by Burch, Druin
The Detroit study showed that the patients given the water were more likely to survive than those given the Sanocrysin. The wonderfully promising drug, in other words, did more harm than good.
The same issue of the American Review of Tuberculosis that published the Detroit report also contained another study, this time from a tuberculosis sanatorium in Kentucky. There a doctor told of giving Sanocrysin to a group of forty-six people. He used no control group, and his conclusion was that the drug was ‘outstanding’. The presence of the two reports in the same publication provided the best possible affirmation that careful trials and control groups, particularly when it came to dangerous drugs and unpredictable diseases like tuberculosis, were absolutely essential.
This should have meant a great deal to the early adopters of streptomycin. Instead it was ignored. The new antibiotic had to wait for further advances in the way doctors weighed up the effects of their drugs, advances that were to come mainly from Britain.
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1 Silver nitrate eye-drops have since been shown to be useless for this condition.
2 He later donated all of Merck’s international patent rights in streptomycin to Rutgers.
15 ‘Sickness in Salonica: my first, worst and most successful clinical trial’
THOUGHTFUL APPROACHES TO figuring out what worked emerged slowly, gradually, and without clear direction. Innovations were ignored, insights passed by, developments left to lead nowhere. Improvements in testing showed no tendency to come together as a trend, a movement, something infectious and impulsively self-propagating. Even tests that sound startlingly modern were often less advanced than they seemed. The work of James Lind is a good example.
Lind is often held up as the man who invented the reliable clinical trial. Born in 1716 in Edinburgh, Lind became a surgeon for the Royal Navy, then greatly troubled by scurvy. The causes of the disease were a mystery, but its effects were well known. Gums bled, teeth and hair fell out, old wounds reopened and ulcers appeared where no wound had ever been. Delusions and hallucinations, bleeding and joint problems, blindness and death: scurvy was a miserable condition.
In 1740, Commodore Anson set out to circumnavigate the globe in order to attack the Spanish in South America. Out of a total crew of 1,900 in six vessels, only 400 survived. The majority were killed by scurvy. The account of the journey, published to literary acclaim in 1748, drew public attention. According to Lind’s survey, the disease killed more Royal Navy sailors than died in armed conflict. He saw scurvy at first hand, sailing in afflicted ships from the 1730s. Lind wrote that his interest in the disease was stimulated by the account of Anson’s voyage. That was possibly a politically astute comment, since Anson rose to become First Lord of the Admiralty. The timing suggests it was not wholly true. The incident for which Lind is praised took place in 1747, the year before publication of the book that was supposed to have inspired it.
Lind was on board the Salisbury, part of the Channel Fleet. With a crew of 350, the ship sailed for ten weeks. Before the voyage was over, eighty sailors were suffering from scurvy. On 20 May 1747, Lind took twelve of these men and divided them into pairs. ‘Their cases were as similar as I could have them. They all in general had putrid gums, the spots and lassitude, with weakness of their knees. They lay together in one place, being a proper apartment for the sick in the fore-hold.’ Lind gave each pair a different treatment: vinegar, cider, sulphuric acid, sea water, a paste made from herbs and Peruvian balsam bark, or citrus fruit. The two who received the fruit made rapid and remarkable recoveries, while the others did not. Read about Lind and you are likely to be told that this was not only the origin of proper trials, but also the experiment that saved sailors from scurvy by demonstrating the powers of fresh citrus.
Neither is true. Lind was behaving in what sounds a modern way, but he had no full understanding of what he was doing. That made a difference. He failed so completely to make sense of his own experiment that even he was left unconvinced of the exceptional benefits of lemons and limes. Unsurprisingly, that meant he convinced no one else of them. People carried on dying of scurvy and doctors, including Lind, continued blindly guessing at treatments without realising they had the methods at hand to actually test them.
