Antiarrhythmic drug therapy review

Although antiarrhythmic drug therapy has declined sharply in the post-CAST device therapy era, limited indications persist and are reviewed concisely here in the Texas Heart Institute Journal.

Podcast at Soundpractice.net

My podcast interview has been posted. If you have half an hour or so with nothing better to do, give it a listen.

Review of diagnosis and management of pleural effusion

here in the October issue of CCJM.

Eye of newt, and toe of frog…

More pseudoscientific med school fluff

This time it’s the University of Manitoba medical school. According to this report from cbc.ca the school’s alternative medicine program “encourages future doctors to find ways to combine old medical philosophies with modern knowledge.” The curriculum, designed for second year students, features acupuncture, yoga, homeopathy and chiropractic. Students “sip ginseng tea while handling bags of dried gecko lizards and jars of toad droppings.”

Dr. Greg Chernish heads the program. “Chernish says combining the benefits of ancient medicine with modern science provides the best care for patients – a concept that surprised student Heather Nowosad. ‘The integration part was surprising for me, because I've always had this belief that it's sort of like people believe in one or the other,’ said Nowosad, who plans to become a family physician.” Don’t feel bad, Heather. Abraham Flexner had that belief too.

Systemic thrombolysis for submassive pulmonary embolism?

The accepted treatment for pulmonary embolism (PE) uncomplicated by hypotension or acute right ventricular failure is heparin (low molecular weight or unfractionated). When PE is complicated by hypotension (classified as massive) there is general acceptance of systemic thrombolysis in addition to heparin. More controversial is the intermediate situation, known as submassive PE, defined as PE with normal blood pressure but in the presence of acute right ventricular dysfunction. Right ventricular dysfunction is generally defined by echocardiography.

A randomized double blind placebo controlled trial in 2002 demonstrated that in submassive PE systemic thrombolysis added to heparin was associated with improved patient stability, less need to add hemodynamic support, but no difference in mortality. Controversy has persisted, and in the October 24 Archives of Internal Medicine are pro and con articles with rebuttals. [1] [2] [3] [4].

CA-MRSA in perspective

In his post today on Staphylococcal infections RangelMD says methicillin resistant staphylococcus aureus (MRSA) infections are not inherently worse than methicillin sensitive (MSSA) infections, community acquired MRSA (CA-MRSA) is not a “super bug”, and the press has sensationalized and distorted the issue. I agree partially---especially with the point about media distortion. I also agree that the “old fashioned” MRSA is not necessarily more virulent than MSSA, although it may be associated with poorer outcomes related to greater difficulty in treatment and greater comorbidities in MRSA infected populations.

Concerning CA-MRSA, however, I feel some need to elaborate since I have posted about its unique attributes before. [1] [2]. Although its predilection for causing minor skin infections often makes it more of a nuisance than a threat to life there is evidence of uniquely heightened virulence and transmissibility in some CA-MRSA clones. These characteristics are associated with the Panton-Vanentine leukocidin, (PVL) found more frequently in CA-MRSA than in other strains. The PVL gene is only rarely found in hospital associated MRSA and MSSA.

Although the somewhat heterogeneous nature of CA-MRSA makes it difficult to generalize, some trends are emerging which raise concerns about increased transmissibility and virulence.

On the death of Lisa McPherson

Lisa McPherson was given Scientology’s “alternative” to psychiatry. On the tenth anniversary of her death under the care of Scientology staffers the Health Fraud List posts these links about the case. This article chronicles the tragedy and the subsequent legal wrangling. A large collection of links on the case is provided here. The wrongful death suit against Scientology lasted seven years and was finally settled last year.

Sloppy media coverage of avian flu

Popular media coverage of avian flu is confusing. This piece from WorldNetDaily is headlined “OUTBREAK! Has feared mutation of avian flu arrived? Doctors in Thailand, Indonesia see 1st signs of human-to-human spread.” The article reports that in Thailand two recent human flu cases can’t be traced to contact with birds. The cases were mild, and doctors speculate that waning virulence may have accompanied a mutation enabling human to human transmission. The problem is that the article cites no report of serologic analysis or evidence that the cases indeed represent the H5N1 avian variety. Moreover, no human disease contacts were mentioned. If there’s anything to this, the article certainly doesn’t inform us.

On down it says “Meanwhile, in Indonesia, the disease is spreading so rapidly, particularly in the capital of Jakarta, some health officials strongly suspect the long-dreaded mutation has already occurred.” Oh? They why does it say a few paragraphs below that only 13 avian flu cases have been confirmed in Indonesia?

And, if human to human transmission is the case here it’s not new. Human to human transmission of avian flu was well documented over a year ago.

The strange story of Dr. John R. Brinkley

Pseudoscientific health providers have a colorful history. They range from alternative practitioners who honestly believe in an unproven method to the purveyors of outright fraud. In this latter category was the fabled Dr. John Brinkley. Not only was he one of the better known “snake oil salesmen” in American history, but he may also be the originator of the infomercial 80 years ago in the early days of radio.

But it seems society in those days was less tolerant of the likes of Dr. Brinkley than now (those of Brinkley’s ilk today seem to be doing quite well). In 1930 both his medical license and his radio station license were revoked. Virtually run out of Kansas, he moved his operation to the Mexican border where he constructed one of the first Mexican border blaster radio stations. You can listen to an NPR report on Brinkley and border radio here. It contains excerpts from Brinkley’s infomercials and as a bonus, about 16 minutes in, an interview with Wolfman Jack, propelled to fame on the third and last incarnation of Brinkley’s station, XERF.

Clostridium difficile: the Quebec strain

DB blogged about a new face of C-diff earlier today—it’s been showing up in healthy members of the community, some of whom had no recent antibiotic exposure. There’s another aspect that is worth our attention and that’s the Quebec strain.

A hypervirulent strain of C. difficile has emerged there over the last three years. A study of the attributable mortality, an editorial and a news piece appear in the October issue of CMAJ.

What’s different about the strain? As reported in these articles: 1) it produces 15-20 times the amount of toxin as the ordinary strains, due to an altered repressor gene; 2) it’s more lethal, with 23% of patients dead at 30 days and an attributable mortality at one year of 16.7%.

The author of the study points out that some patients appear to have died of direct complications of the infection such as shock or perforation while others succumbed to secondary events such as myocardial infarction, venous thromboembolism or secondary infection.

Infection control implications are discussed and the papers offer conjecture about risk factors at the Quebec hospitals. There was no difference in patient characteristics compared to other regions of Canada or the United States (the strain has shown up at a few locations in the US), and no evident difference in the use of antibiotics. The only common thread seemed to be the use of shared bathrooms. The authors conclude: The lack of investment in our hospitals infrastructure over several decades, with shared bathrooms being the rule rather than the exception, may have facilitated the transmission of this spore-forming pathogen, which can survive on environmental surfaces for months. Providing modern medical care within hospitals built a century ago is no longer acceptable.

Medical students’ skulls being filled with mush

Student BMJ is a journal for medical students from the BMJ publishing group. In the November 2005 issue is an article on an alternative modality called Ayurvedic medicine. Ayruveda, the article says, is an ancient healing tradition with roots in India. It goes on to say that Ayruvedic tradition describes health and disease in terms of three fundamental constitutional principles called the doshas. Stephen Barrett’s expose on Ayruveda reports that “Ayurvedic proponents have claimed that the symptoms of disease are always related to the balance of the doshas, which can be determined by feeling the patient's wrist pulse or completing a questionnaire. Some proponents claim (incorrectly) that the pulse can be used to detect diabetes, cancer, musculoskeletal disease, asthma, and ‘imbalances at early stages when there may be no other clinical signs and when mild forms of intervention may suffice.’”
The BMJ publishing group, a division of the British Medical Association, says its mission is "To publish intellectually sound material that will serve the needs of doctors, members, other health professionals, the scientific community, and the public." Its premier journal, BMJ, is widely regarded as a champion of evidence based medicine. So why might a paper on an ancient healing art be published in Student BMJ? To increase students’ cultural awareness, or to alert them to the alternative treatments patients are seeking, perhaps? No. This article in SBMJ actually promotes Ayruveda. The article asks “Is scientific medicine the only way?” The author notes “Studying Ayurveda provided me with an alternative system for categorising and describing states of health and disease.”
So much for intellectually sound material.

