Fibrinolysis for Acute Intermediate-Risk Pulmonary Embolism

Posted by Gelareh Homayounfar • April 10th, 2014

For anyone with an acute pulmonary embolism (PE), your prompt diagnosis and treatment can save a life. In patients with high-risk PE and signs of hemodynamic compromise, fibrinolysis is an established, clear choice that can reduce pulmonary artery resistance, prevent PE recurrence, and reduce mortality. Although fibrinolytic therapy is known to carry risks of major bleeding and stroke, the benefits of treatment outweigh these risks in high-risk PE. However, what is the role of fibrinolysis in normotensive patients with intermediate-risk PE? Does early reperfusion improve outcomes, as compared to standard anticoagulation with heparin? Trials seeking to answer these questions thus far have been inadequately sized, and controversy remains.

In this week’s NEJM, Meyer et al. report the findings of the largest multicenter randomized double-blinded trial of fibrinolysis for the treatment of intermediate-risk PE. Their findings help guide physicians in weighing the risks and benefits of fibrinolysis in this patient population.

In the Pulmonary Embolism Thrombolysis trial (PEITHO), 1006 patients with acute intermediate-risk PE were randomized to receive a single dose of the fibrinolytic tenecteplase plus heparin or to receive placebo plus heparin. Intermediate-risk PE was defined by the absence of hemodynamic instability and the presence of right ventricular dysfunction and myocardial injury at presentation. The primary outcome measure was a composite of death or hemodynamic decompensation within seven days of randomization. Secondary outcomes included death within seven and thirty days, as well as major extracranial bleeding and stroke within seven days.

Treatment with tenecteplase reduced the risk of death or hemodynamic decompensation (from 6% in the placebo group to 3% in the tenecteplase group, p=0.02). There was no statistically significant difference in mortality between the groups at seven or thirty days.

However, with the addition of tenecteplase, there was an increase in major bleeding (from 1% to 6%, p<0.001) and an increase in stroke (from 0.2% to 2%, p=0.003). The majority of the strokes in the tenecteplase group were hemorrhagic. Of those who suffered a hemorrhagic stroke, 40% died within a month of randomization, and the survivors were left with mild-to-moderate disability.

To further define who might benefit from fibrinolysis, the authors noted that patients 75 years of age or younger treated with tenecteplase have lower odds of death or hemodynamic decompensation and lower odds of major extracranial bleeding as compared to patients over 75. While it seems that younger patients benefit more and face fewer risks with tenecteplase than older patients, these differences in outcomes were not statistically significant.

Overall, the findings of the trial suggest that, in patients with acute intermediate-risk PE, fibrinolysis prevents hemodynamic decompensation while increasing the risk of major bleeding and stroke. Unfortunately, the trial was underpowered to detect a difference in mortality, which occurred relatively infrequently in both treatment and placebo groups. Further research and even larger study populations are needed. Nevertheless, this trial is larger than all others seeking to address the same question over the past 40 years combined, and these results can allow for more informed decisions about the treatment of intermediate-risk PE.

In the accompanying editorial, Dr. C. Gregory Elliott, Professor of Medicine at the University of Utah School of Medicine, writes, “What course should physicians chart when confronted with a normotensive patient with acute pulmonary embolism? PEITHO data provide valuable insight, but no definitive answer. PEITHO strengthens the case for risk stratification and for careful monitoring of patients with intermediate mortality risk. PEITHO also shows the relative safety of withholding fibrinolysis unless hemodynamic decompensation occurs. Therefore, it may be that overall risk can be minimized with a strategy of initial anticoagulation and rescue fibrinolysis for hemodynamic decompensation.”

For physicians and patients grappling with treatment decisions after a PE, weighing the benefits and risks of therapy is essential. As NEJM Deputy Editor Dr. John Jarcho notes, “In patients with PE, fibrinolysis is potentially beneficial but also potentially dangerous. The editors believe that clinicians will find it extremely useful to have the data from PEITHO to guide management decisions.”

Gelareh Homayounfar is a fifth-year student at Harvard Medical School who has recently completed a month-long elective at the NEJM editorial offices.

