81

THE LANCET

High-dose FentanylSUPPLEMENTATION of general anaesthesia with in-

travenous narcotics has been practised for morethan 20 years, at first with pethidine2 and laterwith more powerful opiates, natural and synthetic.In this type of’balanced anaesthesia the aim is to

supplement the weak analgesic action of nitrousoxide/oxygen. The technique was introducedbecause of the flammability of diethyl ether anddissatisfaction with trichloroethylene as a supple-ment, but with the advent of halothane these

advantages seemed less important. In NorthAmerica the short-acting analgesic. alphaprodine(’Nisentil’) was a popular supplement to nitrousoxide.4 In the U.K., where alphaprodine is notavailable for clinical use, the choice has fallen

largely on another short-acting analgesic drug, fen-tanyl, which is 130-180 times (w/w) more potentthan morphine, and which in animals has few un-desirable cardiovascular effects.5 Fentanyl is oftencombined with droperidol, in the technique knownas neuroleptanæsthesia (N.L.A.)-the combinationof a neuroleptic with a potent analgesic to inducemental apathy, psychomotor inhibition, and physi-cal immobility.6 Nitrous oxide can be added to in-duce and maintain unconsciousness.7 The fact thatdroperidol and fentanyl are marketed by the samefirm and available in a mixture undoubtedly contri-butes to the popularity of their combined use.

Droperidol is not reliable as a hypnotic and with-out an analgesic it can cause motor restlessness.8 Itis not an intravenous anaesthetic, despite sometimesbeing indexed as such.9 Nevertheless, it is a valu-able drug on account of its ability to block alpha-adrenergic receptors,10 11 prevent vasoconstriction,and cause vasodilatation.The cardiovascular stability attributed to neuro-

lept techniques is partly due to this action of dro-peridol and the effects of the neuroplegic are oftenhard to distinguish from those of the analgesic. 12 13

1. Neff, W., Mayer, E. C., Perales, M. Calif. Med. 1947, 66, 67.2. Mushin, W. W., Rendell-Baker, L. Br. med. J. 1949, ii, 472.3. Dundee, J. W., Brown, S. S., Hamilton, R. C., McDowell, S. A. Anœsthesia,

1969, 24, 52.4. Foldes, F. F., Swerdlow, M., Siker, E. S. Narcotics and Narcotic Anta-

gonists. Springfield, Illinois, 1964.5 Liu, W-S., Bidwai, A. V., Stanley, T. H., Isern-Amaral, J. Anesth. Analg.

1976, 55, 168.6 Dobkin,A B., Pieloch, P. A. Int. Anesth. Clins, 1973, 11, 155.7 Laborit, H., Huguenard, P. Pratique dé l’Hibernotherapie en Chirurgie et

en Médecine Pans, 1954.8 Morrison, J. D., Clarke, R. S. J., Dundee, J. W. Br. J. Anœsth. 1970, 42,

730.9 Anesthestology, 1978 index.

10 Whitwam, J. G , Russell, W. J. ibid. 1971, 43, 581.11 Muldoon, S M., Janssens, W. J., Verbeuren, T. J., Vanhoutte, P. M. ibid.

1977, 49, 211.12 Morgan, M , Lumlev, J., Gillies, I. D. A. ibid. 1974, 46, 288.13. Dobkin, A B., Israel, J S., Byles, P. H Can. Anœsth. Soc. J. 1964, 11, 41.

Fentanyl does seem to have fewer adverse cardio-vascular effects than equivalent doses of other

opiates in man, 14-17 and very large doses are in-creasingly being given. 17-19 The normal adult doseis 1-2 µg/kg,20 from which recovery is usuallyprompt, but FLORENCE1’ has given initial doses of10-15 µg/kg, with increments as required. Shereports remarkable cardiovascular stability withthis technique in 28 patients undergoing elective oremergency reconstruction of the abdominal aorta,and she attributes this to suppression of the sym-pathoadrenal response to surgical stress by thepotent analgesic action of fentanyl, potentiated bythe mild adrenergic blocking effect of droperidol.Nor is stability limited to the cardiovascular sys-tem. HALL and associates, 19 using a total dose of 10µg/kg fentanyl as a supplement to thiopentone/nitrous oxide/relaxant, found less metabolic dis-turbance than in a comparable series supplementedwith 0.5-1.0% halothane: blood-glucose, plasma-cortisol, and plasma-growth-hormone rose in thehalothane group but not in the fentanyl group.These workers suggest that large doses of fentanyl,by inhibiting cortisol and growth-hormone re-

