Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit

Posted by • July 6th, 2016

2016-07-06_12-55-31Ms. G is a 42-year-old woman admitted to your ICU with septic shock in the setting of a urinary tract infection.  She was started on a norepinephrine infusion in the emergency room. Her labs reveal a creatinine of 3.0 mg/dL, increased from a prior baseline of 0.6 mg/dL; pH is 7.3 and potassium is 4.9 mEq/L. Her urine output is dropping, despite the fact that she received crystalloids for fluid resuscitation. In other words, she has clear signs of acute kidney injury (AKI). You remember the “AEIOUs,” the mnemonic for the indications for urgent dialysis – acidosis, electrolyte derangement, intoxications, overload, uremia. Ms. G doesn’t meet any of these criteria yet, but you are worried about her.  Will delaying dialysis cause her harm?

A study published online in May and appearing in this week’s NEJM aims to answer this clinical question.  Prior studies have suggested a possible mortality benefit from early renal-replacement therapy (RRT), which can facilitate tighter control of volume status and potential prevention of uremic complications such as coagulopathy and encephalopathy.  This present trial, which took place in 31 ICUs in France, enrolled adult patients with severe acute kidney injury (AKI) from acute tubular necrosis and who required mechanical ventilation, vasopressors or both and randomized them either an early or delayed strategy for renal-replacement therapy. Dialysis was initiated as soon as possible after randomization in the early strategy, while the patients in the delayed-strategy group were dialyzed only if they met one of several specific indications, such as hyperkalemia, acidemia, uremia, severe oliguria or anuria. Patients in both groups could be treated with either intermittent hemodialysis (HD) or continuous veno-venous hemofiltration (CVVH).

Of 620 patients enrolled, 312 were randomized to early strategy and 308 to delayed strategy.  98% of the patients in the early-strategy group underwent dialysis, as compared with only 51% patients in the delayed-strategy group. The primary outcome was mortality at 60 days, which did not differ between the two groups (48.5% in early vs. 49.7% in delayed group). There was also no difference between the two groups in a number of pre-specified secondary outcomes, including number of ventilator-free days, vasopressor-free days, length of stay in the ICU, and need for RRT at day 28 and 60. The delayed-strategy group had fewer days with dialysis catheters, and notably also fewer bloodstream infections.

Almost 50% of patients in the delayed-strategy group never received dialysis. The patients in the delayed-strategy group also were observed to have more rapid recovery of renal function.

The authors acknowledge several limitations to their study. Notably, 50% of the patients received HD initially, and only 30% received solely CVVH during their treatment. While prior meta-analyses have not supported a benefit of one method of RRT over another in the critical care setting, there are possible downsides to HD that could influence outcomes.  The authors are careful not to overreach the claims based on the trial results; they recommend careful surveillance when deciding to delay RRT and rapid initiation of dialysis if and when acute indications arise.

In an accompanying editorial, Dr. Ravinda Mehta, Professor of Medicine in the Division of Nephrology at the University of California, San Diego, notes that the trial has good methodology and clear outcomes, but highlights the need for “dynamic risk-stratification tools to identify patients who will not need renal replacement therapy.”

So, based on the results of this trial, you opt for a strategy of careful active surveillance for Ms. G. You continue to monitor her urine output and electrolytes closely, not initiating dialysis for now.  You are relieved when she never meets any indications for dialysis.   Her renal function improves, and she makes a full recovery.

The authors of this paper are available to answer your questions and discuss their research from July 6-16 on the NEJM Group Open Forum.  Join the discussion now!

Axial Spondyloarthritis

Posted by • July 1st, 2016

2016-06-27_11-33-18The classic clinical description of ankylosing spondylitis was made in the late 1800s and was refined by the addition of radiographic descriptions during the 1930s. Pathological investigation revealed the importance of enthesitis (inflammation at sites of ligamentous attachment to bone) and synovitis. The identification in 1973 of a very strong association with human leukocyte antigen B27 (HLA-B27) led to heightened awareness of the disorder. The concept of spondyloarthritis was proposed in 1974 to emphasize the interrelatedness of ankylosing spondylitis and several other conditions that had previously been described separately. Spondyloarthritis is currently classified as predominantly axial, affecting the spine, pelvis, and thoracic cage, or predominantly peripheral, affecting the extremities.

