Rumors of homocysteine’s death as a cardiovascular risk factor have been greatly exaggerated

I’ve made this point before. A recent editorial in Stroke entitled “Homocysteine: Call Off the Funeral” provides reasons in addition to those I cited. One factor is the increasing importance of vitamin B12 relative to folic acid as a determinant of elevated homocysteine levels. Increased fortification of foods with folic acid has diminished the incidence of folate deficiency and may be masking milder cases of B12 deficiency. Moreover, the shifting demographic toward an older population has increased the importance of B12 deficiency due to food-cobalamin malabsorption syndrome for which the optimal dose of oral vitamin B12 is unclear. Some of the vitamin trials used doses of vitamin B12 which may have been inadequate to overcome this common absorptive defect.

Declining clinical skills

Herbert L. Fred, MD, professor of Medicine at the University of Texas Health Science Center at Houston, calls it hyposkillia and believes it to be one of the more pervasive threats to our profession. In a recent editorial in the Texas Heart Institute Journal he correctly points out that over reliance on diagnostic technology has led to intellectual laziness and a neglect of basic clinical skills. J. Willis Hurst once said that you must master low technology (history, physical examination, electrocardiography) before you can make effective use of high technology (echocardiography and other imaging modalities).

I would argue that there are other factors. Extremes in evidence based medicine have produced some unfortunate consequences. The shunning of experts, for example, threatens the extinction of the master clinician-teacher. Over reliance on resources like Up To Date and slavish adherence to algorithms have become substitutes for thought. The increasing percentage of precious curriculum time spent on pseudoscience (euphemistically termed “complementary and alternative medicine”) undermines education in the basic sciences.

This dumbing down of clinical skill is ironic coming as it does in the midst of the ACGME’s core competencies initiative. Is outcome based medical education failing? A more optimistic view might be that the outcome project is early in implementation and we have yet to see its benefits. But a proposal written a few years ago in BMJ for the medical school of the future was not promising. In this Renaissance School of General Medicine “….gone will be the days of freestanding courses in biochemistry, physiology and anatomy” and “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.” This is scary.

Inferior vena cava filters remain controversial

The expanding use of IVC filters has outpaced clinical evidence. Most of the current uses of filters are unsupported by high level evidence. JAMA Medical News and Perspectives has a commentary in the March 1 2006 issue. A concise and rigorous statement on IVC filters from the Thrombosis Interest Group of Canada can be found here.

The use of retrievable filters is appealing although evidence is limited. Of three retrievable filters approved for use in the United States only two remain available; one was removed from the market due to a high rate of complications.

Isabel versus Dxplain in a case of giant cell arteritis with atypical manifestations

A while back I mentioned two web based differential diagnosis resources, Isabel and Dxplain. I have access to Dxplain through Merck Medicus and signed up for a free trial of Isabel, so I decided to plug a challenging case into both programs and compare their performance.

The CPC in the February 9 2006 NEJM featured an uncommon presentation of giant cell arteritis dominated by chest pain and respiratory complaints. Myalgias were also present, mistakenly attributed to statin drugs. The following findings were entered into both programs: chest wall pain; ear pain; shoulder pain; myalgias; hoarseness; exertional dyspnea; fatigue; sore throat. Age (elderly) and gender (female) were entered. Although both programs encourage entry of laboratory results you can enter as much or as little data as you wish, and I decided to see how the programs did with only the initial presenting clinical manifestations. I opted not to enter the patient’s sedimentation rate of 90. That would have made it too easy.

Isabel missed the boat entirely with a long list of diagnoses across multiple specialties, with the only rheumatologic diagnosis offered being relapsing polychondritis. Dxplain fared better by coming up with polymyalgia rheumatica. Neither program diagnosed giant cell arteritis or temporal arteritis. So, Dxplain wins the first round. As time permits before my free Isabel trial expires I’ll try more cases and report back.

Clostridium difficile review

This open access CCJM review of C. diff provides an overview of diagnosis and treatment as well as an update on the new NAP 1 strain. A few tidbits--

Fluoroquinolones appear to be more strongly associated than other antibiotics including clindamycin.

The new NAP 1 strain produces more toxin than old strains and may be responsible for recent trends toward more severe disease.

Antiulcer medications add to the risk for disease.

Recent reports of treatment failures with metronidazole have suggested changed treatment recommendations. This review suggests metronidazole as initial treatment for mild disease with consideration of oral vancomycin as initial treatment for moderate or severe cases.

