Risks and Benefits Associated with High vs. Low Target Blood Pressure in Septic Shock Patients

Posted by Rachel Wolfson • April 23rd, 2014

Mr. G is a 59-year-old patient with a history of chronic hypertension who presents to the ICU with septic shock. As his physician, you want to make the best decisions to manage his complicated condition. You recall that the Surviving Sepsis Campaign has guidelines for this very situation, and they recommend reversal of his initial hypotension with vasopressors to a target mean arterial pressure (MAP) of 65 mmHg. However, because Mr. G’s body is accustomed to chronically elevated blood pressures, your intuition tells you that he may benefit from a higher target MAP. After perusing the literature, you find a large retrospective trial that suggests a higher target MAP (>75 mmHg) may help maintain kidney function in patients with chronic hypertension. Furthermore, a small, prospective trial corroborates the benefits of a higher target MAP. Is a higher target MAP the right course for Mr. G? In this week’s issue of NEJM, Asfar et al. attempt to help you answer this question.

In this large, open-label clinical trial, 776 patients with septic shock across 29 centers in France were randomized to resuscitation with either a target MAP of 65-70 mmHg or a higher target of 80-85 mmHg. In addition, patients were stratified according to history of hypertension, because the authors hypothesized that patients with chronic hypertension would benefit more from a higher target MAP. In terms of the primary endpoint—mortality at day 28, there was no difference observed between the 65-70 mmHg and 80-85 mmHg groups. Furthermore, there was no mortality difference observed at 90 days, nor was there any difference in overall rate of serious adverse events between the two groups. There was, however, an increased incidence of de novo atrial fibrillation in the high target MAP group. On the other hand, in the pre-specified stratum of patients with chronic hypertension, the group with the higher target MAP required less renal replacement therapy.

In an accompanying editorial, James A. Russell, MD, points out three main clinical implications of this trial. First, this trial shows that there is no indication for routine use of higher target MAP in septic shock resuscitation given that there was no mortality benefit and that there was an increased incidence of de novo atrial fibrillation in this group. In patients with chronic hypertension, however, he points out that a higher target MAP may be indicated, since it can decrease the use of renal replacement therapy. Finally, after looking at several randomized controlled trials studying vasoactive resuscitation in shock, Russell finds that there are differences in the amounts of fluids vs. vasopressors used for resuscitation across these different trials. He recommends that a more detailed analysis of the proportions of these two treatment modalities, each of which is associated with its own risks, is warranted.

As for Mr. G, your intuition was partly correct. Targeting a higher MAP may help his kidneys, but will he get pulmonary edema if he flips into atrial fibrillation? As with much of medicine, you will have to weigh the benefits against the potential risks. No one ever promised the decision would be easy!

A Million Thanks on Facebook

Posted by Jennifer Zeis • April 21st, 2014

Recently our Facebook page hit a million likes. We’re grateful that so many of you invite us into your down time.

Check out this message from the NEJM Editor-in-Chief, Dr. Jeffrey Drazen, to mark this milestone. And if you haven’t yet, we invite you to like our page to receive Image Challenges, new research, and more right to your Facebook feed. Thanks a million!


59-Year-Old Man with Fatigue, Abdominal Pain, and Anemia

Posted by Sara Fazio • April 19th, 2014

In the latest Case Record of the Massachusetts General Hospital, a 59-year-old man was admitted to the hospital because of fatigue, abdominal pain, new anemia, arthralgias, abnormal liver function, and emotional lability. A peripheral-blood smear showed polychromasia and coarse basophilic stippling of erythrocytes.

Acute abdominal pain has a broad differential diagnosis that includes both intraabdominal and extraabdominal causes. Life-threatening intraabdominal catastrophes, such as gastrointestinal perforation, intestinal infarction, and a ruptured abdominal aortic aneurysm, cause illness within minutes or hours.

Clinical Pearls

What is the typical presentation of acute porphyria?