This new Review Article summarizes the clinical definition of ankylosing spondylitis and axial spondyloarthritis, discusses the pathogenesis of these conditions, and reviews approaches to management.

Table 1. Current and Classic Classifications of Spondyloarthritis.

Clinical Pearl

• Name some features of the inflammatory back pain that characterizes axial spondyloarthritis.

Spondyloarthritis is differentiated from other causes of back pain when the nature and pattern of the pain and the age of the patient are considered. The most typical symptom is inflammatory back pain. Such pain is usually dull and insidious in onset and is felt deep in the lower back or buttocks. Another prominent feature is morning back stiffness that lasts for 30 minutes or more, diminishes with activity, and returns after inactivity. Although initially the back pain is intermittent, over time it becomes more persistent. Nocturnal exacerbation of pain is common, particularly during the second half of the night, forcing the patient to rise and move around. Pain is often present in the thoracic spine as well. Cervical involvement typically occurs late but can predominate. Pain in the chest occurs in more than 40% of patients with spondyloarthritis. If the source of the pain is not accurately diagnosed, patients may be subject to unnecessary diagnostic workups for cardiovascular disease or other intrathoracic diseases. Inflammatory back pain occurs in 70 to 80% of patients with ankylosing spondylitis and is relatively uncommon in patients whose pain has another source.

Table 2. Characteristics of Inflammatory Back Pain.

Clinical Pearl

• What are the classification criteria for axial spondyloarthritis?

In 2009, the Assessment of Spondylo Arthritis International Society (ASAS) formulated classification criteria for axial spondyloarthritis that were based on imaging, clinical, and laboratory criteria. With these criteria, the diagnosis is established in persons who have had back pain for 3 or more consecutive months before reaching 45 years of age, who have had the presence of sacroiliitis confirmed on MRI or plain radiography, and who have at least one clinical or laboratory finding that is characteristic of spondyloarthritis. Alternatively, persons with this history who have a positive test result for HLA-B27 plus two features of spondyloarthritis as detected on clinical examination or laboratory analysis also fulfill the criteria for a diagnosis of axial spondyloarthritis. The various criteria have an additive effect on the certainty of diagnosis. The ASAS criteria for axial spondyloarthritis have been criticized for introducing additional diagnostic heterogeneity, both by including both the imaging and nonimaging diagnostic groups together within the category of nonradiographic axial spondylitis and by including nonradiographic axial spondyloarthritis and ankylosing spondylitis together within the category of axial spondyloarthritis. These criteria will probably undergo further revision in coming years.

Figure 2. Algorithm for the Diagnosis or Exclusion of Axial Spondyloarthritis.

Figure 3. Pathogenic Mechanisms in Axial Spondyloarthritis.

Morning Report Questions

Q: What are some of the extra-articular manifestations of ankylosing spondylitis?

A: Acute anterior uveitis has a lifetime prevalence of 30 to 40% in patients with ankylosing spondylitis. Psoriasis occurs in more than 10% of patients with ankylosing spondylitis, and inflammatory bowel disease in 5 to 10%, with Crohn’s disease being more common than ulcerative colitis. Osteoporosis of the spine and peripheral bones is common in ankylosing spondylitis. The combination of spinal rigidity from the formation of syndesmophytes and osteoporosis within trabecular bone contributes to a spinal fracture rate that is as high as 10% among these patients and is associated with a high risk of devastating spinal cord injury.

Q: How is axial spondyloarthritis managed?

A: Treatment goals for axial spondyloarthritis include reducing symptoms, improving and maintaining spinal flexibility and normal posture, reducing functional limitations, maintaining the ability to work, and decreasing the complications associated with the disease. Nonsteroidal antiinflammatory drugs (NSAIDs), including selective inhibitors of cyclooxygenase 2, are the first-line drug treatment for pain and stiffness. Continuous NSAID treatment is recommended for persistently active, symptomatic disease, with doses adjusted in accordance with the severity of symptoms. For patients whose symptoms are not controlled by NSAID therapy or for whom NSAIDs have unacceptable side effects, the use of tumor necrosis factor (TNF) inhibitors is strongly recommended. In 13 randomized, controlled trials and many open-label studies, five TNF inhibitors —  infliximab, etanercept, adalimumab, golimumab, and certolizumab — have produced rapid, profound, and sustained improvement in both objective and subjective indicators of disease activity and patient functioning. Approximately 60% of patients have an adequate and usually sustained response to TNF inhibitors, often with partial or full remission of symptoms. The long-term use of systemic glucocorticoids is relatively contraindicated, partly because of the increased risk of vertebral osteoporosis, but may be unavoidable in some patients with severe uveitis or inflammatory bowel disease. Whether spondyloarthritis is active or stable, patients are advised to follow an active exercise program designed to maintain posture and range of motion.