Sepsis, Albumin, and the Therapeutic Potential of Improving Oncotic Pressure

Posted by John Staples • April 9th, 2014

In physiology, as in all other sciences, no discovery is useless … we may be certain that every advance achieved in the quest of pure knowledge will sooner or later play its part in the service of man.

—    Dr Ernest Henry Starling,

The Linacre Lecture on the Law of the Heart (1915)

Modern sepsis treatment owes a conceptual debt to British physiologist Dr. Ernest Starling. Starling’s experiments suggested that increasing ventricular end-diastolic volume can increase cardiac output, and this is one of the goals in mind when septic patients are given intravenous crystalloid. In a separate line of work, Starling also described the hydrostatic and oncotic forces that ultimately cause much of this intravenous crystalloid to leak into the interstitium, resulting in pulmonary and peripheral edema that can seriously complicate a septic patient’s ICU course.

In this week’s NEJM, Dr. Pietro Caironi (Universita degli Studi di Milano, Italy) and colleagues report on the therapeutic potential of improving intravascular oncotic pressure in septic patients. The multicenter, open-label ALBIOS trial randomized 1,818 adult patients with severe sepsis to an albumin group or to a control group. Both groups received intravenous crystalloid whenever clinically indicated. The albumin group additionally received daily infusions of intravenous 20% albumin from randomization until ICU discharge or day 28 (whichever came first).

Did daily albumin infusions improve outcomes? Unfortunately not. The 28-day mortality was about 32% in both groups (p = 0.94). There was also no difference on secondary outcomes such as mortality at 90 days, severity of organ dysfunction, or ICU length of stay.

Sepsis carries a high mortality,” says cardiologist and NEJM Executive Editor Dr. Gregory D Curfman, “Rigorously conducted trials allow clinicians to confidently determine which interventions are effective in a particular patient group and which offer little to no benefit.”

Although albumin infusions didn’t confer any survival advantage to ALBIOS study subjects, some hope remains that they might be beneficial in a more select group of patients. Participants in the albumin group had higher mean arterial pressures and lower net fluid balances during the first 7 days, and a post-hoc analysis suggested daily albumin infusions might improve 90-day mortality in the subset of patients with shock. Will albumin play a part in the service of the septic patient? Perhaps the next trial will tell.

Unfolding the Diagnosis

Posted by Sara Fazio • April 4th, 2014

In our latest Clinical Problem-Solving article, a previously healthy, 25-year-old man was admitted to the hospital because of abdominal pain, nausea, vomiting, and weight loss. Fever, chills, and weakness developed 2 weeks before his admission.

In protein loss localizable to the gastrointestinal tract, in most cases, the syndrome of protein-losing enteropathy is associated with diseases localized to the small intestine. However, less commonly, the stomach may be a source of protein loss.

Clinical Pearls

What is the differential diagnosis of large gastric mucosal folds on upper endoscopy?

Large gastric mucosal folds are recognized in a variety of conditions and may reflect mucosal hyperplasia (i.e., an excessive number of mucosal epithelial cells confined to the rugae in the gastric body and fundus) or mucosal hypertrophy. As these conditions have the same gross appearance, biopsy is often necessary to determine the cause. Large nonhyperplastic gastric folds may be caused by conditions including chronic H. pylori gastritis, neoplasms such as lymphoma, adenocarcinoma, and carcinoid, as well as lymphocytic gastritis, sarcoidosis, eosinophilic gastroenteritis, and the Cronkhite-Canada syndrome. Hyperplastic gastropathies include the Zollinger-Ellison syndrome, in which there is an increased number of parietal cells, and Menetrier’s disease, in which the number of surface and foveolar mucous cells is increased.

What is the pathogenesis, epidemiology, and clinical presentation of Menetrier’s disease?

The pathogenesis of Menetrier’s disease is incompletely understood. However, the observation of elevated levels of transforming growth factor alpha (TGF-alpha) in gastric mucous cells of patients with this condition has suggested a role for TGF-alpha-induced hyperplasia. Menetrier’s disease affects men more often than women and is most common between ages 40 and 55 years. Clinical manifestations of Menetrier’s disease include epigastric pain, weight loss, nausea, vomiting, gastrointestinal bleeding, diarrhea, and protein-losing gastropathy. Hypoalbuminemia is present in 20 to 100% of patients, according to different series; this feature helps distinguish Menetrier’s disease from the Zollinger-Ellison syndrome.

