Monthly Archives: May 2016

Scurvy: Why it Took So Long

If the 17th century is seen as the Age of the Scientific Revolution, the 18th marked the Age of Discovery. The ships of many nations were now travelling across the world for commerce, colonization and piracy. They were fitted with cannons to protect them against their enemies and to allow them to attack rich foreign ships laden with treasure. The cannons required a large complement of men in addition to the crew that sailed the ship. Often the ships would be at sea for months at a time without touching land and the provisioning for the very large crew was difficult. Hard Tack, fresh water and occasional bits of stew was the basic ration for most regular seamen. Scurvy was the result and without treatment it led to a horrible death.

The primary lesions of scurvy relate to bleeding and swelling and inflammation of soft tissues and bone. Wounds don’t heal because you can’t make collagen. Bleeding occurs into the skin around the roots of all your hairs, which later fall out. Swollen gums bleed, the jaw bone softens, and eventually your teeth fall out. Hemorrhagic spots develop in your eyelid linings. There’s painful bleeding into your joints, and into the surface membrane of bones, causing crippling pain, and eventually spontaneous breakage of bones. Eventually you’re coughing up blood and possibly asphyxiating. Bleeding develops in the intestines, leading to black, and then bloody, horrifically foul smelling stools. Anemia, weakness. Emotional liability. Bleeding into the sack around your heart so your heart can’t fill with blood and pump. Bleeding around the brain, compressing it, causing headache, vomiting, eventually coma and death as your brainstem is crushed as your swollen brain pushes itself down into the spinal canal. Perhaps your spirit hovers overhead to watch your body committed to the deep.

The situation did not improve between the first publication of Lind’s Treatise and its third and final edition in 1772. Deaths due to scurvy and other diseases far exceeded the number of battlefield deaths during the Seven Years War (1756-1763). Once more the pressure for a cure increased, and sea trials continued without any clear success.

James CookJames Cook (1728-1779)

It was during this period that Captain James Cook organized his first expedition to circumnavigate the world in 1778. He demanded and received every contemporary support for the control of scurvy: ample supplies of Lind’s concentrated juice, large stores of fresh and preserved fruits and vegetables, and a careful selection of crew. (We know that on some of the other voyages, crew members were often selected from the poorest and least healthy parts of the population and at time forcibly brought on board ship.) Cook stopped as frequently as he could to “refresh” the ship and provide the men with fresh food and water. The result was the first truly successful voyage of discovery in health terms: no one died of scurvy, although the disease did occur when there were particularly long stretches away from shore. Cook made his reputation and received the Copley medal from The Royal Society for his success in staving off the disease (Bown, 2003:166). The Copley medal was then, and remains, a prestigious award for outstanding achievements in research in any branch of science.

James Pringle

John Pringle (1707-1782)

Cook’s success was followed by intense scientific wrangling. Rivalrous explanations of Cook’s success were led by Sir John Pringle (1707-82), the then head of the Royal Society. Pringle reviewed the surgeon’s records, and with a strong bias concluded that “sweet-wort” (unfermented beer) was the most effective preventive of scurvy. This turned out to be a major obstacle to the Navy’s acceptance of other solutions, and became the treatment of choice for a number of years, though it was of little value (Carpenter, 1986:17).

The scientific research establishment from Pringle’s time to the early 20th century hindered rather than helped the prevention of scurvy. Researchers and scientists, as well as clinical practitioners transferred successful solutions from one problem area to another: if sweet-wort helps with one problem of digestion, we should try it for scurvy, which appears also to be the same kind of problem. These physicians and scientists were often so committed to their settled explanations and frameworks that they continued to press for wrong-headed solutions in the face of massive evidence to the contrary. The greater their authority, the more resistant they seemed to be to new ideas. Often their intransigence was positively harmful.