Porphyrias are generally inherited and are caused by a deficiency in the activity of one of the enzymes required for normal heme synthesis. Acute porphyria should be considered in a patient with acute, generally recurrent, severe abdominal pain that does not have a clear explanation. Features that are consistent with a diagnosis of acute porphyria include severe neuropathic abdominal pain, nausea, stress or restlessness, pain in the arms and legs, constipation, colonic pseudo-obstruction, tachycardia, episodic hypertension, and SIADH; characteristically dark urine is not present.

What is the differential diagnosis for basophilic stippling?

Basophilic stippling is a hallmark of sideroblastic anemia and of lead poisoning, although it is not a constant feature of the latter. It is also seen in patients with arsenic poisoning, some thalassemias, a deficiency of erythrocyte pyrimidine 5′-nucleotidase, or thrombotic thrombocytopenic purpura.

Morning Report Questions

Q: What are the typical clinical features in lead poisoning?

A: Patients typically present with abdominal pain (“lead colic”), and may also report nausea, dysgeusia, and constipation. Other features consistent with lead poisoning are colonic pseudo-obstruction, joint and muscle pain, acute anemia, basophilic stippling, SIADH, and decline in the blood level of phosphorus (which may be due to renal phosphate wasting). Lead lines, or bluish pigmentation at the gum-tooth line caused by a reaction of lead with dental plaque, are not a reliable indictor of acute lead poisoning. Deposition of lead in bones may be seen with long-term exposure, as may hypertension and neuropsychiatric effects.

Q: How is a diagnosis of lead poisoning made?

A: A diagnosis of lead poisoning is confirmed by measuring the blood lead level; a level of 10 micrograms per deciliter or higher is considered elevated in an adult. The level may be higher than 100 micrograms per deciliter in patients with acute lead poisoning, which is much less common than chronic lead poisoning. Heme biosynthesis is impaired when 5-aminolevulinic acid (ALA) dehydratase is 80 to 90% inhibited; this occurs at a blood lead level of approximately 55 micrograms per deciliter. Lead inhibits many of the enzymes active in the heme biosynthetic pathway, including ALA dehydratase, coproporphyrinogen oxidase, and ferrochelatase, thereby leading to incorporation of zinc instead of iron into protoporphyrin IX (the immediate precursor of heme) and to accumulation of zinc-chelated protoporphyrin in erythrocytes, which is often reflected by an elevated level of zinc protoporphyrin.

Acute Infectious Diarrhea in Immunocompetent Adults

Posted by Sara Fazio • April 19th, 2014

This week’s review article on this topic comes from Dr. Herbert L. DuPont from the University of Texas School of Public Health and Medical School, Baylor St. Luke’s Medical Center, Baylor College of Medicine, and the Kelsey Research Foundation, all in Houston, TX.

In the United States, approximately 179 million cases of acute diarrhea occur each year, amounting to 0.6 bouts per person per year.In one study, the estimated prevalence of diarrhea among adults the month before questioning was 3 to 7%, with the rate dependent on age, and 8% among children 5 years of age or younger.

Clinical Pearls

What are the most common causes of acute infectious diarrhea in the United States?

Noroviruses, the principal cause of gastroenteritis, are responsible for approximately 50% of outbreaks of diarrhea, 26% of cases of diarrhea in U.S. emergency departments, and 13% of office visits for diarrhea. Noroviruses are particularly common in closed populations such as cruise ships, nursing homes, dormitories, and hospitals. Data from the Centers for Disease Control and Prevention indicate that infections with the following bacterial pathogens were detected in descending order of rates per 100,000 people in the United States in 2012: salmonella, 16.4 cases; campylobacter, 14.3 cases; Shiga toxin-producing Escherichia coli O157-H7 strain, 1.1 cases; vibrio, 0.4 cases; and yersinia, 0.3 cases.

What low-inoculum infections often cause secondary spread of illness?