Clinical progress rather than repeat toxin assays should guide management decisions and surgical consultation is recommended when disease progresses during treatment.

Adjunctive measures such as probiotic therapy, IVIG and agents to bind toxin have garnered interest but are not supported by high level evidence.

Antimotility agents including narcotics should be avoided, as they increase the risk for megacolon.

Clinical vignettes on perioperative beta blockers

From Mayo Clinic Jacksonville. Via Post Graduate Medicine.

Diabetes type 1.5

AKA Flatbush diabetes, atypical diabetes, diabetes type 1B and more recently ketosis prone type 2 diabetes. This increasingly recognized but still under appreciated condition was reviewed in the March 7 2006 issue of Annals of Internal Medicine.

With the emergence of this relatively new profile of diabetes the traditional classification has been challenged. Older concepts, though useful and largely true, must now be nuanced. For the past 20 years the defining characteristic of type 1 DM has been that when deprived of exogenous insulin the patient invariably develops ketoacidosis (DKA) in the basal state. In contrast, while type 2 diabetics may develop ketosis under stress (e.g. with myocardial infarction, sepsis, etc.) they never develop DKA in the basal state.

For classic types 1 and 2 these principles remain valid. They were a welcome replacement to the outmoded notion of “adult versus juvenile onset” types and the more recent (and extant but nevertheless confusing) terms “insulin dependent” and “non-insulin dependent” diabetes.

Enter now the new profile which might be described as the occasional but not invariable development of DKA during exogenous insulin deprivation in the basal state. These are the patients who come in with DKA (often with no apparent precipitating stress) but who, weeks or months later, discontinue insulin and do just fine. At times they behave like DM-1; at other times they look for all the world like DM-2.

What’s going on? Since these folks were first noticed in 1987 they tended to be regarded as a fuzzy overlap syndrome, poorly understood. Research in the ensuing years has improved our understanding of the condition and it’s all nicely summarized in the Annals review. Take home points follow.

1) It tends to be seen in African American and Hispanic persons, though not exclusively so. 25% to 50% of African American and Hispanic patients who present with DKA (not to be extrapolated to all African Americans and Hispanics with diabetes) have been reported to exhibit this profile.
2) Unlike classic DM-1, patients tend to be obese at presentation with DKA.
3) It does not appear to be an autoimmune disorder, in contrast to the well documented autoimmune beta cell destruction of classic DM-1. Instead it’s an intermittent reversible beta cell failure.
4) The beta cell failure appears to be, at least in part, an exaggerated form of glucose toxicity. Thus, presentation with DKA may follow a prolonged period of uncontrolled hyperglycemia, with recovery of beta cell function following a period of glycemic control with insulin.
5) More than 80% of patients have a family history of DM-2.
6) This profile of diabetes is to be distinguished from other atypical forms of diabetes including MODY and LADA.

Note---to confuse things, LADA in some writings has been given the designation DM-1.5. One of these days maybe the experts who sit down at meetings and talk about such things will deliver a clarification, written in stone.

Tools to sharpen your baloney detector

The SkepticWiki

Hospitalist consultation for hip fracture surgery

Mayo Clinic Proceedings provided another addition to the growing literature on hospitalist care with this study of hip fracture surgery, comparing hospitalists with traditional primary care physicians for medical consultation. Hospitalist consultation was associated with statistically significant reductions in time to consultation and time to surgery. Cost and length of stay reductions were not statistically significant. Previous literature has suggested that reduced time to surgery is associated with better outcomes.

The discussion section describes practice patterns of hospitalists at the study site (Mayo Clinic Jacksonville) and speculates how hospitalists might improve outcomes for surgical patients.

How good are systematic reviews of alternative medicine?

Only as good as their major reference source, Medline. But Medline is biased toward alternative medicine. I recently pointed out that Medline searches of topics related to Complementary and Alternative Medicine (CAM) were overwhelmingly uncritical. Why? According to this editorial by Wallace Sampson, the process of journal selection for Medline indexing is riddled with conflicts of interest.

He concludes: This situation has resulted in an advocacy-dominated fund of material that biases research reports, systematic reviews, and meta-analyses; alters student research projects and medical school teaching; and biases patient and physician searches.

