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15 May 2012

Update in Pulmonary and Critical Care Medicine: Evidence Published in 2011

Publication: Annals of Internal Medicine
Volume 156, Number 10
This article summarizes studies published in 2011 that influence the practice of pulmonary and critical care medicine. Key studies were identified from ACP Journal Club PLUS among the highest-rated and most-accessed articles in 2011.
In pulmonary medicine, 2 randomized trials evaluated therapy to prevent acute chronic obstructive pulmonary disease (COPD) exacerbations. Daily azithromycin was more effective than placebo in 1 trial, and tiotropium dry powder was more effective than salmeterol in the other. However, physicians must balance these observations against the risk for hearing deficits with daily azithromycin therapy and against the findings of a meta-analysis that suggested that tiotropium mist was associated with increased mortality compared with placebo. For pneumonia, a double-blind, placebo-controlled trial reported that adding dexamethasone to antibiotic therapy reduced the length of hospital stays for nonimmunocompromised patients with community-acquired pneumonia. A systematic review and meta-analysis reported that the use of acid-suppressive drugs was associated with an increased risk for community- and hospital-acquired pneumonia. Finally, the National Lung Screening Trial research team reported that low-dose computed tomography (CT) screening of high-risk patients reduced mortality from lung cancer.
In critical care medicine, a randomized trial of real-time ultrasound guidance versus the landmark approach to subclavian vein cannulation showed that ultrasound increased the success of the procedure and decreased complications. Screening for delirium has become part of routine care in the intensive care unit (ICU). However, when investigators compared expert opinion with results from the commonly used Confusion Assessment Method for the ICU (CAM-ICU) screening tool administered by bedside nurses in routine practice, the tool was insensitive and inadequate for identifying delirium. Health care–acquired infections continue to increase in the ICU. A large randomized trial of active surveillance and expanded use of barrier precautions showed no significant decrease in infection and relatively low adherence to handwashing. Although procalcitonin levels have been shown to be an effective guide for decreasing antibiotic use in some settings, the findings from a randomized trial that used procalcitonin levels to trigger a broadening of antibiotic coverage were negative. The search for therapeutic interventions in the acute respiratory distress syndrome (ARDS) continues to be a challenge. A multicenter, randomized trial of salbutamol for ARDS was stopped early because of increased mortality. Finally, a study of survivors of ARDS revealed important long-term sequelae after 5 years of follow-up.

Pulmonary Medicine

Low-Dose CT for Lung Cancer Improves Survival Compared With Chest Radiography Screening

Aberle DRAdams AMBerg CDet alNational Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409. []
Background: Although screening offers reduced mortality for many common types of cancer, attempts to decrease lung cancer mortality through early detection have been unsuccessful. The development of low-radiation-dose helical CT allows detection of lung cancer at earlier stages. However, no available data demonstrate reduced lung cancer mortality as a result of low-dose CT screening.
Findings: The investigators enrolled 53 454 patients at 33 U.S. medical centers and randomly assigned them to 3 annual screenings with either low-dose CT (26 722 patients) or single-view chest radiography (26 732 patients). Chest radiography detected possible cancer in 6.9% of participants, whereas lose-dose CT detected possible cancer in 24.2%. Most possible cases of cancer proved to be nonmalignant in both the chest radiography (94.5%) and low-dose CT (96.4%) groups. The investigators observed 247 deaths from lung cancer per 100 000 person-years in the low-dose CT group and 309 deaths from lung cancer per 100 000 person-years in the chest radiography group, and they reported a relative risk reduction of 20.0% with low-dose CT screening (P = 0.004). The investigators also reported that low-dose CT screening reduced the rate of all-cause mortality by 6.7% (P = 0.020).
Cautions: Low-dose CT detected possible cancer in almost 1 of 4 participants. Most abnormalities detected by this method were not cancer. Late effects of low-dose radiation from CT remain unmeasured. The enrolled population was slightly younger and better educated than the general at-risk population, and the study was conducted at specialized centers, so the favorable results may not be reproducible in all settings.
Implications: The National Lung Screening Trial provides evidence that screening with low-dose CT can produce a small but significant reduction in deaths from lung cancer in selected settings. Before low-dose CT screening is widely implemented, additional research is needed to refine risk stratification, to safely differentiate benign from malignant lesions, to assess the late effects of radiation from low-dose CT, and to measure cost-effectiveness. Until these issues are resolved, clinicians should redouble their efforts to help patients stop smoking.

