Saumil M. Chudgar, MD

Clinical question: Can C-reactive protein levels (CRP), procalcitonin, TNF-alpha, and cytokine levels predict the need for intensive-care admission more accurately than IDSA/ATS guidelines in patients with severe community-acquired pneumonia (CAP)?

Background: Inflammatory biomarkers, such as CRP and procalcitonin, have diagnostic and prognostic utility in patients with CAP. Whether these inflammatory biomarkers can help triage patients to the appropriate level of care is unknown.

Study design: Prospective case control study.

Setting: Two university hospitals in Spain.

Synopsis: The study included 685 patients with severe CAP who did not require mechanical ventilation or vasopressor support. Serum levels of CRP, procalcitonin, TNF-alpha, IL-1, IL-6, IL-8, and IL-10, as well as Infectious Diseases Society of American/American Thoracic Society (IDSA/ATS) minor severity criteria data, were collected on admission. After controlling for age, comorbidities, and PSI risk class, serum levels of CRP and procalcitonin were found to be significantly higher in ICU patients compared with non-ICU patients. Despite this, these inflammatory biomarkers did not augment the IDSA/ATS guidelines, suggesting that patients who have three or more minor criteria be considered for ICU admission.

The study did suggest that patients with severe CAP and low levels of IL-6 and procalcitonin could potentially be managed safely outside of the ICU. However, hospitalists should be wary of applying the study results due to the small number of ICU patients in this study and the lack of real-time availability of these biomarkers at most institutions.

Bottom line: More studies of inflammatory biomarkers are needed before using them to determine the level of care required for patients with CAP. Until these data are available, physicians should use the IDSA/ATS guidelines to triage patients to the appropriate level of care.

Citation: Ramirez P, Ferrer M, Torres A, et al. Inflammatory biomarkers and prediction for intensive care unit admission pneumonia. Crit Care Med. 2011;39:2211-2217.

IL-13 Antibody Lebrikizumab Shows Promise as a New Therapy for Adults with Uncontrolled Asthma

Clinical question: Can lebrikizumab, an IL-13 antibody, improve asthma control in patients with uncontrolled asthma?

Background: Asthma is a complex disease, with varied patient response to treatment. Some patients have uncontrolled asthma despite inhaled glucocorticoids. It is postulated that IL-13 may account for this variability and that some patients with uncontrolled asthma are poorly controlled due to glucocorticoid resistance mediated by IL-13. Lebrikizumab is an IgG4 monoclonal antibody that binds to and inhibits the function of IL-13. This study was performed to see if this antibody would be effective in patients with uncontrolled asthma despite inhaled glucocorticoid therapy.

Study design: Randomized double-blinded placebo-controlled trial.

Setting: Multiple centers.

Synopsis: The study randomized 219 adult asthma patients who were inadequately controlled despite inhaled corticosteroids to a placebo or lebrikizumab. The primary outcome was improvement in prebronchodilator FEV1 from baseline. Secondary outcomes were exacerbations, use of rescue medications, and symptom scores. Patients were also stratified and analyzed based on surrogate markers for IL-13, which included serum IGE levels, eosinophil counts, and periostin levels.

In patients who were randomized to the lebrikizumab treatment, there was a statistically significant improvement in FEV1 of 5.5%, which occurred almost immediately and was sustained for the entire 32 weeks of the study. The improvement was more significant in patients who had high surrogate markers for IL-13. Despite this improvement in FEV1, there were no differences in secondary outcomes except in patients who had surrogate markers for high IL-13 levels.

Bottom line: In adults with asthma who remained uncontrolled despite inhaled corticosteroid therapy, IL-13 antagonism with lebrikizumab improved FEV1. However, the clinical relevance of these modest improvements remains unclear.

Citation: Corren J, Lemanske R, Matthews J, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088-1098.

Rivaroxaban Is Noninferior to Warfarin for Stroke Prevention in Atrial Fibrillation

Clinical question: How does rivaroxaban compare with warfarin in the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation?

Background: Warfarin is effective for the prevention of stroke in atrial fibrillation, but it requires close monitoring and adjustment. Rivaroxaban, an oral Xa inhibitor, may be safer, easier, and more effective than warfarin.

Study design: Multicenter, randomized, double-blind, double-dummy trial.

