169

described as precipitating agents in accidental hypo-thermia of the elderly (British Medical Journal 1964). Oneof our patients (no. 7) received chlorpromazine the daybefore she was admitted to hospital with accidental

hypothermia of the elderly. She shows the same patternof abnormalities of temperature regulation as the otherpatients (table 11). This may suggest that chlorpromazineprecipitated and accelerated the development of hypo-thermia in this susceptible elderly person.The evidence suggests a lesion of the central nervous

structures which regulate deep body temperature. On thisview these patients approach the poikilothermic state

found in some infants, particularly premature ones

(Mestyan 1962). In the child the temperature-regulatingmechanisms are immature, and in the elderly patientswhom we examined, they are damaged. The report of theRoyal College of Physicians (1966) concluded that the onlyclear xtiological association of accidental hypothermia waswith cold weather. In all the subjects we examined,previous accidental hypothermia of the elderly was

associated with defective temperature-regulating mechan-isms against cold. It is most likely that the derangementis a cause rather than an effect of accidental hypothermiaof the elderly because there is no suggestion that iatrogenichypothermia has such sequela:. Thus the astiologicalfactor in the environment is cold, in the subject it is oftena lesion impairing temperature regulation. This impair-ment which renders the survivors liable to hypothermiahas persisted for periods of up to three years. Con-

sequently they are still at risk from accidental hypothermiaif they are again exposed to moderate cold. Three of thesurvivors in the present series have had more than one

episode. Patients who have recovered from accidental

hypothermia of the elderly should therefore be offeredaftercare designed to reduce the risk of hypothermia,it should be recognised early if it recurs, and treatedbefore the body temperature drops to dangerously lowlevels.

We thank Prof. W. Ritchie Russell for his encouragement. Oneof us (A. L. M.) receives a grant from the National Fund for Researchinto Poliomyelitis and other Crippling Diseases and one (J. L. C.)holds a Rhodes Scholarship at Oxford University.Requests for reprints should be addressed to J. M. K. S., Depart-

ment of Neurology, Radcliffe Infirmary, Oxford.

REFERENCES

Adolph, E. F., Molnar, G. W. (1946) Am. J. Physiol. 146, 507.Barcroft, H., Swan, H. J. C. (1953) Sympathetic Control of Human Blood

Vessels. London.British Medical Association Memorandum (1964) Br. med. J. ii, 1255.British Medical Journal (1964) i, 4.Burton, A. C. (1934) J. Nutr. 7, 497.

— Edholm, O. G. (1955) Man in a Cold Environment. London.— Snyder, R. A., Leach, W. G. (1955) J. appl. Physiol. 8, 269.

Cooper, K. E., Cranston, W. I., Snell, E. S. (1964) ibid. 19, 1032.— Johnson, R. H., Spalding, J. M. K. (1964) J. Physiol., Lond. 174,

46.Hardy, J. D., Stoll, A. M. (1954) Meth. med. Res. 6, 85.Hatfield, H. S. (1950) J. Physiol., Lond. 111, 10P.Howell, T. H. (1948) Lancet, i, 517.Iampietro, P. F., Bass, D. E., Buskirk, E. R. (1958) J. appl. Physiol. 12,

351.Johnson, R. H., Smith, A. C., Spalding, J. M. K. (1963) J. Physiol., Lond.

169, 584.— Spalding, J. M. K. (1966) ibid. 184, 733.

Keele, C. A., Neil, E. (1965) in Samson Wright’s Applied Physiology.London.

Kerslake, D. McK., Cooper, K. E. (1950) Clin. Sci. 9, 31.Krag, C. L., Kountz, W. B. (1950) J. Geront. 5, 227.Martsenkowski, B. I., Zhorova, K. H. S. (1936) Acta med. scand. 90, 582.Mestyan, J. (1962) Lancet, i, 690.Royal College of Physicians of London (1966) Report of Committee on

Accidental Hypothermia.Worster, R. D., McCook, R. D., Rendall, W. C. (1966) J. appl. Physiol.

21, 617.

