Methadone causes sudden cardiac death even in therapeutic doses

Sudden cardiac death was documented during appropriate use of methadone with non-toxic blood levels in this study.

The evidence for fatal cardiotoxicity associated with methadone, due to QT prolongation and torsade de pointes, is mounting. I’ve blogged about it many times starting here.

The latest Medscape Roundtable is up

I and two of my Medscape colleagues discuss the patient interview here.

Too much basic science?

DB of Med Rants has written a series of interesting posts on how to reform the premed curriculum and hints at changes in the medical basic science courses. He has made general recommendations rather than a detailed description of course content. Although I would likely agree with many of the changes he has in mind and certainly respect his extensive expertise and experience as a medical educator I have a few concerns.

His proposals would streamline the basic science portion of the curriculum and encourage a well rounded education in the humanities. He and some of his commenters bemoan the “hard core” basic science courses (organic chemistry is frequently cited) which do not seem, in any direct way, to make one a better doctor. The same could be said, of course, for the humanities. Both content areas are important parts of a solid background for the practice of medicine but neither helps a doctor decide which antibiotic to give or what type of IV fluids to run. Both are important, but in less direct and tangible ways.

My concerns are two fold. First, with basic sciences already being de-emphasized we may be going down a slippery slope. As an example of where this type of thinking may lead consider an article in BMJ from several years ago with these suggestions for the medical school of the future:

From day one the focus of the course will be on "whole patient medicine," which is to be based on holistic consultations with patients in their real contexts. There will be no preclinical-clinical divide, and gone will be the days of freestanding courses in biochemistry, physiology, and anatomy.

A number of schools, apparently, have already adopted this model to one degree or another with problem based learning and other means of integrating the basic science and the clinical portions of the curriculum. This style of learning could be effective. However, the BMJ piece goes on with suggestions which raise concerns that the basic sciences would be slighted:

There will be no exams in anatomy, physiology, or biochemistry, and no one will need to learn by rote the entire Krebs cycle or the names of all those little holes in the skull. All students will have to demonstrate the critical appraisal skills of evidence based practice.

No exams in anatomy, physiology or biochem? I’m sure this isn’t the type of curriculum change DB has in mind but it seems to be the direction things are heading.

More from the BMJ article:

The modular nature of the course will provide a common pathway to careers across the whole spectrum of the health profession from medicine and nursing to management and health promotion. Having learnt together as students in a range of disciplines, our graduates will be well equipped to learn both with and from each other and to continue lifelong interprofessional learning.

The article notes that physicians and allied health professionals would have a “common course with different exit points” implying that physicians would need to be no better trained in basic sciences than would allied health professionals.

My second concern is that medical schools may already have gone too far in reducing basic science teaching as evidenced by observations of medical students which Orac summarized nicely in a post from a couple of years ago. Given the utter credulity of many of today’s medical students toward quackery one has to wonder whether they’re learning any chemistry or physics at all. If students had even a modicum of understanding of these sciences would we be seeing promotions like this or this? Of course I could trot out many, many more examples.

I will continue to follow this debate and look forward to additional posts from DB on the subject.

AHA’s latest scientific statement on CPR still years out of date

You can read the full text of the document here and Medscape’s report here. Despite longstanding and mounting evidence that compression only CPR is superior, the new scientific statement persists in emphasizing traditional CPR with rescue breathing for patients with out of hospital cardiac arrest.

Dr. Gordon Ewy, chief of Cardiology at the University of Arizona Health Sciences Center and director of the Sarver Heart Center, himself a pioneer in CPR research, was not pleased. According to the Medscape report:

That seems like short shrift to Ewy, who said the report doesn't reference "any of the recent scientific data on the exciting developments in continuous-chest compression CPR" or the increasing evidence that bystander-initiated CCC resuscitation for cardiac arrest "is as good and probably better than the approach currently recommended by the AHA. In addition, encouraging continuous-chest compression CPR might be the most effective way of increasing the willingness of bystanders to perform CPR."

For some time now the Sarver Heart Center, in its public education program, has taught compression only CPR. At the same time fire department protocol changes have been introduced in Tucson.

Why is the AHA so far behind the times? As I recently stated in a Medscape Roundtable, I believe it’s a distortion of EBM:

Sometimes, EBM proponents' insistence on patient outcome-based studies slows the wheels of medical progress. The American Heart Association 2005 guidelines for emergency cardiac care provide a recent example. Investigators at the University of Arizona, Tucson, have been publishing evidence for years in support of changes in emergency cardiac care for adult victims of out-of-hospital cardiac arrest.[8,9] Despite this evidence, the guideline authors, dutifully trying to be evidence-based, failed to adopt the new methods because of a reluctance to base changes on anything other than randomized trials. However, the evidence, although based on "low-level" physiologic rationale, was compelling. More recently, the Arizona investigators were vindicated by direct evidence that the new procedures save lives. This situation represents a failure of EBM, not due to any shortcomings of EBM itself, but due to the misappropriation of its principles.

Randomized controlled trials are finally underway to address this issue. But until these trials are completed the AHA should make recommendations based on the best evidence currently available, which favors compression only CPR for out of hospital cardiac arrest. That is what the principles of EBM would have us do rather than wait, paralyzed, until RCTs are completed.

Panda Bear’s blog down

Was it the thought police? Kevin wonders.

Want to delegitimize a disease? Get a drug approved for it!

