How the best of care can be terrible without bedside ultrasound

I just read a "Clinical Problem Solving" case from the New England Journal of Medicine (NEJM). It was entitled Stream of Consciousness and it told the story of a 65 year old man who was a patient at the Brigham and Women's Hospital of Harvard Medical School, arguably one of the finest medical institutions in the world.

These cases are presented in single paragraphs to a clinical expert physician who then comments about his or her thought processes and discusses how he or she would have handled the situation. In this narrative the patient presented to a different hospital in New England with kidney failure and a gradual onset of confusion in the setting of very high blood pressure. He was then transferred to the Brigham and Women's Hospital for further evaluation and treatment. He had lab tests of all color and stripe along with MRI and CT scans of his brain which showed some disconcerting spots. He had a lumbar puncture and his high blood pressure was treated. Eventually, after 2 or 3 days in the hospital (I can't tell from the narrative), an ultrasound was done which showed that his bladder had not been emptying properly, which had caused the kidney failure and probably the high blood pressure. A foley catheter was placed which drained nearly 3 liters(!) of urine after which his blood pressure was much more easily controlled.

The exciting diagnosis was Posterior Reversible Encephalopathic Syndrome (PRES) which was first described in a case series in 1996. It is closely related to eclampsia, a condition of women in labor or directly following labor in which the is injured by high blood pressure leading to seizures and sometimes death. The cause is thought to be leakiness of the blood vessels in the brain related to high blood pressure. It is very important to recognize PRES because prompt treatment to lower the blood pressure can prevent long term brain damage.

This guy had the best of treatment by the best of doctors, but what he really needed was a bedside ultrasound at the first hospital or on arrival at the Brigham. People who read this blog will have noticed that I am a strong proponent (nerd perhaps) of ultrasound performed by a treating physician as part of a physical exam in just about everyone with a significant medical concern. If he had a bedside ultrasound the doctor performing it would have seen that the collecting systems in his kidneys were dilated and that the cause was a massively over-full bladder, likely due to an enlarged prostate. The bladder would have been drained immediately, resulting in correction of his blood pressure and improvement in his kidney function. He might not have needed to be transferred to the larger hospital at all.

Perhaps his physicians at the community hospital did not know how to perform an ultrasound. Still, he would have benefited mightily from prompt point of care ultrasound once he arrived at the Brigham. Head scratching about the cause of his kidney failure might have been curtailed. Blood pressure control would have been more rapidly achieved, benefiting his spotty brain. His very complete and likely very costly evaluation might have been briefer and less expensive. Physicians might have been able to discharge him to home more quickly.

The impact of bedside ultrasound could have been even more profound had it been done even earlier in his course. This fellow's problem emptying his bladder did not happen all of a sudden 3 weeks before he came to the hospital. It is likely that he had mentioned to his primary care doctor some slowness passing urine or a feeling that he hadn't emptied completely. If that physician had performed an ultrasound of the bladder in the office he would have seen that it wasn't emptying properly and would have initiated some kind of treatment before it got to be the size of a large honeydew melon. It is possible, even likely, that this whole near-tragedy could have been prevented.

Bedside ultrasound is not yet the standard of care among internal medicine physicians. It should be, and in the fullness of time, it probably will be.

Comparing the US with other high income countries: how do we pay so much for healthcare?

Healthcare costs in the US are significantly greater than in any other developed country and for this we have a shorter life expectancy than they. We also develop cutting edge technologies and miracle cures and are world leaders in medical research. Just how do we compare with other economically advantaged nations?

In a Special Communication article in the JAMA (Journal of the American Medical Association) this week, Harvard researchers Irene Papanicolas, Liana Woskie and Ashish K. Jha analyzed data from Japan, Australia, Switzerland, Germany, France, the Netherlands, the United Kingdom, Canada, Sweden and Denmark about healthcare and social spending as well as outcomes. It is a huge amount of data gleaned from diverse sources and the authors have presented it beautifully. I will only comment on it and can't possibly do it justice. Still, there are several really interesting facts to point out, so I will dig in.