A physician believed the drug reps, took Vioxx and had a heart attack

Now he’s suing the drug company. “I would never have taken the drug, nor would I have prescribed it to any of my patients, had I known of any of the risks,'' Braun said yesterday in an interview. “You assume that when someone comes in to the office with literature about the drug that what they're telling you is true. You assume this drug is safe.'' Read more.

Paroxetine and recurrent depression in the elderly

From the March 16 NEJM comes this paper reporting a greater than two fold increase in risk of recurrent depression in elderly patients who switch from paroxetine (Paxil, Paxil CR) to placebo after an initial response. The number needed to treat to prevent one recurrence was 4.

New findings on health care disparities

From a large survey reported in the March 16 2006 NEJM:

Over all, “recommended care”, as defined across a spectrum of multiple quality indicators, was delivered just over half the time, a finding consistent with previous studies. Variation among groups was less than the overall quality gap.

There were some surprising findings. Quality scores were higher for women than for men and higher for blacks and Hispanics than for whites.

The authors conclude: “Quality-improvement programs that focus solely on reducing disparities among sociodemographic subgroups may miss larger opportunities to improve care.”

What form of anticoagulation is best for unstable angina and NSTEMI?

The on line edition of NEJM has published, ahead of print, a large study by the OASIS-5 investigators comparing enoxaparin (Lovenox) and fondaparinux (Arixtra) in patients with non-ST segment elevation acute coronary syndromes (unstable angina and NSTEMI). Enoxaparin is a low molecular weight heparin. Fondaparinux is a synthetic pentasaccharide inhibitor of factor Xa. The primary efficacy endpoint was similar in the two groups but bleeding was markedly less in the fondaparinux group. Over all the number needed to treat with fondaparinux instead of enoxaparin to prevent 1 death was 150.

Of particular interest was how these agents were dosed compared to their doses for other indications. Fondaparinux showed non-inferiority despite a relatively low dose in comparison to enoxaparin. The low dose may explain the lower incidence of bleeding. Put another way: both agents are approved for both the prophylaxis and treatment of venous thromboembolism (VTE) with much higher doses for the treatment indication (two or more times the prophylactic dose). However in this study of acute coronary syndrome fondaparinux was administered in its VTE prophylactic dose while enoxaparin was given in its VTE treatment dose.

Both drugs are eliminated by renal excretion. For VTE indications enoxaparin’s labeling allows for dosage adjustment in renal failure whereas fondaparinux carries a contraindication for patients with creatinine clearance less than 30.

An accompanying editorial provides perspective.

Multifocal chorioretinitis in West Nile Virus Infection

A report in Mayo Clinic Proceedings from a West Nile Virus (WNV) outbreak in Tunisia points to a strong association with a characteristic variety of multifocal chorioretinitis. In the survey of patients presenting with a picture of encephalitis or meningoencephalitis, the presence of multifocal chorioretinitis had a 100% positive predictive value for the diagnosis of WNV. The authors suggest that ophthalmologic evaluation be routinely carried out when WNV infection is considered.

Has the homocysteine hypothesis been debunked?

No! But you can bet that’s what the media will say about two studies just released ahead of print by NEJM. One, the NORVIT trial, we already knew about. It was presented at the European Society of Cardiology months ago and I blogged my perspective here. The other, HOPE 2, had findings consistent with NORVIT: non-selective use of folic acid, vitamin B6 and vitamin B12 is ineffective for secondary prevention of vascular events.

Why don’t these results debunk the homocysteine hypothesis? Because the studies didn’t ask that question. These vitamins were tested on patients irrespective of their homocysteine levels. Baseline levels in the study populations were around 12 or 13---hardly what we would consider elevated, and not in the range that has been found to be associated with clear evidence of hypercoagulability in previous studies. What this work does confirm is a) if there is an optimal homocysteine target for cardiovascular health that target is unknown---previous targets of 9-10 were unnecessarily low and b) the popular practice of routine supplementation with B vitamins to prevent vascular events is not warranted. There still may be a role for measurement of homocysteine in selected patients, with consideration for treatment if it’s clearly elevated.

For a good perspective on these studies read the accompanying editorial. Don’t bother with the media reports.

