H7N9 influenza: are we close to a pandemic?

According to this analysis in BMC Medicine the human-to-human transmission efficiency is below the threshold. A decline in the growth of cases has followed closure of live bird markets.  

Combining esmolol and nor epi in septic shock?

Recently published in JAMA:

Importance  β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects...

Results  Targeted heart rates were achieved in all patients in the esmolol group compared with those in the control group. The median AUC for heart rate during the first 96 hours was −28/min (IQR, −37 to −21) for the esmolol group vs −6/min (95% CI, −14 to 0) for the control group with a mean reduction of 18/min (P less than .001). For stroke volume index, the median AUC for esmolol was 4 mL/m2 (IQR, −1 to 10) vs 1 mL/m2 for the control group (IQR, −3 to 5; P = .02), whereas the left ventricular stroke work index for esmolol was 3 mL/m2 (IQR, 0 to 8) vs 1 mL/m2 for the control group (IQR, −2 to 5; P = .03). For arterial lactatemia, median AUC for esmolol was −0.1 mmol/L (IQR, −0.6 to 0.2) vs 0.1 mmol/L for the control group (IQR, −0.3 for 0.6; P = .007); for norepinephrine, −0.11 μg/kg/min (IQR, −0.46 to 0.02) for the esmolol group vs −0.01 μg/kg/min (IQR, −0.2 to 0.44) for the control group (P = .003). Fluid requirements were reduced in the esmolol group: median AUC was 3975 mL/24 h (IQR, 3663 to 4200) vs 4425 mL/24 h(IQR, 4038 to 4775) for the control group (P less than .001). We found no clinically relevant differences between groups in other cardiopulmonary variables nor in rescue therapy requirements. Twenty-eight day mortality was 49.4% in the esmolol group vs 80.5% in the control group (adjusted hazard ratio, 0.39; 95% CI, 0.26 to 0.59; P less than .001).

Conclusions and Relevance For patients in septic shock, open-label use of esmolol vs standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. The observed improvement in mortality and other secondary clinical outcomes warrants further investigation.

This is very promising but I'm not ready to try it at home, just yet. Yes, it does warrant further study.

More discussion at Medpage Today.

Beverage choice and the risk of kidney stones

From a recent paper:

Results The analysis involved 194,095 participants; over a median follow-up of more than 8 years, 4462 incident cases occurred. There was a 23% higher risk of developing kidney stones in the highest category of consumption of sugar-sweetened cola compared with the lowest category (P for trend=0.02) and a 33% higher risk of developing kidney stones for sugar-sweetened noncola (P for trend=0.003); there was a marginally significant higher risk of developing kidney stones for artificially sweetened noncola (P for trend=0.05). Also, there was an 18% higher risk for punch (P for trend=0.04) and lower risks of 26% for caffeinated coffee (P for trend less than 0.001), 16% for decaffeinated coffee (P for trend=0.01), 11% for tea (P for trend=0.02), 31%–33% for wine (P for trend less than 0.005), 41% for beer (P for trend less than 0.001), and 12% for orange juice (P for trend=0.004).

Conclusions Consumption of sugar-sweetened soda and punch is associated with a higher risk of stone formation, whereas consumption of coffee, tea, beer, wine, and orange juice is associated with a lower risk.

What's unhealthy about obesity?

Inflammation, mainly. This fascinating article discusses inflammation as a key determinant of unhealthy versus healthy obesity and its role in driving all the nasty components of the metabolic syndrome.

H7N9 influenza: what we know so far

The Annals of Internal Medicine recently reviewed the topic.

Points made in the review:

The virus produces severe disease.

Population immunity is unlikely.

It appears to be sensitive to commonly available antiviral agents.

Human to human transmission potential is unknown.

Hypertension in the ICU

This review discusses definitions of acute hypertensive syndromes, the relevant pathophysiology and treatment approaches.

The antibiotic development pipeline for gram negative infections: how's it going?

According to the recent report from IDSA (free full text) there's been some progress but not nearly enough. There are a few drugs in phase 3 trials but they do not address all the emerging threats.