HEPATIC COMA DUE TO

ACUTE HEPATIC NECROSIS TREATED BY

EXCHANGE BLOOD-TRANSFUSION

E. A. JONESM.B., B.Sc. Birm., M.R.C.P.HON. ASSISTANT LECTURER

D. CLAINM.B. Cape Town, M.R.C.P.

RESEARCH FELLOW

H. M. CLINKM.B. Lond.

LECTURER IN HÆMATOLOGY

M. MACGILLIVRAYM.B. Lond., B.Sc. W’srand, M.R.C.P.

CONSULTANT PHYSICIAN IN ELECTROENCEPHALOGRAPHY

SHEILA SHERLOCKM.D. Edin., F.R.C.P., F.R.C.P.E., F.A.C.P. (Hon.)

PROFESSOR OF MEDICINE

From the Departments of Medicine and Electroencephalography,Royal Free Hospital, London W.C.1

Summary Seven patients in hepatic coma, due toacute hepatic necrosis, have been treated

with exchange transfusions using 5-58 litres of fresh bloodper patient. In four patients the acute hepatic necrosis wasdue to virus hepatitis, in two it followed multiple exposuresto halothane, and in one it was associated with therapywith a monoamine-oxidase inhibitor (phenelzine). Threepatients showed striking improvement in the level ofconsciousness and in two of these and one other there was

unequivocal improvement in the electroencephalogram.Three patients had severe oliguria. All seven patientsultimately died. Initial improvement in the prothrombin-time was not always maintained. Thrombocytopenia wasprogressive. A severe bleeding tendency developed orpersisted in all patients. Necropsy in six patients showedsevere massive hepatic necrosis with distortion of thehepatic architecture to such a degree that if survival hadensued macronodular cirrhosis would have been inevitable.

Introduction

THE mortality-rate for hepatic coma developing duringthe course of acute hepatic necrosis is extremely highdespite the usual therapy for hepatic coma and cortico-steroids (Katz et al. 1962, McDonald and de la Harpe 1963,Cook and Sherlock 1965). However, the liver has such anenormous capacity for regeneration that, in patients whosurvive, both liver-cell function and hepatic architecturemay return to normal. All such lesions should thereforebe regarded as potentially reversible. It follows that

therapy should be directed towards providing hepaticsupport during the period when the patient is essentiallywithout a liver, so allowing time for regeneration. Methodswhich are being assessed include exchange blood-transfusions (Berger et al. 1966, Trey et al. 1966,Saunders 1967), cross-circulation with human volunteers(Burnell et al. 1965), and perfusion of the patient’s bloodthrough the cooled isolated pig’s liver (Eiseman et al.1965, Eiseman 1966). We describe here results of

exchange blood-transfusion in seven patients in hepaticcoma due to acute hepatic necrosis.

Patients and MethodsThe four female and three male patients were aged from

56 to 68 years (table i). Two patients (nos. 4 and 6) had a historyof recent, multiple, anaesthesias using halothane and one (no. 2)had taken a monoamine-oxidase inhibitor, phenelzine, imme-diately before the development of jaundice. In the other fourcases (nos. 1, 3, 5, and 7) virus hepatitis was diagnosed byexcluding other possible causes of acute hepatic necrosis.

170

TABLE I-PATIENTS STUDIED AND SERUM BIOCHEMICAL VALUES BEFORE TREATMENT

The depth of coma has been graded clinically from i to iv.Grade I equals confused, grade n, drowsy, grade ill, stupor,and grade iv, coma. At the time of starting treatment all thepatients were in deep coma (grade iv) except no. 4 who wasstuporose (grade 111). The duration of coma had varied fromto 4 days.

