973

a-D-glucose-1-phosphate and lysergic-acid diethyl-amide had no effect on rheumatoid arthritis or on thetuberculin reaction in man.The possibility is discussed that the means by which

cortisone diminishes the tuberculin reaction in the

guineapig and in.man may differ.We gratefully acknowledge the cooperation of the patients

taking part in this study. We are indebted to the NuffieldFoundation for their generosity. in making, the grant whichenabled these studies to be undertaken ; to Merok & Co.for their gift of cortisone to the joint committee of the NuffieldFoundation and the Medical Research Council, part of whichwas used in these studies, and to this same committee forA.C.T.H.; to Dr. H. H. Green, of the Ministry of Agricultureveterinary research laboratories, for the gift of P.P.D.; and toDr. H. M. Sinclair for his advice on ascorbic-acid estima-tions. We also thank ’Roche Products Ltd. for giving usglucose-1-phosphate, and Sandoz Products Ltd. for givingus lysergic acid. Finally we are indebted to Prof. G. W.Pickering for his encouragement and to Dr. D. A. Long formuch helpful discussion and for suggesting the trial of

glucose-I-phosphate and lysergic acid.

REFERENCES

Cornforth, J. W., Long, D. A. (1952) Lancet, i, 950.Fisher, N., Harington, C., Long, D. A. (1951) Ibid, ii, 522.Järvinen, K. A. J. (1951) Brit. med. J. ii, 1377.Leahy, R. H., Morgan, H. R. (1952) Abstr. J. clin. Invest. 31, 646.Long, D. A. (1952) Personal communication.

— Miles, A. A. (1950) Lancet, i, 492.— — Perry, W. L. M. (1951a) Ibid, i, 1085.— — — (1951b) Ibid, ii, 902.

Lovell, R. R. H., Goodman, H. C., Hudson, B., Armitage, P.,Pickering, G. W. (1953) Clin. Sci. 12, 41.

Rinkel, M., DeShon, H. J., Hyde, R. W., Solomon, H. C. (1952)Amer. J. Psychiat. 108, 572.

Roe, J. H., Kuether, C. A. (1943) J. biol. Chem. 147, 399.

CONTROL OF BLOOD-PRESSURE IN

OPERATION FOR PHÆOCHROMOCYTOMA

CHARLES C. COBBB.A., B.M. Oxfd, M.R.C.P.

PHYSICIAN

JEAN HALLM.B. Lond., D.A.

ANÆSTHETIST

R. A. HALLCh.M. Leeds, F.R.C.S.

SURGEON

COUNTY HOSPITAL, YORK

THOUGH phaeochromocytoma is rare it is beingdiagnosed more often, and will become increasinglyimportant if it can be shown to be amenable to safe

surgical removal. Complete and lasting cure of an

otherwise fatal disease is thus possible.The subject has been reviewed by Mac Keith (1944)

and Walton (1950) in this country, Burrage andHalsted (1948) and Cahill and Aranow (1949) in America,and others.Our purpose in reporting this case is to record the

successful control by benzodioxane (’ Piperoxane ’)of the rise in blood-pressure on handling the tumour,and by l-noradrenaline (1-artereiiol) of the fall of pressureafter its removal.

CASE-RECORD

A married woman, aged 30, was first seen at the medicaloutpatient clinic in April, 1951. She complained that forthe previous six months she had had headaches, usuallyvertical and- coming on towards evening. She also hadattacks of faintness with loss of power in the limbs and withtingling in the hands. After three or four minutes thepower would return to the limbs, with simultaneous flushingof the face and pulsation in the head. These attacks hadbecome increasingly frequent, occurring almost every otherday. The headaches had, however, improved a little. Asthe attacks became stereotyped, she noticed in additionpallor of the face, arms, and hands ; palpitation ; achingin the shoulders ; cramping abdominal pain ; nausea ;salivation; and sweating. Between the attacks she feltperfectly well, though she had recently tended to constipationard increased nocturnal frequency of micturition. Herpast history was irrelevant, but she had had infective hepatitis