Heparin induced thrombocytopenia and open heart surgery—news from Chest 2005

The annual meeting of the American College of Chest Physicians recently took place in Montreal. One of the presentations (reported in eMedicine news) concerned the prevalence of heparin-platelet factor 4 (HPF4) antibodies in patients about to undergo open heart surgery. HPF4 antibodies are found in patients with heparin induced thrombocytopenia (HIT) and are instrumental in its pathogenesis. The Milwaukee investigators screened patients before surgery and found antibodies in 5.4%. Antibody positivity was associated with longer ICU stays and a higher incidence of prolonged mechanical ventilation, limb ischemia, renal dialysis and gastrointestinal complications. These findings raise the question of whether all cardiac surgery candidates should be screened.

I’m anxious for some details not available in this sound bite version. What was the mechanism of the bad outcomes associated with antibody positivity? How many of those patients actually met criteria for HIT?

We previously knew that many cardiac surgery patients (up to 50 %!) treated with unfractionated heparin (UFH) test positive for antibodies during their perioperative course but of those only 2% develop HIT. In contrast, fewer orthopedic surgery patients treated with UFH develop antibodies but substantially more antibody positive patients in the orthopedic group develop HIT. Thus the presence of antibodies is more predictive in orthopedic patients than in cardiac surgery patients. [1]

An iceberg model has been proposed for HIT. [2] At the base of the iceberg is a relatively large number of patients who have antibodies. Toward the surface is a smaller number who develop a drop in the platelet count, and at the tip of the iceberg are those who develop thrombosis. The interacting risk factors are complex and the actual number of antibody positive patients who develop HIT seems to vary with the patient population, as the above data suggest.

A warning form the Infectious Disease Society of America

The Infectious Disease Society of America (IDSA) has written a white paper about the rising problem of antimicrobial resistance. Compounding the problem is an alarming trend: research and development for antibiotics is waning. After investigating the problem for over a year the IDSA concluded that antibiotic development is not profitable in today’s environment. The executive summary warns “The pipeline of new antibiotics is drying up. Major pharmaceutical companies are losing interest in the antibiotics market because these drugs simply are not as profitable as drugs that treat chronic (long-term) conditions and lifestyle issues. Drug R&D is expensive, risky, and time-consuming. An aggressive R&D program initiated today would likely require 10 or more years and an investment of $800 million to $1.7 billion to bring a new drug to market.”

The report recommends incentives such as patent extensions, liability protection, and relaxation of FDA requirements for clinical studies. It warns of emerging serious infections without effective treatments unless there is prompt action to promote antibiotic development.

Elevated troponin in non-cardiac critical illness---what does it mean?

This is a controversial situation that comes up frequently in the ICU, especially in patients with sepsis. It was the subject of a prospective study published September 28 in Critical Care. Earlier literature has suggested that elevated troponin in the setting of sepsis is associated with left ventricular dysfunction [1] [2] [3] [4] [5] and mortality [2] [6] [3] [4] [5]. These same studies demonstrate elevated troponin in close to half of sepsis patients.

In keeping with previous reports, the Critical Care paper found troponin elevation in almost half of their population of ICU patients. About half of those with elevated troponin were found to meet previously defined criteria for myocardial infarction. The new finding in this study was that among patients with elevated troponin only those meeting criteria for myocardial infarction had a worse outcome. Troponin elevation absent other criteria for MI was not associated with a worse prognosis.

Although the mechanism of elevated troponin is non-cardiac critical illness remains uncertain this study adds significantly to our understanding of the problem.

Another paper challenges metformin’s contraindications

This time it’s specifically in reference to heart failure, which is listed as a contraindication in the product labeling. As I recently blogged, the vast post marketing experience with metformin indicates that it is safe, and that lactic acidosis has been difficult to attribute to it despite widespread contraindicated prescribing.

This large observational study from Diabetes Care showed that heart failure patients treated with metformin, as monotherapy or in combination with sulfonylureas, had significantly lower rates of mortality and hospitalization than those treated with sulfonylurea monotherapy. The average follow up period was 2.5 years. The mechanism may be the alleviation of hyperinsulinemia.

The authors suggest that the strict labeling of metformin may represent unfounded concerns which have deprived patients of beneficial treatment, and challenge the precautionary principle with this statement: Although "patient safety" studies often seem to focus on finding and reducing the use of previously widely prescribed medications that are of unproven benefit or even harmful, our study should serve as a reminder that there is another side to the patient safety coin—some medications that are currently considered contraindicated may have been defined as such on the basis of little or no evidence beyond pathophysiological rationale. Since this rationale alone is considered insufficient evidence for efficacy, it should also be insufficient to declare harm. We believe that the onus in the patient safety literature should shift to acknowledge that both types of patient safety issues can lead to suboptimal prescribing practices.
Well said.

Hemostatic risk factors for arterial thrombosis

Although venous thrombophilic states have recently been well defined the hemostatic (non-atherosclerotic) risks for arterial clotting have been less clear. The topic is reviewed here in Atherosclerosis, Thrombosis and Vascular Biology. The review points out that homocysteine, fibrinogen, C-reactive protein, lupus anticoagulant and anticardiolipin antibody assays are justifiable tests. Somewhat surprisingly, in those patients with concomitant vascular risk factors, in those <55 years old, and in women, testing for factor V leiden and prothrombin mutation may be justifiable.

More resources on CA-MRSA

[1] [2]

More evidence regarding panic disorder and heart disease

I recently posted this regarding myocardial perfusion changes during panic attacks. Now this study (Psychosomatic Medicine) suggests an epidemiologic association (almost two fold risk of coronary disease in patients with panic disorder) which is even worse if depression coexists.

The emerging threat of community acquired methicillin resistant Staphylococcus aureus

Methicillin resistant Staphylococcus aureus (MRSA) has been well known for decades as a nosocomial pathogen. More recently MRSA has been increasingly reported in the community. Community acquired MRSA (CA-MRSA) tends to present as a new strain with features which distinguish it from the more familiar nosocomial MRSA. I found this helpful review in September’s Mayo Clinic Proceedings. (The abstract is linked here. Full text open access will be available in March 2006).

Although some community isolates appear to have escaped from hospitals, the new strains (“true” CA-MRSA) arise de novo in the community. Here are some important distinctions pointed out in the review:

1) CA-MRSA has a unique genetic determinant of resistance---the type IV Staphylococcal cassette cartridge (SCC).
2) Unlike the “old” MRSA which has multiple drug resistance, CA-MRSA is typically sensitive to many non beta lactam antibiotics. Sensitivity patterns have regional variation and tend to show a typical pattern in a given region, which may be the clinician’s principal clue that CA-MRSA rather than the older strain is present.
3) CA-MRSA appears to be more virulent than other S. aureus strains, in part due to expression of the Panton-Valentine leukocidin.
4) CA-MRSA appears to have increased transmissibility and infectivity compared to other S. aureus strains.
5) Skin infections, soft tissue infections and necrotizing pneumonia are characteristic compared to other strains, and necrotizing fasciitis has been reported. Bacteremia and endocarditis are less characteristic.


Perhaps the most troubling aspect of CA-MRSA is its emergence as a cause of community acquired pneumonia. The authors state: “It is now prudent to consider CA-MRSA as an etiology of severe CAP in the correct clinical context. Severe necrotizing pneumonia with or without hemoptysis after an influenzalike illness in high-risk patients warrants therapy directed against MRSA.” The antibiotics of choice for pneumonia are vancomycin and linezolid.

Medical journals promote pseudoscience

Recently I picked on medical schools for promoting unscientific health claims [1] [2]. Today a medical journal got my attention and reminded me that the compromise of science by “mainstream” medicine is pervasive, and not confined to medical schools. What’s ironic is that the journal is BMJ, supposedly a champion of evidence based medicine. This week’s issue contains a review of the homeopathy promoting book “Passionate Medicine: Making the Transition from Conventional Medicine to Homeopathy.” Trouble is, the review is favorable to the book, giving it a four star (the highest) rating. Worse, four homeopathy promoting links are posted on the same page as the review.

