Tuesday, November 24, 2015

How sick are our sepsis patients? Not as sick as our coding says they are!

There's been a push for “improved” coding in the last few years. Purported benefits include better accuracy in the medical record and improved quality of research that is drawn from administrative databases. The real effect of today's coding trends, as many of us already know on the ground, has been quite the opposite as illustrated in this recent study which looked at septic patients:


We assessed trends from 2005 to 2013 in the annual sensitivity and incidence of discharge ICD-9-CM codes for organ dysfunction (shock, respiratory failure, acute kidney failure, acidosis, hepatitis, coagulopathy, and thrombocytopenia) relative to standardized clinical criteria (use of vasopressors/inotropes, mechanical ventilation for greater than or equal to 2 consecutive days, rise in baseline creatinine, low pH, elevated transaminases or bilirubin, abnormal international normalized ratio or low fibrinogen, and decline in platelets)...


Acute organ dysfunction codes were present in 57,273 of 191,695 (29.9 %) hospitalizations with suspected infection, most commonly acute kidney failure (60.2 % of cases) and respiratory failure (28.9 %). The sensitivity of all organ dysfunction codes except thrombocytopenia increased significantly over time. This was most pronounced for acute kidney failure codes, which increased in sensitivity from 59.3 % in 2005 to 87.5 % in 2013 relative to a fixed definition for changes in creatinine (p = 0.019 for linear trend). Acute kidney failure codes were increasingly assigned to patients with smaller creatinine changes: the average peak creatinine change.. The mean number of dysfunctional organs in patients with suspected infection increased from 0.32 to 0.59 using discharge codes versus 0.69 to 0.79 using clinical criteria (p less than 0.001 for both trends and comparison of the two trends). The annual incidence of hospitalizations with suspected infection and any dysfunctional organ rose an average of 5.9 % per year (95 % CI 4.3, 7.4 %) using discharge codes versus only 1.1 % (95 % CI 0.1, 2.0 %) using clinical criteria.


Coding for acute organ dysfunction is becoming increasingly sensitive and the clinical threshold to code patients for certain kinds of organ dysfunction is decreasing. This accounts for much of the apparent rise in severe sepsis incidence and severity imputed from claims.

Among the motivations for this more aggressive coding are the potential for hospitals to get paid more under the prevailing crazy DRG scheme and improved public report cards for doctors, which are severity adjusted, based on codes.

The result is that research based on administrative databases is becoming increasingly suspect and public report cards are nearly meaningless. The consumer public doesn't know this but it probably doesn't matter given research that they largely ignore public reporting.

Monday, November 23, 2015

Review article: cholangiopathies

Cholangiocytes (ie, the epithelial cells that line the bile ducts) are an important subset of liver cells. They are actively involved in the modification of bile volume and composition, are activated by interactions with endogenous and exogenous stimuli (eg, microorganisms, drugs), and participate in liver injury and repair. The term cholangiopathies refers to a category of chronic liver diseases that share a central target: the cholangiocyte. The cholangiopathies account for substantial morbidity and mortality given their progressive nature, the challenges associated with clinical management, and the lack of effective medical therapies. Thus, cholangiopathies usually result in end-stage liver disease requiring liver transplant to extend survival. Approximately 16% of all liver transplants performed in the United States between 1988 and 2014 were for cholangiopathies. For all these reasons, cholangiopathies are an economic burden on patients, their families, and society. This review offers a concise summary of the biology of cholangiocytes and describes a conceptual framework for development of the cholangiopathies. We also present the recent progress made in understanding the pathogenesis of and how this knowledge has influenced therapies for the 6 common cholangiopathies—primary biliary cirrhosis, primary sclerosing cholangitis, cystic fibrosis involving the liver, biliary atresia, polycystic liver disease, and cholangiocarcinoma—because the latest scientific progress in the field concerns these conditions.

