In the years since Lenore’s death CF has been found to be caused by a mutation in the cystic fibrosis trans-membrane conductance regulator  (CFTR) gene that regulates ion transportation (ions like chloride hence the traditional sweat chloride test for CF) and therefore fluid flow within cells. One specific mutation is the G551D mutation (substitution of aspartic acid for glygine at position 551), and the new drug Kalydeco specifically targets the abnormal protein in these specific CF patients. Kalydeco helps the defective protein work more normally, and so reduces the abnormalities in CF patients with this specific mutation.

Unfortunately only about 1 in 25 CF patients have this specific mutation in the CFTR genetic code. The rest have some combination of the other at least 1000 known mutations. The most common CFTR mutation is called F508del (a 3 nucleotide deletion at location 508 leading to a missing phenylalanine amino acid “F”) and about 1 in 30 Caucasians have this specific mutation in the CFTR gene. Kalydeco is not effective in patients who are homozygous for the F508del mutation.  This homozygous F508del mutation is the most common genetic code in CF patients. IN the 4% of CF patients with at least one copy of the G551D mutation Kalydeco has been shown to be effective in reducing CF symptoms, and is an exciting breakthrough.

Patients with the G155D mutation produce a protein that is able to make it to the cell membrane, where Kalydeco allows it to function much more normally.  In patients with the F508del mutation the protein fails to fold in a way that allows it to move to the cell membrane, and so a drug like Kalydeco cannot function.  Scientists are working on possible medications that could allow the migration of the other defective genes to the cell membrane where use in combination with Kalydeco could potentially be effective.

It is exciting not just for the 1200 U.S. patients with this specific type of CF, but also because it is an example of how genetic research, gene analysis in genetic disorders, and great basic science can lead to novel therapy for genetic disorders.

The rapid approval of Kalydeco is a great example of the new expedited FDA approval process for drugs that have the potential to be novel or breakthrough products where there is currently no effective therapy, or the drug is a major advance in therapy.  It took only 3 months for Kalydeco to get FDA approval, even faster than the promised fast-track approval promised for special circumstance drugs.

The catch in this whole process is the incredible anticipated cost of Kalydeco.  In a Wall Street Journal article the estimated annual cost of Kalydeco is reported to be $294,000.  Since the anticipated number of patients eligible to receive this orphan drug is so small, and because of the novel and documented improvements demonstrated in patients using Kalydeco it is expected that insurers will pay for the cost of the medication. If all 1200 eligible patients take Kalydeco the annual cost at this price would be $353 million annually.  Still this price is not Guinness world record. Two more expensive drugs are Soliris for a rare condition parosysmal nocturnal hemoglobinuria at $409K annually and Elaprase for the rare genetic disorder Hunter Syndrome , a polysaccharide storage disorder, at $375K annually. These are examples of orphan drugs with very limited markets where the cost of development is shared by very few patients.

I look forward to seeing more examples of genetic research leading to personalized medications for individuals.

Screening for prostate cancer has been all over the news recently, with the USPSTF proposed recommendation against routine PSA screening, and is a classic example of the risks of screening tests. The strongest argument against PSA screening is overdiagnosis and exposure of men to invasive prostate biopsies, and potentially dangerous therapy for prostate cancers that will never become clinically significant in some unknown but likely high percentage of cases. One of the primary reasons I don’t anticipate a dramatic reduction in PSA testing in primary care is because it is perceived by physicians that they are much less likely to be sued for complications of care caused by overdiagnosis of prostate cancer than if a patient is diagnosed with advanced prostate cancer and who has not been offered PSA screening. I suspect at least some physicians are going to be afraid to do the right thing even if they are convinced that the evidence supports not doing PSA screening.

Far less emotional and dramatic are consequences of defensive medicine precipitated by the ordering of imaging tests. It is commonplace for a physician to order an MRI of a patient’s knee early in the course of management of a knee injury.  In an NEJM study of randomly chosen men without a complaint of knee pain the incidence of finding a meniscus tear on knee MRI was 31%.  A finding of adrenal masses on abdominal CT scan is very common.  In one study the incidence of an adrenal mass finding on abdominal CT in patients without a known malignancy was 5%. In this same study of 973 consecutive patients of the 973 zero were found to be malignant.  This is exactly my experience, i.e. I’ve never had one of these turn out to be a cancer. Yet once an adrenal mass is found it is almost always recommended as a part of the radiologists report to have it reevaluated at least one, often twice or more to assure “stability.” It is unusual for a primary care physician not to order these follow up tests, more defensive medicine.  The risk of radiation exposure from abdominal CT scanning is not insignificant.

Treatment of sore throat, acute short-duration sinusitis, otitis media and acute bronchitis with antibiotics is very common.  It may be defensive medicine or just taking the path of least resistance, but there are very real risks of antibiotic therapy and almost all the evidence and expert opinion argues against the use of antibiotics in these conditions. With the increasing incidence of Clostridium difficiele infections, and increasingly virulent and antibiotic resistant C. diff as well as the other risks of side effects of specific antibiotics their use is far from risk free.

Nearly every new highly sensitive imaging technique is also very good at finding incidental variations of normal and abnormalities for which radiologists are reluctant to recommend no further evaluation, This is defensive medicine on the part of radiologists, as well as good business on their part in our fee-for-service environment.  What business person of sound mind is going to put themselves at legal risk and at the same time recommend against a test that is in their financial interest.  The risk to patients is more than just the risk of further radiation.  Often the tests also lead to invasive tests or treatments, all of which have their own risks.

Many blood tests have the same risks, including tests like CA-125 for ovarian cancer, of course PSA, but also things as simple as a CBC. A CBC with a low white blood cell count is usually either normal or the result of a recent viral illness. Still it usually leads to a follow up test to assure a return to normal. If it persists low it may lead to referral to a hematologist who often orders a bone marrow evaluation.  These are not only moderately painful but can have uncommon serious complications.

Essentially every test or procedure we do entails some risk. Ordering tests for defensive medicine reasons when the chances of finding clinically important and helpful results is fairly low makes the chances of finding false positives or overdiagnosis and leading to complications that would never have happened if the testing had not been done relatively higher. The cost of defensive medicine is not just in dollars.

