A New Combination Therapy to Help Prevent COPD Exacerbations?

Posted by Rachel Wolfson • June 8th, 2016

2016-06-01_14-11-44You walk into your office to see, once again, Mr. Jones, at 64-year-old male who suffers from chronic obstructive pulmonary disorder (COPD). Mr. Jones is recovering from a recent visit to the ED due to his third COPD exacerbation event this year. He’s frustrated with his recurrent COPD exacerbations, and wants to know if his current treatment plan really is the best way to prevent them.

Treatment guidelines for prevention of COPD exacerbations recommend either inhaled corticosteroids (ICS) with long-acting β2-agonists (LABA) or an inhaled long-acting muscarinic antagonist (LAMA). However, the dual bronchodilator regimen of LABA/LAMA has yet to be tested in comparison to the ICS/LABA combination. To address the efficacy of this treatment plan, Wedzicha et al report the results of the FLAME trial in this week’s issue of NEJM. The authors enrolled over 3000 patients across 43 countries in this multicenter, randomized, double-blind, non-inferiority study. In terms of their primary endpoint, the LABA/LAMA regimen, indacaterol/glycopyrronium or IND/GLY, reached non-inferiority in comparison to the ICS/LABA regimen, salmaterol/fluticasone or SFC. In addition, IND/GLY showed superiority in reducing the annual rate of exacerbations in comparison to SFC, and prolonged time to first moderate or severe exacerbation. Although high blood eosinophil count had previously been suggested to be a biomarker that indicates better response to ICS/LABA treatment, blood eosinophilia, above or below 2%, did not impact the outcome of this trial. There was no detectable increase in adverse events with IND/GLY vs. SFC in fact there were fewer episodes of pneumonia, 3.2% in the IND/GLY group vs. 4.8% in the SFC group, P,0.02.

From these outcomes, the authors conclude that IND/GLY appears more effective at reducing exacerbations in comparison to SFC. In an accompanying editorial, however, James Donohue, MD, cautions against immediately switching your patients, like Mr. Jones, to this treatment regimen. He warns that more trials, especially those of longer duration and with patients with more severe co-morbidities are needed.

Knife and Gun Club: The Rez Edition

Posted by Ken Bernard • June 7th, 2016

2016-06-03_14-09-26In 1989, Eugene Richards published the visual chronicle of scenes from the Denver Country Hospital Emergency Department.  Anyone who has worked in an emergency department (ED) would recognize the grainy photos that put on display the gruesome injuries that people incur as a result of senseless violence.

Let’s face it — in addition to unscheduled primary care and geriatric medicine, much of what we manage in the ED is trauma.  My wife has pointed out that when an emergency doctor is having an interesting, productive, and intellectually engaging day at work, it means someone else is having an extremely bad day.  And over these past months on the reservation, I have noticed a stunning amount of trauma as a result of violence, many of which involve family members and a majority that are complicated by drugs, alcohol, or both. These experiences have left me questioning what might be causing such a stunning disregard for human life in our tiny part of the world.

For example, in one recent week during three separate night shifts, our ED cared for a limb-threatening gunshot wound, a bowel-eviscerating stab wound, five assault and batteries, and a homicide victim who died after a gunshot wound to the chest.  At the same scene where the last patient was found and brought into the ED, another person was killed as a result of a gunshot wound to the head.  In addition, I evaluated a sexual assault victim of intimate partner violence and a victim of elder abuse that absolutely broke my heart.

The Navajo Nation covers a land area of roughly 27,000 square miles, about the same size of West Virginia, with a population of about 180,000. An FBI report in 2013 found that the homicide rate per capita on the rez outpaced that of places like Boston and Seattle, major metropolitan areas that have significantly higher population density.  The per capita homicide rate here is four times the national average.  And even more concerning is that it seems to be affecting native children and adolescents to a much high degree, as reports show that American Indian and Alaska Native (AIAN) children suffer disproportionately from abuse and violence that result in rates of post-traumatic stress disorder that are similar to those seen in service members returning from war.  Here kids are twice as likely to die before the age of 24 when compared to all other races in the U.S.  Tucked back amidst the red rocks, spiritual mesas, and sacred peaks is one of the most dangerous places to grow up in America.

The causes of such trauma and violence are difficult to pin down, but likely result from a confluence of factors including systemic issues arising from complex and contrived jurisdictional tribal laws, an underfunded and understaffed law enforcement force, severe poverty and unemployment, undertreated and undiagnosed mental health conditions, the proliferation of illegal drug-use and alcohol abuse, and the proliferations of gang activity and broken families, due to many of the same issues above

It seems there is a desperation and loneliness which seems to have led to a staggering disregard for the traditional values of Native people — those of community, family, love, generosity, and harmony.