A Man with Cloudy Vision

Posted by • July 1st, 2016

2016-06-27_11-38-42Syphilis can cause uveitis and retinitis. The uveitis can be anterior, posterior, or both (panuveitis) and can occur with or without a hypopyon (usually without).

A 50-year-old man with psoriatic arthritis and HIV infection presented with cloudy vision, decreased hearing, and gait instability. Two months earlier, the patient had begun taking antiretroviral medications. A diagnostic test result was received. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What is the most common retinal infection in patients with human immunodeficiency virus (HIV) infection?

Cytomegalovirus retinitis is the most common retinal infection in patients with HIV infection and is manifested by hemorrhagic or granular areas of retinitis with very slow progression.

Clinical Pearl

• What type of uveitis is associated with psoriatic arthritis?

Uveitis is a common finding in patients with psoriatic arthritis; such patients typically have nongranulomatous anterior uveitis (confined to the anterior chamber). Posterior-segment findings occasionally occur and include macular edema.

Morning Report Questions

Q: Describe some of the features of ocular syphilis.

A: Syphilis can affect every part of the eye and can result in a multitude of findings. It can cause retinal vasculitis, serous retinal detachment, posterior placoid chorioretinopathy, neuroretinitis, multifocal retinitis, and other findings, including ground-glass retinitis. Superficial retinal precipitates can also be present; they are presumed to be focal inflammatory accumulations on the retinal surface. In fact, superficial retinal precipitates are strongly suggestive of syphilis.

Figure 2. Imaging Studies of the Right Eye.

Q: How is ocular syphilis managed? 

A: In patients with ocular syphilis, especially those who present with an acute onset of symptoms, prompt initiation of antibiotic treatment is essential to prevent irreversible vision loss. A lumbar puncture is recommended for all patients with ocular syphilis or otosyphilis to determine whether there is concomitant involvement of the central nervous system, but antibiotic treatment should not be delayed if the patient declines to undergo a lumbar puncture or if the procedure cannot be performed promptly. Normal results of a cerebrospinal fluid analysis do not rule out ocular syphilis, because Treponema pallidum may infect the eye without infecting the brain or meninges. Immediate treatment for ocular syphilis should be given regardless of the results of cerebrospinal fluid analysis. Ocular syphilis, otosyphilis, and neurosyphilis (i.e., syphilis with brain or meningeal involvement) all require treatment with a 10-to-14-day course of high-dose intravenous penicillin. Glucocorticoids, such as prednisone, are often given concurrently with intravenous penicillin in patients with acute ocular syphilis or otosyphilis to reduce inflammation. After the course of intravenous penicillin is completed, some clinicians also give intramuscular penicillin G benzathine. Patients whose initial results of cerebrospinal fluid analysis are consistent with neurosyphilis should undergo a repeat lumbar puncture 6 months later to assess the response to treatment; some cases of neurosyphilis require retreatment.

Extending Aromatase-Inhibitor Treatment in Breast Cancer

Posted by • June 29th, 2016

2016-06-27_9-52-07I am approaching the end of my general surgery residency and trying to decide on a sub-specialty going forward.  Over the past 2 years I have found myself drawn to the field of breast surgery, in large part due to the large breadth of research being done in the field.  Research in breast cancer has pioneered many of the current oncologic concepts and therapy that exist today for many cancers beyond breast cancer.  However, we are far from having all the answers and are constantly trying to further our understanding of the disease.  Additionally, patient desires, emotions, and fears play a large factor, oftentimes making treatment decisions more of an art than a science.  A common theme that seems to emerge from much of the breast cancer research is the balance of risks and benefits, coupled with the patient’s concerns and preferences.  Decisions are required at almost every stage of breast cancer treatment: Lumpectomy or mastectomy…or even bilateral mastectomies? Radiation or no radiation?  Chemotherapy or no chemotherapy?  Adjuvant endocrine therapy or no endocrine therapy?  And now, another big question to be answered- how long should we continue that endocrine therapy?