In US dollars, our spending per person per year is higher than any other country in this group. We spend the equivalent of $9403 in public and private money on healthcare for each of us. Our closest competitor is Sweden at $6808 and the UK comes in at $3377, in last place. This is 17.8% of our gross domestic product. Sweden spends 11.9% of its GDP and the UK 9.7%. How did we get so expensive?

First, the researchers wanted to test the assertion that American healthcare is expensive because people use too much of it. That is a complex question, but generally speaking the answer is no. We place right in the middle of the pack in hospitalizations for heart attacks, pneumonia, lung disease and mental illness. Germany is the leader there. We do get more cardiac bypasses and angioplasties, far more knee replacements and a few more caesarian sections and CT scans. We don't get more hip replacements. We have more outpatient visits but not more hospitalizations. This is not the key issue.

They also wanted to test the hypothesis that we spend more in healthcare because we don't allocate as much on "social spending" which is defined as benefits to people who are in bad circumstances. We are neither the highest nor the lowest in this category, though we are on the low end, near Australia and Canada. I'm not at all sure that supporting people once they are in trouble should be the definition of "social spending." It seems to me that money spent on education or a healthy environment, walkable cities, good jobs and opportunities for vibrant aging would be more likely to affect healthcare spending than social welfare. Perhaps spending on those is difficult or impossible to measure.

Health expenditures are quite different in different countries. The US, for instance, spends much more than the other countries on administration, think billing clerks and insurance companies. We spend 8% of our budget on this stuff. Surely we could follow the examples of Japan, France, Denmark, Sweden and the UK, all of whom keep these costs to under 3%. That would be an enormous amount of money saved without jeopardizing vital services.

We are neither high nor low in our spending on preventive healthcare, though I think they are doing different prevention than we are.

We have fewer primary care physicians compared to specialists than France and Canada, but not than the rest of the countries, which surprised me.

We spend more money on prescription drugs than any other country, equivalent to $1443 per person, twice as much as the average for all of the countries combined. We lead the pack in use of generics, but apparently that doesn't matter because even our generics are expensive.

There is a measurement called "horizontal inequality" which I hadn't heard of before. It is the likelihood of seeing a doctor in the last 12 months and whether that correlates strongly with wealth. In the US it does. Wealthy people see doctors pretty often and poorer ones do not. We are significantly worse in this regard than in Canada, France, Germany or the UK. The other countries did not have data to evaluate that. The reason for this is pretty clear: in every other country healthcare is available at a cost that is affordable, either by private insurance or government coverage, to 99-100% of the population. We are at 90%.

We do not look very stellar when it comes to certain outcomes. Our maternal mortality is 3 times as high as the next highest country, the UK. Our infant mortality is also higher, though not as egregiously so. Our life expectancy is 3 years shorter than the average of all of these countries, at 78.8 years. We are among the best, however, in mortality from strokes and heart attacks, and it is easier to get in to see a primary care doctor or specialist in the US than most other places.

We are more obese (70% obese or overweight), but not more likely to smoke or drink to excess. Our doctors are paid considerably more, but there are fewer of them per number of patients, so that apparently balances out.

Americans are the people least happy with their healthcare system. 19% feel the system works well and 23% believe it needs to be completely rebuilt. But none of these privileged countries to which we are compared is doing a great job, in the view of their citizens. Germans are happiest, but only 60% of them think their system works well. Canada pleases only 35% of its people. Worldwide, it seems like there may be quite a bit of room for improvement.

The authors of this study conclude that the costs of pharmaceuticals, devices, labor and administration are the main drivers of higher healthcare costs in the US. That is a good starting place for explaining how our system got to be so much more expensive than other countries. I'm curious, though, about how other countries develop good systems, what processes they have that are not good, either inefficient or providing poor care, and how they have evolved, since that could be helpful in moving all of us in the right direction. The United States continues to be one of the most productive innovators in the world, sometimes jettisoning expensive and useless routines and replacing them with ones that serve us better. Our innovations often drive savings and better outcomes in other countries. We need to learn from them as well.

This article is a good way to look at "how is American healthcare so expensive?" The why of it is more complex. Several commentary articles accompany this one, with delightfully different conclusions. It's a fascinating subject. I'll keep looking into it and write when I find the answer.