Concerning Lyrica, the first drug ever FDA approved for the treatment of fibromyalgia, the New York Times has this to say:

For patient advocacy groups and doctors who specialize in fibromyalgia, the Lyrica approval is a milestone. They say they hope Lyrica and two other drugs that may be approved this year will legitimize fibromyalgia…

I’m not so sure. Although occasional experts through the years have been skeptical of the existence of fibromyalgia its status as a disease, by and large, has been secure for decades, well defined by textbooks and professional societies. But that won’t stop the pharmaceutical industry haters from suddenly, after all these years, crying “disease mongering!” “Medicalization!” It’s started already and we can expect it to ramp up substantially as Pfizer’s ad campaign picks up speed and other companies gain approval of their drugs for fibromyalgia. Corporate hatred will be fuelled as the new approvals become cash cows for some companies.

I think the Times has it bass ackwards. Fibromyalgia, a long established disease, will suddenly be questioned simply because drug companies stand to profit by it.

Glycemic control, crystaloid vs colloid debates remain unsettled

The SepNet investigators recently reported their two by two factorial trial in NEJM. Intensive glycemic control (112 mg/dl vs 151 mg/dl) was not associated with improved mortality or organ failure scores but was associated with more severe hypoglycemia and other adverse effects. Pentastarch was compared with modified RL and was associated with increased renal failure.

Retired Doc comments here.

Music therapy for depression

Medscape Medical News reports on a Cochrane review showing that a treatment program incorporating music therapy works better for depression than standard therapy alone. So, is it woo? No. Although music therapy and other non-pharmacologic modalities have been trotted out as examples of alternative medicine, such therapies aren’t woo because they’re scientifically plausible and are backed by at least a modicum of supporting evidence.

It’s been said many times that there is no alternative medicine---there’s that which has been proven to work and that which has not. But it isn’t always that simple. Some legitimate non-pharmacologic therapies, such as those employing diet, exercise, and relaxation (and perhaps music) are often co-opted under the CAM umbrella. That creates problems as these therapies are lumped with others whose advocates accept a lower standard of scientific proof or no proof at all, thus blurring the distinction between science and woo. Worse, these evidence based but “soft” non-pharmacologic modalities may be the initial focus of academic departments of integrative medicine, providing a foot in the door of academic medicine for real woo to come later. As Orac recently pointed out the CAM academic department becomes a Trojan horse:

Since when did using dietary interventions as medical treatment for heart disease become "alternative," CAM, or integrative, rather than just medicine? Forgive me, but most of this is nothing more than mainstream medicine repackaged as CAM to sell it to a credulous public. True, such "soft" interventions as hypnotism, relaxation,acupuncture, and massage are included, but most of the interventions discussed would not be out of place in the paradigm of "conventional" medicine, which makes me wonder why they are called "alternative." In reality, what bothers me about the whole concept of CAM is that it's basically a Trojan horse through which some therapies that might be evidence-based and could easily be integrated into our standard armamentarium of medical therapies are the "foot in the door" behind which hardcore woo lumped together as CAM follow, woo such as homeopathy, craniosacral therapy, reiki, and even reflexology, all of which I have encountered on wepages for academic centers devoted to CAM.

Communication between hospitalists and PCPs

Anecdotes are not data but these are compelling. Via Kevin.

When EMR alerts supplant thought and judgment

Dr. Wes with an example.

Woo is on the march

And it’s advancing and growing throughout academic medicine, almost faster than Orac can update his Academic Woo Aggregator. His latest update contains some gems.

CME thought police alert!

CME and its funding are objects of a brewing controversy. An increasingly vocal group of people is calling for radical changes in CME delivery, including an end to drug company support. A post form Retired Doc alerted me to the latest developments. The Macy Foundation has issued recommendations for reform of CME. The seven page executive summary has been released with a lengthier monograph anticipated later this year. Many opinions and assumptions were presented as “findings.” The long and the short of the recommendations is that there be an end to any form of drug company funding for CME and that CME offerings shift from didactic lectures to point of care learning activities.

Those who are familiar with my earlier postings on this issue know that I disagree with these recommendations on several levels. (For detailed commentary on what I think is wrong with such recommendations see my posts here, here, here and here. Such posts were usually inspired by my personal reflections after coming home from high quality lecture based industry supported CME programs like the Mayo Clinic update in hospital medicine and Bob Wachter’s UCSF/SHM sponsored hospital medicine course).

There have been some noteworthy reactions to the report on and off the blogs. Pathophilia questions certain assumptions in the report. Where’s the evidence, for example, that industry funding of CME leads to poor patient outcomes? Or that drug company interests and good patient care are always in conflict? The overarching premise of the report is that doctors lack the critical thinking skills necessary to evaluate educational presentations. But today’s information technology makes it easy to check CME presentations against primary sources. (Doctors who don’t care enough about the quality of their educational experience to do this probably read the New York Times health pages uncritically, too!).

According to the Carlat Psychiatry Blog Harvard neurologist Martin Samuels had a thing or two to say about the report. I wish I had a transcript of Samuels’s statements---we have to rely on the recollections of Dr. Carlat who was attending a meeting where Samuels made his remarks. I don’t know if Dr. Carlat’s account is a fair rendering of what was said. Carlat, who makes no bones about the fact that his blog is very biased, does not appear to be in sympathy with Samuels’s views.

