Clinical research with 2 oranges and 1 lemon per day: the first clinical trial
Learn from the first controlled clinical trial in history. In this story there are ships, bleeding gums, and citrus fruits.
Original picture by Katherine McCormack
(Spanish version below)
In the 16th century, long maritime expeditions began to take place in which the ships' crews could spend months without setting foot on dry land. Some of them have a distant but specific destination. Others, like the expedition of Magellan and Elcano, set sail for the unknown. Welcome to the realm of scurvy, the plague of the sea.
Scurvy is a disease resulting from vitamin C deficiency. Malnourished sailors began to feel terrible fatigue. The hair fragments and falls out. There are hemorrhages in the skin, and muscles, thrombosis in the veins. Gums swell, become infected, bleed, teeth can fall out. The wounds do not heal, hemorrhages begin to occur in the internal viscera, and psychiatric problems appear (frightening terrors). The last phase is characterized by jaundice, edema, fever, convulsions, shock, and death.
After reading this you have probably decided to drink orange juice. Relax, your gums are safe with your current diet.
But the diet of sailors on long voyages was not like what you can buy at the supermarket. Sailors who spent months at sea quickly used up fresh foodstuff and had to eat foods that were easily preserved and provided calories, such as cereals and salted meats, which do not contain vitamin C.
Scurvy was less common on ships from southern European countries, such as Spain and Portugal, probably due to the greater supply of fresh fruits and vegetables. Several preventive remedies were recommended, some of them related to the consumption of foods that today we know are rich in vitamin C, others were not effective, but they were used anyway. In any case, there was no official recommendation in this regard in the English navy.
James Lind (1716-1794) was a surgeon from Edinburgh. At the age of 23, he went to sea to learn the art of naval surgery.
Bay of Biscay, May 1747. Lind is 31 years old and takes part in a patrol in the English Channel. He has been sailing almost continuously for 8 years.
The ship sailed 8 weeks ago. Scurvy begins to take its toll.
Lind chooses 12 sailors with scurvy symptoms of similar severity and divides them into pairs (6 pairs). Each pair received a different diet: A) cider, B) elixir of vitriol, C) seawater, D) a paste of garlic, mustard seed, horseradish, balsam of Peru, and gum myrrh (I do not know the taste of such a mixture), E) vinegar or F) citrus fruits (2 oranges and 1 lemon per day). The first controlled clinical trial was born.
In 6 days, the sailors who enjoyed the citrus fruits were cured.
Lind's own description of his experiment in his treatise on scurvy, www.jameslindlibrary.org.
In 1748 Lind ended his period as a naval surgeon and returned to Edinburgh. Five years later he published his Treatise on Scurvy, which included a review of over 50 books on the treatment of scurvy.
It took 42 years for the Admiralty to order the distribution of lemon juice to sailors, a period during which countless sailors presumably died of scurvy. There has been speculation that Lind himself did not clearly state in his treatise that citrus was the key against scurvy and that he also advocated other ineffective treatments such as fresh air and exercise.
Perhaps, being the first prospective controlled study, he himself failed to gauge its value, nor was he able to convey the importance of his finding.
Curiosities
Vitamin C is also called ascorbic acid, precisely derived from the Latin word for scurvy: scorbutus.
Lind defended in his own treatise that scurvy was due to excessive transpiration.
In 1794 it was decided to administer lemon juice mixed with grog (rum diluted with water) to prevent scurvy on the ship Suffolk. There were no cases of scurvy on her 23-week voyage.
Lind described that in his experiment, after citrus, cider was the second-best treatment. However, cider does not contain vitamin C and does not prevent scurvy.
Citrus fruits were expensive in Lind's England, which may have contributed to delaying their preventive use. In fact, the cheaper lime soon became the citrus fruit of choice.
You can visit the James Lind Library website, a website that discusses the history of controlled clinical trials.
Bibliography
Arun Bhatt, Evolution of Clinical Research: A History Before and Beyond James Lind, PICR Jan 2010
Jeremy Hugh Baron, The scurvy of sailors before and after James Lind: a reappraisal, Nutrition Reviews
Marcus White, James Lind: The man who helped cure scurvy with lemons. BBC News
Wikipedia: scurvy
You can also find links in the text I have used to write this post
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Versión en Español
Durante el siglo XVI se empiezan a realizar largas expediciones marítimas en las que las tripulaciones de los barcos pueden estar meses sin pisar tierra firme. Algunas tienen un destino lejano pero concreto. Otras, como la expedición de Magallanes y Elcano, se adentran en lo desconocido. Bienvenidos al reino del escorbuto, la peste del mar.
