Episode 25: Salt Water

 in Podcasts  tagged biostatistics / cholera / history / IV fluids by

Intravenous or IV fluids are a ubiquitous treatment in medicine, and one of the most cost-effective treatments that we have, costing less than a cup of coffee in the developing world. But it wasn’t always this way. In this episode, called Salt Water, we go back to the second great cholera epidemic, where a young doctor developed IV fluids to help fight this mysterious disease, only to see his invention abandoned for over half a century. We also have a new #AdamAnswers about bloodletting. So join us for another rollicking adventure of Bedside Rounds, a tiny podcast about fascinating stories in clinical medicine!

 

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Transcript

This is Adam Rodman, and you’re listening to Bedside Rounds. This episode is called “Salt Water,” and it’s about how a treatment that costs less than your morning coffee but saves countless lives around the world was born out of the cholera epidemic in 19th century England, only to be abandoned less than a year later. I am talking about, of course, IV or intravenous fluids. 

Our story starts on the English coast in 1831. The mood is tense. A wave of revolutions has just struck Europe, leading to the toppling of the French King (think “Les Miserables”). Even closer to home, labor riots have broken and for the first time raised the specter of revolution. But perhaps the most disturbing news trickles in from far away — dark rumors coming out of the East about the “blue cholera”. A disease called “cholera” was nothing new, of course — it was well-known to English doctors as a seasonal diarrhea associated with summer and meat consumption. We’d probably today call that disease today food poisoning or dysentery. This was before germ theory, and the classification of diseases was still in its infancy. 

In any event, it was clear that this disease was something horrifyingly new. Its victims would be struck with a watery diarrhea, and within a day or two would were dead, their skin a pale blue-grey that gave the disease its moniker. The Western scientific world first heard whispers of the disease from China, though historians now believe the outbreak started in what is now Indonesia and the Phillipines. British doctors first encountered it in British India. One of the early descriptions of this disease came from Lord Bentinck, writing from his military post in Bahadurpur. I’ve got the full letter in the show notes, if you want to review it yourself. To him, cholera was an incredibly efficient invading army, marching up the Ganges River, decimating villages as it traveled. He had set his medical officers to study the disease, and they had come to two possible conclusions about how it was spread –firstly was contagion – spread by touch. The second was by foul air and bad smells, which is the miasmatic theory of disease and was widely accepted until the germ theory felled it.  He closes his letter with a dire prediction: “I see with pain the progress of cholera and our unreverent opinion here is that no part of Europe will be exempt from it.”

And Lord Bentick was right. The disease snaked its way up the Ganges and into the major trade routes. By August 1830, cholera had appeared in Moscow, and then throughout Russia. The death toll was massive – 100,000 dead, and over a quarter of a million infected. Next it pushed into Central Europe and the Baltic states, leaving similar destruction in its path. Before this epidemic would end, millions would lose their lives. Back in England, the Lancet – the preeminent medical journal that was then only 10 years old — published a fold out map of Europe that allowed readers to trace out the spread of cholera across continental Europe, leading inexorably to the British Isles .

But back to the English Coast. The United Kingdom has traditionally relied on the English Channel to protect it from foreign invaders, and starting in 1831 the newly organized Board of Health was taxed and stopping cholera at its shores. The board met swiftly and reviewed the literature on the disease, instituting a 10-day quarantine on all ships arriving from the Baltics.

It didn’t work, and what happened next should still serve as a potent reminder to the climate change “skeptics,” anti-vaxxers, and all other deniers of science. Fear of the economic impact of quarantine led local business leaders in the port city of Sunderland to form an “anti-cholera party,” which despite the name was not against the disease, but against the Board of Health, and ships were allowed to flaunt the quarantine. The first confirmed victim was a 12 year-old girl in October named Isabella Hazard,who lived near the docks. From her it spread quickly throughout the town; the only group that was spared was the barracks, as the commander had listened to the authorities and immediately quarantined his own men. With cholera now on the loose, the Board leapt into action, isolating the town, cleaning the streets twice a day, handing out blankets to the poor. These were all attempts to control noxious odors, based on their understanding of miasma, though they probably did actually help since cholera is primarily transmitted through tainted drinking water. Despite their best efforts, by early 1832 the disease had spread throughout the country. It was the plague that broke the camel’s back, so to speak. The foreignness of the disease, the failure of doctors to stop the outbreak, and the widespread belief that hospitals were intentionally killing cholera patients to use as dissection specimens led to “cholera riots” throughout the country. A print published in the Lancet shows the “blue girl”, a young woman in the late stages of cholera, that struck fear through the educated classes. The Church of England even regarded the outbreak as a possible “Act of God” to punish the nation for prior transgressions, and in the Summer a prayer begging for God’s mercy was read in every church in England.