Setting: 1,178 sites in 45 countries.

Synopsis: The study included 14,264 patients with nonvalvular atrial fibrillation who were randomized to either fixed-dose rivaroxaban (20 mg daily or 15 mg daily for CrCl 30-49 mL/min) plus placebo or adjusted-dose warfarin (target INR 2.0 to 3.0) plus placebo. The mean CHADS2 score was 3.5. The primary endpoint (stroke or systemic embolism) occurred in 1.7% of patients per year in the rivaroxaban group and 2.2% per year in the warfarin group (hazard ratio for rivaroxaban 0.79; 95% CI: 0.66 to 0.96, P<0.001 for noninferiority). There was no difference in major or nonmajor clinically significant bleeding between the two groups (14.9% rivaroxaban vs. 14.5% warfarin, hazard ratio=1.03, 95% CI: 0.96 to 1.11, P=0.44). There were fewer intracranial hemorrhages (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group.

Bottom line: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolization, with a similar risk of major bleeding and a lower risk of intracranial hemorrhage or fatal bleeding.

Citation: Patel MR, Mahaffey K, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891.

Apixaban More Effective and Safer than Warfarin for Stroke Prevention in Atrial Fibrillation

Clinical question: How does the effectiveness and safety of apixaban compare with warfarin for stroke prevention in atrial fibrillation?

Background: Until recently, warfarin has been the only available oral anticoagulant for stroke prevention in patients with atrial fibrillation (AF). The oral factor Xa inhibitors have shown similar efficacy and safety, without the monitoring requirement and drug interactions associated with warfarin.

Study design: Prospective randomized double-blind controlled trial.

Setting: More than 1,000 clinical sites in 39 countries.

Synopsis: This study randomized 18,201 patients with atrial fibrillation or flutter and at least one CHADS2 risk factor for stroke to receive oral apixaban or warfarin therapy. Exclusion criteria were prosthetic valves and severe kidney disease. The median duration of follow-up was 1.8 years, and the major endpoints were incidence of stroke, systemic embolism, bleeding complications, and mortality.

Compared with warfarin, apixaban reduced the annual incidence of stroke and systemic embolism from 1.6% to 1.3% (HR 0.79, 95%: CI 0.66 to 0.95, P=0.01 for superiority), and reduced mortality (HR: 0.89, 95% CI: 0.80 to 0.998). For the combined endpoint of stroke, systemic embolism, MI, or death, the annual rate was reduced from 5.5% to 4.9% (HR: 0.88, 95% CI: 0.80 to 0.97). All measures of bleeding were less frequent with apixaban: major 2.1% vs. 3.1% (HR: 0.69, 95% CI: 0.60 to 0.80), and combined major and minor bleeding 4.1% vs. 6.0% (HR: 0.68, 95% CI: 0.61 to 0.75). The annual rate for the net outcome of stroke, embolism, or major bleeding was 3.2% with apixaban and 4.1% with warfarin (HR: 0.77, 95% CI: 0.69 to 0.86).

Bottom line: Compared with warfarin therapy, apixaban is more effective and safer for stroke prevention in patients with atrial fibrillation.

Citation: Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

Ultrasonography Is Useful in Diagnosis of Pneumothorax

Clinical question: Is transthoracic ultrasonography a useful tool to diagnose pneumothorax?

Background: CT is the diagnostic gold standard for pneumothorax, but it is associated with radiation exposure and requires patient transport. Chest radiograph is easy to perform but may be too insensitive for adequate diagnosis. Ultrasonography’s diagnostic performance for detecting pneumothorax needs further evaluation.

Study design: Systematic review and meta-analysis.

Setting: Critically ill, trauma, or post-biopsy patients were identified in each of the studies.

Synopsis: The meta-analysis of 20 eligible studies found a pooled sensitivity of ultrasound for the detection of pneumothorax of 0.88 (95% CI: 0.85 to 0.91) and specificity of 0.99 (0.98 to 0.99) compared with sensitivity of 0.52 (0.49 to 0.55) and specificity of 1.00 (1.00 to 1.00) for chest radiograph. Although the overall ROC curve was not significantly different between these modalities, the accuracy of ultrasonography was highly dependent on the skill of the operator.