BMJ has been taken to task for this sort of thing before and Quackwatch has BMJ on its list of nonrecommended periodicals.

Controversy in treatment of deep vein thrombosis

The treatment of deep vein thrombosis (DVT) has been controversial concerning prevention of the post thrombotic syndrome (PTS). Although systemic thrombolytic therapy is superior to conventional anticoagulation in restoring venous flow and preserving the function of the venous valves, it is associated with greater risk of hemorrhage and its effect on meaningful clinical outcomes has been disputed.

The hemorrhage risk of systemic thrombolysis has spurred interest in local interventional modalities including catheter directed local thrombolysis and catheter extraction techniques. This review from the American Journal of Medicine explores such techniques for the prevention of PTS and discusses the complication of venous gangrene (phlegmasia cerula dolens) which may be amenable to such strategies. It draws upon experience from the National Venous Thrombosis Registry suggesting improved health related quality of life outcomes for patients treated with interventional strategies as opposed to conventional anticoagulation alone.

The take home message is that physicians should be aware that such modalities are available and should familiarize themselves with the capabilities at their individual hospitals. Physicians should be prepared to resort to these strategies in the desperate situation of venous gangrene complicating massive DVT and consider offering the techniques to selected patients with DVT for the prevention of PTS.

The paper unfortunately did not mention that the widely accepted modality for prevention of PTS, compression stockings fitted to 30-40 mm Hg, work pretty well for this purpose.

More on the disruptive physician

Medscape General Medicine recently posted a provocative discussion on this topic, which I had blogged about November 5. There appears to be a burgeoning power struggle between hospital administrators (and their lawyers) and some rank and file physicians. It’s an unintended consequence of the Health Care Quality Improvement Act of 1986, which sought to protect hospital peer review. It provides immunities for hospitals in the peer review process, greatly enhancing their power to discipline physicians. Some physician groups are concerned that this has lead to abuses of peer review as hospitals, for a variety of reasons, increasingly seek to control doctors, setting increasingly narrow boundaries for behavior. A related development has been the emerging notion of the “disruptive physician.” Originally conceived with the good intention of addressing the genuine problems of incompetence and abusive physician behavior, the concept has come to be used as a pretext for stifling dissent, eliminating economic competition and abusing the peer review process.

This article and an accompanying editorial discuss the related issues of sham peer review and the abuse of the “disruptive physician” concept.

Hype versus evidence in patient safety

At last----a refreshingly sober assessment of medical errors and patient safety, here in CMAJ.

Don’t forget the thyroid in chronic urticaria

There is a high prevalence of thyroid autoimmunity in patients with chronic urticaria. The patient with urticaria and anti-thyroid antibodies may be euthyroid, hyperthyroid or hypothyroid. The mechanism of the association is poorly understood. The Thyroid and Urticaria is a review of the topic in the October issue of Current Opinion in Allergy and Clinical Immunology.

Some patients may achieve remission with L-thyroxine, which of course is indicated for those who are hypothyroid. Such treatment of euthyroid patients is not supported by high level evidence and is controversial.

Thyroid testing should be considered in patients with chronic urticaria. Knowledge of this association could help a patient and might come in handy some day on internal medicine boards.

Irresponsible diet hype is being offered by the media

Don’t trust popular media for health information
The lay press lacks nuance and perspective in reporting on medicine and health, with the result that the consumer gets served an endless series of hyped up sound bites. These sound bites are often superficially contradictory, leading readers to wonder if medical science can make up its mind about much of anything. Nowhere is this better illustrated than in the popular coverage of diet trends.

The latest offering is this shocking headline: “Low-Carb Diet: An Alarming, New Danger.” Then, in bold type, the first sentence of the article reads “Low-carbohydrate diets may lead to dramatic weight loss, but dieters pay a big price for their thinner waistlines.” The article goes on to say that the diets lead to reduced myocardial energy storage and impaired cardiac relaxation. This is based on an Oxford University study that was apparently presented at the American Heart Association last week.

In attempting to dig deeper I was unable to find quality reporting on the study. The AHA will have some of the meeting presentations posted on the web later this month. I did find this from the British Heart Foundation, which sponsored the study. Their web page says that myocardial energy storage was measured by magnetic resonance spectroscopy. There were no clinical endpoints studied.

What’s irresponsible about the reporting is this study is far too preliminary and too low-level to warrant prime time. Specifically, the study period was all of two weeks, and the study population consisted of 19 subjects (the investigators themselves along with some of their friends and family!). Not exactly high level evidence. It’s hypothesis generating at best.

Next I did a Google news search and got this. Sure enough, the usual parade of contradictory sound bites appeared. The first few hits tell me low carb is bad (it reduces energy stores in the heart)---but, the next few headlines say it’s good for the heart (it helps improve the metabolic syndrome). So what’s the deal? Is low carb good for us? Yes and no, if you follow the popular press. Good last week, deadly today. What will it be tomorrow?

All this, of course, is rubbish. Science doesn’t move like the daily news. Its progress is gradual, with each new set of observations integrated cautiously with what was known before. There are no pat answers about low carb diets. They are probably good for some patients and bad for others. Basic research paints an enormously complex picture and suggests that it depends on one’s genetic makeup and associated risk factors.

If I were not such a passionate believer in open sharing and expression of ideas I’d be calling for a media ban at scientific sessions. I guess we shouldn’t blame them for being faithful to the interests of their stockholders. After all, hype sells.

The down and dirty on avian flu

Here’s some information from the infectious disease folks at Vanderbilt (Vanderbilt Reporter, November 4) which cuts through the hype and tells you the essentials.

Hypertensive headache?

We were traditionally taught that hypertension is a silent killer, and that the notion of hypertensive headache is a myth. This meta-analysis in Circulation reports that antihypertensive treatment prevents headache, NNT=30, without regard to antihypertensive class. Four classes of medication with differing mechanisms of action were studied. Maybe our patients knew what they were talking about all along.

Community acquired methicillin-resistant staphylococcus aureus: what to tell the family

Many young and otherwise healthy patients are now being hospitalized with community acquired methicillin-resistant staphylococcus aureus (CA-MRSA) infections. Family members, taking notice when we place these patients on contact isolation, naturally want to know if they should take similar precautions when the patient goes home. Here’s a little blurb from Patient Care on how to counsel patients and family at discharge.

This is a big deal for a couple of reasons. First, as pointed out in the Patient Care article, CA-MRSA seems to be more transmissible than the “old” and more familiar MRSA. Worse, at least some CA-MRSA strains are hyper-virulent, associated with severe and rapidly progressive infections such as necrotizing pneumonia, due in part to the Panton-Valentine leukocidin. The issue of CA-MRSA pneumonia was reviewed in last April’s Current Opinion in Infectious Disease (subscription required).

Giant cell arteritis

Here’s a review on a must not miss diagnosis, giant cell arteritis (GCA). Of particular interest to me are the following points:

1) GCA can have unexpected late extra-cranial manifestations such as aortic aneurysm.
2) Steroids must be started as soon as the diagnosis is suspected and need not await temporal artery (TA) biopsy. Biopsy results are not affected by several days of steroid treatment. (This comes in handy if the patient presents with signs and symptoms of GCA late on a Friday afternoon).
3) Bilateral TA biopsy is sometimes necessary.
4) Combining the erythrocyte sedimentation rate with the C-reactive protein is superior to either test alone. In a population of patients undergoing TA biopsy, combined abnormal results of both tests was associated with a specificity of 97%. *

What is the supposed mechanism of homeopathy?

Where better to find out than from its supporters? Here’s a pro-homeopathy alt med blog found via the Health Fraud List. This post from the blog outlines the “mechanism.”
Concerning the dilution of the remedy it says “Once we reach the 12C potency, according to chemical science, there should be no more physical substance left in the dilution……..Potencies above 12C work very effectively as though there was still a material substance present. Even though there is nothing left of the original physical substance, the medicine acts as though there were.” Then how could there be any biological effect? Reading on----“the vital force in the water, which now holds the impression from the original substance, acts upon the vital force of whoever takes the medicine.”

