Concern over MOC goes beyond the blogs

This just published article from Cleveland Clinic examines the evidence concerning MOC, its unintended consequences and the current status of the controversy. I don't have access to the full text but Dr. Wes provides a nice sampling here.

Growing resentment and misery over MOC

Dr. Robert M. Centor, the blog author at DB's Medical Rants, opines on this subject from time to time and did so again yesterday. He has a wide readership and his posts on topics such as this usually generate lively discussion. He talked around some questions in need of elaboration but unfortunately the comments on his site seem to be disabled at present, so I'll weigh in here. He raised the following issues:

Career long learning is essential.
All would agree with that premise, but Dr. Centor didn't address the real rub, which is the question of how best to promote and advance it and whose responsibility it is. Mature professionals realize that they as individuals know best how to direct their learning as opposed to some outsider such as the ABIM. That's inherent in the notion of self assessment. (Note that not even state licensing boards dictate the type of CME content doctors are required to learn).

MOC is not evidence based.
From his post:

These regulations have face validity to the regulators, but practicing physicians just see the time and hassle that each step creates. Regulators want us to practice “evidence-based medicine”, but they do not want to practice “evidence-based assessment”...

The ABMS goes much further than knowledge however. And these activities feel like busy work, and many physicians complain that these activities have no reasonable outcome data to support the hassles involved.

The process is counterproductive.
He wrote:

When the physician community loses faith in the process, then we should reconsider the process. Making physicians angry with the process seems counterproductive.

Dr. Centor is a good listener and feels the pain of the rank and file internist. But what does he plan to do about the situation? As Chair of the Board of Regents for ACP he is positioned to do a great deal. If ACP were to partner with AAPS in their effort it might tip the balance toward a favorable resolution of the struggle.


Meanwhile, as internists grow increasingly miserable the ABIM is digging in, holding fast to its policies and proposing even more hoops for docs to jump through such as this one:

ABIM could require candidates to achieve a perfect score on questions related to costs and redundant care as a requirement for admission to secure exams for initial certification or MOC.

More concerning than the latest requirements from the Board are the general trends. See where things are headed?

Paul Kempen responded here.

American Board of Internal Medicine to all the old farts out there: you're still certified for life---well, sort of

The push back against ABIM's Maintenance of Certification program (MOC) is growing by leaps and bounds. Most of this, as far as I can tell, is coming from docs who certified after 1990 and already had to recertify every 10 years but are now upset over the additional hoops created by ABIM for them to jump through. Missing from most of the discussions is how this affects the older docs who certified before 1990---who were “grandfathered” and told their certification was good for life. I'm afraid some of my older colleagues have slept through what happened. I wasn't aware of it until a few months ago.

So what am I talking about? Well, for the grandfathered internists who choose not to perform the “voluntary” recertification activities the Board is coming as close to de-certifying them as they can without actually taking the certification away and having to say “Sorry. We lied.”

How does it work? It's in the way they report your certification status. Go to their website and look up the name of a grandfathered colleague (this portion of the site is open to the public). Those not participating are designated as Certified but right under that it says Meeting Maintenance of Certification Requirements: No.

What will the public think? What will credentialing bodies think? While this will confuse some people it comes across loud and clear to most as nominally certified but not really certified.

For additional information see here.

Dalbavancin: about to be launched

A Dalvance drug rep will be bringing lunch to a hospital near you, and soon. So you might as well learn a little about it now. Here's a summary at Academic Life in Emergency Medicine. Here's more from Medscape ID.

You can think of dalbavancin as a second generation vanco but there are some unique properties, particularly its pharmacokinetics which enable once weekly dosing.

Dalvance is the first drug to benefit from the FDA's new fast track process for antibiotics. From the FDA bulletin:

Dalvance is the first drug designated as a Qualified Infectious Disease Product (QIDP) to receive FDA approval. Under the Generating Antibiotic Incentives Now (GAIN) title of the FDA Safety and Innovation Act, Dalvance was granted QIDP designation because it is an antibacterial or antifungal human drug intended to treat serious or life-threatening infections.

“Today’s approval demonstrates the FDA’s commitment to encouraging increased development and approval of new antibacterial drugs, providing physicians and patients with important new treatment options,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research.

As part of its QIDP designation, Dalvance was given priority review, which provides an expedited review of the drug’s application. Dalvance’s QIDP designation also qualifies it for an additional five years of marketing exclusivity to be added to certain exclusivity periods already provided by the Food, Drug and Cosmetic Act.

Here are a few of my questions and concerns:

There was a mild signal of liver toxicity in clinical trials.

It will probably be very expensive.

Given the many options for gram positive infections that we already have exactly where will this drug fit in?

The drug's approval is narrow in scope. What off label uses might be appropriate as we gain more experience?

Many patients with skin infections do not need MRSA coverage at all. That's a matter for clinical judgment.

I don't anticipate heavy usage of this drug. It's one more option, which is great.

The concluding comments of the Academic Life in Emergency Medicine post came across to me as a little hard line:

Even if the company adjusts the price to less than $100 per dose, hospital antimicrobial stewardship programs need to rationalize and limit the use of this new antibiotic for cases when cheaper non-inferior treatments have failed.

Rationalize? How rational is it to wait for treatment failure before considering another option that might be better for the patient? He goes on:

Advertisers’ persuasion of better compliance for “high-risk patients,” convenience, and non-inferiority, are not enough to challenge the standard care of SSTIs in the ED.

