Informed consent: how informed?

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a candidate for implantation and the complexities ofsurgery in young children. There is additional

uncertainty about the effects of growth on the

long-term fate of the implant. Luxford et al8reportedthe outcome of implantation in a 2-year-oldprelingually deaf child. Her behaviour improved afterimplantation and she was able to produce a few moreintelligible words.With respect to implantation in elderly people,

Horn et al9 reported a successful outcome in patientsover 65 years. The results of their survey suggest thatthis group did just as well as younger adults.Thus, cochlear implants are now established as a

recognised treatment for profound deafness and manymore deaf people could benefit from them. In the UKthe Government has agreed to fund implantationwithin the National Health Service; previously suchoperations had been financed by charitable donations.The existing implantation centres are to be fundedand several additional centres are being establishedaround the country. In other European countries andin North America, cochlear implantation has beenwell established for several years.

1. Editorial. Cochlear implantation for the profoundly deaf. Lancet 1988; i:686-87.

2. Gantz BJ, Tyler RS, Knutson JF, et al. Evaluation of 5 different cochlearimplant designs: audiologic assessment and predictors of performance.Laryngoscope 1988; 98: 1100-06.

3. Wilson BS, Finley CC, Lawson DT, Wolford RD, Eddington D,Rabinowitz WM. Better speech recognition with cochlear implants.Nature 1991; 352: 236-38.

4. Cohen ML, Hoffman RA, Stronschen M. Medical or surgicalcomplications related to the Nucleus multichannel cochlear implant.Ann Otol Rhinol Laryngol 1988; 97 (suppl 135): 8-13.

5. Webb RL, Lenhardt E, Clark GM, et al. Surgical complications with thecochlear multiple-channel intracochlear implant. Ann Otol RhinolLaryngol 1991; 100: 131-36.

6. Balkany T, Gantz B, Nadol JB. Multichannel cochlear implants inpartially ossified cochleas. Ann Otol Rhinol Laryngol 1988; 97 (suppl135): 3-7.

7. McCormick B. Paediatric cochlear implantation in the UK-a delayedjourney on a well marked route. Br J Audiol 1991; 25: 145-49.

8. Luxford WM, House WF, Hough JVD, et al. Experiences with theNucleus multichannel cochlear implant in three young children. AnnOtol Rhinol Laryngol 1988; 97 (suppl 135): 14-16.

9. Horn K, McMahon NB, Lewis JS, et al. Functional use of the Nucleus22-channel cochlear implant in the elderly. Laryngoscope 1991; 101:284-88.

Informed consent: how informed?

Most activities carried out by doctors have a simplebenevolent aim, even if the means of achieving it maybe tortuous and the outcome sometimes questionable.Medical research shares this aim with one vitaldifference-the patient who participates in researchmay not benefit personally and may beinconvenienced or even harmed. If there are rewardsto be reaped others may therefore reap them later.What motivates patients to participate in research?For some, participation is a purely philanthropicgesture; other reasons include direct financialinducements, a desire to oblige the doctor, or the hopeof obtaining the latest treatment. For researchers thefirst motive is the ideal, but in the enterprise society

various inducements are assuming greaterimportance.To avoid harming the participants, there have to be

constraints-eg, ethical committee review. Anotherpowerful constraint is telling the patient what he isvolunteering to undergo. The Nuremberg WarCrimes judges laid down ten basic principles, of whichthe first was that voluntary consent of the subject wasessential. This consent requires that the subjectshould have sufficient knowledge and comprehensionof what is proposed for him to make an

"understanding and enlightened decision".

Knowledge includes understanding the nature,purpose, and methods of the study, and the possibleeffects on the subject. The Declaration of Helsinki2re-emphasised these fundamental obligations on

medical researchers. Like other self-evident truths,the need for informed consent has not always beenuniversally recognised, even after the Nurembergjudges stated it so plainly. The columns of the Lancetbear witness to "research by fraud"3 and researchverging on "common assault",4 in which patientsparticipated in pure research disguised as clinical

investigation or treatment. Pappworth,s 5 in hiscelebrated polemic, described dental extractions inwhich cardiac catheterisation was carried out

unknown to the patient. It is difficult not to

sympathise with his conclusion that there was afraudulent element in this research. Even more

questionable was the attitude of the cardiologist withwhom this work was discussed-he felt that it wouldbe sufficient, to secure their consent, to tell patientsthat a small sample of blood was to be removed.

Such happenings are far removed from the

guidelines produced for the modem generation ofclinical researchers.6,7 There are two reasons for amore enlightened approach. First, cynical deceptionseldom survives exposure even before formalmechanisms to correct abuses have been established.For this reason autocrats, whether medical or political,are well advised to avoid too much media exposure.Secondly and more creditably, medical practice hasbeen increasingly concerned with respect for patientsas autonomous beings whose needs include freedomto plan their own lives and happiness.8

Discussion may not be enough for patients toacquire sufficient knowledge to make informeddecisions. The Royal College of Physiciansrecommends an information sheet, time to reflect, and(in most cases) a written consent form.6 TheAssociation of the British Pharmaceutical Industry(ABPI) is less specific but also favours written consentand provision of all "pertinent information". Butwhat is relevant/pertinent? Patients may have

difficulty grasping concepts of probability and risk,especially of "minimal risk". Even the simple analogyof travelling as a scheduled passenger on an airline9 islikely to deter many potential recruits. A list of adverseeffects may be factually correct but nevertheless

present a bleak picture to the uninitiated.