Challenge experiments involving volunteers and epidemiologic studies show that infections with shigella, Shiga toxin-producing E. coli, noroviruses, rotaviruses, giardia, and cryptosporidium are easily spread by low inoculums of agents that often cause secondary spread of illness. Shigella and noroviruses, the most communicable pathogens, have a high potential for person-to-person spread, which is related to the low amounts of inoculum required, the environmental stability of the organisms, and the common occurrence in young children who are likely to spread infection. Limited data from volunteer challenge studies suggest an intermediate dose response for most salmonella and campylobacter strains. Secondary spread occasionally occurs with salmonella strains, and the infection rate among infants is high, suggesting transmission at lower amounts of inoculum.

Morning Report Questions

Q: When is it necessary to send a stool sample to identify the pathogen involved?

A: The determination of the precise cause of diarrhea is costly, and in most cases of nonsevere diarrhea it is not necessary. Assessment of a stool sample to determine the cause of illness should be reserved for patients at high risk for definable diarrhea or cases in which identification of the pathogen would be important. Stool samples should be obtained from patients with any of the following conditions: acute diarrhea that is severe or associated with fever (greater than or equal to 38.5 degreesC), severe diarrhea or diarrhea associated with a severe coexisting condition in a hospitalized patient who is receiving antibiotics (with testing only for C. difficile toxins), persistent diarrhea (greater than or equal to 14 days’ duration), profuse cholera-like watery diarrhea, dehydration, and dysentery. In addition, samples should be obtained from elderly or immunocompromised patients with diarrhea and persons employed as food handlers, those confined to a nursing home, and those who work in a day-care center. Identification of the pathogen is also important in an outbreak of diarrhea.

Q: When are antibiotics indicated in the treatment of acute infectious diarrhea?

A: Empirical antibiotic therapy is recommended for sporadic cases of febrile dysentery, especially those associated with toxicity that suggests the possibility of systemic infection, as well as for severe cases of travelers’ diarrhea or hospital-associated or antibiotic-associated diarrhea. Antibiotics are indicated in only a small percentage of patients with an established infectious cause of acute diarrhea; in these patients, antibiotics can shorten the illness, decrease transmission, and prevent complications, including death. In selecting specific therapy for most cases of acute diarrhea, an etiologic diagnosis must be established. Currently, antibiotic therapy is not helpful in cases of mild salmonella diarrhea, and it lengthens shedding for 3 weeks or longer. Some antibiotics induce Shiga toxin-encoding phage and may precipitate the hemolytic-uremic syndrome. Therefore, in an outbreak of bloody diarrhea, antibiotics are not currently recommended for patients with minimal or no fever who have Shiga toxin-producing E. coli infection.

Table 1. Recommendations for the Diagnosis and Treatment of Organism-Specific Enteric Infection in Adults.

Take the Critical Care Challenge

Posted by Jennifer Zeis • April 18th, 2014

In this month’s Critical Care Challenge, our  77-year-old patient is on mechanical ventilation in the ICU after an emergency colon resection, complicated by septic shock and acute liver failure. Since it appears his stay in the ICU will be prolonged, what measures would you take to optimize his long-term recovery?

Participate in the poll and share your comments. The editors’ recommendations and the related review article will appear on April 23.

If you’ve missed previous articles in the series, check out the Critical Care Medicine page.

NEJM Group Announces the Launch of NEJM Knowledge+

Posted by Karen Buckley • April 17th, 2014

NEJM Group is excited to announce the launch of NEJM Knowledge+ Internal Medicine Board Review, a self-assessment and continuous learning solution that employs the very latest adaptive learning technologies to increase learning efficiency and knowledge retention.