Drug costs and copays

Drug costs in the US are higher than in in any other industrialized country in the world. Our cost for an insulin glargine (long acting insulin) pen is $76.80 and in Canada, so very few miles away, it costs $19.60. The latter price is reasonable. The former price can make the difference between being able to afford a life saving drug and dying. It is illegal, however, for a US citizen to buy his or her insulin, or any other drug available in the US, from another country.

Costs of pharmaceuticals in other countries are usually regulated by the government. Not so in the US. This is due to the lobbying power of US pharmaceutical companies. Because US citizens pay more for our drugs, we do have earlier access to newly released products than other countries if we can afford them. Our deep pockets help make new drug development attractive to drug companies. For people whose lives depend on the development of a new drug, this is very important. For the vast majority of patients, however, high drug costs can be at least burdensome and often crushing.

Healthcare costs were a major subject in the most recent issue of the JAMA (Journal of the American Medical Association.) Pharmaceutical costs were discussed in a brief article from the Medical Letter on Drugs and Therapeutics.

Not all drugs in the US are expensive, however. Such staples as lisinopril for high blood pressure and simvastatin for elevated cholesterol cost only a few dollars per month. When we go to the pharmacy and pick up these prescriptions, and the pharmacy submits the claim to our insurance companies, we pay a few dollars as a copay and go away generally happy. The low price we pay, or so we think, is thanks to the fact that our insurance is helping us out.

Tucked in the back of the issue is a letter by four health policy PhD's (Karen Van Nuys et. al.) from the University of Southern California. They researched overpayments at pharmacies by patients for drugs whose actual costs to the insurance companies is lower than what the patient pays. That's right. For some drugs, mostly the less expensive generic ones, the patient pays the pharmacy more than the pharmacy charges the insurance company and the insurance company pockets the difference. In some of these cases, the contract the insurance company has with the pharmacist prohibits the pharmacist from telling the patient about this.

I find this infuriating primarily for the lie involved. I know that insurance companies are primarily interested in making a profit, and so they do. If they couldn't turn a profit, they would go out of business. That's how it works. But it bothers me that they make patients believe that they are helping them pay for medication when they aren't. Each patient usually only loses a few dollars on the prescription for which they are overcharged (except a few on the list they published, including the nasal spray fluticasone and the antibiotic amoxicillin/clavulanate, for which the overpayment was $12 to nearly $20 per prescription), but the insurance company makes a bundle on the huge number of transactions.

Drug costs are crippling to many people, especially those with chronic diseases. Insurance companies should at least be honest about their contribution to this problem.

South Sudan trip: take 4

I have just returned from Old Fangak, Jonglei State, South Sudan after my fourth trip. I seem to have earned a welcome there for teaching bedside ultrasound to anyone who will learn and doing ultrasound whenever anybody asks. Also I cook a mean soup and make delicious chocolate sauce in which a homesick American can dip a piece of local deep fried bread dough.

The hospital I visit is a community health center which has morphed into a full service hospital for tens of thousands of people displaced by chronic civil war. Jill Seaman, a doctor friend from my home town and a champion of treatment for complex and fatal tropical diseases (particularly Kala Azar and tuberculosis), has coordinated the multiple functions of this center for years. It serves as a distribution point for food aid, a triage center for war wounded when the war is close by, a referral center for treatment of tuberculosis and Kala Azar and now a major outpost for Doctors Without Borders (Medecins sans Frontieres--MSF) in this area of the country. It also takes care of patients with rashes and fractures, splinters and pneumonia, delivers babies, nurses the dying and treats those with chronic diseases such as epilepsy, heart failure, asthma and sadness.

It sits on the bank of the Zaraf River, so named for the giraffes that roamed here before they were killed or driven off by war and hard times. The river is a beautiful slow moving thing that flows past the hospital on its way to the Blue Nile and then to Juba, South Sudan's horribly dysfunctional capitol city. Tropical birds of vast variety roost in the tamarind trees at the hospital and fish in the river, including egrets, kites and ibis. There is a vibrant open market, selling mostly cheap Chinese goods but also fish and locally grown vegetables, teas and nuts. (Also delicious dough creations for dipping in chocolate sauce when you get the chance.) The war seems always to be going on somewhere, but this year it was not too close. Still, nearly everyone has suffered some terrible loss.

