Someone else's research, that is
Keith S. Taber
Imagine you have a painful and debilitating illness. Your specialist tells you there is no conventional treatment known to help. However, there is a new – experimental – procedure: a surgery that may offer relief. But it has not yet been fully tested. If you are prepared to sign up for a study to evaluate this new procedure, then you can undergo surgery.
You are put under and wheeled into the operating theatre. Whilst you experience – rather, do not experience – the deep, sleepless rest of anaesthesia, the surgeon saws through your breastbone, prises open your ribcage with a retractor (hopefully avoiding breaking any ribs),
reaches in, and gently lifts up your heart.
The surgeon, pauses, perhaps counts to five, then carefully replaces your heart between the lungs. The ribcage is closed, and you are sown-up without any actual medical intervention. You had been randomly assigned to the control group.
How can we test whether surgical interventions are really effective without blind controls?
Is it right to carry out sham operations on sick people just for the sake of research?
Where is the balance of interests?
(Image from Pixabay)
Research ethics
A key aspect of planning, executing and reviewing research is ethical scrutiny. Planning, obviously, needs to take into account ethical considerations and guidelines. But even the best laid plans 'of mice and men' (or, of, say, people investigating mice) may not allow for all eventualities (after all, if we knew what was going to happen for sure in a study, it would not be research – and it would be unethical to spend precious public resources on the study), so the ethical imperative does not stop once we have got approval and permissions. And even then, we may find that we cannot fully mitigate for unexpected eventualities – which is something to be reported and discussed to help inform future research.
When preparing students setting out on research, instruction about research ethics is vital. It is possible to teach about rules, and policies, and guidelines and procedures – but real research contexts are often complex, and ethical thinking cannot be algorithmic or a matter of adopting slogans and following heuristics. In my teaching I would include discussion of past cases of research studies that raised ethical questions for students to discuss and consider.
One might think that as research ethics is so important, it would be difficult to find many published studies which were not exemplars of good practice – but attitudes to, and guidance on, ethics have developed over time, and there are many past studies which, if not clearly unethical in today's terms, at least present problematic cases. (That is without the 'doublethink' that allows some contemporary researchers to, in a single paper, both claim active learning methods should be studied because it is known that passive learning activities are not effective, yet then report how they required teachers to instruct classes through passive learning to act as control groups.)
Indeed, ethical decision-making may not always be straight-forward – as it often means balancing different considerations, and at a point where any hoped-for potential benefits of the research must remain uncertain.
Pretending to operate on ill patients
I recently came across an example of a medical study which I thought raised some serious questions, and which I might well have included in my teaching of research ethics as a case for discussion, had I known about before I retired.
The research apparently involved surgeons opening up a patient's ribcage (not a trivial procedure), and lifting out the person's heart in order to carry out a surgical intervention…or not,
"In the late 1950s and early 60s two different surgical teams, one in Kansas City and one in Seattle, did double-blind trials of a ligation procedure – the closing of a duct or tube using a clip – for very ill patients suffering from severe angina, a condition in which pain radiates from the chest to the outer extremities as a result of poor blood supply to the heart. The surgeons were not told until they arrived in the operating theatre which patients were to receive a real ligation and which were not. All the patients, whether or not they were getting the procedure, had their chest cracked open and their heart lifted out. But only half the patients actually had their arteries rerouted so that their blood could more efficiently bathe its pump …"
Slater, 2018
The quote is taken from a book by Lauren Slater which sets out a history of drug use in psychiatry. Slater is a psychotherapist who has written a number of books about aspects of mental health conditions and treatments.
Fair testing
In order to make a fair experiment, the double-blind procedure sought to treat the treatment and control group the same in all respects, apart from the actual procedure of ligation of selected blood vessels that comprised the mooted intervention. The patients did not know (at least, in one of the studies) they might not have the real operation. Their physicians were not told who was getting the treatment. Even the surgeons only found out who was in each group when the patient arrived in theatre.
It was necessary for those in the control group to think they were having an intervention, and to undergo the sham surgery, so that they formed a fair comparison with those who got the ligation.
