Primecuts – This Week In The Journals

March 14, 2011

By Aviva Regev 

Faculty Peer Reviewed

Spring is in the air: warmer weather, longer days, flowers blooming, and of course, seasonal allergies.  While allergies may be a common cause of respiratory complaints in an outpatient setting, patients suffering from shortness of breath in the hospital are likely to be suffering from some more serious ailments.  The focus of this week’s Primecuts will be on two of the major players in this group: congestive heart failure (CHF) and pneumonia.

 Shortness of breath is a cardinal symptom of CHF, and loop diuretics are a mainstay of therapy.  While patients are maintained on oral diuretics, about 90% of those admitted for acute decompensations are treated with IV diuretics.  Though the practice is extremely common, there is some uncertainty as to the best strategy – bolus or continuous infusion, and high or low dose.  A randomized controlled trial by Felker et. al.[1], published in NEJM last week, investigated outcomes with different methods of dosing and found no benefit to continuous infusion over bolus administration.  Patients with a history of chronic CHF presenting with acute decompensated heart failure who had been on oral loop diuretics for at least a month were randomized to receive either high or low dose furosemide administered by bolus or continuous infusion.  Low dose was defined as the same as the patient’s outpatient furosemide dose and high dose was 2.5 times that amount.  Though the 308 patients made up four treatment groups, the results were analyzed by comparing patients who had received bolus vs. continuous infusion, regardless of dose; a separate comparison of high vs. low dose, regardless of timing, was also performed.  The study was not powered to pick out between-group differences, i.e. low-dose bolus vs. high-dose bolus.

 The results found no significant differences between bolus vs. continuous infusion in either of the primary endpoints of patient’s global assessment of symptoms or change in serum creatinine in the first 72 hours.  There were also no significant differences between those groups in the secondary endpoints of patient-reported dyspnea, changes in body weight and net diuresis, worsening of renal function, worsening of heart failure, or treatment failure.   There was, however, a significant improvement in dyspnea as well as greater weight loss and diuresis in the group receiving high dose diuretics compared to low dose.  Though more patients in the high-dose group had transient worsening renal function, they had fewer serious adverse events, including cases of renal failure.

 Heart failure is an independent risk factor for death from venous thromboembolism, according to Piazza et. al. [2] in this week’s American Journal of Medicine.  Among patients with deep vein thrombosis (DVT) or pulmonary embolism (PE), those with a history of heart failure had twice the rate of in-hospital death and a 60% increase in mortality within 30 days.  This increased mortality is despite the fact that those with heart failure were significantly more likely to have received prophylaxis against DVT/PE than those without heart failure if they had either had major surgery or been hospitalized for a condition unrelated to venous thromboembolism within three months.   

 Moving on to the lungs, we come to the dreaded multidrug-resistant hospital-acquired pneumonia.  A study in Lancet Infectious Disease [3] this month came to a provocative conclusion: patients treated according to the current guidelines actually had increased mortality, even when adjusted for the severity of illness.  The guidelines, by the American Thoracic Society and Infectious Diseases Society of America, recommend empirically treating patients with hospital-acquired pneumonia with double gram-negative coverage and either linezolid or vancomycin.  Patients were classified as either receiving compliant treatment or non-compliant treatment, with the most common reason for non-compliance being lack of a second drug with gram-negative coverage.  Though overall the baseline demographics were similar between the two groups, the compliant group was significantly more likely to have severe sepsis, an important factor in mortality.  However, a propensity score evaluating the risk of death of each patient independent of their treatment was factored into the analysis to account for the fact that sicker patients may be more likely to receive compliant treatment, and even among patients with severe sepsis non-compliant treatment was associated with reduced mortality.  Another interesting finding from the study was that there was no significant difference in activity of the drug regimen against pneumonia pathogens between the two groups, which begs the question of whether double-covering gram-negatives increases activity against these organisms at all.  Patients treated with either colistin or an aminoglycoside as the second gram-negative antibiotic had higher rates of kidney injury, which likely contributed to their mortality.  The study was prospective and observational, so a randomized trial will likely be necessary before the guidelines change.

 As if a bad bout of pneumonia wasn’t bad enough, patients who are hospitalized for pneumonia are at risk of having cardiovascular events within 90 days of their admission, according to Perry et al. [4] in the American Journal of Medicine.  The study excluded patients who had a prior history of the specific cardiovascular event in question and found that within the given time frame, the incidence of myocardial infarction was 1.5%, congestive heart failure 10.2%, arrhythmia 9.5%, unstable angina .8%, and stroke 0.2%.  Most of the events occurred while patients were still in the hospital.