Morning Report Questions

Q: How is Menetrier’s disease diagnosed and treated?

A: The diagnosis of Menetrier’s disease is usually established by demonstrating extreme foveolar hyperplasia with glandular atrophy and decreased parietal cells on biopsy in a patient with large gastric folds on endoscopy. Treatment includes medications to relieve nausea and gastric pain. A high-protein diet is prescribed to offset the loss of protein. Partial or total gastrectomy is sometimes advocated for patients with intractable pain, hypoalbuminemia, edema, hemorrhage, or pyloric obstruction, or in cases in which malignancy cannot be ruled out. A small single-blinded trial of patients with severe Menetrier’s disease treated for 1 month with cetuximab (a monoclonal antibody that blocks epidermal growth factor receptor signaling) showed significant improvement in quality of life and in biochemical indexes (increased parietal-cell mass and gastric acidity); however, more data are needed to inform the role of this medication in treatment.

Q: What infections have been associated with a Menetrier’s disease-like condition?

A: A Menetrier’s disease-like condition with transient protein-losing gastropathy, hypoalbuminemia, and marked gastric rugal hypertrophy has been reported in association with CMV [cytomegalovirus] infection, mainly in pediatric patients. Menetrier’s disease has also been reported in association with H. pylori. CMV-associated Menetrier’s disease differs from classic Menetrier’s disease in its acute self-limited course and more focal involvement of the gastric fundus, antrum, or both.

Thrombosis Risk after 6-Weeks Postpartum

Posted by Sara Fazio • April 4th, 2014

Using administrative claims data, the authors of a new study published in NEJM found significantly increased risks for primary thrombotic events beyond the 6-week postpartum period, when the risk is well recognized to be high. However, absolute increases in risk from 7 to 12 weeks after delivery were small.

Pregnancy significantly increases the risk of thrombosis. This heightened thrombotic risk rises further during the postpartum period, which is conventionally defined as the 6 weeks after delivery.

Clinical Pearls

What is known about the prothrombotic state of the postpartum period and what are current recommendations for women at high risk for venous thromboembolism?

As compared with the nonpregnant state, the 6-week postpartum period is associated with increases by a factor of 3 to 9 in the risk of  stroke, by a factor of 3 to 6 in the risk of myocardial infarction, and by a factor of 9 to 22 in the risk of venous thromboembolism. It is unknown whether these risks remain increased after the conventionally defined 6-week postpartum period. Guidelines for the treatment of thrombotic disorders during pregnancy advise the discontinuation of prophylactic therapy at 6 weeks after delivery in women at high risk for venous thromboembolism.

In this study, what was the odds ratio of having a thrombotic event within 6 weeks after delivery compared to the same period one year later?

Significantly more thrombotic events occurred within 6 weeks after delivery than during the same period 1 year later (411 events, or 24.4 events per 100,000 deliveries, vs. 38 events, or 2.3 events per 100,000 deliveries), corresponding to an absolute risk difference of 22.1 (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.8 (95% CI, 7.8 to 15.1).

Morning Report Questions

Q: What did this study demonstrate with respect to thrombotic risk in women after the 6-week postpartum period?

A: In the period of 7 to 12 weeks after delivery, there was a modest but still significant increase in the number of thrombotic events, as compared with the same period 1 year later (95 events, or 5.6 events per 100,000 deliveries, vs. 44 events, or 2.6 events per 100,000 deliveries), corresponding to an absolute risk difference of 3.0 (95% CI, 1.6 to 4.5) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.5 to 3.1). The risk was no longer significantly elevated after 12 weeks, with an odds ratio of 1.4 (95% CI, 0.9 to 2.1) for the period of 13 to 18 weeks after delivery and an odds ratio of 1.0 (95% CI, 0.7 to 1.4) for the period of 19 to 24 weeks after delivery. In post hoc exploratory analyses, the thrombotic risk was increased during the period of 13 to 15 weeks after delivery (odds ratio, 2.0; 95% CI, 1.1 to 3.6) but was no longer elevated in the period of 16 to 18 weeks (odds ratio, 1.0; 95% CI, 0.6 to 1.8).