sponses, may greatly reduce the catabolic responseto trauma. The concept of stress-free anxsthesiawith large doses of fentanyl has been the subject ofa symposium,23 at which STANLEY and WEBSTER24recorded its efficacy as the sole anaesthetic agent inmitral-valve surgery.On the debit side, respiratory depression may

persist,25 sometimes for several hours,26 after use offentanyl during anaesthesia. Even thoughFLORENCE found no postoperative respiratorydepression after 50 µg/kg, in another series sherecorded a respiration rate of 6 per minute 5 hoursafter smaller doses17 and commented that high-dose fentanyl anaesthesia cannot be recommendedwithout the instant availability of expert staff. Res-piratory depression can be rapidly reversed bynaloxone, but this antagonist can cause psycho-motor agitation resembling an acute withdrawalstate.18 Even small doses of fentanyl cause respira-tory depression, and intracranial pressure rises, soit should be used with caution in patients with in-

14. Zauder, H. L., Del Guercio, L. R. M., Feins, N., Barton, N., Wollmann, S.Anesthesiology, 1965, 26, 206.

15. Prys-Roberts, C., Kelman, G. R. Br. J. Anœsth. 1967, 39, 134.16. Edmonds-Seal, J., Prys-Roberts, C. ibid. 1970, 42, I207.17. Florence, A. M. Anœsthesia, 1978, 33, 439.18. Freyc, E. Anœtsthesist, 1975, 24, 145.19. Hall, G. M., Young, C., Holdcroft, A., Alaghband-Zadeh, J. Anœsthesia,

1978, 33, 924.20. Epstein, B. S., Levy, M. L., Them, M. H., Coakley, C. S. Anesthes. Rev.

1975, 2, 24.21. Choneim, M. M., Mewaldt, S. P., Thatcher, J. W. Psychopharmacologia,

1975, 44, 61.22. Goroszeniuk, T., Whitwam, J. G., Morgan, M. Anœsthesia, 1977, 32, 209.23. Wood, C. (editor) Stress-free Anaesthesia. R. Soc. Med. int. Congr. Symp.

Ser. no. 3, 1978.24. Stanley, T. H., Webster, L. R., ibid. p. 27.25. Becker, L. D., Paulson, B. A., Miller, R. D., Severinghaus, J. W., Eger,

E. I. Anesthesiology, 1976, 44, 291.26. Adams, A. P., Pybus, D. A. Br. med. J. 1978, i, 278.

82

tracranial lesions.27 Lead-pipe rigidity of muscleshas been recorded with fentanyl as with other

opiates, but is not common.Potent synthetic analgesics have been adminis-

tered repeatedly to many thousands, perhaps evenmillions, of patients with chronic pain, with no sus-picion of harm to the liver. Because of its brevityof action, fentanyl is not likely to be used forchronic pain relief, but the chemically related com-pounds, pethidine, anileridine, and phenoperidinehave a clean bill. This safety record is cheering inview of INMAN and MUSHlN’S new analysis of

reports of jaundice after halothane, which seems toconfirm the risk of liver damage after repeat expo-sure to this very versatile anaesthetic agent. 28Hypersensitivity, another troublesome problem inclinical anæsthesia,-29 has not been reported withfentanyl and probably not with any form of neuro-leptanxsthesia. There is certainly an impetus toexplore the potential of analgesic supplementationof anaesthesia, and high-dose fentanyl is worthy offurther study. More detailed work on technique isneeded, with investigations on the role of physo-stigmine in reversal of its action,30 31 and othercombinations such as diazepam/pentazocine shouldnot be forgotten. Besides their possible advantagesto patients, non-volatile anxsthetic agents offer anattractive answer to operating-theatre pollution.