Nevertheless, something in Lind’s behaviour was important. Not in the manner of a discovery, flashing out upon the world and changing it for ever. More after the style of a thought floating in the air, past a man who caught at and almost kept hold of it. Nearly two centuries later, in the years before the Second World War, ideas about trials were seeping into people’s consciousness with new power. Lind was being increasingly held up as an example of something to aspire to, and even if that was based on a misunderstanding it said something important about what doctors were now learning to value. One of that new breed of doctors was a man named Archie Cochrane.
Archibald Leman Cochrane was born in 1909, growing up in Galashiels, in southern Scotland. His family were wealthy, he was intelligent, confident and from an early age showed both a love for sport and a dislike of unthinking authority. Sport dominated his early life, until he ripped the muscles of his right leg apart playing rugby at Cambridge. Temporarily crippled, he discovered a deep enjoyment of reading and thinking. It persisted once his leg healed.
An inability to ejaculate, as well genuine interest in the ideas of Freud, took him across Europe in pursuit of a psychoanalytic cure. Then he was off to the Spanish Civil War, refusing to sign up as a communist but believing that the Spanish republic was worth fighting for, and that fascists were worth fighting against.1 Despite not having finished his medical studies, in 1936 Cochrane was nevertheless put in charge of the casualty clearing station at a small military hospital in Spain. There were more people there who needed medical help than there was help to give. That gave Cochrane a taste for rationing, for thinking about how to allocate scarce medical resources in the most efficient way possible. He noticed that one of the surgeons dealt with certain types of patients exceedingly slowly. ‘A nurse told me, as he did later, that he was not a very experienced abdominal surgeon. I then decided to give priority on his lists to orthopaedic cases and accept that some abdominal cases would consequently die. I think I was right.’
This was a fruitful start, as well as a mark of Cochrane’s quality. He denied medical care to some people so that as many as possible would live. In his 1989 memoir, he told of the casualties arriving during one particular battle:
The first case was lying on his right side with his face partially hidden. His left thorax was completely shattered. I could see a heart faintly beating. I signalled to the nurse, by dropping my thumb, that the case was hopeless (language was dangerous). I moved left to see the next case and, by chance, glanced back. To my horror I recognised the face of Julian Bell.
Too disturbed by the sight of his dying friend to trust his own judgement, Cochrane quickly got a second opinion. His colleague reassured him that his impulse was correct. The injuries were too severe. Acting humanely, when there was too little help to go around, meant abandoning people that could not be quickly helped with real hope of saving them. Julian was in Spain working as a volunteer ambulance driver for the republican forces. He died shortly afterwards from the effects of the bomb that had destroyed his chest.
Returning to England to finish his medical training, Cochrane was frightened that his year’s absence, his new appearance and his left-wing sympathies would make the hospital reject him. Sunburnt and with ‘a striking red Van Dyck beard’, he nervously tested his reception, deliberately joining the ward round of University College Hospital’s most right-wing physician. ‘Ah, there you are, Cochrane,’ was his greeting. ‘How nice to see you. Had an interesting weekend?’
Noting the political convulsions in Germany, Cochrane loathed the prospect of Europe’s descent into conflict but saw no way out. ‘I had always considered that fascism had to be fought and that war was therefore inevitable. But I hated the idea of being involved in war again, knowing what
it was like.’ For Archie, when it came to both medicine and in politics, the fact that reality was harsh was no excuse for failing to face up to it.
After qualifying as a doctor, Cochrane helped University College Hospital prepare for casualties, and then he enrolled in the army. He was sent first to a field ambulance unit in Dorset and then, after a course at the London School of Hygiene and Tropical Medicine, was posted to Egypt. He sailed from Glasgow, finding companionship on the way with another doctor, Richard Doll. The two passed the voyage talking, organising concerts and studying Arabic. (Doll remembered their differences in approach. They studied, ‘Archie from a large tome that began with the Arabic script and me from the Berlitz paperback Teach Yourself Arabic in Three Months.’) After a period in Egypt, horrified at the conditions of the country’s poor, Cochrane’s language skills led him in a new direction. A commando battalion containing refugees from Spain needed a doctor; was he willing? He was. The physical demands of his new role as a commando were difficult, at least to begin with. ‘I remember a particularly arduous long desert march,’ Cochrane recalled, ‘with limited water supplies. Colonel Young, for whom I developed a great respect, advised me to march just behind him and not to worry if I hallucinated.’