Tiotropium Dry Powder Inhalation Is More Effective Than Inhaled Salmeterol for the Prevention of Acute Exacerbations of COPD

Vogelmeier CHederer BGlaab Tet alPOET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med. 2011;364:1093-1103. []
Background: Long-acting bronchodilators are the cornerstone of evidence-based treatment to reduce the risk for exacerbations and control the symptoms of patients with moderate to very severe COPD. However, no available evidence specifies whether long-acting anticholinergic bronchodilators or long-acting β2-agonist bronchodilators are preferable.
Findings: This 1-year, randomized, double-blind, placebo-controlled, parallel-group trial compared the effects of treatment with tiotropium, 18 µg/d, with that of salmeterol, 50 µg twice daily, on the incidence of acute exacerbations of at least moderate severity in patients with moderate to severe COPD and a history of exacerbations in the year before the study. A total of 7376 patients were randomly assigned to receive tiotropium (3707 patients) or salmeterol (3669 patients). Compared with salmeterol, tiotropium increased the time to the first exacerbation (187 vs. 145 days) and reduced the risk for an exacerbation (hazard ratio [HR], 0.83 [95% CI, 0.77 to 0.90]; P < 0.001). Tiotropium also increased the time to the first severe exacerbation (HR, 0.72 [CI, 0.61 to 0.85]; P < 0.001) and reduced moderate to severe exacerbations (0.64 vs. 0.72 per year; rate ratio, 0.89 [CI, 0.83 to 0.96]; P = 0.002) and severe exacerbations (0.09 vs. 0.13 per year; rate ratio, 0.73 [CI, 0.66 to 0.82]; P < 0.001). The incidence of serious adverse events and death was similar.
Cautions: Fewer patients in the tiotropium group prematurely withdrew from the study (585 [15.8%] vs. 648 [17.7%]; tiotropium HR, 0.88 [CI, 0.78 to 0.98]; P = 0.020). Preferential early discontinuation of salmeterol therapy may have contributed to the observed benefit of tiotropium. A post hoc analysis suggested that the benefit of tiotropium was independent of the use of inhaled glucocorticoids.
Implications: Compared with salmeterol, tiotropium reduces acute exacerbations of COPD among patients with moderate to very severe COPD and a history of exacerbations. This difference may guide the choice of long-acting bronchodilator therapy for COPD. The benefit of tiotropium seems to be independent of the use of inhaled glucocorticoids, although additional research is needed to address this issue.

Daily Azithromycin Reduces the Frequency of Moderate or Severe Exacerbations of COPD

Albert RKConnett JBailey WCet alCOPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-98. []
Background: Acute exacerbations of COPD remain important causes of morbidity and mortality for patients with COPD, despite treatment with inhaled long-acting β2-agonists, corticosteroids, and anticholinergics. Macrolide antibiotics have immunomodulatory, anti-inflammatory, and antibacterial effects that might reduce the frequency of acute exacerbations of COPD. However, no large randomized trials have examined the effect of macrolide antibiotics on the frequency of acute exacerbations of COPD.
Findings: The investigators conducted a randomized, placebo-controlled trial to test the effect of azithromycin, 250 mg daily for 1 year, on the frequency of COPD exacerbations in 1142 patients with COPD. Study patients were at increased risk for exacerbations of COPD and had no hearing impairment, resting tachycardia, or risk for prolongation of the corrected QT interval. Compared with placebo, azithromycin increased the time to the first exacerbation (median, 266 days [CI, 227 to 313 days] vs. 174 days [CI, 143 to 215 days]; P < 0.001). Azithromycin also reduced the frequency of moderate or severe COPD exacerbations (1.48 vs. 1.83 per patient-year; P = 0.010). Scores on the St. George's Respiratory Questionnaire improved more in the azithromycin group than in the placebo group.
Cautions: Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%; P = 0.040). The effect of daily azithromycin on microbial resistance patterns remains unknown. The cost-effectiveness of this intervention is undefined.
Implications: Daily azithromycin in addition to usual therapy decreases the frequency of COPD exacerbations and improves quality of life for selected patients with COPD. Clinicians should consider this strategy for patients with COPD exacerbations who are not at increased risk for cardiovascular arrhythmias or ototoxicity.