Not enough to even challenge standard care? It seems to me that the convenience advantage is pretty substantial. This is an illustration of the difference between two approaches to medicine: medicine by committee and evidence based medicine (EBM). The author of the post is advocating medicine by committee. It's incompatible with EBM because it proscribes two of EBM's essential components in decision making about whether to use dalbavancin: the individual patient's unique attributes, preferences and values and the judgment and expertise of the treating clinician.

Vancomycin, Zosyn and nephrotoxicity: should we be worried?

I hope readers will understand my using the name Zosyn instead of the more clunky piperacillin/tazobactam. I think the term “gone viral” well describes this concern. That is, the notion of the “nephrotoxic toxic vanc/zosyn combo” is spreading like wildfire (on the wards, via email, etc) though not so much through “official” media. It wasn't even mentioned in the nephrology or ID talks at the recent Society of Hospital Medicine national meeting. It's been difficult to find good information. But Academic Life in Emergency Medicine recently posted a topic review. As usual they did a great job. Their bottom line:

While there is no definitive link between pip-tazo and risk of AKI, there have been 5 different groups, with internal medicine and ICU patients, showing a possible association. To me, this adds one more reason to at least think twice about reflexively ordering pip-tazo for every sick patient.

In other words the evidence favoring the nephrotoxic association is low level but more and more is coming in in bits and pieces, adding to the concerns.

What I get tentatively from the available data, and this is just a hunch:

Vancomycin as nephrotoxic all by itself is a difficult sell for me. Maybe in patients who experience very high trough levels, but I don't know.

Zosyn as monotherapy appears to have nephrotoxic potential.

Vancomycin seems to potentiate the nephrotoxicity of Zosyn.

Antidotes for target specific oral anticoagulants: coming soon

Currently available options for reversal of TSOACs are limited. However, specific antidotes are in the pipeline and were the subject of this recent review.

They include:

PRT064445 (Portola Pharmaceuticals)

A recombinant Xa variant. Reverses anti Xa agents.


aDabi-Fab (Boehringer Ingelheim)

A humanized Fab fragment for reversal of dabigatran.


PER977 (Perosphere Inc and Daiichi Sankyo)

A small synthetic molecule which is a broad spectrum antidote, binding TSOACs, fondaparinux and low–molecular-weight heparins.

Update on the Surviving Sepsis Guidelines

This recent article in the Annals of Emergency Medicine is nothing new, and it is already a little out of date because it does not acknowledge the recent process trial results. But I have linked it here because it has a table that nicely compares and contrasts the current guidelines with the 2008 guidelines.

Vancomycin dosing: the right way and the wrong way

Current guidelines for MRSA targeted vanc dosing have been around for a while now and should be pretty familiar but inappropriate dosing is still a problem. “Hang a gram and call it a day” all too often prevails. This was the topic of an update at Academic Life in Emergency Medicine recently.

TPA for acute ishcemic stroke: trends in usage

From the Get with the Guideline-Stroke database:

Methods and Results—We analyzed all AIS patients (n=1 9093 895) and those arriving less than or equal to 2 hours and treated with tPA less than or equal to 3 hours after onset (n=50 798) from 2003 to 2011 in the American Heart Association’s Get with the Guideline–Stroke (GWTG–Stroke). Categorical data were analyzed by Pearson χ2 and continuous data by Wilcoxon test. Intravenous tPA use less than or equal to 3 hours after onset increased from 4.0% to 7.0% in all AIS admissions and 42.6% to 77.0% in AIS patients arriving less than or equal to 2 hours and fully eligible for tPA (P less than 0.001). In univariate analysis, tPA use increased over time, especially in those aged greater than 85 years, nonwhite, and with milder strokes (National Institutes of Health Stroke Scale 0–4). Door-to-image time (median 24 versus 20 minutes) and door-to-tPA time (median 81 versus 72 minutes) also improved, with ≈65% of tPA-treated patients getting brain imaging less than or equal to 25 minutes after arrival. Multivariable analysis showed that with each additional calendar year, the odds that an eligible patient would receive tPA increased by 1.37-fold, adjusting for other covariates.

Slow uptake. In 2003, eight years post NINDS, only 42.6% of eligible patients were treated. By 2011, sixteen years post NINDS, it's up to 77%. If you present to an ER eligible for TPA, with each passing year your odds of getting treated increase 37%.

Thrombolysis for ischemic stroke has an interesting history. Its slow uptake in clinical practice is due in part to a massive and highly organized push-back from the discipline of emergency medicine. Maybe that's not entirely a bad thing. Contrast it with those treatments that were rushed to widespread implementation after a single clinical trial only to suffer a reversal.

RSV can cause severe disease in adults

Particularly the elderly according to this paper:

Methods. A retrospective cohort study was conducted on all adults (greater than or equal to 18 years) admitted to 3 acute care general hospitals in Hong Kong with virologically confirmed RSV infection during 2009–2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547)...

Results. The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively. Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival. Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza.

Conclusions. RSV can cause severe lower respiratory complications in older adults, resulting in respiratory failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly addressed.