While several previous studies have examined prolonged effects of extended adjuvant endocrine therapy, no study had specifically looked at extended aromatase-inhibitor therapy or duration of adjuvant endocrine therapy of more than 10 years.  An recent article in NEJM by Goss et al. addresses this question with a double-blind, randomized, placebo-controlled trial.  This study, the MA.17R trial, enrolled postmenopausal women with primary breast cancer who had previously received about 5 years of an adjuvant aromatase inhibitor, preceded by tamoxifen in the majority of women, and assigned them to either daily letrozole or placebo for 5 years.  Randomization was stratified based on several potential confounding factors: lymph-node status, prior receipt of adjuvant chemotherapy, the interval between the last dose of aromatase inhibitor and randomization, and the duration of prior receipt of tamoxifen.  The primary end point was disease-free survival, including any recurrence of breast cancer (local, regional, or metastatic) or the development of a new primary breast cancer.

1918 patients were randomized with 959 patients in each group.  Baseline characteristics of age, stage, and prior adjuvant endocrine therapy were similar between the two groups.  Overall daily adherence (assessed with questionnaires) was low, but similar between the two groups, 62.5% among those receiving letrozole and 62.3% among those receiving placebo.   5 year disease-free survival was 95% (95% confidence interval [CI], 93 to 96) in the letrozole group and 91% (95% CI, 89 to 93) in the placebo group. The hazard ratio for disease recurrence or the occurrence of contralateral breast cancer comparing letrozole to placebo was 0.66 (95% CI, 0.48 to 0.91; P=0.01).  The results remained similar when looking at the previously specified stratification groups.  There was no significant difference in overall survival between the 2 groups or when analyzing any of the prespecified subgroups.  Extended letrozole therapy significantly reduced the annual incidence rate of contralateral breast cancer with an annual incidence rate of 0.21% in the letrozole group and 0.49% in the placebo group (P =0.007),  with a hazard ratio of 0.42 (95% CI, 0.22 to 0.81).

Few women in both groups discontinued assigned treatment due to toxic effects (5.4% in the letrozole group vs. 3.7% in the placebo group) and non-bone related toxicity was low in both groups.  However, there was a higher rate of bone fracture and new onset osteoporosis in the letrozole group as well as a higher mean loss of bone mineral density in the hip.  The placebo group actually had an increase in bone mineral density in the hip and spine likely due to discontinuation of their prior endocrine therapy and concurrent use of bone-protecting medications, rates of which were high across both groups.  Overall quality of life was similar for both groups.

While results of this study appear promising, there are some limitations to the interpretation.  In the accompanying editorial, Drs. Chlebowski and Budoffoint out that the “the favorable side-effect profile in the MA.17R trial may be due to the self-selection of women who had limited side effects during previous treatment with letrozole.”  Additionally, the greatest effect seems to be in preventing contralateral breast cancers as opposed to reducing recurrences and there was no effect on overall survival which Chlebowski and Budoff  says “should not be surprising” as “the participants, who in most cases underwent randomization approximately 10 years after the time of diagnosis, have passed the peak risk of recurrence and a considerable proportion of their remaining risk as well.”  Regardless of these caveats, the results of this study have potentially large implications for changing treatment in post-menopausal breast cancer.  In the end, this will likely be another story of shared decision making as, per the editorialists, “oncologists and patients with breast cancer weigh the risks and benefits of the use of long-term adjuvant endocrine therapy.”

A Man with a Pruritic Rash

Posted by • June 24th, 2016

2016-06-17_12-33-39Although human T-lymphotropic virus type 1 (HTLV-1) is a retrovirus, it seems to induce a precancerous state that can lead to adult T-cell leukemia–lymphoma (a subtype of cutaneous T-cell lymphoma), instead of being directly carcinogenic. HTLV-1 is associated with a long latency period, and most affected patients are exposed to the virus early in life. The four clinical variants of adult T-cell leukemia–lymphoma — acute, lymphomatous, chronic, and smoldering — affect the clinical presentation and prognosis.