So, at the risk of reading between the lines, I get that Samuels had two objections. First, he noted that one of the conference participants, Dr. Denise Basow, is an executive for UpToDate. That, Samuels said, is a conflict of interest that “should have been declared.” As Carlat points out Dr. Basow’s affiliation was listed at the end of the document but was not highlighted as a conflicting interest. Many readers of the report, such as members of the press, who are unfamiliar with UpToDate, would not realize what a potentially huge conflict of interest it really is. And I mean huge. The conflict exists on more than one level. First, UTD is in direct competition with free-of-charge on line pharmaceutical industry supported CME providers, one of which, emedicine, is a similarly formatted and ever improving point of care “look up” resource. Emedicine, which remains free of charge despite continuous updates and improvement in its content, could be seen as a growing threat to UpToDate’s market. And if industry support goes away emedicine might well go away.

And there’s another dimension to the conflict. Let’s examine that by looking in more detail at a few of the report’s “findings” and recommendations:

Insufficient emphasis is placed on individual learning driven by the need to answer the questions that arise during patient care.

CE does not make adequate or creative use of Internet technology, which can help clinicians examine their own practice patterns, bring medical information to them during patient care, and aid them in learning new skills.

Integrate continuing education into daily clinical practice.

Traditional lecture-based CE has proven to be largely ineffective in changing health professional performance and in improving patient care. Lecture formats are employed excessively relative to their demonstrated value.

Information technology is essential for practicebased learning by: Providing access to information and answers to questions at the time and place of clinical decision-making
(point-of-care learning).


The CE enterprise should shift as rapidly as possible from excessive reliance on presentation/lecture-based formats to an emphasis on practicebased learning.

To automate credit procedures for point-ofcare learning.


There is too much emphasis on lectures and too little emphasis on helping health professionals enhance their competence and performance in their daily practice. With Internet technology, health professionals can find answers to clinical questions even as
they care for patients, but CE does not encourage its use or emphasize its importance.

It’s interesting that these recommendations and opinions all refer to things provided by UpToDate. Without question UpToDate is the principal vendor of this type of point of care, practice based, automated CME tracking service, at least outside those which are industry supported (e.g. emedicine and Medscape). The report is chock full of recommendations that are favorable to UpToDate’s commercial agenda.

As Dr. Carlat pointed out UTD has no industry support. Heck, it is the industry, and a real cash cow at that. (For an eye opening look at UTD’s pricing and licensing tactics from a medical librarian’s point of view read this).

Perhaps if Dr. Basow had recused herself the outcome would have been the same. We don’t know the extent of her influence. Nevertheless the appearance of a conflict of interest is strong.

Samuels also seemed to object to the general tone of the document. He said: "I find this report to be self-righteous and self-serving. It is so hypocritical that it will fall like a stack of cards." Although that comment well characterizes the UpToDate issue it’s an apt criticism of the entire document which implies that doctors lack critical thinking skills, don’t care enough to consult primary sources and are unable to decide for themselves what their learning needs are. (Anyone who knows Dr. Samuels and his genius and passion for teaching and learning has to take his observations seriously).

Disclosures, disclaimers and personal reflections:

I have no drug company ties.

I have my own personal subscription to UpToDate. It is one of many sources I consult. I believe it is a useful resource with limitations, one being that doctors may over-rely on it as a “look up” resource, resulting in a simplistic and possibly dangerously formulaic approach to clinical decisions. See posts here and here for a more lengthy discussion of UpToDate.

I believe doctors have different learning needs and styles. It’s a bit insulting when outsiders think they know my learning needs better than I do. When I need outside help identifying weaknesses in my knowledge there are various self assessment tools I can use.

I believe learners should seek a balance between case oriented material based on focused clinical questions and background material which might take the form of didactic lectures, textbooks or narrative reviews. A strong shift toward practice based learning as recommended by the Macy report may slight pathophysiology and background material about diseases, thus dumbing down the CME experience.

Exposing quackery in medical education

Academic medical woo (maybe we should start calling it quackademic medicine) has, in recent weeks, received increased coverage in the blogosphere and beyond. I’m encouraged by this groundswell of interest. Medical education needs a good Flexnerian housecleaning. What better tribute could be paid to Abraham Flexner a century after his seminal report? If Flexner could see what’s happening in academic medicine today he would be appalled. He was not in sympathy with integrative medicine. Wikipedia has this to say about the impact of the Flexner Report:

Medical schools that offered training in various disciplines including eclectic medicine, physiomedicalism, naturopathy and homeopathy, were told either to drop these courses from their curriculum or lose their accreditation and underwriting support. A few schools resisted for a time, but eventually all complied with the Report or shut their doors.

(If you’re interested in primary sources read Chapter 10 of the original report where you’ll find some pretty harsh language concerning integrative medicine).

Soon after the Flexner Report and for decades thereafter medical education and practice gradually became more scientific, long before Guyatt and colleagues coined the term evidence based medicine. (I reviewed some of the history of twentieth century medicine’s scientific progress in a recent post here). Ironically, in fact, it was about the time the evidence based medicine movement was birthed in 1992 that pseudoscience under the rubric of complementary and alternative medicine was getting its foot in the door of medical schools. Since then medical education has turned its back on Flexner’s warnings and devolved from its scientific underpinnings.

If there’s any chance to expunge quackery promotion from academic medicine it has to start with exposure. Recent blog and media reactions have been modestly encouraging. Here’s a roundup of the past few weeks along with some observations.