’within the previous year and had made a good recovery.She had two children, aged 71/2 years and 18 months ;pregnancy and parturition were normal on both occasions.On examination the patient appeared healthy. No

abnormality was found on physical examination except apalpable right kidney, the significance of which at the timewas doubtful. The patient had, however, hypertension(170/120 mm. Hg when sitting). Subsequent examinationproved that this was persistent, but the blood-pressure waslabile and showed changes according to posture-e.g., lying225/125 mm. Hg; standing 160/100 mm. Hg. The patientwas admitted to hospital twice for investigation, but thedescribed attacks were not observed. Nothing abnormal wasfound in the urine. Intravenous and retrograde pyelographysuggested a deformity of the right renal pelvis, but the changeswere minimal. The basal metabolic rate was + 15%.The benzodioxane test was made on two occasions by two

different observers ; the method used was that described byGoldenberg et al. (1947). On the first occasion the testwas considered positive, but on the second inconclusive.In the absence of a more clear-cut diagnosis it was decided

to explore the right suprarenal area, and, if no tumour werefound, to do the right side of a bilateral thoracolumbar

sympathectomy.Operation (Dec. 3; 1951).-Premedication with ’ Ornnopon

gr. 1/3 and scopolamine gr. 11150 was given. Anaesthesiawas induced one and a half hours later with 20 ml. of 5%thiopentone and 15 mg. of d-tubocurarine chloride intra-

venously, and an orotracheal tube was passed. Anaestheaiawas maintained with nitrous oxide and oxygen ; respira-tion was assisted by manual compression of the rebreathingbag for the first seven minutes. To facilitate the rapidadministration of benzodioxane and noradrenaline an

intravenous-drip infusion was set up.The right suprarenal area was exposed extraperitoneally

through the bed of the resected eleventh rib (Fey’s incision),and a tumour was found largely taking the place of thesuprarenal gland. The blood-pressure, which had been160/90 mm. Hg before induction, rose immediately thetumour was palpated very gently, but was reduced at onceby an injection of benzodioxane (piperoxane) 15 mg. into theintravenous tubing close to the vein (fig. 1).Removal was started by ligaturing all vessels at a distance

from the gland, without manipulating it. When it became

necessary to lift one pole from its bed to reach the vesselson the posterior aspect, there was a second rise in blood-pressure, which was only halted by a further injection ofbenzodioxane 15 mg., and a third injection of 13 mg. wasnecessary to reduce it.The tumour was removed, leaving two small pieces of

apparently normal suprarenal tissue, which had been freedfrom it. The blood-pressure began to fall at once and wasallowed to do so until it reached 110/80 mm. Hg, when theintravenous bottle was exchanged for one to which had

previously been added noradrenaline (’Levophed’) 8 mg. perlitre. The rate of the drip was adjusted to deliver 8 {jt.g.a minute, and this raised the systolic pressure to about130 mm. Hg without materially altering the diastolic pressure.

Fig. I-Blood-pressure during operation. P<*emedication was givenbefore administration of thiopentone. -

974

Fig. 2-Postoperative blood-pressure.

The blood-pressure, which had been estimated as far aspossible every two minutes during the operation, was recordedat five-minute intervals thereafter for three hours, and

subsequently at longer intervals. For the first four and ahalf hours the same dosage of noradrenaline was continued ;but, as the pressure gradually rose, the dose was reducedto 2 t,g. a minute, and this substance was discontinued

altogether after a further eleven hours (fig. 2).Postoperatively the patient had a mild atelectasis, which

rapidly resolved, and she left hospital on the twelfth post-operative day. She was seen regularly until she left thedistrict after six months. At that time her blood-pressurehad stayed steady at about 130/90 mm. Hg since the operationand ten months after operation she reported that she remainedentirely free from symptoms.

Pathology.-The excised tissue consisted of a roundedtumour measuring 6 X 4 X 3 cm., across which was

stretched a thin layer of suprarenal tissue. The microscopicalappearances were typical of a chromaffin suprarenal tumour.LTnfortunately a biological assay was impossible.

DISCUSSION

The original diagnosis was made tentatively from thehistory of the characteristic attacks. Little supportwas gained from physical examination or from thedoubtful results of the pharmacological test. Despiteadmission to hospital no opportunity presented itselffor a reliable observer to witness a paroxysm and thereforeto detect any change in the blood-pressure. Tests which

depend on provoking an attack of hypertension wereconsidered unsafe. These included the histamine testof Roth and Kvale (1945), starvation, injection ofadrenaline, and pressure on the supposed site of the

tumour, although the latter procedure might have givenvaluable evidence of its presence and situation. Theinsufflation of air round the kidneys was deemed unsafe.Both false-positive and false-negative results of the

benzodioxane test have been published (Dana andCalkins 1949, Goldenberg and Aranow 1950, Wilson1950, Conley and Junkerman 1951, Soffer 1952, Tulloh1952). Goldenberg and Aranow (1950) mention the

possibility, in the case of false-negative results, that thedose of benzodioxane might be too small, and this mayexplain the different findings in the two tests in our case.The same considerations apply to the use of benzo-