As an emergency department physician who sees the traumatic aftermath but who has individual patient encounters that are episodic and transactional, I was left wondering what is my profession’s role in injury and trauma prevention.  It is vital and should be incorporated into every setting where we care for acutely injured patients.  As emergency physicians on the front lines, we should be at the vanguard of trauma and injury prevention, and control and educate ourselves of the science and evidence-based practices of trauma and injury prevention.

But where to start?

The Center for Disease Control and Prevention is a good resource, and have outlined a systems-based approach to injury prevention. And we, as emergency medicine physicians, can recognize and flag important signals of homicide or suicide clusters, in addition to being effective screeners for intimate partner violence, child and elder abuse, and unsafe social environments for our patients.  Once high-risk individuals are identified, a community-wide agency network is needed to provide needed support.  Perhaps we could partner with national organizations or trauma centers to engage in population and public health research that could help determine which interventions are the most effective and sustainable.

As a profession, our duty to our patients is to always keep them safe and show them how much we care.  Much more than dispensers of medical knowledge and remedies we are advocates, protectors, and promoters of wellness.

What do you think could strengthen our Native communities and help keep them safe from violence?  Please share and thank you for your efforts!

The Hidden Lesion

Posted by Carla Rothaus • June 3rd, 2016

112The repeated occurrences of clots involving the veins in the proximal left leg raise suspicion for the May–Thurner syndrome (compression of the left iliac vein by the overlying right iliac artery).

A 24-year-old woman presented to the ED with pain in the left leg. She had been training for a 5-km race when, 2 days before presentation, she had crampy pain in her left leg, extending to the left lower abdomen and buttock, plus leg swelling and exertional dyspnea. A new Clinical Problem-Solving summarizes.

Clinical Pearl

• What subset of patients with iliofemoral deep-vein thrombosis may benefit from thrombolysis or thrombectomy?

Selected patients with extensive, acute iliofemoral deep-vein thrombosis who have good functional capacity, favorable life expectancy, and a low risk of bleeding may benefit from early thrombus removal in the form of thrombolysis or thrombectomy. These interventions are invasive and carry procedural risks, including hemorrhage, but they also preserve venous valve function. Thus, they may prevent the onset of the post-thrombotic syndrome, a debilitating long-term complication of deep-vein thrombosis that is characterized by leg swelling, claudication, and ulceration due to valvular incompetence and venous outflow obstruction.

Clinical Pearl

• Is thrombophilia testing indicated in patients who present with a first provoked episode of venous thromboembolism?

Thrombophilia testing is not indicated in patients who present with a first, provoked episode of venous thromboembolism, because the risk of recurrent thrombosis is not greatly affected by the presence of a heritable thrombophilia. The American Society of Hematology recommends against routine thrombophilia testing in patients with provoked venous thromboembolism if the thrombotic event can be readily attributed to a transient, major risk factor. For unprovoked venous thromboembolism, guidelines from consensus groups are less clear and often differ.

Morning Report Questions

Q: What are some clinical features of the May–Thurner syndrome?  

A: The May–Thurner syndrome, or the iliac vein compression syndrome, is the most frequently recognized anatomical abnormality that confers a predisposition to deep-vein thrombosis of the proximal left leg. Patients typically present in their third, fourth, or fifth decade, and there is a strong female preponderance, with a 2:1 ratio of affected women to men. Although the left common iliac vein is classically affected, compression of the left external iliac vein, and even compression of the right iliac vein have also been described.

Q: Is the MayThurner syndrome easy to diagnose and how successful are available therapies? 

A: Making the diagnosis of the May–Thurner syndrome requires a high index of suspicion. Intravascular ultrasonography is more sensitive than traditional angiography in detecting venous obstruction and stenosis. Magnetic resonance imaging can be useful, but the degree of stenosis may be difficult to assess once thrombosis and inflammation have occurred. Case series have shown excellent long-term outcomes after combination therapy with catheter-directed thrombolysis, iliac vein stenting, and anticoagulation; recurrent ipsilateral deep-vein thrombosis owing to stent occlusion has been reported to occur in fewer than 15% of adults treated with this approach and can be managed with repeat thrombolysis and stent placement. Anticoagulation therapy is usually continued for 6 months to a year after stenting, to allow for full endothelialization of the stent. Patients in whom the post-thrombotic syndrome develops may be given extended anticoagulation therapy owing to venous stasis.

Figure 3. Pelvic Venograms.

Figure 4. Intravascular Ultrasonography.