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A study by Simel and Feussner10 now confirmswhat many have suspected-a patient’s decision aboutparticipating in a study depends on what he is toldabout it. These researchers sought to recruit patientsattending hospital with various disorders to a shamclinical trial. Half were randomised to a comparison ofusual treatments versus drugs that may act twice asfast and half to a trial of drugs that may act half as fastas normal treatment. More patients agreed to

participate in the first protocol than in the second (67vs 42%) and interview indicated that the simplestatement about speed of action played a powerful partin preferences. More than one conclusion emergesfrom this study. The first, drawn by the investigators,is that the provision of quantitative information islikely to facilitate a patient’s decision. The more

sceptical reader may be left wondering about thecurious incompleteness in information provided forparticipants in this "study". If the trial drug in thesecond protocol worked only half as fast why was thetrial being carried out at all? The rational patientpresumably concluded that there were compensatoryadvantages not documented in the protocol:alternatively, were there hidden benefits to the

investigator rather than to the patient? What feelingswere elicited about an institution which is apparentlyanxious to test an inferior mode of treatment? 58% of

patients seem to have drawn their own conclusionsabout a study as presented to them in clearly deficientoutline.

Existing guidelines for trials inevitably tend todwell on potential risks. Perhaps investigators shouldbe more open about sharing with patients the potentialbenefits and purpose of their studies. The final

message from Simel and Feussner’s work is possiblythe most depressing-the philanthropic motive seemsto have been conspicuous by its absence, most patientsbeing motivated by the desire to obtain somethingbetter for themselves. In the face of limitedinformation on which to base a decision the greatergood was not a major consideration. The age ofaltruism may be passing in this as in other areas ofmedicine.

1. The Nuremberg Code, 1947. In: Duncan AS, Dunstan GR, WelbournRB, eds. Dictionary of medical ethics. London: Darton, Longman andTodd, 1981: 130-32.

2. The Declaration of Helsinki. In: Duncan AS, Dunstan GR, WelbournRB, eds. Dictionary of medical ethics. London: Darton, Longman andTodd, 1981: 132-35.

3. Ogilvie H. Whither medicine? Lancet 1952; ii: 820-24.4. Cullinan ER. The physician’s obligation to society. Lancet 1958; i: 944.5. Pappworth MH. Human guinea pigs: experimentation on man. London:

Routledge & Kegan Paul, 1967: 192-93.6. Royal College of Physicians working party on research involving patients.

London: RCP, 1990: 15-19.7. Association of the British Pharmaceutical Industry. Guidelines of good

clinical research practice. London: ABPI, 1988: 8-9.8. Byrne P. Issues in the ethics of medical research. In: Byrne P, ed.

Medicine in contemporary society: Kings College Studies 1986-1987.London: King Edward’s Hospital Fund for London, 1987: 9-39.

9. Royal College of Physicians working party on research on healthyvolunteers. London: RCP, 1986: 5.

10. Simel DL, Feussner JR. A randomized controlled trial comparingquantitative informed consent formats. J Clin Epidermiol 1991; 44:771-77.

Cholesteryl ester transfer proteinCholesterol is an essential component of the

membranes of every human cell. Cholesterol is

required for tissue repair, growth, and cell turnover; inspecialised cells of the gonads, adrenals, and skin it isthe precursor of steroid hormones and vitamin D.’

However, about 4-6 g of cholesterol enters thecirculation each day, which greatly exceeds theseessential requirements.2 Since there is no system forcholesterol catabolism in the peripheral tissues theexcess cholesterol arriving at the periphery must bereturned to the liver if it is to be eliminated. The

process by which this comes about is termed reversecholesterol transport.Much is now known about the outward flow of

cholesterol from the liver, but the sequence of eventsin reverse cholesterol transport has been a harder nutto crack. A remarkable apolipoprotein, apo B1003present in very-low-density lipoprotein (VLDL) inwhich cholesterol is secreted from the liver, persiststhroughout the conversion of VLDL to low-densitylipoprotein (LDL) and finally allows the receptor-mediated cellular uptake of LDL. Radiolabelling ofapo B can therefore be used to follow this sequence.Serum high-density lipoprotein (HDL), theconcentration of which is inversely related to coronaryheart disease risk, has long been implicated in reversecholesterol transport,3 but the rate of removal of itsprotein moiety (mainly apolipoprotein AI and All)from the circulation is too slow to explain this form oftransport if catabolism of the whole HDL particle bythe liver is required.4 A clue to the enigma of reversecholesterol transport has now been found in an oldobservation: cholesterol is insoluble in water but willdissolve slowly in serum,s where it becomes

incorporated into HDL and VLDL.6 HDL acceptsfree cholesterol initially onto its surface. The enzymelecithin:cholesterol acyl transferase (LCAT) esterifiesthis cholesterol. The resulting cholesteryl ester (whichis even more hydrophobic than free cholesterol) entersthe lipid droplet at the core of HDL. There is someevidence that cells have a receptor for HDL thatfacilitates the egress of cholesterol;7 a small rapidlymetabolised subfraction of HDL may be the initial

acceptor.8 This subfraction contains apo AI and

phospholipid and has prebeta rather than the usualalpha electrophoretic mobility-hence the name

prebeta HDL.9 Prebeta HDL may be releasedperipherally when triglyceride-rich lipoproteinsundergo lipolysis.9 HDL can probably deliversome of its cholesterol directly to the liverwithout the whole lipoprotein particle beingcatabolised.10

In many species, including man, there is an

alternative route for the disposal of cholesteryl ester inHDL10 via transfer to VLDL, a process dependentupon a hydrophobic 74 kDa glycoprotein called

cholesteryl ester transfer protein. 1,11,12 This proteinshuttles triglycerides in the opposite direction out of