A 65-year-old man with end-stage renal disease and a history of syphilis presented with a leg injury and a diffuse pruritic rash. A recent serologic test had been positive for human T-lymphotropic virus type 1. A diagnostic procedure was performed. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What are some general features of cutaneous T-cell lymphoma?

Cutaneous T-cell lymphoma can be manifested by pruritic scaly plaques and papules that usually occur on the buttocks and other nonphotodistributed areas and appear gradually. There are many types of cutaneous T-cell lymphoma. Mycosis fungoides accounts for the majority of cases of T-cell lymphoma with cutaneous involvement (approximately 65%), whereas adult T-cell leukemia–lymphoma accounts for less than 1% of cases. Mycosis fungoides can be manifested by a patch, plaque, or tumor and may also progress to involve the lymph nodes and viscera.

Clinical Pearl

• HTLV-1–associated adult T-cell lymphoma–leukemia occurs most commonly in patients living in what geographic regions?

HTLV-1–associated adult T-cell leukemia–lymphoma occurs most frequently in patients who live in areas where HTLV-1 is endemic, such as the Caribbean basin, southwestern Japan, and parts of South American and central Africa, but it can also be identified in the United States.

Figure 1. Clinical Photographs.

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

Morning Report Questions

Q: Is adult T-cell leukemia–lymphoma difficult to distinguish from mycosis fungoides?

A: The diagnosis of adult T-cell leukemia–lymphoma with cutaneous involvement is challenging because it mimics other forms of T-cell lymphoma with cutaneous involvement, particularly mycosis fungoides. Skin biopsies from patients with adult T-cell leukemia–lymphoma often initially lead to a diagnosis of mycosis fungoides. Findings that suggest that cutaneous patches or plaques are caused by adult T-cell leukemia–lymphoma instead of mycosis fungoides include increased expression of CD25 and distribution of the patches or plaques in photodistributed areas. Among patients who live in areas where HTLV-1 is endemic, serologic testing for HTLV-1 may be positive both in those with adult T-cell leukemia–lymphoma and in those with mycosis fungoides. Thus, in a patient who has HTLV-1 infection, the accurate diagnosis of adult T-cell leukemia–lymphoma requires evidence of proviral DNA integration, obtained by means of direct polymerase-chain-reaction testing of skin lesions.

Figure 3. Skin-Biopsy Specimen (Immunoperoxidase).

Table 2. Features of Mycosis Fungoides and Adult T-Cell Leukemia–Lymphoma.

Q: What is the prognostic implication of cutaneous involvement in adult T-cell leukemia–lymphoma?

A: Approximately 50% of patients with adult T-cell leukemia–lymphoma have some form of cutaneous involvement, such as patches, plaques, papules, nodules, tumors, erythroderma, or purpura. The type of skin lesion is of prognostic importance, since the survival rate is lower among patients with erythroderma or tumors than among patients with only patches or plaques. Among patients with acute or lymphomatous adult T-cell leukemia–lymphoma, cutaneous involvement has been associated with a decreased survival rate.


Body-Mass Index in Adolescents

Posted by • June 24th, 2016

2016-06-17_10-36-07Overweight and obesity in adolescents have increased substantially in recent decades and affect a third of the adolescent population in some developed countries. Twig et al. assessed the risk of fatal cardiovascular events in adulthood according to the body-mass index range during adolescence, using a national database of 2.3 million Israeli adolescents in whom height and weight were measured between 1967 and 2010.

In this study, a range of values for body-mass index that were well within the accepted normal range in adolescence predicted increased cardiovascular and all-cause mortality during 40 years of follow-up. A new Original Article summarizes.

Clinical Pearl

• In developed countries, how do trends in cardiovascular mortality among young adults compare to those among older age groups?

In contrast to the steep decline in the rate of death from cardiovascular causes among older age groups, cardiovascular mortality among young adults has not decreased or the decline has slowed in several developed countries.

Clinical Pearl

• Is the association between body-mass index and increased risk of subsequent cardiovascular mortality limited to those who are overweight or obese?

Some, although not all, studies suggest that a BMI that falls within the upper-normal range in adolescence is associated with an increased risk of death from cardiovascular causes, although a determination of the BMI threshold that is associated with such an increased risk remains uncertain.

Morning Report Questions

Q: Is there evidence of an association between an adolescent BMI in the mid-normal range and an increased risk of subsequent cardiovascular mortality?