Catheter-Associated Urinary Tract Infection

Posted by Carla Rothaus • June 3rd, 2016

2016-05-31_11-31-21Catheter-associated urinary tract infection (UTI) is a common device-associated infection in the United States and one of the most common health care–associated infections worldwide. Preventing health care–associated infection in general, and catheter-associated UTI in particular, has emerged as a priority in the United States, with government agencies taking a lead role. The Agency for Healthcare Research and Quality, along with the Health Research and Educational Trust (the research and education affiliate of the American Hospital Association) and its partners, launched a nationwide effort to implement the Comprehensive Unit-based Safety Program (CUSP) to reduce catheter-associated UTIs in U.S. hospitals. Saint et al. report the results from the first four of nine cohorts of hospital units in the June 2, 2016, issue of the New England Journal of Medicine.

In this study of an educational program to prevent catheter-associated urinary tract infection, implemented in more than 10% of U.S. acute care hospitals, both catheter use and catheter-associated UTI rates were significantly decreased in the non-ICU setting. A new Original Article summarizes.

Clinical Pearl

• To what extent is catheter-associated urinary tract infection preventable?

Up to 69% of catheter-associated UTIs are considered to be avoidable, provided that recommended infection-prevention practices are implemented.

Clinical Pearl

• How much success have efforts beginning in 2009 had in reducing the rate of catheter-associated UTI in acute care hospitals?

Catheter-associated UTI was the first hospital-acquired complication chosen by the Centers for Medicare and Medicaid Services in 2008 as the basis for denial of additional payment to hospitals. In 2009, the Department of Health and Human Services released the “National Action Plan to Prevent Health Care–Associated Infections: Road Map to Elimination,” which provided strategic guidance for preventing infections in acute care hospitals. The goal was to reduce the rates of catheter-associated UTI by 25% by 2013. Despite these efforts, national data indicate that the incidence of catheter-associated UTI increased by 6% from 2009 to 2013.

Morning Report Questions

Q: What kinds of interventions might contribute to a decrease in catheter-associated UTI in acute care hospitals? 

A: In the Comprehensive Unit-based Safety Program, key interventions were as follows: conducting a daily assessment of the presence and necessity of an indwelling urinary catheter; avoiding the use of an indwelling urinary catheter by considering alternative urine collection methods, such as intermittent straight catheterization; and emphasizing the importance of aseptic technique during insertion of a catheter and proper maintenance after insertion. Additional recommended interventions were as follows: providing feedback to the units’ nurses and physicians on catheter use and catheter-associated UTI rates and providing training to address any identified gaps in knowledge about urinary management processes (i.e., proper insertion and maintenance of indwelling urinary catheters, use of alternative urine collection methods, and prevention of infectious and noninfectious consequences of urinary catheter use). Education on the prevention of catheter-associated UTI was provided to participating units through in-person meetings, coaching calls, and webinars. In addition, monthly national content calls were conducted, during which experts provided education on both technical and socioadaptive aspects of catheter-associated UTI prevention. The leaders also led monthly coaching calls with the participating units in the leader’s state to review data trends, discuss unit-specific issues, and share best practices in the prevention of catheter-associated UTI.

Table 1. Program Recommendations and Examples of Interventions.

Figure 1. Study Timeline.

Q: Did the interventions in the Comprehensive Unit-based Safety Program reduce rates of catheter-associated UTI?

A: Saint et al. found that a collaborative effort focusing on both technical and socioadaptive interventions can reduce catheter-associated UTI rates in the non-intensive care unit (ICU) setting. Data on catheter use and catheter-associated UTI rates were collected during three phases: baseline (3 months), implementation (2 months), and sustainability (12 months). In an adjusted analysis, the rates decreased from 2.40 to 2.05 infections per 1000 catheter-days (incidence rate ratio, 0.86; 95% confidence interval [CI], 0.76 to 0.96; P=0.009). Reductions occurred mainly in non-ICUs, where catheter-associated UTI rates decreased from 2.28 to 1.54 infections per 1000 catheter-days (incidence rate ratio, 0.68; 95% CI, 0.56 to 0.82; P<0.001). The rates did not change significantly in the ICUs.

Table 3. Multivariable-Regression Estimates of Changes in Catheter-Associated UTI Rates, According to Unit Type.

Catheter-Associated Urinary Tract Infections

Posted by Joshua Allen-Dicker • June 2nd, 2016

118In your role as Unit Medical Director, you regularly meet with nursing leadership for 6-West.  Today, they bring to your attention several cases from the last month: a 67-year old female admitted for severe pneumonia who initially rapidly improved on antibiotics, but then developed a new fever and was found to have a urinary tract infection; an 83-year old male admitted for elective hip replacement who became obtunded and hypotensive on hospital day 3, and was found to have a urinary tract infection; and a 77-year old male with heart failure on a furosemide drip who this morning was found to have a new leukocytosis that was preliminarily being attributed to a urinary tract infection.  All of them had urinary catheters in place prior to and at the time of their diagnoses.  One nurse states, “I think we could have prevented these events.  How can we work together to decrease the risk of CAUTI for all our patients?”  