Designed specifically for Internal Medicine and Internal Medicine subspecialists, the product includes:

  • Over 4000 questions covering nearly 1500 key learning points
  • Two timed practice exams that simulate the actual board exam
  • Desktop, iPad, and iPhone access – wherever and whenever it’s convenient for you
  • Opportunity to earn 250 AMA PRA Category 1 CME Creditstm
  • Opportunity to earn 80 ABIM MOC points which also satisfy the new ABIM patient safety requirement (Medical Knowledge points)
  • Robust, multi-faceted progress and performance reporting

We partnered with Area9 — a physician-led pioneer in adaptive learning — to create this first-of-its-kind platform with smart technology that actually continuously assesses your knowledge, study habits, and schedule, selecting from thousands of learning opportunities and presenting just what you need to become fully prepared. NEJM Knowledge+ presents questions based on what you know already, what you need to study more, what you are struggling to master, what you think you know better than you do, and what you might be forgetting .  For a fun and informative look at how we’ve used adaptive learning check out our animated video.

NEJM Knowledge+ is planned as a family of products to support self-assessment, learning, and board certification in internal medicine and other specialties.  Future review products in other specialties will all be designed to help clinicians efficiently self-assess their learning needs, meet their certification requirements, prepare for the board exams, and incorporate lifelong learning into their schedules more easily.

To learn more about NEJM Knowledge+ visit http://knowledgeplus.nejm.org. You’ll find lots of great information, videos, our question of the week, blog, and more.

To take advantage of our Charter Offer and receive a 20% discount on NEJM Knowledge+ Internal Medicine Board Review click here.

The Massachusetts Medical Society designates this enduring CME activity for a maximum of 250 AMA PRA Category 1 Credits™. Physicians should claim only credit commensurate with the extent of their participation in the activity.
NEJM Knowledge+ Internal Medicine Board Review has been accepted by the American Board of Internal Medicine for 80 points toward the Self-Evaluation of Medical Knowledge (Part 2) requirement of Maintenance of Certification (MOC).

Ledipasvir–Sofosbuvir for Previously Treated HCV

Posted by Carla Rothaus • April 16th, 2014

The old adage, “The more things change, the more they stay the same,” simply does not apply when it comes to the treatment of hepatitis C virus (HCV). The mainstay of HCV treatment for many years has included interferon (peginterferon, since 2001) and ribavirin. While relatively effective for patients with HCV genotypes 2 and 3, this regimen achieves a sustained virologic response – undetectable serum HCV RNA after treatment – in only 40% of patients with HCV genotype 1, the cause of more than 70% of all cases of chronic HCV in the United States.  Sequencing of the viral genome and characterization of HCV proteins led to development of the direct-acting HCV NS3/4A protease inhibitors telaprevir and boceprevir, which, when combined with peginterferon and ribavirin, improve response rates for patients with genotype 1. Yet patients who fail this regimen have historically had no treatment options. Now, however, a new generation of direct-acting antivirals is poised to take center stage, changing the outlook for this and other “difficult-to-treat” subgroups. Currently approved regimens – limited by formidable side effects, suboptimal treatment adherence, and viral resistance, and unavailable to those for whom interferon is contraindicated – will likely give way to safer, shorter duration, and easier-to-administer interferon- and ribavirin-free regimens. A multitude of clinical trials are underway, investigating these new therapies in a variety of clinical settings.

In this week’s NEJM, Afdhal et al. report the findings of a study involving patients with HCV genotype 1 who have failed treatment with prior interferon-based therapy. Building upon promising phase 2 trial results, they conducted a multicenter phase 3, randomized, open-label study of a fixed dose, once-daily oral combination pill containing sofosbuvir, a nucleotide analogue HCV NS5B polymerase inhibitor approved by the FDA in late 2013, and ledipasvir, a new experimental HCV NS5A protein inhibitor. Eligibility criteria included age 18 years or older, chronic HCV genotype 1 infection, and failure to achieve a sustained virologic response to prior peginterferon and ribavirin treatment, either with or without a protease inhibitor. Four hundred and forty patients, all of whom received the same daily dose of sofosbuvir and ledipasvir, were randomized 1:1:1:1 to one of four treatment groups, including ledipasvir-sofosbuvir for 12 weeks or 24 weeks, either with or without ribavirin. Randomization was stratified by genotype (1a or 1b), prior treatment response (no response versus relapse or virologic breakthrough) and presence or absence of cirrhosis. The primary endpoint was the rate of sustained virologic response at 12 weeks after the end of therapy (SVR 12); SVR 24 was a secondary endpoint.