Bottom line: When performed by a skilled operator, transthoracic ultrasonography is as specific, and more sensitive, than chest radiograph in diagnosing pneumothorax.

Citation: Ding W, Shen Y, Yang J, He X, Zhang M. Diagnosis of pneumothorax by radiography and ultrasonography: a meta-analysis. Chest. 2011;140:859-866.

Risk Prediction for Hospital Readmission Remains Challenging

Clinical question: Can readmission risk assessment be used to identify which patients would benefit most from care-transition interventions, or to risk-adjust readmission rates for hospital comparison?

Background: Multiple models to predict hospital readmission have been described and validated. Identifying patients at high risk for readmission could allow for customized care-transition interventions, or could be used to risk-adjust readmission rates to compare publicly reported rates by hospital.

Study design: Systematic review with qualitative synthesis of results.

Setting: Thirty studies (23 from the U.S.) tested 26 unique readmission models.

Synopsis: Each model had been tested in both a derivation and validation cohort. Fourteen models (nine from the U.S.), using retrospective administrative data to compare risk-adjusted rates between hospitals, had poor discriminative capacity (c statistic range: 0.55 to 0.65). Seven models could be used to identify high-risk patients early in the hospitalization (c statistic range: 0.56 to 0.72) and five could be used to identify high-risk patients at discharge (c statistic range: 0.68 to 0.83), but these also had poor to moderate discriminative capacity. Multiple variables were considered in each of the models; most incorporated medical comorbidities and prior use of healthcare services.

Bottom line: Current readmission risk prediction models do not perform adequately for comparative or clinical purposes.

Citation: Kansagara D, Englander H, Salanitro A, et. al. Risk prediction models for hospital readmission: a systematic review. JAMA. 2011;306:1688-1698.

Intravenous Fluids for Acute Pancreatitis: More May Be Less

Clinical question: What is the optimal volume of fluid administration for treatment of acute pancreatitis?

Background: Current guidelines for management of acute pancreatitis emphasize vigorous administration of intravenous fluids to reduce the risk of pancreatic necrosis and organ failure. This recommendation is based upon animal studies, and has not been subjected to clinical evaluation in humans.

Study design: Prospective observational cohort.

Setting: University-affiliated tertiary-care public hospital in Spain.

Synopsis: This study enrolled 247 patients admitted with acute pancreatitis to determine the association between the volume of fluid administered during the first 24 hours and the development of persistent organ failure, pancreatic fluid collection or necrosis, and mortality. The volume and rate of fluid administered were determined by the treating physician. Patients were classified into three groups: those receiving a volume <3.1 L, 3.1 to 4.1 L, or >4.1 L.

After multivariate adjustment, those receiving <3.1 L had no increased risk of necrosis or any other adverse outcome, compared with those who received the middle range of fluid volume.

Patients receiving >4.1 L had a higher risk of persistent organ failure (OR: 7.7, 95% CI: 1.5 to 38.7), particularly renal and respiratory insufficiency, and fluid collection development (OR: 1.9, 95% CI: 1 to 3.7) independent of disease severity. Pancreatic necrosis and mortality were similar in the three groups.

Bottom line: Administration of large-volume intravenous fluids (>4.1 L) in

the first 24 hours was associated with worse outcomes, although residual confounding cannot be excluded in this nonrandomized study.

Citation: de-Madaria E, Soler-Sala G, Sanchez-Paya J, et al. Influence of fluid therapy on the prognosis of acute pancreatitis: a prospective cohort study. Am J Gastroenterol. 2011;106:1843-1850.

Clinical Outcomes in Saddle Pulmonary Embolism

Clinical question: What are the treatments used and outcomes associated with saddle pulmonary embolism?

Background: Saddle pulmonary embolism is a risk for right ventricular dysfunction and sudden hemodynamic collapse. There are limited data on the clinical presentation and outcomes in these patients.

Study design: Retrospective case review.

Setting: Single academic medical center.

Synopsis: In this retrospective review of 680 patients diagnosed with pulmonary embolism on CT at a single academic medical center from 2004 to 2009, 5.4% (37 patients) had a saddle pulmonary embolism.