Table 2. Number and Rate of Postpartum Thrombotic Events during Sequential 6-Week Intervals after Labor and Delivery.

Q: What characteristics of patients were associated with a higher risk of postpartum thrombosis?

A: As compared with patients without postpartum thrombosis, those with postpartum thrombotic events were older, were more likely to be white or black than Hispanic or Asian, were less often privately insured, and were more likely to have risk factors for thrombosis. There was also a significantly higher risk within 6 weeks after delivery among women who had undergone cesarean section than among those who had undergone vaginal delivery.

Table 1. Baseline Characteristics of the Patients, According to the Presence or Absence of a Postpartum Thrombotic Event.

Adenoma Detection Rate and Colorectal Cancer

Posted by Daniela Lamas • April 2nd, 2014

Your patient recently celebrated her 50th birthday. After a few weeks of partying, she’s ready to turn to the less glamorous work that comes with having lived half a century.  First up is the colonoscopy.

She’s impressively well informed and so it’s not a surprise when she comes to your primary care office with a question. She read that the percentage of a gastroenterologist’s colonoscopies that find pre-cancerous polyps, the so-called “adenoma detection rate,” is an important marker of a doctor’s ability to perform high-quality colonoscopies. She wants to know what you think – is one colonoscopy as good as another, or should she care about the adenoma detection rate?

Your gut answer is yes. After all, various professional societies have recommended adenoma detection rate cut-offs of higher than fifteen percent for female patients and twenty-five percent for male patients as indicators of quality colonoscopies. And the Center for Medicare Services recently proposed that this rate become a reportable quality measure.

But the data supporting this assumption have been scant – until now. In this week’s issue of NEJM, Douglas Corley and colleagues report that yes, patients of physicians with a higher adenoma detection rate have lower rates of colon cancer in the years after colonoscopy.

To investigate their question, researchers examined the records of approximately 300,000 colonoscopies, performed by 136 gastroenterologists. They calculated the adenoma detection rate for each gastroenterologist and found this figure to range broadly between physicians, from a low of under 10 percent to a high of just over 50 percent. The researchers then followed the patients who’d undergone colonoscopies for up to 10 years and monitored for the development of interval cancers – defined as colon cancer diagnosed between six months and ten years after colonoscopy.

The findings are impressive. When researchers split the patients into five groups based on their physicians’ adenoma detection rates, they found that the risk of interval cancers – that includes advanced colon cancer and fatal colon cancer – decreased in a linear fashion as adenoma detection rates increased.  That meant patients of physicians with the highest adenoma detection rates were nearly half as likely to be diagnosed with an interval cancer than those whose physicians were in the lowest group. In fact, each one percent increase in adenoma detection rate brought with it a three percent decrease in interval cancer risk and a five percent decrease in risk of fatal colon cancer.

In their discussion, the authors note that in addition to better detection of pre-cancerous lesions leading to decreased rates of subsequent cancers, it’s also possible that those physicians who detected more adenomas performed better resections. That question isn’t answered by the current results. We also don’t know the effect of different qualities of bowel preparation, length of the exams in the different groups, or differences in the complication rates.

Ultimately, these results establish an association between higher adenoma detection rates and decreased colon cancer incidence, not a causal link. Despite that limitation, the authors conclude that their findings “support the validity of adenoma detection rate as a quality measure of physicians’ performance of colonoscopy in community practice.”

For your patient? Just get the colonoscopy.

Nutrition in Critical Illness

Posted by Sara Fazio • March 28th, 2014

The latest review in the Critical Care series covers current knowledge related to the initiation of enteral or parenteral feeding among critically ill patients in the ICU.

Critically ill patients who require vital organ support in the intensive care unit (ICU) commonly have anorexia and may be unable to feed volitionally by mouth for periods ranging from days to months. Unless such patients are provided with macronutrients in the form of enteral or parenteral nutrition, they accumulate an energy deficit that rapidly reaches proportions that contribute to lean-tissue wasting and that are associated with adverse outcomes.