Kevin, in typical pithy style, nailed it by pointing out that the infiltration of woo is weakening the credibility of academic medicine and damaging the evidence based medicine movement. His post was titled A step backward for academic medicine. Indeed academic medicine is moving backward, but I would characterize it as more of a slide down a slippery slope, a slide that’s picking up speed.

Dr. Wallace Sampson’s rich posts from the last two weeks on the new Science Based Medicine blog examine the origins and consequences of the infiltration of pseudoscience (which he, like Flexner, terms sectarianism). He cites several examples including a recent melding of pseudoscience and mainstream medicine at Harvard University and its astonishingly uncritical coverage in, of all places, Science Magazine.

Sampson documents a broad and uncritical societal acceptance of CAM at a time when a self-doubting and overly self-critical medical establishment was vulnerable, succinctly pointing out that “the press wowed and academics cowed…”

In a post yesterday Orac noted increased media attention to CAM which, unfortunately, ranges from promotional to only partially critical. The latter article, though, from U.S. News and World Report (USNWR), made this perceptive observation: “The setting for the unorthodox therapy—an academic medical center—would have been startling just five or 10 years ago.” Yes, there was a time, a decade or two ago, when the promoters of quackery would have been laughed off the podium of most medical school classrooms.

The USNWR quoted Andrew Weil as advocating an inconsistent evidentiary standard for medical claims, a “sliding scale” of evidence in which treatments with lower risk would require an easier standard of proof. Orac notes the logical extension of that argument by pointing out that true homeopathic remedies, consisting of only water, would require no proof at all. (Maybe the burden of proof would decrease in proportion to the number of dilutions of the remedy!). On its face that argument might have some appeal. After all, if it’s harmless why question it? Aside form the obvious theoretical objection (that all scientific claims should require rigorous scientific proof) there are practical consequences to that argument which become apparent on closer examination.

The article also provided examples of academic woo that even Orac wasn’t aware of. No doubt he’ll be updating his Academic Woo Aggregator soon.

Finally, let me mention (again) the latest Medscape Roundtable in which colleagues and I debated the issue of CAM teaching in medical school. This was a unique opportunity to take the issue (apologies to Dr. Anonymous) “beyond the blog” to the vast audience of Medscape.

A recurring question was raised in many of the postings: what’s driving the infusion of woo into academic medicine? One obvious factor is money. Consumer demand for woo is high and patients are willing to pay out of pocket for it. There being no scientific basis for most of these therapies, a desire to take patients’ money may be reason enough for some folks on the administrative side of academic medical institutions.

But there are other, perhaps less well appreciated reasons. One is irrational anti-corporate hatred and the growing popular distrust of the pharmaceutical industry, leading many to seek “alternatives.” It doesn’t take extreme googling to document numerous examples.

Other reasons include political correctness and postmodernism which I discussed at some length here. Wallace Sampson and Kimball Atwood IV, in a commentary in the Medical Journal of Australia, describe the effects of postmodernism with its “multiple ways of knowing” on medicine:

In the postmodern catechism, facts and science are artefacts of social constructions, and modern medicine expresses political hegemony over other, subjugated forms of healing, such as naturopathy and homoeopathy.

Postmodern CAM also tolerates contradiction without need for resolution through reason and experiment, resulting in a medical pluralism. Various “schools” and philosophies of healing — each inconsistent with the others, such as chiropractic, homoeopathy, orthomolecular medicine, and traditional Chinese medicine — create a scientific multiculturalism. Implausible proposals and claims become tolerable and comfortable, and the CAM advocate’s burden of proof is shifted to disproof by the science community, which that community accepts without major objection.

Finally, and somewhat paradoxically, the rise in unfounded CAM modalities may be an unintended consequence of the EBM movement. EBM advocates devalue scientific rationale and physiologic plausibility. (That reflects a very popular distortion, not a core principle, of EBM). Again, from the Medical Journal of Australia paper:

Evidence-based medicine (EBM), relying on results of randomised trials, should be a bulwark against the Absurd. However, the heterogeneity of clinical trial methods and designs, differing population bases, and varying endpoints often result in heterogeneity of outcomes. This has precluded systematic reviews of CAM methods from defining a line of inefficacy. EBM also does not include plausibility or consistency with basic science in its methods and reviews, leaving each to physician and patient interpretation.

In another editorial Dr. Sampson further laments the distortion of EBM leading to uncritical acceptance of implausible research claims:

The second is a paradoxical consequence of "evidence-based medicine" (EBM). EBM, in the form of RCTs and their systematic reviews (SRs), is a means for accumulating and ranking data. EBM is not a means for interpreting the significance of the data. Significance depends in part on plausibility. EBM is independent of physiology and ignores plausibility.

Plausibility depends on prior reliable observations, physical and chemical laws, pharmacological principles, and advocates' economic and legal misadventures. The
National Center for Complementary and Alternative Medicine spends $100 million/year on implausible research and training grants. In performing RCTs on implausible proposals, clinical research has taken a wrong turn and departed from rationality.

So where’s it all going? Are medical schools really becoming Hogwarts schools of witchcraft and wizardry? Maybe so! If we’re not there yet we’re headed there with increasing velocity. The boosters of CAM education are organized. Many academic medical centers have formed a Consortium for Integrative Medicine. The Consortium is supported by big money and seeks to promote integrative medicine. A careful reading of the pages of their website suggests an agenda for medical education based on experiential and promotional learning rather than critical analysis.