El escorbuto es la enfermedad que resulta del déficit de vitamina C. Los marineros desnutridos comenzaban sintiendo un terrible cansancio. El pelo se fragmenta y se cae. Hay hemorragias en la piel, en los músculos, trombosis en las venas. Las encías se hinchan, se infectan, sangran, los dientes pueden caer. Las heridas no cicatrizan, empiezan a haber hemorragias en vísceras internas y problemas psiquiátricos (temibles terrores). La última fase se caracteriza por ictericia, edema, fiebre, convulsiones, shock y muerte.
Tras leer esto probablemente has decidido beberte un zumo de naranja. Tranquilo, tus encías están a salvo con tu dieta actual.
Pero la dieta de los marineros de las largas travesías no era como la que puedes comprar en el supermercado. Los marineros que pasaban meses en alta mar gastaban rápidamente los alimentos frescos y tenían que consumir comida que se conservara fácilmente y que aportara calorías, como cereales y carne salada, que no contienen vitamina C.
El escorbuto era menos frecuente en barcos de países del sur de Europa, como España y Portugal, probablemente por el mayor aprovisionamiento de fruta y verdura fresca. Se recomendaban diversos remedios preventivos, algunos de ellos relacionados con el consumo de alimentos que hoy sabemos que son ricos en vitamina C, otros no eran efectivos, pero se usaban. En cualquier caso, no había una recomendación oficial al respecto en la armada inglesa.
James Lind (1716-1794) fue un cirujano de Edimburgo. Con 23 años se echó a la mar para aprender el arte de la cirugía naval.
Golfo de Vizcaya, mayo de 1747. Lind tiene 31 años y participa en una patrulla en el canal de la Mancha. Lleva 8 años navegando de forma casi continua.
El barco hace 8 semanas que zarpó. El escorbuto empieza a hacer estragos.
Lind elige a 12 marineros con síntomas de escorbuto con similar gravedad y los divide por parejas (6 parejas). Cada pareja recibió una dieta diferente: sidra, elixir de vitriolo, agua de mar, una pasta a base de ajo, semillas de mostaza, rábano picante, bálsamo del Perú y goma mirra (desconozco el sabor de semejante mezcla), vinagre o cítricos (2 naranjas y 1 limón al día). Nace el primer ensayo clínico controlado.
En 6 días los marineros que gozaron de los cítricos sanaron.
Descripción del propio Lind de su experimento en su tratado sobre escorbuto, www.jameslindlibrary.org
En 1748 Lind pone fin a su periodo de cirujano naval, y vuelve a Edimburgo. Cinco años después publica su Tratado sobre Escorbuto (Treatise on Scurvy), que incluía una revisión de más de 50 libros sobre el manejo del escorbuto.
El Almirantazgo tardó 42 años en ordenar la distribución de zumo de limón a los marineros, periodo en el cual presumiblemente murieron innumerables marineros de escorbuto. Se ha especulado que en realidad el propio Lind no señaló claramente en su tratado que los cítricos eran la clave, y defendía además otros tratamientos no efectivos como el aire fresco y el ejercicio.
Quizás, al ser el primer estudio controlado prospectivo, él mismo no supo calibrar su valor, ni supo transmitir la importancia de su hallazgo.
Curiosidades
La vitamina C también se llama ácido ascórbico, precisamente derivado de la palabra en latín para el escorbuto: scorbutus.
Lind defendió en su propio tratado que el escorbuto se debía a un exceso de transpiración.
En 1794 se decidió administrar zumo de limón mezclado con grog (ron diluido en agua) para prevenir el escorbuto en el barco Suffolk. No hubo casos de escorbuto en su viaje de 23 semanas.
Lind describió que en su experimento, tras los cítricos, la sidra era el segundo mejor tratamiento. Sin embargo, la sidra no tiene vitamina C y no previene el escorbuto.
Los cítricos eran caros en la Inglaterra de Lind, eso pudo ser un factor que contribuyó a que se demorara su uso preventivo. De hecho, la lima, más barata, pronto fue el cítrico de elección.
Puedes visitar la página web de la James Lind Library, un sitio web en el que se habla de la historia de los ensayos clínicos controlados.
Bibliografía
Arun Bhatt, Evolution of Clinical Research: A History Before and Beyond James Lind, PICR Jan 2010
Jeremy Hugh Baron, Sailors' scurvy before and after James Lind–a reassessment, Nutrition Reviews
Marcus White, James Lind: The man who helped to cure scurvy with lemons. BBC news
Wikipedia: scurvy
Puedes encontrar también links en el texto que he usado para escribir este post