Read about control of variables
It was necessary to have double-blind study (neither the patients themselves, nor the physicians looking after them, were told which patients were, and which were not, getting the treatment), because there is a great deal of research which shows that people's beliefs and expectations make substantial differences to outcomes. This is a real problem in educational research when researchers want to test classroom practices such as new teaching schemes or resources or innovative pedagogies (Taber, 2019). The teacher almost certainly knows whether she is teaching the experimental or control group, and usually the students have a pretty good idea. (If every previous lesson has been based on teacher presentations and note-taking, and suddenly they are doing group discussion work and making videos, they are likely to notice.)
It was important to undertake a study, because there was not clear objective evidence to show whether the new procedure actually improved patient outcomes (or possibly even made matters worst). Doctors reported seeing treated patients do better – but could only guess how they might have done without surgery. Without proper studies, many thousands or people might ultimately undergo an ineffective surgery, with all the associated risks and costs, without getting any benefit.
Simply comparing treated patients with matched untreated patients would not do the job, as there can be a strong placebo effect of believing one is getting a treatment. (It is likely that at least some alternative therapies largely work because a practitioner with good social skills spends time engaging with the patient and their concerns, and the client expects a positive outcome.)
If any positive effects of heart surgery were due to the placebo effect, then perhaps a highly coloured sugar pill prescribed with confidence by a physician could have the same effect without operating theatres, surgical teams, hospital stays… (For that matter, a faith healer who pretended to operate without actually breaking the skin, and revealed a piece of material {perhaps concealed in a pocket or sleeve} presented as an extracted mass of diseased tissue or a foreign body, would be just as effective if the patient believed in the procedure.)
So, I understood the logic here.
Do no harm
All the same – this seemed an extreme intervention. Even today, anaesthesia is not very well understood in detail: it involves giving a patient drugs that could kill them in carefully controlled sub-lethal doses – when how much would actually be lethal (and what would be insufficient to fully sedate) varies from person to person. There are always risks involved.
"All the patients, whether or not they were getting the procedure had their chest cracked open and their heart lifted out."
(Image by Starllyte from Pixabay)
Open heart surgery exposes someone to infection risks. Cracking open the chest is a big deal. It can take two months for the disrupted tissues to heal. Did the research really require opening up the chest and lifting the heart for the control group?
Could this really ever have been considered ethical?
I might have been much more cynical had I not known of other, hm, questionable medical studies. I recall hearing a BBC radio documentary in the 1990s about American physicians who deliberately gave patients radioactive materials without their knowledge, just to to explore the effects. Perhaps most infamously there was the Tuskegee Syphilis study where United States medical authorities followed the development of disease over decades without revealing the full nature of the study, or trying to treat any of those infected. Compared with these violations, the angina surgery research seemed tame.
But do not believe everything you read…
According to the notes at the back of Slater's book, her reference was another secondary source (Moerman, 2002) – that is someone writing about what the research reports said, not those actual 'primary' accounts in the research journals.
So, I looked on-line for the original accounts. I found a 1959 study, by a team from the University of Washington School of Medicine. They explained that:
"Considerable relief of symptoms has been reported for patient with angina pectoris subjected to bilateral ligation of the internal mammary arteries. The physiologic basis for the relief of angina afforded by this rather simple operation is not clear."
Cobb, Thomas, Dillard, Merendino & Bruce, 1959
It was not clear why clamping these blood vessels in the chest should make a substantial difference to blood flow to the heart muscles – despite various studies which had subjected a range of dogs (who were not complaining of the symptoms of angina, and did not need any surgery) to surgical interventions followed by invasive procedures in order to measure any modifications in blood flow (Blair, Roth & Zintel, 1960).
Would you like your aorta clamped, and the blood drained from the left side of your heart, for the sake of a research study?
