ASPECTS OF EPIDURAL MORPHINE

583 ure." There is no mention of positive end-expiratory pressure being instituted. This paper demonstrates the need to do more caesarean sections under some form of regional technique, and, if this is contraindicated, then general anaesthesia with all the precautions should be used. Antacids and Sellick’s manoeuvre are no longer thought of as foolproof techniques for preventing

aspiration. Department of Anesthesiology, L niversity of Louisville School of Medicine, Louisville, Kentucky 40201, U.S.A.

DEEPAK MEHROTRA JOAN C. PAUST

SIR,—The tragic cases described by Dr Whittington and colleagues will strike fear into the heart of any anaesthetist. Vomiting and aspiration have always been a leading cause of maternal anaesthetic mortality, and the search for a safe anocsthetic regimen continues. Now that antacids and cricoid pressure have been discredited, I suggest that metoclopramide be tried. This drug can rapidly produce forward gastric emptying without the agony of gastric drainage in an already combative parturient. While not approved by the U.S. Food and Drug Administration for use in the pregnant patient, metoclopramide may provide the answer to this dangerous problem. Spinal anaesthesia remains the only guarantee against pulmonary aspiration, but it is not applicable in all cases. I would like to hear from other anaesthetists concerning the use of metoclopramide in this context. 3501 Ferndell Tract, Sarasota, Florida 33580, U.S.A.

BARRY G. SMILER

AUTOIMMUNE HÆMOLYTIC ANÆMIA ASSOCIATED WITH CIMETIDINE

SIR,—Eight cases of granulocytopenia1-8 and changes in cellular immunity9 after cimetidine have been reported. We describe here autoimmune hamiolytic anaemia (AHA) after cimetidine treatment. In November, 1977, cimetidine (1 g/day) was administered for duodenal ulcer to a 50-year-old man for 10 days. A second course of oral cimetidine was started on Jan. 10, 1978, at the same dosage, and

stopped on the ninth day because of his weakness and low-grade fever. Within 2 days he became weaker, pale and jaundiced and urine became dark. On Jan. 26 he was admitted to our department, pale and slightly icteric, with moderate dyspnoea and tachycardia (122/min.). No signs of respiratory-tract infection. Liver 2 cm below costal margin. Neither spleen nor lymph nodes palpable. Hb 4.3g/dl; red blood-cells 1 160 000 µl, white blood-cells 16 500/µl (neutrophils 80%; eosmophils 1%; lymphocytes 15%; metamyelocytes 4%); late normoblasts 3/100 WBC; platelets 33000/µl. Red cell morphology: anisocytosis, several spherocytes, marked polycromasia. Reticulocytes 8-4%. Bilirubin 2.21 mg/dl (indirect 1.85). Erythrocyte sedimentation-rate 160/164. Serum lactic dehydrogenase 487 mU/ml. Serum iron 223 µg/dl. Plasma haemoglobin 1 mg/dl (normal <3 mg/dl). The urine was negative for haemoglobin and hasmosiderin. C3 95 mg/dl. All other

ER, Whittington JM. Agranulocytosis four months after cimetidine therapy. Lancet 1977; ii: 294-95. 2. Johnson NMcl, Black AE, Hughues ASB, Clarke SW. Leucopenia with cimeudine. Lancet 1977; ii: 1226. 3. Ufberg MH, Brooks CM, Bosanac PP, Kintrel JE. Transient neutropenia in a patient receiving cimetidine. Gastroenterology 1977; 73: 635-38. 4. Lopez-Luque A, Rodriguez Cuartero A, Perez-Galvez N, Pomares-Mora J, Pena-Janez A. Cimetidine and bone marrow toxicity. Lancet 1978; i: 444. 5. James C, Prout BJ. Marrow suppression and intravenous cimetidine. Lancet 1 Craven

1978; i: 987. 6. Corbett CL, Holdsworth CD. Fever, abdominal pain and leucopenia during treatment with cimetidine. Br Med J 1978; i: 753-54. 7. Klotz SA, Kay BF. Cimetidine and agranulocytosis. Ann Int Med 1978; 88: 579-80. 8 Possnet

