Nature, Nurture, and The Uterine Environment

An article published by Nicholas Kristof in The New York Times, At Risk From the Womb, discusses the mounting evidence that the uterine environment – rather than genes or environment alone – has an important impact on development. Several new studies have demonstrated that the mother’s health directly affects the long-term mental and physical health of the developing fetus. A recent article discusses new evidence that women who gain more weight during pregnancy tend to have larger-than-average babies who are prone to childhood obesity (see Gain in Pregnancy Is Linked to Weight Problems in Children). Evidence is mounting that maternal stress – which causes the release of cortisol in the bloodstream – can have negative effects on childhood development.

As this new field of research expands, it is important to keep in mind that for many of these studies – especially those which measure psychological health, intellectual development, and social interactions as outcomes – the multitude of confounding factors makes it difficult to tease out which factor – genes, environment, or uterine environment – were the primary cause in each case. All three of these influences are likely important in different ways – but how important, and how they interact with one another, are more difficult questions.

The impact of this recent news on young mothers, pregnant woman, and woman who have had a miscarriage can be devastating. I have seen several women who, after reading these articles, are wondering if it is their fault that their fetuses and children have health problems. Maybe if they had been thinner, or less stressed, or had eaten better during their pregnancy…things would be different. The new evidence is giving them concrete reasons to feel guilty – and even these feelings of guilt may have an impact on the health of their baby, thus the vicious cycle goes on.

So for the women who are asking themselves these questions, remember that it is a combination of factors – genes, environment, and uterine environment – which come together to influence the health of a baby. We can alter these to some extent, but not completely. And in the end, there is no scientific formula which guarantees that we are optimizing all conditions for a child. During pregnancy, the main tenets of success are relatively basic, and include (1) eating a healthy diet, both before and after the baby is born, to give them the nutrients they need and to reinforce important lifestyle habits for later down the road (2) maintaining a balance in life and finding ways to relieve stress – exercise, yoga, walking, and the list goes on (3) keeping regular appointments with your doctor, to check how you and the baby are doing, to get all of your questions answered, and to make any adjustments to your lifestyle that may be necessary.

Between a Rock and a Hard Place: ACGME Passes New Duty Hour Regulations

Yesterday, the ACGME officially approved new duty hour regulations to be effective July 2011. The initial proposals have been a hot topic of discussion since they were first introduced in June. Read a prior post, Resident Duty Hours: Loopholes in the New Regulations, for a more detailed analysis of the fine print. The current interns and second year residents are now officially “the residents who got the short end of the stick.” No one seems to care. We labored through intern year and we survived. Yes, it was difficult, but we made it. So did all of our predecessors. And now we are limiting hours to “protect” interns – we are switching the pyramid such that senior residents, rather than interns, are spending more time in the hospital. The senior residents, PGY-2 and above, will now be required to stay for 24 hours – the interns must leave after 16 hours.

Great idea in theory, but far more difficult in practice. Hospitals across the country are going to struggle to comply with these new regulations. Options include switching to a night float system, bringing in more hospitalists and PAs, or – and this seems like the least reasonable, but the most likely – just let the senior residents sweat it out. They can deal. Right…

I am curious how many people who sit on the ACGME board were interns when the new computer order systems began to replace handwritten charts. With the advent of computer ordering, residents are more closely monitored and are required to place electronic orders in a timely fashion – or else. I cannot count the number of times that I have been running a code, intubating a patient, placing an urgent central line – and have been interrupted because I need to find a computer to type in a laundry list of orders. Regulations and systems can be helpful – but they become a problem when they are so cumbersome that they compromise patient care.

And this is where the intern comes into play. Although the job of an intern is tiring because of the hours, it is not overwhelmingly difficult from an intellectual standpoint. An intern can always ask for help. As senior residents, however, we rely on interns to help us with some of the more mundane tasks – order writing, note writing, etc. Although these tasks may seem mundane, (1) they are important and (2) in retrospect, I realize that I learned a lot from them – by directing a patient’s care on the micro level, even if I am only writing orders that someone else has instructed me to write, I gained substantial amounts of medical knowledge during my intern year by doing, rather than by reading or thinking.

Another problem is that second year is not easy. Do the board members remember what it was like to be a second year resident, and do they have a sense of what it is like now? I worked as an intern in the medical intensive care unit in my last month of intern year, and one month later I worked as the senior resident in the coronary care unit. Which was harder, and which did I need to be less fatigued for? Most definitely the latter. In those first months of second year, fresh out of intern year, residents run the intensive care units, the emergency department, the medical floors. And it is important that we have time to think. If we are bombarded with our job as a senior resident and the tasks of the intern – order writing, note writing, etc. – we cannot do either well. In a 24-hour time period, it is the senior resident – more than the intern – who needs a short nap. After all, the seniors – not the interns – should be the ones making critical decisions about patient care in the middle of the night.