My niche, other than cooking, is to teach ultrasound and be an internist. The ultrasound teaching is an extension of my enthusiasm for bedside ultrasound which is very useful in a place like this, where there are two portable ultrasound machines (one in French, through MSF) and no x-rays or CT scans. Being an internist has benefits too, since internal medicine is all about making sense of multiple complex symptoms or chronic diseases. I learn more tropical medicine each time I visit, but am hardly an expert. What I can do is recognize patterns of disease that can lead to effective treatments, and improvise treatment from what is available.

My trip in ultrasounds:

Before I arrived in Old Fangak, in the week before I left home, I got an email from Jill with a brief clip of an ultrasound of a boy's heart.

This clip was taken by pointing an iPhone camera at an ultrasound machine and shooting a little video. It shows a normal boy's heart surrounded by a huge collection of fluid. The boy was short of breath, but had walked in. The condition had come on slowly. In Old Fangak, collections of fluid around the heart and lungs are usually due to tuberculosis and often respond quite quickly to a combination of steroids (prednisolone) and anti-tuberculosis medication. I told her that it was what she thought it was and that she should try her usual trick. Jill has gradually expanded her comfort with ultrasound beyond obstetrics but this was such a dramatic finding that she wanted another pair of eyes. When I arrived, this boy was one of the first patients I saw, and his pericardial effusion was almost gone about a week after starting treatment.

In the next bed in the hospital was another teenage boy with heart failure. He had been coming to the clinic for shortness of breath but despite medication had become so swollen and weak that he had been admitted. His ultrasound showed that his mitral valve was the problem.

 

Rheumatic fever is overwhelmingly a disease of poverty and lack of access to medical care. It starts with strep throat, then a few weeks later develops into an inflammation that can involve the heart. Years later the heart valves can become scarred. In his case, there is severe mitral stenosis, with very little blood flow through the valve separating the left atrium and ventricle, leading to stretching of the left atrium, abnormal heart rhythm and increased pressure in the vasculature of the lungs. Seeing this condition will lead to more appropriate medication and possibly even a heart procedure if he can get to the doctors in Khartoum (in the country of Sudan) who do free heart surgery.

Tuberculosis is common in South Sudan and the hospital at Old Fangak is a major treatment center for people who live with it. Patients who are diagnosed with TB take up residence in the TB compound in the village where they get daily observed treatment for the 6 months it takes to cure the disease. The compound is an area with a few buildings, a couple of latrines and enough flat ground for people to camp while they get their daily tablets. The patients get enough food, a mosquito net, a blanket and a dedicated though thinly stretched staff of mostly nationals who help them to survive while they get better. At clinic a few days after I arrived, a guy who was getting treatment for TB came in feeling short of breath even though he had been on appropriate treatment for a few weeks.

The ultrasound of his heart showed some thick stuff between the pericardium and the heart which doesn't allow the heart to fill properly. He had tuberculous pericarditis which had transitioned to a nasty constrictive effusive mess. He was treated with steroids in addition to his TB tablets which may reduce the inflammation and allow the heart to function properly. In a perfect world he would also have the option of surgery to remove the rind of constricting tissue.

A strikingly graceful and beautiful 6 year old girl came to clinic with her equally striking mother, troubled with breathing problems. She was able to walk long distances, but not fast and got out of breath easily. On exam she had a very loud heart murmur. It is not terribly uncommon to see congenital heart disease, and I expected that she had a ventricular septal defect (VSD), a hole in the wall between the two main chambers of the heart. When I looked with the ultrasound I saw nothing at all. Since her heart sounds were a little louder on the right side of her chest, I looked for her heart there. Sure enough, she was turned around. Her liver was on the left, heart on the right. And she did have a VSD.

Jill sent the little ultrasound clip to the heart surgeons in Khartoum. They may be interested. It would be wonderful for her to have treatment at a dedicated pediatric heart surgery department in a major referral hospital because her heart is really weird and repairing may not be straightforward. Such a thing costs a lot of money, and she and her mother have none.