Sunday, November 22, 2015

Catastrophic thrombotic syndromes

This designation was formerly termed thrombotic storm. The new terminology recognizes that this is a group of disorders with a common phenotype. An updated free full text review can be found here in Blood's How I Treat series. From the abstract of the paper:

Catastrophic thrombotic syndromes are characterized by rapid onset of multiple thromboembolic occlusions affecting diverse vascular beds. Patients may have multiple events on presentation, or develop them rapidly over days to weeks. Several disorders can present with this extreme clinical phenotype, including catastrophic antiphospholipid syndrome (APS), atypical presentations of thrombotic thrombocytopenic purpura (TTP) or heparin-induced thrombocytopenia (HIT), and Trousseau syndrome, but some patients present with multiple thrombotic events in the absence of associated prothrombotic disorders. Diagnostic workup must rapidly determine which, if any, of these syndromes are present because therapeutic management is driven by the underlying disorder. With the exception of atypical presentations of TTP, which are treated with plasma exchange, anticoagulation is the most important therapeutic intervention in these patients. Effective anticoagulation may require laboratory confirmation with anti–factor Xa levels in patients treated with heparin, especially if the baseline (pretreatment) activated partial thromboplastin time is prolonged. Patients with catastrophic APS also benefit from immunosuppressive therapy and/or plasma exchange, whereas patients with HIT need an alternative anticoagulant to replace heparin.

Saturday, November 21, 2015

The ongoing controversy over cholesterol and statins

A provocative article in the World Journal of Cardiology challenges some simplistic assumptions.

Below are a few of the points made in the article.

Total cholesterol is a poor predictor of risk

This has been known for decades. The authors cite findings from the Framingham study in which total cholesterol levels in patients with coronary disease overlap highly with levels in patients free of coronary disease. That is illustrated in this figure. But to say these findings negate the cholesterol hypothesis ignores the distinction between population attributable risk and relative risk. The findings, despite a well documented correlation between cholesterol levels and coronary disease risk, are explained by the multitude of other factors, in addition to cholesterol levels, that contribute to risk. Other factors must be taken into account and in the Framingham study the ratio of total cholesterol to HDL was a strong predictor.

In multiple clinical trials dietary interventions aimed primarily at reducing cholesterol levels failed to impact coronary disease outcomes

Diet trials may have been confounded by increased carbohydrate intake which activated the metabolic syndrome phenotype in many patients. On the other hand, cholesterol lowering drug trials have shown reductions in events. This is not just due to pleiotropic effects of statins, as there is evidence from non statin cholesterol lowering drug trials of event reduction.

Interventions to reduce risk need to be viewed in perspective

For example: cholesterol lowering diets have not been proven to reduce events; statins achieve a relative risk reduction of about 30%; the Mediterranean has been reported to achieve a 70% relative risk reduction.

Though a risk factor, a singular focus on cholesterol reduction is misguided

Carotid doppler flow measurements

---to assess volume responsiveness.

Friday, November 20, 2015

The heart in Duchenne and Becker muscular dystrophy

Free full text review.  From the article:

To conclude, heart involvement is common in both DMD/BMD and female carriers. Serial cardiac evaluation, including clinical examination, ECG, Holter monitoring, echocardiographic and CMR study, is the “sine qua non” for this population. Early detection of heart involvement should motivate early cardiac treatment with ACE inhibitors and b-blockers to delay serious cardiac complications.

Calcium blocker overdose

There is a spectrum of management options based on severity, starting with general supportive measures and progressing through modalities such as high dose insulin with glucose, lipid rescue and ECMO. Here is a mini-lecture from the Mayo EMBlog.

Thursday, November 19, 2015

Bundled payments: will they help?

A recent paper in Circulation looked at bundled payments for health care. The focus was on cardiovascular disease which has been a major target of criticism for over utilization. In addition, the cardiovascular service line has probably accumulated more experience in bundled payment than other specialities.

The article, despite making some unwarranted claims and confusing the terminology of health care does make some valid points and is worth the read.

In general, bundling of payments tends to bring costs down. What is most desirable in health care, of course, is adherence to evidence based medicine. The perfect world would be one in which all providers practiced perfect evidence based medicine 100% of the time. The appropriate question then, is, what would perfect adherence to EBM do to health care costs? Despite the claims of many policy experts, we don't know whether it would decrease costs, have a neutral effect or even increase costs. Abundant literature suggests that departure from evidence based medicine comes in the form of both over utilization and under utilization.

The discussion in the article, as do many discussions of health care today, centers around the contrast between fee for service medicine and the various models of bundled payment and characterizes health care in the US as being fee for service. That is simplistic, because inpatient care is under the Prospective Payment System (DRGs) is not fee for service. In the US the situation is complex and we operate under a variety of incentives. The assumption that one incentive is better than another dominates much of the discussion. However, any time someone does health care for a living, no matter the particular incentive, a conflict exists. Fee for service medicine creates a positive cost incentive. Bundled payments provide negative incentives. Who's to say which is better for patients? There's room for vigorous debate.