The 24-hour rule has also been changed with these new regulations, from 24 hours of patient care plus 6 hours of transfer of care to 24 hours of patient care plus only 4 hours of transfer of care. I find it almost comical that we are going to try to cut hours in the intensive care units, where rounding on new patients can take until noon or beyond – which far exceeds the proposed limit. The loophole I mentioned before – that residents can stay later to take care of one patient – is going to be used to excess, and not necessarily for the right reasons. There is no possible way to finish medical rounds earlier than we do on post-call days. Programs are already struggling to meet the current work-hour regulations.

Good ideas in theory are not always good ideas in practice. Although the ACGME has good intentions in mind (I agree with the principles behind them), the hospitals are left to fend for themselves. With limited money and limited residents, these new regulations put hospitals between a rock and a hard place. And ultimately, that will put senior residents in a difficult situation. I hope that implementation of these new policies will be a matter of concern – it is easy to publish guidelines, but much more difficult to execute them appropriately.

Needlestick Injuries

Yesterday I cared for a nurse who was in tears – she had a needle stick exposure in the hospital and is nine weeks pregnant. Needle stick injuries are far too common in the hospital – approximately 600,000 to 800,000 needle stick and other percutaneous injuries are reported annually among US health care workers. And the true frequency is underestimated given that many health care workers do not report needle stick injuries. The operating room, of course, presents the greatest risk. Needle stick injuries place health care workers at risk for transmission of HIV, Hepatitis B, and Hepatitis C. An article in The New England Journal of Medicine, Needlestick Injuries Among Surgeons in Training, discusses the prevalence of needle sticks among surgery residents – and the all too high frequency (51%) with which they go unreported.

Here is some of the basic information. First question: if the percutaneous exposure involves a patient with Hepatitis B, HIV, or Hepatitis C, what is the seroconversion rate for the exposed person? For Hepatitis B, the seroconversion ranges from 23 to 62%, with higher rates associated with patients who are HBeAg positive, as compared to HBeAG negative. The seroconversion rate for HIV is 1:300, or 0.3% from a hollow-bore needle stick injury (Marcus, Surveillance of health care workers exposed to blood from patients infected with the human immunodeficiency virus, The New England Journal of Medicine 319: 1118–1123). The seroconversion rate for Hepatitis C is 1.8%.

Next question: how effective is treatment? For Hepatitis B, multiple doses of HBIG within 1 week of percutaneous exposure to HBsAg-positive blood provides 75% protection from HBV infection (Stevens et al., Perinatal hepatitis B virus transmission in the United States, JAMA 253: 1740-5). Hepatitis B vaccination (assuming you have an appropriate vaccine response, which can be determined by checking antibody titers) prior to a percutaneous needle exposure is the best way to prevent seroconversion.

For HIV, information is limited because seroconversion rates are low and studies are limited by small sample sizes. In one retrospective case-control study, after controlling for other risk factors for HIV transmission, use of zidovudine was associated with a reduction in the risk of HIV infection by 81% (95% CI of 43%-94%) (Cardo et al., A case-control study of HIV seroconversion in health care workers after percutaneous exposure, The New England Journal of Medicine 337: 1485-90). To be most effective, the treatment should be administered within an hour of possible exposure and no longer than 72 hours post-exposure.

For Hepatitis C, there is no approved prophylactic treatment available. There is no vaccine and no cure for the disease. And the virus, which can ultimately cause liver failure, is a serious one.

An excellent resource for more information, complete with references, is Updated U.S. Public Health Service Guidelines for the Management of Occupational Exposures to HBV, HCV, and HIV and Recommendations for Postexposure Prophylaxis.

There are a couple of frustrations with this process. First, although these percentages are useful when looking at the data objectively, it becomes difficult when it happens to you. After all, what do percentages matter if you end up on the wrong side of the data? What if you are the 1 in 300 who will convert to HIV or the 1 in 56 who will convert to HCV? The HIV post-exposure prophylaxis (PEP) medications have quite severe side effects, including nausea, vomiting, malaise, fatigue, and – for the pregnant woman – unknown consequences on fetuses less than 12 weeks. Thus, PEP is not without its consequences.

Second, it is still possible for patients to refuse to get tested for HIV. Laws vary on a state-by-state basis regarding the requirements for patient consent. This process can be frustrating for the exposed health care worker – and with good reason. Their lives are at stake – and no matter how small the risk, it still exists. The patient’s status can help the health care worker make a better informed decision regarding PEP.