DN, Stem RS, Graber SE, Krantz SB. Cimetidine-induced neutropenia, a possible dose-related phenomenon. Arch Int Med 1979; 139: 584-86. 9 Avella J, Binder HJ, Madsen JE, Askenase PW. Effect of histamine H2-receptor antagonists on delayed hypersensitivity. Lancet 1978; i: 624-26.

biochemical and enzymatic measurements were normal. Boneexamination: marked striking erythroid hyperplasia. Chest X-ray normal. Serology for pleuropneumonia-like organisms was negative. Direct Coombs test was positive with monospecilic antisera to IgA (3+), IgM (2+), C3 (3+). Indirect Coombs test was positive (2+) (24 h at 370C 1/64; 24 h at 200C 1/128 ; 24 h at 4°C 1/32). A complete, warm, IgA and IgM type antierythrocytic autoantibody with anti-I specificity (by Resolve ’Ortho’ test) was detected. Serum activity on normal RBCs was unchanged after heating at 560C for 30 min but disappeared after treatment with mercaptoethanol. Donath-Landsteiner and Ham tests were negative. Betamethasone, 8mg/day for 10 days, then 4 mg/day, was started, plus folic acid. On Feb. 2 reticulocytes were 40% and all serological tests became negative. Therapy was stopped on Feb. 14, at an Hb level of 11.5 g/dl, and the patient was discharged. Hb returned to normal in 2 weeks. After 16 months follow-up without any therapy, there has been no relapse. The list of drugs which may be responsible for the appearance of antierythrocytic antibodies is very long. Identification serum

marrow

of

a drug as the offender is usually based on appearance of autoantibody during or immediately after treatment with the drug; disappearance (within a variable period of time) of autoantibody once the drug is withdrawn; frequent association between drug administration and autoantibody detection. In our patient, the first two criteria were met. If cimetidine was responsible for the AHA, what was the

mechanism? H2-receptors are present on the surface of cells other than gastric parietal cells; they have been found on T-lymphocytes1O and their function seems to be related to the immune response." Cimetidine affects cellular immunity in humans,9 in terms of increased skin reactivity to common antigens, possibly as a result of impaired activity of T suppressor cells. By a similar mechanism, humoral immunity could also be affected. In our patient the appearance of IgM and IgA with anti-I specificity can be interpreted as an abnormal early response against a common circulating antigen. AHA may be a potential complication of cimetidine treatment. Because of its rarity, this side-effect should not interfere with the clinical use of the drug. However, AHA might be considered an example of a number of consequences of druginduced change in the immune response. Indeed, in some of the reported cases of cimetidine related granulocytopenia2,3 there

signs of peripheral destruction (active granulopoiesis with suggesting an immunological mechanism. Considering that prolonged and repeated courses of cimetidine are the rule in most patients, the possible development of (or the in-

were

left shift), fluence

on

preexisting)

Medical Clinic, Second Faculty of Medicine, University of Naples,

Italy

autoimmune disorder should be noted. BRUNO ROTOLI SALVATORE FORMISANO

FIORELLA ALFINITO

ASPECTS OF EPIDURAL MORPHINE

SIR,—Obstetricians and obstetric anaesthetists will be

es-

pecially interested in the report’ that epidural injections of morphine 2 mg provided considerable amelioration of severe acute or chronic pain. The remarkable absence of any interference with motor or autonomic nervous function and relatively long duration of action would provide considerable advantages over regional analgesia with local anaesthetic agents for relief of pain in labour. In our trial (to be published in full elsewhere2) lumbar epidural injections of 2 mg preservative-free morphine in 8 ml 10. Plaut M, Lichtenstein LM, Henney CS. Properties of a subpopulation of T cells bearing histamine receptors. J. Clin Invest 1975; 55: 856-74. 11. Rocklin RE. Modulation of cellular immune responses in vivo and in vitro by histamine receptor-bearing lymphocytes. J Clin Invest 1976; 57: 1051-58. 1. Behar M, Magora F, Olshwang D, Davidson JT. Lancet 1979; i: 527-28. 2. Husemeyer RP, O’Connor MC, Davenport HT. Failure of epidural morphine to relieve pain in labour. Anæsthesia (in press).