Most patients with saddle pulmonary embolism were hemodynamically stable and responded to standard therapy with unfractionated heparin. The mean length of stay was nine days, 46% received an inferior vena cava filter, 41% were treated in an ICU, and 5.4% (two patients) died in the hospital. Thrombolytics were used in only 11% of patients, most of which had sustained hypotension and/or were mechanically ventilated.

Bottom line: Most patients with saddle pulmonary embolus in this single institution study did not receive thrombolytics and had overall low mortality.

Citation: Sardi A, Gluskin J, Guttentag A, Kotler MN, Braitman LE, Lippmann M. Saddle pulmonary embolism: is it as bad as it looks? A community hospital experience. Crit Care Med. 2011;39:2413-2418.

Clinical Shorts

Pancreaticojejunostomy Is Superior To Endoscopy As Treatment For Advanced Chronic Pancreatitis

In this small prospective trial of 31 patients with advanced chronic calcific pancreatitis, patients who initially underwent a pancreaticojejunostomy had less pain and required fewer re-interventions than patients who had endoscopic treatment during a median follow-up of six years.

Citation: Cahen DL, Gouma DJ, Bruna et al. Long-term outcomes of endoscopic vs surgical drainage of the pancreatic duct in patient with chronic pancreatitis. Gastroenterology. 2011;141:1690-1695.

Routine surveillance for patients with Barrett’s esophagus called into question

In this nationwide cohort of patients in Denmark, the annual risk of developing adenocarcinoma in patients with Barrett’s esophagus was 0.12%, which is markedly lower than previously reported estimates of 0.5%, uapon which the guidelines for screening are based.

Citation: Hvid-Jensen F, Pedersen L, Funch-Jensen P, et al. Incidence of adenocarcinoma among patients with Barrett’s esophagus. N Engl J Med. 2012;365:1375-1383.

Consider hepatitis E testing in suspected drug-induced liver injury

A serologic survey of patients in the U.S. with acute liver injury attributed to drugs found 16% had evidence of hepatitis E, representing 3% of the acute disease in the population studied.

Citation: Davern TJ, Chalasani N, Fontana RJ, et al. Acute hepatitis E infection accounts for some cases of suspected drug-induced liver injury. Gastroenterology. 2011;141:1665-1672.

Pressure redistribution mattresses reduce pressure ulcers

A cost-effectiveness analysis supported using pressure redistribution mattresses to prevent pressure ulcers in long-term care residents; additional study is needed to determine the cost-effectiveness of emollients and cleansers.

Citation: Pham B, Stern A, Chen W, et. al. Preventing pressure ulcers in long-term care. Arch Intern Med. 2011;171:1839-1847.

Screening chest x-rays still do not prevent death from lung cancer

A randomized controlled trial of annual screening chest radiography enrolling nearly 155,000 patients, 52% of whom were current or former smokers, yielded no reduction in mortality from lung cancer.

Citation: Oken MM, Hocking WG, Kvale PA, et al. Screening by chest radiograph and lung cancer mortality. JAMA. 2011;306:1865-1873.

Abnormal QT-interval duration is associated with increased mortality

A cross-sectional study found that shortened or prolonged QT-interval duration, even if still within the reference range, is associated with increased mortality risk.

Citation: Zhang Y, Post WS, Dalal D, Blasco-Colmenares E, Tomaselli GF, Guallar E. QT-interval duration and mortality rate. Arch Intern Med. 2011;171:1727-1733.

Issue

The Hospitalist - 2012(03)

Publications

The Hospitalist

Read more about In the Literature: Physician Reviews of HM-Related Research

Sections

Author(s)

Saumil M. Chudgar, MD

Noppon Setji, MD

Thomas A. Owens, MD

Author(s)

Daniel M. Kaplan, MD

Saumil M. Chudgar, MD

Noppon Setji, MD

Thomas A. Owens, MD

In This Edition

Literature At A Glance

A guide to this month’s studies

IDSA/ATS guidelines for community-acquired pneumonia

Improved asthma with IL-13 antibody

Rivaroxaban vs. warfarin for stroke prevention in atrial fibrillation

Apixaban vs. warfarin for stroke prevention in atrial fibrillation

Ultrasonography more sensitive than chest radiograph for pneumothorax

Current readmission risk models inadequate

Optimal fluid volume for acute pancreatitis

Low mortality in saddle pulmonary embolism