Pringle was himself, not only President of the Royal Society, but a Copley medalist. He associated scurvy with rotten foods and believed in giving sailors foods such as sweet-wort. This unfermented beer was supposed to ferment in the stomach and correct the problem. Pringle was not alone in putting obstacles in the way of a scientific solution to the problem of scurvy. Later, other figures such as Sir Robert Christison (1797-1882) President, British Medical Association and physician to Queen Victoria, Jean-Antoine Villemin (1827-92) of the French Academy of Medicine, William A. Hammond (1828–1900) U.S. Surgeon General, and even Lord Lister (1827–1912) advocated dramatically false or misleading views about scurvy (Carpenter, 1986). This was largely because they did not understand the nature of a deficiency disease like scurvy.

Sir_Gilbert_Blane_by_Martin_Archer_Shee

Sir Gilbert Blane (1749-1834)

In the face of the medical establishment, progress could still be made on the policy front. Gilbert Blane, a physician from an upper class family, joined the navy in 1781 as Physician to the Fleet. From this position he had privileged access to the Admiral. After a short time he wrote that scurvy “may be infallibly prevented or cured by fresh vegetables and fruit, particularly oranges, lemons or limes” (Carpenter, 1986:92). His early letters to the Admiralty did not overcome the obstacle raised by the superior scientific authority of Pringle. However, he persevered, and in 1793 he instituted a test on one ship with the help of a friendly Admiral. Each man received two-thirds of an ounce of lemon juice mixed into the daily ration of grog. The ship took 23 weeks to reach India without touching land. Several men showed some symptoms of scurvy, but those soon disappeared after an increased dose of lemon juice. By the time the ship reached Madras, no one was affected by the disease.

In 1795, soon after Blane became a Commissioner on the Board of the Sick and Wounded Sailors, the Board recommended a daily allowance of three quarters of an ounce of lemon juice as part of the daily ration. After this date, the incidence of scurvy dropped very quickly. Just as the poor health of sailors due to scurvy was thought by some historians to be a factor in the British loss during the American Revolution, their good health after the elimination of scurvy was considered to be a major factor in the British maritime victories during the Napoleonic Wars (Porter, 2002).

The puzzle about the application of controlled trial results to policy has a very simple solution. It is quite clear with a close reading of Lind’s text. After he describes his clinical trial Lind declares the efficacy of oranges and lemons in the treatment of scurvy but,

As oranges and lemons are liable to spoil, and cannot be procured at every port, nor at all seasons in equal plenty and it may be inconvenient to take on board such large quantities as are necessary in ships for their preservation from this and other diseases the next thing to be proposed is the method of preserving their virtues entire for years in a convenient and small bulk. It is done in the following easy manner. [Lind, 1753 #67, Pg. 156.]

And our heart stops as Lind goes on to describe in great detail a process of heating the juice in a glazed earthen basin to almost boiling to allow the water to evaporate and produce a thick syrup (called  a “rob”) that can be reconstituted at sea. In this way the “virtues of twelve dozen of lemons or oranges may be put into a quart-bottle, and preserved for several years.” [Lind, 1753 #67, Pg. 157.]

We now know that boiling citrus juice for many hours severely reduces the amount of Vitamin C in the resulting syrup, and the reconstituted juice significantly dilutes whatever is left. It would not, and indeed did not prevent scurvy. But this “rob” rather than fresh oranges and lemons was Lind’s clear recommendation in his book. Moreover there is good evidence that the rob was used repeatedly with little good effect.

We can conclude that even though Lind believed fresh orange juice was a cure for scurvy, Lind was justified in believing that fresh orange juice was a cure for scurvy because of the trial. And it was true that fresh orange juice was a cure for scurvy. However we cannot conclude that Lind knew that fresh orange juice was the cure for scurvy because he also believed that the potency of the cure would be maintained if he boiled the juice down to a syrup or “rob.” (This is a real life example of a famous philosophical counterexample to the justified true belief model of knowledge that was first presented by Edmund Gettier in the Journal Analysis in 1963.)