How Doctors Die by Ken Murray a FP at USC.  

It is largely anecdotal, but is a really an interesting perspective on how at least some physicians choose to forgo futile end-of-life treatments because they know the limits of modern medicine first hand.

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Afghanistan remains a challenge to immunize both because of it’s remote areas and because of its civil war.  The Taliban are reported to have remained cooperative with immunization efforts, but in any country at war coordination and extraordinary safety measures must remain a constant barrier.

A nice article in the N.Y. Times discusses this issue and is worth the read:

After Years of Decline, Polio Cases in Afghanistan Triple in a Year

As a Rotarian and contributor to Polio Plus this remains an interest of mine.  Also see previous posts on this topic:

Polio Eradication

Eradication of Polio: It’s Happening

This may seem overly simplistic or even crass but progress notes only serve three purposes:

1. Facilitate good patient care: The primary purpose of progress notes is to allow the provider and any other providers who may care for the patient the future to have the information they need to accomplish optimal care. In most cases this really is very little information. I remember early in my career a retiring physician asked me if he could send me some of his patients when he retired. I was a bit shocked to see that he kept his entire patient record on a single 5 x 8 filing card. It was written in pencil and he simply erased any no longer relevant information when he needed more room to write a new progress note. If a patient had strep throat he simply wrote  a dated entry: “strep-penicillin.” It was quite clear that the patient had strep throat and was treated with penicillin and that’s really all anyone needed to know to provide good care for the patient. Needless to say although that progress note accomplished this goal it would’ve failed miserably for purposes 2 and 3 below.
2. Function as a legal document: Another important function of progress notes is to document care in a way that functions as legal document. As a physician today doing what it takes to avoid being sued for malpractice is a daily reality. We spend a great deal of effort and time documenting our care in order to try to make a case that our care meets standards of practice, and make our care defensible in case of a malpractice suit. This part of progress notes is usually simply detailing the history, physical findings and thought process behind treatment plans.
3. Get paid: In our third-party payment system the amount we get paid is based on the CPT code that we submit to the insurance company. Each CPT code for evaluation management services (this is medical coder talk for office or hospital visits) has documentation requirements to support that level of service. I won’t get into the complexities of this system but one purpose of progress notes is to include the language needed and the bullet points required for the level of service bill.

I think if physicians have a clear understanding that these are really the only purposes of a progress note it helps facilitate efficient charting. It also helps think about what each of our progress notes needs to contain. When a patient is seen for a very low risk condition and a low-level of service is being billed a brief note that documents what’s necessary to provide excellent care in the future is all it’s really needed. When higher levels of risk are involved a more detailed document to function in case of a lawsuit is needed. By deciding what level of service we plan to bill for the visit we can quickly decide how much documentation is needed to support that level of billing. In my experience most of the time primary care physicians obtain the history and to the physical examination required for higher levels of visit than they bill for, and much of this history and physical doesn’t need to be documented in progress notes unless a level of billing is used that requires that documentation.

Use of an EMR can make entering a great deal of information into progress notes very easy and one of the drawbacks of EMR’s is that the progress notes produced tend to be much longer and include information not helpful for patient care. It’s easy to understand why EMR’s are used to do this level of documentation when you look at the advantages of this documentation for purpose number three (Get Paid).  The trick is to leave out information not needed for any of the three purposes above, and not insert lots of EMR generated details just because it’s easy to do and it’s better to have more information that an auditing insurance company, or worse governmental payer wants to see to justify the CPT code submitted.  This excess data can actually detract from the usefulness of the progress note’s function #1.

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Let’s look at the evidence for transmission of the various STDs by oral-genital contact.

HIV:  Human Immunodeficiency Virus, the cause of AIDS, is the STD many fear most.  It can be transmitted when a body fluid containing the virus gains access to another person’s mucous membranes or bloodstream.   Unquestionably HIV is transmitted by anal and vaginal intercourse.  There are at least a few cases where it is believed that the HIV virus was transmitted to the receptive partner after oral sex with ejaculation.  Oral sex without ejaculation into the mouth is theoretically possible, but is felt to be extraordinarily unlikely. The risk of contracting HIV from a single incidence of anal intercourse with with ejaculation and no condom use with an HIV infected male has been estimated at 1:100.  Extensive study has been done in trying to find out what the incidence of contracting HIV from oral sex with ejaculation with an HIV infected male, but these studies all have confounding variables.  The real problem is that all of these studies have been in gay male populations, and a low percentage of the men had only oral sex.   On second and subsequent interviews many times the history changed, and made other routes of transmission more likely.  In one study it was estimated that there were zero cases of conversion in a population after over 35,000 incidences of oral sex.  All said, although it is possible to contact HIV from oral sex, the chances are very low. Low enough that if oral sex is a behavior that replaces anal intercourse in gay men the benefit of avoiding the high risk behavior likely greatly outweighs the risks of oral sex in this situation.

Herpes Simplex:  This may be the most common STD transmitted by oral sex.  Up to 70% of teens are estimate d to have been infected with the herpes simplex 1 virus, the cause of >90% of oral herpes cases.  Many others, and many of the same people also have been infected with the herpes simplex 2 virus, the cause of >90% of genital herpes.  The problem with herpes simplex is that despite popular belief, an infected person can shed the herpes virus at times when they have no symptoms or visible evidence of infection. It is believed to be  fairly common to transmit the herpes simplex virus either from the mouth to the genitalia, or from the genitalia to the mouth during oral sex.  The incidence of HSV transmission by oral sex is not well studied.

Gonorrhea:  Gonorrhea, caused by the bacteria Nisseria gonococcus, is an STD that typically causes painful urination and  a discharge of pus from the urethra in men.  In women it can be asymptomatic, can cause a vaginal or cervical discharge, or can cause more serious infection of the fallopian tubes and or ovaries, called Pelvic Inflammatory Disease (PID).  Gonorrhea can also infect the throat or tonsils.  The route of this infection appears to be oral sex, generally receptive oral sex with the penis in the mouth.  It is less clear whether cunnilingus can transmit gonorrhea although it is felt that this is very rare if it ever happens.  Men likely only contact gonococcus from vaginal or anal intercourse or from an infected partner during receptive oral sex.

