A tale of two studies – 268 years apart

by Carolyn Thomas   ♥   @HeartSisters 

I wrote last week about patients who tend to believe medical studies whose findings they like – but not so much if they don’t.  Hardly surprisingly, many physicians may also tend to promote the results of studies when conclusions match their own clinical experience – and not so much if they don’t. That’s exactly what Dr. James Lind worried about, too – way back in the year 1753.  Dr. Lind’s story may have been one of the earliest examples of what’s often called the “bench to bedside” delay between research findings and the time they take to ultimately trickle down to alter actual patient care.   .    .     . 

It was 268 years ago when Dr. Lind, a Scottish physician who had served with Britain’s Royal Navy as a ship surgeon’s mate, published what he called “A Treatise On The Scurvy”. (1)

 Appalled by the high death rates he had encountered at sea caused by scurvy among sailors on long sea voyages, Dr. Lind designed a scientific experiment for selected sailors, all suffering with scurvy, while out at sea onboard the 50-gun warship Salisbury.  He knew that symptoms of scurvy typically began after 2-3 months at sea.  Like all good scientists, he explained his methodology in his Treatise:

“Their cases were as similar as I could have them. They all in general had putrid gums, the spots, and lassitude, with weakness of the knees. They lay together in one place, and had one diet common to all.”

Dr. Lind was thus illustrating for future generations of researchers the need to guard against selection bias by keeping confounding factors constant – clinical conditions, environment and basic diet. He believed that “the putrefaction of the body caused by scurvy” might be prevented with acids. He divided the men into pairs that would each receive a different daily treatment – for example, vinegar, cider, citrus fruit, etc. His Treatise was also an early example of a systematic review of 54 books that had already been written on the subject of scurvy (he wrote abstracts summarizing his views on each of those 54 books). His small but important experiment is widely considered by medical historians, in fact, as the first example of a controlled clinical trial.(1)

The sailors with scurvy who responded most dramatically were those who had been given two oranges and one lemon every day – a solid dose of vitamin C.  In fact, Dr. Lind wrote that one of the sailors in the oranges-and-lemon group was apparently deemed so improved and so fit for duty after only six days of the treatment that he was “appointed to attend the rest of the sick”.

Dr. Lind’s experiment at sea essentially changed marine history – although it took decades for the rest of the medical profession to catch up. 

Despite the definitive findings described in his study, Dr. Lind was hesitant to recommend the use of oranges or lemons to prevent and treat scurvy.  He believed that the Royal Navy brass – although acutely aware of the deadly consequences of scurvy among its seafaring sailors – would fight against his recommendation for fruit that was both expensive and perishable.  But another reason was the worry he described in his Treatise – a fear that physicians of the day would not be willing to either endorse this new treatment or to abandon any of their own longstanding alternatives  (although largely based on anecdotal experiences leading inevitably to poor results).

He was right to be worried. University-trained European physicians with no experience of either the disease or its cure persisted in reviews of conflicting literature.(2)  In fact, it took over 40 years before the Royal Navy could finally be convinced to make lemon juice a compulsory part of the seafarer’s daily diet to prevent scurvy.  One can only imagine how many career sailors suffered or died needlessly during those four decades of waiting.

Fast forward 268 years to 2021 – and a new clinical study that may, like Dr. Lind’s scurvy experiment, change forever how another serious medical condition is treated.

Or will it?

A new study called the TTM2 trial published in the New England Journal of Medicine looked at a standard treatment choice in patients who have suffered an out-of-hospital cardiac arrest, based on treatment guidelines that currently recommend therapy called targeted temperature management (TTM) or targeted hypothermia.  This means cooling a patient’s body to between 32-36°C to help avoid a fever (normal body temperature is 37.2°C). Cooling is hardly a new concept in medicine, by the way: the idea that cooling a person can slow biological processes – and subsequently death – was first described by Hippocrates around 450 B.C., who advised packing wounded soldiers in the snow).

Out-of-hospital cardiac arrests are notoriously likely to be fatal. The stats are grim: fewer than 10% of people who suffer an out-of-hospital cardiac arrest will survive it, and even if they happen to be in the hospital at the time, survival rates are lower than 20% for in-hospital cardiac arrest.(3)  So physicians will understandably consider almost any intervention to help improve those outcomes for their patients.

