Primecuts – This Week In The Journals

April 22, 2015

By Luke O’Donnell, MD

Peer reviewed

This week , winter finally gives way to a suggestion of spring and as temperatures flirt with the non-frigid range of the thermostat, more people—including the older among us—are leaving their apartments to enjoy the outdoors. A study this week in Circulation looked at sports-related sudden cardiac arrest (SCA) in this age group [1].

SCA represents a major public health issue worldwide accounting for almost half of cardiovascular mortality [1]. Circulation this week published the first comprehensive epidemiological assessment of SCA in sports activity among middle-aged participants in the United States. The research analyzed data from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) which is an ongoing community-based prospective study of out-of-hospital SCA in Portland. Since 2002, any case of SCA has undergone a comprehensive evaluation including investigation of the circumstances of the SCA, pre-arrest medication record, and available autopsy data [1].

Per this study, middle age (rather cruelly) begins at 35 years and continues to age 65. This age range included 1247 case of SCA of which only 5 percent (63 cases) where sports related. Further assessment showed that the mean age of sport-related SCA was 51.1 plus or minus 7.7 years. SCA was significantly higher in men—RR 18.68 (CI 2.12-139.56). While the reasons for this gender-gap are unclear, the researchers felt that it might be secondary to increased rates of intense sport activity in middle-aged man compared to women, as well as underlying gender-related pathophysiological differences, including discrepancies in electrical conduction and plaque formation/rupture [1].

The other big finding in this analysis was most sports-related SCA was in cardiovascular risk factors. 16 percent of cases had known pre-existing cardiac disease such as coronary artery disease (CAD), atrial fibrillation (AF), and heart failure. 56 percent of patients had greater than one cardiovascular risk factors including diabetes mellitus, dyslipidemia, systemic hypertension, and smoking disorder. Of all the sports-related SCA cases, 36 percent had reported typical cardiovascular symptoms in the week preceding the SCA, such as a recent chest pain or dyspnea presentation [1].

The conclusion drawn by the authors was that the media overblows the risks of sport-related SCA. This study supports that sport-related SCA in middle-aged individuals is a relatively small portion of the overall SCA burden, reinforcing that exercise is a high-benefit, low risk activity [1]. Targeted education to patients with cardiovascular risk factors should include education on the necessity for chest pain and dyspnea evaluations as this could represent possible cardiac compromise.

Published as well this week is literature that furthers the discussion on the appropriate treatment of extended-spectrum beta-lactamase (ESBL) bacteria.

ESBL is found chiefly in Escherichia coli, Klebsiella pneumonia, Klebsiella oxytoca, and Proteus species. The unifying characteristic among these bacteria is the ability to hydrolyze third-generation cephalosporins and aztreonam, but on a whole can be inhibited by commercially available beta-lactamases inhibitors—such as clavulanic acid, sulbactam, and tazobactam. The effectiveness of piperacillin-tazobactam (PTZ), however, for the treatment of extended-spectrum beta- lactamase (ESBL) bacteremia is controversial.

Since first discovered 30 years ago in Germany, ESBL bacteria have posed a serious therapeutic challenge. Although many of these organisms are inhibited by tazobactam, EBSL organisms also have additional resistance mechanism such as the presence of AmpC B-lactamase—an emerging beta-lactamase with resistant to current inhibitors. One controversy that has emerged is whether or not carbapenems should be the empiric treatment choice in suspected ESBL bacteremia. More liberal use of carbapenems could propagate resistance, however, it could be more effective than PTZ for treating the critically ill patient.

Researchers at John Hopkins investigate 14-day mortality in patients with proven ESBL bacteremia who were empirically treated with PTZ versus carbapenems [2]. After ESBL bacteremia was confirmed with culture, all studied patients were switch to carbapenems. This retrospective study included 331 unique patients from January 2007 to April 2014 with a definitive end point of death [2].

In the study, 48% (103) received PTZ empirically and 52% (110) received carbapenems empirically. There were 17 deaths (17%) in the PTZ group and 9 (8%) deaths in the carbapenem group within 14 days of positive blood cultures. The adjusted risk of death was 1.92 (95% CI, 1.73 to 3.45) times greater for patients receiving empiric PTZ compared to empiric carbapenems [2].

Based on this study, patients who have expected ESBL bacteremia—such as those with supporting previous culture data—should receive empiric carbapenems [2,3].

As noted in the Clinical Infectious Diseases editorial commentary that accompanies the study, carbapenems may be the best empiric therapy for patients with serious blood stream infectious caused by ESBL-producing bacteria [3]. Obviously this is a constantly changing frontier, one in with bacteria are continuously adapting and additional research is necessary. Investigation is now focusing on being able to determine the causative agent of bacteremia in a day or less. Novel beta-lactamase inhibitors such as avibactam and relebactam are in the advanced stages of clinical development. A novel cephalosporin, ceftolozane, combined with tazobactam, has accompanying data from in vitro studies to suggest extended activity over most ESBL producing bacteria, and could become an effective agent to reduce the necessity of carbapenem use [3].