Prehypertension is a risk factor

From a recent meta-analysis:

Methods

Databases (PubMed, EMBASE and the Cochrane Library) and conference proceedings were searched for prospective cohort studies with data on prehypertension and cardiovascular morbidity. Two independent reviewers assessed the reports and extracted data. The relative risks (RRs) of CVD, coronary heart disease (CHD) and stroke morbidity were calculated and reported with 95% confidence intervals (95% CIs). Subgroup analyses were conducted on blood pressure, age, gender, ethnicity, follow-up duration, number of participants and study quality.

Results

Pooled data included the results from 468,561 participants from 18 prospective cohort studies. Prehypertension elevated the risks of CVD (RR = 1.55; 95% CI = 1.41 to 1.71); CHD (RR = 1.50; 95% CI = 1.30 to 1.74); and stroke (RR = 1.71; 95% CI = 1.55 to 1.89). In the subgroup analyses, even for low-range prehypertension, the risk of CVD was significantly higher than for optimal BP (RR = 1.46, 95% CI = 1.32 to 1.62), and further increased with high-range prehypertension (RR = 1.80, 95% CI = 1.41 to 2.31). The relative risk was significantly higher in the high-range prehypertensive populations than in the low-range populations (χ2= 5.69, P = 0.02). There were no significant differences among the other subgroup analyses (P less than 0.05).

Conclusions

Prehypertension, even in the low range, elevates the risk of CVD after adjusting for multiple cardiovascular risk factors.

Of particular interest, results of the analysis of low end versus high end prehypertension supports the long held view that a continuum of risk exists over a wide range of blood pressure extending down to levels many would consider “normal.” Although treatment implications are unknown accumulating evidence will no doubt expand the range of identified risk.

Related commentary here.

Subsegmental PEs: How important are they?

CT pulmonary angiography has opened up a can of worms. Although less sensitive than VQ scanning for clinically significant pulmonary emboli (based on the findings of PIOPED I & II) it often detects isolated subsegmental filling defects which do not correlate with clinical findings. In such a setting, according to the results of PIOPED II, the positive predictive value of CTPA is poor. This might occur if a peripheral filling defect is found as an “incidentaloma” when chest CT is done for some other reason or, more likely, when done indiscriminately following an inadequate pretest clinical assessment. In either case it's often a false positive.

This has led to criticism of the overuse of CTA and questions regarding the significance of peripheral filling defects when the findings don't fit the clinical picture (see here and here).

It doesn't mean, however, that subsegmental defects are never important. What if the clinical findings do suggest PE? A recent study was cited by the bloggers at Academic Life in Emergency Medicine. From the paper (SSPE stands for subsegmental PE):

We analyzed 3728 consecutive patients with clinically suspected PE. SSPE patients were contrasted to patients with more proximal PE and to patients in whom suspected PE was ruled out, in regards of the prevalence of thromboembolic risk factors and the 3-month risks of recurrent venous thromboembolism (VTE) and mortality. PE was confirmed in 748 patients, of whom 116 (16%) had SSPE; PE was ruled out in 2980 patients. No differences were seen in the prevalence of VTE risk factors, the 3-month risk of recurrent VTE (3.6% vs 2.5%; P = .42), and mortality (10.7% vs 6.5%; P = .17) between patients with SSPE and those with more proximal PE. When compared with patients without PE, aged greater than 60 years, recent surgery, estrogen use, and male gender were found to be independent predictors for SSPE, and patients with SSPE were at an increased risk of VTE during follow-up (hazard ratio: 3.8; 95% CI: 1.3-11.1). This study indicates that patients with SSPE mimic those with more proximally located PE in regards to their risk profile and clinical outcome.

The key phrase in the above abstract is clinically suspected PE. If the peripheral filling defect fits the clinical picture it matters. If it doesn't fit, or is an incidentaloma, it's a different ballgame.

This paper raises broader questions about whether PE anatomy as assessed by CTA (i.e. clot burden, location) matters at all. Certainly we know from prior studies that hemodynamic findings and physiologic data (RV function, biomarkers) mean more than anatomy. A study from 2012 in Chest, for example, found no correlation between overall anatomic clot burden and clinical outcome. It did, however, in contrast to the Blood paper referenced above, find a correlation (though barely statistically significant) between location (proximal versus distal) and clinical outcome in the subset of hemodynamically stable patients (not in the overall cohort). More discussion on that paper can be found at PulmCCM.

Metformin associated lactic acidosis: what hospitalists need to know

Phenformin, an older generation biguanide and metformin's precursor, was in its last days on the pharmaceutical market during my training. It had caused hundreds, maybe even thousands of deaths from lactic acidosis before the FDA finally yanked it in 1978. In an unprecedented move the HEW secretary declared phenformin an “imminent hazard to the public health.”

So, naturally, when metformin was launched 17 years later, despite a purported lower incidence of lactic acidosis, its clinical use was approached with great caution and vigilance. Over time in the post marketing experience, in contrast to that observed with many other drugs, these cautions were relaxed as metformin proved to be a much safer and more forgiving drug than its predecessor.

Just how great, then, is the threat of lactic acidosis with metformin? That was the question of a recent study. Metformin associated lactic acidosis is very uncommon but can occur when metformin accumulates and is highly fatal. From the study:

All cases of lactic acidosis (pH, less than or equal to 7.35; arterial lactate, greater than or equal to 5 mmol/L) related to metformin accumulation (plasma level greater than or equal to 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. Results. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p less than 0.0001, R = - 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases)... 