The first paragraph of the article reads:

Episode-based, “bundled” payments have come to the forefront of the national discussion on combating rising healthcare costs. In the currently dominant fee-for-service model for reimbursement, hospitals, physicians, and postacute care providers file distinct claims and are paid separately for provided services even when they are related to a single episode of care. However, this approach to payment encourages fragmented care, with little incentive for resource stewardship, coordination, or communication across multiple providers. In contrast, bundled payments seek to align the interests of providers..

Aside from the incorrect implication that hospitals are under fee for service reimbursement what about the alignment of interests that bundling purports to achieve? Under fee for service payment individual providers fight with the payer for reimbursement. Under bundled payment the fight is with each other for a piece of the pie. What kind of alignment is that?

The paper addresses the evidence on bundling. In short, it is preliminary. We do have experience to draw on from Medicare's Prospective Payment System but the newer models under discussion today are largely in experimental stages. A few cautions statements can be made. In general bundled systems seem to curb the rate of cost increases. The effect is modest. In the case of Medicare's Prospective Payment System the cost savings have been counterbalanced by a shift to outpatient treatment which is still largely paid on the fee for service model. This can be viewed as an escape valve from the negative cost incentives so that hospitals can survive. It has resulted in shorter hospital stays and that may have caused increased readmission rates.

These concluding remarks from the paper are correct:

Given this mixed picture of the evidence, it is important to place bundled payments in an appropriate context. On one hand, the future of bundled payments remains largely uncertain.

A number of bundled payment models are now under investigation as pilot projects by the Center for Medicare and Medicaid Innovation. Which of these will see mainstream implementation, if any, and when, is unknown.

Brain abscess

A review in Neurohospitalist. Free full text.

Wednesday, November 18, 2015

Industry supported CME: asking the wrong questions

Larry Husten's latest rant on industry supported CME is a confusing, frustrating read. It asks the wrong questions and makes unwarranted assumptions. Though he is correct in his particular criticism of a handful of industry supported offerings on testosterone replacement he is wrong in his overall view of industry supported CME. The testosterone courses, which I won't elaborate on here, speak for themselves as a bad example. Shameful as they are they're just a collection of anecdotes not representative of the overall situation. But Husten seems prone to hasty generalization.

Let me digress here for clarity. Husten's use of the phrase “continuing medical education” (CME) has a dog-whistle meaning that differs from its meaning in plain language. In plain language it's the pursuit of life long learning physicians engage in after completion of residency or fellowship. Though mostly informal and self directed it's the most important part of a physician's education post formal training. One of my medical school mentors, the late Thomas E. Brittigham, in a memo to his students, described it this way:

Dr. Carl Moore, chairman of the Department of Medicine at Washington University, tells me he finds it necessary to read medicine 3-4 hours every day...

In the dog-whistle meaning, CME is more restricted. It's a set of officially sanctioned activities in which physicians claim credit hours to meet minimum requirements. It is, or should be, relatively small in the grand scope of a physician's career learning. Put another way, as a practicing physician, if your studying is confined to what you are required to do for credit for you are in trouble. That's not to say accredited CME is unimportant but it's not nearly enough. We lose perspective with undue emphasis on minimum requirements.

Husten's post opens with:

Does anyone really think that commercially supported continuing medical education (CME) is truly independent?

That's confusing even beyond the use of dog-whistle words. Commercial support means dependency by definition. Many educational offerings would cease to exist without industry support. Few on either side of the debate would disagree so why the question? It obfuscates by substituting a tautology, requiring no thought, for real questions that are nuanced and could be debated vigorously, such as whether support degrades education or negatively impacts patient outcomes.

Though not made clear at the beginning of the post, Husten thinks accredited CME is OK as long as it is not done in collaboration with another industry:

Let me be clear: I don’t oppose CME in general. In any profession, and medicine in particular, CME is absolutely essential. But commercially supported CME is another matter entirely..

Well, if there is a distinction between supported and non supported offerings beyond mere perception it's not based on evidence. Husten ignores that. From his post:

Let’s first look at that “proven track record” claim. To be clear: there are no good studies showing the value of commercially-funded CME.