Catheter associated urinary tract infection (CAUTI) affects about 2 million patients per year.  Its mechanism of infection is understood, the technical means to prevent it are known, and it remains a high-profile topic of national concern.  Despite this, recent data from the Centers for Disease Control and Prevention indicate that between 2009 and 2012 the US national CAUTI rate actually rose by 3%.  This week’s NEJM contains a study that informs our efforts to minimize CAUTI.

Saint et al. report on a partnership between The Agency for Healthcare Research and Quality and the American Hospital Association known as Comprehensive Unit-based Safety Program (CUSP) to Reduce CAUTI.  This effort was launched nationally with the goal of implementing best practices to prevent CAUTI at United States Hospitals.  Since 2011, nine cohorts of hospital units have been recruited.  Participating units agreed to form local teams focused on CAUTI prevention, collect and share relevant data, and participate in ongoing interventions.  Interventions included technical/educational (e.g. appropriate use, aseptic insertion, proper maintenance, and timely removal of catheters) as well as “socio-adaptive”, a term the authors use to describe aspects related to the challenges of improvement implementation.  Beyond this, local teams were empowered to tailor CAUTI prevention initiatives to meet their unique situations and needs.  Ongoing mentorship was provided by project leadership.

Saint et al. now present data on the CAUTI rate and the proportion of patients with indwelling catheters collected from CUSP to Reduce CAUTI’s first 4 cohorts between March 2011 and November 2013.  In the 926 analyzed hospital units, study authors found that adjusted CAUTI rates significantly decreased from 2.4 to 2.05 per 1,000 urinary catheter-days.  During this time, catheter utilization rate also significantly decreased from 20.1% to 18.8%.  On subgroup analysis, authors found that these effects were predominantly driven by non-ICU units.  In fact, in the subset of ICU units, there was neither a significant change in the rate of catheter utilization nor in the CAUTI rate.

At this point, you may be asking yourself, So what? We’ve known for a long time that appropriate use, aseptic insertion, proper maintenance, and timely removal of catheters can help prevent CAUTI.  How is this news?  The significance of CUSP to Reduce CAUTI relates to its focus on teams, communication, problem solving, and implementation mentoring to achieve change in clinical practice.  As patient safety expert Dr. Lucien Leape commented in NEJM in 2014, “The key is recognizing that changing practice is not a technical problem… but a social problem of human behavior and interaction.” CUSP to Reduce CAUTI succeeds by addressing both the technical as well as the social.

While providing us with hope for attainable change in preventing CAUTI in the non-ICU setting, Saint et al. do leave us wondering about the future of CAUTI prevention efforts in the ICU.  In an accompanying editorial, Dr. Susan Huang of UC Irvine School of Medicine draws attention to several factors, both patient-specific and general, that may have complicated CAUTI reduction efforts for critically ill patients in this study.  Among them, ICU patients may require longer use of catheters (and a resulting increased risk for CAUTI) as a direct result of their critical illness.  There may also be an inappropriate perceived need for longer use of catheters in this population, a potential social barrier to catheter discontinuation.  Lastly, successive changes to the definition of CAUTI may have resulted in increased rates of CAUTI beginning in 2012, and decreased rates beginning in 2015.  For the data presented by Saint et al. (collected between 2011 and 2013) this may have underestimated the benefits of CUSP to Reduce CAUTI.

Recognizing the importance of CAUTI prevention, you organize a team of interested nurses, patient care technicians, resident and attending physicians, and administrators.  You engage hospital leadership and contact other units in your hospital who have lower CAUTI rates than yours.  While several members of the group are developing a nursing-driven catheter discontinuation protocol, you begin to think about what social barriers to change might exist to this intervention.  

Have you participated in a CAUTI prevention project on your unit?  What barriers to change did you face?

Don’t miss the NEJM Quick Take video summary on this study:

Cryptogenic Stroke

Posted by Carla Rothaus • May 27th, 2016

2016-05-23_14-38-46Cryptogenic ischemic strokes are symptomatic cerebral infarcts for which no probable cause is identified after adequate diagnostic evaluation. In general, the percentage of ischemic strokes that are classified as cryptogenic has declined over time as diagnostic testing has advanced. However, stroke that is cryptogenic after a standard diagnostic evaluation remains a common clinical challenge, accounting for 20 to 30% of all ischemic strokes and therefore occurring in 120,000 to 180,000 patients each year in the United States. As compared with strokes of determined origin, cryptogenic ischemic strokes typically result in less severe presenting neurologic deficits, less final disability, and lower mortality.

One quarter of ischemic strokes are cryptogenic (no obvious cause). Additional investigation involves assessment for arteriopathies, cardiac sources of embolism (in particular, occult low-burden atrial fibrillation), and disturbances of coagulation. A new Clinical Practice summarizes.