Corticosteroids in sepsis

“Megadoses” of glucocorticoids were in vogue for sepsis treatment in the 1970s and early 1980s. The practice was abandoned in the late 1980s when studies suggested lack of benefit and possible harm. More recent evidence has suggested benefits of lower pharmacologic doses of hydrocortisone in patients with septic shock. Consequently, hydrocortisone treatment is included in the surviving sepsis guidelines and the sepsis bundle. Part of the rationale for such treatment is the new concept that patients in septic shock have “relative adrenal insufficiency”, a form of decreased adrenal reserve which differs from classic Addison’s disease. Although evidence in favor of corticosteroid treatment for septic shock is accumulating, controversy persists concerning how relative adrenal insufficiency should be defined and how patients should be selected for treatment. Some of the unanswered questions are now being addressed in the CORTICUS trial. It’s all nicely updated in December’s issue of CCJM.

Practicing medicine----can we self-actualize?

First described by Kurt Goldstein, the notion of self-actualization was popularized by Abraham Maslow in his description of the hierarchy of needs. Simply put, the theory holds that along the path to achievement of one’s potential (self-actualization) is a hierarchical progression of prerequisite needs to be met.

R. Whit Curry, Jr, MD, Professor of Community Health and Family Medicine at the University of Florida, writes in the March 11 issue of Patient Care about the seemingly joyless struggle of practicing medicine. He challenges us to get past the “baggage” of the medical profession and self-actualize by focusing on the uniquely positive aspects: the satisfaction of helping and making a difference, the joy of learning and the privilege of glimpsing a fascinating slice of life.

But the hierarchy of needs is an obstacle course which can be difficult to ascend at times. The baggage of medicine can suck the joy right out of us; it gets in the way of the path to self-actualization. This baggage must be shed in order to achieve professional satisfaction. Maslow’s categories of needs have parallels in medicine: physiological needs (sleep deprivation, overwork); safety (looming threats of litigation and Medicare audits); love/belonging (patient complaints, critical colleagues, family stress, sense of isolation) and esteem (law suits, culture of blame).

These are difficult issues. The joy of practicing medicine (or self-actualization, professional satisfaction, call it what you will) can be elusive. Those who achieve it are of a special breed. Without a major cultural shift they will remain an elite group. (I wonder---can you blog your way to self-actualization?).

Invasive group A strep anecdote

A 44 year old nursing home employee jammed her hand in a wheel chair. Her thumb became red and swollen and she was dead within 3 days, evidently of group A streptococcal necrotizing fasciitis. Read here.

Everything you wanted to know about community acquired MRSA---

can be found in the March 7 2006 issue of Annals of Internal Medicine. A study from Atlanta found that 63% of staphylococcal skin and soft tissue infections were due to CA-MRSA, underscoring the need to direct empiric therapy of such infections toward CA-MRSA. Empiric antibiotic selection in 2/3 of these cases was inadequate. (Kidney Notes cited this paper).

Despite the vast increase in CA-MRSA infections this nation wide survey of colonization rates revealed that in noninstitutionalized persons the prevalence of any Staph aureus nasal colonization was 31.6% but only 0.84% for MRSA. There is no clear explanation for this seemingly discordant finding. Perhaps transmission and invasion of CA-MRSA does not correlate with nasal carriage, reflecting differences in transmissibility and pathogenesis compared to “old” MRSA strains.

An editorial in the same issue offers these pearls about CA-MRSA, some of which I’ve mentioned before:

1) CA-MRSA is a distinct form of MRSA. It is not a spread of the old nosocomial strain to the community---it’s a new bug which is distinguished by its genome, its pathogenicity and its antimicrobial sensitivity pattern. Indeed the distinction between hospital and community is becoming blurred, as the new strain is showing up increasingly in hospitals.

2) Almost all CA-MRSA (and virtually none of the traditional MRSA) produce the Panton-Valentine leukocidin (PVL). This toxin causes tissue necrosis, possibly explaining the association of CA-MRSA with necrotizing fasciitis and severe necrotizing pneumonia. The fact that such severe necrotizing sequelae are seen only in a small minority of CA-MRSA infections suggests the necessity of variable co-factors conspiring with PVL to produce severe infections. The presence of PVL may be responsible for the necrotic center characteristic of the much more common skin infections leading to the frequent mistaken impression of spider bite.

3) CA-MRSA isolates are sensitive to tetracyclines, trimethoprim-sulfamethoxazole and clindamycin. Although the use of such agents is popular the author cautions that they have not been studied in clinical trials. Clindamycin has the added problem of frequent acquired resistance which can be anticipated if the isolate is resistant to erythromycin and predicted in the micro lab with the “D” test. For severe infections vancomycin or linezolid should be used. Daptomycin is acceptable if there is no pulmonary involvement.