That raises another ethical issue – the extent of pain and suffering and morbidity it is fair to inflect on non-human animals (which are never perfect models for human anatomy and physiology) to progress human medicine. Some studies explored the details of blood circulation in dogs. Would you like your aorta clamped, and the blood drained from the left side of your heart, for the sake of a research study? Moreover, in order to test the effectiveness of the ligation procedure, in some studies healthy dogs had to have the blood supply to the heart muscles disrupted to given them similar compromised heart function as the human angina sufferers. 1
But, hang on a moment. I think I passed over something rather important in that last quote: "this rather simple operation"?
"Considerable relief of symptoms has been reported for patient with angina pectoris subjected to bilateral ligation of the internal mammary arteries. The physiologic basis for the relief of angina afforded by this rather simple operation is not clear."
Cobb and colleagues' account of the procedure contradicted one of my assumptions,
At the time of operation, which was performed under local anesthesia [anaesthesia], the surgeon was handed a randomly selected envelope, which contained a card instructing him whether or not to ligate the internal mammary arteries after they had been isolated.
Cobb et al, 1959
It seems my inference that the procedure was carried out under general anaesthetic was wrong. Never assume! Surgery under local anaesthetic is not a trivial enterprise, but carries much less risk than general anaesthetic.
Yet, surely, even back then, no surgeon was going to open up the chest and handle the heart under a local anaesthetic? Cobb and colleagues wrote:
"The surgical procedures commonly used in the therapy of coronary-artery disease have previously been "major" operations utilizing thoracotomy and accompanied by some morbidity and a definite mortality. … With the advent of internal-mammary-artery ligation and its alleged benefit, a unique opportunity for applying the principles of a double-blind evaluation to a surgical procedure has been afforded
Cobb, Thomas, Dillard, Merendino & Bruce, 1959
So, the researchers were arguing that, previously, surgical interventions for this condition were major operations that did involve opening up the chest (thorax) – thoracotomy – where sham surgery would not have been ethical; but the new procedure they were testing – "this rather simple operation" was different.
Effects of internal-mammary-artery ligation on 17 patients with angina pectoris were evaluated by a double-blind technic. Eight patients had their internal mammary arteries ligated; 9 had skin incisions only.
Cobb et al, 1959
They describe "a 'placebo' procedure consisting of parasternal skin incisions"– that is some cuts were made into the skin next to the breast bone. Skin incisions are somewhat short of open heart surgery.
The description given by the Kansas team (from the Departments of Medicine and Surgery, University of Kansas Medical Center, Kansas City) also differs from Slater's third-hand account in this important way:
"The patients were operated on under local anesthesia. The surgeon, by random sampling, selected those in whom bilateral internal mammary artery and vein ligation (second interspace) was to be carried out and those in whom a sham procedure was to be performed. The sham procedure consisted of a similar skin incision with exposure of the internal mammary vessels, but without ligation."
Dimond, Kittle & Crocket, 1960
This description of the surgery seemed quite different from that offered by Slater.
These teams seemed to be reporting a procedure that could be carried out without exposing the lungs or the heart and opening their protective covers ("in this technique…the pericardium and pleura are not entered or disturbed", Glover, et al, 1957), and which could be superficially forged by making a few cuts into the skin.
"The performance of bilateral division of the internal mammary arteries as compared to other surgical procedures for cardiac disease is safe, simple and innocuous in capable hands."
Glover, Kitchell, Kyle, Davila & Trout, 1958
The surgery involved making cuts into the skin of the chest to access, and close off, arteries taking blood to (more superficial) chest areas in the hope it would allow more to flow to the heart muscles; the sham surgery, the placebo, involved making similar incisions, but without proceeding to change the pattern of arterial blood flow.
The sham surgery did not require general anaesthesia and involved relatively superficial wounds – and offered a research technique that did not need to cause suffering to, and the sacrifice of, perfectly healthy dogs. So, that's all ethical then?
The first hand research reports at least give a different impression of the balance of costs and potential benefits to stakeholders than I had originally drawn from Lauren Slater's account.
Getting consent for sham surgery
A key requirement for ethical research with human participants is being offered voluntary informed consent. Unlike dogs, humans can assent to research procedures, and it is generally considered that research should not be undertaken without such consent.