Antiarrhythmic drugs for resuscitation from cardiac arrest

A recent systematic review and meta-analysis took another look. New research has not changed what we've known for years:

Ten randomized controlled trials and seven observational trials were identified. Amiodarone (relative risk (RR), 0.82; 95% confidence interval (CI), 0.54 to 1.24), lidocaine (RR, 2.26; 95% CI, 0.93to 5.52), magnesium (RR, 0.82; 95% CI, 0.54 to 1.24) and nifekalant were not shown to improve the survival to hospital discharge compared with placebo, but amiodarone, lidocaine, and nifekalant were shown to be beneficial to initial resuscitation, assessed by the rate of return of spontaneous circulation and survival to hospital admission, with amiodarone being superior to lidocaine (RR, 1.28; 95% CI, 0.57 to 2.86) and nifekalant (RR, 0.50; 95% CI, 0.19 to 1.31). Bretylium and sotalol were not shown to be beneficial.

Metabolic syndrome increased the risk for progression to ESRD

---in patients with stage 3 or 4 CKD in this study.

Practical aspects of the novel oral anticoagulants

Here's some more info form a review in CCJM.

Biphosphonates and the risk of atrial fibrillation

From a recent study in Chest:

Results: Six observational studies (n = 149,856) and six RCTs (n = 41,375) were included for analysis. On pooling observational studies, there was an increased risk of AF (OR, 1.27; 95% CI, 1.16-1.39) among bisphosphonate users. Further, analysis of RCTs revealed a statistically significant increase in the risk of serious AF (OR, 1.40; 95% CI, 1.02-1.93) and no increase in the risk of stroke (OR, 1.07; 95% CI, 0.85-1.34) or cardiovascular mortality (OR, 0.92; 95% CI, 0.68-1.26) with the use of bisphosphonates.

Conclusions: Evidence from RCTs and observational studies suggests a significantly increased risk of AF requiring hospitalization, but no increase in risk of stroke or cardiovascular mortality, with the use of bisphosphonate.

Pharmacologic treatments in ARDS

Neuromuscular blocking agents, corticosteroids and nitric oxide, among other agents, are discussed in this review.

The use of neuromuscular blocking agents was systematically studied and found to be beneficial early in the course of ARDS, for 48 hours, in this trial. The study population consisted of patients with a pO2 to FiO2 ratio of below 150. Ventilator mechanics and oxygenation were improved. Mortality benefit was confined to patients with a ratio of below 120. Prolonged post treatment paresis was not observed more frequently in the treatment group. This result was supported in a meta-analysis. UpToDate considers neuromuscular blockade potentially beneficial in severe disease, probably safe when used within limitations as illustrated by recent clinical trials but not recommended for routine use and in need of further study.

Inhaled nitric oxide may buy some time as a rescue modality but has not been shown to improve clinical outcomes.

Corticosteroids have been considered in a variety of situations in both early and later stages of ARDS, and remain controversial. At present the only clearly established role is in specific steroid responsive conditions (e.g. acute eosinophilic pneumonia) causing ARDS.

The use of biomarkers to guide antimicrobial therapy

Many biomarkers have been looked at. For adult hospitalized patients procalcitonin is the most promising. An evidence summary is contained in two companion articles, here and here.

Dietary determinants of incident DM 2

Diets characterized by high Mediterranean diet score and low glycemic load were beneficial in this study.

CT calcium scoring: who and when?

There are a couple of good articles on this topic in a recent issue of CCJM (here and here).

CT calcium scoring has been widely misunderstood by both health professionals and the public for a number of reasons. My own confusion concerned the pathophysiologic rationale. After all we were taught that calcification of atherosclerotic plaques was characteristic of advanced coronary artery disease, right? Moreover it was all too often the young, soft (and presumably non-calcified) plaques, those little blisters on the endothelial lining, that ruptured and caused catastrophic events. How then could calcium imaging be an early detection tool let alone one to assess preclinical risk? Those questions bugged me for a while and had me digging in Big Robbins, Braunwald's Heart Disease and the Path Guy for better answers. I wanted to know exactly when in the pathogenic sequence of atherosclerosis calcification occurred.

It turns out my assumptions were simplistic. Although atherosclerosis may be well underway when calcification occurs, calcium incorporation is not confined to the late stages of the process. Evidently calcium is incorporated before significant stenosis is seen even though considerable plaque maturation may have occurred. This is due in part to the phenomenon of outward remodeling. Moreover, plaques that rupture may be mature plaques but whose fibrous caps have been eroded by inflammatory mediators.

That said, non-calcified plaques can still rupture, making the use of calcium scoring in symptomatic patients problematic, one of the discussion points in the first of the two CCJM articles. Those authors agree with the prevailing view which is that scoring is useful mainly for the screening of asymptomatic patients and has little role in symptom evaluation. Cardiac calcium scoring for symptomatic patients gets little mention in U.S. Guidelines. An older guideline focused on cardiac CT in general gives it no better than a IIb recommendation. The current unstable angina/NSTEMI guidelines, which include evaluation of undifferentiated patients with chest pain, do not recommend it at all.