Chlamydia:  There is less data about transmission of Chlamydia by oral sex.  It is generally felt to be possible to transmit Chlamydia both as the person performing and the person receiving fellatio.  The incidence of this is just not known.

Syphilis:  Syphilis is fairly uncommon in the US, but transmission of syphilis during oral sex is relatively easy, and is felt to be a relatively common cause of transmission, possibly up to 15% of cases in some areas of the US.

HPV:  HPV is probably the most prevalent STD in the world today. The HPV virus can be transmitted to the throat or mouth during oral sex.  The incidence of this is poorly understood, but there is an increasing rate of HPV positive head and neck cancers in the last 30 years.  Many experts feel that this correlates to increasing acceptance of oral sex.  Oral cancer has historically been primarily a disease of older adults with a long history of smoking and drinking, or in younger persons who use oral tobacco.  In recent years the incidence in younger non-tobacco users has increased, and many of these cancers are HPV positive on testing.

Hepatitis:  There is debate whether hepatitis B can be transmitted by oral sex, but if possible it is felt to be very unlikely.   Hepatitis A can clearly be transmitted by oral-anal sex, and is much more common in the gay male population than in the heterosexual population.

In summary oral sex is not safe sex, but it is far less risky than either vaginal or anal intercourse regarding STD transmission.  In addition the risk of pregnancy in heterosexual oral sex is near zero.   Avoiding receiving ejaculate in the mouth greatly lowers the risk of transmission of HIV, though probably not the risk of herpes, gonorrhea, or HPV.  Condom use for men, or use of a dental dam in women seems effective in markedly reducing the risk of most STDs with oral sex, but may not be common practice.

Psychological Issues:  Oral sex is clearly an intimate act.  Most psychologists agree that sex, either oral sex or sexual intercourse, brings a relationship to a different level.  How this type of intimacy affects a relationship, the self esteem of the participants, and future feelings about relationships and intimacy are subjects worthy of consideration, but I know of no research into this topic.

So, “How safe is oral sex?”  What do you want to tell your children about oral sex as a part of their sex education? You can decide now based on the discussion above and whether it involves men having sex with other men (MSM)  vs. heterosexual oral sex.  One risk of labeling oral sex a high-risk behavior in MSM is that it may leave gay men feeling that its risk is equal to anal intercourse, which is far from the truth.  If oral sex is an alternative to anal intercourse for MSM then it greatly reduces the risk of HIV transmission.

Not surprisingly warfarin leads the list and causes almost 1/3 of medication related hospitalizations.  I’ve discussed warfarin in an earlier post on medications with a narrow therapeutic window.  Next in line was insulin, which led to 14% of the admissions, likely due mostly to hypoglycemia and the attendant problems like seizures and coma.  Anti-platelet drugs like aspirin and clopidogrel (Plavix) was next at 13%, and oral diabetes medications next at 11%.

Combined these medications led to >2/3 of medication related hospitalizations in the elderly. How can you avoid these mishaps?

• If you are on warfarin be sure to understand the nuances of the drug regarding diet, medication interactions, and be sure to follow through with your recommended anticoagulation clinic visits.
• Use a weekly medication container to place your medications into to avoid duplicate doses of medications and unintentional overdoses.
• With diabetes medications like insulin and oral medications be sure to let your physician know if you are having low blood sugar problems, know how to manage days when you are sick or unable to eat regularly, and work hard to avoid being in situations where you are not able to eat properly.
• With anti-platelet drugs avoid excess alcohol, use of other NSAID products, and let your physician know if you are having acid-dyspeptic symptoms or note blood in the stool or emesis.

Even if you do everything right, know that these medications have inherent risks, and don’t hesitate to seek medical attention if you develop problems with the meds. Also be sure to let any physician treating you know that you are on these meds.  Consider carrying a current medication list to give to any physician you see so they can keep your medications in mind when they treat you.

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Gluten Enteropathy, or celiac disease (sometimes called celiac sprue), is a condition where the lining of the small bowel is damaged by antibodies to gluten found in wheat, rye, barley, malt and some other grains.  When people who are gluten sensitive eat food containing gluten their small bowel becomes inflamed, the villi that contain enzymes to help digest foods to allow their absorption become atrophic and dysfunctional, and they lose weight, become ill and just feel terrible.  For many years it was felt that gluten enteropathy was rare in the United States, and was primarily a European problem.  As late as 1999 the teaching in U.S. medical schools was that only 1:10,000 Americans had gluten enteropathy. Beginning in the early 1990’s research began to show that the incidence was much higher, and it is now estimated that as many as 1:100 Americans has gluten sensitivity.  This for unknown reasons seems to  be a real increase in the last half century, and not be just a product of increased awareness and better testing.

Gluten sensitivity can be dramatic or subtle, and difficult to diagnose.  A battery of blood tests often including Anti-tissue Transglutaminase Antibodies(Anti-tTG) IgA,  Anti-tG IgG, Anti-Gliadin Antibodies, Anti-Endomysial andibodies, or other antibody tests  if positive can suggest the diagnosis. A negative test has a higher predictive value at ruling out celiac disease than a positive test has at confirming the diagnosis (the tests are more highly sensitive than they are specific).  To confirm the diagnosis requires a small bowel biopsy that is usually obtained by upper GI endoscopic exam.

Once diagnosed with celiac disease a person has to learn how to eat a gluten free diet in a society where wheat and other gluten containing food is nearly everywhere.  Fortunately more and more prepared foodstuffs are being marketed all the time, and more recipes, support groups, and nutritional advice is available than ever before.

I just read a very interesting article in the N.Y Times by Keith O’Brien that nicely outlines the history of the emergence of gluten enteropathy in the U.S., and the market leadership by General Foods in bringing gluten free food products to market to capitalize on the growing market for gluten free products.  You may enjoy reading:

Should We All Go Gluten Free?