The study results showed high SVR 12 rates in all four groups, reportedly among the highest to date for HCV genotype 1: 94% and 96% for the 12 week groups without and with ribavirin, respectively, and 99% for both 24 week groups. Virologic relapse after the end of treatment occurred in 11 of 440 patients (2%), all from the 12 week treatment groups. All sustained virologic responses achieved at 12 weeks persisted at 24 weeks after the end of treatment. Ribavirin did not affect response rates with either 12 or 24 weeks of treatment. In the 12-week group only, response rates were slightly lower in patients with cirrhosis, compared to those without cirrhosis, although the study was not powered to allow confident intergroup comparisons. Mild to moderate adverse events were seen in all groups, with serious adverse events limited to a small number of patients in the 24-week groups; no participant had to discontinue treatment due to an adverse event.

In an accompanying editorial, Drs. Jay Hoofnagle and Averell Sherker of the National Institutes of Health characterize the study results as “striking,” stating that the availability of safe and effective oral therapies will remove most of the limitations and barriers to treatment. Their enthusiasm is tempered, however, by concerns about the high price tag for these therapies, saying, “Costs alone cast a pall over the stunning success in achieving the long-hoped-for goal of a well-tolerated and successful therapy for hepatitis C.”

NEJM Deputy Editor Dr. Mary Beth Hamel adds, “The recent development of several novel direct-acting antivirals represents a major advance in hepatitis C therapy, and offers the potential to save many lives.”

Test Yourself! Interactive Medical Case Now Available

Posted by Jennifer Zeis • April 15th, 2014

A 65-year-old woman presented to an urgent care clinic with a 1-week history of fatigue, dyspnea on exertion, and daily fevers of up to 38.9°C. She reported no chills but did have night sweats. She had difficulty breathing, especially when climbing stairs and when attempting to sleep while lying supine. She had no cough, sore throat, chest pain, edema of the legs, rash, or gastrointestinal symptoms.

The latest Interactive Medical Case, A Woman with Fever and Dyspnea, is now available for you to test your therapeutic and diagnostic skills. In addition, you may now earn two ABIM Maintenance of Certification (MOC) points for each case you take.

Interactive Medical Cases are online simulations based on a real patient’s experience of illness. You follow interactive steps through an evolving patient’s history, diagnosis, and management, from presentation to outcome. During the presentation of the case, you access videos, lab results and brief commentary that explain concepts important for diagnosis and treatment.

Browse the list of Interactive Medical Cases. Try one or all 29 cases and earn points toward your requirements now!

Take the Case Challenge

Posted by Jennifer Zeis • April 13th, 2014

Peripheral-Blood Smear (Wright–Giemsa stain)

A 59-year-old man was seen in an outpatient clinic because of fatigue, abdominal pain, anemia, arthralgias, and abnormal liver function. What is the diagnosis? Is it alcohol-induced sideroblastic anemia? Lead poisoning? Or something else?

Read the case description for the next Case Record of the Massachusetts General Hospital, and then vote and comment now on NEJM.org. In a few days, find the answer in the full text of the Case Record to be published April 17.

Follow the conversation with #NEJMCases on Twitter or Facebook.

Hypersensitivity to Hymenoptera Stings

Posted by Sara Fazio • April 12th, 2014

Anaphylactic reactions after a hymenoptera sting should be treated promptly with intramuscular epinephrine. Patients who have had such a reaction should carry injectable epinephrine and be referred to an allergist for insect-specific testing and subcutaneous immunotherapy if indicated.  The latest Clinical Practice review on this topic comes from the University of South Florida Morsani College of Medicine’s Dr. Thomas B. Casale and the University of North Carolina at Chapel Hill School of Medicine’s Dr. A. Wesley Burks.

Although anaphylaxis due to an insect bite has been reported in a small number of cases, stings from insects belonging to the order Hymenoptera are among the most important causes of systemic allergic reactions.