Throughout the rest of his life Lind did not understand the outcome of his experiment. In later years when he became an academic physician and the successful head of the first sailors’ hospital at Haslam, he continued to try a whole range of other cures for scurvy with no success.

As patients we have learned to our dismay that there are many other cases where the conclusions of controlled trials turn out to be either ineffective or positively harmful, often because some aspects of the effect of a trial are not properly understood. This is not necessarily due to negligence, but to an inherent limitation of such trials in particular and to the justified true belief model of knowledge in general. Lind’s failure to see the importance of freshness in the juice is but the first example of this limitation and it accompanies the very first trial.

Of course there can be other parts of trials that are not in fact controlled and can have serious impact on the meaning of the results. One of my patient colleagues was asked to bring the patient’s perspective to the design of a particular controlled drug trial of an anti-depressant. The trial made sure that patients were not taking any prescription drugs that might interfere with the drug being studied. My colleague asked if they made sure that the patients had not also used herbal remedies like St. Johns wort that might have an effect (as many people have done for millennia.) In the trial they had ignored the effects of all herbal remedies and only excluded other prescription drugs. If my colleague was right, they could no longer claim that the results came only from the intervention that they had made. Often it is not clear what must be controlled in the various arms of a trial. We know, for example, that many drugs prescribed for older people or pregnant women are not tested on them, with occasionally disastrous consequences.

There is a growing struggle with some opposition from pharmaceutical companies to understand more vigilantly the limits of the results of controlled trials and also to monitor patients more thoroughly after they take new medications because of the risk of hitherto unknown side effects on their particular cohort. This kind of uncertainty about how to apply the results of trials to individual patients is a useful conclusion. We must be especially vigilant in prescribing drugs for the growing number of patients who will be long term users of drugs to control the effects of chronic diseases.

Outbreaks of scurvy recurred in the 19th century. For example there were outbreaks in France where scientifically developed infant formula was substituted for mother’s milk and in the Royal Navy itself when the fresh citrus juice was replaced with an adulterated version of lime juice.

 

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The Story of Scurvy: The Controlled Trial

James Lind Black and White

James Lind (1716-1794)

If the 17th century is seen as the Age of the Scientific Revolution, the 18th marked the Age of Discovery. The ships of many nations were now travelling across the world for commerce, colonization and piracy. They were fitted with cannons to protect them against their enemies and to allow them to attack rich foreign ships laden with treasure. The cannons required a large complement of men in addition to the crew that sailed the ship. Often the ships would be at sea for months at a time without touching land and the provisioning for the very large crew was difficult. Hard Tack, fresh water and occasional bits of stew was the basic ration for most regular seamen. Scurvy was the result and without treatment it led to a horrible death.

The primary lesions of scurvy relate to bleeding and swelling and inflammation of soft tissues and bone. Wounds don’t heal because you can’t make collagen. Bleeding occurs into the skin around the roots of all your hairs, which later fall out. Swollen gums bleed, the jaw bone softens, and eventually your teeth fall out. Hemorrhagic spots develop in your eyelid linings. There’s painful bleeding into your joints, and into the surface membrane of bones, causing crippling pain, and eventually spontaneous breakage of bones. Eventually you’re coughing up blood and possibly asphyxiating. Bleeding develops in the intestines, leading to black, and then bloody, horrifically foul smelling stools. Anemia, weakness. Emotional liability. Bleeding into the sack around your heart so your heart can’t fill with blood and pump. Bleeding around the brain, compressing it, causing headache, vomiting, eventually coma and death as your brainstem is crushed as your swollen brain pushes itself down into the spinal canal. Perhaps your spirit hovers overhead to watch your body committed to the deep. (Anderson, 2000 )

 

George Anson, First Baron Anson (1697-1762) (by Joshua Reynolds)

Thousands of common seamen died of scurvy during long voyages of exploration, colonization and especially during the naval wars of the 17th and 18th centuries. In a particularly famous case, in 1740 George Anson led a flotilla of six warships with more than 1900 men on a trip around the horn of South America to capture Lima Peru from the Spanish. He ended up travelling around the world, gaining enormous riches, but only 188 original crew members returned. Most of the deaths were due to scurvy. Anson, now rich and famous, published a best-selling account of his trip. His expedition intensified the rush to find a cure for scurvy.