So, let’s see. The original active ingredient, though diluted so many times that no molecules remain in the water, leaves an “impression.” That impression is held in the vital force of the water, which in turn acts upon some vital force in the patient. Got it? Aren’t you glad this is supported by your tax dollars?

Statin use in elderly patients

Here’s a review in Clinical Cardiology with some useful perspectives on statin use. It makes a case for the safety and effectiveness of aggressive lipid lowering across the spectrum of age and risk. Keep in mind one caveat: be cautious regarding choice and dose of statin in patients on clopidogrel to prevent stent thrombosis. (I previously blogged about that here).

How did pseudoscience get admitted to medical school?

My recent post (scroll down) entitled “What is happening to our medical schools” took medical education to task for promoting pseudoscience. A commenter (Retired Doc) asked how this was allowed to happen and suggested in his own insightful post that it may be a form of political correctness.

Several trends over the past 15 years are at play. In his book review of the Institute of Medicine Report on Complementary and Alternative Medicine Stephen Barrett points to a subsidiary of the NIH which has poured large sums of money into the promotion of bogus claims. This funding was paralleled by an explosion of consumer interest in Complementary and Alternative Medicine (CAM) driven by the Internet. These two forces created a substantial financial incentive for medical institutions to become involved in CAM.

And although to a large extent it’s about money, it’s not entirely about money. There is also an important philosophical shift towards postmodernism, in which political correctness plays an important part. The postmodern view has influenced not only art, literature and politics, but also science. It places the individual’s internal reality above any external truth. To the postmodernist it’s not THE truth but rather MY truth and YOUR truth. It asks “Who is to say one version of truth is more valid than any other.” One can begin to see how this might lead to an eclectic view of medicine.

The movement’s influence is described in this important paper in Lancet entitled Postmodern Medicine. Author JA Muir Gray notes in the introduction that “Postmodernism is characterised by relativism, namely that there are no such things as objective facts…..” Good news there for the alt med folks. It goes on to say “Postmodernism also challenges the objectivity that science has claimed is its defining characteristic as spurious and unsupportable, and although many different theories are encompassed by the term ‘postmodernism’, a suspicion of science lies at the core of such theories.” Gray points out that postmodern medicine is driven in part by increasing regard for patient values and preferences, the rise of consumerism over paternalism and increasing concern for the unintended adverse consequences of science. These are beneficial trends to be sure, but in his defense of postmodernism Gray doesn’t seem overly concerned about its disregard for science. Citing a striking parallel to my previous commentary on the mixing of science and pseudoscience in medical schools Gray notes “The relativism of the postmodern world can be seen in Blackwells, Oxford's most famous bookshop, where evidence-based texts on gastroenterology are sold alongside a book on colonic irrigation.”

I am reminded of a conversation with an acquaintance extolling the benefits of her favorite alternative modality. As I pressed for a scientific defense she finally relented and said “well, OK, I can’t explain how it works, but I just know it works for me.” On a larger scale such thinking is behind the fallacious attempt to justify pseudoscience by citing its rising popularity among consumers. Perception equals reality in postmodern thinking, no matter the science. Postmodernism is a dangerous trend in medicine and is a driving force behind the explosion of CAM.

What is happening to our medical schools?

Abraham Flexner is turning over in his grave.Almost a century ago Abraham Flexner, a secondary school educator, was commissioned by the Carnage Foundation to study medical education in the United States and Canada. The conclusion of the Flexner Report was scathing. Medical education was a sorry state of affairs. (Download the original report here ---large pdf file).

As a result of the report medical schools closed, others merged, and those that survived instituted major reforms. Medical education for the twentieth century and beyond was to have scientific underpinnings. The Flexner Report has since been celebrated as a pivotal document in medical education.

But what would Abraham Flexner think of medical education at the dawn of the twenty first century? Have medical schools backslidden? Sadly, medical education has forgotten some of Flexner’s warnings, as evidenced over the past decade by the increasing uncritical acceptance of unscientific teaching in the medical curriculum. This conclusion is supported both by systematic research and examples such as this uncritical homeopathy promotion by the University of Maryland Medical Center. (Thanks to the Health Fraud List for this link).

I do not oppose the right to teach or practice alternative medicine, or patients’ rights to choose it. The problem is that much of alternative medicine is a separate realm, outside the biological model. Thus it can not “complement” science based practice nor can it be “integrated” with it. Yes, it’s a free market place of ideas. The homeopath, the colonic irrigator and the herbalist have every right to compete in this market and patients have a right to choose. I would submit, however, that their practices cannot be integrated with mine. And, although medical students need to be made aware that such practices exist, medical schools should not be promoting them.

Flexner asserts precisely this notion. Let’s examine a portion of the Flexner Report concerning science based medicine. (The portion of the Flexner Report discussed here has been reproduced on this page from Homeowatch). Referring to homeopathy and other unscientific methods as “dogma” the report notes “The ebbing vitality of homeopathic schools is a striking demonstration of the incompatibility of science and dogma. One may begin with science and work through the entire medical curriculum consistently, exposing everything to the same sort of test; or one may begin with a dogmatic assertion and resolutely refuse to entertain anything at variance with it. But one cannot do both. One cannot simultaneously assert science and dogma;”. So, from this passage in Chapter X of the report comes a strong message: institutions of medical education must decide what they’re all about. Choose science or choose another path. One or the other please, not both. Clearly Flexner’s mandate left no room for “complementary” or “integrative” solutions.

Another offering from the University of Maryland School of Medicine Center for Integrative Medicine is Reiki. The course description for Reiki level II says the student will learn to “send distant healing to others as well as to past or future events.” Maybe Harry Potter should apply. In the Advanced Reiki training course the student will “learn how to use crystals and stones with Reiki and create a Reiki grid that will continue to send Reiki to yourself and others after it is charged.”

This sort of thing is going on to an increasing degree at numerous medical schools. Here’s a sampling from the University of New Mexico Health Science Center. Or, just Google up any medical school and combine a search term for your favorite alternative modality.

I hope our medical schools don’t devolve into institutes for the eclectic healing arts. In 1910 Abraham Flexner cleaned house in American medical education. By 2010 we may need him back.

Medication discrepancies at the transitions of health care

Quality improvement efforts in medication safety have traditionally focused on errors during hospitalization. In contrast, medication errors at the transitions between hospital and home have received little attention. I pointed this out before. A recent issue of Archives of Internal Medicine contains this study which found medication discrepancies between home and hospital medication lists in about 14% of patients. Risk factors for discrepancies were the number of medications taken and the diagnosis of heart failure. Discrepancies were associated with an increased risk of readmission. The Joint Commission on Accreditation of Healthcare Organizations is now focusing on this problem. Attention to this aspect of quality and safety is long overdue.

The Thrombosis Interest Group of Canada

This is an excellent open-access resource on clinical issues in thrombosis. It contains a series of evidence based topic reviews, a summary of the ACCP conference guidelines on antithrombotic therapy and more.

Guillain-Barré Syndrome

I think I’ll put this article from Archives of Neurology on the must read list for hospital medicine. This nuts-and-bolts review focuses on the supportive aspects of care (if you want the latest on IVIG or plasmapharesis you’ll want to look elsewhere). In the treatment of patients with Guillain-Barré Syndrome the devil’s in the details of such things as DVT prophylaxis, pain management, respiratory care, skin care and rehab. This review, while acknowledging a lack of high level evidence, covers them all nicely. I’ve linked to the abstract but the full text is worth having. It definitely belongs in your library if you’re a hospitalist or a critical care doc.