 On to an infection more likely to be picked up abroad than in an ICU, a new method for discriminating between active and latent tuberculosis has been described in Nature Medicine [5].  CD4+ cells play a key role in immunity against Mycobacterium tuberculosis (Mtb), and these cells produce cytokines such as interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), and interleukin-2 (IL-2).  While patients with latent TB had Mtb-specific CD4+ cells that were largely polyfunctional and produced all three cytokines, those with active infection had an increase in the proportion of Mtb-specific CD4+ cells with a dominant TNF-a response.  The cutoff was defined as greater than 37.4% of Mtb-specific CD4+ cells with a TNF-a response and this was validated using a group of 101 patients with the investigator blinded to their diagnosis of latent or active disease.  The assay was found to have a sensitivity of 67%, a specificity of 92%, a positive predictive value of 80%, and a negative predictive value of 92%.

 In other health news, a boon for lupus sufferers: a new drug has been approved to treat SLE [6,7].  Benlysta (belimumab) is the first drug to be approved for SLE in since Plaquinil (hydroxychloroquine) and corticosteroids in 1955.  The only other approved treatment for lupus is aspirin.  Belimumab inhibits B-lymphocyte stimulator (BLyS) protein.  BLyS is a member of the TNF family and promotes the survival and proliferation of B-cells [8].  It is elevated in patients with lupus, as well as those with rheumatoid arthritis and Sjogren’s syndrome.  There are some limitations to belimumab – it was not found to be effective in African Americans, who have a three times greater incidence of lupus than whites, though the drug will be studied further in this group of patients.  Furthermore, it was not tested in patients with active lupus affecting the kidneys or the CNS, so the effect on these patients is unknown.

 As we wrap up this week’s Primecuts, we look across the globe to Japan, reeling in the wake of the massive earthquake and tsunami of March 11th.  With the worst hit areas still partially inaccessible to rescuers, the death toll is likely to continue to rise as more victims are identified and those who survived the initial event succumb to their injuries or a lack of food and water [9].  While Japan’s infrastructure may make it better equipped to deal with such a disaster than Haiti or Indonesia, Japan faces another crisis those nations did not: the leak of radiation from a nuclear power plant.  Though the scope of the leak is still being assessed, the government has begun to distribute potassium iodide pills to reduce the risk of thyroid cancer in those exposed to radiation [10].  Those in the vicinity of the reactor still have an increased risk of cancer in the long term [11].  Unfortunately, there is little we can do besides watch with baited breath as the saga unfolds.

Aviva Regev is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Barbara Porter, MD, section editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1.  Felker G, Lee K, Bull D, et. al.  Diuretic strategies in patients with acute decompensated heart failure.  N Engl J Med 2011 March 3;364:797-805.  http://www.nejm.org/doi/full/10.1056/NEJMoa1005419

2.  Piazza G, Goldhaber S, Lessard D, et. al.  Venous thromboembolism in heart failure: preventable deaths during and after hospitalization.  Am J Med 2011 March;124:252-259.  http://www.amjmed.com/article/S0002-9343(10)00930-7/abstract

3.  Kett D, Cano E, Quartin A, et. al.  Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study.  Lancet Infect Dis 2011 March;11:181-89. http://www.thelancet.com/journals/laninf/issue/vol11no3/PIIS1473-3099(11)X7028-7

4. Perry T, Pugh M, Waterer G, et. al.  Incidence of cardiovascular events after hospital admission for pneumonia.  Am J Med 2011 March; 124:244-251. http://www.amjmed.com/article/S0002-9343(10)01006-5/abstract

5.  Harari A, Rozot V, Enders F, et. al.  Dominant TNF-a+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.  Nature Medicine 2011 March;17(3):372-7. http://www.nature.com/nm/journal/v17/n3/full/nm.2299.html#auth-1

6.  U.S. Food and Drug Administration.  FDA approves Benlysta to treat lupus.  March 9, 2011.  Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm246489.htm

7.  Pollack, A.  F.D.A. Approves Benlysta, a New Lupus Drug.  New York Times [Internet].  March 9, 2011.

8. Rahman A, Isenberg D. Mechanisms of Disease: Systemic Lupus Erythematous.  N Engl J Med 2008;358:929-39.  http://www.nejm.org/doi/full/10.1056/NEJMra071297

9. Fackler M, McDonald M.  Japan pushes to rescue survivors as quake toll rises.  New York Times [Internet].  12 March 2011.  Available from: http://www.nytimes.com/2011/03/13/world/asia/13japan.html?pagewanted=1&hp

10. Broad W. Danger posed by radioactivity in Japan hard to assess.  New York Times [Internet].  12 March 2011. Available from: http://www.nytimes.com/2011/03/13/science/13radiation.html?hp

11. Warry R.  Health effects of radiation exposure.  BBC News [Internet]. Available from: http://www.bbc.co.uk/news/health-12722435

 

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