The second CCJM paper, a companion editorial, takes a more positive view of this controversial use of calcium scoring:

Taken together, these data suggest that the absence of coronary calcification in people at low to intermediate risk indicates a very low likelihood of significant stenotic coronary artery disease and foretells an excellent prognosis.

These data have already been incorporated into the British National Institute for Health and Clinical Excellence (NICE) guidelines, in which calcification scoring is an integral part of the management algorithm in patients with chest pain who are at low risk.

I was initially surprised that the NICE guidelines would embrace it. It's not so surprising on further consideration given that it is cheaper than invasive or noninvasive angiography or stress imaging.

For the more widely accepted indication of asymptomatic screening it is important to keep in mind that the test is considered optional at best. That is, no clinical scenario is given a class I recommendation. Its main advantage in asymptomatic patients is that it will reclassify a fair number of asymptomatic patients who are clinically determined to be at intermediate risk.

Borrelia miyamotoi

---causing an illness resembling human granulocytic anaplasmosis.

Anterior precordial lead ST segment depression in inferior STEMI

Dr. Smith discusses such a case in his ECG blog. He makes some teaching points on various aspects of the case. Concerning the anterior precordial ST depression frequently seen in inferior STEMI we were formerly taught that it signifies “ischemia at a distance,” that is, in the distribution of the left coronary system. That was a myth. We now know that it's the mirror image of posterior STEMI. In fact, as a rule, true ST segment depression does not localize an ischemic process. ST elevation does, T wave inversion does but ST depression does not. It can signify ischemia somewhere but doesn't tell you specifically where.

Universal acetaminophen level screening on all overdoses?

It's easy enough to do but how helpful is it? Results in the literature are mixed. The number needed to screen, depending on the population studied, varies from 45 to over 300. There's an interesting literature review and comment thread at Academic Life in Emergency Medicine.

What happened to unstable angina?

Braunwald and Morrow ask this question in a recent review in Circulation. It seems we’ve gone full circle:

It appears that we have now come full circle in our definition of symptomatic ischemic heart disease. Before the 1930s, 2 manifestations, stable angina and AMI, were recognized. Patients in the gray zone between stable angina and AMI that we now call UA were described 75 years ago and at first appeared to be quite rare. Over the next half-century, they were recognized with increasing frequency, and by 25 years ago, about one half of all patients with NSTE-ACS were considered to have UA. However, use of ever more sensitive biomarkers of myocardial necrosis, especially cTn, has steadily chipped away at the fraction of patients with NSTE-ACS without MI who therefore are still considered to have UA.

In the 70s terms such as “intermediate coronary syndrome” and “pre-infarction angina” were commonplace and conveyed a sense of urgency. The increasing sensitivity of cardiac biomarkers has gradually chipped away at those designations. They have all but vanished now with the advent of the more sensitive troponin assays.

The HDL controversy

This issue was reviewed recently in Cirulation. The HDL story is not over. Some of the points of the review:

The epidemiologic association between low HDL levels and cardiovascular disease is very strong.

The risks associated with low HDL can be moderated by nonpharmacologic means.

The main controversy regarding HDL concerns pharmacologic management. Early studies with niacin (e.g. the Coronary Drug Project) and fibrates (Helsinki I) showed reduction in cardiovascular events. However, several more recently conducted trials failed to show improvement attributable to pharmacologic treatment directed toward HDL. This is in part attributed to confounders such as concomitant statin treatment.

Questions for future and ongoing research include patient selection for treatment and new approaches in the pipeline.

Postural tachycardia syndrome (POTS)

Recent review in Circulation, free full text.

PFO closure for stroke prevention: how does the evidence add up?

Three RCTs had failed to show benefit, so a meta-analysis was done and recently published:

Results

Three RCTs met inclusion criteria. The pooled data provided 2,303 patients, of which 1,150 were in the PFO closure group and 1,153 in the medical therapy group. In the ITT analysis, there were 43 events (3.7%) of the composite end point in the closure group compared with 61 events (5.3%) in the medical therapy group, with a trend in favor of the PFO closure (OR = 0.70; 95% CI, 0.47–1.05, P = 0.08). The incidences of TIA, ischemic CVA, and bleeding were not statistically different between the groups. There was a trend for the more frequent occurrence of atrial fibrillation in the PFO closure group (OR = 3.29; 95% CI, 0.86–12.60, P = 0.08). In the AT analysis, the composite end point was significantly less frequent in the PFO closure group (OR = 0.62; 95% CI, 0.41–0.94, P = 0.02).

