distension, does not mention the prophylactic use of epidural analgesia. Gynaecologists who operate on conscious patients under epidural analgesia know full well that postoperative abdominal distension is neither so great nor so prolonged as it is when similar patients are operated upon under conventional general anaesthesia. This is because of a number of factors. Opiates, which can cause ileus, are not required before or after the operation. Haemostasis is easily obtained because of the mild hypotension, and the operating-time is shortened. Contraction of the bowel reduces the need for restraining packs, while the fact that the patient is conscious encourages gentleness in handling the abdominal contents. Your comment on gut motility refers to work on monkeys, who hardly share the same dietary habits as ourselves. On return to the ward, because the epidural has been "topped up", the patient can soon drink and eat because she

(a) Monitoring of the haemostatic mechanism has been recommended in low-dose heparin therapy.1 (b) A randomised prospective study2 in 175 general surgical patients reported a bleeding and wound-complication rate of 27% in patients receiving low-dose heparin. A rate of 1 -4% was reported in control patients not given heparin. Such hamorrhagic complications of the heparin regimen feature prominently in most of the thirty-one trials referred to by Kakkar. (c) The table did not state that anti-thrombin III depletion had occurred in patients receiving subcutaneous heparin therapy. There are several reports of such depletion following intravenous heparin therapy. (d) The information on contraindications was taken from the A.B.P.I. Data Sheet Compendium under the entries for the various companies who market low-dose heparin. (e) In a study of patients undergoing cholecystectomy3 the lysability of thrombi before and after infusion of dextran 70 was studied. The results indicated that dextran infused into patients during surgery increased lysability of thrombi. (1) The South Wales dextran trial clearly demonstrated that the infusion of 1 litre of dextran 70 during and after surgery did prevent death from pulmonary embolism. A further study of the same regimen is nearing completion and should endorse this finding. Mr Watts (Oct. 21, p. 899) makes a plea against blanket therapy using prophylactic heparin or dextran. I agree that administering a potentially dangerous agent to many surgical

in order to avert thromboembolic disaster in a few is undesirable. This practice could be abandoned if a reliable predictive test for the development of deep-venous thrombosis becomes available. In the meantime, all adult patients requiring surgery under general anaesthetic are at risk. Mr Wilson and Dr Brown (Oct. 21) record a fatal reaction to dextran. Such a tragedy is rare, and a slow initial adminis-

patients

1.

Hardy, J. A. A Candid Examination of what has been Advanced on the Colic of Poitou; p. 104. London, 1778. 2. Waldron, H. A. Med. Hist. 1973, 17, 392. 3. Legge, J. M., Goadby, K. W. Lead Poisoning and Lead Absorption; p. 1. London, 1912. 4. Aub, J. C., Fairhall, L. T., Minot, A. S., Rezinkoff, P. Lead Poisoning; p. 3. Baltimore, 1926. 5. Browning, E. Toxicity of Industrial Metals; p. 153. London, 1961. 6. Hunter, D. The Diseases of Occupations; p. 238. London, 1975. 7. Sigerist, H. E. Bull. N.Y. Acad. Med. 1937, 13, 597. 8. Littré, E. Oeuvres complètes d’Hippocrates; vol. v, p. 164. Paris, 1846. 9. Nicander. Theriaca et Alexipharmaca. Venice, 1499.

1. 2. 3.

String, S. T., Barcia, P. J. Am. J. Surg. 1973, 130, 570. Pachter, H. L., Riles, T. S. Am. Surg. 1977, 186, 669. Aberg, M., Bergentz, S. E., Hedner, U. Ann. Surg. 1975, 185, 342.

1316 tration

rate of dextran with a close observation of the patient strongly recommended. Approximately 5 patients out of every 1000 adults undergoing major surgery without thromboembolism prophylaxis are liable to die from major pulmonary embolism. As the search for the ideal prophylactic agent continues, surgeons should consider the advantages of dextran. are

University Department of Surgery, University Hospital of Wales, Heath Park, Cardiff CF4 4XN