Clinical Pearl

• What are some of the causes of cryptogenic stroke that may be discovered after more specialized testing?

In patients with ischemic stroke that is considered to be cryptogenic after standard evaluation, causes that are most often found after more specialized testing include occult atherosclerosis, including nonstenosing but unstable plaques at intracranial and cervical sites or stenosing plaques at the thoracic origins of the common carotid and thoracic vertebral arteries; nonatherosclerotic arteriopathies, such as dissection or vasculitis; hypercoagulable states; cardioembolism from medium-grade sources, such as low-burden paroxysmal atrial fibrillation or dilated cardiomyopathy of moderate degree; and paradoxical embolism.

Clinical Pearl

• What is the most common cause of cryptogenic stroke in young adults?

The age of the patient influences the likelihood of various causes. In young adults 18 to 30 years of age, dissection is most common, but thrombophilias and congenital cardiac disease are also noteworthy causes. In persons 31 to 60 years of age, early-onset atherosclerosis and acquired structural cardiac disease are increasingly common. In patients older than 60 years of age, occult atrial fibrillation becomes more frequent.

Morning Report Questions

Q: What patient characteristics increase the likelihood that protracted cardiac monitoring will reveal occult atrial fibrillation? 

A: Technology to detect infrequent paroxysmal atrial fibrillation has dramatically improved over the past decade, with the development of mobile cardiac telemetry systems that may be worn externally for 2 to 4 weeks, subcutaneous loop recorders with battery lives enabling detection for 1 to 3 years, and in patients needing therapeutic internal pacemakers or defibrillators, implantable therapeutic devices with the capability to detect atrial fibrillation for 3 years or more. Among patients whose ischemic strokes are cryptogenic after conventional inpatient evaluation, prolonged outpatient cardiac monitoring detects low-burden atrial fibrillation in 15%. Patients with low-burden paroxysmal atrial fibrillation have a lower risk of stroke than patients with chronic or high-burden paroxysmal atrial fibrillation. However, their risk of stroke is higher than that among persons without atrial fibrillation. As little as a single 1-hour episode of atrial fibrillation during 2 years of monitoring has been associated with a doubling in the risk of ischemic stroke. The characteristics of patients that increase the likelihood that protracted monitoring will uncover low-burden atrial fibrillation include older age and higher CHA2DS2-VASc score (on which scores range from 0 to 9, with higher scores indicating greater risk), cerebral infarct topographic features (such as multiple vascular territories and cortical location), and indexes of left atrial cardiopathy, including left atrial dilatation, strain, and reduced emptying fraction, left atrial appendage size and single-lobe morphologic features, p-wave dispersion on ECG [electrocardiogram], frequent atrial premature beats, and elevated N-terminal pro–brain natriuretic peptide serum levels.

Q: When a patent foramen ovale is found during the work up of cryptogenic stroke, how is one to know if it is causally related?

A: A patent foramen ovale is present in approximately one quarter of the general patient population but in one half of patients with cryptogenic stroke. A Bayesian attributable risk analysis of pooled data from 12 studies suggested that among patients with cryptogenic stroke who had a patent foramen ovale, the patent foramen ovale is probably causally related to the stroke in approximately half. Features that increase the likelihood of a causal relationship include younger age; Valsalva maneuver at the onset of stroke; extended plane or car travel preceding the stroke; concomitant venous thrombosis in the leg or pelvis; coexisting venous hypercoagulable state; coexisting atrial septal aneurysm; history of migraine with aura; cortical location, multiplicity, and large size of cerebral infarcts; and absence of hypertension, diabetes, and smoking.

Figure 1. Algorithm for the Identification and Diagnostic Evaluation of Patients with Cryptogenic Ischemic Stroke or Transient Ischemic Attack (TIA).

Table 1. Suggestive Findings on History and Physical Examination in Patients with Cryptogenic Stroke.

A Pregnant Woman with Fever

Posted by Carla Rothaus • May 27th, 2016

104Listeriosis is a rare but notorious cause of chorioamnionitis. Listeriosis is caused by Listeria monocytogenes, an environmentally ubiquitous, facultative, anaerobic gram-positive bacillus. In humans, listeriosis is almost exclusively a foodborne disease, and unheated processed meats and unpasteurized soft cheeses can be contaminated with listeria; pregnant women should avoid eating such foods. Listeriosis is a nationally notifiable disease in the United States.

A 31-year-old woman who was pregnant with dichorionic, diamniotic twins presented at 35 weeks of gestation with fever, rigor, malaise, myalgias, anorexia, and loose stools. A chest radiograph revealed patchy right basilar opacities. Diagnostic test results were received. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What are some of the risk factors for chorioamnionitis?

