Update in Pulmonary and Critical Care Medicine

Updates4 May 2010Update in Pulmonary and Critical Care MedicineFREEAnthony F. Suffredini, MD, Henry Masur, MD, and Joseph P. Lynch III, MDAnthony F. Suffredini, MDFrom the National Institutes of Health, Bethesda, Maryland, and David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.Search for more papers by this author, Henry Masur, MDFrom the National Institutes of Health, Bethesda, Maryland, and David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.Search for more papers by this author, and Joseph P. Lynch III, MDFrom the National Institutes of Health, Bethesda, Maryland, and David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-152-9-201005040-00247 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail This article summarizes studies published in 2009 that have important implications for the practice of pulmonary and critical care medicine. In pulmonary medicine, 2 trials provide insight into the management of patients with chronic obstructive pulmonary disease (COPD). Inhaled tiotropium added to standard respiratory therapies reduced mortality during 4 years of therapy in nonsmoking patients. In another study, the combination of inhaled salmeterol plus inhaled fluticasone (which reduces mortality in patients with severe COPD) improved health status and reduced exacerbations in patients with mild COPD. For patients with asthma, inhaled salmeterol without corticosteroids worsened airway hyperresponsiveness (AHR), hospitalizations, and mortality. A short-term study showed that salmeterol increases mononuclear cell levels of brain-derived neurotrophic factor, a mediator of AHR, and that these effects were reversed with fluticasone propionate. For patients with pneumonia, guideline-concordant therapy is correlated with better outcomes for community-acquired pneumonia (CAP). Finally, a multicenter study of patients with pneumonia showed that procalcitonin could reduce rates of antibiotic exposure and antibiotic-associated adverse events.In critical care medicine, 3 studies shed light on optimal management of critically ill patients with sepsis: NICE-SUGAR (Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation) showed that intensive glucose control in critically ill patients was associated with increased hypoglycemia and increased mortality, suggesting that this strategy should be discarded. A systematic review of corticosteroids as adjunctive therapy for septic shock showed that low-dose corticosteroids reverse shock and may improve survival. In selected patients, an experienced team of therapists and nurses can mobilize mechanically ventilated patients and improve functional outcomes. With regard to other syndromes seen commonly in the intensive care unit (ICU), an observational study of the timeliness of appropriate antibiotics in patients with pneumonia reinforced the need for prompt operational strategies to choose and deliver appropriate empirical therapy. Many articles emphasized the effect of H1N1 influenza in 2009 on morbidity and mortality, presaging what could occur when a more severe pandemic occurs. A study from Canada emphasized that even with a mild strain of influenza that produced low-severity illness in most patients, a substantial number of patients needed ICU care, raising the question of whether enough ICU resources will be available when a more severe pandemic occurs. A study assessing line-related sepsis showed that using chlorhexidine-impregnated sponges to cover the insertion site can reduce the incidence of infectious complications. New interventions, although effective individually, must be interpreted in the context of other, established beneficial interventions.Chronic Obstructive Pulmonary DiseaseTiotropium May Reduce Mortality in COPD While Patients Continue Therapy Celli B, Decramer M, Kesten S, et al; UPLIFT Study Investigators. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180:948-55. [PMID: 19729663]Background: The long-term effect of pharmacologic therapy for COPD is controversial. The UPLIFT (Mortality in the 4-Year Trial of Tiotropium) study was a 4-year randomized, controlled trial (RCT) reported in 2008. It evaluated the effect of inhaled tiotropium (an anticholinergic agent) on the rate of decline in FEV1 in patients with COPD. Although this rate with tiotropium did not differ from that with placebo, benefits were observed in several secondary end points, including health-related quality of life, risk or hospitalization for a COPD exacerbation, respiratory failure, and all-cause mortality. However, a more complete evaluation of the timing and causes of deaths is needed to better understand the effect of tiotropium therapy.Study Design: An independent adjudication committee evaluated deaths during and after the 4-year study. A total of 5993 patients with COPD from 37 countries were randomly assigned to receive tiotropium or placebo in addition to their usual respiratory medications (except for