Here is a discussion of the article at Medpage Today.

This will be spun various ways. My summation is that while the evidence is inconclusive and no one can make a high level claim for closure over medical therapy the as treated analysis suggests that patients who successfully completed device therapy did better. The true practice of evidence based medicine in this situation will require a nuanced conversation with the patient. Statements like “we need to fix this hole in your heart to keep you from having another stroke” are unfounded. Dismissive statements like “PFO closure doesn't work” only reflect one's misunderstanding of the proper application of EBM.

The prevention of stroke in patients with PFO is, to say the least, controversial. It would seem plausible for device therapy to be superior to medical treatment and for systemic anticoagulation over antiplatelet therapy though neither has been proven convincingly. The UptoDate authors “suggest” medical over device therapy and “suggest” antiplatelet therapy over anticoagulation unless there is a specific reason to favor anticoagulation in the individual patient.

Management of acute pancreatitis: can we be evidence based?

Evolving concepts and controversies are addressed in a recent review published in the Cleveland Clinic Journal of Medicine. The article is available as free full text. A few take home points will be mentioned here.

The optimal timing of CT scanning is based on the fact that the yield for detecting necrosis is relatively poor until 72 hours or so after presentation. Earlier scanning may be indicated in certain clinical circumstances suggestive of complications. Scanning at the time of presentation is justified if the diagnosis is unclear. That is to say that CT scanning provides just one of the three diagnostic criteria, the other two being clinical and laboratory. If those two are present CT is not necessary to make the diagnosis.

There has been a gradual shift in thinking about severity assessment. While prognostic assessment may be helpful in anticipating complications, advising patients and assembling resources it may not be as useful in an algorithmic approach to management as once thought. For example, a clinical determination of severe pancreatitis defines the patient as having pancreatic necrosis. In the traditional view that would be an indication for antibiotic therapy. But that thinking is not supported by evidence and no longer holds sway. In addition, the role of severity assessment as a target for fluid resuscitation is unclear. Traditional thinking held that assessment of pancreatitis as severe targeted patients for more aggressive initial fluid administration. A study form 2011 by Warndorf and colleagues, however, found the opposite: it was the patients with milder (so called “interstitial”) pancreatitis who benefited most, suggesting that the window of opportunity is lost once pancreatitis progresses to severe.

There are many clinical tools available for severity assessment. Traditional tools (e.g. Ranson) are falling out of favor because they require observation over time and cannot classify patients within the first 24 hours. Some more recently validated methods, particularly the SIRS determination, are simpler to use and enable severity assessment on the front end.

Current concepts in fluid resuscitation have become more nuanced. The traditional view of “more is better” was based mainly on theory, animal data and low level human studies. Despite those limitations it held sway until challenged a couple of years ago by a study I cited here. According to that study fluids in excess of 4.1L in the first 24 hours were associated with harm. The thinking is shifting from “the more the better” to “shoot for the optimum.” Under resuscitation may lead to pancreatic ischemia at the microcirculatory level triggering necrosis, mediator release, SIRS, vascular collapse and distant organ failure. Too much fluid on the other hand may lead to organ congestion and compartment syndrome.

In addition, fluid resuscitation should be front loaded. The Warndorf paper reported that patients given greater than one third the 72 hour total volume in the first 24 hours had better outcomes. Of note, that group also had lower total 72 hour volumes.

As to the actual amount to give, the CCJM review says:

Optimum resuscitation is controlled fluid expansion averaging 5 to 10 mL/kg per hour, with 2,500 to 4,000 mL given in the first 24 hours.

The way to accomplish this in an average sized individual is to front load in the first several hours. Such a protocol was described in a 2011 paper by Wu and colleagues. It is based on an aggressive initial bolus followed by high volume maintenance fluid rates for the first few hours but then calls for a sharp reduction in IV rate if the BUN comes down a bit at either of two lab checkpoints starting around 8 hours following presentation. Patients treated according to that protocol received less total fluid than those who were not and the total amount received came fairly close to the upper range recommended in the CCJM review. Outcomes were not improved with use of the protocol but the patient numbers were small. What was found was that patients treated with lactated Ringer's did better than those treated with saline whether on or off protocol. Again the numbers were small and the outcomes were soft: SIRS and CRP.