Tiotropium Delivered by Mist Inhaler, Not Dry Powder, May Increase the Risk for Mortality

Singh SLoke YKEnright PLet al. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2011;342:d3215. []
Background: Inhaled tiotropium benefits patients with COPD by alleviating symptoms and reducing the risk for acute COPD exacerbations. Two formulations of inhaled tiotropium are available: a dry powder inhaler delivered with a Handihaler device (Boehringer Ingelheim, Ridgefield, Connecticut) and a solution delivered as a mist. Pharmacokinetic studies have shown higher peak plasma doses with the Respimat Soft Mist Inhaler (Boehringer Ingelheim) than with the Handihaler device. Data concerning the risk associated with tiotropium delivered by the mist inhaler were unavailable.
Findings: The investigators performed a systematic review and meta-analysis of data from 5 randomized, controlled trials of tiotropium solution that compared a mist inhaler with placebo for long-term management of COPD. The tiotropium mist inhaler was associated with a significantly increased risk for death (90 of 3686 vs. 47 of 2836; relative risk, 1.52 [CI, 1.06 to 2.16]); P = 0.020) and cardiovascular death (HR, 2.05 [CI, 1.06 to 3.99]). The tiotropium mist inhaler also had a higher risk for mortality than placebo at both the low (5-µg) dose (HR, 1.46 [CI, 1.01 to 2.10]; P = 0.020) and the high (10-µg) dose (HR, 2.15 [CI, 1.03 to 4.51]; P = 0.040). The number needed to treat with the low dose for a year for 1 additional death to occur was estimated to be 124 (CI, 52 to 5682).
Cautions: Meta-analyses can identify, but not resolve, potential safety issues. Current data do not demonstrate an increased risk for stroke, heart attack, or death associated with tiotropium dry powder inhalation.
Implications: These data suggest that the tiotropium mist delivery system slightly increases risk for cardiovascular death and that excessive doses endanger some patients with COPD. The mist delivery system is not approved for use in the United States. Of note, another meta-analysis (1) suggested that cardiovascular events and mortality were reduced with tiotropium, but results were not reported separately for the dry powder and mist formulations. The 2 methods of delivery are being compared in an ongoing randomized trial. For most patients with moderate or severe COPD, the benefits of tiotropium delivered as a dry powder exceed the risks. Caution is advised for patients with a history of malignant cardiac arrhythmias.

Dexamethasone Decreases Hospital Length of Stay for Patients With Community-Acquired Pneumonia