anticholinergic drugs).Findings: All-cause mortality during drug treatment was 13.6% in the placebo group and 12.8% in the tiotropium group (hazard ratio [HR], 0.84 [95% CI, 0.73 to 0.97]; P = 0.016). At study completion (1440 days), mortality was lower in the tiotropium group (14.4% vs. 16.3%; HR, 0.87 [CI, 0.76 to 0.99]; P = 0.034). At 1470 days (4 years of treatment plus 30 days), mortality rates were 14.9% and 16.5% with tiotropium and placebo, respectively (HR, 0.89 [CI, 0.79 to 1.02]; P = 0.086). The most common cause of death in both groups was lower respiratory disorders.Cautions: The placebo group had more premature discontinuations of the study drug, and patients who discontinued prematurely had more severely depressed FEV1, which might have biased the results.Implications: Long-term treatment with tiotropium (with or without concomitant respiratory medications) may reduce mortality in patients with COPD. The beneficial effect on mortality observed, however, was no longer significant 30 days after the 4-year treatment period: Statistical significance was observed at the end of the protocol-defined treatment period (P = 0.034) but not 30 days thereafter (P = 0.086). This difference may have been due to an excess number of deaths in the tiotropium group after discontinuation of therapy. In addition, the benefit of tiotropium on mortality was noted in nonsmokers but not current smokers, suggesting that the noxious effects of smoking may override the benefits of therapy.A Post Hoc Evaluation of Salmeterol and Fluticasone for Mild COPD Jenkins CR, Jones PW, Calverley PM, et al. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study. Respir Res. 2009;10:59. [PMID: 19566934]Background: In 2007, an RCT reported that treatment with inhaled salmeterol (a long-acting β-agonist) together with inhaled fluticasone propionate (an inhaled corticosteroid) decreased mortality in patients with severe or very severe COPD. However, data on the value of this combination in patients with milder COPD are lacking.Study Design: The investigators performed an unplanned (post hoc) analysis of data from the TORCH (Towards a Revolution in COPD Health) study, a 3-year RCT of 6112 patients with moderate to severe COPD (prebronchodilator FEV1 <60% predicted) in which patients were randomly assigned to treatment with inhaled salmeterol, fluticasone propionate, both drugs in combination, or placebo. Overall, the patients had a mean age of 65 years and a mean FEV1 of 44%, 76% were male, and 44% were current smokers. The trial excluded patients with asthma or more than 10% reversibility in airway obstruction. In this secondary analysis, the authors assessed outcomes according to patients' Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage (a classification of disease severity): moderate (GOLD stage II, FEV1 ≥50% to <80%; n = 2156), severe (GOLD stage III, FEV1 ≥30% to <50%; n = 3019), and very severe (GOLD stage IV, FEV1 <30%; n = 937).Findings: Compared with placebo, combination therapy improved postbronchodilator FEV1 by 101 mL in patients with GOLD stage II (CI, 71 to 132 mL), 82 mL in patients with GOLD stage III (CI, 60 to 184 mL), and 96 mL in patients with GOLD stage IV (CI, 54 to 138 mL) disease. Combination therapy reduced the rate of COPD exacerbations by 31% in patients with baseline GOLD stage II disease (CI, 19% to 40%) and by 26% in patients with GOLD stage III disease (CI, 17% to 34%). No reduction in the rate of exacerbation was seen in patients with GOLD stage IV disease (14% [CI, −4% to 29%]). Combination therapy improved patient-reported health-related quality of life in all 3 stages. Finally, in this exploratory analysis, mortality was reduced with combination therapy in patients with baseline GOLD stage II disease (HR, 0.67 [CI, 0.65 to 0.98]) but not in those with GOLD stage III (HR, 0.95 [CI, 0.73 to 1.24]) or IV (HR, 0.70 [CI, 0.4 to 1.05]) disease.Adverse events were similar across treatment groups and increased with disease severity. The incidence of pneumonia was higher in the fluticasone propionate and combination groups, regardless of GOLD stage, when compared with placebo or salmeterol.Cautions: The analysis was post hoc and must be viewed as hypothesis-generating only. The study was not designed to test for differences between GOLD stages or differences between treatment groups within GOLD stages. The numbers of patients in each group differed, and the analysis of treatment subgroups within stages was underpowered.Implications: According to this hypothesis-generating study, 3 years of treatment with combined inhaled salmeterol and fluticasone propionate may improve health-related quality of life and reduce exacerbations and mortality in patients with moderate (GOLD stage II) COPD. Further prospective studies are required to assess whether combination therapy has a clinically meaningful benefit in patients with moderate COPD.AsthmaA Possible Molecular Link for the Effects of Long-Acting β-Agonists and Corticosteroids in Asthma Lommatzsch M, Lindner Y, Edner A, et al. Adverse effects of salmeterol in asthma: a neuronal perspective. Thorax. 