Read about voluntary informed consent
Of course, there is nuance and complication. The kind of research where investigators drop large denomination notes to test the honesty of passers by – where the 'participants' are in a public place and will not be identified or identifiable – is not usually seen as needing such consent (which would clearly undermine any possibility of getting authentic results). But is it acceptable to observe people using public toilets without their knowledge and consent (as was described in one published study I used as a teaching example)?
The extent to which a lay person can fully understand the logic and procedures explained to them when seeking consent can vary. The extent to which most participants would need, or even want to, know full details of the study can vary. When children of various ages are are involved, the extent to which consent can be given on their behalf by a parent or teachers raises interesting questions.
"I'm looking for volunteers to have a procedure designed to make it look like you've had surgery"
Image by mohamed_hassan from Pixabay
There is much nuance and many complications – and this is an area researchers needs to give very careful consideration.
- How many ill patients would volunteer for sham surgery to help someone else's research?
- Would that answer change, if the procedure being tested would later be offered to them?
- What about volunteering for a study where you have a 50-50 chance of getting the real surgery or the placebo treatment?
In Cobb's study, the participants had all volunteered – but we might wonder if the extent of the information they were given amounted to what was required for informed consent,
The subjects were informed of the fact that this procedure had not been proved to be of value, and yet many were aware of the enthusiastic report published in the Reader's Digest. The patients were told only that they were participating in an evaluation of this operation; they were not informed of the double-blind nature of the study.
Cobb et al, 1959
So, it seems the patients thought they were having an operation that had been mooted to help angina sufferers – and indeed some of them were, but others just got taken into surgery to get a few wounds that suggested something more substantive had been done.
Was that ethical? (I doubt it would be allowed anywhere today?)
The outcome of these studies was that although the patients getting the ligation surgery did appear to get relief from their angina – so did those just getting the skin incisions. The placebo seemed just as good as the re-plumbing.
In hindsight, does this make the studies more worthwhile and seem more ethical? This research has probably prevented a great many people having an operation to have some of their vascular system blocked when that does not seem to make any difference to angina. Does that advance in medical knowledge justify the deceit involved in leading people to think they would get an experimental surgical treatment when they might just get an experimental control treatment?
Coda – what did the middle man have to say?
I wondered how a relatively minor sham procedure under local anaesthetic became characterised as "the patients, whether or not they were getting the procedure had their chest cracked open and their heart lifted out" – a description which gave a vivid impression of a major intervention.
The heart is pretty well integrated into the body – how easy is it to life an intact, fully connected, working heart out of position?
Image by HANSUAN FABREGAS from Pixabay
I wondered to what extent it would even be possible to lift the heart out from the chest whilst it remained connected with the major vessels passing the blood it was pumping, and the nerves supplying it, and the vessels supplying blood to its own muscles (the ones that were considered compromised enough to make the treatment being tested worth considering). Some sources I found on-line referred to the heart being 'lifted' during open-heart procedures to give the surgeon access to specific sites: but that did not mean taking the heart out of the body. Having the heart 'lifted out' seemed more akin to Aztec sacrificial rites than medical treatment.
Although all surgery involves some risk, the actual procedure being investigated seemed of relatively routine nature. I actually attended a 'minor' operation which involved cutting into the chest when my late wife was prepared for kidney dialysis. Usually a site for venal access is prepared in the arm well in advance, but it was decided my wife needed to be put on dialysis urgently. A temporary hole was cut into her neck to allow the surgeon to connect a tube (a central venous catheter) to a vein, and another hole into her chest so that the catheter would exit in her chest, where the tap could be kept sterile, bandaged to the chest. This was clearly not considered a high risk operation (which is not to say I think I could have coped with having this done to me!) as I was asked by the doctors to stay in the room with my wife during the procedure, and I did not need to 'scrub' or 'gown up'.
Bilateral internal mammary artery ligation seemed a procedure on that kind of level, accessing blood vessels through incisions made in the skin. However, if Lauren Slater had read up some of the earlier procedures that did require opening the chest, or if she had read the papers describing how the dogs were investigated to trace blood flow through connected vessels, measure changes in flow, and prepare them for induced heart conditions, I could appreciate the potential for confusion. Yet she did not cite the primary research, but rather Daniel Moerman, an Emeritus Professor of Anthropology at University of Michigan-Dearborn, who has written a book about placebo treatments in medicine.