A patient who had fevers and had been in the hospital the previous week with them came to the clinic because he hadn't gotten better. He had an even higher fever and abdominal pain. His thin abdomen clearly had a lump in it. Ultrasound showed that it was a fluid filled mass about the size of a large grapefruit in his liver.

The lump was a liver abscess and in South Sudan the most common cause of this is an intestinal parasite called Entamoeba histolytica, or ameba for short. He was treated with a common antibiotic, metronidazole, and was significantly better the next day. His pain and his lump persisted, though. We worried that he might not be improving, but on the fourth day he felt much better and the lump, which had stayed big all this time, had shrunk to half its size. By the time I left he was looking like a normal guy. Small miracles.

An older lady was brought in by her grown daughters because of fever and pain. Tuberculosis most often presents as a lung infection in the US, but in Sub-Saharan Africa it is not at all uncommon for it to be primarily in other organs, even spread diffusely through the body and sparing the lungs. Her ultrasound showed clear lungs, but a collection of juicy lymph nodes near her aorta.

These would be likely to represent lymphoma in the US, but she probably has TB. Her daughter then pointed out that her leg was swollen. My second generation Vscan ultrasound has a transducer that can look at structures such as veins, and she had a big clot in the right leg, up to the groin. The central circular structure has some grayish material in it and doesn't collapse when I push, indicating that it is filled with clot.

A blood clot in the leg often suggests malignancy, and she may have cancer rather than TB, but TB can be associated with blood clots too! It was possible to order in a shipment of anticoagulant injections for her, and it was there within a few days, so she may be able to resolve the clot. She will not get lifelong blood thinners as she would in the US because it's just not practical. If she has TB, effective treatment may take care of her risk. If she has lymphoma her prognosis is not good.

There are rotating doctors through MSF who staff an emergency room, available to treat patients whose problems can't wait for clinic hours. Sometimes they would ask me to do an ultrasound when the diagnosis was a mystery. A teenage boy came in with the feeling that he couldn't urinate. He had had trouble with his bladder off and on for the previous year. When he had blood in his urine he was dosed with praziquantel, the anti-parasitic medication that treats schistosomiasis. Schistosomiasis is caused by a tiny organism that lives in bodies of fresh water, including the Zaraf River, and most of our patients have been infected by it. A single dose of praziquantel rids the body of the parasite, which can infect the bladder and cause inflammation and scarring. He had persistent irritation when he urinated so had then been treated for a standard bladder infection with antibiotics. He may have improved but his symptoms brought him back to the ER. He was miserable.

His ultrasound showed a round object that made a shadow right in the middle of his bladder. I've seen patients with bladder stones before, but they were always older men with large prostates or chronic urinary catheters. It turns out that bladder stones are not uncommon in the tropics in boys. I find nothing in the far reaching tubes of the internet that explains why, though a 1961 article suggests that there may be some nutritional factor involved. The surgeon rotating through MSF had seen the condition before and did a small operation to remove the stone. The boy was very pleased and showed me the gnarly egg sized thing on evening rounds.

There were other stories, medical and otherwise, and more ultrasounds. Pointing an ultrasound at patients with various illnesses taught me things I couldn't learn from reading. I think I infected some of the other doctors and clinicians with the urge to look inside with ultrasound, and the more they do the better they will get. Once again, it was a privilege to work with Jill and her dedicated staff and the other fellow travelers who swoop in and out like I do, trying to make a difference.

On not moving and other dangerous sports

I finally finished reading the many journals piled up on my dining room table, which have been shunted to other flat surfaces for projects or the visits of friends. I didn't read them all well, but I touched them all and read what interested me.

The early October edition of the Annals of Internal Medicine particularly caught my eye. There were two major articles that looked at determinants of health in a slightly different way.

The first used data from the Cleveland Clinic's electronic medical record to see whether the standard prediction calculator that we use to estimate a person's risk for cardiovascular disease works as well in poor as in not-poor neighborhoods. They found that it did not work nearly as well in poor neighborhoods. In fact, whether you have a heart attack or stroke is more determined by whether you live in a poor area of town than whether you have the traditional collection of risk factors for heart disease such as high blood pressure, smoking, diabetes and high cholesterol.