James Lind (1716-1794)

The traditional story of how the cure was finally discovered is largely about James Lind, an Eighteenth Century naval surgeon who performed the first recorded controlled trial. Today, controlled clinical trials have become the gold standard of evidence based medicine: subjects are randomly allocated to one or other of different arms of the study and the results are analyzed to determine which of the treatments are effective.

In 1747 while Lind was a surgeon on the HMS Salisbury there was a second outbreak of scurvy. He selected twelve sailors suffering from the disease and divided them into six groups of two. All were given a similar diet of “water gruel sweetened with sugar in the morning; fresh mutton broth often times for dinner, at other times boiled biscuit with sugar etc and for supper barley and raisins, rice and currants sago and wine or the like.”[Lind, 1753 #67, Pg. 145.] He then used the following treatments (here quoted in full but reformatted with modern bullet points to differentiate the six groups, leaving the original spelling but clarifying some terms in square brackets):

  • Two of these were ordered each a quart of [hard apple] cider a-day.
  • Two others took twenty-five “gutts” [drops] of elixir vitriol [dilute sulfuric acid], three times a-day, upon an empty stomach; using a gargle strongly acidulated with it for their mouths.
  • Two others took two spoonfuls of vinegar three times a-day upon an empty stomach; haveing their gruels and their other food well acidulated with it, as also the gargle for their mouth.
  • Two of the worst patients, with the tendons of the ham rigid, (a symptom none of the rest had), were put under a course of sea-water. Of this they drank half a pint every day, and sometimes more or less as it operated, by way of gentle physic [laxative].
  • Two others had each two oranges and one lemon given them every day. These they ate with greediness, at different times, upon an empty stomach. They continued but six days under this course, having consumed the quantity that could be spared.
  • The two remaining patients, took the bigness of a nutmeg three times a-day, of an “electuary” [medicinal paste] recommended by an hospital surgeon, made of garlic, mustard seed, rad. Raphan[dried radish root], balsam of Peru [resin from the balsam tree] and gum myrrh; using for common drink barley-water well acidulated with tamarinds; by a decoction of which, with the addition of cremor tartar [potassium hydrogen tartrate], they were gently purged three or four times during the course. [Lind, 1753 #67, Pp. 145-146.]

 

The trial offered clear results. The two sailors given oranges and lemons, even though it was for only six days were much improved; one of them was “appointed nurse to the rest of the sick”[Lind, 1753 #67, Pg. 146.].  The results are indeed utterly clear, the conclusion overwhelming.

Lind says that the citrus fruit provided to the sick seamen was all “that could be spared.” The fruit was from the supply kept for officers. Some ships, like George Anson’s returned from long voyages with their officers alive and most seamen dead because the provisions for officers contained foods that saved them, but these, because they were scarce, were not shared with the crew even as they became ill. The size of the crew could not allow it and there was no understanding of the disease that would warrant it. It should also be noted that large numbers of crew members were needed not only to help with navigation but to man the cannons that gave these warships their advantage in battle and the health condition of many of crew members was poor to begin with.

From the patient’s point of view we wonder what happened to the two patients who were given orange and lemons for six days. When they went off these rations, did the scurvy return? We are pretty sure that all the other subjects died. Did the two also die?