Electroencephalograms (E.E.G.) were graded from 1 to 6

(table 11). In the six patients studied the E.E.G. grade wasinitially between 3 and 5.The serum bilirubin, aspartate transaminase, albumin, urea,

glucose, potassium, chloride, and bicarbonate were estimatedby standard methods. Arterial blood Pc02, and pH, weremeasured using a Severinghaus PC02 electrode and E.I.L. glasscapillary pH meter. In the patients treated the serum-bilirubininitially ranged from 3-9 to 34 mg. per 100 ml., serum-aspartate-transaminase from 30 to 570 i.u. per litre, and the serum-

TABLE II-E.E.G. GRADES

albumin from 2-5 to 4 g. per 100 ml. Five patients hadhypokalaemia (nos. 1, 3, 4, 5, and 6) and one patient (no. 3) washypoglycwmic. In three patients (nos. 3, 4, and 7) the arterialblood pH varied from 7-48 to 7.62 and the Pc02 ranged from20 to 31 mm. Hg.Two patients were oliguric (nos. 3 and 7) with daily urine

volumes less than 400 ml. One patient (no. 2)- had prerenalazotmmia due to draining of ascites through a recent laparotomyscar: serum-sodium was 100 mEq. per litre, serum-chloride77 mEq. per litre, and serum-bicarbonate was 25 mEq. per litre.Three patients (nos. 1, 4, and 7) showed purpura. The

one-stage (Quick) prothrombin-time was prolonged in all casesfrom 23 to 330 seconds (control 12-14 seconds). The platelet-counts were at least 100,000 per c.mm.TreatmentThe standard regimen included purgation with magnesium

sulphate, complete dietary protein withdrawal, intravenous10-20% dextrose, correction of hypokaloemia, and neomycinelixir by nasogastric tube (in adults 1 g. 4-hourly). Vitamin Kl10 mg. intramuscularly daily was given routinely. Five patients(nos. 1, 3, 5, 6, and 7) were given corticosteroids in dosesequivalent to hydrocortisone 200-400 mg. a day in adults and150 mg. in a child. Six patients (nos. 1, 2, 4, 5, 6, and 7) weregiven broad-spectrum antibiotics systemically. One patient(no. 6) with hypoalbuminaemia, received a total of 100 g.salt-free albumin intravenously.Exchange blood-transfusions were performed through

Seldinger polyethylene catheters. One catheter was insertedinto the superior vena cava via the median antecubital vein andthe other into the superior vena cava through a femoral vein.

The position of the tip of each catheter was checked radio-graphically. Fresh (drawn within 24 hours), heparinised wholeblood was used. Blood was infused through one catheter andwithdrawn through the other simultaneously. The rates ofinflow and outflow were augmented and regulated by means oftwo Watson-Marlow pumps. In adult patients, 3-9 litres ofblood were exchanged in any one day. It has been estimatedthat exchanging 5-5 litres in an adult man results in the replace-ment of about 80% of the blood-volume (Berger et al. 1966).The central (right atrial) venous pressure was monitored usinga Baxter central-venous-pressure monometer. A completeexchange transfusion took from 1 to 3 hours. At the end of theexchange procedure the clotting-time was corrected to thepre-exchange value with intravenous protamine sulphate.

Results

Between two and fifteen exchanges were performed oneach patient. The total amount of blood exchanged variedbetween 5 and 58 litres per patient. All the patients died.

Patient no. 1, a child, regained consciousness the dayafter starting exchange transfusions. He was able to talkand to recognise people (grade i). In two other patients(nos. 4 and 6) the level of consciousness improved to theextent that they became able to answer simple questionsand to obey simple commands (grade 11). In all threecases the clinical improvement lasted less than 3 days.Two other patients (nos. 2 and 3) became transientlylighter to the extent that they opened their eyes to

command (grade 111). In the remaining two patients(nos. 5 and 7) there was no detectable improvement in thelevel of consciousness. The E.E.G. grade unequivocallyimproved in three patients (nos. 1, 2, and 6). The leastabnormal E.E.G. achieved was grade 2 (no. 2). Clinicaldepth of coma showed poor correlation with the E.E.G.grade.The serum-bilirubin usually fell briskly during the

exchange transfusion, to values about a third lower thanbefore treatment. During the next 24 hours it rose to thepre-exchange value.