The battalion sailed to Crete, with the author Evelyn Waugh serving as intelligence officer. Cochrane was briefed by a senior officer on the mission: ‘He told me, in a rather apologetic way, that casualties were going to be high and that as it was likely that I would be killed he was taking the unusual step of sending a second medical officer with the battalion.’
Cochrane survived, but the Allied invasion of Crete went disastrously wrong. At the end of May the remaining Allied troops surrendered. Life as a prisoner of war started off haphazardly for Cochrane. As a doctor who spoke German fluently, he was thrust into responsibility. He struggled with hostile prisoners speaking a babble of languages, with conditions that were often appalling, and with sadism and murderousness from the German guards. Battered by indignity, exhaustion, hunger and loneliness, he fortified himself by holding ever more tightly to those things that he felt mattered most: his efforts to write poetry and to provide the best medical care he could.
Interned at Salonica, Cochrane watched as bodies and morals collapsed under the stress of starvation and imprisonment. Six hundred calories a day were too little. The toilets within the barrack houses were too poor and too few, and at night the prisoners were forbidden from using the extra ones immediately outside their huts. As July became August the Germans began shooting some of their prisoners, randomly and without reason. ‘Then came a day I shall never forget,’ said Cochrane. A New Zealand orderly was shot while working in the camp hospital. Then a Yugoslav orderly, then another New Zealander. One of the men died of his wounds. Cochrane, in a fury, demanded an audience with the camp Kommandant. He was refused. That night, hearing prisoners using the outside toilets, a guard threw in a hand grenade. It exploded in the middle of men trying to relieve themselves. The next morning the Kommandant publicly congratulated the guard.
That afternoon, Cochrane got his meeting:
I had recovered from my wild rage and decided to try another line. I said in fluent German – and in German I have a rather upper-class accent – how much I had admired German culture in the past. I mentioned the usual names – Goethe, Heine, Beethoven, and Mozart – and how much had been contributed to medicine through Robert Koch and, more recently, the discovery of the sulphonamides. How shocked I was therefore to find Germans, in breach of the Geneva Convention, trying to starve prisoners of war to death, murdering medical orderlies, and attempting to shoot doctors and dentists.
Shaming people into behaving more like human beings seemed to work. After Cochrane’s outburst, the prisoners were treated better. Shootings stopped. Illnesses began to become the major problem. Cochrane was supplied with aspirin and a little quinine, but nothing else. Epidemics of diphtheria, typhoid and hepatitis began. ‘I told those with typhoid to lie still on their own faeces and I would see they were well hydrated and given as much glucose as I could get out of the Germans.’ Hepatitis actually became popular: while you were sick with it, you lost your appetite. That was a torment which hungry men were glad to be rid of.
As the summer passed, Cochrane noticed another condition appearing. Men’s legs and ankles began to swell. It looked to be the result of famine, the same sort of process that bloats the bellies of babies dying of starvation. Cochrane begged to be allowed extra help – some blood tests and some senior medical advice – but the Germans refused him. ‘Doctors are superfluous,’ they told him.
The numbers of men affected by the swelling seemed to be increasing rapidly. Cochrane went to the camp’s cooks and got figures for the number of men incarcerated, then used them to calculate day-to-day changes in rates of the disease. The numbers frightened him, and made him feel that some sort of action was essential. Persuading the Germans was more difficult.
In England, Cochrane had been taught the traditional story that James Lind had invented the clinical trial and saved the British Navy from scurvy. Inspired by that example, Cochrane took twenty of the prisoners, all with swelling rising up to their thighs. He divided them into two groups, installing each into a separate ward room of his camp hospital. To one he gave extra yeast supplements, bought on the black market with his own money. The others got vitamin C tablets.