By Keith O’Brien November 25, 2011. 

My guess is that you know someone dealing with the need to eat gluten free.  Fortunately as awareness grows and resources become more easily available providing a gluten free meal is less onerous than it was just a decade ago.

I am also learning more about various nutritional deficiencies that can accompany celiac disease.  The malabsorptive condition seen in patients with celiac disease can lead to several well documented vitamin deficiencies that are uncommon otherwise.  Deficiencies in almost all of the fat soluble vitamins and B vitamins are more common in celiac patients than in the general population.  I recently saw a 17 year old girl in the office with known celiac disease who had been well controlled on a gluten free diet for several years. She was found to be both vitamin B12 and folic acid deficient when evaluated for anemia and fatigue.

As a medical community we have become more aware and educated about celiac disease in recent years, and it is good to see that the marketplace is stepping up to meet the demand for gluten free products and make existence easier for this significant minority of Americans with gluten sensitivity.

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With estimates ranging from $35 billion to a whopping $850 billion, the true costs of “defensive medicine” are difficult to pinpoint. A variety of government reports, physician surveys and studies have attempted to pinpoint exactly how much of U.S. healthcare costs are generated by defensive medicine, but the varied definitions of “defensive medicine” make the real number hard to determine.

Defensive medicine refers to the costs associated with doctors protecting themselves from medical malpractice lawsuits. These costs include liability insurance premiums, malpractice judgments and settlements, and sometimes extend to unnecessary testing or other physician services provided to patients solely to avoid malpractice claims. Indirect costs associated with defensive medicine can also include “assurance behaviors,” such as ordering tests or delivering additional services that have only marginal medical value, or no value at all, to discourage malpractice lawsuits—which can cost more than even earning PhDs. A 2005 study published in the Journal of the American Medical Association discovered that doctors may perform these unnecessary services in the hopes that if a malpractice claim were to arise, the court would be satisfied that the physician met the standard of care.

A Look Behind the Numbers

The Congressional Budget Office estimated that defensive medicine accounted for $35 billion—or 0.2 percent—of the total U.S. healthcare expenditures for 2009. This figure is significantly lower than the estimated $650 to $850 billion in annual expenditures attributed to defensive medicine by Gallup and Jackson Healthcare surveys of physicians. The Jackson Healthcare survey gathered data from thousands of physicians across the United States on the indirect and direct costs generated by defensive medicine, concluding that physicians considered defensive medicine the primary driving force behind rising healthcare costs—the result of an overly litigious healthcare environment.

Nine out of ten surveyed physicians said they practice defensive medicine, and general estimates predicted an average of 34 percent of overall healthcare costs arise from defensive medicine. A subsequent Gallup poll of physicians found that approximately 73 percent of surveyed physicians admitted to practicing defensive medicine within the past year, but estimated overall costs at only 26 percent. The 2005 JAMA study by researchers from Columbia and Harvard Universities also revealed that for physicians practicing in “high-risk” specialties, these monetary figures may be much higher; 59 percent of the physicians surveyed admitted to ordering more diagnostic tests than medically necessary to prevent malpractice litigation. Plus, the physicians avoided caring for high-risk patients, referred patients to other specialists, prescribed more medications than medically necessary and suggested unneeded invasive procedures—all to avoid malpractice lawsuits. Another study by the American Academy of Orthopedic Surgeons discovered that defensive medicine accounts for a startling 20 percent of all imaging orders, and half of these imaging orders were for expensive MRIs.

Why the Disparities?

So why is the Budget Office’s number so low when the Jackson Healthcare survey is so high? Because physicians aren’t regularly logging every single expenditure arising from defensive medicine, and no one is entirely sure what even qualifies as “defensive,” quantifying the costs with exact accuracy is nearly impossible. The great differences in estimated costs, however, is likely due to the particular expenditures included in the figures for defensive medicine. For instance, the CBO’s low estimate of $35 billion includes “malpractice insurance premiums together with settlements, awards and administrative costs not covered by insurance,” but does not include unnecessary procedures, medications and other services, so long as they are covered by insurance. This difference in accounting is more than enough to explain the disparity.

The Jackson Healthcare survey adds a myriad of other direct and indirect costs to the CBO’s numbers, including all the excessive diagnostic testing and medical services provided in the spirit of defensive medicine. The survey results then translate the percentages into dollar amounts using the calculations of estimated overall U.S. healthcare spending released by the Centers for Medicare and Medicaid Services. Thus, this number includes more items than the CBO’s report, and bases its numbers on another estimate.

With healthcare costs rising rapidly in the United States, combined with increasing tort reform and malpractice fears, defensive medicine is becoming a more and more expensive slice of the healthcare-cost pie. Regardless of the actual monetary amount, defensive medicine practices strain not only Medicare and Medicaid, but also the insured and uninsured healthcare consumer alike, contributing to increasing prices for medical services and greater costs to insurance companies. Unless something is done to relieve the legal pressures placed on physicians, defensive medicine will continue to generate billions of dollars in healthcare expenditures every year.