He's right. But he neglects to point out that neither is there good evidence showing the value of non supported CME. Despite today's obsession with course evaluations, feedback and attempts to link educational activities with outcomes there's no robust evidence either way. Education is a multi-layered, complex interaction between teacher and learner that doesn't lend itself to measurement to the degree we would hope, at least outside the closely structured environment of medical school and residency. Husten is correct in pointing out a burden of proof but he, like others who call for the elimination of industry supported CME, also has a burden of proof. It is unsustainable.

Husten is critical of the accrediting body for CME, the ACCME. Sure, we'd all like for the ACCME to do a better job but there is no basis for the extreme claims made in the post. He writes:

But let’s be very clear here: these “protections” are just window dressing, designed to give the appearance of objectivity and transparency. The ACCME is supposed to be a watchdog but everyone knows that it is the commercial CME industry’s lapdog.

Again, burden of proof. Evidence please. It's true that the accreditation process under ACCME is imperfect, as exemplified by the testosterone courses, but Husten provides no evidence that this happens any more with commercially supported activities than with non supported activities. I'm an extensive consumer of both types and can just as easily point to questionable examples of unsupported CME [1] [2] [3] [4] [5].

Concerning the motivation of commercially-funded providers he asks:

Or does anyone really think that it has the primary goal of delivering quality medical education?

The answer of course is no, whether supported or unsupported, because virtually all CME providers have a proprietary interest, even those popularly revered as “clean.” (Just look at Up to Date or MKSAP and their business models). Very few do it as a labor of love. The few who do are mainly in social media, and hardly any of those activities are accredited. Fact is, the entire world of accredited CME is its own industry. It's all a business, but Husten and others seem to think it's fundamentally different when there is collaboration with a second business.

It astonishes me that so many participants in this debate take the intellectually lazy way out by turning to simple litmus tests. Industry supported means bad. Non supported means good. It isn't that easy. Every offering, regardless of the business model, should be evaluated on its own merits.

I recently returned from a hospital medicine course run by Mayo Clinic. It had all the quality and scientific rigor you'd expect from Mayo. It also had industry support. There were numerous drug company displays in the exhibit area. Of the 18 or so credit hours offered, I noted only one half hour lecture that was questionable. Its content area was not represented among the displays or supporting companies. I thanked a couple of the exhibitors because I realized that this course would not exist in anything like its present form without their support. The inquisition against industry supported CME is restricting doctors' options. That's why this discussion matters.

Tuesday, November 17, 2015

Blastomycosis the great mimic

This may be the best review of blastomycosis I've read.

Some key points:

Unlike many other fungal infections blasto is not an opportunist. The typical patient profile is the healthy outdoorsy woodsman type. Anyone can be afflicted with severe disease.

Blasto is a great mimicker. In the lungs it can present as community acquired pneumonia, ARDS, nodules, just about anything. Skin manifestations include verrucous lesions, ulcerative lesions (e.g. resembling pyoderma gangrenosum), subcutaneous nodules resembling panniculitis among others. Involvement of other organs is also seen.

The author states:

This infection causes manifestations which mimic many other more commonly diagnosed conditions and must always be considered by clinicians practicing in the endemic region.

Saturday, November 14, 2015

Acute respiratory distress syndrome: what's evidence based and what's not?

This question was recently addressed in a review published in Baylor University Medical Center Proceedings.

The review opens with a discussion of definitions and criteria. It is important to note that the recently adopted Berlin criteria have placed ARDS into three categories, refined the radiographic definitions and eliminated the old designation ALI. The category distinctions are essential in considering various treatment options and discussing current research literature.

Below is a listing of treatment modalities under popular discussion and their current status.

Low tidal volume ventilation

Mortality benefit in ARDSnet trial.
Status: evidence based.

High peep

Although no benefit was seen in the ARDSnet (ALVEOLI) trial a subsequent meta-analysis that included other studies showed a mortality benefit for moderate and severe ARDS.
Status: evidence based for moderate or severe ARDS.

High frequency oscillation

No benefit, possible harm in clinical studies.
Status: not evidence based, not recommended.

Airway pressure release ventilation

No mortality benefit but improvement in other measures.
Status: evidence based for lower level outcomes.


The CESAR study showed a mortality benefit in severe ARDS but there were methodologic concerns. There has been extensive lower level experience.
Status: evidence based for severe ARDS but caveats apply. Widely considered a rescue modality.

Inhaled vasodilator therapy

No clear benefit.
Status: not evidence based.