A: The large size of the study by Twig et al., which incorporated more than 42 million person-years of follow-up, provided adequate statistical power to assess the associations within the currently accepted normal range of BMI values. Excess all-cause mortality (including cardiovascular mortality) starting at the 50th percentile of adolescent BMI values confirmed the findings of an earlier study on a portion of this cohort. Thus, the classification of BMI according to the accepted normal range (i.e., the 5th to 84th percentiles and a BMI ranging from 18.5 to 25.0) may underestimate the risk associated with being overweight in adolescence. This inference is supported by findings of the current study of Twig et al. that there is a graded increase in the risk of death starting at the mid-normal range of adolescent BMI (50th to 74th percentiles) and that the high-normal BMI range (75th to 84th percentiles) was associated with hazard ratios of 2.2 for coronary heart disease and 1.8 for total cardiovascular causes.

Table 2. Duration of Follow-up and Cause of Death, According to Percentile of BMI during Adolescence.

Table 3. Hazard Ratios for Cause of Death, According to Percentile of BMI during Adolescence.

Figure 2. Body-Mass Index (BMI) during Adolescence and Subsequent Cardiovascular Mortality.

Q: Does the association between cardiovascular mortality and increased BMI in adolescence take decades to become evident?

A: Twig et al. found that, in calculations of the risk of death from total cardiovascular causes at different follow-up times and 10-year intervals, the association between cardiovascular mortality and increased BMI was evident by 10 years of follow-up (hazard ratio, 2.0; 95% CI, 1.1 to 3.9) and was more pronounced during the follow-up period from 30 to 40 years (hazard ratio, 4.1; 95% CI, 3.1 to 5.4).

Sudden Cardiac Death in the Young

Posted by • June 22nd, 2016

2016-06-22_10-01-53Fatal heart conditions are shocking and tragic when they are sudden and unexpected, and especially when they occur in the young. Occasionally the public is reminded of this via a news story of a high school or professional athlete who collapses suddenly and dies during a sporting event. Often, the first manifestation of a serious heart condition in the young is also the last.

What are common causes of sudden cardiac death in the young?  

A number of structural and arrhythmogenic heart conditions are associated with sudden cardiac death.  The list includes hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathies, myocarditis, congenital long-QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia.  Most of these conditions have a genetic basis.

What is this study about?

In this week’s issue of NEJM, Bagnall and colleagues present their findings from a prospective population-based observational study evaluating the incidence and cause of sudden cardiac death in individuals ages 1-35 years in Australia and New Zealand during a 2-year period from 2010 to 2012.  The investigators collected autopsy information, demographic information, and clinical data, including genetic and laboratory information, about the deceased.

How is sudden cardiac death defined?

Various criteria have been used to define sudden cardiac death in the medical literature.  However, the investigators defined sudden cardiac death as a sudden unexpected death in an otherwise healthy person within one hour of symptom onset, or within 24 hours of being seen well by others. Sudden unexplained death was defined as sudden cardiac death without clear cause of death identified after a complete and comprehensive autopsy examination.

What did they find?

Four hundred ninety sudden cardiac death cases were identified.  The mean age was 24 years with a male predominance of slightly greater than 70% of the cases.  Nearly 40% of the individuals died during sleep.  The annual incidence was 1.3 per 100,000 persons aged 1-35 years.  The age group at highest risk for sudden cardiac death was those in the 31-35 years group (3.2 per 100,000).

Forty percent of the cases had structurally normal hearts and were designated sudden unexplained deaths. The most common explained causes of sudden cardiac death were coronary artery disease (24%) and inherited cardiomyopathies (16%).   For all age subgroups, unexplained death was the most common finding except for those 31-35 years, where coronary artery disease was most common.

In nearly 30% of the sudden unexplained death cases, a clinically relevant cardiac gene mutation was identified.  During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 12% of the families.

What is my take-away?

Unexplained sudden cardiac deaths in the young account for 40% of the cases.  While we often think about coronary artery disease as a disease occurring in the older population, nearly 25% of the cases in this study had coronary artery disease leading to sudden cardiac deaths with the highest risk in those in the older age group (31-35).  Genetic testing was able to identify a clinically relevant cardiac gene mutation for nearly one-third of the sudden unexplained death cases and increased the likelihood of identifying a possible cause of death in individuals over autopsy alone. According to NEJM Deputy Editor Dr. John Jarcho, “This study suggests that genetic testing is a useful addition to standard autopsy procedures in cases of sudden cardiac death in the young. However, there still remain many such cases for which no cause can be found.”