Clinical Pearls

What were the results of the Trophic vs. Full-Energy Enteral Nutrition in Mechanically Ventilated Patients with Acute Lung Injury (EDEN) trial?

In the EDEN trial, investigators addressed the question of how much enteral nutrition should be administered early during critical illness. In this study, 1000 relatively young and well-nourished patients with acute lung injury who were in the ICU and who were considered to be eligible for enteral nutrition were randomly assigned to receive either just a small amount of (trophic) enteral feeding for 1 week in the ICU or full enteral feeding from the time of admission onward. Although the patients in the group receiving trophic feeding accumulated a substantially greater nutritional deficit than did the group receiving full enteral feeding for 1 week, there was no between-group difference in acute or long-term functional outcomes.

Figure 1. Comparison of Macronutrient Intake and Outcomes of Five Randomized, Controlled Trials Evaluating Nutrition during Critical Illness.

How does gastric residual volume impact the ability to feed patients enterically during critical illness?

Among patients in the ICU, gastric emptying is often slow or impaired, which can result in large gastric residual volumes with enteral feeding. Since regurgitation of gastric content can lead to aspiration pneumonia, enteral feeding is often discontinued inpatients who are found to have large gastric residual volumes. The Gastric Residual Volume during Enteric Nutrition in ICU Patients (REGANE) trial (involving 329 patients) showed that gastric residual volumes up to 500 ml could be safely tolerated. The Effect of Not Monitoring Residual Gastric Volume on the Risk of Ventilator-Associated Pneumonia in Adults Receiving Mechanical Ventilation and Early Enteral Feeding (NUTRIREA 1) trial (involving 449 patients) showed that the omission of the measurement of gastric residual volumes did not increase the incidence of aspiration or related complications. Interestingly, the two studies showed that allowing large gastric residual volumes increased the amount of enteral feeding that was administered early during critical illness but did not affect clinical outcomes.

Morning Report Questions

Q: What were the results of the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC) trial?

A: In a large, randomized, controlled trial — the EPaNIC trial — patients in the intervention group received early parenteral nutrition to supplement insufficient enteral nutrition. After 1 week in the ICU, the delivered enteral nutrition in the two study groups was approximately 20% of the estimated energy requirements. Unexpectedly, patients who received insufficient enteral nutrition had an earlier live discharge from the ICU and hospital, a lower incidence of new ICU infections and of ICU-acquired weakness, and a lower duration of vital-organ support than did patients receiving supplemental parenteral nutrition. There were substantial cost savings in the group not receiving the parenteral nutrition, which were explained largely by a reduced need for antibacterial and antifungal drugs. Results were consistent regardless of the type or severity of illness.

Q: What are recommendations about the type of lipids employed in nutritional formulations?

A: The type of lipid used in nutritional formulations may affect inflammation. N-3 fatty acids that are present in fish oil have been shown to have antiinflammatory effects, n-9 fatty acids that are present in olive oil have a more neutral immune effect, and n-6 fatty acids in soybean oil are proinflammatory. On the basis of low circulating levels of n-3 fatty acids in patients with acute lung injury and the proinflammatory properties of n-6 fatty acids, the lipid profile of nutrients for such patients was hypothesized to contribute to the development or worsening of acute lung injury. In three pioneering studies involving a total of 411 patients, a modified enteral-feeding program with increased ratios of n-3 fatty acids to n-6 fatty acids resulted in reduced rates of death and new organ failure, along with reduced durations of stay in the ICU, as compared with a feeding program that was based on lipids present in corn or canola oil. The most recent and largest trial, the OMEGA study, was stopped prematurely for futility when it showed no benefit with the enteral administration of n-3 fatty acids plus antioxidant supplements in 272 patients. In addition, this study showed fewer ventilator-free days and longer stays in the ICU among patients in the n-3 group. Parenteral preparations based on fish oil have not been shown to benefit patients in the ICU, and the use of olive oil (an n-9 fatty acid), as compared with soybean oil, did not affect either inflammation or outcomes in a trial involving 100 patients in the ICU. Currently, the lack of high-quality evidence precludes any recommendation on the use of specific lipids in critically ill patients.