The second took data from a large and ongoing study looking at disparities in stroke incidence based on race and region. They used accelerometers to see what patterns of exercise and lack of exercise were associated with health, specifically heart attacks and strokes and death from these. As one would imagine, being more active is better than being less active. The average person in the study (all of whom were meant to represent average Americans) was sedentary for over 12 hours of a 16 waking hour day, sitting or lying around for over 77% of the time. But it didn't just matter how many hours a person was active in a day, but also how they broke up their sedentary time. It was best to be less sedentary, but if you were more sedentary it was best if you got up and moved around a bit every 10 minutes or so. The people who were less active and had longer bouts of inactivity were 5 times more likely to be dead at the end of 5 years than the people who were more active and had shorter bouts of inactivity. For the active people, it didn't matter that much if they had long episodes of inactivity, but for the inactive ones, it really mattered.

It is tempting to say that poverty and inactivity do not cause ill health, it is ill health that causes poverty and inactivity, but the authors did a pretty good job correcting for this. There may be other factors at work, and I'm sure there are, but it does appear that it is good to walk and move around frequently, even if briefly. It is also true that a person's health suffers in measurable ways when he or she is ground down by poverty. These studies highlight, once again, that efforts put in to making it easier to be healthy by improving the way people live may have benefits much greater than putting a similar amount of money or resources into providing healthcare once a person has already become sick.

Vitamin C and Sepsis: cheap and effective?

Sepsis is one of the most common diagnoses in our hospital that leads to admission to the intensive care unit. Sepsis is the syndrome that comes from uncontrolled, usually bacterial, infection and is not uncommonly fatal. Bacteria are everywhere and live in and on us, in balance with each other and supporting our bodily functions. Occasionally they invade our tissues resulting in infection. The body responds by releasing white blood cells which kill the bacteria by various mechanisms including producing chemicals that make us feel sick. These chemicals raise our temperature, cause our blood vessels to dilate, lowering our blood pressure and raising our heart and breathing rates. Sometimes this whole process causes kidney, heart and lung failure as well as delirium. The infections that can cause sepsis can involve all kinds of bacteria or other microorganisms and start in any of a large number of areas including the skin, lungs, kidneys, brain and abdominal organs.

Our usual treatment of sepsis involves finding the source of the infection and treating that if necessary (removing a diseased appendix or draining an abscess), giving antibiotics to kill the bacteria and giving fluids to fill up the blood vessels which find themselves empty because of being dilated and leaky. We often need to give oxygen because the lungs get wet and give medication that raises the blood pressure by contracting the blood vessels (pressors.)

Despite all of these treatments, sepsis is still sometimes fatal when vital organs fail in ways we can't reverse.

In June of 2017 Dr. Paul Marik, a very accomplished critical care physician trained in South Africa, Canada and the US, published an observational study from his practice at the Eastern Virginia Medical School about treating sepsis with vitamin C in addition to our usual routine. He had been frustrated to see in his practice that patients with severe sepsis were dying despite the best medical care. In one year 19 of 47 such patients died at his institution. When a patient is dying of sepsis it is possible to see it at the bedside, like a slow motion car wreck. The patient is delirious and often unable to breathe adequately. They are placed on a ventilator on supplemental oxygen. Their blood pressure is low and their pulse is high. They are given fluid and pressors in increasing doses which helps a bit, but the fluid leaks into the lungs causing them to fail and the pressors increase the heart rate and the heart beats more sluggishly and the kidneys fail so the fluid builds up further and they die.

Dr. Marik was apparently aware of pharmacology research in treatment of conditions like sepsis and was aware of animal studies showing improved survival with the use of vitamin C. The evidence is pretty compelling. He decided to try using moderately high doses of vitamin C along with thiamine and hydrocortisone, all of which have theoretical benefit it treating severe sepsis, in a patient who was clearly going down the tubes. The patient improved rapidly and survived the episode. He tried it a few more times and became convinced that it should be part of his routine treatment. After a year of using the Vitamin C 1.5 grams IV every 6 hours for 4 days or until discharged from the intensive care unit along with thiamine 200 mg and hydrocortisone 50 mg every 6 hours, the death rate from severe sepsis in his institution had plummeted, from 40% to 8.5%. He published this in an article in the journal Chest in June of 2017. It was picked up by news organizations and blogs and podcasts and has been adopted at many organizations. There has been reasonable skepticism because his study was observational rather than placebo controlled meaning that factors other than the new protocol could have been involved. A double blind study is underway to more clearly define whether his protocol is effective.