Announcing NEJM Resident 360

Posted by • June 21st, 2016

res360_logoNo one said residency would be easy. But it doesn’t have to be quite so hard. NEJM Resident 360, a new website and discussion platform from NEJM Group, gives residents the information, resources, and support they need to approach each rotation with confidence.

  • Rotation Prep helps residents solidify their foundational medical knowledge with materials that have been written and curated by a team of physician experts, fellows and residents, and are mapped to 14 common residency rotations in internal medicine. Each rotation includes brief topic overviews, links to landmark trials, and review articles from NEJM and other highly respected sources, and a selection of questions from NEJM Knowledge+.
  • Learning Lab provides further educational and interactive tools that explain the medical literature, demonstrate procedures, and hone diagnostic skills.
  • Resident Lounge and Career sections feature resources that address social pressures and aim to inspire and assist with professional growth, including podcasts, blog posts, and professional articles.
  • Discussions engage residents with experts and one another on a variety of clinical, career, and resident life topics.

Residents are encouraged to register with NEJM Resident 360 by creating a personal profile, which enables participation in discussions. Access to Rotation Prep is a benefit of any institutional or individual subscription to an NEJM Group product: the New England Journal of Medicine, NEJM Journal Watch, or NEJM Knowledge+.

For more information, visit


A Woman with a Pleural Effusion

Posted by • June 16th, 2016


A 52-year-old woman presented with a unilateral pleural effusion. Several weeks later, uterine bleeding, pelvic fullness, and bloating developed. Magnetic resonance imaging revealed a large pelvic mass. Diagnostic procedures were performed. A new Case Record of the Massachusetts General Hospital summarizes.

Clinical Pearl

• What is the most common benign solid ovarian tumor?

Although only 4% of all ovarian masses are ovarian fibromas, they are the most common benign solid ovarian tumor.

Clinical Pearl

• What is the ovarian cancer symptom index?

A pelvic mass in a postmenopausal woman always raises concerns about ovarian cancer. The ovarian cancer symptom index is a tool used to predict or screen for ovarian cancer. According to this index, additional diagnostic testing for possible ovarian cancer is indicated in the presence of at least one of the following symptoms: abdominal pain; urinary frequency, urinary urgency, or both; and increased abdominal size, bloating, early satiety, or a combination thereof. The symptoms must be frequent and have occurred for less than a year. This index is 90% specific among women older than 50 years of age and 79.5% sensitive for advanced-stage disease.

Morning Report Questions

Q: Ovarian fibromas are associated with what syndromes?

A: Large fibromas (>10 cm in greatest diameter) are associated with ascites in 10 to 15% of cases and associated with ascites and a pleural effusion (the Demons–Meigs syndrome) in 1% of cases. In rare cases, fibromas may be part of the nevoid basal-cell carcinoma syndrome (Gorlin’s syndrome), which is characterized by the presence of multiple basal-cell carcinomas, keratocysts of the jaws, tumors of the central nervous system, fibromas, and skeletal malformations; in patients with this syndrome, ovarian fibromas are typically bilateral, multinodular, and associated with calcifications.

Figure 2. Imaging Studies of the Pelvis.

Figure 3. Resection Specimen.

Q: What are some of the features of the Demons–Meigs syndrome?

A: In 1887, Demons first described a syndrome in which various benign ovarian diseases were associated with the development of a pleural effusion. The description of this syndrome was further refined in a report of seven cases of ovarian fibroma with pleural effusion (usually unilateral and often on the right side) and pelvic fluid or ascites. Only 1 to 2% of patients with ovarian fibromas present with the Demons–Meigs syndrome. In such patients, the CA-125 level is often elevated, and thus it can be difficult to distinguish the Demons–Meigs syndrome from cancer. The hallmark of this syndrome is that removal of the ovarian mass results in permanent resolution of the pleural effusion.