Chorioamnionitis complicates 1 to 4% of births in the United States. It is typically caused by ascending infection with endogenous vaginal or cervical bacteria. Associated risk factors before the onset of labor or membrane rupture include bacterial vaginosis, maternal alcohol or tobacco use during the pregnancy, and colonization of the mother’s vagina, rectum, or urinary tract with group B streptococcus.

Clinical Pearl

• How does the rate of listeriosis in pregnant women compare to that in the general population?

In 2010 in the United States, the overall reported rate of listeriosis was only 2.7 cases per 1 million people. Pregnant women, however, are particularly susceptible to listeria and contract the disease at a rate that is 10 to 20 times the rate in the general population; up to 1 in every 4 reported cases of listeriosis in the United States occurs in a pregnant woman. The overwhelming majority of affected women are otherwise healthy. Most diagnoses are made in women who are in the third trimester of pregnancy. Women with multiple gestations are at an increased risk.

Morning Report Questions

Q: What are some of the clinical features and potential complications of listeriosis in pregnant women? 

A: The onset of listeriosis can occur anytime from 3 to 70 days after exposure; the typical incubation period for invasive disease is longer in pregnant women (2 to 4 weeks) than in nonpregnant persons (1 to 14 days). Pregnant women with listeriosis may be asymptomatic or present with an influenza-like or nonspecific febrile illness, sometimes accompanied by gastrointestinal symptoms. Malaise, nausea, loose stools, rigors, arthralgias, and myalgias are typical of the disease. Most pregnant women with listeriosis have leukocytosis. Pregnancy-associated L. monocytogenes infections can have catastrophic results, such as fetal loss, preterm delivery, serious neonatal illness, or neonatal death. As a consequence of maternal bacteremia and transplacental transmission of infection, infants may have an early-onset sepsis syndrome that occurs at birth or shortly thereafter.

Figure 2. Blood Specimens.

Q: What is the usual treatment of severe infections with listeria? 

A: Ampicillin and gentamicin are active against L. monocytogenes. These antibiotics are typically used in combination for the treatment of severe infections with listeria, although no controlled trials have established a standard antibiotic choice or duration of treatment for this infection.

Primary Prevention of Cardiovascular Events — A Pragmatic Approach

Posted by James Yeh, M.D. M.P.H. • May 25th, 2016

2016-05-06_16-09-35Ms. Barnstable is a 66 year-old woman who is seeing you for an annual physical check-up today.  She does not take any medications and is a smoker.  She asks if there are drugs that she should be taking to lower her risks for heart attacks and strokes. Besides smoking cessation counseling, what do you tell her about drugs for primary prevention of CV events?

What is the Heart Outcomes Prevention Evaluation (HOPE)-3 trial?

In this trial, recently reported in three papers in NEJM, investigators asked whether giving fixed doses of rosuvastatin and candesartan/hydrochlorothiazide to adults who do not have cardiovascular disease but have an intermediate risk of cardiovascular events (annual risk of about 1%) regardless of cholesterol levels, inflammatory markers status, or hypertension status can prevent future cardiovascular events.

The investigators employed a 2 x 2 factorial design to simultaneously test multiple different hypotheses. They randomized 12,705 adults (men ≥55 year-old and women ≥65 year-old) from 21 countries to receive either rosuvastatin (10 mg daily) or placebo, and to receive either candesartan/hydrochlorothiazide (16mg/12.5 mg daily) or placebo.

Three comparisons were analyzed:

There were two co-primary outcomes:

  • The composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke
  • The first composite outcome plus resuscitated cardiac arrest, heart failure, and revascularization

Who are in the study?

The mean age was 65.7 years and 46% of the participants were women. The baseline mean LDL cholesterol level was 128 mg/dL and mean blood pressure was 138/82 mm Hg.

What were the results?

During the median follow-up time of 5.6 years, rosuvastatin lowered the mean LDL cholesterol level by 35 mg/dL and the anti-hypertensive drugs lowered the mean systolic/diastolic BP by 6/3 mm Hg.

The rate of the first co-primary outcome (composite of CV death, nonfatal stroke, and nonfatal MI) was significantly lower in the combination therapy group compared to dual-placebo (3.6% vs. 5.0%; HR 0.71, 95% CI 0.56 to 0.9; P=0.005).  The rate of the second co-primary outcome (composite of first co-primary plus resuscitated cardiac arrest, heart failure, and revascularization) was also lower with combination therapy (4.3% vs. 5.9%; HR 0.72; 95% CI 0.57 to 0.89; P=0.003).

What were the results of blood-pressure treatment alone and statin therapy alone?

The rate of the first co-primary outcome was lower with rosuvastatin versus placebo (3.7% vs. 4.8%; HR 0.76; 95% CI 0.64 to 0.91; P=0.002). These results were consistent in subgroup analyses regardless of baseline cholesterol level, C-reactive protein level, blood pressure, and race or ethnic group.