584 0.9% saline

were given to ten women in established labour. severity of pain was assessed with a 10 cm linear analogue scoring system of the type recommended by Scott and Huskisson,3 before and 30 min after morphine. Only three women recorded an apparent slight improvement in the severity of pain, and the mean score after epidural morphine (7.5) was greater than the mean initial score (6.8). In all women subsequent epidural injection (via the same catheter) of 8 ml 0.375% plain bupivacaine provided satisfactory analgesia, the mean score 30 min after bupivacaine being 0.5. The failure of epidural morphine 2 mg to provide adequate analgesia in labour is in contrast to the reported efficacy of epidural morphine 2 mg in the treatment of severe pain other than labour. The explanation for this discrepancy is uncertain, but perhaps the increased vascularity of the epidural space in pregnancy is responsible for rapid clearance of injected morphine so that effective concentrations of morphine in the cerebrospinal fluid and spinal cord are not reached. Other investigators may be encouraged to use larger doses of epidural morphine but we would repeat Mathews’ warning4 against the indiscriminate use of morphine preparations which may contain preservatives.

The

Our use of the term "selective spinal analgesia" is supported by Bromage’s findings: epidural narcotics are capable of selective spinal blockade of nociception in man, the only qualifying criterion apparently being that the stimulus is "noxious" in some manner. This view is supported by Yaksh and Pert’s animal studies of spinal narcotics where dose-dependent, stereospecific, naloxone-reversible analgesia has been reported; the analgesia was "pure", as assessed by spinal reflexes and behavioural responses to noxious stimuli. One of us (P.R.W.) has recently found that doses of epidural pethidine, equivalent to those used in man, produces selective analgesia, as assessed by tail flick and hot-plate tests in rabbits and rats. The input to, and organisation of, the dorsal horn, are still in doubt, further emphasising that much is to be learned about fundamental aspects of the spinal action of narcotics. We have found that non-selective cerebral effects, respiratory depression (supported by Scott and McClure’s letter of June 30) and sedation may result from high cerebrospinal-fluid concentrations. Further we have observed an initial local-anaesthetic effect, with classical sign of sympathetic blockade, when pethidine is injected directly into the CSF in concentrations in excess of 2%. Higher concentrations of pethidine approach the potency of

Clinical Research Centre, Harrow, Middlesex HA1 3UJ

R. P. HUSEMEYER M. C. O’CONNOR H. T. DAVENPORT

as a local anaesthetic, while the other narcotics in concentrations have a lesser degree of local-anaesthetic effect.

procaine

high

M. J. COUSINS C. J. GLYNN P. R. WILSON L. E. MATHER J. R. GRAHAM

Department of Anaesthesia

SIR,-We agree substantially with the observations of Professor Bromage’s group (July 21, p. 151). Their data are in

and Intensive Care, Flinders Medical Centre, Bedford Park, South Australia 5042

harmony with our initial report of a "selective" afferent blockade following epidural pethidine (May 26, p. 1141). However, their conclusions with regard to symvenous occlusion plethysmography and ice response to examine reflex efferent sympathetic vasomotor activity by applying ice outside the blocked area; normal ice response was retained, indicahing normal efferent activity. Sudomotor activity, as measured by the cobalt-blue sweat test, is also a direct measure of efferent sympathetic activity; no change in this test was observed in the feet. These data indicate that efferent sympathetic activity within the blocked area is not directly altered. However, we did find small increases in blood-flow at rest, indicating either reduced afferent activity or a peripheral vascular effect of the narcotic. Bromage’s group reported increased tolerance of cold and reduced blood-pressure response to cold discomfort, when a "blocked" limb was placed in ice, indicating blockade of afferent noxious activity elicited by cold. Their observations of altered psychogalvanic response (PGR) to the Valsalva manoeuvre are also consistent with reduced afferent activity since their blocks are in the thoracic region; the PGR response is not confined to the sympathetic nervous system. However, both the ice response and PGR were normal if the stimulus was applied outside the blocked area. Thus their studies provide indirect evidence of normal efferent sympathetic activity. Our own studies provide direct evidence of retention of normal efferent vasomotor and sudomotor activity in the blocked limb. The significance of alterations in afferent input which, Bromage et al. report, may reduce efferent sympathetic activity despite unblocked sympathetic efferents remains to be seen. We have observed transient hypotension in postoperative patients when severe pain was relieved by epidural pethidine 100 mg during the first 24 h after surgery; the hypotension lasted only 45 min and could have been partly due to direct vascular effects of blood-borne pethidine; this is supported by the measurements of increased blood-flow by venous occlusion plethysmography. Such hypotension was not seen in patients with chronic pain.

