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Wednesday, January 17, 2018

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.

Friday, January 12, 2018

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.

Tuesday, January 2, 2018

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.