Though based only on physiologic rationale (lower microcirculatory pH in the pancreas is believed to activate enzymes and promote inflammation) and the one small study with soft endpoints the CCJM review recommends LR over saline.

Additional discussions in the review focus on nutrition (enteral is better than parenteral, NG is as good as jejunal, and enteral nutrition reduces infection), compartment syndrome (an emerging concern in pancreatitis) and the management of walled off necrosis and fluid collections.

FFP versus 4 factor PCC for warfarin reversal

4 factor PCC was associated with faster INR reversal, a lower red cell transfusion requirement and a better safety profile in this study.

Note that PCC is favored over FFP in the latest ACCP guidelines.

Treatment of ventricular arrhythmias in the post-CAST era: beyond device therapy

Some take home points from a recent review:

The CAST study changed our thinking about drug treatment of ventricular arrhythmias but it did not eliminate the practice altogether.

Drug treatment of ventricular arrhythmias is not indicated for prevention of sudden cardiac death but two indications remain: symptom control and prevention or treatment of tachycardia induced cardiomyopathy.

PVC burdens of more than 15% of heart beats as well as frequent runs of VT, even if asymptomatic, have been associated with the development of tachycardia induced cardiomyopathy.

There has been a shift toward safer drugs (e.g. beta blockers).

Some of the outflow tract and fasicular ectopic rhythms are amenable to ablation.

Outflow tract and fasicular tachycardias have characteristic morphology and their sites of origin can often be identified on the surface electrocardiogram.

Renal Denervation as a treatment for resistant hypertension

This is gaining enthusiasm, devices are proliferating and research is ongoing. Free full text review here via Medscape. More data are needed to answer concerns about renal function decline related to the procedure and the durability of antihypertensive effect.

More information on azithromycin and the risk of sudden cardiac death

This CCJM review covers many of the same points I recently blogged here.

The role of obesity in atrial fibrillation

Atrial fibrillation is increasingly being recognized as a disease of obesity and the metabolic syndrome. A nice review (free full text) on the topic was recently published. Background here.

Systemic sclerosis review

This review, available in free full text from Mayo Clinic Proceedings, is the best I've seen on this topic. Points I found interesting:

The traditional classification of SS into diffuse and limited (aka scleroderma vs CREST) is simplistic. Finer gradations based on the extent of skin involvement or rate of progression of skin disease may be more meaningful. Also, specific disease profiles based on auto antibody associations are emerging. Antibody-phenotype associations are shown in one of the tables in the article. Although the associations are not absolute (and there is a certain amount of overlap) the specific antibodies are fairly predictive such that antibody profiling early in the course of the disease is beneficial.

There are four pathophysiologic dimensions to SS: vasospasm, obliterative vasculopathy, tissue fibrosis and autoimmunity.

There is no “treatment for SS” per se. Treatment is directed at disease manifestations. Immunosuppression directed against autoimmune processes that drive certain clinical manifestations is recommended in selected circumstances but none of it is supported by high level data.

Corticosteroids, in disfavor because they increase the risk of renal crisis, should be used sparingly if at all.

Novel anticoagulants versus LMWH for VTE prophylaxis in orthopedic patients

A systemic review in the Annals of Internal Medicine:

Data Synthesis: Six good-quality systematic reviews compared NOACs with low-molecular-weight heparin (LMWH) for thromboprophylaxis after THR or TKR. Risk for symptomatic deep venous thrombosis, but not risk for death or nonfatal pulmonary embolism, was reduced with factor Xa inhibitors compared with LMWH (4 fewer events per 1000 patients). Conversely, the risk for major bleeding increased (2 more events per 1000 patients). Outcomes of dabigatran did not significantly differ from those of LMWH. Indirect evaluation of NOACs by common comparison with LMWH showed nonsignificantly reduced risks for venous thromboembolism with rivaroxaban compared with dabigatran (risk ratio [RR], 0.68 [95% CI, 0.21 to 2.23]) and apixaban (RR, 0.59 [CI, 0.26 to 1.33]) but increased major bleeding. New oral anticoagulants have not been compared with warfarin, aspirin, or unfractionated heparin.

Limitations: Head-to-head comparisons among NOACs were not available. Efficacy is uncertain in routine clinical practice.

Conclusion: New oral anticoagulants are effective for thromboprophylaxis after THR and TKR. Their clinical benefits over LMWH are marginal and offset by increased risk for major bleeding.