Five patients (nos. 2, 3, 4, 6, and 7) became azotaemic.The two patients (nos. 3 and 7) with initial oliguria showedno improvement in renal function and the blood-urea roseprogressively. Patient no. 2, with pre-renal azotaemia, peri-pheral vasoconstriction, hypotension, and haemoconcen-tration, was given an infusion of hypertonic saline solutionbefore exchange. Clinical and biochemical improvementensued, so that by the third day the blood-urea had fallenfrom 134 to 90 mg. per 100 ml. Oliguria subsequentlydeveloped and the blood-urea rose progressively.

After vitamin Kl and the initial exchange transfusionall patients showed decreases in prothrombin-time. How-ever, in four patients (nos. 1, 3, 4, and 7) the prothrombin-time subsequently increased in spite of continuingexchanges. One patient (no. 5) died soon afterwards. Inthe other two (nos. 2 and 6) the improvement in pro-

171

TABLE III-THE EFFECT OF EXCHANGE TRANSFUSIONS

thrombin-time was maintained. In patient no. 1 the

prothrombin-time became unrecordable due to the

development of a circulating anticoagulant. In all patientsthe platelet-count fell and levels as low as 20,000 per c.mm.were recorded. In patient no. 1, one of the three patientswith purpura, the haemorrhagic diathesis did not progressbut in the other two (nos. 4 and 7) huge hasmatomasdeveloped in relation to the Seldinger intravascularcatheters. In patient no. 4 hypotension developed andpersisted. A total of 12 units (pints) of fresh blood wastransfused and surgical intervention was necessary to stopthe haemorrhage into the tissues. In patient no. 7 massivegastrointestinal haemorrhage developed terminally. Twoothers, without purpura on admission (nos. 3 and 6)developed widespread ecchymoses during treatment.

Sternal-marrow biopsy was performed in three patients,and in each instance the specimen showed erythroid andmegakaryocytic hyperplasia.One patient (no. 1) developed a bacteraemia, a Klebsiella

being isolated from the blood 24 hours after startingexchange transfusion.Four patients (nos. 3, 4, 6, and 7) were alkalotic. The

mean arterial blood pH was 7-62, 7-51, 7-49, and 7-48respectively. The PC02 varied between 18 and 37 mm. Hg.In five instances the arterial pH was measured before andimmediately after an exchange, there being a mean fall of0-084.The duration of survival after the start of therapy varied

between a half and 16 days. All the patients died of liverfailure, in two (nos. 4 and 6) with complicating broncho-pneumonia, in five (nos. 2, 3, 4, 6, and 7) with azotaemia,in three (nos. 2, 3, and 7) with oliguria, and in one (no. 7)with massive gastrointestinal haemorrhage.

In four patients (nos. 3, 4, 6, and 7) the weight of theliver at necropsy was reduced, in two (nos. 3 and 4) to verylow levels. At necropsy, liver histology revealed, in 6cases, evidence of recent gross necrosis of liver cells anddistortion of hepatic architecture with condensation ofreticulin. Some surviving liver cells were present andthere was some evidence of regeneration.Illustrative Case-report (Case 6)

This 66-year-old retired sewage worker was in good healthuntil, on Dec. 12, 1966, acute retention of urine developed andon Dec. 14 he underwent a retropubic prostatectomy. Twounits of blood were transfused and halothane was administered.Postoperatively he was febrile. On the third day mild jaundicewas noticed, the serum-bilirubin being 2-2 mg. per 100 ml.The fever subsided on the fourth day. On Dec. 28 pyrexiarecurred. At this time the serum-bilirubin was 0-9 mg. per100 ml. and the serum-glutamic-pyruvic-transaminase (S.G.P.T.)was 14 I.U. per litre. Staphylococcus aureus was isolated fromthe operation wound, urine, and sputum. Cloxacillin was givenand the pyrexia subsided. Urinary retention persisted and onJan. 10, 1967, the patient was cystoscoped under halothane

anaesthesia. 5 days later he was jaundiced and next day the totalwhite-cell count was 21,000 per c.mm. of which 65% werepolymorphs. On Jan. 17 the serum-bilirubin was 11-2 mg. per100 ml. and the S.G.P.T. was 675 i.u. per litre. On Jan. 19 hebecame drowsy and uncooperative and on the next day he wastransferred to the Royal Free Hospital.On examination the patient was deeply jaundiced with

striking fetor hepaticus. He was comatose (grade iv) andrestless. Hepatic dullness was reduced and the spleen was notpalpable. There was slight sacral oedema. Purpura was absent.Besides the standard treatment for hepatic coma, the patientwas given hydrocortisone 400 mg. daily and parenteral anti-biotics. Daily exchange blood-transfusions were performed(see figure). The central venous pressure remained normalthroughout. The first eight exchanges were not associated withany appreciable improvement in the level of consciousness andthe E.E.G. grade remained between 4 and 6. After the ninthexchange he responded to painful stimuli. After twelve