Doctors from around the country arrived in Sunderland to treat the sick – so-called “cholera tourists.”  And from them it’s not hard to understand where the public’s suspicion of doctor’s might come from. The “medicine” they inflicted on the denizens of Sunderland was mostly a form of “benevolent homicide,” as a future reviewer would write.

Before we get into medical practice of the day, let’s discuss what cholera does to the body. Today we know that cholera is caused by a rod-shaped bacteria called vibrio cholerae. Transmission is usually fecal-oral, which means exactly what you think. The bacteria itself isn’t invasive, but it makes a potent toxin that leads to losses of copious amounts of watery diarrhea, referred to now as “rice water stool.” It looks like urine, and the amount excreted each day can be up to 20 liters. The volume depletion is so severe that it rapidly leads to hypovolemic shock and hypoxia, causing the pale blue-grey color that gave the disease its epithet. 

So with today’s understanding of the pathophysiology of the disease, treatment is basically restoring the body’s fluids — you lose fluids, we give them back. We use oral rehydration salts in mild cases, or intravenous fluids if people are really sick. The particularly horrifying thing about the treatments during the epidemic is that doctors basically did the opposite – making their patients vomit, have more diarrhea, and bleeding them. One Liverpool physician treatment patients by injecting pressurized enemas every 30 to 60 minutes. And when it came to bleeding, doctors noted that veins were collapsed and bled poorly, which makes perfect sense because these patients are profoundly dehydrated. Doctors at the time responded by puncturing arteries instead to get even more blood. Every one of these therapies was based on centuries of tradition and was taught in the finest medical schools. And they all killed their patients.

But not all these cholera tourists brought death upon the people of Sunderland. Dr. William Brooke O’Shaughnessy was a 22 years old Irishman, barely graduated from Edinburgh Medical School.  He too noted the poor bleeding of cholera patients. which he theorized was due to “universal stagnation of the venous system” — the idea that cholera somehow depleted the oxygen-carrying components of the blood, which were then unknown — hemoglobin wouldn’t be discovered for two more decades. His theory was that he could counteract this by dissolving oxygen-carrying salts in water and injecting it directly into patients’ veins. He did just this to a dog, who apparently did just fine  In Sunderland, he actually ran experiments on the blood of cholera patients, and making measurements of the salts — “electrolytes” are just fancy names for salts —  found that the blood of cholera patients was dangerously low in both salt and water.  Armed with this evidence, he quickly modified his theory, and published his results in a landmark paper in the Lancet, stating that the treatment of cholera should seek to “restore the blood to its natural specific gravity,” and “restore its deficient saline matters” either by drinking or infusing aqueous fluids directly into the veins. I’ve said before the nineteenth century is one of my favorite periods in medical history, because it’s when medicine truly starts to become a science. Here is a young man – he’d be only a first year medical-student today — who developed a hypothesis, performed detailed experiments, changed his theory based on the evidence, and then developed what is essentially still the first-line treatment of cholera. And it just so happens to go directly against the medical orthodoxy of the day.