Conclusions. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission.

There was an accompanying editorial which, according to a post at The Poison Review, contains a lot of pearls. Unfortunately I am unable to access the full text but the Poison Review post lists a few of them:

Evaluate patients started (or continued) on metformin for contraindications to the drug.

Screen patients on metformin who present with a gastroenteritis-type syndrome or other conditions that predispose to dehydration for metabolic acidosis (my feeling is that an initial blood gas would be unnecessary since checking the electrolytes and anion gap should suffice).

Consider early hemodialysis in patients presenting with MALA — this would both help remove the drug and correct severe acidosis.

Add metformin toxicity to the differential diagnosis in appropriate patients suspected of having sepsis, mesenteric ischemia, or respiratory failure.

Know that metformin-induced metabolic acidosis does indeed exist, and that these patients are typically extremely ill.

Realize that with proper care these patients can survive, even if they’ve presented with amazingly low pH readings.

STEMI versus NSTEMI: misunderstood, misapplied, revisited

I have written a number of posts about the binary distinction of “STEMI versus NSTEMI” for acute coronary syndrome. In those posts I have cited many examples of unintended consequences of this terminology and developed the premise that it's an artificial distinction which is often misapplied. Despite some push back and numerous questions I stand by the premise. The idea is not original with me. It was this paper from a fewyears ago, which I have cited several times since, that first alerted me to the problem.

My last post on this topic, judging form a nice Facebook avalanche I received, garnered some attention. Now might be a good time to revisit the issue.

If the question stirs debate in some minds perhaps there are a few basic problems with “STEMI/NSTEMI” we can at least agree about as starting points:

The terms STEMI and NSTEMI are simple surrogates to denote complex pathologic processes.

Flaws are inherent in the simplistic use of surrogates even though they can be clinically useful at times.

STEMI and NSTEMI are descriptive terms which lead to diagnosis based on simple pattern recognition.

Diagnosis by pattern recognition tends to ignore complexities of electrophysiology which are clinically important.

While electrocardiographic patterns can provide powerful clues they do not equate to pathologic processes in simple fashion.

The late J. Willis Hurst, master clinician and teacher of electrocardiography, published many articles on the subject. In this one from the American Journal of Cardiology he offered several suggestions for addressing the problem. One was that the electrocardiographic interpretation should not stop with pattern description but go on to include a list (differential diagnosis) of conditions associated with the pattern.

STEMI is a surrogate for acute coronary occlusion. But when the above exercise in differential diagnosis is carried out acute coronary occlusion will appear in the interpretation of many NSTEMI electrocardiograms. This was illustrated in a post from a couple of years ago at Dr. Smith's ECG blog.

Here are some of the points he made in that post:

STEMI and NonSTEMI are arbitrary terms that may confuse the clinician.

"STEMI" should mean "coronary occlusion" (or near occlusion, without good collateral circulation -- in other words, it needs thrombolytics or emergent angiogram with PCI).

NonSTEMI should mean "MI without occlusion."

"STEMI-equivalent" is a good term for "coronary occlusion".

Many STEMI-equivalents have no significant ST elevation, as you may have seen from many of my posts.

In some STEMI-equivalents (posterior STEMI, lateral STEMI, posterolateral STEMI), ST depression is the only, or most visible, feature of the ECG.

These are points I have made many times before, often via citation from Dr. Smith's posts. The difficulty lies in the fact that when using the electrocardiogram for emergency decision making we need something simple that we can use at a glance. The unfortunate reality is that in today's performance driven world we've made STEMI/NSTEMI too simple.

Z-drugs, cognition and driving

The Z-drugs are the newer generation hypnotics zolpidem, zopiclone, and zaleplon. These drugs are increasingly reported to impair cognition and driving. The main safety consideration is time from ingestion. From a recent review:

Z-drugs are short-acting GABA agonists that reduce sleep latency without disturbing sleep architecture. Bizarre behavioral effects have prompted warnings on the prescription, dispensation, and use of Z-drugs. Psychomotor impairment, falls, and hip fractures are more likely to occur with Z-drugs that have longer half-lives, that are taken at higher-than-recommended doses and when mixed with other psychoactive substances including alcohol. Zopiclone and higher doses of zolpidem are more likely to cause anterograde amnesia than zaleplon. Z-drugs, especially zolpidem, are associated with complex behaviors such as sleepwalking, sleep-driving, and hallucinations. Patients taking zopiclone and zolpidem have an increased risk of motor vehicle collisions, over double that of unexposed drivers. Driving impairment occurs with zopiclone and higher doses of zolpidem but is unlikely to occur after 4 h post-zaleplon administration. The residual effect of Z-drugs on next-day cognitive and psychomotor performance has significant impact on lifestyle, safety, and occupational considerations, including motor vehicle and machine operation. The risk–benefit analysis of Z-drugs in the treatment of insomnia, particularly in the elderly, may not favor treatment due to the increased risks of falls and motor vehicle collisions.

Avoiding IV contrast hazards: facts, myths, FAQs

Here's a great podcast andaccompanying notes from ercast. For further reading here's the American College of Radiology's Manual on Contrast Media. TMI for a quick read but a useful reference to have.