Meijvis SCHardeman HRemmelts HHet al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;377:2023-30. []
Background: Early diagnosis and initiation of appropriate antibiotic therapy remain the mainstays for treatment of community-acquired pneumonia; however, it continues to cause substantial morbidity, mortality, and health care costs. Adjunctive therapy may have a role in these problems. Corticosteroids, which are potent inhibitors of inflammation, may accelerate the resolution of inflammation in patients with community-acquired pneumonia, allowing for earlier hospital discharge. Few controlled trials have studied corticosteroids as adjunctive therapy to antibiotic treatment of community-acquired pneumonia.
Findings: The investigators conducted a prospective, randomized, double-blind, placebo-controlled trial in which adults (aged >18 years) were randomly assigned to receive intravenous dexamethasone, 5 mg, or placebo for the 4 days after admission. The dexamethasone group had a shorter length of stay than the placebo group (median, 6.5 days [interquartile range, 5.0 to 9.0 days] vs. 7.5 days [interquartile range, 5.3 to 11.5 days]; P = 0.048). Adjusted for baseline characteristics, the HR for discharge was 1.46 (CI, 1.13 to 1.89) favoring earlier discharge for patients who received dexamethasone compared with control patients. In-hospital mortality and severe adverse events were infrequent, and the rates did not differ between groups.
Cautions: The study was conducted in 304 randomly assigned adults at 2 teaching hospitals in the Netherlands, so the results cannot be generalized to all patients with community-acquired pneumonia. Immunocompromised patients were excluded and patients with COPD were underrepresented, with a higher proportion in the dexamethasone group.
Implications: Early diagnosis and initiation of appropriate antibiotics remain the mainstays for treatment of community-acquired pneumonia. These data suggest that concomitant administration of intravenous dexamethasone, 5 mg/d, can reduce length of hospital stay when added to antibiotic treatment in nonimmunocompromised patients with community-acquired pneumonia. These observations need to be independently confirmed in other settings before this approach can be widely accepted.

Acid-Suppressive Drug Use Is Associated With Increased Risk for Pneumonia

Eom CSJeon CYLim JWet al. Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ. 2011;183:310-9. []
Background: Acid-suppressive drugs, such as proton-pump inhibitors, are widely prescribed. Because these drugs increase gastric pH and allow bacterial colonization of stomach contents, they may also increase susceptibility to respiratory infections. However, observational studies and randomized, controlled trials have yielded inconsistent conclusions about the association between use of acid-suppressive drugs and risk for pneumonia.
Findings: The investigators conducted a systematic review and meta-analysis to determine whether use of acid-suppressive drugs is associated with increased risk for pneumonia. The study involved a search of MEDLINE (PubMed), EMBASE, and The Cochrane Library from inception through 28 August 2009. In a meta-analysis of 8 observational studies, the risk for pneumonia was higher among patients receiving proton-pump inhibitors (adjusted odds ratio, 1.27 [CI, 1.11 to 1.46]) and H2-receptor antagonists (adjusted odds ratio, 1.22 [CI, 1.09 to 1.36]). Meta-analysis of 23 randomized, controlled trials showed that use of H2-receptor antagonists was associated with increased risk for hospital-acquired pneumonia (relative risk, 1.22 [CI, 1.01 to 1.48]).
Cautions: The presence of gastroesophageal reflux disease or ethanol consumption may be confounders—patients who receive acid-suppressive drugs frequently have gastroesophageal reflux disease or consume ethanol, and both factors may predispose to aspiration pneumonia. This analysis also does not consider health care–associated pneumonia, which is distinct from community- and hospital-acquired pneumonia. Health care–associated pneumonia is characterized by recent hospitalization, residence in nursing homes or long-term care facilities, or receipt of hemodialysis or intravenous chemotherapy.
Implications: Use of a proton-pump inhibitor or H2-receptor antagonist may identify a person with increased risk for either community- or hospital-acquired pneumonia. This insight helps clinicians to estimate the pretest probability for the diagnosis of pneumonia and should be considered a potential element for clinical prediction rules. Caution in prescribing acid-suppressive drugs for patients with increased risk for pneumonia seems wise.

Critical Care

Real-Time Ultrasound Guidance Improves the Rate of Subclavian Vein Cannulation and Decreases Complications