Even more disturbing is medical student activism for non-evidence based and implausible CAM. The American Medical Student Association (AMSA), the largest (some 68,000 strong) and best organized medical student society in the U.S., suggests, through its various publications, chelation therapy for multiple ailments, TCM, therapeutic touch, qigong and fasting. These students are our future academic leaders and even now are participating in CAM curriculum development at some schools.

What can be done about it? Although the rising chorus of voices against pseudoscientific medical education is encouraging the chorus is small, and the situation, from where I sit, is not good. At this late point nothing short of all out war on quackademic medicine will be effective. It can be done. It’s not unprecedented. Just look at the lobby against deceptive pharmaceutical company marketing. They have web sites. They’re making documentary films. They’re writing books. They have visibility. We need to be similarly organized.

The ENHANCE study: media hype more than corporate interest trumps EBM!

It’s been a busy week. I haven’t been able to keep up with the dizzying barrage of hyped up soundbites in the wake of ENHANCE. Now that I’ve carved out a little time I’d like to weigh in and try to put the study in perspective. Where to begin? Time constraints don’t allow as thorough an analysis as I’d like to attempt now, so this post may be the first of several on the topic.

I’ll start by mentioning a few of the more thoughtful blog reactions that alerted me to this issue, and with which I partially agree. DB has a series of entries [1], [2], [3], [4] and Retired Doc weighs in with two posts [5], [6].

Despite claims that drug company marketing hijacks evidence based medicine the larger problem, in my view, is the hijacking of EBM by popular media (as happened after the Avandia meta-analysis). If the pharmaceutical industry sat on the ENHANCE results for almost two years as has been reported, it’s cause for concern. In today’s climate you can hardly blame the drug companies, though, for going slow and painstakingly examining the nuances of a controversial study before releasing the information. Once a study like this is out the media salvo (which tends to be adverse to the drug companies) takes over the discussion, stifling reasoned debate, spreading distortion, ignorance and more heat than light. I would submit that in some cases distorted media coverage is worse than no information at all.

So let’s put aside the New York Times for a moment and go to a reliable source. The American Cardiology had this to say in its commentary on the trial: According to the American College of Cardiology (ACC), this study deserves serious thought and follow-up. Yes indeed. But we’ve seen very little of that in the media reaction. The ACC’s summary of the trial contains essential facts for a proper understanding of the issue, largely ignored by the media. It deserves a careful read. I’ll offer a few observations here.

The study patients had familial hypercholesterolemia (FH) with a mean pre-treatment LDLC of 319mg/dl. LDLC was reduced by 41% in the Zocor group (to 188) and by 58% in the Vytorin group (to 134). That’s significant in view of the apparent “shock” that both treatment groups in ENHANCE showed atherosclerosis progression. But it’s not shocking at all. Although there are some conflicting data, previous studies have generally shown that it takes much lower LDLC levels than 134mg/dl to halt atherosclerosis progression. Although an on-treatment LDLC level above which atherosclerosis progression occurs is not precisely known multiple studies (such as this one) suggest it’s around 100mg/dl. Therefore while post treatment LDLC of 134mg/dl in a patient with FH is quite impressive it would not be expected to halt progression.

Although non-progression of atherosclerosis (or, better yet, regression) should predict favorable clinical outcomes and is thus desirable there is no direct evidence that such results are required in order to produce clinical benefit. Multiple lipid trials, in fact, overwhelmingly suggest otherwise. Many trials which achieved more modest LDLC targets than those associated with non-progression (4S, CARE, WOSCOPS, AFCAPS/TEXCAPS to name a few) have been associated with reduction in clinical events.

A New York Times piece egregiously distorted the results of ENHANCE, quoting one cardiologist as saying the results were “shocking” and implying that Vytorin caused atherosclerotic plaque progression to almost double:

The Enhance trial was meant to prove that Vytorin’s combination of Zetia and Zocor would reduce the growth of fatty plaque in the arteries more than Zocor alone. Instead, the plaque actually grew almost twice as fast in patients taking the combination.

There are many distortions and faulty assumptions in the article. First of all, ENHANCE measured carotid intima-media thickness (IMT), a controversial surrogate for atherosclerosis, not atherosclerotic plaques. Secondly, there was no significant difference in the rate of progression between the two treatment groups. At p=0.29, the results of IMT progression difference didn’t even approach statistical significance.

Do the ENHANCE results negate the value of LDLC reduction? Not by a long shot. The evidence that LDLC reduction matters is convincing and includes diet trials, non-statin drug trials and epidemiologic data.

If an ongoing trial fails to show that Vytorin reduces clinical events, that will be shocking. Given what we know now, if I had FH I would do everything I could to reduce my LDLC. If my treatment options were confined to Zocor and Vytorin I would choose Vytorin hands down.

Calcium blocker overdose

This topic is reviewed in the American Journal of Critical Care, via Medscape. While the review covers multiple modalities in the overall management it emphasizes the use of insulin and glucose (hyperinsulinemic euglycemic therapy, HET). Although HET is physiologically sound and has had impressive results the experience with patients is small and the optimal regimen is not known. A proposed protocol is linked here.

Basic science fix in virology

Lots of good on line resources compiled here. (Via Life Sciences Education).

Amiodarone review

A Clinician’s Corner feature in JAMA.