When patients come into the hospital, they should agree to consent to HIV testing if a percutaneous exposure occurs. The health care worker should not be exposed to unnecessary anguish – and uncertainty – during this process simply because a patient refuses to consent. As health care workers, we willingly put ourselves at risk every day – for transmission of TB, meningitis, influenza, H1N1, and the list goes on. When the H1N1 pandemic broke last year, there were very few health care workers who refused to come to work – we were all there for our patients. Many emergency department workers put themselves at risk for physical and verbal abuse on a daily basis. I do not know many emergency health care workers who have not been exposed to blood, vomit, viruses, and other bodily fluids during their career. As a group, health care workers must accept that there are certain risks that come with this profession. But, to ease the added burden and stress that comes along with percutaneous exposure, the laws regarding patient consent in these situations need to be re-examined.

Mysteries of the Human Mind

An article by Zimmer published yesterday in The New York Times, Sizing Up Consciousness by Its Bits, discusses the theories of Dr. Tononi on consciousness. Dr. Tononi is a psychiatrist and neuroscientist at the University of Wisconsin. Tononi is not the first to develop theories on the mysteries of human consciousness. Consciousness has been explored by philosophers and scientists throughout history, beginning in the 1600s when Descartes first used the term “conscientia” in the way modern speakers use the term “conscience.”

Robert Fludd (1574-1637). Utriusque cosmi maioris scilicet et minoris metaphysica, physica atque technica histori. Oppenheim, 1619.

In the medical world, the concept of consciousness is of particular interest for patients who are in a vegetative state. Are these patients truly conscious? Do they feel pain? Is an internal thought process preserved? The idea of consciousness is also important for patients undergoing surgery. Although rare (approximately one to two in 1000 cases), there are patients who are effectively paralyzed but not sedated while they are under anesthesia. As a result, although they are awake, they are unable to speak or move, and are thus unable to communicate. This concept is referred to as “anesthesia awareness.”

Needless to say, the experience is quite traumatic. Although patients do not feel pain (only pressure receptors remain activated), they can often recall most if not all the details of their experience, including the conversation in the room and the particular details of the surgery. A recent article in CNN, Awake during surgery: ‘I’m in hell’, discusses the personal experience of Carol Weiher. This story follows the 2007 release of Ri-Teon, a Korean film (Return orWide Awake in English translation) that increased national awareness of awake anesthesia.

Whether Tononi’s Integrated Information Theory is groundbreaking or will change the course of consciousness research in years to come – I cannot say. But his work is a constant reminder of how little we really know about consciousness – and about the human brain. Our mappings of it are increasingly complex, but what triggers it to work – and think – in different ways still cannot be well explained.

Dreams never cease to amaze me. For the last couple of nights, I have been plagued by nightmares – vivid, intense, and seemingly endless dreams that I am taking care of a dying child in the intensive care unit. I wake up in a cold sweat, just as the child is taking her last breaths and I am preparing to intubate her. I wake up to the ring of my alarm clock and feel as though I have worked the entire night in the hospital.

A recent movie, Inception, addresses the concept of lucid dreaming. It is a technique by which people try to make themselves aware, while in a dream, that they are in fact dreaming. The idea is fascinating. Many philosophers and artists have attributed their inspiration to dreams. The world of dreams provides us with a way to tap into our mind from a completely different angle – these parts of our consciousness are often not reachable by the awake mind. They can allow us to better understand ourselves. This is only a preliminary conglomeration of thoughts – just the tip of the proverbial iceberg of the fascinations of consciousness,  dreams, and the human mind.

Medical Ethics: Medicine for the Benefit of Our Patients

A recent article in The New York Times, New Drugs Stir Debate on Rules of Clinical Trials, discusses the highly controversial matter of a new drug, PLX4032, which has demonstrated new promise for patients with melanoma in early clinical trials. The drug, which targets a specific genetic mutation known as B-RAF, has resulted in symptomatic relief and shrinkage of tumors, mainly for patients with metastatic melanoma who express the targeted mutation. The overall prognosis for metastatic melanoma is poor and death usually occurs less than a year after diagnosis – at best. This new drug offers hope to patients – if not for survival, then at least for improvement of symptoms.

The article comes at an opportune time, as I am reading The Immortal Life of Henrietta Lacks. Henrietta Lacks is the African-American woman from whom the famous HeLa cells originated. This novel tells the story of her and her family. Although Henrietta was never aware that her cells were being used for experimentation, they now weigh more than 50 million metric tons – the equivalent of a hundred Empire State Buildings – and can wrap around the Earth three times. They helped researchers develop drugs to fight herpes, leukemia, influenza, hemophilia, and Parkinson’s disease.