Fragou MGravvanis ADimitriou Vet al. Real-time ultrasound-guided subclavian vein cannulation versus the landmark method in critical care patients: a prospective randomized study. Crit Care Med. 2011;39:1607-12. []
Background: Ultrasound guidance for central venous access is becoming the standard of care for lines placed by using the internal jugular approach. However, the subclavian vein is more commonly used in the ICU and is associated with fewer catheter-related infections. Although complications, such as pneumothorax and arterial puncture, occur more frequently with this approach than with the internal jugular approach, ultrasound guidance for the placement of these lines is not routine.
Findings: This prospective randomized trial compared the use of a real-time, ultrasound-guided approach with that of a landmark technique for subclavian vein access in 463 randomly assigned patients receiving mechanical ventilation in a single ICU. Sixty-two patients were excluded from analysis: 42 could not be placed in the Trendelenburg position and 20 had evidence of thrombosis on ultrasonography. For the 401 patients included in the final analysis, the rate of subclavian vein cannulation was significantly higher in the ultrasound group than in the landmark group (100% vs. 87.5%; P < 0.050), whereas the number of attempts and the time to secure access were significantly lower in the landmark group than in the ultrasound group (1.1 vs 1.9 attempts and 26.8 vs. 44.8 seconds, respectively), as was the overall complication rate. There was no difference in catheter misplacements between the 2 groups.
Cautions: Patients who required emergent line placement were excluded. The lines were all placed by physicians with more than 6 years of experience, who reported that the ultrasound method was complex. Thus, the potential benefits from ultrasound guidance may not be immediately realized in other ICUs. The landmark technique included ultrasonography of the infraclavicular area to rule out thrombosis, which could have influenced the approach. However, this probably would have increased the success rate in the landmark group, thus reducing the advantage of ultrasonography.
Implications: Previous studies that showed a significant benefit of ultrasound-guided internal jugular venous access have substantially changed clinical practice. This study demonstrates a similar benefit of real-time ultrasound guidance for subclavian access, which suggests that the technique should be incorporated into practice when ultrasound is available. Of note, however, the ultrasound method for subclavian access was considered complex by experienced clinicians, so translating this practice into other ICUs may require additional training.

The CAM-ICU Is Less Sensitive and Specific in Routine Care Settings Than in Research Settings

van Eijk MMvan den Boogaard Mvan Marum RJet al. Routine use of the Confusion Assessment Method for the intensive care unit: a multicenter study. Am J Respir Crit Care Med. 2011;184:340-4. []
Background: Delirium occurs in up to 89% of patients in the ICU and is associated with increased morbidity and mortality, but it often goes unrecognized. Many guidelines recommend that patients in the ICU be screened for delirium, and several simple tools are available. One commonly used tool is the CAM-ICU, which has been demonstrated in clinical trials to be easy to administer, sensitive, and specific. However, the performance of the CAM-ICU in routine, nonresearch settings is unknown. This prospective study was done to determine the diagnostic ability of the CAM-ICU when used in routine practice by bedside nurses in the ICU.
Findings: Panels of 3 experts each evaluated 282 patients in 10 ICUs, and the panel's diagnosis was compared with the CAM-ICU assessments made by the bedside nurses. The expert panels were multidisciplinary and included psychiatrists, geriatricians, and neurologists with extensive clinical experience in diagnosing and caring for patients with delirium. The CAM-ICU results were regularly used in the clinical care and assessment of the patients in the participating institutions. Of the 282 patients, 101 were comatose and were excluded from the analysis. The expert panels diagnosed delirium in 75 of the 181 noncomatose patients. The CAM-ICU identified delirium in 35 of the 75 patients; it had a respective sensitivity and specificity of 47% and 98%. Positive predictive value was 95%, and negative predictive value was 72%. The sensitivity was higher in 3 centers where the CAM-ICU was routinely used for the attending intensivist's evaluation and was lower when applied to critically ill neurologic patients and those with hypoactive delirium.
Cautions: The bedside nurses were not monitored when they performed the CAM-ICU, so it may not have been correctly administered; however, the nurses were experienced and worked in centers with a history of using the tool.
Implications: Recognizing delirium in critically ill patients is important, and the CAM-ICU has been shown to be a highly sensitive and specific screening tool in research settings. However, it was not as sensitive or specific in this study of daily practice. The findings emphasize the need for cautious use and interpretation of the results from this tool. Other methods, such as expert consultation, may need to be considered when patients are being screened for delirium.