Also new this week, The New England Journal of Medicine (NEJM) published an investigation into the effectiveness of aerosolized measles vaccination [4], which investigators to ease the injection-related concerns of many Southern California parents.

Aerosolized measles vaccination has been used in Mexico since the 1980; however, data investigating its effectiveness is inconsistent due to heterogeneous study design, biased reports, and small sample sizes [4].

The World Health Organization (WHO), Center for Disease Control (CDC), and American Red Cross recruited nearly 2500 children to receive their primary dose of measles vaccine either by subcutaneous injection or aerosolized formulation in an open label trial in Prune, India. The children were then tested at day 91 to determine seropositivity via an enzyme-linked immunosorbent assay (ELISA) against measles IgG antibodies or via plaque reduction neutralization test (PRNT). In the aerosolized vaccination group, 84.5% (95% CI 82.5 to 88) had seropositivity determined to be greater than 0.1 optical-density units on ELISA or more than 120mlU per ml via PRNT. The subcutaneous group has a 94.6% (95% CI, 92.7-96.1) show seropositive by these means [4].

The end conclusion was that aerosolized vaccine against measles was immunogenic, but inferior to the subcutaneous vaccine with respect to seropositivity [4]. The ease of administration and the lack of hypodermic needle use, however, could possibly make up for this shortcoming in resource-limited areas. Further investigation in seropositive after two administrations of aerosolized vaccination and age-specific response is necessary [4].

Other studies circulating in this week’s literature include:

The NEJM published an investigation of alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-Kexin type 9 (PCSK9). Inhibition of PCSK9 allows for increased degradation of low-density lipoprotein (LDL). The study included 2341 patient at high risk for cardiovascular events who had LDL cholesterol levels of 70mg /dL or more on maximum tolerated statin therapy. Patient received alirocumab subcutaneous injection verse placebo injection every 2 weeks for 78 weeks. At 24 weeks, the mean percent change from baseline in calculated LDL cholesterol level was negative 62 percent (P< 0.001). The actual effects on mortality are unclear. In post-hoc analysis, there was a 42 percent reduction in fatal coronary artery disease, non-fatal stroke, fatal stroke, unstable angina. Only 1.7 percent in the alirocumab group experienced these events versus 3.7 percent in the placebo group. When coronary artery disease requiring revascularization and congestive heart failure exacerbation where included, however, the difference between the two groups was not significant. [5]

The Lancet published an article investigating the effectiveness of antidepressants for recurrent depression versus taping off antidepressants with emphasis on mindfulness-based cognitive therapy (MBCT)—a psychosocial intervention that teaches patients with depression some practical skills to stay well long-term. While MBCT was not superior to maintenance antidepressant treatment, both forms of treatment had positive outcomes in terms of recurrence, residual depressive symptoms, and quality of life. [6]

There was little evidence that nighttime physician staffing models affect patient outcome per an article published in Chest this week. ICUs without physician at night may exhibit reduced hospital mortality that is possibly attributed to differences in end-of-life care practices. [7]

Dr. Luke O’Donnell is a 2nd year resident at NYU Langone Medical Center and a hopeful rave club denizen

Peer reviewed by Greg Schrank, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons.


1, Marijon E, Uy-Evanado A et Al. Sudden Cardiac Arrest During Sports Activity in Middle Age. Circulation. 131. 1384-1391. 2015.

2, Tamma P, Han J et al. Carbapenem Therapy is Associated With Improbed Survival Compared With Pipercillin-Tazobactam for Patient With Extended-Spectrum Beta-Lactamase Bactermia. Clinical infectious Disease. 2015 (60), 1319-1325.

3, Perez F et Bonomo R. Bloodstream Infection Caused by Extended-Spectrum Beta-Lactamase-Producing Gram-Negative Bacteria: How to Define the Best Treatment Regiment? Clinical infectious Disease. 2015 (60), 1326-1329.

4, Low N, Bavdekar A et al. A Randomized Controlled Trail of an Aerosolized vaccine against Measles. New England Journal of Medicine. 372(16), 1519-1529, 2015.

5, Robinson J, Farnier M et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. New England Journal of Medicine. 372(16), 1489-1499, 2015.

6, Kuykenm W, Hayes R et al. Effectiveness and cost-effectiveness of mindful-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomized controlled trail. The Lancet Online.

7, Kerlin M, Harhay M et al. Nighttime Intensivist Staffing, Mortality, and Limits on Life Support. Chest. 147(4), 951-958. 2015.