New evidence on IVC filters: low level but compelling

From a recent large database of patients with unstable PE:

Results
Among 21,095 unstable patients with pulmonary embolism who received thrombolytic therapy, in-hospital all-cause case fatality rate was lower in every age group who received a vena cava filter in addition to thrombolytic therapy (P = .0012 to less than .0001). Patients aged greater than or equal to 81 years showed the greatest absolute reduction of case fatality rate with filters (19.3%). Among 50,210 unstable patients who did not receive thrombolytic therapy, case fatality rate also was lower in every age group who received a vena cava filter (all P less than .0001). Patients aged greater than or equal to 81 years with vena cava filters showed the greatest absolute risk reduction of case fatality rate (27.7%).

Conclusion
Vena cava filters are associated with a reduced in-hospital all-cause case fatality rate in unstable adults with pulmonary embolism, irrespective of age.

This use of IVC filters is common and there is wide practice variation. It is not considered strictly evidence based, the only clearly recognized indication being a patient with acute proximal DVT and an absolute contraindication to systemic anticoagulation. The evidence quality of the findings presented above is low but at least suggests that many of the clinicians appearing to practice non-evidence based medicine (by filling in for non-evidence with clinical judgment) were right all along.

May-Thurner syndrome

Here is a case report and brief topic discussion from the SHM 2014 abstract presentations. This condition is easily overlooked but its diagnosis has treatment implications. From the abstract:

May-Thurner syndrome is due to significant compression of left common iliac vein between right common iliac artery & lumbar vertebral body. It’s clinical prevalence is 2-3% of all lower extremity DVT’s and it results in intimal hyperplasia causing anatomical obstruction & stasis. It is commonly seen in women between the ages of 20-50... 

Although May-Thurner syndrome is a rare cause of DVT, it can cause recurrent episodes of DVT, PE, Chronic venous insufficiency & life threatening thrombosis. Clinicians should look for May-Thurner syndrome in young women between ages 20- 50 (even though they are on OC pills) who present with extensive Left leg DVT as Catheter directed thrombolysis, angioplasty & stenting can cure the condition.

Hospitalization increases the risk of gout attacks

In this study.

Intravenous interferon-beta-1a (FP-1201): promising pharmacotherapy for ARDS?

From the Lancet RespiratoryMedicine:

Pulmonary vascular leakage occurs early in acute respiratory distress syndrome (ARDS). Mortality is high (35–45%), but no eff ective pharmacotherapy exists. Production of anti-infl ammatory adenosine by ecto-5ȸ-nucleotidase (CD73) helps maintain endothelial barrier function. We tested whether interferon-beta-1a (IFN-beta-1a), which increases CD73 synthesis, can reduce vascular leakage and mortality in patients with ARDS...

We then tested the safety, tolerability, and effi cacy of intravenous human recombinant IFN- beta-1a (FP-1201) in patients with ARDS in an open-label study (comprising dose-escalation and expansion phases). We recruited patients from eight intensive care units in the UK. Eligible patients were aged 18 years or older, had ARDS, and were being treated with assisted ventilation. We established an optimal tolerated dose (OTD) in the first, dose-escalation phase. Once established, we gave all subsequently enrolled patients the OTD of intravenous FP-1201 for 6 days...

By day 28, 3 (8%) of 37 patients in the treatment cohort and 19 (32%) of 59 patients in the control cohort had died—thus, treatment with FP-1201 was associated with an 81% reduction in odds of 28-day mortality (odds ratio 0·19 [95% CI 0·03–0·72]; p=0·01).

It's only a phase II trial and it looks too good to be true. If it is confirmed in high level studies it will be a breakthrough in the treatment of ARDS.

Via Respiratory Therapy Cave.

Hepatic hydrothorax, spontaneous bacterial empyema and the contraindicated chest tube

Here is a case presentation from the SHM 2014 abstract collection which serves as a reminder that chest tube drainage is contraindicated in hepatic hydrothorax even if the fluid is infected.

The choosing wisely list in allergy and immunology

Here it is.

A sampling:

Don’t routinely do diagnostic testing in patients with chronic urticaria.
In the overwhelming majority of patients with chronic urticaria, a definite etiology is not identified. Limited laboratory testing may be warranted to exclude underlying causes. Targeted laboratory testing based on clinical suspicion is appropriate. Routine extensive testing is neither cost effective nor associated with improved clinical outcomes. Skin or serum-specific IgE testing for inhalants or foods is not indicated, unless there is a clear history implicating an allergen as a provoking or perpetuating factor for urticaria.

Don’t recommend replacement immunoglobulin therapy for recurrent infections unless impaired antibody responses to vaccines are demonstrated.
Immunoglobulin (gammaglobulin) replacement is expensive and does not improve outcomes unless there is impairment of antigen-specific IgG antibody responses to vaccine immunizations or natural infections. Low levels of immunoglobulins (isotypes or subclasses), without impaired antigen-specific IgG antibody responses, do not indicate a need for immunoglobulin replacement therapy. Exceptions include IgG levels less than 150mg/dl and genetically defined/suspected disorders. Measurement of IgG subclasses is not routinely useful in determining the need for immunoglobulin therapy. Selective IgA deficiency is not an indication for administration of immunoglobulin.

Don’t diagnose or manage asthma without spirometry.
Clinicians often rely solely upon symptoms when diagnosing and managing asthma, but these symptoms may be misleading and be from alternate causes. Therefore spirometry is essential to confirm the diagnosis in those patients who can perform this procedure. Recent guidelines highlight spirometry’s value in stratifying disease severity and monitoring control. History and physical exam alone may over- or under-estimate asthma control...