Learning evidence based medicine by doing

I’ve commented before on the gap between the theory and practice of evidence based medicine. New York-Presbyterian Hospital/Columbia University has developed a unique method of teaching EBM to emergency medicine residents which may help bridge the gap. A series of two hour EBM exercises has been incorporated into the curriculum. The sessions, entitled “Evidence Detectives”, consist of a case presentation followed by a supervised exercise in all the steps of EBM, including question formulation (using the PICO format), “live” on line searching, critical appraisal and article selection, and finally discussion of applicability to the case at hand.

This project, in the early stages of development, impresses me as a wonderful way to teach the essential skills of EBM. I would like to see CME workshops of this type for practicing physicians.

In order to carve out time for the sessions some of the more traditional aspects of the curriculum were cut, with elimination of the traditional journal club and less time for didactics. (The elimination of the journal club concerns me. I’ve already blogged on the importance of “background reading”).

The project was reported in a recent issue of Academic Emergency Medicine.

Are you a disruptive physician?

The phrase “disruptive physician” has been bandied about at medical staff meetings lately. Apparently, most hospital medical staffs have provisions in their bylaws for sanctioning physicians deemed to be disruptive irrespective of their clinical competence. I’ve always been a bit uneasy about this, since any behavior or opinion someone else (such as a nurse or an administrator) finds objectionable could be categorized as disruptive.

Of course there are occasional examples of physician behavior clearly detrimental to patient care such as intoxication, sexual impropriety and threatening or intimidating behavior so severe as to preclude an effective working relationship among staff. Such episodes require an organized, explicit institutional response. The notion of a disruptive physician policy to deal with these situations is sound. But how do you define disruptive behavior? Greg Piche in his Health Care Law Blog recently remarked “The definition of what constitutes disruptive behavior in most of these policies is left so inordinately broad and so diaphanously vague as to render them effective tools for silencing responsible criticism….” His examples of behaviors that could be considered disruptive are concerning; having a disagreeable personality or willingness to speak out against the administration could perhaps result in a disciplinary proceeding.

So this concerns me. Although the original notion of a disruptive physician policy may be valid it could have the unintended consequences of stifling original thought and dissent. This editorial from the Journal of American Physicians and Surgeons warns about abuse of the concept. Please read the whole article, particularly the little ditty at the end.

Disclosure: I have occasionally bumped heads by playing the medical staff curmudgeon role.

The list of drugs that prolong the QT interval and cause torsades de pointes

is growing so rapidly that clinicians need help in keeping up. Here’s a useful resource: The Center for Education and Research on Therapeutics at the University of Arizona Health Sciences Center, spearheaded by Raymond L. Woosley, MD, PhD Vice President for Health Sciences there. Dr. Woosley has an extensive background on the clinical pharmacology of antiarrhythmic drugs. The site is a frequently updated listing of drugs that cause or increase the risk of TDP. The lists are categorized according to degree of risk and strength of recommendation.

Under diagnosis of alpha 1 antitrypsin deficiency

A survey in the September issue of Chest reminds us that we are under diagnosing alpha 1antitrypsin deficiency (AATD). The study of 1020 patients with AATD revealed an average of 8.3 years from symptom onset to diagnosis. 20% of patients went through four or more physicians before being diagnosed. Timeliness of diagnosis did not improve between 1968 and 2003.

AATD is easy to diagnose, so why are we doing so poorly? Clinicians under appreciate the fact that AATD can be present in any patient with COPD. It is not, as popularly believed, confined to the rare non-smoker with emphysema or to those patients with primarily lower lobe disease. Moreover, it may not be widely known that current guidelines cast a broad net for screening patients for AATD. In reviewing this topic I was surprised to learn that the World Health Organization, the American Thoracic Society and the European Respiratory Society recommend that ALL patients with COPD be tested for AATD.

The joint statement of the American Thoracic Society/European Respiratory Society was published in the American Journal of Respiratory and Critical Care Medicine in 2003. Here is a partial list of patients for whom screening was definitely recommended (type A recommendation):

1) Symptomatic patients with a diagnosis of emphysema or COPD
2) Patients with asthma whose pulmonary function does not completely normalize after aggressive treatment
3) Individuals with unexplained liver disease
4) Asymptomatic patients with persistent obstruction on pulmonary function tests with known risk factors
5) Adults with necrotizing panniculitis

Panic attacks---not so benign

They may be bad for your heart (American Journal of Cardiology).

COPD and cardiovascular disease

Two recent offerings from the medical literature suggest an association between COPD and cardiovascular disease that may be under-appreciated. In this study from Chest patients with COPD had twice the rate of hospitalization for a composite of cardiovascular outcomes, adjusted for pre-study cardiovascular risk factors. The follow up period was just under three years.

This paper from the European Heart Journal reports unrecognized heart failure in 20% of patients with stable COPD. Approximately half the heart failure cases had systolic left ventricular dysfunction and half had primarily diastolic dysfunction. Surprisingly, none had right sided heart failure. The authors suggest that right sided failure is characteristic of more advanced COPD than was represented in this study. The reasons for the association may be both physiologic (e.g. ventricular interdependence) and epidemiologic (overlapping risk factors, particularly smoking).

The pioglitazone controversy continues

Pioglitazone (Actose) and rosiglitazone (Avandia) are members of the thiazoladinedione (TZD) class of oral medications for type 2 diabetes. These agents have been surrounded by controversy because their predecessor in the TZD class, troglitazone (Rezulin), was withdrawn from the market because of liver toxicity. Although their beneficial effects on metabolic risk factors for macrovascular disease have long been known, outcome based data regarding protection against such events have been lacking until very recently and the Public Citizen Health Research Group has placed TZD drugs on its “do not use” list.

Recently the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events) demonstrated the efficacy of pioglitazone in preventing macrovascular events. I blogged it here following presentation of the results but shortly after the announcement and before final publication a BMJ opinion piece was harshly critical of the study. My response to the BMJ commentary is here.

Now PROactive has been published in Lancet October 8 along with a commentary by Hannele Yki-Järvinen. Unlike the BMJ editorial the Lancet commentary acknowledges the clinical benefit of pioglitazone in decreasing macrovascular events. The major controversy about the PROactive results concerned the lack of statistical significance for the primary outcome and reliance on the secondary outcome. But Yki-Järvinen points out that inclusion of procedure related endpoints in the primary outcome could have biased the results against pioglitazone and implies (as I said before) that the primary outcome would have reached statistical significance with a longer follow up period, as the curves were diverging at study’s end. The commentary poses questions about the clinical significance of the increase in heart failure and how it might counterbalance the improvement in vascular outcomes.

So is it time for Public Citizen to change its “do not use” recommendation? They defend the recommendation on the basis that the TZDs “may be less effective than other drugs for diabetes and cause liver damage, weight gain, anemia and heart failure.” PROactive and other evidence suggests that this statement may be unfounded. How can the question of effectiveness of TZDs compared to other agents be answered? Because different classes of medication for diabetes have mechanisms of action which are complementary to one another it may be simplistic to ask whether one class of agents is as effective as another. It now appears that pioglitazone can join metformin as another agent capable of improving macrovascular outcomes. As for liver damage, none was found in PROactive. Weight gain (4 kg more than placebo) was seen, but the clinical significance is unknown and anemia was not mentioned. The problem of heart failure remains troubling although no new heart failure concerns were raised by the study.

Why is Alzheimer’s disease getting all the attention?

This study published in Radiology, evaluating structural changes and cerebral blood flow in elderly demented patients compared with age-matched cognitively intact individuals, found reduced cerebral blood flow in the demented patients suggesting that vascular disease is an important factor in dementia in the elderly. We’ve gone through phases in our understanding of dementia. In the nineteenth century dementia was synonymous with general paresis of the insane, later understood to be caused by syphilis. A half century ago dementia was widely believed to be primarily a vascular disease, leading to a proliferation of vasodilators such as ergoloid mesylates, cyclandelate, and papaverine, none of which worked. More recently we’ve better appreciated Alzheimer’s disease. Does the article in Radiology bring us full circle with regard to “vascular dementia?” No, but it suggests that perhaps our emphasis on Alzheimer’s disease has lead to an under appreciation of vascular mechanisms. Here’s info on multi-infarct dementia and Binswanger’s dementia.