Radiotherapy for Chronic LymphaticLeukaemia

DAMESHEK’S description of chronic lymphaticleukaemia (C.L.L.) as an "accumulative disorder ofimmunologically incompetent lymphocytes"’ is stillvalid today, though we now recognise that the dis-ease has proliferative features as well. Moreover,the abnormal cells are not completely inert: the useof immunological markers shows that the greatmajority of cases are characterised by monoclonalpopulations of lymphocytes of B lineage,3 althoughT-cell C.L.L. also occurs. The accumulation of these

morphologically mature-looking lymphocytes grad-ually obliterates the normal lymphoreticularnetwork, with a blood and marrow lymphocytosis,lymphadenopathy, hepatosplenomegaly, and (even-tually) involvement of extralymphatic tissues.4 Thesource within the lymphoreticular system of thisabnormal clone probably varies, but once estab-

27. Miller, R., Tausk, H. C., Stark, D. C. C. Can. Anœsth. Soc. J. 1975, 22,502.

28. Inman, W. H. W., Mushin, W. W. Br. med. J. 1978, ii, 1455.29. Watkins, J., Ward, A. M. Adverse Responses to Intravenous Drugs. London,

1978.30. Brebner, J., Hadley, L. Can. Anœsth. Soc. J. 1977, 23, 547.31. Thompson, D. E. A. ibid. 1976, 23, 582.1. Dameshek, W. Blood, 1967, 29, 566.2. Theml, H. D., Love, R., Begemann, H. A. Rev Med. 1977, 28, 131.3. Brouet, J. C., Seligmann, M. Clins Hemat. 1977, 6, 169.4. Sweet, D. L., Golomb, H. M., Ultmana, J E. ibid. p. 185.

lished it leads to profound changes in lymphocytecirculations and in immunological homoeostasis, ofwhich hypoimmunoglobulinaemia and a propensityto autoimmune disorders are the most obviousclinical features.The kinetics of this abnormal lymphopoiesis,

and the severity of immune depression, differ fromone patient to another,6 and this helps to explainthe extremely variable natural history of the dis-order and the difficulties encountered in assessingthe relative merits of various therapies. Most stu-dies of c.L.L. report median survivals of from 3 to6 years from the start of therapy or the onset ofsymptoms,’ 8 though when survival proves to beshort, physical and laboratory findings at diagnosistend to be more abnormal than those in longer sur-vivors. RAI9 and RUNDLES10 have attempted a com-prehensive staging of the disease, based on a com-bination of clinical and laboratory data. Thus,patients who had only bone-marrow and blood

lymphocytosis were deemed to have stage-0 diseaseand those who also had lymphadenopathy, stage I;patients with stage-11 disease had, in addition, anenlarged spleen or liver, or both; while in stage III,anxmia was present, and stage-IV patients hadthrombocytopenia which was always an ominousfeature, irrespective of other clinical signs. BINETand his colleaguesll have proposed a slightly dif-ferent staging protocol which accords special sig-nificance to a group of patients with lymphocytosisand splenomegaly, in whom the disease is relativelybenign. Classifications of this type correlate wellwith prognosis:9 thus in RAI’S series, although themedian survival for the whole group was 71

months, for those with grade-III and grade-IV dis-ease it was only 19 months-considerably worsethan the survival of many patients with acute lym-phoblastic leukaemia.

The aims in the treatment of c.L.L. have, hith-erto, been control of the disease and its epipheno-mena rather than radical cure; indeed one view is

that, as in chronic myeloid leukaemia, survival is

little influenced by therapy. 12 " In some patientsdeath is due to immune deficiency-and immunedeficiency is rarely improved by palliative therapydesigned to reduce the mass of leukæmic cells.Since the introduction of chlorambucil and predni-solone over 20 years ago, radiotherapy has beenlargely relegated to a secondary role in the treat-ment of resistant splenomegaly, large nodal masses,or those producing obstructive symptoms.

5. Stryckmans, P. A., Debusscher, L., Collard, E. ibid. p. 1596. Lopez-Sandoval, R., Moayeri, H , Sokal, J. E Cancer Res. 1974, 34, 1467. Huguley, C. M. Yb Med. 1970, p. 317.8. Huguley, C. M. Cancer Treat. Rev. 1977, 4, 2619. Rai, K. R., Sawitsky, A , Cronkite, E. P., et al Blood, 1975, 46, 219

10. Rundles, R. W., Moore, J. O. Cancer, 1978,42, suppl p. 941.11. Binet, J. L., Leporrier, M., Dighiero, G., et al. Cancer, 1977, 40, 85512. Silver, R. T Semin. Hœmat. 1969, 6, 34413. Boggs, D. R., Sofferman, S. A., Wintrobe, M M., Cartwright, G. E Am. J

Med. 1966, 40, 243.