There is some history that leads us to be skeptical. In 2001, Eli Lilly released a biological product called Xigris (activated protein C) which was observed to have improved survival of sepsis by over 6%. It was terribly expensive and was eventually found not to be effective and to cause increased bleeding. It was withdrawn from the market. Several years ago there was evidence that tight control of blood glucose was good for pretty much anything that put our patients in the intensive care units, especially sepsis. Even patients without diabetes were often started on intensive insulin therapy and, after spinning our wheels with this protocol for over a year, it became clear that it was more likely to harm than help in most cases.

Vitamin C has been around for a long time. Linus Pauling, a Nobel Prize winner in chemistry, championed its use in high doses, orally, for prevention and treatment of all kinds of diseases. Research did not support use of high dose oral vitamin C and it faded from prominence. Vitamin C is not very well absorbed when taken orally. In patients with sepsis, vitamin C levels are very low. Vitamin C acts as an anti-oxidant, which makes the blood vessels behave more normally in septic animals, and perhaps septic humans as well. Researchers have also noticed low vitamin C levels in patients with trauma or severe burns or toxic exposures which have similar effects on the blood vessels. In animal models of sepsis, intravenous vitamin C reduced mortality.

A colleague of mine decided to try the vitamin C, thiamine and hydrocortisone protocol and convinced the pharmacy in our small hospital to stock intravenous vitamin C. It is not cheap, but neither is it expensive, compared to most of the stuff we use in hospitals for critically ill patients. A vial containing 25 grams of vitamin C costs around $100. Thiamine and hydrocortisone have negligible cost. My colleague was the first to use it in our hospital and felt that his patient got better more quickly than he had expected from previous experience without using this protocol. I have now used it about 3 times, with patients who were critically ill with sepsis, and they have done well. They get better faster and with fewer complications than we had seen before, but we are not doing a study and cannot be objective. Each patient I treat with sepsis receives care that is probably better than the patient before him or her because I have had one more experience to learn from.

There have been many changes in the last year in how I treat sepsis. I have been more wary of giving excessive fluid to my patients after reading several critical care physicians' critiques of high volume resuscitation, including Dr. Marik's. In previous years I had been very generous with fluids, such that often after 24 hours of "resuscitation" of patients with low blood pressures and sepsis they would have taken in over 5 liters of fluid more than they had put out, with ongoing waterlogging over the next few days. This led to uncomfortable swelling and slower return of normal body functions. It may also have been physiologically unhelpful in ways I had not noticed. I am more frugal now, and more likely to start pressors after moderate hydration. In my training we were taught never to give drugs that caused constriction of blood vessels (vasoconstrictors, pressors) by way of a regular intravenous line, but to always insert a central venous catheter. I am often hesitant to place a central venous catheter in my septic patients because it could lead to various complications and can be time consuming when time is crucial and uncomfortable to the patient. It appears that pressors can often be safely given via a good peripheral IV and so I am more likely to use them early. In addition to attending to supporting vital signs, I try to protect my patients' sleep and mobilize them earlier. I use fewer and different medications to sedate them, which makes their brains recover more quickly. Perhaps some of the improved outcomes I'm seeing are not entirely from IV vitamin C.

Nevertheless, it appears that vitamin C may be an important advance in treating severe sepsis. It is not likely to be harmful. There are ongoing studies which may or may not settle this question. Presently one study is looking at vitamin C alone. It may be that the cocktail including thiamine and hydrocortisone is more effective, or that an approach that combines many interventions will be superior when it also includes vitamin C. It is difficult to know and the studies may be difficult to complete as the standards of care change.