Upper Gastrointestinal Bleeding

Posted by • June 16th, 2016

2016-06-14_13-45-23Peptic ulcers, which are primarily due to Helicobacter pylori infection or the use of nonsteroidal antiinflammatory drugs (NSAIDs), occur in the stomach or duodenum and are the most frequent cause of upper gastrointestinal bleeding. Most patients who are hospitalized with upper gastrointestinal bleeding should undergo endoscopy within 24 hours, after appropriate resuscitation and transfusion to a hemoglobin level greater than 7 g per deciliter.

Peptic ulcers, often due to Helicobacter pylori or the use of nonsteroidal antiinflammatory drugs (NSAIDs), commonly cause upper gastrointestinal bleeding. Endoscopic therapy, proton-pump inhibitors, therapy for H. pylori infection, and nonuse of NSAIDs are described. A new Clinical Practice summarizes.

Clinical Pearl

• When is endoscopic therapy indicated for a bleeding peptic ulcer?

Endoscopic features of ulcers are key in predicting risk and determining management strategies. Rates of further bleeding are highest among patients with active bleeding and nonbleeding visible vessels. Endoscopic therapy with injection (e.g., of epinephrine or alcohol), thermal devices (such as bipolar electrocoagulation probes or heater probes), or clips is performed in patients who have ulcers with active bleeding or a nonbleeding visible vessel. Endoscopic therapy may be considered for ulcers with adherent clots, for which randomized trials show heterogeneous results. Flat, pigmented spots and clean-base ulcers, which are detected at endoscopy in approximately 70% of patients with ulcer bleeding, are associated with low rates of serious rebleeding (5.6% and 0.5%, respectively, in a pooled analysis).

Figure 1. Initial Treatment of Patients with Ulcer Bleeding, According to the Endoscopic Features of the Ulcer.

Figure 2. Endoscopic Hemostatic Therapies.

Clinical Pearl

• How should a patient with recurrent bleeding after endoscopic therapy be managed?

If bleeding recurs, endoscopic therapy should be repeated. A randomized trial involving patients with rebleeding after endoscopic therapy showed that surgery was avoided in 73% of cases and adverse events were significantly less common with endoscopic therapy than with surgical therapy. Transcatheter arterial embolization or surgery is performed if repeat endoscopic therapy fails. Complications of bleeding or perforation occur in approximately 0.5% of patients who undergo endoscopic therapy.

Morning Report Questions

Q: What is the recommended approach to the diagnosis and treatment of H. pylori infection in a patient with a bleeding peptic ulcer? 

A: In patients with ulcers or erosions, biopsy specimens should be obtained from lesion-free areas of the gastric body and antral mucosa for assessment of H. pylori infection. If this testing is negative for H. pylori, subsequent retesting (e.g., with a stool test or breath test) has been recommended because some observational studies suggest decreased sensitivity of testing during acute upper gastrointestinal bleeding. Patients with H. pylori infection should receive therapy to eradicate the bacteria. A meta-analysis of randomized trials of such therapy showed significantly less rebleeding in patients who received this therapy than in patients who did not receive treatment for H. pylori infection and in those who received maintenance antisecretory therapy. Eradication of H. pylori should be confirmed after therapy with a breath test, a stool test, or, if repeat endoscopy is performed for another reason, gastric biopsy. Patients must not receive bismuth or antibiotics for at least 4 weeks and should not receive proton-pump inhibitors for at least 2 weeks before testing to avoid false negative results; histamine H2-receptor antagonists are permissible. In a systematic review of studies with a mean follow-up of 11 to 53 months, the incidence of rebleeding was only 1.3% among patients with confirmed eradication of H. pylori.

Q: What alternative therapy is recommended for patients who have bleeding ulcers while taking NSAIDs? 

A: Patients who have bleeding ulcers while taking NSAIDs should discontinue NSAIDs permanently, if possible. If NSAIDs must be resumed, a combination of a cyclooxygenase-2 (COX-2)–selective NSAID and a proton-pump inhibitor is recommended. Studies have shown rates of rebleeding of 4 to 6% within 6 months among patients who had a bleeding ulcer and were subsequently treated with COX-2–selective NSAIDs alone or traditional NSAIDs plus a proton-pump inhibitor. A 12-month double-blind trial showed significantly less ulcer rebleeding with a COX-2–selective NSAID plus a proton-pump inhibitor than with a COX-2–selective NSAID alone (0 vs. 9%).

Figure 3. Long-Term Treatment of Patients with Bleeding Ulcers, According to the Cause of the Ulcer.