Lind published a description of his experiment in A Treatise of the Scurvy in 1753. The book was very successful, translated into other languages and widely distributed.  But despite their knowledge of Lind’s discovery, the British Navy only introduced fresh citrus juice to the sailor’s diet in 1795. The cost of this delay was enormous: far more sailors died of scurvy than in battle. During the Seven Years War of 1756 to 1763 the level of death was horrific: of the 184,893 men who were in the navy, 133,708 died “of diseases and missing” and only 1,512 were “killed in engagements and by accidents” (The Annual Register, or a View of the History, Politics, and Literature, For the Year 1763, 1790, Pg. 50.) In addition some historians have argued that Britain’s failed naval blockade during the American revolutionary War, largely due to scurvy, was a major factor in the success of the American Revolution. (Carpenter).

The delay in the implementation of Lind’s results has been extensively used to illustrate and bemoan the time gap between research results and their application. It has become a standard example in the literature, with different emphases on the various lessons and conclusions to be drawn from it. Herbert Spencer, the 19th century father of Social Darwinism, a proto-libertarian, and sometime beloved of George Eliot, claimed that the story of scurvy demonstrated the ineffectiveness of government and its bureaucracies (Spencer, 1887). More recent medical historians declare that the delay was because, “Surprisingly, the Navy took no notice of Lind’s results” (Coleman, 1985:94). More recently, still others, like Jonathan Lomas, a Canadian with an interest in knowledge transfer, assert that this was an early example of continuing resistance of practitioners to apply the results of scientific research – a classic case of poor knowledge transfer (Lomas, 2002).

Although it was one among many, Lind’s book was a best seller for its time. It was widely circulated, translated into other languages and printed in three editions over the next 15 years. It made Lind’s reputation. When the Navy built an enormous hospital at Haslar devoted to treating sailors, Lind became its first director, despite the failure of his solution to be effectively implemented. He held this post quite honorably and continued to experiment with the sailors who came there until he retired, whereupon he was succeeded by his son.

Pierre Simon Laplace (1749-1827)

Pierre-Simon-Laplace_(1749-1827)

Perhaps the most extreme and secular view of mechanical materialism was espoused by LaPlace in the century late 18th century. By that time, the modern understanding of Boyle’s view of the body had spread to many physicians, but not the general public, much as quantum physics is understood by physicists, but not by many laymen today. The outdated physics and mathematics of that time continues to influence our current thinking in much the way Galen’s humoral theory remained deeply embedded in medicine. A good example of such an outdated idea that remains influential today is LaPlace’s Demon. Pierre Simon LaPlace wrote in 1814:

We may regard the present state of the universe as the effect of its past and the cause of its future. An intellect which at a certain moment would know all forces that set nature in motion, and all positions of all items of which nature is composed, if this intellect were also vast enough to submit these data to analysis, it would embrace in a single formula the movements of the greatest bodies of the universe and those of the tiniest atom; for such an intellect nothing would be uncertain and the future just like the past would be present before its eyes. Aphilosophical Essay on the Probabolities (note :  Laplace, Pierre Simon, A Philosophical Essay on Probabilities, translated into English from the original French 6th ed. by Truscott,F.W. and Emory,F.L., Dover Publications (New York, 1951) p.4)

This is the clearest and most deeply accepted account of mechanistic determinism that we have. Of course there can be no such being as Laplace describes. We do not expect to ever have such a formula because physics has passed that point. The new quantum mechanics concluded that there are many phenomena that are complex and by their very nature unpredictable. Yet many of us still believe foolishly, that the world is deterministic and hence that there can be no free will.

Although we now recognize that LaPlace’s notion of a completely deterministic universe is not possible, it is still deeply embedded in our thinking. Much as we continue to take hot chicken soup to combat the common cold we continue to consider that a deterministic and mechanistic account of all our actions remains feasible. This is to take away from us any immediate responsibility for our own actions including our health.

If our chemical mechanical body is controlled entirely by forces beyond our individual control then we must wait for their interventions to set us straight. This view gives our bodies over to the medical scientists who are the only ones who truly understand the laws that govern them and hence how to repair them.  The development of this view accompanied the rise of modern scientific medicine, It had its height in the first part of the 20th Century and although it remains a strong tendency today, the patient`s partnership in all aspects of healthcare is growing.