dioxane during operation, and the dosage (15 mg.),which was calculated for our patient from the makers’table, need not necessarily be suitable for another person.This dose produced an immediate fall in the initialrise of pressure, but did not protect for more thanfive minutes against a further rise when the tumourwas handled. Repetition of the same dose becamenecessary during the subsequent fifteen minutes beforethe tumour was removed, and there did not appear tobe any cumulative action. We were impressed by theprompt rise of pressure on minimal handling of thetumour, indicating its high degree of activity.Swan (1951) and Pantridge and Burrows (1951)

used ’ Dibenamine’ to control excessive rise of blood-pressure, but the long action of this agent seems torender it less suitable than benzodioxane for use duringoperation.

Bartels and Cattell (1950) attribute, hypotension andcollapse after removal of the tumour to left ventricularfailure from excess of circulating adrenergic substances.but the satisfactory results obtained where noradrenalinehas been used in the hypotensive phase strongly supportthe generally accepted view that hypotension resultsfrom sudden deprivation of these substances (Swan1951, Pantridge and Burrows 1951).Cases have been recorded (Crowther 1951) in which

the hypotensive phase was treated with adrenalineinfusion. It seems to us that the side-actions of adrena.line, which are known to vary from patient to patient,may be undesirable. In particular, the rise of blood.pressure from adrenaline is obtained partly at leastby increase of cardiac output, and not necessarily bypure increase in the peripheral resistance. Though somepatients may respond satisfactorily to adrenaline,noradrenaline is theoretically the preferable agentbecause it probably constitutes the major part of theactive material of which the patient has been deprived(Golden berg and Aranow 1950, Crowther 1951, Pantridgeand Burrows 1951, Swan 1951).

SUMMARY

Phaeochromocytoma was successfully treated bysurgical removal.

v treated by

The blood-pressure was satisfactorily controlled bothduring and after operation by benzodioxane andnoradrenaline.

These agents may reduce the risks in treating thisdisorder.The levophed (l-noradrenaline) used in this case was

provided by Bayer Products Ltd. shortly before this drugbecame ordinarily available.

REFERENCES

Bartels, E. C., Cattell, R. B. (1950) Ann. Surg. 131, 903.Burrage, W. C., Halsted, J. A. (1948) Ann. intern. Med. 28, 838.Cahill, G. F., Aranow, H. jun. (1949) Ibid, 31, 389.Conley, J. E., Junkerman, C. L. (1951) J. Amer. med. Ass. 147, 921.Crowther, K. V. (1951) Brit. med. J. i, 445.Dana, G. W., Calkins, E. (1949) Bull. Johns Hopk. Hosp. 84, 283,Goldenberg, M., Aranow, H. jun. (1950) J. Amer. med. Ass. 143,

1139. &mdash; Snyder, C. H., Aranow, H. jun. (1947) Ibid, 135, 971.

Mac Keith, R. (1944) Brit. Heart J. 6, 1.Pantridge, J. F., Burrows, M. M. (1951) Brit. med. J. i, 448.Roth, G. M., Kvale, W. F. (1945) Amer. J. Sci. 210, 653.Soffer, A. (1952) J. Amer. med. Ass. 148, 538.Swan, H. J. C. (1951) Brit. med. J. i, 440.Tulloh, H. P. (1952) Ibid, i, 531.Walton, J. N. (1950) Lancet, i, 438.Wilson, G. M. (1950) Addendum to article by Prunty, F. T. G.,

Swan, H. J. C. Lancet, i, 759.

THE ADRENERGIC AMINES OF HUMANBLOOD

H. WEIL-MALHERBEM.D. Heidelberg, D.Sc. Durh.

DIRECTOR OF RESEARCH

A. D. BONEF.I.M.L.T.

CHIEF TECHNICIAN, RESEARCH DEPARTMENT

RUNWELL HOSPITAL, WICKFORD, ESSEX

A FLuo’RiMETBic method for the estimation ofadrenergic amines in plasma has recently been described(Weil-Malherbe and Bone 1952a), in which the amines arefirst isolated by adsorption on a column of alumina(Lund 1949) and then, after elution, treated withethylene diamine (Natelson et al. 1949) to form relativelystable fluorescent condensation products. The methodestimates the sum total of adrenaline and noradrenaline.It was, however, noticed at an early stage that thecondensation product formed from adrenaline diftetedin fluorescence from the noradrenaline derivative, thefluorescence of adrenaline being from yellow to orangeand that of noradrenaline green. We realised that thisdifference could be used as the basis of a differential