 

And of course, what happened next shouldn’t surprise you – what always happens when a young upstart questions long-held traditions. Everybody started to do the right thing! Ha, of course not. Immediately after his article in the Lancet, infusion of IV saline did actually start to spread. Most prominent was Thomas Latta, who used a syringe normally for bloodletting to inject his own salt solution. He reported on remarkable transformations of patients returning from the brink of death. O’Shaugnessy was impressed, and wrote, “The results of the practice described by Drs. Latta exceed my most sanguine anticipations.” He reported miraculous recoveries after infusions of anywhere between 3 and 20 liters. But by summer time – the same time the Church of England was begging God for mercy – the pendulum had swung. Reports of side effects – swelling of the brain, infections, the splitting apart of blood cells, and even death from sepsis trickled in. And studies, including one in the Lancet, showed that treatment with saline was associated with a far higher mortality rate than other solutions. In retrospect, this was likely all due to selection bias — IV fluids were reserved for the truly sickest patients; if you’ll recall from episode 14: The First Trial, the first true double-blind RCT wouldn’t be conducted until 1948.

Just as quickly as they had started to flow into patients’ veins, IV fluids were relegated to this dustbin of medical history, and old standards like calomel and opium held the day. Ultimately, it seems likely that the treatment was too far ahead of its time – sterilization to prevent contamination of the fluids would take another 30 years, and it would be another 50 until doctors in Germany demonstrated the superiority of IV fluids in resuscitating dogs. It was then attempted in patients suffering hemorrhage and by the end of the nineteenth century, IV fluids had become widespread, including for the treatment of cholera. The disease that laid entire cities to their death now has a mortality rate of well under 1% with oral and IV fluid hydration.

O’Shaugnessy, by inventing one of the most essential treatments in modern medicine, should be upper there with Jenner, Semelweiss, and Lister, but I’d suspect most doctors don’t know his name. Fortunately, the talented young man did not fade into obscurity – he moved to India, became a professor of chemistry, and introduced the first telegraph service in the nation. He is also known for his experimentations with cannabis – he introduced the drug to England, and his case report of using it to treat the spasms of tetanus is probably the first mention of medical marijuana in the West. He was eventually knighted, though not for his work on cholera, and died at the ripe age of 79. It’s a small comfort that he lived long enough to watch his IV fluids become the standard of care for many conditions.

That nineteenth century debate about IV fluids — it isn’t really over. While they’re unquestionably beneficial in any number of conditions, there’s controversy about what the ideal make up of the salts should be, how much to give, and how quickly to give them. Sit down a critical care physician, a surgeon, and a nephrologist and ask them their opinions of IV fluids, and I promise you’ll have a lively discussion.

 

You probably don’t think that much about cholera, but it’s also alive and well. There are 3-5 million cases a year, and between 100,000 and 120,000 deaths, the vast majority in Africa. And just like in the 1832 outbreak in England, sometimes we – the doctors – are the problem. Just look at the most recent outbreak in Haiti, introduced by UN aid workers, and the deplorable attempts by the UN to cover it up. 

 

IV fluids remain essential in treatment of these patients — it’s on the WHO’s essentials list, and in the developing world can cost under a dollar for a bag. Of course, in Las Vegas or New Orleans, hung over revelers are willing to pay something like $200 for a similar infusion. But no matter how much it costs, we’re all richer for Dr. O’Shaungessy’s experimentation and discovery.

 

Ugh, that was a horrible pun. Okay, that’s it, I’m done. Show’s over! But wait — it’s time for this month’s #AdamAnswers!

This one comes from a user on one of my favorite subreddits, r/AskHistorians, from the user AustroHungarian1. They ask: 

If bloodletting was rubbish, why was it considered as a medical procedure for such a long time?

The timing is perfect, since bloodletting was a treatment of choice in cholera. My answer to the thread is in the shownotes — and I did dash it out in the morning before attending, and more importantly before I drank my coffee, so don’t judge me too harshly. It’s about how a young British surgeon did a randomized trial during the Napoleonic Wars that showed bloodletting was atrociously bad — a number needed to kill of almost FOUR, meaning for every four wounded soldiers you bled, one would die — and how these results were lost until 1987, when they were found in a locked trunk! And then how the first proto-epidemiologists started looking into bloodletting about a decade later and used the new field of statistics to show that it probably didn’t work that great. And finally how germ theory provided a new theoretical framework for disease and took the intellectual sails out of bloodletting. Fascinating stuff, and it’d probably make a good episode in and of itself.