The rate of the first co-primary outcome was not different with candesartan/hydrochlorothiazide than with placebo (4.1% vs. 4.4%; HR 0.93; 95% CI 0.79 to 1.10; P=0.40).  In a pre-specified subgroup analysis, blood pressure treatment when compared to placebo did lower the incidence of the co-primary outcome of CV death, nonfatal stroke, and nonfatal MI in the tertile of study participants with systolic BP > 143.5 mm Hg (4.8% vs. 6.5%) but did not have a significant effect in either of the two lower tertiles (P for trend =0.02) .

So should everyone receive combination therapy of statin and anti-hypertensives?

The addition of anti-hypertensive regime with fixed doses of candesartan/hydrochlorothiazide to fixed rosuvastatin did not differ significantly than rosuvastatin therapy alone in reducing the incidence of CV death, nonfatal stroke, and nonfatal MI (3.6% vs. 3.8%).

How do I reconcile the blood-pressure intervention results with the SPRINT trial?  

In an accompanying editorial, William Cushman (Veterans Affairs Medical Center, Memphis) and David Goff (University of Colorado Anschutz Medical Campus) caution that the overall negative results of the blood-pressure–lowering component of HOPE-3 could be due to the treatment of a lower-risk group in HOPE-3 than the SPRINT trial, where participants had subclinical CV disease or a ten-year Framingham CV risk score > 15%.  Further more, “the difference in systolic blood pressure between the active-treatment and control groups that was seen in SPRINT was twice the difference seen in HOPE-3 because the treatment regimen was more intensive.” Therefore, the low doses of the anti-hypertensive agents used in HOPE-3 may help explain the result.

What is my take-away?

For patients at intermediate risks for cardiovascular events, irrespective of the cholesterol level or hypertension status, taking a fixed dose of statin reduced this risk. The addition of fixed doses of anti-hypertensives to the statin therapy did not reduce this risk unless the patient was hypertensive.

Don’t miss the NEJM Quick Take video summary of the SPRINT trial:

A Man with Olfactory Hallucinations

Posted by Carla Rothaus • May 20th, 2016

2016-05-13_13-00-38Involvement of the nervous system is reported in 5 to 15% of patients with sarcoidosis, although autopsy series indicate that the frequency of lesions in the nervous system may be higher.

A 32-year-old man presented with a 1-year history of olfactory hallucinations and a 6-week history of intermittent numbness and paresthesias on the left side. MRI revealed a nodular focus of enhancement in the medial right temporal lobe. A diagnostic procedure was performed. A new Case Records of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What is the most common abnormality reported in cases of neurosarcoidosis?

Basilar meningeal involvement with an associated cranial neuropathy (usually involving the facial nerve) is the most common abnormality reported. Involvement of the facial nerve can be either unilateral or bilateral, and bilateral involvement can be simultaneous or sequential.

Clinical Pearl

• What are some of the other clinical manifestations of neurosarcoidosis?

Optic nerve involvement may occur alone or in association with other lesions. Leptomeningeal involvement, either focal or diffuse, may be observed in association with cranial neuropathies or in isolation. Disease in the region of the infundibular stalk may result in endocrinopathies caused by alteration of the hypothalamic–pituitary axis. Dural involvement may be manifested by a discrete mass that may mimic meningioma. Neurosarcoidosis with parenchymal involvement is less frequent than neurosarcoidosis with meningeal involvement.

Figure 1. MRI of the Head.

Figure 2. Brain-Biopsy Specimen (Hematoxylin and Eosin).

Morning Report Questions

Q: What is the prognosis of neurosarcoidosis? 

A: Clinical experience and a few long-term studies have shown that the response to therapy and the prognosis depend on the clinical syndrome. Lymphocytic meningitis, mononeuropathies of the facial nerves, multiple cranial neuropathies, and polyradiculoneuropathies respond to relatively short courses of glucocorticoids, are associated with a good long-term prognosis, and are generally not debilitating. In contrast, patients with sarcoidosis affecting the parenchyma of the brain, the spinal cord, or the conus medullaris and cauda equina or with granulomatous involvement of the optic nerves and hypothalamic and pituitary regions often have a protracted and progressive course over a period of years. Such patients respond partially to glucocorticoids and glucocorticoid-sparing immunosuppressive medications, such as methotrexate, azathioprine, and mycophenolate, but they require treatment for years.

Q: How is neurosarcoidosis treated? 

A: Immunosuppressive drugs, predominantly glucocorticoids, are the backbone of therapy for neurosarcoidosis in all its forms, but biologics such as TNF-α inhibitors are now an important part of the treatment. TNF-α inhibitors may be useful when the usual immunosuppressive therapy is inadequate or is associated with an unacceptable side-effect profile. The rationale for the use of TNF-α inhibitors is evidence of the role of the cytokine TNF-α, which is generated in granulomas, in causing tissue damage and perpetuating the granulomatous process. The most commonly used TNF-α inhibitor is infliximab, which is a chimeric monoclonal antibody that inhibits both soluble and membrane-bound TNF-α.