45-Year-Old Man with a Rash

Posted by Sara Fazio • March 28th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 45-year-old man was admitted to the hospital because of diffuse, purple, blanching livedo over his arms and legs and signs of severe sepsis. Three days before presentation, the patient was bitten on his hands and forearms while bathing his dog. A diagnostic test result was received.

With respect to infections related to dog bites, one needs to consider organisms that colonize human skin and can be inoculated into the soft tissue through a dog bite. Staphylococcal and streptococcal species are common infecting organisms that can cause sepsis. Pasteurella multocida and Capnocytophaga canimorsus are considered normal oral flora in dogs.

Clinical Pearls

What are the characteristics of infection with Pasteurella multocida after a dog bite?

Infection with P. multocida, a gram-negative coccobacillus, can resemble the rapidly progressive soft-tissue infections caused by Streptococcus pyogenes, and there can be evidence of a wound infection hours after injury. P. multocida infection commonly causes cellulitis or abscesses; it can cause bacteremia, pneumonia, meningitis, and endocarditis, although these infections are less common. The organism is easy to culture and relatively sensitive to antibiotic agents.

What are the manifestations of Capnocytophaga canimorsus infection?

C. canimorsus is a fastidious gram-negative bacillus that can cause overwhelming infection after a dog or cat bite. Patients with C. canimorsus infection present with symptoms ranging from cellulitis and local infection to meningitis, endocarditis, sepsis, and shock. Many cases of severe systemic C. canimorsus infection are associated with such underlying risk factors as splenectomy, alcoholism, cirrhosis, or immunosuppression, although in approximately 40% of cases, no identifiable risk factor is found. The end of the incubation period for C. canimorsus is typically marked by the abrupt onset of symptoms. Physical examination usually reveals a purpuric rash that can evolve to purpura fulminans and frank gangrene. The clinical manifestations of sepsis are caused by a profound inflammatory response that leads to microvascular injury and endothelial damage; if hypoperfusion and inflammation persist, then disseminated intravascular coagulation, gangrene, multiorgan failure, and death can occur. A patient’s clinical history is the key to the diagnosis of C. canimorsus infection, because the organism is difficult to culture and may take up to 14 days to identify.

Morning Report Questions

Q: What are the tenets of treating patients with sepsis?

A: The guidelines of the 2008 Surviving Sepsis Campaign include fluid resuscitation for intravascular volume expansion, with crystalloids for urine output (goal, >0.5 ml per kilogram per hour), optimization of mean arterial pressure at more than 65 mm Hg, maintaining central venous pressure at a goal of 8 to 12 mm Hg and central venous oxygen saturation at >70%. Lactic acid clearance should be monitored closely, because it indicates the success of the resuscitation in improving tissue perfusion. Patients should be pancultured and soon after arrival receive broad-spectrum antibiotics in addition to circulatory support.

Q: What is purpura fulminans?

A: Purpura fulminans is a syndrome most commonly related to an acute infectious process that is characterized by intravascular thrombosis and hemorrhagic skin infarction. It is rapidly progressive, and accompanied by disseminated intravascular coagulation and overall vascular collapse. The hallmark findings in acute infectious purpura fulminans are fever, hypotension, large purpuric skin lesions, and disseminated intravascular coagulation. Meningococcus infection is commonly associated with this condition, but it may also present in the setting of infection with varicella zoster virus, gram-negative bacilli, staphylococci, Rickettsia species, streptococci, and measles virus. Pathologic examination often reveals diffuse arterial and venous thrombosis. Microscopic foci of acute inflammation may be present in the vascular adventitia.

Prevalence of Health Care–Associated Infections

Posted by Joann Schulte • March 26th, 2014

Over 30 years ago, Dr. Robert Haley, now a professor of medicine at UT Southwestern in Dallas, led the CDC in pioneering work to apply epidemiology methods to hospital infection control.  The Study on the Efficacy of Nosocomial Infection Control Project (SENIC), published in 1985, found that hospitals with active infection control programs had 32% lower incidence of nosocomial infections.   SENIC was the cornerstone of efforts to monitor, control and prevent infections in health care settings.  A study published this week in NEJM shows the work is still vital and needed.