But I actually want to address the bigger question, if you’ll allow me AustroHungarian1, why does any medical procedure last for such a long time if it doesn’t work? Even moreso if it’s harmful?

In the case of bloodletting, the ostensible answer is that our methods of testing a hypothesis — the scientific method essentially — hadn’t been invented. Bloodletting goes back to antiquity, but the first real medical trial with different treatment groups wasn’t until James Lind in 1747. The first modern randomized controlled trial would have to late until 1949. 

I said ostensible, and that’s because I think the actual reason is a little more discomfiting. After all, the theoretical basis and trial evidence should have demolished bloodletting but it’s still in the first edition of Davidson’s Principles and Practice of Medicine, which was published in 1952. It’s used to “relieve venous congestion when all other methods have failed.” If that seems comfortably in the past, there are plenty of examples from the last few decades of procedures doctors do that are useless, or even harm patients: using medications that suppress bad rhythms after heart attacks, estrogen replacement therapy, surgeries for a torn meniscus, placing a stent in the heart for asymptomatic coronary artery disease. All of these things have had large trials showing that they’re useless, or even harmful — but many were done for decades, and some are still done today. They may have even been done to you or someone you know — something with presumably great access to care like George W. Bush, the former American president, received a heart stent for no symptoms

 

So how does this happen? We’re in an age where we can reasonably expect self-driving cars and drones delivering my groceries in the next few years. Can we not expect medical therapies that actually work?  The reasons are complicated, and I’m not going to go into them all, but I think the overarching explanation should sound familiar to anyone who listens to my show. Essentially, prior to the past few decades, doctors basically designed new treatments that “made sense” — that were based on a pathophysiological understanding of disease. If someone’s coronary artery is blocked, and we know blocked arteries cause heart attacks, why WOULDN’T you want to open it up again? If estrogen appears to protect women from heart disease, and estrogen drops after menopause, why WOULDN’T you want to give it back to women? Trials are also very expensive to run, and we’ve set up a medical system that pays doctors for doing stuff, not taking a step back and analyzing data.

 

And if you think about it — that’s what happened with bloodletting. It made sense, at least from the medical framework of the day, the humoral system. It literally took the birth of the whole new fields of epidemiology and biostatistics to prove it wrong, though probably want really killed it off was the development and acceptance of a new framework in which it didn’t fit — the germ theory of disease. And this is why I love your question, AustroHungarian1 — because I can easily ask, “if meniscal repair surgery is rubbish, why is it still practiced today?” or “if stenting coronary arteries in asymptomatic heart disease is rubbish why is it still practiced today?” and the answers are basically the same. Our predecessors aren’t that different from us after all. 

By the way, this phenomenon is called medical reversal, and there’s a great book on the subject called “Ending Medical Reversal,” by Drs. Prasad and Cifu. Vinay Prasad in particular was one of my heroes at OHSU during my residency training, so you should definitely check it out. 

Okay, that’s it for #AdamAnswers! Do you have a burning question about medicine that you want me to address? Tweet at me @AdamRodmanMD!

 

That’s it for the show! Hope you guys enjoyed it! This was the last of an era — I actually did most of the research and writing somewhere over Africa while I was moving back to the United States, and I’m recording it in my still not-fully-unpacked apartment in Boston. Not gonna lie — it’s a strange feeling to be back. But that also means there will be some new exciting things coming for Bedside Rounds. So stay tuned! You can listen to the whole back catalogue on the website at www.bedside-rounds.org, on Apple Podcasts or your preferred podcast retrieval method. If you’re a Tweeting kind of person, I’m on Twitter @AdamRodmanMD and facebook page is /BedsideRounds. All of the sources are in the shownotes, and I’ll be posting some cool images to the facebook page and Twitter over the next several days.

 

And of course, as always while I am actually a doctor and I don’t just play one on the internet, this podcast is intended to be purely for entertainment and informational purposes, and should not be construed as medical advice. If you have any medical concerns, please see your primary care provider.