Coronary-Artery Bypass Grafting

Posted by Carla Rothaus • May 20th, 2016

93Appropriate selection of patients for coronary-artery bypass grafting (CABG) is critical to ensure good outcomes. The evaluation of patients for CABG relies on a systematic assessment of the characteristics and coronary anatomy known to be associated with a survival benefit from CABG as compared with medical therapy or percutaneous coronary intervention (PCI). There is increasing evidence that treatment decisions for patients with complex coronary artery disease are best made through a process of shared decision making that includes the patient, the patient’s family, an interventional cardiologist, a cardiac surgeon, and ideally, the patient’s general cardiologist or primary care physician.

Coronary-artery bypass grafting (CABG) is very commonly performed. CABG improves survival among patients with multivessel coronary disease; those with more severe coronary disease, diabetes, or left ventricular dysfunction are especially likely to benefit. A new Review Article summarizes.

Clinical Pearl

• What is the most serious complication of CABG?

Stroke remains the most serious complication of CABG, occurring in 1 to 2% of patients in the perioperative period. Notable risk factors for stroke include a history of neurologic events, advanced age, peripheral or cerebrovascular disease, and diabetes. Aortic atherosclerosis is also a major risk factor for stroke after CABG because of the necessary manipulation or clamping of the ascending thoracic aorta. The use of a single aortic cross-clamp and epiaortic ultrasonography during CABG have been associated with a reduction in the risk of stroke over the past decade.

Clinical Pearl

• In patients with coronary artery disease, what coexisting conditions are associated with a benefit of CABG over PCI?

Patients with multivessel coronary artery disease and diabetes have an increased cardiovascular risk as compared with those without diabetes, and they have a survival benefit from CABG as compared with PCI. Patients with left ventricular dysfunction or mitral-valve disease also have an increased cardiovascular risk and have a survival benefit from CABG.

Morning Report Questions

Q: What were the results of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) study regarding the relative benefits of CABG versus PCI? 

A: Recent trials and observational studies have updated previous work by including higher-risk patients and reflecting changes in practice. The most important was the SYNTAX study, which randomly assigned 1800 patients with either three-vessel or left main coronary artery disease to CABG or PCI. Evaluation of each participant included determination of the SYNTAX score (a measure of the extent and complexity of coronary artery disease) and the anticipated complexity of PCI. SYNTAX scores are used to classify the complexity of coronary artery disease as low (≤22), intermediate (23 to 32), or high (≥33). Overall, patients with three-vessel disease in the SYNTAX trial had a survival benefit with CABG as compared with PCI (rate of death, 9.2% vs. 14.6%, P=0.006). In patients with the least complex three-vessel disease (SYNTAX score ≤22), PCI was noninferior to CABG. In patients with more complex disease (SYNTAX score ≥23), CABG was superior to PCI. The survival benefit of CABG over PCI for patients with multivessel coronary artery disease has been confirmed in other studies and appears to be consistent when PCI is performed with second-generation drug-eluting stents. In the SYNTAX study, the outcomes of the two procedures were indistinguishable in patients with isolated left main coronary artery disease or left main coronary artery disease and single-vessel coronary artery disease (SYNTAX score <33). However, in patients with left main and two- or three-vessel coronary artery disease (SYNTAX score ≥33), there was a significant reduction in the rate of the composite end point of death, myocardial infarction, stroke, or repeat revascularization with CABG as compared with PCI (29.7% vs. 46.5%, P=0.003).

Q: Are there studies comparing CABG to PCI in patients with acute coronary syndromes? 

A: The evidence in favor of CABG is almost entirely based on studies of patients with stable ischemic heart disease. Nevertheless, the recommendations for CABG are commonly extended to include patients with acute coronary syndromes, including unstable angina and stable non–ST-segment elevation myocardial infarction. In practice, more than 60% of CABG procedures are performed during an acute care hospitalization and 29% follow a recent myocardial infarction. The best initial treatment for patients with acute ST-segment elevation myocardial infarction is reperfusion therapy with either PCI or fibrinolytic therapy. As compared with CABG, PCI restores coronary blood flow more rapidly, preserves myocardium, and improves outcomes. In this patient population, CABG is reserved for those who have a coronary anatomy that is not amenable to PCI or who have mechanical complications, such as ventricular septal defect, myocardial rupture, or papillary-muscle rupture with acute, severe mitral regurgitation.

Figure 1. Coronary-Artery Bypass Grafting.

Table 1. Indications for Coronary-Artery Bypass Grafting (CABG).