2009;64:763-9. [PMID: 19237390]Background: Long-term use of inhaled β-agonists without concomitant corticosteroids has been associated with a paradoxical loss of asthma control; worsening AHR; and increases in asthma exacerbations, hospitalizations, and mortality. The mechanisms responsible for these effects are not known. The neurotrophin brain-derived neurotrophic factor (BDNF) has been linked to several features of asthma and may mediate AHR. Systemic concentrations of BDNF are increased during asthma exacerbations and correlate with AHR. Corticosteroids prevent allergen-induced increases in AHR and reduce BDNF concentrations. The effects of β-agonists on BDNF in asthma, however, have not been studied.Study Design: Airway hyperresponsiveness and BDNF in serum and platelets were measured in 18 adults with mild allergic asthma at baseline after 14 days of treatment with the inhaled long-acting β-agonist salmeterol and after a subsequent 14 days of combination therapy with inhaled salmeterol plus fluticasone propionate. The study also assessed the effects of salmeterol on BDNF release from mononuclear cells of normal human peripheral blood in vitro.Findings: Monotherapy with salmeterol significantly increased serum and platelet BDNF concentrations and increased AHR, and these effects were subsequently abrogated by combination treatment. Although AHR increased in 12 of 18 persons after salmeterol monotherapy, the change in AHR was not statistically significant when all participants were analyzed. Airway hyperresponsiveness improved with combination therapy compared with baseline in 15 patients (83%) and compared with salmeterol monotherapy in 16 patients (89%). Salmeterol also increased BDNF release by mononuclear cells, an effect inhibited by co-incubation with fluticasone.Cautions: The study was small, lacked a placebo or treatment crossover, and included only patients with mild asthma. Whether the findings are representative of patients with more severe or nonallergic asthma requires further study.Implications: Brain-derived neurotrophic factor may mediate AHR and worsens asthma control in patients with asthma who are treated with long-term β-agonist monotherapy. Inhaled corticosteroids may ameliorate this effect. The results emphasize current recommendations to combine regular β-agonist therapy for asthma with inhaled corticosteroids and to discourage long-term β-agonist monotherapy.PneumoniaAdherence to Antibiotic Guidelines for Community-Acquired Pneumonia Was Associated With Improved Outcomes McCabe C, Kirchner C, Zhang H, et al. Guideline-concordant therapy and reduced mortality and length of stay in adults with community-acquired pneumonia: playing by the rules. Arch Intern Med. 2009;169:1525-31. [PMID: 19752411]Background: Community-acquired pneumonia remains a major cause of morbidity and mortality worldwide. A 2007 clinical practice guideline from the American Thoracic Society and Infectious Diseases Society of America (ATS/ISDA) recommends specific antimicrobial regimens according to specific risk factors, previous antibiotic use, and resistance patterns. The ATS/ISDA recommendations, however, have not been validated in prospective randomized trials.Study Design: To assess the effect of therapy according to ATS/ISDA guidelines, the outcomes of adults hospitalized for CAP from 1999 to 2003 at 113 U.S. community and tertiary care centers were assessed according to whether initial antibiotic therapy was concordant with the guidelines.Findings: Of 54 619 adults, 35 477 (65%) received initial antibiotic therapy concordant with 2007 ATS/IDSA guidelines. Overall, 30-day mortality was 5.8%. Patients who received guideline-concordant therapy had lower mortality than those who did not, even after adjustment for multiple confounding variables (odds ratio [OR], 0.70 [CI, 0.63 to 0.77]). Guideline-concordant therapy was associated with lower rates of sepsis and renal failure but no difference in respiratory failure. Patients receiving guideline-concordant therapy were transitioned from parenteral to oral antibiotics an average of 0.57 days sooner and had a shorter length of stay (LOS) regardless of pneumonia severity (mean reduction, 0.66 days; P < 0.001). In univariate exploratory analyses, the risk for death correlated with the use of specific classes of antimicrobials, with reductions observed in patients receiving initial empirical therapy with second- or third-generation cephalosporins, macrolides, or fluoroquinolones. In addition, even after adjustment for pneumonia severity, antibiotic coverage with activity against Legionella species was less likely to have occurred in patients who received cefepime (OR, 0.26), carbapenems (OR, 0.31), piperacillin–tazobactam (OR, 0.33), or vancomycin (OR, 0.43), and mortality was higher in patients receiving these