The article by Dr. Shelley MacGill and colleagues in 10 geographically diverse states is a prevalence study estimating 4% of patients had a hospital-acquired infection (HAI) during 2011.  Such prevalence surveys have been used in other countries to describe the scope of HAIs.   The current work by CDC and 183 U.S. hospitals included 11,282 patients and found the Clostridium difficile was the most common pathogen, causing 12.1% of HAIs.  The No. 2 pathogen was Staph aureus.  The most common types of infections were pneumonia (21.8%), surgical site infections (21.8%) and gastrointestinal infections (17.1%).

The investigators also reported device-related infections caused by central lines, catheters and ventilators and other devices, caused 25.6% of HAIs.   However, infections not associated with devices or operative procedures caused about half of all HAIs reported in the study.  The authors suggested that more work is needed to define the risks for those HAIs and development of effective prevention measures.  Currently most hospitals limit their reporting to device-related HAIs, surgical site infections and infections caused by C. difficile and methicillin-resistant S. aureus.  The current study is important because it provides a more complete modern picture on the overall HAI burden and its distribution across a spectrum of patient types.

A limitation of the study is that it focused on hospitals, not other health care facilities such as skilled-nursing facilities and other long-term care facilities.  Further work is needed in those areas since hospital stays have become shorter and many patients are now cared for in rehabilitation and chronic facilities.

Clearly the work that Dr. Haley started in health-care infections has taken root and may need expansion beyond the acute-care setting.

Global Health Author Q&A: Anne Mills of the London School of Hygiene and Tropical Medicine

Posted by Jennifer Zeis • March 24th, 2014

In a feature for Now@NEJM, we ask the authors of the Global Health review article series — all with different backgrounds, experiences, and perspectives — the same set of questions.

Answers from Anne Mills, D.H.S.A., Ph.D., of the London School of Hygiene and Tropical Medicine, London

Professor Mills is the author of the February 6, 2014, article, “Health Care Systems in Low- and Middle-Income Countries.”

What do you regard as the most significant triumph in global health within the past decade?

I don’t think it is yet a triumph, but at least there is virtually universal recognition that a health care system exists and is critical for delivering effective preventive and curative health care for the population in low and middle income countries.

Though I don’t think we have done a good enough job of describing what a health care system is and its importance. Anyone growing up in a high-income country appreciates the benefits of a health care system every day. They go to their primary care practitioner; they use their hospitals. They understand the relationship between their hospital and the broader management and regulatory system within which it is located. I struggle to understand how donors in the rich world can be blind to the importance of a health care system in supporting the delivery of specific interventions.

I don’t think we have done a good enough job of describing what a health care system is and its importance.

In the coming decade, which arena of global health do you feel warrants increased attention and awareness?

Of course the health care system! Low- and middle-income countries need to build or strengthen an efficient and effective health care system. We need better knowledge on the best design features for health care systems in differing country contexts. For this we need much greater funding for health system research. This is an important area of scientific enquiry but not yet sufficiently recognised as such.

How can we best harness the revolution in IT to improve health outcomes in the developing world?

IT has a critical role to play in supporting the delivery of health care. It can connect remote practitioners to central sources of advice. It can provide information to patients on how best to manage their condition and it is the basis of management information systems which can help monitor and improve health care delivery.

When American physicians think of global health, many are dissuaded from a global health career because they cannot spend a majority of their time abroad.  What are other ways for physicians to contribute to this discipline?

It is critical that global health be “everyone’s business.” To improve health outcomes in the world we need much greater awareness of health disparities across the world, and especially of what can be done to reduce them. Physicians, as highly educated professionals, have a critical role to play in spreading information and encouraging informed debate.


Benign Paroxysmal Positional Vertigo

Posted by Sara Fazio • March 21st, 2014

Benign paroxysmal positional vertigo is characterized by brief spinning sensations, which are generally induced by a change in head position with respect to gravity. Treatment involves canalith-repositioning maneuvers, which are reviewed in detail in this new Clinical Practice article.

Benign paroxysmal positional vertigo (BPPV) is by far the most common type of vertigo, with a reported prevalence between 10.7 and 64.0 cases per 100,000 population and a lifetime prevalence of 2.4%.