Moerman does write about the bilateral internal mammary artery ligation, and the two sham surgery studies I found in my search. Moerman describes the operation:
"It was quite simple, and since the arteries were not deep in the body, could be performed under local anaesthetic."
Moerman, 2002
He also refers to the subjective reports on one of the patients assigned to the placebo condition in one of the studies, who claimed to feel much better immediately after the procedure:
"This patient's arteries were not ligated…But he did have two scars on his chest…"
Moerman, 2002
But nobody cracked open his chest, and no one handled his heart.
There are still ethical issues here, but understanding the true (almost superficial) nature of the sham surgery clearly changes the balance of concerns. If there is a moral to this article, it is perhaps the importance of being fully informed before reaching judgement about the ethics of a research study.
Work cited:
- Blair, C. R., Roth, R. F., & Zintel, H. A. (1960). Measurement of coronary artery blood-flow following experimental ligation of the internal mammary artery. Annals of Surgery, 152(2), 325.
- Cobb, L. A., Thomas, G. I., Dillard, D. H., Merendino, K. A., & Bruce, R. A. (1959). An evaluation of internal-mammary-artery ligation by a double-blind technic. New England Journal of Medicine, 260(22), 1115-1118.
- Dimond, E. G., Kittle, C. F., & Crockett, J. E. (1960). Comparison of internal mammary artery ligation and sham operation for angina pectoris. The American Journal of Cardiology, 5(4), 483-486.
- Glover, R. P., Davila, J. C., Kyle, R. H., Beard, J. C., Trout, R. G., & Kitchell, J. R. (1957). Ligation of the internal mammary arteries as a means of increasing blood supply to the myocardium. Journal of Thoracic Surgery, 34(5), 661-678. https://doi.org/https://doi.org/10.1016/S0096-5588(20)30315-9
- Glover, R. P., Kitchell, J. R., Kyle, R. H., Davila, J. C., & Trout, R. G. (1958). Experiences with Myocardial Revascularization By Division of the Internal Mammary Arteries. Diseases of the Chest, 33(6), 637-657. https://doi.org/https://doi.org/10.1378/chest.33.6.637
- Moerman, D. E. (2002). Meaning, Medicine, and the "Placebo Effect". Cambridge University Press Cambridge.
- Slater, Lauren (2018) The Drugs that Changed our Minds. The history of psychiatry in ten treatments. London. Simon & Schuster
- Taber, K. S. (2019). Experimental research into teaching innovations: responding to methodological and ethical challenges. Studies in Science Education, 55(1), 69-119. doi:10.1080/03057267.2019.1658058 [Download this paper.]
Note:
1 To find out if the ligation procedure protected a dog required stressing the blood supply to the heart itself,
"An attempt has been made to evaluate the degree of protection preliminary ligation of the internal mammary artery may afford the experimental animal when subjected to the production of sudden, acute myocardial infarction by ligation of the anterior descending coronary artery at its origin. …
It was hoped that survival in the control group would approximate 30 per cent so that infarct size could be compared with that of the "protected" group of animals. The "protected" group of dogs were treated in the same manner but in these the internal mammary arteries were ligated immediately before, at 24 hours, and at 48 hours before ligation of the anterior descending coronary.
In 14 control dogs, the anterior descending coronary artery with the aforementioned branch to the anterolateral aspect of the left ventricle was ligated. Nine of these animals went into ventricular fibrillation and died within 5 to 20 minutes. Attempts to resuscitate them by defibrillation and massage were to no avail. Four others died within 24 hours. One dog lived 2 weeks and died in pulmonary edema."
Glover, Davila, Kyle, Beard, Trout & Kitchell, 1957
Pulmonary oedema involves fluid build up in the lungs that restricts gaseous exchange and prevents effective breathing. The dog that survived longest (if it was kept conscious) will have experienced death as if by slow suffocation or drowning.