W. TUDOR DAVIES

"EXHAUSTED" PLATELETS CONTINUE TO CIRCULATE

SIR,-Reports in The Lancet of Sept. 2 (p. 501) and Sept. (p. 679) concerning platelets give unexpected support to a hypothesis proposed in my Carlo Erba lecture. I suggested that, in health and in disease, the platelets continually undergo, but to different degrees, a process equivalent to the invitro release reaction, and although some released elements are found in the plasma, the platelets usually continue to circulate. In vitro, when platelets in citrated plasma are suitably stimulated, they lose granules and secrete, among other substances, A.D.P., serotonin (5-H.T.), platelet factor 4 (P.F.4) and 23

and 18 found that in thrombotic patients there was a striking decrease in intra-platelet p.p.4 but the platelet-count remains normal. In addition there was a clear inverse relation between this intra-platelet P.F.4 and the concentration of plasma heparin-neutralising activity which probably measures "r.F.4-like activity" released in the plasma. The results of a similar study are reported in fig. 1. In further support of the concept of the continued circulation of exhausted platelets, we have measured the M.D.A. production by platelets maximally stimulated by thrombin; patients with high levels of heparin-neutralising activity and short clotting-times, and controls, were studied. Fig. 2 shows that the ability of the patients’ platelets to generate M.D.A. is decreased relative to the controls; the platelets are exhausted, yet they remain in the bloodstream. Fig. 2 shows that the amount of M.D.A. formed is apparently inversely related to the plasma heparin-neutralising activity. This observation is further evidence linking the non-specific clotting test of hepar8. 9.

O’Brien, J. R., Etherington, M. D. Thrombos. Hœmostas. 1976, 36, 649. O’Brien, J. R., Shuttleworth, R. D., Etherington, M. D. Unpublished.

P-thromboglobulin (p-T.G.); malondialdehyde (M.D.A.) is liberated in the plasma as a byproduct of prostaglandin synthesis. After the release reaction the platelet may be called "exhausted" ; in vitro the release reaction almost invariably proceeds to completion with the formation of coarse aggregates that could not possibly circulate. It might be thought that platelets that have undergone the release reaction in the bloodstream would be quickly removed, as suggested by the rapid fall in the platelet-count in florid diffuse intravascular coagulation (D.I.C.) and the short half-life found in clinical conditions in which the platelets are likely to be activated.2 However, Reimers et al.3 removed platelets from the rabbit, separated them from the plasma to prevent aggregation, and then treated them with thrombin, thus inducing the release reaction; when these "exhausted" platelets were returned to the rabbit they continued to circulate with a normal half-life and even had some haemostatic capacity. Thus exhausted platelets can circulate. Patients with severe valvular heart-disease have platelets with significantly less releasable A.D.P. than controls.4 Presumably they have already released some A.D.P. in vivo. My colleagues and I have reported a decrease in the aggregation response to A.D.P. during and immediately after major operations, yet with no drop in platelet-count.5 These platelets were less reactive when studied and may have undergone partial release in vivo. A less florid form of D.I.C. has been described with an apparent loss of storage granules from the platelets which continued to circulate.6 In idiopathic thrombocytopenic purpura the platelet halflife is decreased, but the circulating platelets are reported to be depleted of 5-H.T. and with an inverse increase in the plasma level (Sept. 23, p. 679). In migraine there is usually no fall in platelet-count yet the plasma-5-H.T. may rise prodromally and falls to about half during the attack (Sept. 2, p. 501).’ This again suggests that during the attack exhausted platelets are circulating which can release no more 5-H.T. If platelets are frozen and thawed they liberate intra-platelet P.F.4 which can be detected by a clotting test. Mr Etherington

Fig. 1-Heparin thrombin clotting-time of platelet-poor plasma. A long time indicates little heparin-neutralising activity; plot is against units of heparin neutralised by the patients’ platelets after freezing and thawing three times.

O’Brien, J. R. Carlo Erba lecture, delivered in Milan,

on May 29, 1978. Harker, L.A., Slichter, S.J. New Engl. J. Med. 1970, 283, 1302. 3. Reimers, H. J., Kinlough-Rathbone, R. L., Cazenave, J. P., Senyi, A. F.,

1. 2.

UNITS HEPARIN NEUTRALIZED BY PLATELETS -

RRR HEPARIN THROMBIN CLOTTING TIME (SECS.)

Hirsh, J., Packham, M. A., Mustard, J. F. Thrombos. Hœmostas. 1976,

35, 151. 4. Beurling-Harbury, C., Galvan, C.A. Blood, 1978, 52, 13. 5. O’Brien, J. R., Etherington, M. D., Jamieson, S. Lancet, 1971, ii, 741. 6. Pareti, F. I., Capitanio, A., Mannucci, P. M. Blood, 1976, 48, 511. 7. Antony, M., Hinterberger, H., Lance, J. W. Archs Neurol. 1967, 16, 544.

Fig. 2-Platelet malondialdehyde production. A platelet button prepared from E.D.T.A. platelet-rich plasma was resuspended and strong thrombin was added. After an hour at 370C malondialdehyde was estimated by fluorimetry.