Case 6: fulminant hepatitis after multiple halothane anaestheticstreated by exchange-transfusing 116 units (pints) blood in 15 days.The depth of coma and E.E.G. showed improvement from the 8th

to 1.3th day and then deteriorated. Blood-urea increased. Serum-bilirubin fell after the 7th day but rose again after the 12th. Therewas a progressive thrombocytopenia. Prothrombin-time was notgreatly prolonged. Patient died on day 16.

172

exchanges the patient was much lighter, and able to answersimple questions, although the plantar responses were stillextensor. The E.E.G. had improved from grade 4 to betweengrades 2 and 3. The serum-bilirubin fluctuated, falling notablywhen the volume of blood exchanged was increased from 3 to 5litres daily. Blood-urea rose but urine volume remained withinnormal limits. The platelet-count fell progressively. Theprolonged prothrombin-time was partially reduced and thisimprovement was maintained. Clinical improvement was

transitory. On the fourteenth day widespread ecchymoses andclinical and radiological signs of bronchopneumonia appeared.He again became comatose and the E.E.G. grade deteriorated.Increasing tachypnoea and hypotension developed and he diedon the sixteenth day after admission.Necropsy revealed a necrotising tracheobronchitis, bilateral

bronchopneumonia (from which Proteus was isolated), acutegastric erosions, and two large black ulcers in the duodenum.The liver was reduced in size and its consistency was soft. Thecut surface revealed small lobules and accentuation of the lobulepattern by deep red centrolobular areas. Histology showed thefeatures of massive hepatic necrosis.

Discussion

The purpose of exchange blood-transfusion is to providea temporary hepatic support for a patient with potentiallyreversible liver failure. This form of treatment has no

place in the management of hepatic coma complicatingirreversible chronic hepatocellular disease, such as

cirrhosis.

Trey et al. (1966), from Cape Town, reported recoveryof consciousness after exchange transfusion in seven

patients in hepatic coma due to acute hepatitis. Two diedlater. Five of the patients were children and none hadoliguria. Berger et al. (1966), from Boston, reportedrecovery after exchange transfusions of one adult in

hepatic coma due to acute hepatitis. Of our seven patientsthree showed a striking improvement in the level ofconsciousness and two of these and one other showed anunequivocal improvement in the E.E.G. All seven patientsdied. Only one was a child and he showed the moststriking improvement in the level of consciousness.Hepatic coma might be more easily reversible in childrenthan adults with or without the use of exchange blood-transfusions, perhaps because of better underlying cerebralfunction. Exchange transfusion may also be more effectivein the child who has a smaller blood-volume. The hepaticchanges in our patients were probably more severe than inthose treated by Trey et al. (1966). Moreover, three hadsevere oliguria. On the whole, the amounts of bloodexchanged were comparable to, and in the child definitelygreater than, those exchanged in the Cape Town andBoston patients. Even if our patients had survived,necropsy showed such severe distortion of hepatic archi-tecture that a macronodular cirrhosis would have beeninevitable. The provision of such large volumes of freshblood constituted considerable demands on hsematologyservices. If the patient’s condition does not improveappreciably after a few exchanges (perhaps two or three)the underlying disease may be of such severity that furtherexchanges are unlikely to be beneficial.