The CORTICUS study hits the pages of NEJM

Retired Doc and Case Blog have already linked to the paper. The study failed to show benefit from stress doses of corticosteroids in patients with septic shock.

This isn’t news. Although it was just published in Thursday’s NEJM the study has been out for a while and I have referenced it several times. But with its publication in a high profile medical journal it is now susceptible to sound bite reporting. Any spin that “steroids are out” is simplistic.

Like any research findings this study must be interpreted in light of what was known before. Earlier data suggesting that corticosteroids were useful were collected from more severely ill patients than those in CORTICUS. In my November post about discussion of this issue at the Mayo update in hospital medicine I noted that while blanket recommendations for steroids in patients with sepsis are no longer justified, critical illness related corticosteroid insufficiency (CIRCI) is common in patients with septic shock and a judicious strategy of patient selection focusing on more ill patients such as those reported in earlier studies may be warranted. Moreover, classic adrenal insufficiency as may be cause by adrenal infarction, adrenal hemorrhage or prior corticosteroid therapy warrants evaluation and treatment and represents a separate issue.

In my top ten issues post about the sepsis bundle I predicted a more restrictive recommendation for corticosteroids based on the CORTICUS findings. In a subsequent post on the release of the new Surviving Sepsis Guidelines I noted that the guidelines, apparently taking into account CORTICUS, had downgraded the steroid recommendation and recommended more limited patient selection.

Archived RW notes recycled: FAQs concerning my criticisms of complementary and alternative medicine

Recently while researching for an off the blog project on complementary and alternative medicine I ran across one of my old posts in which I tried to address, in one long blog entry, recurring questions and objections concerning my many criticisms of CAM. I made a tongue-in-cheek comment at the end that the post would settle all questions once and for all. Well, it didn’t. I get the same recurrent objections. So maybe it’s time to address the FAQs again. The old post, buried deep in the blog archives, does this as well as anything new I might come up with now, so I figure it deserves a reposting here to get it back on the front page for a few days. Here it is.

Frequently asked questions on woo and mainstream medicine

“Woo” is a term for certain implausible and outlandish claims of complementary and alternative medicine (CAM). The term has recently been popularized on the blogosphere by Orac and others and has been a subject of several recent posts of mine which have drawn numerous criticisms and questions. Rather than address them piecemeal in my comment threads I decided a more effective way to answer my detractors would be in the form of a frequently asked questions (FAQ) post, so here goes.

Many of mainstream medicine’s conventional treatments are not evidence based. Aren’t they a form of woo?
No. Although some conventional methods fail to measure up to best evidence they are at least based on known anatomy and physiology. They have some plausibility in the observable biophysical model in contrast to the “vital forces”, nebulous “energy fields” and “non-local powers of the mind” which are characteristic of woo.

You seem to focus a lot of your criticism on woo. Isn’t non-evidence based conventional medicine harmful too?
Yes, of course. Moreover, there are harmless forms of woo just as there are harmless conventional breaches of EBM. All departures from best evidence are problematic and need to be addressed, whether woo-based or not.

Then why make a distinction?
Because of important differences in the ways the problems manifest themselves. Mainstream medicine applies a double standard and that’s what I’m trying to expose. People in the mainstream are appropriately critical of conventional deviations from best evidence and are trying to correct the situation. But due to the nature of the problem---a complex interplay of system and cognitive failures---the fix is not easy. In contrast (and here’s where the real hypocrisy comes in) mainstream medicine uncritically embraces woo, applying to it a much easier evidentiary standard and often no standard at all. The remedy for the problem of woo would be much simpler, too. Mainstream medicine could simply say no. Woo, by definition patently implausible, is easy to spot. There’s nothing complicated about it. It’s not a system problem. It’s there in mainstream medicine purely by choice. That fact raises another important distinction. If mainstream departure from EBM is a complex system problem and woo is there by choice then woo constitutes a more serious ethical problem.

But if patients want woo shouldn’t we let them seek it out?
By all means. We must respect our patients’ right to choose, and there are plenty of woo facilities outside the mainstream which can accommodate them. It’s quite another thing, though, if we misinform patients by putting our mainstream reputations and credentials behind false promotions. It’s just plain dishonest.

I’ve been reading all these statistics about the increasingly large numbers of patients who are seeking alternative medicine, or “woo” as you call it. They’re even paying for it out of their own pockets. Shouldn’t we in mainstream medicine accommodate them?
Not unless we decide all we’re interested in is taking their money, or in basing best practice on a popularity contest. These don’t strike me as good reasons.

Some woo based methods seem to be little more than relaxation and exercise techniques. What’s wrong with that?
Nothing, as long as you don’t make false claims. Go ahead and recommend relaxation and exercise, but if you promote it, for example, as Qigong you’re promoting all the paranormal theories of “vital energy healing” that go with the package. If you’re a mainstream medical practitioner and put your good name and credentials behind such false claims you’re being unethical.

Now, will this settle the misunderstandings once and for all (as Dr. RW braces for the next salvo)?

Malaria review

This review in Resident and Staff Physician contains an algorithm for management of suspected cases as well as information on the recently approved NOW rapid malaria antigen test.

Serial electrocardiography in the ER

Acute coronary syndrome is a fluctuating process usually caused by an unstable plaque which is in a dynamic state of clot formation and lysis. This, combined with variable artery spasm may cause total occlusion alternating with recanalization. Accordingly, the electrocardiogram may fluctuate frequently in the early period of ACS. The authors of a paper in the American Journal of Emergency Medicine make a case for serial electrocardiograms during the patient’s ER workup, sometimes at intervals as short as 5 minutes, to enhance the sensitivity of detection of ACS.