Recruitment maneuvers

No clear benefit.
Status: not evidence based but sometimes considered as a rescue modality.

Prone positioning

Mortality benefit demonstrated for patients with a PO2 to FIO2 ratio of less than 150.
Status: evidence based for patients selected on the basis of PO2 to FIO2 less than 150 (does not fit neatly into the Berlin classification).

Neuromuscular blockade

Mortality benefit early in severe ARDS, used for 48 hours. Note: steroids were given to less than half the patients in both groups in the major trial with no significant difference in usage or incidence of prolonged paralysis, between groups.
Status: evidence based for brief usage early in severe ARDS.


This has been a topic of controversy and mixed reports but overall the evidence points to a mortality benefit if used early in moderate or severe ARDS.
Status: Evidence based for early use in moderate or severe ARDS and recommended by a recent consensus statement.

Friday, November 13, 2015

Histology matters in ARDS

From a very important new study and accompanying commentary we can learn some valuable lessons:

Out of 101 patients undergoing lung biopsy only slightly more than half had DAD.

Among those who had other processes specific diseases were found that led to changes in treatment including antimicrobial treatment and corticosteroids.

Unfortunately the study found no clinical characteristics that differentiated ARDS with DAD from other processes.

Thursday, November 12, 2015

Compatibility of lactated ringers and antibiotics

Now that people are increasingly using lactated ringers as the go to resuscitation fluid this issue will arise more frequently. The main concern is with ceftriaxone. Although I have heard mention of problems with other antibiotics I was not able to find any documented issues other than with ceftriaxone. The principal contraindication for concomitant use of LR and ceftriaxone is in neonates. They can be used together in adults but certain precautions apply. Here are two references outlining them [1] [2].

Tuesday, November 10, 2015

What's left of early goal directed therapy after ProCESS, ARISE and ProMISe?

A recent review, seeking to answer that question and summarizing the evidence, concluded:

Conventional management that focuses on early antibiotics and targeted resuscitation has contributed to improvements in survival of patients with septic shock over the last decade. New evidence from the ProCESS, ARISE and PRoMISe trials, however, suggests that structured ‘early goal-directed resuscitation’ with routine placement of a central venous catheter, monitoring of mixed venous oxygen saturation and aggressive red cell transfusion does not improve outcomes in most patients with septic shock. The nuances of fluid and vasopressor administration in early septic shock remain incompletely defined. Further, development and validation of practical methods for accurately assessing optimal fluid administration is needed. Future studies that seek to address these issues will likely benefit from emerging novel techniques, including molecular diagnostics and adaptive trial designs.

EGDT works but, like the Mediterranean diet, it is a bundle of interventions. Questions left unanswered by the Rivers study revolved around which of the components of the bundle were responsible for benefit and how they might be optimally used. These questions were partially answered in ProCESS, ARISE and ProMISe. Now I'm going to rant.

CVP and ScvO2

Findings in the three new trials suggested that invasive monitoring of these parameters was not mandatory for improved outcomes. The findings unleashed an immediate fire-storm of criticism of EGDT which was simplistic and misguided, saying in effect that these interventions were worthless and that EGDT was “dead.” There was no warrant for such statements. What the new trials demonstrated was merely that we still do not know the best way to perform hemodynamic assessment. Patients in the non-EGDT arms of these trials underwent careful noninvasive clinical hemodynamic assessment. So invasive may be no better than noninvasive but no one would argue that critically ill patients don't need ongoing hemodynamic assessment. That means therapy is, whether by invasive or noninvasive means, directed to goals. Viewed from that perspective EGDT is very much alive.

What's ironic is that among those same people who are trashing EGDT there's been a flurry of interest in newer methods of hemodynamic assessment, some of which are cumbersome, based on things like point of care echo and pulse pressure variation. All are aimed at providing EGDT! One of the more popular ones, IVC imaging, is nothing more than a surrogate for CVP. Others aim to estimate cardiac output. We got a chance to try that a couple of decades ago with the PA catheter and look what happened. None of these newer methods have been subjected to the rigors of the RCT. If they ever are, perhaps in a decade or so, they may all go the way of the CVP line, who knows?

There may be a conflict of interest at play. After all, critical care types love point of care echo. Why hasn't there been more interest, for example, in impedance cardiography which is arguably just as well validated and certainly provides more continuous data in real time?