Don’t rely on antihistamines as first-line treatment in severe allergic reactions.
..By definition, anaphylaxis has cardiovascular and respiratory manifestations, which require treatment with epinephrine. Overuse of antihistamines, which do not treat cardiovascular or respiratory manifestations of anaphylaxis, can delay the effective first-line treatment with epinephrine. 

Epinephrine should be administered as soon as the diagnosis of anaphylaxis is suspected. Antihistamines are second-line supportive therapy for cutaneous non-life-threatening symptoms (hives), but do not replace epinephrine as the first-line treatment for anaphylaxis.

Don’t routinely order low- or iso-osmolar radiocontrast media or pretreat with corticosteroids and antihistamines for patients with a history of seafood allergy, who require radiocontrast media.
Although the exact mechanism for contrast media reactions is unknown, there is no cause and effect connection with seafood allergy. Consequently there is no reason to use more expensive agents or pre-medication before using contrast media in patients with a history of seafood allergy. A prior history of anaphylaxis to contrast media is an indication to use low- or iso-osmolar agents and pretreat with corticosteroids and antihistamines.

Patients with a history of seafood allergy are not at elevated risk for anaphylaxis from iodinated contrast media. Similarly, patients who have had anaphylaxis from contrast media should not be told that they are allergic to seafood...

The mechanism for anaphylaxis to radio-iodinated contrast media relates to the physiochemical properties of these media and is unrelated to its iodine content. Further, although delayed-type hypersensitivity (allergic contact dermatitis) reactions to iodine have rarely been reported, IgE-mediated reactions to iodine have not, and neither type of reaction would be related to IgE-mediated shellfish allergy nor to contrast media reactions. Patients with a history of prior anaphylaxis to contrast media are at elevated risk for anaphylactic reaction with re-exposure to contrast media.

Patients with asthma or cardiovascular disease, or who are taking beta blockers, are at increased risk for serious anaphylaxis from radiographic contrast media.

Don’t routinely avoid influenza vaccination in egg-allergic patients.
Of the vaccines that may contain egg protein (measles, mumps, rabies, influenza and yellow fever), measles, mumps and rabies vaccines have at most negligible egg protein; consequently no special precautions need to be followed in egg-allergic patients for these vaccines. Studies in egg-allergic patients receiving egg-based inactivated influenza vaccine have not reported reactions; consequently egg-allergic patients should be given either egg-free influenza vaccine or should receive egg-based influenza vaccine with a 30-minute post-vaccine observation period. Egg-allergic patients receiving the yellow fever vaccine should be skin tested with the vaccine and receive the vaccine with a 30-minute observation period if the skin test is negative. If positive, the vaccine may be given in graded doses with appropriate medical observation.

Egg protein is present in influenza and yellow fever vaccines and in theory could cause reactions in egg-allergic patients. However, in 27 published studies collectively 4,172 patients with egg allergy received 4,729 doses of egg-based inactivated influenza vaccine (IIV) with no cases of anaphylaxis, including 513 with severe egg allergy who uneventfully received 597 doses. The CDC’s Advisory Committee on Immunization Practices recommends that egg-allergic persons receive IIV as a single dose without prior vaccine skin testing and be observed for 30 minutes afterwards for any possible allergic reaction. If the reaction to the ingestion of eggs was hives only, the vaccine can be administered in a primary care setting, whereas if the reaction to the ingestion of eggs was more severe, the vaccine should be administered in an allergist/immunologist’s office. Two new IIVs not grown in eggs have been approved for patients 18 years and older: Flucelvax, prepared from virus propagated in cell culture, and Flublok, recombinant hemagglutinin proteins produced in an insect cell line. For egg-allergic patients 18 years of age and older, either egg-based IIV can be used with the precautions above or egg-free IIV can be used.

Vocal cord dysfunction versus asthma

Here’s an article about the Pittsburgh Vocal Cord Dysfunction Index.

From the paper:

RESULTS: We identified symptoms of throat tightness and dysphonia, the absence of wheezing, and the presence of odors as a symptom trigger as key features of vocal cord dysfunction that distinguish it from asthma.

The tool needs further validation.

Via Hospital Medicine Virtual Journal Club.

ET CO2 to help exclude PE?

Now that’s an interesting idea. It looks like it could come in handy. From a recent study:

...consecutive patients with suspected pulmonary embolisms (PEs) were enrolled over 6 months in 2012. Symptoms, demographic date, Wells’ score, D-dimer levels and the gold standard computed tomography pulmonary angiogram (CTPA) results were collated for analysis. ETCO2 was measured within 24 hours of presentation in all 100 patients. Patient ages ranged from 18 years to 93 years. PE was diagnosed in 38% of cases…All patients positive for a PE obtained an ETCO2 less than 4.3 kPa (32.3 mmHg). This point (4.3 kPa) had a sensitivity and specificity (100% and 68% respectively), with a negative predictive value of 100% and positive predictive value of 66%. ETCO2 may reliably be used to screen and exclude patients with suspected PEs.

Via Hospital Medicine Virtual Journal Club.

Airway pressure release ventilation (APRV)

There's a nice rundown on APRV over at Resus Review.