we

wish

to comment on

pathetic activity.

We used

3. Scott J, Huskisson EC. Graphic representation of 175-84. 4. Mathews E. Epidural morphine. Lancet 1979;i: 673.

pain.

Pain

1976; 2:

SIR,-Behar et al. reported that small doses of epidural morphine (by acting on the opioid receptors in substantia gelatinosa cells in the posterior horn of spinal cord) are effective in treatment of acute and chronic pain. The onset of action was reported to be 2-3 min and duration 6-24 h, so multiple injections of morphine would be needed through an epidural catheter. We have administered 2 mg of epidural morphine in 10 ml saline as a single epidural injection with the patient seated at L3 - L4’ All the patients had remarkable relief of pain and we can confirm that there was no loss of other sensations and no signs of sympathetic block or muscle weakness. Three patients with chronic pain did not pass urine for 12 h. Unlike Behar et al. we observed a big difference in onset and total duration of relief between those with with chronic pain: in chronic pain relief

acute was

and those

experienced

RESULTS OF EPIDURAL MORPHINE ADMINISTRATION

*Amputations (4), ulcer, frozen pelvis, perinatal tear.

fApgar score>

8 in all cases.

585 sooner and lasted longer (see table). This long duration of effect in chronic pain is a major clinical advantage. The difference suggests of some difference in basic mechanisms of pain transmission and perception.

Departments of Anæsthesiology, Pharmacology and Surgery, K E.M. Hospital and Seth G. S. Medical College, Bombay 400 012, India

ARUNA R. BAPAT NILIMA A. KSHIRSAGAR R. D. BAPAT

SURVIVAL OF PANCREATIC ISLET ALLOGRAFTS

SIR,-Dr Garvey and his Oxford colleagues (May 5,

p.

971)

made in my paperl on the rejection of islet allografts and the possibility of circumventing these problems. The pendulum has certainly swung during the past few years, from the early hope that pancreatic islets might be immunologically privileged to a more pessimistic view following disappointing experience with islet allograft immunosuppression. Some reports (reviewed by Schulak and Reckard2), including ones from the Oxford group, indicate that antilymphocyte serum (ALS) is at least a moderately effective immunosuppressive agent for prolonging islet allograft survival. Moreover, the number of islets needed and actually used in most studies for normalising the hyperglycxniia of a diabetic rat or mouse is about one-tenth of that found in the normal pancreas.’ This implies that there are no functional reserves should some kind of stress be put on the allograft, and rejection of even a small proportion of the grafted islets, indicated by the onset of hyperglycaemia, will be interpreted as a total failure of the graft, despite the possibility that most of the implanted islets may still be viable. I share the scepticism of Garvey et al. concerning the use of ’Nucleopore’ chambers as a tool for preventing rejection of al10grafted islets. Their letter gives further convincing evidence to support such doubts. We were similarly unable to reproduce the results of Strautz,4 suggesting that obesehyperglycaemic mice may be cured by implantation of islets isolated from their lean littermates and subsequently encased in ’Millipore’ chambers. However, even in our study5 substantial growth of the implanted islets was noted. Furthermore, Theodorou and Howell’s work with diffusion chambers in pancreatic islet-cell transplantation6 suggests that islets transplanted in this way are unlikely to be able to maintain an accurate minute-by-minute regulation of blood-glucose. I think that it is too early to rule out the possible advantages of long-term culture in vitro of islets as a method for reducing their antigenicity; culture techniques provide a very efficient method for storing islet cells for long periods before transplantation. It is true that we were unable to show prolonged survival of mouse islet allografts cultured for 10 days.7 However, Lafferty et a1.8 had to culture thyroid glands for 4 weeks to get prolonged allograft function. We have now extended our studies to the intrasplenic implantation of 4-week cultured islets from C57BL/6J (H-2b) mice to alloxan-diabetic