The hematocrit target of 30 used in the Rivers study was not picked out of thin air. It was based on physiologic rationale that the higher the oxygen carrying capacity the better, but that above levels of about 30 increases in blood viscosity begin to counterbalance benefits. The new trials suggested that lower targets are appropriate, but they by no means negate the hemoglobin and hematocrit as useful goals.


Dobutamine was not addressed in the review but it was one of the interventions in the Rivers study. Findings from the new trials suggested that dobutamine did not need to be given in a rigid protocolized fashion. Non-EGDT patients got dobutamine but at a lower frequency. Following the announcement of the new findings there appeared to have be a rising interest in using point of care echo to guide the use of dobutamine in patients with septic shock. In one sense this looks like a retreat from evidence based medicine. That is, there seems to have been a shift in dobutamine usage from the way it was specifically tested in a randomized controlled trial to usage according to physiologic rationale. But it's more complicated than that because dobutamine was part of a bundle. We still don't know exactly what role dobutamine has in septic shock. The most we can say from the study findings is that judgment of the individual clinician is as effective as adherence to a rigid protocol.

Medical cannabis: evidence, policy and unintended consequences

Here's a new review in the Yale Journal of Biology and Medicine.

Key points:

Cannabinoids (drugs produced by pharmaceutical companies) have been reported effective for appetite stimulation, analgesia and relief of nausea. The effects are modest and other currently available drugs appear to be more effective. Evidence is lacking for other conditions.

Cannibas (e.g. marijuana plant products) has not been validated for medical use in systematic research, although there are anecdotal reports including dramatic testimonials.

Doctors face a conundrum in states that allow medical cannabis. According to the review:

Medical marijuana schemes create problems for prescribers. Laws allowing physicians to prescribe cannabis conflict with U.S. federal law, which does not allow the use of cannabis for any purpose. Under the U.S. Constitution, federal laws pre-empt state laws [4,48]. The Bush administration threatened to strip doctors of their licenses to practice if they recommended marijuana to their patients. Even when the U.S. courts removed this threat, physicians remained reluctant to recommend cannabis because of concerns that they would be legally liable for any harms experienced by their patients [47,51]. In the absence of data, physicians also found it difficult to decide to whom they should recommend cannabis, in what amounts, and for how long [54,55]. These challenges have been ignored by a small number of physicians, who advertised their preparedness to provide patients with a medical recommendation for a fee.

Medical cannabis initiatives may deliver little more than de facto legalization of recreational marijuana.

Albuterol in the treatment of ARDS

From a recent review:


This meta-analysis of randomized controlled trials aimed to systematically evaluate the value of albuterol in the treatment of patients with acute respiratory distress syndrome (ARDS).


Randomized controlled trials on albuterol treatment of ARDS from its inception to October 2014 were searched systematically. The databases searched included: PubMed, Ovid EMBASE, Ovid Cochrane, CNKI, WANFANG and VIP. The trials were screened according to the pre-designed inclusion and exclusion criteria. We performed a systematic review and meta-analysis of the randomized controlled trials (RCTs) on albuterol treatment, attempting to improve outcomes, i.e. lowering the 28-day mortality and ventilator-free days.


Three RCTs involving 646 patients met the inclusion criteria. There was no significant decrease in the 28-day mortality (risk difference=0.09; P=0.07, P for heterogeneity=0.22, I2=33%). The ventilator-free days and organ failure-free days were significantly lower in the patients who received albuterol (mean difference=–2.20; P less than 0.001, P for heterogeneity=0.49, I2=0% and mean difference=–1.71, P less than 0.001, P for heterogeneity=0.60, I2=0%).


Current evidences indicate that treatment with albuterol in the early course of ARDS was not effective in increasing the survival, but significantly decreasing the ventilator-free days and organ failure-free days. Owing to the limited number of included trails, strong recommendations cannot be made.

Monday, November 09, 2015

Uncritical acceptance of chelation trial results continues

I recently pointed out an American Heart Association publication's surprisingly credulous view of chelation therapy. Now there's more from Cardiobrief citing this quote of none other than Eugene Braunwald:

Eugene Braunwald gave a strong endorsement to TACT2 in the press release: “The results of TACT were both surprising and intriguing. I am very pleased that TACT2 is building on these findings to determine if they can be replicated in diabetic patients who have experienced a myocardial infarction – a particularly high risk group of patients in need of effective therapy.”