A few important things to keep in mind about APRV:

Its main use is hypoxemic respiratory failure, typically ARDS.

Its purported advantages which include preserving spontaneous breathing and the ability to recruit alveoli without lung overdistention or adverse hemodynamics are physiologically appealing but supported only by low level data.

Though gaining in popularity its role is not well established and it is generally relegated to a rescue modality, to be used when conventional methods are not working.

Autopeep is intentional but ventilation is on a lower portion of the compliance curve than with conventional ventilation.

If some parts of the above linked post are difficult to understand it may be helpful to read the review published in CCJM which I linked in this post.

Antibiotic stewardship recommendations from the CDC

This summary of the recommendations was published as free access in JAMA. The recommendations focus on, among other things, over diagnosis of common indications for antibiotic therapy, e.g. UTI and pneumonia.

Neurology pearls and tips: altered mental status

This post is derived from talks given by Dr. S. Andrew Josephson, neurohospitalist at UCSF, at the 2014 SHM national meeting (neurology pre-course). The material overlaps with a talk he also gave at UCSF's 17th annual hospital medicine conference about which I posted here. Dr. Josephson wrote the section on delirium in the latest edition of Harrison's. It is well worth the read for those who want to dive deeper on this topic.

Delirium: definitions, diagnosis

Delirium is defined, and distinguished from dementia, in terms of both its acuity (hours to days) and the specific dimension of cognition that is impaired, principally attention though just about any domain can be affected.

Delirium is thus, in a sense, an acute ADD and best tested by an attention maneuver, e.g. repeating digits forward. Less than 5 (the average person can do 7) indicates an attention deficit and therefore suggests delirium.

Demented patients who are not delirious can pass this test. Put another way, demented patients can be assessed for delirium. On the other hand, testing for dementia (via a tool such as the MMSE) may not be possible in delirious patients due to the prevailing attention deficit.

Confusion of these categories may result if the patient has Lewy body dementia since that condition is characterized by acute fluctuations in cognition, as part of the disorder itself, as well as visual hallucinations and periods of agitation. Additional references on that topic can be found here. [1] [2]

The relationship between delirium and dementia

 While the two disorders are defined separately there is some overlap and many patients have both. Though severe sepsis, intoxications and metabolic disturbances can produce delirium in a young person with a previously healthy brain, in some cases dementia or a previously asymptomatic early neurodegenerative process is the underlying substrate which makes the patient susceptible. In such instances delirium can be considered a failed stress test in an aging brain. Delirium triggers in these patients, who tend to be elderly, are milder and include drugs and infections. Anticholinergics top the list of offending drugs in the elderly. Infections are more often than not outside the CNS but, adds Dr. Josephson, you should have a low threshold for doing an LP if the patient's mental status does not improve promptly with treatment. (As an aside, an abnormal urinalysis without fever or localizing symptoms is a common weak explanation for altered mental status and a often a pretext for inappropriate use of antibiotics).

Treatment of delirium

You are far more likely to be called for agitated delirium than for non-agitated delirium and when you are called the first request, likely as not will be for pharmacologic treatment, or “something to calm the patient down.” While drugs are sometimes indicated that's the least favored option and belongs at the bottom of the list.

Treatment or removal of the underlying precipitant is the most important component. The second modality is management of the patient's environment by verbal reorientation, family visits, elimination of unnecessary lines and catheters, etc. (Believe it or not, those non-pharmacologic measures are effective). Drug therapy is sometimes necessary but it's a last resort and the wise clinician approaches it with hesitation. (Unique exceptions, appropriately treated with benzodiazepines, are alcohol or sedative withdrawal and stimulant toxidromes).

So what if you have to resort to drugs? There are a few caveats. First, benzos are generally to be avoided as they will convert agitated delirium into a non-agitated delirium (which may be worse) and ultimately prolong its duration. As stated above alcohol withdrawal and a few related conditions for which benzos are first choice are the exceptions. Antipsychotics (major tranquilizers) represent the only remaining alternatives in the pharmacopoeia. They are generally regarded as the drugs of first choice but there is no evidence that they improve ultimate outcomes. They are associated with cardiac risks and are contraindicated in dementia with Lewy bodies (DLB), in which case they can produce autonomic instability, a worsened alteration of mental status and a rigid state which may not be reversible. (There are a couple of antipsychotics in the atypical class, eg quetiapine, which may be permissible in very low doses).

Those are some sobering facts and represent a lot of stuff to sort through on a busy call night when you are being pressured to prescribe something to calm the patient down!

Things you might not think of

HSV-1 meningoencephalitis may have nonspecific manifestations and be associated with negative test results initially so consider early empiric treatment.

Seizure related altered mental status (either due to a prolonged post-ictal state or non-convulsive status) tends to be under recognized and can only be diagnosed with EEG.

Wernicke's encephalopathy (WE), due to its changing epidemiology (no longer primarily a disorder of alcoholics) is likely to be under recognized. Dr. Josephson recommends thiamine 100 mg IV be administered to nearly all altered patients. If WE is established or strongly suspected clinically very high doses of thiamine such as500 mg IV tid may be more appropriate. For more on thiamine deficiency and WE see this post.

What about using procholinergic drugs?