Prothrombin-time improved with exchange transfusionsbut this was usually not maintained. A significanthaemorrhagic diathesis was not always prevented bycontinuing exchanges. Platelet-count fell appreciably andthe thrombocytopenia must have contributed to the

bleeding tendency. The cause of the thrombocytopenia isnot clear: dilution of platelets by the exchanged blood, theeffect of heparin on platelets, or possible development of

platelet antibodies must be considered. Platelet infusions

may be a necessary adjunct to exchange transfusions.The serum-bilirubin fell significantly, subsequent rises

were presumably due to diffusion of interstitial bilirubininto the vascular compartment. Hypoglycsemia was

observed in only one patient, but has been noted byDr. S. J. Saunders and co-workers in Cape Town and mayprove resistant to therapy (Saunders 1967). The serum-albumin should also be maintained at normal or near-normal levels by infusions of salt-free human albumin.If this is not done appreciable ascites may develop duringrecovery (Saunders 1967).Three patients developed severe oliguria: and in such

patients this usually indicates a fatal outcome (Hecker andSherlock 1956). It constituted an additional factor impair-ing the level of consciousness and the E.E.G. grade.Concomitant peritoneal dialysis might have been beneficialin these patients, but haemodialysis alone has not provedeffective in the treatment of hepatic coma (Sherlock 1961).Exchange transfusions effectively dilute cellular and pro-tein elements of the blood whereas dialysis may result indiluting any diffusable extracellular substances which maybe present in excess. The apparent greater effectivenessof exchange transfusion over dialysis suggests that a majorfactor responsible for hepatic coma may be protein boundand non-dialysable.Exchange blood-transfusion is simple and does not

require elaborate technique. Since the nature of thebiochemical disturbance in hepatic coma remains un-certain the rationale cannot be precisely defined, but anyimprovement may result from either the washing out of" toxic " substances in the blood or from addition ofdeficient factors to the circulation. Such factors might bepoisoning the brain or inhibiting hepatic regeneration.The main complications seem to be haematoma formationin relation to intravascular catheters, and sepsis. Furtherevaluation of the efficacy and the indications must awaitmore experience. Trey et al. (1966) consider that exchangetransfusion should be used in cases of acute hepaticnecrosis where there is a rising serum-bilirubin associatedwith clinical deterioration. If exchanges are performedearlier, inevitably a greater proportion of those treatedwould have recovered spontaneously. The clinical courseof acute hepatic necrosis, whatever the treatment, is veryvariable. One patient (treated by standard measures)recovered after 7 weeks of coma (McDonald and de laHarpe 1963). A definitive appraisal of the value of thistechnique may have to wait results of a controlled trial.This may have to be world-wide since the number ofpatients with acute hepatic necrosis is few.We thank the Ingram Fund for financial support of D. C.; the

R. Franklin Carter Memorial Fund for help with technical assistance;the Medical Research Council for financial support; and the staff ofthe chemical pathology and haematology departments for their help.

Requests for reprints should be addressed to S. S.REFERENCES

Berger, R. L., Liversage, R. M., Chalmers, T. C., Graham, J. H.,McGoldrick, D. M., Stohlman, F. (1966) New Engl. J. Med. 274, 497.

Burnell, J. M., Thomas, E. D., Ansell, J. S., Cross, H. E., Dillard, D. H.,Epstein, R. B., Eschback, J. W., Hogan, R., Hutchings, R. H., Motulsky,A., Ormsby, J. W., Poffenbarger, P., Scribner, B. H., Volwiler, W.(1965) Am. J. Med. 38, 832.

Cook, G. C., Sherlock, S. (1965) Lancet, i, 175.Eiseman, B. (1966) Ann. R. Coll. Surg. 38, 329.- Liem, D. S., Raffucci, F. (1965) Ann. Surg. 162, 329.

Hecker, R., Sherlock, S. (1956) Lancet, ii, 1121.Katz, R., Velasco, M., Klinger, J., Alessandri, H. (1962) Gastroenterology,

42, 258.McDonald, R., de la Harpe, P. L. (1963) J. Pediat. 63, 916.Saunders, S. J. (1967) Colston Papers: Liver diseases. Oxford (in the press).Sherlock, S. (1961) Gastroenterology, 41, 1.Trey, C., Burns, D. G., Saunders, S. J. (1966) New Engl. J. Med. 274, 473.