Early goal directed therapy: cost effectiveness and implementation

A decision analysis was published in Critical Care Medicine, using data from the Henry Ford Health System, Medicare, the U.S. Public Health Service, and the American Thoracic Society. Despite perceived expense and implementation barriers EGDT reduces hospital costs and saves lives. An ICU based model (transfer patient to ICU then begin EGDT) was the least effective. EGDT is best done by the emergency department or a mobile response team.

The Journal Watch Emergency Medicine summary of the article is here.

Hypereosinophilic syndromes

This open access review provides an update on classification, nomenclature, clinical manifestations and treatment.

Via Orphanet Journal of Rare Diseases.

Analysis of electrocardiographic ST segment and T wave abnormalities

I have added the American Journal of Emergency Medicine to the list of journals I browse regularly. Since I haven’t browsed back issues before I will occasionally post old articles from the journal as long as they are still relevant, such as this one from the July 2001 issue on the various causes of ST and T wave abnormalities. Included is a discussion of the effects of bundle branch block, hypertrophy, ischemia and digitalis effect as well as criteria to distinguish between primary and secondary ST and T abnormalities in patients with bundle branch block.

Mechanical Ventillation in severe asthma

Although this review in Critical Care is a bit dated I’m posting it now because it has just become available as free full text access and is one of the better articles I’ve seen on the subject. It focuses on dynamic hyperinflation (aka auto-peep) as the underlying cause of most complications of mechanical ventilation in these patients.

MEN type 1 review

Via Orphanet Journal of Rare Diseases.

New CMS rules concerning hospital reimbursement and adverse events

Recently JAMA published a commentary on this issue with a focus on urinary tract infections (UTIs). The new policy has sparked controversy and was number 6 in my top ten list of issues in hospital medicine for 2007.

Urinary tract infection is not a particularly good example for examination of the controversy. The rule concerning UTI is among the least controversial and is not as manifestly unfair as those concerning patient falls and decubitus ulcers. Although there will be unintended consequences (expect a sharp rise in urine cultures on admission whether clinically indicated or not, especially in nursing home patients) hospitals may find constructive ways to respond to the rule, such as designating urinary catheter cops to do daily chart reviews and coax doctors to remove catheters after 48 hours unless there’s a darn good reason to leave them in. Some patients will still acquire UTIs in the hospital in spite of this and other best practices. Unfortunately, these infections will nevertheless be considered “mistakes.”

I was particularly interested in the authors’ analysis of the financial incentives involved. Although I don’t have data to refute it, it seems flawed to me:

Simply stated, the IPPS tolerates and even financially rewards poor performance by hospitals that fail to prevent hospital-acquired complications such as catheter-associated UTIs. For example, at the University of Colorado Hospital, the care of a patient with acute myocardial infarction discharged alive without a complication or comorbidity or a major complication or comorbidity would result in a Medicare reimbursement of $5436.66. The care of an identical patient with the complication or comorbidity of UTI would result in a reimbursement of $6721.44 and that of an identical patient with the major complication or comorbidity of Escherichia coli sepsis and infection due to indwelling catheter would result in a reimbursement of $8905.43.

The rule change is designed to eliminate these perverse financial incentives.

So they’re saying, in effect, that hospitals have been incentivized to allow patients to experience complications! But that’s based on the dubious assumption that the increase in DRG reimbursement exceeds the added cost of caring for patients who have experienced complications in the hospital. The example given assumes that an extra $3468.77 would more than pay for an episode of sepsis. But what if the patient’s sepsis requires 10 days of big gun antibiotics, the use of activated protein C, consumes the resources of an early goal directed therapy team and requires 5 days in the ICU? Hospital resource managers know better and, ever since the advent of DRGs in 1984, have considered such events to be costly.

Paraneoplastic neurologic syndromes

Reviewed in the Orphanet Journal of Rare Diseases.

Pravastatin use in patients with liver disease

Statin use in patients with liver disease is controversial but the concerns are diminishing. Now a RCT demonstrates that pravastatin in high doses can be safely used. From Hepatology.

Practical aspects of enteral feeding

A nuts and bolts review with sample order sets.

Pulmonary-renal syndromes

---were recently reviewed in Critical Care. I was unable to access full text but the abstract had a few important reminders so I’m linking it here.

Therapeutic hypothermia after cardiac arrest: it’s not getting done

An article in Emergency Medicine News asks why. For one thing, simple though it seems, it’s hard to implement and requires an institutional commitment. Another reason is no one is promoting it despite the fact that we’re five years out from published studies now. Where’s Joint Commission?

Surviving Sepsis 2008

In a December 27th post (one of my top ten issues in hospital medicine for 2007) I offered some predictions on what the first update of the 2004 guidelines would look like. Little did I know that the new guidelines would be published in a matter of days. (I’m not sure exactly when they were posted but I first found them, as a special article in the January issue of Critical Care Medicine, on December 31).

Thus far I have only seen the abstract. The full text of the guidelines, which currently requires a subscription, should soon be published free on the SCCM web site. What changes were made from the old guidelines? How did I do with my predictions? The abstract lists the recommendations and their grades, so I’ll take a stab.