In this new TTM2 trial, researchers in Europe, Australia and the U.S. studied 1,900 comatose adults who had had an out-of-hospital cardiac arrest, and treated with either targeted hypothermia or “normothermia”.  The study not only identified potential harms of the TTM therapy (“Therapeutic hypothermia is associated with a higher risk of cardiac arrhythmia“)  but also found that TTM “does not appear to benefit any patient group.”

PulmCrit creator Dr. Josh Farkas, who teaches Pulmonary and Critical Care Medicine at the University of Vermont, offered an enlighteningly direct take on the TTM2 study results, in his article called “A History of Hypothermia for Cardiac Arrest, 2002-2021 (RIP)”:

“It is increasingly clear that hypothermia is merely an unnecessarily aggressive approach to avoiding fever. With two robust studies showing no benefit from hypothermia (TTM1 & TTM2), it’s no longer possible to justify the cost and harms of hypothermia, outside of a clinical trial. However, we must not throw out the baby with the bathwater. Temperature control may be critically important for post-cardiac arrest patients. As we transition away from hypothermia, we must do so cautiously.”

‘True believers in hypothermia will continue to try to poke holes in TTM2 (good luck with that – the study is a methodological fortress).  Or they will say that their patient population is different (actually, results in TTM2 are robust across every subgroup analysis).

“The bottom line is that the theoretical and evidentiary basis for post-cardiac arrest hypothermia in adult humans was never there to begin with.  It just doesn’t work.”

Unlike Dr. James Lind back in the 1700s, who was reluctant to put forward his scurvy study recommendations due to worry that physicians would be unwilling to endorse them in daily practice, Dr. Paul Young, one of the TTM2 researcher team, had no such qualms, adding via Twitter this week:

”  The  TTM2 trial data should herald the end of the era of therapeutic hypothermia for adult cardiac arrest.”

It’s far too early, of course, to predict how long it will take physicians to embrace the findings of newly published research. The average “bench to bedside” lag time is currently estimated to be about 17 years.  A number of physicians have already responded via social media to the TTM2 study results this past week, some declaring that they will continue to treat their cardiac arrest patients with targeted hypothermia as they have been doing for almost 20 years. Others report that they may still consider TTM for some cardiac arrest patients, but will now aim for “mild” hypothermia closer to 36°C compared to the cooler 33° option.  Many, however, herald the results of the TTM2 study using words like “cataclysmic” (Dr. Stephan A. Mayer in New York) or “definitely game-changing” (Dr. Jan Hansel in Lancaster, England).

I especially appreciated this considered reaction: “I like that TTM2 has basically landed on us Goldilocks-ing our post-cardiac arrest patients: Not too hot, not too cold. Do no harm. Supportive care.”  (Dr. Christopher Nemeh in Houston, Texas).

Time will tell. We can only wait and wonder if this study’s recommendations will take 40 years to evolve into the new standard of care for cardiac arrest patients.

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1. Collier R. “Legumes, lemons and streptomycin: a short history of the clinical trial”.  CMAJ. 2009 Jan 6; 180(1):23-4.

2. Banks Sir Joseph. “The Endeavour Journal of Sir Joseph Banks. Journal from 25 August 1768-12 July 1771”  A Project Gutenberg of Australia eBook No.0501141.

3. Mary Newman, Sudden Cardiac Arrest Foundation, American Heart Association’s Heart & Stroke Statistics – 2020 Update, January  29, 2020.

♥ 

Q:   Is faster always better? Should research results be adopted by physicians sooner than they are now to ensure bedside practices are updated according to best-quality studies?

 Image of lemons and ice:  Andreas Riedelmeier, Pixabay

NOTE FROM CAROLYN:   I wrote more about different types of heart disease , including sudden cardiac arrest, in my book, “A Woman’s Guide to Living with Heart Disease”. You can ask for it at your local library or favourite bookshop, or order it online (paperback, hardcover or e-book) at Amazon, or order it directly from my publisher, Johns Hopkins University Press (use their code HTWN to save 30% off the list price).

See also:

Is sudden cardiac arrest the same as a heart attack?

Cardiac research and the mystery of the missing facts

Why your own story is not scientific data