Two lessons in the interpretation of medical literature from a fascinating paper in Medscape General Medicine

Anticoagulation Therapy for Venous Thromboembolism, a review in Medscape General Medicine, stunningly concludes: “Anticoagulants have not been shown to be efficacious in reducing morbidity and/or mortality or safe in VTE treatment.”
Lesson one: Evidence based medicine (EBM) doesn’t always give us the answer.
The Medscape review points out that anticoagulant therapy became the standard based on a single small randomized controlled trial published in Lancet in 1960 which would be considered unacceptably flawed by today’s EBM standards. Moreover, subsequent studies in support of anticoagulation for venous thromboembolism (VTE) were of the sort the EBM crowd frowns on (observational studies, comparisons with historical controls, etc.).

But the Lancet study, flawed as it was, had striking results in favor of treatment. Anticoagulation became the standard, and it has since been considered unethical to do any more placebo controlled randomized trials. The totality of the subsequent evidence, although low level by EBM standards, is compelling. For me, the treatment of VTE with anticoagulants is justified even though it will probably never be “evidence based.” This thoughtful and thorough review in the Journal of Internal Medicine makes that point better than I can.
Lesson two: Financial conflicts of interest aren’t the only ones that need to be disclosed.
Note the following author information for the Medscape paper.Disclosure: David K. Cundiff has no significant financial interests or relationships to disclose. Mr. Cundiff has disclosed that he withdrew warfarin from a patient with lower limb deep vein thrombosis on the grounds that the risk of bleeding in this case seemed to be higher than the benefit of anticoagulant treatment. The patient later died of pulmonary embolism and Mr. Cundiff subsequently lost his medical license because of this case.
Kind of makes you want to read the paper a little more carefully, eh?

What’s so special about Up to Date?

Wonders The Krafty Librarian, who reports doctors’ reactions when a local health system decided to restrict Up to Date access to on campus users. (Linked at Grand Rounds by Hospital Impact). Up to Date is expensive and very restrictive in its access options. Institutional subscriptions generally only provide on site access. Apparently it’s prohibitively expensive for many institutions to provide home access for all users. Like the Krafty Librarian I wonder why so many folks swear by it.

She writes: “But is UpToDate's content really that much more superior to FirstConsult and eMedicine that doctors are willing to put up with a product that seems to have extremely restrictiveve access policies and is not rapidly expanding into needed areas like the handheld and EMR market? Or are physicians apathetic? They know about UpToDate, they know it is a good product, but they don't care to learn or be bothered with other products because they are sticking with the one that they are familiar with come hell or high water.”

Hmmm--- I have mixed feelings. Apparently, according to one of the links in the post, emedicine has an institutional edition which requires a paid subscription. This is news to me, and I’m struggling to understand how it differs from the free version of emedicine I was already familiar with. So is Up to Date really that much better than the free version of emedicine? Emedicine seems to be a work in progress, and is getting better and better. However, it doesn’t seem as well organized or as extensively linked as Up to Date. It’s a large and growing collection of stand alone monographs. And, if renowned expertise in the authorship is important, Up to Date has the edge with a list of contributors that reads like a parade of stars. Also, it’s advertising free, and the free version of emedicine is not (if that’s important to you).

But Up to Date may be living largely on reputation. As the Krafty Librarian points out, doctors are familiar with it and trust it. I don’t agree with some of my colleagues who think it’s all they need, or that it’s even the best resource. I use it extensively and have a personal subscription so I can access it at home (very important to me), but I find it complementary to many other resources. Disadvantages include imprecise searching (you usually have to combine searching and browsing) and somewhat limited graphics. I think there may be other resources that provide a better bang for the buck.

Warfarin after acute coronary syndrome?

The pendulum has been swinging on this issue for years. A meta-analysis published in the August 16 issue of Annals of Internal Medicine favors warfarin added to aspirin for patients with ACS. Patients who received coronary stents were excluded. Warfarin was associated with decreases in myocardial infarction, ischemic stroke and need for revascularization. Benefits outweighed the bleeding risks in all but those patients stratified as high risk for bleeding. There was no effect on mortality.

For patients with ACS who do not receive stents we now have two antithrombotic agents to consider adding to aspirin, these being clopidogrel and warfarin. Patient selection for treatment with one agent or the other will be complex, and will need to take into account risk factors, cost, and patient preference.

Statins and clopidogrel together: Do we have the final answer?

Not yet, in spite of the profusion of studies that have been published ever since the first report in Circulation of an in vitro interaction between clopidogrel and atorvastatin. Clopidogrel is a pro-drug which is metabolized to the active drug by CYP3A4, while atorvastatin is metabolized by the same enzyme. Atorvastatin attenuated the anti-platelet action of clopidogrel in vitro, in a dose dependent fashion.

The latest offering is a recent study in the European Journal of Clinical Investigation in which the effect of clopidogrel on platelet function was tested during concomitant administration of several statins in healthy subjects. Simvastatin and fluvastatin, but not atorvastatin, pravastatin or rosuvastatin, attenuated the effect of clopidogrel. The dose of atorvastatin was only 20mg daily.

An earlier study had concluded that none of five statins, including atorvastatin, attenuated the anti-platelet effect of clopidogrel. The range of atorvastatin doses in that study was 10-40mg.

The clinical significance of the interaction is controversial, with this recent outcome based study suggesting no significant clinical effect, but with other evidence suggesting the interaction may indeed be clinically adverse.

Despite several studies and substantial expert opinion pointing to the safety of concomitant use of statins and clopidogrel I remain concerned because of a lack of data concerning statin dosage effects. My specific concern is that the in vitro evidence suggests that the interaction is dose dependent, and the highest atorvastatin dose purportedly shown to be safe with clopidogrel was 40mg. This is particularly important in view of recent recommendations that 80mg atorvastatin be initiated in the early period following acute coronary syndrome.

Government run health agencies would prefer a double standard

And apparently they have been enjoying one for some time, at least when it comes to reporting malpractice awards and settlements to the National Practitioner Data Bank., as reported here in the New York Times. The law requiring reporting to the Data Bank explicitly applies to federal government health services as well as the private sector. However, the new inspector general has found that non-compliance on the part of government health services is routine. The excuses cited by the federal agencies, such as the NIH and the Indian Health Service, are that sometimes the records get lost, or that they just plain don’t think they should have to comply.

What’s being done about it? The Times piece concludes with:
“Betty James Duke, administrator of the health services agency, said she would soon recommend changes to ‘ensure greater compliance’ with the reporting requirements. But in discussions with the inspector general's staff, federal agencies did not make any firm commitments. ‘It was not clear whether they would fully comply,’ Mr. Levinson wrote.”

Non medical

A blog devoted to cool stuff about Google maps.

Intensive glycemic control in critical illness

This is a hot topic in hospital medicine. I’ve discussed the tension between “patient oriented” and “disease oriented” medical literature. In my opinion we need to read both. Here’s a patient oriented review of intensive in patient insulin therapy from last October’s Cleveland Clinic Journal of Medicine. Here is a disease oriented study and an accompanying editorial from a recent issue of the Journal of Clinical Investigation.

For me, empirical evidence is more interesting and meaningful when coupled with pathophysiologic rationale. (I hope the EBM Mafia isn’t watching).

Stephen Barrett takes courageous stand against Institute of Medicine Report

Stephen Barrett wrote this critical review (via Medscape) of the Institute of Medicine (IOM) book on complementary and alternative medicine (CAM). The National Center for Complementary and Alternative Medicine (NCCAM), a subsidiary of the NIH, commissioned the IOM to write the report. Barrett accuses both the NCCAM and the IOM of promoting unsound health claims. The report, Barrett says, uncritically accepts implausible health methods. In my opinion he nails the issue in stating “Methods that are plausible should be tested with well-designed clinical trials. The rest should be discarded” (Italics mine). I have previously argued that it is wasteful to study scientifically implausible treatments. He goes on: “Despite all the alleged experts involved in its preparation, the IOM report does not contain a single word of criticism against methods that are sufficiently irrational to be discarded now. Instead, it makes broad, sweeping generalizations and attempts to set an agenda for the widespread adoption of ‘CAM’ research and teaching.”