Brittany is a blogger-in-residence at PhDs.org 

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In the study patients had their colon cleared of feces and a large volume replacement with feces of another person, usually a relative. The reports that I could find did not go into detail as to just how this was accomplished, but it must involve clearing the existing feces from the sick patient’s colon, and replacing it with the feces of another person. I can just imagine the response I’d get from the nurses asked to do this if I ordered it on the hospital’s medical ward. I suspect it would be something like, “You want me to do what?” or “Are you sure another course of vancomycin is not a better choice?” Care of a sick patient getting a bowel prep for colonoscopy is no fun, but following that with a large volume feces enema! Now that has a very high “yuck” factor. Add to that collecting the feces and storing it for transplant and you have a procedure that is certain to bring a groan from the staff tasked with executing the details.
Hopefully we as a medical community can get past this prejudice against handling feces. The study, if it holds up to further scrutiny, sounds almost too good to be real. Dr. Mark Mellow and others from Integris Baptist Medical Center in Oklahoma City reported on 77 of the toughest C. diff. patients. These patients were old, had an average duration of the C. diff illness of 11 months, and 31 of the 77 were hospitalized, homebound or in a nursing home when the procedure was performed. Nearly all had been treated with vancomycin and other traditional therapies. 91% of the patients no recurrence at 3 months follow up, and this rose to 98% with additional treatment and repeat fecal transplant.
The procedure has a lot of things to overcome, the Yuck factor being just one. It has no pharmaceutical backing, i.e. no one has patent on feces, and so there is not big money to back further studies. Still, hospitals who are losing big money on long hospitalizations for patients with C. diff. colitis should be very excited to have a low tech, low cost treatment that really works for a disease that has been a huge problem leading to long and expensive hospitalizations. Also the procedure is somewhat sensational which may induce others to replicate the study and report their findings. Look at how much press the initial case presentation has garnered. Hopefully these factors will lead to further study and result in convincing evidence that this is an effective and safe treatment of refractory C. diff. and we will get past the smelly and yucky excuses not to perform fecal transplant. It sounds like the procedure is still a ways from ready for prime time, but it sure sounds promising. Human feces is a tremendously complicated ecosystem, and the thought that we can somehow kill off all the bacteria in the gut and get them to grow back right without replacing them with the real thing is maybe naïve. Fecal transplant may be just the answer to a stinky problem.

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We still commonly use a relatively few medications with a narrow therapeutic window, notably warfarin, digoxin, and lithium, but many others have fallen out of favor because safer effective treatments have become available. For fun and historical perspective let’s look at some of the drugs with troublesomely narrow therapeutic windows.

Thoephylline:  Prior to the widespread use of inhaled corticosteroids, long acting inhaled beta agonists, more aggressive use of short burst courses of oral corticosteroids, and new medications like spireva, Singular, and others the mainstay of asthma and COPD management was theophylline. With a non-linear metabolism (the serum levels do not gradually and steadily increase with increased dose, but rather jump quickly at times with minor dose changes), severe toxic side effects at only slightly supra-therapeutic serum levels, and many drug interactions, theophylline toxicity was a common cause of ICU admission for many years.

Digoxin:  Digoxin is still used for many patients, but not nearly as often, and usually at considerably lower doses than when it was considered a key part of management of most patients with CHF and tachyarrythmias of many types. We have learned a great deal about CHF treatment in the last 20 years, and digoxin plays at most an ancillary role in cardiology today for most heart conditions. This is nice as often life threatening arrhythmias were commonplace in years past, and digoxin toxicity was extremely common.

Tricyclic Antidepressants: These are a prefect example of a narrow therapeutic window. At a daily dose of 300 mg daily, amitripylene ingestion of as little as 4-5 days of dosing could be lethal. In contrast ingestion of a full month prescription of most SSRIs is unlikely to be life-threatening. Amitriptylene, imipramine, nortriptylene, desipramine and later some tetracyclics like trazodone were the only effective antidepressants available prior to Prozac, and the SSRIs have been popular not just because of their lack of bothersome side effects. The fact that lethal overdose of an SSRI is extremely uncommon, whereas ICU admissions and deaths from tricyclic intentional and unintentional overdose were daily occurrences 30 years ago. We rarely use the tricyclic antidepressants in doses needed for depression today.

Warfarin:  We still use warfarin plenty, but new directly acting drugs like Pradaxa, Xarelto and apixaban are becoming available for prevention of stroke in atrial fibrillation, and are likely to be used in the future for DVT therapy. It remains to be seen whether bleeding complications will be significantly less problematic, but it is clear that the therapeutic window with warfarin is about as narrow as they get. A patient therapeutic on 5 mg daily, may be significantly over-anticoagulated at a dose of 6 mg daily, and with many drug interactions, dietary variation of vitamin K ingestion, and patient compliance issues with frequent INR monitoring this is a major factor in patient care.

Aminoglycoside antibiotics:  These remain a very effective therapy for many gram negative bacterial infections, but have in large part been replaced with much less toxic drugs. Use of these antibiotics requires close monitoring of serum levels and renal function to assure both therapeutic serum levels and non-toxic levels.

Lithium:  Lithium remains an effective therapy for the mania associated with bipolar disorder, but the narrow therapeutic window where serum levels below 0.5 usually not effective, but levels much above 1.0 leading to toxicity, drugs with a much wider therapeutic window are often preferred by patients and physicians alike. (Visit this Lithium side effects resource)

Aspirin:  No not 81-325 mg daily for their anti-platelet effect, but three Ecotrin or Bufferin 325 mg tablets four times daily. Prior to the huge list of NSAIDs beginning with ibuprofen and naproxen, high dose aspirin was the standard of therapy for rheumatoid arthritis, osteoarthritis and most inflammatory disorders.  Who remembers checking salicylate levels, watching for tinnitis and bleeding ulcers or hemorrhagic gastritis from aspirin toxicity.  I don’t miss those days.

Other drugs like many of our chemotherapy agents still remain in widespread use despite the need to push dosing to levels where toxicity is expected, but overall the development of safer and improved drugs has made consideration of the therapeutic window much less of a day-to-day concern than it was just a couple of decades ago.

Please leave your stories about use of drugs with narrow therapeutic window issues for readers to enjoy. Leave your e-mail in the subscribe area on the right side bar to be notified of future DrPullen.com posts, and follow on Twitter @DoctorPullen to get additional thoughts and health care commentary.

• Discount Drug Coupons: In every state except Massachusetts the use of manufacturer coupons to reduce the copay for brand name drugs is legal. Federal insurance plans Medicare and Medicaid disallow these coupons, as their real effect is to negate the intent of the payer (the U.S. government and its taxpayers in the case of Medicare and Medicaid) to force the individual patient to pay a premium in the form of higher copayments in order to use higher price brand name drugs. The effect is to give incentive to patients to use cheaper generics, save money themselves and save money for the health care system. Discount drug coupons take the incentive away from the individual patient and end up raising the cost of health care. Pfizer hopes that physicians and patients will make use of these coupons and help them retain market share instead of using less expensive generic atorvastatin.
• Making deals with the pharmacy benefits managers that insurance companies use to give rebates or market share incentive deals that in essence give larger profits to these companies if patients use Lipitor instead of generic atorvastatin. These pharmacy benefits managers have considerable power in the choices patients have and drugs they are dispensed.