Clinical Pearls

What is the antigentic cross-reactivity between Hymenoptera species?

The Hymenoptera insects whose stings cause allergy are generally from three families: Apidae (honeybees and bumblebees), Vespidae (hornets, wasps, and yellow jackets), and Formicidae (fire ants). The molecular characteristics of the venoms from the three families of Hymenoptera are sufficiently different that there is very little antigenic cross-reactivity. Within families (e.g., vespids), there can be substantial cross-reactivity among the allergens present in the venoms; however, honeybee and bumblebee allergies are distinct.

Table 1. Characteristics of Hymenoptera.

Figure 1. Hymenoptera.

What is the pathophysiology of an allergic reaction to a Hymenoptera sting, and how common is an anaphylactic reaction?

In sensitized persons, a sting can cause the injected venom to bind to venom-specific IgE on mast cells, cross-linking high-affinity IgE receptors and subsequently leading to the rapid release of mast-cell mediators, including histamine, leukotrienes, prostaglandins, and platelet-activating factor. The released mast-cell mediators can cause a spectrum of allergic reactions, from local reactions (affecting small or large [greater than or equal to 10 cm] areas) or urticaria to anaphylaxis and even death. Patients with large local reactions usually do not have a systemic reaction to subsequent stings (with systemic reactions occurring in <10% of these patients), nor do children with isolated urticaria. However, a previous systemic reaction in a patient with venom-specific IgE is associated with a high risk of subsequent systemic reaction, which may occur in 30 to 60% of these patients. Anaphylaxis due to a hymenoptera sting causes at least 40 deaths per year in the United States, although this number is probably an underestimate. Severe systemic allergic reactions occur in approximately 0.4 to 0.8% of children and 3.0% of adults.

Morning Report Questions

Q: What are the risk factors for a severe reaction to a Hymenoptera sting and how should it be treated?

A: Acute systemic reactions typically occur very rapidly after a hymenoptera sting but may be delayed for several hours or be biphasic. The factors associated with an increased risk of severe reaction include being stung by a honeybee (greater risk than with other hymenoptera), underlying mast-cell disorders with elevated serum-tryptase levels at baseline, a previous severe reaction, preexisting cardiovascular disease, and concomitant treatment with a beta-blocker, angiotensin-converting-enzyme inhibitor, or both. Anaphylaxis can present with a spectrum of signs and symptoms affecting multiple organ systems, including the skin, gastrointestinal tract, cardiovascular system, nervous system, and both the upper and lower respiratory tracts; hallmarks of anaphylaxis are the development of hypotension or the involvement of more than one organ system. The treatment of anaphylaxis in the emergency department should include epinephrine for any patient who has more than cutaneous symptoms; epinephrine should also be considered in adults with urticaria alone. H1-antihistamines can help relieve cutaneous signs and symptoms. For respiratory symptoms, supplemental oxygen and inhaled beta2-agonists should be used. For patients with hypotension, volume resuscitation is indicated, with 1 to 2 liters of 0.9% (isotonic) saline infused rapidly (e.g., a dose of 5 to 10 ml per kilogram in the first 5 to 10 minutes in an adult, and 10 ml per kilogram in a child).

Table 2. Clinical Features of Anaphylaxis.

Q: Who should receive venom immunotherapy?

A: Subcutaneous immunotherapy should be considered in all patients who have had a systemic allergic reaction to an insect sting and who have a positive skin test or a positive result on an in vitro test for venom-specific IgE antibodies. Children 16 years of age or younger who have had isolated cutaneous systemic reactions to insect stings have a very low risk of subsequent reactions and do not require venom immunotherapy. Venom immunotherapy is also generally not necessary in patients who have had only a large local reaction, because their risk of subsequent systemic reactions is relatively low. However, patients with unavoidable or frequent exposures (e.g., beekeepers) may benefit, because observational data indicate that, after immunotherapy, local reactions are reduced in size and duration.

Table 3. Criteria for Positive Skin Tests.