It is known that the brains of patients with dementia are deficient in acetylcholine. Also, delirium is known to be precipitated by anticholinergic agents. So why not give the delirious patient a dose of Aricept, for example? The idea has been studied. According to Dr. Josephson's chapter in Harrison's, however, clinical trials have yielded mixed results so it's not ready for prime time. I mention it here because it is an appealing idea which will undoubtedly be the subject of future research.

Rhabdomyolysis: what the hospitalist needs to know

These are some of the take home points from a recent review.


The causes are diverse

In addition to the originally described physical injuries there is a long list of other causes:

Prolonged down time
Numerous endocrine and metabolic disorders
Infections
Seizures, agitation
Hyperthermia syndromes (NMS, heat stroke, etc. The review fails to mention serotonin syndrome).
And many others


The list of causative drugs is long

Usually we think of recreational drugs, alcohol, statins, daptomycin and psych drugs but there are many more.


How do you diagnose it?

The diagnosis is based on clinical circumstances and an elevated CK level. Urine myoglobin may be unhelpful, as it is a “send out” test in many hospitals. A positive urine dipstick for heme with few or no RBCs on microscopic is a clue to the presence of myoglobin.


What level of CK elevation puts the patient at risk for AKI?

From the review:

The CK level for clinical concern is uncertain; an arbitrary value of 500 to 1,000 IU/L, or five to 10 times the upper limit of normal is frequently used to define rhabdomyolysis. Higher CK levels correlate with a greater degree of muscle injury, but levels correlate marginally with the development of AKI or mortality.3,4,6,40-43 A reasonable consensus recommendation suggests close monitoring of renal function in patients with CK levels greater than 5,000 IU/L and creatinine greater than 1.5 mg/dL.44 Some studies suggest that patients with CK levels less than 5,000 IU/L are not at risk of developing AKI42,44; otherwise, it is difficult to use the magnitude of the CK value to estimate the risk of kidney injury. Serial CK measurements should be monitored; increasing levels, or failure of levels to decline despite therapy, suggest ongoing muscle injury or the development of renal failure.

Treatment: don't forget the basics

Remove/correct the underlying cause.
Monitor and address complications (electrolyte disturbances, compartment syndrome).
Involve nephrology early.


What volume of resuscitation fluid?

From the review:

IVF should be administered rapidly as an initial bolus...

Large amounts of IVF within the first 24 h are associated with improved outcomes.1 No specific rate of infusion or target urine output has been demonstrated to be superior to another. For the first 24 h after presentation, as little as 3 L to as much as 24 L have been administered effectively. A target of 6 to 12 L within 24 h is a reasonable goal, as long as complications from volume overload can be avoided.

What type of resuscitation fluid?

It has been debated whether normal saline or Ringers lactate is better but there is no high quality evidence to suggest one over the other.


What about bicarb and urinary alkalinization?

This approach has been suggested in some publications but high quality evidence in support of it is lacking.


Is there a role for diuretics (loop or mannitol)?

The review mentions the option of using loop diuretics to maintain urine flow but, absent high quality evidence, makes no strong recommendation.

Resuscitation fluid: which and how much

One old and a few emerging debates dominate this field. A recent NEJM review helps provide clarity.


The old debate: colloid versus crystalloid

With few exceptions there's no good evidence that one is better than the other (except that starch is bad). That situation has not changed during my entire career.


New debate: is saline bad (should we be using some other crystalloid?)

From the review:

The strong ion difference of 0.9% saline is zero, with the result that the administration of large volumes of saline results in a hyperchloremic metabolic acidosis.36 Adverse effects such as immune37 and renal38 dysfunction have been attributed to this phenomenon, although the clinical consequences of these effects is unclear.39

This has led to renewed interest in so called “balanced” crystalloids, and low level evidence suggests they may be better. The review cites a couple of low level studies in which alternative crystalloids were associated with better outcomes but points out that there may be unintended consequences to such an approach:

Crystalloids with a chemical composition that approximates extracellular fluid have been termed “balanced” or “physiologic” solutions and are derivatives of the original Hartmann's and Ringer's solutions. However, none of the proprietary solutions are either truly balanced or physiologic41 (Table 1).

Balanced salt solutions are relatively hypotonic because they have a lower sodium concentration than extracellular fluid. Because of the instability of bicarbonate-containing solutions in plastic containers, alternative anions, such as lactate, acetate, gluconate, and malate, have been used. Excessive administration of balanced salt solutions may result in hyperlactatemia, metabolic alkalosis, and hypotonicity (with compounded sodium lactate) and cardiotoxicity (with acetate). The addition of calcium in some solutions may generate microthrombi with citrate-containing red-cell transfusions.

High level randomized trials are needed.

New debate: how much? Is less more?

Most would agree that aggressive resuscitation is warranted on the front end but it is increasingly apparent that cumulative positive fluid balance over days is associated with microcirculatory and organ congestion and all the consequences associated therewith.


So what should we do?

Until we get some high level clinical trials we have clinical judgment informed by low level data and physiologic rationale along with a few suggestions form the experts. The authors didn't make any strong statements but offered some things to think about:

Consider alternative crystalloids in some patients (this essentially means Ringer's lactate). Like one's choice of pressors, the decision will be based on patient attributes and therapeutic objectives.

Front load then back off.

Consider special situations (e.g. brain injury).

Shingles vaccine

Here (via the Clinical Correlations blog) is a nice summary of the evidence supporting the vaccine along with a discussion of the slow uptake in clinical practice.