Clinical Pearls

• What are the typical presentation, epidemiology, and risk factors for the development of BPPV?

The condition is characterized by brief spinning sensations, usually lasting less than 1 minute, which are generally induced by a change in head position with respect to gravity. Vertigo typically develops when a patient gets in or out of bed, rolls over in bed, tilts the head back, or bends forward. Even though patients with BPPV occasionally report persistent dizziness and imbalance, a careful history taking almost always reveals that their symptoms are worse with changes in head position. Many patients also have nausea, sometimes with vomiting. Attacks of BPPV usually do not have a known cause, although cases may be associated with head trauma, a prolonged recumbent position (e.g., at a dentist’s office), or various disorders of the inner ear. Spontaneous remissions and recurrences are frequent; the annual rate of recurrence is approximately 15%. Patients with BPPV are at increased risk for falls and impairment in the performance of daily activities. The prevalence of idiopathic BPPV is increased among elderly persons and among women, with peak onset between 50 and 60 years of age and a female-to-male ratio of 2:1 to 3:1.

• What is the underlying pathophysiological process in BPPV?

The fundamental pathophysiological process in BPPV involves dislodged otoconia from the macula of the utricular otolith that enter the semicircular canals. When there is a change in the static position of the head with respect to gravity, the otolithic debris moves to a new position within the semicircular canals, leading to a false sense of rotation. BPPV usually arises from the posterior semicircular canal, which resides in the most gravity-dependent area of the labyrinth; this type of BPPV accounts for 60 to 90% of all cases.

Morning Report Questions

Q: How is the diagnosis made in patients with BPPV that involves the posterior canal?

A: In patients with BPPV that involves the posterior canal, nystagmus is typically induced with the use of the Dix-Hallpike maneuver. In this maneuver, with the head turned to one side at angle of 45 degrees, the patient is moved from a sitting position to supine position, with the head hanging below the examination table. The induced nystagmus is upbeat and ipsiversive torsional (the upper pole of the eyes beats toward the side of the affected [lower] ear). When there is movement of otolithic debris (canalolithiasis) in the posterior canal away from the cupula, the endolymph flows away from the cupula, stimulating the posterior canal. The nystagmus usually develops after a brief latency period (2 to 5 seconds), resolves within 1 minute (typically within 30 seconds), and reverses direction when the patient sits up. With repeated testing, the nystagmus diminishes, owing to fatigability. If the otoconia become attached to the cupula (cupulolithiasis), the evoked nystagmus is similar to that observed in canalolithiasis but is usually longer in duration. A positive response to the Dix-Hallpike maneuver, in which the nystagmus beats in the correct direction, is the standard for diagnosing BPPV involving the posterior canal.

Table 2. Diagnosis and Treatment of Benign Paroxysmal Positional Vertigo According to the Affected Canal.

Figure 1. Use of the Dix-Hallpike Maneuver to Induce Nystagmus in Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.

Video. Maneuvers to Diagnosis and Treat Benign Paroxysmal Positional Vertigo.

Q: How is BPPV treated?

A: BPPV typically resolves without treatment. A prospective longitudinal study showed that the median interval between the onset of symptoms and spontaneous resolution in untreated patients was 7 days when the horizontal canal was affected and 17 days when the posterior canal was affected. However, canalith-repositioning maneuvers can be used to treat BPPV promptly and effectively. Medications are primarily used to relieve severe nausea or vomiting. For example, Epley’s canalith-repositioning maneuver was designed to flush mobile otolithic debris out of the posterior canal and back into the vestibule. The otoconia move around the canal with each step of the maneuver and eventually drop out into the vestibule, where they can be resorbed. Each position should be maintained until the induced nystagmus or vertigo dissipates, but always for at least 30 seconds. The success rate with Epley’s maneuver is about 80% after one session and increases to 92% with repetition up to four times. The Semont maneuver can also be used to treat BPPV involving the posterior canal.

Figure 2. Epley’s Canalith-Repositioning Maneuver for the Treatment of Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.

Figure 3. Semont’s Repositioning Maneuver for Benign Paroxysmal Positional Vertigo Involving the Right Posterior Semicircular Canal.