If Pfizer is successful in their attempts to retain significant market share of the $11 billion in annual sales of Lipitor, the #1 grossing U.S. drug for the last several years we can be sure other pharmaceutical companies will follow suit as their drugs lose their patent. Don’t be fooled by drug discount coupons. They may save you dollars in select situations where an expensive drug is clearly the best alternative, but in my opinion are rarely good choices, and certainly not in the case where their sole purpose is to convince us to use a more expensive brand name of a drug where a generic alternative is available. Everyone wants to reign in the cost of medical care, and discount drug coupons are trying to circumvent incentives to lower the cost of health care.

I’d be in support of either the federal government or each of the states following the MA lead and make drug discount coupons illegal.

This is both exciting and frightening. It raises huge questions including who if anyone should get this testing. Here is a list of some of the issues that come to my mind as we start the process of figuring out the role of this new technology:

1. Increased Abortions and Earlier Abortions of Down’s Syndrome Pregnancies:  One consequence of a more accurate test for Down ’s syndrome if it leads to more widespread testing or women for this condition is that more women will face the decision of abortion or not.  Now women first face the question, “Would I abort my pregnancy if I knew I had Down’s syndrome, and if so am I willing to undergo a test that could cause miscarriage to get that information.”  With the Sequenom™  MaterniT21™  test women will be able to get much more definitive information without a test that puts their fetus at risk from the test itself. This may lead to more women choosing to be tested. Putting aside the whole “pro-life vs. pro-choice” debate, the opportunity for earlier diagnosis will make technically easier and less physically traumatic abortions possible in women who have a Down’s Syndrome pregnancy.
2. Who should be Eligible for the Test?:  Although the risk of Down ’s syndrome rises with increasing maternal age many Down’s Syndrome babies have young Moms.  With a more accurate and less dangerous test available should all or more women be offered the test?
3. Who should pay for the testing?: This is a very complicated question.  This test is not going to be inexpensive.  On the Sequenom™  press release they suggest that the cost will approximate the cost of amniocentesis testing.  They do not make it clear if this means the cost of the amniocentesis test itself, the cost of the genetic testing of the cells obtained, or both.  If the test is done it will lead to higher costs for prenatal care as the test itself will significantly increase the overall cost of prenatal care.  On the other hand the cost of having a Down ’s syndrome baby is not inconsequential.  Down ’s syndrome children sometimes have major other congenital deformities, and the long term cost of education, support as adults, and associated family and societal costs are real and significant. A comprehensive cost-benefit analysis of this process will be interesting to see when it becomes available. These issues themselves will lead to ethical and moral choices.
4. Lower Incidence of Down’s Syndrome:  If this tests becomes widely used, and if more women choose to abort pregnancies with Down’s Syndrome fetuses, the incidence of Down’s Syndrome could significantly decline.  While many may consider this the desired outcome, some Down’s Syndrome supporters fear that this may lead to reduced support and reduced research into drugs and other techniques to help Down’s children.

I’m sure I’ve only touched the surface of the ethical, emotional, medical, moral and financial issues this new MaterniT21™ test from Sequenom™ and likely others to follow will bring.  It seems a near certainty that with the ability to sample fetal cells from maternal blood other genetic tests like tests for cystic fibrosis, sickle cell disease, and many others will follow.

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I Got Mine

This topic comes to mind again this year as we have plenty of influenza vaccine, on time this year and ready for distribution.  A prior version of this post was posted in 2010.  I have strong enough feelings on the subject to repost an updated version.  If anything good came of the Swine Flu epidemic on 2009 it was that more Americans get immunized not than ever before.

This year as every previous year Dr. Pullen was first in line at our office for my influenza vaccination.  I take seriously the mantra primum non nocere, first do no harm. It’s hard to imagine doing more harm than seeing a patient with influenza on Monday, and on Wednesday, the day before I get sick, sneezing and passing the influenza germ to one of my vulnerable older patients, or a pregnant woman, or a young baby who then dies from influenza.  This scenario is just inexcusable given that I could have avoided harming the patient if I had received the recommended and easily available influenza vaccination. It would be immoral and irresponsible to put my patients at that type of risk unnecessarily.  I encourage, coax, tease, and everything short of intimidate my employees and fellow physicians to get their influenza vaccination also.  School teachers, emergency workers, and others in close contact with the public should similarly feel morally compelled to get influenza vaccination. It is our moral responsibility.

I also got a Tdap vaccination last year also, even though was several years until I was due a tetanus shot.  See Dr. Pullen Gets His Tetanus Booster  Shot Years Early!  My thinking was the same, try to avoid a pertussis infection, and not put my patients at risk.

It’s a small step from discussing health care workers and influenza and pertussis vaccination, to talking about parents and childhood vaccinations.  The parent who chooses not to vaccinate their children against measles and pertussis puts not only their own child, but other children in the community and the school who may be at particular risk for complications from these infections in danger.  These children at high risk may catch these infections from these unimmunized children.  As a parent I’d feel terrible if my child died or became brain injured from measles, but I’d also feel horrible if my child passed Pertussis or measles on to a child with leukemia, or HIV because I chose to not immunize my child.  I appreciate that this is a free society, and we can make our own personal choices about health care including immunizations. It’s not illegal to decline recommended immunizations, but in many cases it is irresponsible and not living up to our community moral responsibility. Parents who choose not to immunize their children and take advantage of the herd immunity of the majority of children whose parents responsibly immunize their kids are just ignorantly selfish.  They think they are protecting their children from risks of immunizations, though a great mass of evidence refutes this point of view.  In fact they are putting both their own child, and other children who lack immunity through no choice of their own or their parents at risk.

I’m anticipating a rash of angry comments calling me a mouthpiece of the brainwashed physicians of organized medicine.  Don’t believe them.