The changes were mainly in the recommendation grades. Recommendations were graded as strong (grade 1) or weak (grade 2). For grade 1 recommendations the risk/benefit ratio had to be clearly in favor of the recommendation. For grade 2 recommendations the risk/benefit ratio was “less clear.” Although the grading scheme differs from that of the 2004 A-E categories I was able get an idea of whether a given recommendation was strengthened or weakened.

The recommendations which were the focus of my post were activated protein C (apC or Xigris), corticosteroids and glycemic control. In my discussion of aPC I cited negative evidence that has come out since the 2004 guidelines and predicted that the guideline authors would weaken their recommendation for aPC and it appears that’s what they’ve done. The 2004 guidelines carried a strong recommendation (grade B on an A-E scale) whereas the 2008 recommendation is grade 2 (weak recommendation) on a 1-2 scale. Moreover, the authors added a strong recommendation (grade 1) against the use of aPC in children.

Concerning corticosteroids I predicted, citing the CORTICUS study, that the new guideline recommendations would be more restrictive. It appears that they are although the differences in wording are subtle. The grading of the recommendation went from C (A-E) to 2 (1-2, weak recommendation) and the indications became more limited. The old guidelines recommended corticosteroids for all patients who required pressor agents after volume repletion. The new ones restrict steroids to those patients whose blood pressures are poorly responsive to combined fluid and pressor therapy.

For glycemic control the guidelines strengthened the general recommendation that glycemic control should be implemented but weakened the recommendation for the specific target of 150mg/dl, in keeping with my previous remarks:

Just about the only thing everyone agreed on this year was that hyperglycemia should not be ignored in hospitalized patients. The unresolved questions relate to what target for what indication.

Other changes of note include the removal of a weak recommendation for vasopressin to be considered as an adjunct in patients refractory to fluid resuscitation and high dose pressors. This probably reflects recent papers suggesting difficulty in patient selection and adverse effects. This study from 2005 showed that, although outcomes may improve with the early use of vasopressin, its initiation after titration of norepinephrine to doses exceeding 0.6mcg/kg/min was associated with increased mortality. Moreover, the use of vasopressin was associated with elevated liver function tests and thrombocytopenia. The VASST study (unpublished as far as I know) showed no overall difference in mortality with vasopressin and again showed that the effect depended on the dose of norepinephrine administered at the time vasopressin was started.

The 2008 guidelines added a strong recommendation against routine use of PA catheters in the management of ALI and ARDS, in keeping with the findings of the Fluid and Catheter Treatment Trial.

I should make a final point about aPC (Xigris). With the benefit of time, additional evidence and an examination of the first update of the Surviving Sepsis Guidelines we are in a good position to revisit the question of whether the guidelines are, according to the accusations of some, merely marketing disguised as evidence based medicine. The available evidence in 2004, from a single randomized controlled trial, was that aPC improved mortality in patients with severe sepsis with a high risk of death. Though far from perfect the trial was the best and most current evidence the guideline authors had to work with. Its inclusion in the guidelines was appropriate according to the principles of evidence based medicine. But the naysayers who accused the guideline authors of being in the pockets of Pharma made up their own EBM principle, seemingly out of thin air: judge, and sometimes reject, evidence by the company it keeps. That, as I pointed out, was more of an attack on the authors than an appeal to evidence.

When newer evidence published 3 years after the SSS guidelines raised concerns about the risk/benefit ratio of Xygris I posted it here and suggested that the guideline authors would need to reconsider their recommendation in the update. A reasonable synthesis of the new evidence with what was known before is that Xigris saves lives, but in which patients? Patient selection is difficult and, according to the evidence synthesis, should take into account time to anticipated treatment (perhaps restricting it to patients who can be treated within 24 hours of the first organ failure), bleeding risks (perhaps employing stricter criteria for exclusion) and risk of death (in which we consider restricting it to patients in septic shock or with a combination of multiple organ failures and APACHE II scores above 25). Given this evidence, when it came time to update the guidelines for 2008, what choices did the guideline writers have? Given that Xigris can save lives in carefully selected patients, its elimination from the guidelines would have been inappropriate. What the writers seem to have done was give Xigris the lowest possible grade of recommendation without eliminating it. That, it seems to me, is the best they could do given the evidence at hand.

I’ll examine the full text of the guideline once I can access it and post a follow up if indicated. I hope it puts to rest once and for all the notion of marketing disguised as EBM.

New blog intends to hold the medical profession to standards of science

Science Based Medicine, a blog devoted to upholding the principles of science in medicine, was launched yesterday. It’s a team effort by several leaders in the fight against pseudoscience. The inaugural post offers some perspectives on science:

Science is nothing more than a systematic and careful use of evidence and logic to evaluate factual claims. And good science possesses certain virtues that are not unique to science but generic to all intellectual endeavors: fairly accounting for all available evidence, using valid and internally consistent logic, using unambiguous concepts and language, proper use of statistics, being quantitatively precise and accurate, and above all being honest.

Yes, science is systematic and internally consistent. It is bound by certain rules. It is not, like integrative medicine, a smorgasbord of diverse ways of getting at the truth.

Medpundit’s farewell post

Every once in a while, when I’m forced to examine my priorities in a more serious way, I realize that some day blogging may have to go. Medpundit has decided it’s time to quit and posted her final entry yesterday. Medpundit was one of the longest running medical blogs and one of the ones that got me interested in blogging.