And, concerning CAM teaching, Barrett points out the increasing uncritical adoption of unscientific claims in medical school curricula. He cites this paper by Stanford professor of medicine Wallace Sampson, M.D. on medical school teaching of alternative medicine. Sampson’s survey indicates that medical schools often present baseless alternative medicine claims uncritically or, worse, actively promote them. This open access full text article is worth reading in its entirety. Sampson writes “With inadequate approaches that fail to uphold criteria for validity and plausibility, so called ‘evidence-based’ medicine remains fluid and loses its value to help physicians discern what is truly useful.” Bingo! Sampson makes valid suggestions for reform of the medical school curriculum.

The saga of the pulmonary artery catheter

Medpundit posted about this the other day. Here’s my perspective.

Bedside pulmonary artery catheterization, more commonly known as Swan-Ganz catheterization, began life around 1970. As an internal medicine house officer in the late 70s I watched it come into vogue long before the rigors of evidence based medicine. Offered initially as a tool for management of myocardial infarction it soon enjoyed a broader range of use in critically ill medical patients. In the 1980s papers by Shoemaker and colleagues [1] [2] suggested that aggressive protocol driven therapy guided by the pulmonary artery catheter (PAC) improved outcomes in high risk surgical patients.

In the 1990s several papers addressed PAC guided therapy to maximize oxygen delivery in septic patients, with negative results [3] [4]. In 1996 the SUPPORT investigators published a prospective cohort study of outcomes associated with the use of the PAC in a variety of critically ill patients. This oft-quoted and controversial study suggested harmful effects of the PAC and was followed by editorial commentary suggesting that it was time to pull the catheter. Many writers called for prospective randomized trials of PAC and the American College of Cardiology and other professional societies published guidelines for use of the catheter based on the best evidence at the time.

Subsequently, higher level studies have failed to show benefits of the PAC. Finally, in the October 5 issue of JAMA are two studies and an editorial which suggest we may be approaching the final chapter of the PAC saga. The ESCAPE trial, looking at severely ill patients with heart failure, was a bust. In the same JAMA issue this meta-analysis showed no benefit of the PAC across a spectrum of critical illness. An accompanying editorial is linked here.

It’s been a long and interesting ride. If the ongoing FACTT study fails to show benefits of the PAC in patients with ARDS it may indeed be time to pull the catheter.

Should metformin’s contraindications be contraindicated?

The real test of a drug’s safety is to get it out to the market and into the hands of providers who ignore the labeling and contraindications. Some drugs, like cisapride, prove to be unforgiving of such indiscretions and are taken off the market. That’s the situation that gets most of the attention. Metformin may be different. It seems to be a more forgiving drug. The biguanides, of which metformin is a member, are well known to precipitate lactic acidosis, yet the condition has been difficult to attribute to metformin in the post marketing experience despite widespread contraindicated prescribing. Here’s a point- counter point on the question in a recent issue of CMAJ.

Will the labeling be relaxed for metformin? I don’t know. For now I’ll continue to observe the labeling.

Remembering Hemo the Magnificent

Longer ago than I care to admit a popular educational resource for kids was a series of Bell Telephone sponsored films on a variety of science topics. The series was made for TV in the mid to late 50s and later distributed to schools. The one I remember best was Hemo the Magnificent. It combined humorous Disney style animation with human actors to take the student on a virtual tour of the circulatory system. Clever production elements and analogies (such as nervous pathways illustrated by telephone lines and little men operating levers representing pre-capillary sphincters) held us baby boomers in rapt attention and indelibly etched the circulatory system in our minds.

Fast forward to generation X and this paper in Advances in Physiology Education. The survey of undergraduate students found a high rate of misconceptions about circulatory function and offers fascinating insight about how we learn. When asked to trace the flow of blood a student might draw a path around the perimeter of the body. When asked about the principal function of the lungs some students said it was to filter the blood, others said to convert oxygen into carbon dioxide. There was confusion about distinctions between arteries, veins and capillaries. Worse, these college students were pursuing a career in elementary education.

Despite improvements over time major misconceptions persisted through the end of the course. Equally concerning was the fact that one on one interviews with students uncovered many more misconceptions about the circulation than standard tests, suggesting that students can conceal major areas of misunderstanding on routine testing.

The authors point out that faulty preconceptions about course material hinder learning. Learning is a synthesis of new content and what the student thought before. If the student’s prior thoughts are flawed the learning is less effective. The discipline of physiology, the study of how the body works, may be uniquely susceptible to prior thinking. Early on children begin to develop a mental model based on their interpretations of body sensations. Although the model becomes more sophisticated over time it remains flawed. The teaching of physiology might be more effective if teachers could identify student misconceptions, then employ means to help students unlearn or modify them. The authors conclude that new methods of assessment and teaching are needed. I would add that perhaps we should resurrect Hemo the Magnificent.

Dialysis for dummies

Hospitalists are increasingly called on to participate in the care of dialysis patients. Now it’s more important than ever for us to know a little about dialysis. Here’s a nice review from Southern Medical Journal with the basics.

Hepatoadrenal syndrome

This paper in Critical Care Medicine is noteworthy because it demonstrates an unexpectedly high rate of adrenal insufficiency in patients with severe acute and chronic liver failure, and suggests that treatment with hydrocortisone improves outcome in those patients demonstrated to have adrenal insufficiency. Perhaps we should be doing rapid cortrosyn stimulation tests on these patients at hospital admission. This is useful information with the potential to change hospital practice.

Furosemide and albumin administration in acute lung injury

A recent paper in Critical Care Medicine adds another piece to our understanding of the controversy surrounding fluid management in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In patients with ALI/ARDS and low total serum protein (<6g/dl) the investigators compared furosemide with albumin to furosemide with placebo. The albumin group had better outcomes in terms of oxygenation and hemodynamic stability. The use of albumin was associated with less shock, the need for fewer fluid boluses, and consequently better ability to maintain negative fluid balance.

Historically the controversy has centered around two related questions, one being whether it’s better to maintain positive or negative fluid balance in ARDS (the “wet vs. dry” debate) and the other issue being the use of albumin in general.

Evidence to date seems to favor the dry school (patients with negative fluid balance and who lost weight did better in this study and those who dropped their wedge pressure did better in this one). The level of evidence in these studies is somewhat low, and better answers await completion of FACTT, an ARDSnet sponsored study prospectively comparing wet and dry strategies. (The study also has arms comparing central venous catheter vs. pulmonary artery catheter monitoring).

The albumin controversy has an interesting history. Used indiscriminately in the past, it fell into disfavor after this meta-analysis of albumin use in a variety of critical illnesses including ARDS. Survival differences in this analysis were not significantly different but the point estimates suggested harm with albumin administration.

I can remember when it was popular to administer albumin with loop diuretics for ARDS based on little more than physiologic plausibility. People began to decry the use of albumin when evidence based medicine came on the scene. This study in Critical Care Medicine suggests an evidentiary basis for albumin, but the authors caution that more studies, looking at more meaningful outcomes, are needed. I look forward to knowing whether patients have fewer days of mechanical ventillation, shorter ICU stays and better survival.

Hormone replacement hype

A recent issue of The American Journal of Obstetrics and Gynecology reports that doctors have an inflated perception of the risks of hormone replacement therapy (HRT). The survey of Florida physicians found that primary care doctors were more likely to overestimate the risk than Ob-Gyns. The authors felt the respondents were confused between relative risk difference and absolute risk difference.

This is illustrated by data from the Women’s Health Initiative (WHI) study of estrogen and progesterone in which the relative risk numbers, when considered alone, exaggerate the perception of harm from HRT. This may have resulted in distorted media reporting of the study. For example, considering only the relative risks, there was a 29% increase in coronary heart disease events, a 26% increase in breast cancer, a 41% increase in stroke, and a doubling of pulmonary embolism. Unfortunately these figures are deceptive because they ignore the low baseline rate of events. Translated into absolute risk, HRT was associated with only 7 excess coronary heart disease events per 10,000 patient years, 8 more breast cancers, 8 more strokes, and 8 more PEs. These numbers represented the true magnitude of harm but seemed to be buried in the fine print of much of the popular reporting. An editorial in the same issue of JAMA cautioned against taking relative risk out of context, correctly pointing out that absolute risk data provided the true measure of effect. Although the editorial put the study in perspective it was given little notice in popular reporting.