I expected, and feared, failure. I noted the numbers each morning. There was no difference between rooms for the first two days; on the third day there was a slight difference; and on the fourth it was definite.
The men taking yeast grew markedly better, a result that was remarkable for two reasons. First for the influence that Cochrane’s findings gave him: his numbers appeared to have a persuasive power that his unaided complaints previously lacked. ‘I suddenly realised that I had truly shaken the Germans.’ Part of his success seemed to be down to the ghost of James Lind. The German doctors, too, came from universities where he was held up as a bright example.
The sheer passion of the odd-looking British doctor also had an effect. ‘My face was emaciated and deeply jaundiced, but it was surrounded by a mass of red hair and an impressive red beard.’ Cochrane’s legs were swollen also, his own disease easily apparent. The Germans listened to him courteously and promised to help.
Despite his apparent success, Cochrane was worn out by worry and illness. He was convinced that his trial was wrong, that the cause of the swelling was not a shortage of yeast but just an overall famine of food. Ten people in each group were simply so few that an apparent difference had emerged by chance. Nothing real, just the effect of one group of ten happening to feel better than another. ‘I returned to my room and wept. The outlook seemed helpless.’
The next day, though, was brighter. Not only did the Germans supply the yeast that had seemed to help, they also everyone’s daily calories by a third. Health in the camp improved, and with it the morale of all the prisoners.
As regards the trial, I have always felt rather emotional about it and ashamed of it. I was testing the wrong hypothesis, the numbers were too small, and they were not randomised. The outcome measure was pitiful and the trial did not go on long enough. On the other hand, it could be described as my first, worst, and most successful trial.
Cochrane learnt that a bad trial can easily give a false result. He did not believe that it was lack of yeast that caused the illness, only lack of calories. He also took to heart the lesson that any trial at all, even a mistaken one, was the sort of thing that doctors were now being swayed by. They might not be able to distinguish good methods from bad, but they knew that methods mattered. That was a step forwards.
As the war went on, Cochrane was transferred from Greece into Germany, ending up at a camp at Elsterhorst. It was where the majority of tuberculous Allied prisoners were sent, and the treatment options available to the British doctors were reasonably broad. That is, they were largely the same as those available in the hospitals of the
day. Tuberculosis could affect any part of the body; it took up most medical time when it affected the lungs. Since Koch’s work the causative organism could be spotted in a patient’s spit, but that did not solve the question of how to deal with it. The only available antibiotics, the sulphonamides, were of no use. At the camp, as in London, the doctors could prescribe bed-rest, a common treatment for tuberculosis. They could also deliberately deflate men’s lungs. The idea was that the lungs could then rest, recovering from their infection. The British doctors were free to decide when such procedures should be undertaken. It was a freedom that troubled Cochrane. He became acutely aware that such decisions were never made on the basis of anything other than an individual doctor’s personal opinions.
Even outside prison camps, tuberculosis was the developed world’s biggest infectious killer of young men. And despite their relatively good medical care, a lot of the tuberculous prisoners died. The Germans had a policy, which Cochrane applauded, that the doctor caring for a patient was always in charge of organising the funeral. ‘It was a good idea in that it brought home to physicians their case fatality rate.’ Cochrane could see its benefit in terms of improving the accuracy of a doctor’s experience; doctors too easily remembered their successes and forget about their failures. He also saw the human gain, the need to learn languages and religious customs, to grapple with the emotions as well as the therapeutics of looking after the very sick.
Part of the problem, he realised, was that the pressure to do something for the dying – anything at all – outweighed the need to take care that your actions did not make things worse. Cochrane began by trying to avoid deflating his patients’ lungs, convinced that it could do more harm than good. Yet it was difficult: whenever he did intervene, his patients were glad of it. They longed to see their doctor doing something. Despite his awareness of doubt, despite the knowledge that he might well be making these patients worse, Cochrane found that deflating their lungs made him feel better too. The pressure to act, even for the worst, was overwhelming.