If vitamin C is shown to truly be helpful in sepsis, it will be in studies that are not funded by pharmaceutical companies. All large and convincing studies are expensive and vitamin C has been around for a very long time and profits no company to any great extent. It is amazing that it has even been studied, when you think about it. It appears to be pretty safe and I intend to continue to use it in severely septic patients until I see evidence that it doesn't work. I may even consider using it in patients with other conditions that cause fluid retention due to vascular leakage. I am not convinced that adequate studies will be done to generate evidence to guide my treatment, which is a small but significant tragedy, and due to the fact that we rely on pharmaceutical companies to fund research on drugs. This has led to disappointments such as Xigris, which have made us shy of innovation.

Menopausal Estrogen Replacement: can we start using this again safely?

Estrogen is a miracle drug for many women who experience the drenching sweats, sexual dysfunction and frustrating brain betrayals associated with entering menopause. It comes in expensive patches, less expensive pills or injections, as well as vaginal creams or rings. It has gone in and out of favor with the medical community for decades.

Estrogen is the main ingredient in most birth control pills and has been studied extensively in that context as well as in the setting of women whose ovaries have ceased to produce it as they age. It can increase the risk of migraines, blood clots in the legs or lungs, it can cause benign liver tumors and facial pigmentation. It causes growth of the endometrial cells that line the uterus and can increase benign and malignant tumors in that organ. Some breast cancer cells are sensitive to estrogen and can grow when they are exposed to it, so patients with breast cancer try to stay away from it. In addition to treating the annoying symptoms of menopause, it also increases bone strength and maintains a healthy vaginal lining.

In 2002, at the height of an era of estrogen optimism, when physicians mostly believed that estrogen was good for every woman after menopause, the huge Women's Health Initiative study (WHI) which had started in 1991, reported that the use of estrogen plus progesterone increased the risk of heart attacks, strokes and breast cancer. Doctors responded quickly, and there was a drastic decrease in estrogen prescription. Women still wanted the remedy that relieved their symptoms, but physicians insisted that they stop taking it or at least taper down to very low doses and warned them of dire side effects at each appointment. Eight years later, in 2010, an extension of the study was announced which showed that there were more benefits and fewer risks that had been reported. A nuanced approach was more clearly needed. In that year I wrote a blog which reported on the very mixed results of that trial. I concluded that estrogen was definitely not all bad and was clearly good for some people and for some indications.

This year (actually 2017, which is officially last year as of 2 days ago) another extension of the WHI was released. The article presenting the data can be accessed here.The editorial addressing the findings can be found here. The important points are:

1. At 18 years after the study began, there is no difference in all cause mortality between hormone users and non-users. There is also no difference in mortality related to breast cancer, strokes or heart attacks.
2. There still appears to be a striking difference between women who take estrogen alone vs. those who take estrogen and progesterone with respect to developing breast cancer. There is a slight increase in breast cancer risk among women who take estrogen and progesterone which persists after they stop. But there is a more significant reduction in risk of breast cancer among women who take estrogen alone. Women who take estrogen plus progesterone, however, are significantly protected against developing endometrial cancer.
3. Women who start taking estrogen (with or without progesterone) around the time of menopause have a reduction in all cause mortality (their death rates were lower) during the time they were in the study. 

Sadly, the study, with its beautiful design and over 100,000 participants doesn't entirely answer the question in the title. It appears that taking estrogen and progesterone for about 5.6 years or estrogen alone for about 7.2 years was safe in the setting of this study. Perhaps it was even beneficial. The study did not, however, answer the question of whether taking estrogen for longer than this is safe or whether it provides more or fewer health benefits.

Taking a tangent to the story of hormone therapy for menopause, I would like to express great respect for Bernadine Healy MD who, as the new directory of the National Institutes of Health (NIH) in the early 1990's, secured public funding for the WHI. Such a large study was only possible through federal funding and has provided excellent long term guidance on various issues in women's health which had otherwise been addressed without adequate data. The results continue to accrue and we can expect to see new answers over the next several years, including benefits or lack of benefits for high dose cocoa flavanoids (think dark chocolate), exercise and other aspects of healthy aging. These are questions whose answers would not attract the monetary support of drug or device manufacturers and could only be answered with public support. May the NIH continue to have such good leadership.