Undue emphasis on relative risk difference is deceptive. Such emphasis can be used not only to exaggerate harm but also to inflate the apparent effectiveness of treatment, as is sometimes done in pharmaceutical company advertisements.

Why aren’t doctors more savvy about this issue? Maybe we should pay less attention to the popular news reports and concentrate more on the primary sources.

Constrictive pericarditis: the great mimicker

The July issue of the Journal of General Internal Medicine has a case report of constrictive pericarditis presenting as protein-losing enteropathy. This is one of many deceptive presentations of constrictive pericarditis which have been reported including liver disease, Budd Chiari Syndrome, refractory pleural effusions, chylous ascites, chylothorax, and lymphopenia with hypogammaglobulinemia. These unusual manifestations are, in one way or another, consequences of systemic venous hypertension.

Clinically, constrictive pericarditis looks a lot like restrictive cardiomyopathy. Differentiation between the two has been difficult, but is crucial, as constrictive pericarditis is surgically treatable if diagnosed early. Recent advances in echocardiography and cardiac doppler have improved the diagnostic approach which is outlined in this review. The distinction can be made with echo-doppler but it is operator dependent, requiring a focused approach with detailed attention to the respiratory cycle. This isn’t the type of information you’re likely to get from a routine echo report unless you tell the technician exactly what you’re looking for.

Beware of dementia bias

All other things being equal, patients with dementia who are admitted to the ICU do just as well as those without dementia according to this study in the June issue of Critical Care Medicine. A higher percentage of patients in the dementia group (46% vs. 11%) were from nursing homes.

Although there may be legitimate reasons to withhold ICU care in some demented patients (such as advance directives) we can’t base the decision on a presumption of poor clinical outcome.

Computers, evidence based medicine and the problem oriented medical record

After blogging about evidence based medicine (EBM) and the problem oriented medical record (POMR) recently I wondered what Lawrence Weed, originator of the POMR, had been up to lately. It turns out he founded Problem-Knowledge Couplers, the PKC Corporation. They have developed software for medical record keeping and decision support. Concerning EBM and the POMR I opined that we haven’t done a very good job at either. It looks like these folks are on to something that may help us do better at both. Here’s an article about Lawrence Weed in Healthcare Informatics.

Disclosure: I have no interest in PKC.

Watch for major changes in emergency cardiac care

Dr. Gordon Ewy and his group at the University of Arizona are quietly marshalling evidence that challenges the current practice of cardio-pulmonary resuscitation (CPR). One of their latest publications is found here in Circulation. The investigators reviewed resuscitation records of patients experiencing out of hospital cardiac arrest in greater Tucson. Standard automated external defibrillator (AED) protocols were used. This resulted in frequent interruption of chest compressions such that compressions were performed only 43% of the time during resuscitation efforts. Initial defibrillation attempts did not restore perfusing rhythm is any patients, and survival was no better than their historical control.

What is the clinical importance of these observations? Over time following the onset of ventricular fibrillation (VF) myocardial ATP rapidly depletes. The result is that rapidly over time the relative effectiveness of electrical defibrillation diminishes in comparison to chest compressions as the initial modality of treatment, culminating in unresponsiveness to defibrillation unless reperfusion via adequate chest compression (and consequent repletion of myocardial ATP) is accomplished first. [1]

This has lead to the concept of the three phases of CPR: the electrical, the hemodynamic and the metabolic phases. These phases correspond to time periods of roughly 0-5 minutes, 5-10 minutes, and longer, respectively. During the electrical phase initial defibrillation is the most important. That’s in keeping with popular teaching. However, during the hemodynamic phase compression becomes the most important initial intervention, because by that time there is little hope that defibrillation will restore spontaneous circulation unless there is pre-treatment with chest compression to replete myocardial energy stores. The hemodynamic phase is the one often encountered by responders to out of hospital cardiac arrest. (The metabolic phase, during which measures to decrease brain metabolism such as therapeutic hypothermia are of importance, will not be discussed here).

The Arizona group has also demonstrated that current practices of rescue breathing may compromise myocardial perfusion due to delays and interruptions in chest compression . This and related evidence, coupled with survey data indicating reluctance of bystanders to perform mouth to mouth rescue breathing has lead these researchers to teach continuous compression CPR to the public and institute local fire department protocol changes in Tucson.

Although the American Heart Association (AHA) and International Liaison Committee on Resuscitation (ILCOR) strive to be evidence based and tend to await high level evidence before recommending changes in emergency cardiac care, expect the following or some semblance thereof to show up eventually in the recommendations: 1) The lay public will be taught compression only CPR; 2) the initial modality for emergency personnel responding to out of hospital cardiac arrest, unless compressions are already in progress, will be a prolonged and continuous series of compressions before defibrillation is attempted.

CAVEATS:

1) For witnessed VT or VF in the health care setting immediate defibrillation remains the initial modality (remember the electrical phase!).

2) This new thinking does NOT apply to pediatric codes or other arrests of suspected respiratory origin. Rescue breathing remains a higher priority in those situations.

Xigris in perspective

The ADDRESS trial of activated protein C (Xigris) was just published in NEJM. Though it was touted in the press as a breaking development it was really nothing new. Maybe September 28 was a slow news day in healthcare. I wouldn’t have bothered posting it here, but now that it’s been hyped some perspective is needed.

ADDRESS is old hat not only because it was announced months ago but also because it merely confirms what we already knew from a subset analysis of the earlier PROWESS trial: that the optimal use of Xigris is exactly according to the way FDA has labeled it and the company (Eli Lilly) has promoted it all along. Specifically, it is indicated as an adjunct to antibiotics and general supportive care in patients with severe sepsis who have an APACHE-2 score of at least 25.

FDA approval of Xigris was based on PROWESS, analysis of which revealed that the benefits of Xigris were confined to the subset of patients with the higher APACHE-2 scores. The FDA restricted its approval to this group of patients and then required Lilly to conduct a randomized controlled trial (ADDRESS) to specifically assess those patients with lower scores. As anticipated from PROWESS, ADDRESS found no overall survival difference. Although there was no overall difference a trend toward increased mortality with Xigris was seen in patients with recent surgery, as had previously been gleaned from PROWESS in the lower risk patients. Increased mortality was also observed with Xigris in the subset of patients who were the first enrollees at their respective research sites, suggesting a learning curve with the drug, and highlighting the importance of experience. This finding bolsters the suggestion of some that the use of Xigris be restricted to intensivists or other designated specialists.

Unfortunately the study was somewhat hyped in the press. Xigris looked like a flop in some reports and like poison in others, not to mention that most of the news reports were just plain confusing.

Finally: Clinical outcome-based data in favor of thiazolidinediones

On September 12 at the 41st European Association for the Study of Diabetes meeting the results of the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) were announced. As reported by Medscape the study of over 5000 type 2 diabetic patients showed a decrease in macrovascular complications in patients treated with pioglitazone (Actose). The 10% relative risk reduction for the primary composite endpoint of seven macrovascular events did not reach statistical significance. However for the composite of stroke, MI and death the 16% reduction was statistically significant.

Other findings included a highly statistically significant >50% reduction in patients needing to add long term insulin. In addition to a significant fall in HbA1C the pioglitazone group experienced a statistically significant rise in HDL and fall in triglyceride levels confirming a beneficial effect on the “metabolic syndrome”, the principal dyslipidemia of type 2 diabetes. No new safety concerns were noted in the study.

This is a significant advance because it has previously been difficult to demonstrate a beneficial effect on macrovascular disease with insulin or oral agents, with the exception of metformin. Pioglitazone and rosiglitazone were reviewed last year in NEJM.

Now will the Public Citizen Health Research Group finally remove Actose from its black list?