See these references on the safety of childhood immunizations.

Prenatal and Infant Exposure to Thimerosal From Vaccines and Immunoglobulins and Risk of Autism  (there is none).

Data Fail to Support Thimerosal-Autism Link

The end of the autism/vaccine debate?

Book Is Rallying Resistance to the Antivaccine Crusade

Also see the great video at the top of the Musical Docs page Immunize: The Vaccine Anthem.

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Dr. Pullen Got His Tetanus Booster Years Early! 

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Any standard public health or medical school prevention text includes (or ought to include) some version of the figure below, which illustrates that the leading causes of death in the U.S. at the turn of the century (heart disease, cancer, stroke) were actually surrogates for what have come to be known as the actual causes of death: unhealthy behaviors such as tobacco use, poor diet, and physical inactivity.

The most effective preventive services that primary care clinicians provide, then, are not screening tests but counseling interventions that aim to change one or more of these behaviors for the better. Community-level initiatives such as tobacco-free restaurants and campuses, pedestrian-friendly cities, and increasing access to nutritious food sources play a critical role in changing health-related behaviors, too.

Unfortunately, the impact of behavioral or “lifestyle” approaches to prevention is likely to be limited by two factors: 1) even intensive interventions produce very modest benefits; and 2) behaviors don’t exist in a vacuum, but are largely shaped by economic and social circumstances. Family medicine professor and former U.S. Preventive Services Task Force member Steven Woolf has published a number of studies showing that the risk of death is strongly associated with levels of college education and income; his research team at Virginia Commonwealth University worked with the Robert Wood Johnson Foundation to develop an interactive County Health Calculator that illustrates how many premature deaths could be avoided by eliminating educational and income disparities.

Researchers from Columbia University went a step further by publishing “Estimated Deaths Attributable to Social Factors in the United States” in this month’s issue of the American Journal of Public Health. Using estimates derived from the literature on social determinants of health and year 2000 mortality data, they found that the “actual” causes of death looked like this:

1) Low education: 245,000
2) Racial segregation: 176,000
3) Low social support: 162,000
4) Individual-level poverty: 133,000
5) Income inequality: 119,000
6) Area-level poverty: 39,000

Clearly, we know a great deal more about successful strategies for fighting clinical and behavioral causes of death than we do about social causes, some of which often appear intractable. But I could not agree more with the authors’ conclusion that “these findings argue for a broader public health conceptualization of the causes of mortality and an expansive policy approach that considers how social factors can be addressed to improve the health of populations.” The point being: poverty, discrimination, and low education aren’t just social or political issues best left to non-clinicians – they’re health issues, too.

Originally posted by Dr. Kenny Lin at Common Sense Family Doctor Friday, August 26, 2011

Can Cancer Ever Be Ignored?  by Shannon Brownlee and Jeannie Lenzer

I especially like the article’s visual.  It raises the seldom stated but often considered axiom that every good primary physician knows:  If you don’t want to know the answer, don’t ask the question.

Dr. Kenny Lin, a key player in the PSA debate as the ex-USPSTF point investigator on the PSA screening dilema who resigned in protest of political pressure to withhold new recommendations to make PSA screening a grade D (as in don’t do it) for PSA screening in healthy males that was based on the best available evidence but was politically unacceptable writes another excellent discussion of the topic:

The Meeting that Wasn’t Revisited by Kenny Lin MD.

Stay tuned for the latest on this controversy.  Subscribe to DrPullen.com to not miss a post.  You can choose to subscribe to all posts, or just by category.  Just enter your e-mail address in the subscribe area at the right.

NOTE THAT SINCE THIS WAS POSTED THE USPSTF HAS POSTED A PROPOSED UPDATE TO THEIR RECOMMENDATIONS FOR PSA TESTING FOR MED AS A “D” RECOMMENDATION, i.e. RECOMMENDING AGAINST USE OF PSA AS A PROSTATE CANCER SCREENING TOOL.

At the crux of these comments is that the required elements of this wellness exam bear little resemblance to what most patients would consider a physical exam.   CMS intentionally made up brand new CPT codes for these exams so that they are not considered the same service as a preventative care “physical exam” code for an adult patient.  Those cynics among us suspect that the primary reason for this was financial. Medicare did not want to use the age adjusted RVU payment multiplier for this newly authorized service.  In order to justify a mush lower payment amount they simply defined a new service as a Medicare Wellness Exam.  The RVU for a preventative service code is considerably higher than the code for a routine office visit, so Medicare conveniently chose to reimburse the Medicare Wellness Exam at the level of a routine office visit, not as at physical exam level.  That when combined with the fact that Medicare uses a compensation scale per RVU that is considerably lower than all commercial insurers make doing a Medicare wellness exam for an elderly patient pay considerably less than a typical office visit for younger insured patient with modestly complex medical problems.

Given that a family physician who wants to stay in business cannot spend twice the time of a regular office visit on a Medicare Wellness Exam that pays considerably less, the required elements of the Medicare Wellness Exam visit consume much of the time a reasonable physician can allot for the visit.

Making this all the more complicated for patients is that Medicare patients in my practice for years have become used to not being able to have a wellness visit, and so I have tried to provide these services broken into pieces at the time of disease management visits.  This rather sudden change has left patients wondering what I’m doing spending my time at a wellness exam discussing things that may seem silly to them, or may not be what they perceive as having much to do with wellness.  Most patients coming in for a wellness exam reasonably expect this to include a medical history, a medical exam and addressing preventative services due as well as at least documenting and formulating a plan for future evaluation of any concerns they bring up at the visit.  This seems reasonable, except that the Medicare proscribed wellness exam has to include an assessment of:

• Patient fall risk
• Depression screening
• Addressing their end of live decision status
• Ability to accomplish a variety of needed daily tasks like managing money, shopping, housework, and transportation needs, and other activities of daily living.
• Vision assessment
• Hearing assessment
• Assessment of immunization status
• Assessment of other USPSTF category A & B preventative services due, including colon cancer screening, breast cancer screening, prostate cancer screening discussion, and diabetes screening.