Henrietta Lacks, circa 1945.

Although Henrietta died from cervical cancer over 60 years ago, her cells are immortal and have spanned the entire globe. The story is a remarkable one – but it brings to the surface the troubling questions of medical ethics. Henrietta was never asked permission for her cervical cells. Nor was her family notified of their significance until many years later.

HeLa cells.

Within the woven tapestry of history, there are several stories of physicians and researchers breaching ethical boundaries. The first recorded autopsies were performed by doctors in Alexandria around 300 BC. Da Vinci and Michelangelo performed autopsies to better understand human anatomy for the purpose of art. These autopsies were performed in secret and were generally frowned upon by the community. And there are countless stories of the abuse of live human subjects – the Tuskegee syphilis study, during which 400 men died after researchers had discovered that penicillin could cure them. The list goes on. James Marion Sims performed pelvic surgeries without anesthesia in the mid-1800s. Wendell Johnson spearheaded the infamous “Monster Study” which involved placing children under intense psychological pressure in an attempt to cause stuttering.

The controversy over PLX4032 is yet another in a long list of medical ethics issues. The current clinical trial assigns patients randomly to receive dacarbazine or PLX4032. Unlike other clinical trials, however, patients and physicians known which drug patients are receiving because dacarbazine is administered intravenously while PLX4032 is administered orally. Dacarbazine is a cytotoxic drug, with a plethora of adverse effects, which has demonstrated minimal effectiveness for tumor shrinkage (15 to 20%) but has not demonstrated any effect on prolonging overall survival for patients with metastatic melanoma.

Some physicians and researchers argue that PLX4032 should go through a full phase III clinical trial in order to answer the most important question: Does PLX4032 prolong survival in melanoma patients? The trial will also provide good data for comparing it against other targeted drugs for melanoma which will be emerging soon.

But I think the drug should be administered to patients who request it. First, the clinical trial is limited by the fact that it cannot be double-blinded. Patients’ and physicians’ knowledge of the treatment they are receiving inevitably skews the results. When a patient knows he is receiving dacarbazine – a drug with minimal effectiveness for his cancer – the effect is worse than placebo. He does not even have hope that he may be receiving the newer drug.

Secondly, the new drug works by an entirely different mechanism than dacarbazine. PLX4032 targets a specific mutation in tumor cells. Dacarbazine is an alkylating agent which inserts itself between the DNA strands in both normal and tumor cells. Because of its broad effects, it is used for treatment of several cancers, including Hodgkin’s lymphoma, sarcoma, and pancreatic cancer. If comparison is the primary goal, it would be much more beneficial to compare drugs with similar mechanisms – take another drug that targets a mutation in melanoma cells and compare PLX4032 to that.

Thirdly, even if patients are assigned to the dacarbazine group, they should be given the option to switch to the PLX4032 group if they are not tolerating side effects of dacarbazine or if they are not responding to treatment. With this method, we would be able to gather preliminary data to compare the effectiveness of the two drugs. Another possibility is combination therapy – compare dacarbazine plus PLX4032 to PLX4032 alone. This would provide important information to clinicians – and it may provide enough evidence to minimize the use of a toxic drug.

Fourth, regardless of effectiveness of PLX4032 at prolonging survival, it alleviates symptoms. It may do so even better than our traditional pain medications such as morphine, because it targets the source of the pain rather than simply masking it. For this purpose alone, as long as the drug has passed various safety trials, it should be administered to patients who are in pain due to melanoma. Dacarbazine is certainly not a competitor in this area – and in patients with a median survival of 6 to 12 months, shouldn’t comfort be a primary concern?

Fifth, dacarbazine is a drug of the past and PLX4032 is a drug of the future. As we become more adept at understanding the mechanisms behind certain tumor cells – specific both to the type of cancer and to the individual – we will become better at developing targeted therapies. Just as bloodletting through leeches is now largely a therapy of the past (and a therapy which was the standard of care for almost every disease through the early 1800s), the current chemotherapy regimens will someday be outdated. Their replacement? Gene targeting drug therapy.

Lastly, sometimes we need to acknowledge that the public knows best, and sometimes we need to sacrifice theoretical science for humanity. People need hope. As physicians and researchers, we need to work better to establish trust – and hope – between the research world and the patient world. After all, we make no progress in medical science without patients – courageous patients like Henrietta Lacks, who have sacrificed themselves, whether they knew it or not, for the greater good. As clinicians, we need to honor this and we, too, sometimes must be willing to sacrifice ourselves – and pristine research –  for the benefit of humanity.

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