antibiotics.Cautions: This was an observational study only. Given the lack of randomization, it is possible that persons receiving guideline-concordant therapy differed fundamentally from those receiving discordant therapy. Furthermore, data on the microbial cause of pneumonia were lacking, making it impossible to determine whether the observed mortality and other outcome differences reflect inadequate coverage of specific pathogens (particularly Legionella species).Implications: The use of ATS/IDSA guidelines was associated with improved outcomes (mortality, LOS, transition to oral antibiotics) in adults with CAP. The greater mortality observed in patients receiving certain antibiotic regimens may have been explained by a lack of coverage against “atypical” organisms (for example, Legionella, Mycoplasma, and Chlamydia species) with either a macrolide or fluoroquinolone. Although the hypothesis requires validation, adherence to clinical practice guidelines for CAP should be encouraged.Health Care–Associated Pneumonia: Worse Outcomes Than Hospital-Acquired or Community-Acquired Pneumonia Venditti M, Falcone M, Corrao S, et al; Study Group of the Italian Society of Internal Medicine. Outcomes of patients hospitalized with community-acquired, health care-associated, and hospital-acquired pneumonia. Ann Intern Med. 2009;150:19-26. [PMID: 19124816]Background: In 2005, the ATS/IDSA guidelines proposed a new category of pneumonia—health care–associated pneumonia (HCAP)—as an entity distinct from CAP and hospital-acquired pneumonia (HAP). Patients with HCAP include those who have recently been hospitalized, have resided in nursing homes or long-term care facilities, or have received hemodialysis or intravenous chemotherapy. Guidelines for empirical treatment were published but have not been validated in prospective studies.Study Design: To evaluate the causes and outcomes of CAP, HAP, and HCAP, a prospective observational study of adults with pneumonia admitted to 55 hospitals in Italy was performed during 2 surveillance periods of 1 week each.Findings: A total of 362 patients with pneumonia were evaluated: 223 patients (61.6%) had CAP, 90 patients (24.9%) had HCAP, and 49 patients (13.5%) had HAP. The mean age was 75.5 years, and 48.6% had at least 2 comorbid conditions at the time of diagnosis of pneumonia. Compared with patients with CAP, patients with HCAP had higher mean Sequential Organ Failure Assessment scores (3.0 vs. 2.0), were more frequently malnourished (11.1% vs. 4.5%), and had more frequent bilateral (34.4% vs. 19.7%) and multilobar (27.8% vs. 21.5%) involvement on chest radiography. Patients with HCAP also had higher mortality rates (17.8% [CI, 10.6% to 24.9%] vs. 6.7% [CI, 2.9% to 10.5%]) and longer mean LOS (18.7 days [CI, 15.9 to 21.5 days] vs. 14.7 days [CI, 13.4 to 15.9 days]). Logistic regression analysis revealed that depressed consciousness (OR, 3.2), leukopenia (OR, 6.2), and receipt of antimicrobial therapy not recommended by the 2005 ATS/IDSA guidelines (OR, 6.4) were independently associated with increased hospital mortality. Of note, patients with HCAP were more likely to receive empirical therapy inconsistent with the 2005 ATS/IDSA guidelines (P < 0.001): Adherence to guideline recommendations was 58.7% for CAP, 69.4% for HAP, and only 26.7% for HCAP (P < 0.001).Cautions: The number of patients with HCAP was relatively small, and microbiological data were not provided. The study included only patients requiring hospitalization; therefore, the results may not apply to outpatients. Given the observational nature of this study and the lack of randomization, additional studies are required to determine optimum therapy for HCAP.Implications: Clinicians should recognize HCAP as a distinct form of pneumonia because it is associated with higher mortality and increased LOS compared with other types and is frequently managed inadequately with potentially inappropriate initial antibiotic therapy. Selection of antibiotics for HCAP should include coverage of methicillin-resistant Staphylococcus aureus and multidrug-resistant gram-negative rods, as recommended in a 2008 consensus statement by the IDSA.Critical Care MedicineUsing Serum Procalcitonin Levels to Guide Antibiotic Use in Lower Respiratory Infections Schuetz P, Christ-Crain M, Thomann R, et al; ProHOSP Study Group. Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA. 2009;302:1059-66. [PMID: 19738090]Background: Because symptoms and signs are frequently unreliable in distinguishing bacterial from viral lower respiratory tract infection (LRTI), unnecessary antibiotic use is common. Higher and protracted elevations in serum procalcitonin levels correlate with more severe systemic infections, bacteremic CAP, and slower bacterial clearance. Small (often single-center) studies have suggested that procalcitonin-based clinical algorithms reduce antibiotic use but have not been sufficiently powered to assess whether such algorithms are associated with adverse outcomes.Study Design: An RCT done in the emergency departments of 6 Swiss tertiary care hospitals assessed the of a procalcitonin-based to antibiotic therapy. The investigators randomly assigned patients with to antibiotic care by a procalcitonin-based or standard guidelines Serum procalcitonin was measured at each and results were available within 1 In the procalcitonin the or of antibiotics was for patients with procalcitonin levels less than and was for patients with procalcitonin levels less than or of antibiotics was for patients with procalcitonin levels greater than and was in patients with procalcitonin levels greater than Patients who were hospitalized had procalcitonin and antibiotics were or according to the levels and The rates of adverse outcomes were similar in the procalcitonin and control groups vs. [CI, to 0.4 The mean of antibiotic exposure was shorter in the procalcitonin group than the control group vs. days; [CI, to with significant reductions in the subgroups of patients with CAP vs. days), exacerbation of COPD vs. days), and vs. adverse effects were less frequent in the procalcitonin group vs. [CI, to Patients with severe or comorbid conditions were Use of a end adverse can The rate of combined adverse outcomes to be lower in the procalcitonin but the mortality rate was In patients with the use of serum procalcitonin levels to antibiotic use results in lower rates of antibiotic exposure and antibiotic-associated adverse effects without an in adverse outcomes compared with standard on procalcitonin levels can reduce antibiotic use and antibiotic Glucose in Patients Was Associated With and Mortality at 90 S, et al; NICE-SUGAR Study Investigators. Intensive glucose control in critically ill patients. J Med. [PMID: a study reported decreased mortality and other benefits with an intensive in patients in the recommended glucose control as in The study, however, was done at a did not study patients in the ICU and substantial of glucose as of Although a benefit of intensive glucose control was not seen in multiple subsequent studies or in a an increased risk for hypoglycemia was and the and benefits of to in critically ill patients are Design: A RCT of critically ill and patients compared to intensive glucose control blood glucose to to or glucose control The end was death from cause at 90 The groups were similar at baseline and included patients with a of and were patients, had 31% had an and Chronic Evaluation II greater than had severe and received At 90 in the group had compared with in the group for intensive [CI, to P = analysis suggested that the results did not differ between or patients or whether the had or severe The time was lower in the group than in the group (HR, [CI, to P = hypoglycemia occurred in of patients in the group and in the group (OR, 14.7 [CI, to P < 0.001).Cautions: The group had more premature discontinuations from the assigned treatment and more patients received and recommendations for intensive glucose control has not been as beneficial in critically ill patients. therapy to results in increased mortality compared with a of less than and an increased risk for The study of the need for a more to the of recommendations, including of findings from additional and Therapy in Patients May et al. and therapy in mechanically critically ill a controlled trial. [PMID: Patients with critical illness frequently including and which the quality of life of long-term during such as to such of to from and of may reduce these adverse of In addition, small, observational studies that and in the ICU may improve long-term and outcomes.Study Design: The investigators randomly assigned critically ill adults who had received less than of at 2 hospitals to either and during periods when was or and therapy. The outcome was the number of patients to independent functional status at hospital A to treatment assessed this patients were randomly assigned to the and and 55 patients were randomly assigned to The (a of of of was and more than of patients had sepsis their In the several were during including at in or 2 or more Intensive care unit and hospital LOS and of did not differ between the The group had less at hospital vs. P = these the end of to an independent functional status at hospital was in patients in the group compared with patients in the control group (P = Patients who were not independent their critical illness were the results may not be to all critically ill patients. of and therapy in critically ill patients requires appropriate and experienced is not a of critical illness and in the A team of therapists and nurses can with and in selected mechanically ventilated patients. including may to improved functional outcomes in patients in the Corticosteroids as Therapy in et al. Corticosteroids in the treatment of severe sepsis and septic shock in a systematic JAMA. [PMID: performed in the to showed that of

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