I've ranted on this extensively before and will only restate here that of all major clinical trials I can recall in my long career TACT is one of the most conflicted. It's beyond merely controversial. Anyone interested in digging deeper on this issue should read this article.

Biomarkers in the diagnosis and monitoring of infections

In a large retrospective study of 1006 patients, an ESR of 100 mm/hour or more had low sensitivity of 0.36 among patients with infection, 0.25 among those with malignant neoplasms, and 0.21 among patients with noninfectious inflammatory disorders. However, specificity was high...

C-reactive protein has some advantages over ESR because it seems to be a better measure of an acute-phase response and is also more sensitive than ESR to subtle changes in the acute-phase response [1]. It is primarily produced by the liver in response to cytokines...

With mild to moderate stimulus, such as uncomplicated skin infection, cystitis, or bronchitis, it can rise to 50–100 mg/L within 6 hours [8]. Low levels of elevated CRP, with values between 2 mg/L and 10 mg/L, may be seen with “metabolic inflammatory” states such as smoking, uremia, cardiac ischemia, and other low level noninfectious inflammatory conditions...

Procalcitonin is the peptide prehormone of calcitonin that, under normal conditions, is secreted by the C-cells of the thyroid gland in response to hypercalcemia or as a result of medullary carcinoma of thyroid. In systemic inflammatory conditions and, in particular, bacterial infections, PCT secretion is stimulated by various cytokines such as IL-1, IL-6, and tumor necrosis factor-alpha. In viral infections, the PCT production is downgraded...

Osteoarticular Infections

The likelihood of diabetic foot osteomyelitis increases with ESR value of more than 70 mm/h [19]. In another prospective study, the sensitivity and specificity of CRP for the diagnosis of osteomyelitis at a level of more than 14 mg/L was 0.85 and 0.83; the sensitivity and specificity of ESR at a level more than 67 mm/hour was 0.84 and 0.75; and the sensitivity and specificity of PCT at a level more than 0.30 ng/mL was 0.81 and 0.71...

The authors recommended that ESR be used for the follow-up of patients with osteomyelitis [20].

Concerning sepsis, the review notes:

In a meta-analysis..the authors concluded that PCT is a helpful biomarker for early diagnosis of sepsis.. The cutoff for PCT concentrations differed between 0.5 ng/mL and 2.0 ng/mL, with a median of 1.1 ng/mL. The pooled sensitivity and specificity of serum PCT levels in the early diagnosis of sepsis was noted to be 0.77 (95% CI, 0.72–0.81) and 0.79 (95% CI, 0.74–0.84), respectively [29]...

Another meta-analysis examining patients with bacteremia concluded that low PCT levels can be used to rule out the presence of bacteremia [32]...

Concerning pneumonia:

Procalcitonin levels can be useful in early identification of bacterial pneumonia, guide antibiotic management, and help stratify patients with a higher risk.. In a randomized trial involving 302 consecutive patients, PCT guidance substantially reduced antibiotic use in lower respiratory tract infections without compromising outcomes from withholding antibiotics. In the PCT group, antibiotic treatment was based on serum PCT concentrations as follows: strongly discouraged, less than 0.1 µg/L; discouraged, less than 0.25 µg/L; encouraged, greater than 0.25 µg/L; strongly encouraged, greater than 0.5 µg/L [36]. A Cochrane database review of more than 14 trials also concluded that the use of PCT to guide initiation and duration of antibiotic treatment in patients with pneumonia was not associated with higher mortality rates or treatment failure...

There is also at least moderate evidence that PCT guidance to discontinue antibiotic therapy does not increase morbidity..and that PCT guidance does not increase mortality, hospital length of stay, or ICU admission rates in patients diagnosed with pneumonia in an inpatient...

This is of interest given PCT's ability to distinguish between viral and bacterial infection and recent surprising findings pointing to a high frequency of viral infections as etiology of community acquired pneumonia.

A meta-analysis involving both adult and pediatric studies reported that the serum concentrations of CRP had a sensitivity that ranged from 0.69 to 0.99 and a specificity that ranged from 0.28 to 0.99. The authors concluded that CRP may have a good NPV, but the overall usefulness in diagnosing meningitis remained uncertain.

The use of biomarkers is an emerging hot topic in infectious disease. As we have seen before with D dimer and BNP/pro-BNP there will be some misuse with the hope that further study and dissemination of information will refine our approach.