The healthy, active and otherwise well 67 year old may think many of these queries re irrelevant, and they may in fact be irrelevant.  Some may even feel insulted that I’m asking about their risk of falling and managing their household when they want to talk about their risks of heart disease, diabetes, stroke and cancer.  The frail, near blind and near death 96 year old living with family may have difficulty with so many of these issues that to adequately cover even some of them would require more time than can be allotted to the entire exam.  Many of these patients may feel this visit should include a much more comprehensive hands-on physical exam than is realistic in the visit given the mandated topics to cover and the time reasonably expected for the level of compensation allowed.

Still other patients will expect their chronic health conditions, or various other complaints to be addressed at this visit.  Their shoulder hurts, their ankles swell, they have some constipation, and their back aches in bed at night.  It is difficult to tell the patient that this visit is only for the mandated Medicare Wellness Exam issues and not to address their multiple chronic health problems.  Yet other patients really don’t want a Medicare Wellness Exam at all, rather they want a problem focused visit but want to have the visit billed as a Medicare Wellness Exam because it is paid by Medicare without copayment or deductible payments by the patient.

It is simply not realistic to try to complete the mandated Medicare wellness exam points, do a history and physical exam in the traditional sense, and have time to even listen to other complaints.  To try to listen to and also address these complaints is even less likely.

I think Medicare is way off base in setting rigid and rigorous expectations for a wellness exam.  Allowing the patient and the physician to set an agenda that meets the patient’s needs and expectations would have been a much wiser approach. The concept of giving patients the opportunity to see their physician once annually to address their personal preventative care issues without making a laundry list of mandated issues to include in the visit could have been great.  As it is now the visit becomes a race to cover the mandated topics while trying to include at least some of the reasons the patient wants to be seen.  This is one more example of the Medicare rule-makers just trying too hard standardize care and mandate excellence, with the unintended consequences of forcing every American over age 65 and on Medicare to be subjected to essentially the same one-size-fits-all Medicare Wellness Exam.

What is Hospice?

Hospice is not a death sentence. It is an opportunity to live life to the fullest until you die.

I have been a Hospice volunteer since 1994. It is my passion. To be of service to others during such an important and intense time of life is an honor. The more I give, I am repaid tenfold. In order to qualify for Hospice a patient must be  diagnosed with a terminal illness that if it were to progress at the normal rate, would only have six months to live. To be eligible a patient can’t be involved in treatment to try cure the illness. Their doctor must write a referral for the patient to be evaluated for Hospice care.

Once enrolled, if the patient lives to the six month timeframe they can be evaluated and reinstated in the program. Hospice provides many services that assist both the patient and the family. I have had many conversations with family members and friends of terminally ill patients who were anxious because of unresolved issues with the patient or because they just felt they needed to share something and had not done so. I always encourage them to make time to talk about the issues. It will be too late once the patient has passed. If left unresolved these situations can lead to the survivor feeling regret, sadness, guilt or frustration. Grief is natural but adding the pressure of not talking openly before someone dies can make the grieving process much harder.

Many patients have talked with me about the importance of relationships in their life. They have never expressed regret about wishing they had more money, possessions or fame. It is so important to most people to know that they don’t have any unfinished business, which allows them to pass peacefully. Once a patient has been diagnosed with a terminal illness, Hospice is the best way to have their wishes met. The Hospice team; Nurse, CNA, Chaplain, Social Worker, Medical Director, Volunteer Coordinator and Volunteers work together to accomplish the patients desires. This team effort helps address the patient’s complete needs; physical comfort, emotional and spiritual support. Treating the entire patient is very important. Then, after the patient passes the family has a great support system and grief counseling, and support groups available anytime there is a need. I have had many heart-to-heart talks with patients in addition to fun and silly times together. After every assignment I take time to reflect on the experience. I have always learned something from each patient. The patients and families have always thanked me and said how much my service and the Hospice services in general made a positive difference.

I encourage anyone interested in Hospice or in volunteering to call your local Hospice organization. If you have questions please contact me at christinalufkin1@yahoo.com. Christina is also available for interviews or guest speaking engagements. Christina Lufkin, Author “Live with Purpose:Die with Dignity” www.christinalufkin.weebly.com

Comments by Dr. Pullen:  Over the years I have had nothing but positive experiences with hospice.   When my Mom passed last spring Hospice was involved and they definitely made for a better experience all around. See my post, Saying Goodbye.  Hospice has several major advantages from a flexibility and financial standpoint also for terminal patients.  The Medicare reimbursement for Hospice is on a per-diem basis, and the Hospice team has a great deal of flexibility in choosing services to provide to patients, many of which would not be eligible for regular Medicare coverage.

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I don’t watch televangelist Pat Robertson but interestingly his recent response to the question about the moral issues facing the spouse of an institutionalized patient with advanced Alzheimer’s disease has pushed this type of dilemma into the public eye.  This and similar very difficult and sticky personal, ethical, religious situations usually are relegated to individuals, families and friends to face quietly and personally.  That is likely where they belong, maybe in consultation with one’s personal pastor or confidant.  Certainly live on a televangelist’s show is no place to have the issue of an individual debated. The New York Times ran an article that addresses some of these issues that makes for a thoughtful read:

Robertson Stirs Passions With Suggestion to Divorce an Alzheimer’s Patient

By ERIK ECKHOLM

Published: September 16, 2011

With his suggestion this week that a man whose wife was far “gone” with Alzheimer’s should divorce her if he wanted a new companion, the television evangelist Pat Robertson stumbled into treacherous moral terrain, setting off storms of criticism and questions about a disease that shatters lives and families.

Other conservative Christian leaders were swift to condemn his remarks as a call to violate the biblical sacrament of marriage. Many doctors and patient advocates had a more complex response, with many suggesting that Mr. Robertson, 81, had repeated misleading stereotypes about Alzheimer’s but had also broached an important subject, how spouses and other family members of dying patients can prevent their lives from being engulfed and start to move on. Read more

Here is a clip from Pat Robertson’s show where he addresses this issue.