question

some statements

1. Andersson A. Islet

implantation normalises hyperglycæmia caused by streptozotocin-induced insulitis. Lancet 1979; i: 581-84. 2. Schulak JA, Reckard CR. Experimental transplantation of pancreatic islet

allografts. J Surg Res 1978; 25: 562-71. DRA, Morris PJ. The effect of increasing islet numbers on survival of pancreatic islet allografts in immunosuppressed diabetic rats. Transplan-

3. Finch

tation

1977; 23: 104-06.

4. Strautz RL. Studies of

hereditary-obese mice (obob) after implantation of pancreatic islets in Millipore filter capsules. Diabetologia 1970; 6: 306-12. 5. Swenne I, Reibring L, Petersson B, Andersson A. Growth of pancreatic islets of normal mice after transplantation into obese-hyperglycemic mice littermates. Acta Endocrinol 1979; suppl. 227: 70-71. 6. Theodorou NA, Howell SL. An assessment of diffusion chambers for use in pancreatic islet cell transplantation. Transplantation 1979; 27: 350-53. 7. Andersson A, Buschard K. Culture of isolated pancreatic islets: its applications for transplantation purposes. Trans Am Soc Artif Intern Organs 1977; 23: 342-45. 8 Lafferty KJ, Cooley MA, Woolnough J, Walker KZ. Thyroid allograft immunogenicity is reduced after a period in organ culture. Science 1975; 188: 259-61.

8 weeks after implantation into alloxan-diabetic mouse, showing normal morphology. (HaEmatoxytin and eosin; reduced to 3/5 of x 250.)

Intrasplenic islet allografts

C57BL/Ksl (H-2a) mice without immunosuppression. Five animals receiving non-cultured islets returned to hyperglycaemia after 4-7 days of normal blood-glucose. Of three animals given about 400 4-week cultured islets each one remained normoglycamuc for 4 weeks but subsequently became slightly hyperglycaemic, suggesting rejection. Spleen sections revealed islets partly infiltrated with lymphocytes. The second animal remained normoglycaemic, perfectly normal islets being found in the spleen at 8 weeks (see figure). The third animal, now normoglyca:mic for 8 weeks, together with any further successful recipients, will be followed up for longer. Moreover, Lacy et al.9 have recently reported that culture of islets at +24°C for 7 days resulted in islet allograft survival of 100 days. Clearly, endocrine pancreas transplantation does present considerable immunological problems. Nevertheless, it seems plausible that further efforts at improving techniques for preparing islet tissue could offer the hope of better results in attempts at curing human diabetes by islet cell transplantation. Department of Histology, University of Uppsala, S-751 23 Uppsala, Sweden

A. ANDERSSON

SIR,-Dr Garvey and colleagues doubt if organ culture before transplantation can facilitate allografting of pancreatic islets. This is probably a fair comment in respect of islets or fetal pancreas cultured in an atmosphere of 5% CO2 and air, although Lacy et al.’ have reported that islets cultured in this way at 24 °C can be transplanted to allogeneic rats, provided the recipient is given a dose of immunosuppressive antilympho-

cyte serum at the time of transplantation. Our studies of the effect of organ culture on thyroid allograft immunogenicity2 showed that tissue immunogenicity can be eliminated by organ culture for 3-4 weeks in an atmosphere Davie JM, Finke EH. Prolongation of islet allograft survival folin vitro culture (24°C) and a single injection of ALS. Science 1979; 204: 312-13. 1. Lacy PE, Davie JM, Finke EN. Prolongation of islet allograft survival following in vitro culture (24°C) and a single injection of ALS. Science

9.

Lacy PE,

lowing

1979; 204: 312-13. 2.

The origin and mechanism of the tion. Immunol Rev 1977; 35: 231-62.

Lafferty KJ, Woolnough J.

allograft

reac-