A Program of Active Surveillance and Increased Barrier Precautions Did Not Decrease the Transmission of Resistant Bacteria

Huskins WCHuckabee CMO'Grady NPet alSTAR*ICU Trial Investigators. Intervention to reduce transmission of resistant bacteria in intensive care. N Engl J Med. 2011;364:1407-18. []
Background: Despite tremendous efforts to reduce transmission of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) in the ICU, they continue to cause significant morbidity and mortality.
Findings: In this cluster randomized trial, more than 9000 admissions to 18 ICUs (medical, surgical, and medical–surgical) were studied to compare the effect of an intervention that included both active surveillance and the expanded use of barrier precautions with that of existing practice (control) on the incidence of MRSA or VRE colonization and infection. Health care providers in the intervention ICUs had access to the surveillance culture results, were trained in the intervention, and were provided with reports on the use of gloves during the early phase of the study. In both the intervention and control ICUs, monitors randomly observed contacts between providers and patients. The rates of colonization or infection with MRSA and VRE did not significantly differ between the patient groups. Although this outcome is disappointing, the use of barrier precautions was greater in the intervention ICUs. However, data on the actual use of barrier precautions by the providers is sobering. When contact precautions were specified in the intervention ICU, gloves and gowns were used for only 82% and 77% of contacts, respectively, and only 69% of providers performed hand hygiene after contact. The corresponding data for the control ICUs were 72% for gloves, 59% for gowns, and 59% for hand hygiene.
Cautions: In the intervention group, an average of 5 days elapsed between when a surveillance culture was obtained and when the results were available. During that time, the patients were assigned to care with universal gloving and were transitioned to contact precautions (which includes the use of gowns) only if culture results were positive. As noted, adherence to barrier precautions was less than anticipated. Both of these factors could have limited the effectiveness of the intervention.
Implications: These results are humbling. One of the most important things that health care providers can do to prevent health care–associated infections is to wash their hands. Yet, even in the setting of a well-designed clinical trial in which monitors openly observed clinical practice, handwashing occurred far less than 100% of the time.

Procalcitonin Levels Are Not Useful for Guiding the Escalation of Antibiotic Therapy

Jensen JUHein LLundgren Bet alProcalcitonin And Survival Study (PASS) Group. Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial. Crit Care Med. 2011;39:2048-58. []
Background: When, how, and why to use antibiotics in the ICU are often confounding questions. Many studies have examined the use of procalcitonin as a biomarker to guide some of those decisions. Procalcitonin levels increase with bacterial infection and seem to correlate with the severity of infection, whereas decreasing levels are associated with resolution of infection, so it is a potentially valuable indicator to use in algorithms of antibiotic administration. Most of the focus to date has been on using procalcitonin levels to indicate when to decrease or stop antimicrobial therapy. Whether procalcitonin levels could be used to guide the escalation of antibiotic therapy has not been evaluated.
Findings: This randomized, controlled trial, performed in the medical–surgical ICUs of 9 hospitals, enrolled 1200 patients. Patients were randomly assigned to a procalcitonin group, in which procalcitonin levels informed an antibiotic-escalation algorithm and enhanced diagnostic studies, or a standard-of-care–only group that received international guideline–driven antibiotic therapy. Procalcitonin levels were measured daily in a central laboratory, and the results were available to the investigators in the procalcitonin group within 8 hours of samples being drawn.
As expected, the use of broad-spectrum antimicrobial therapy was increased in the procalcitonin group, and the procalcitonin group received antibiotics for a longer period in the ICU (6 vs. 4 days); however, mortality did not differ between the groups. Patients in the procalcitonin group received mechanical ventilation for longer periods, had longer ICU stays, and had evidence of prolonged renal dysfunction than did the standard-of-care group. Of note, the sensitivity of procalcitonin for infection in this study was low (about 59%).
Cautions: The study was done in a single country, Denmark, which has a low prevalence of drug-resistant bacteria, so the results might differ in a population with a high level of antibiotic resistance.
Implications: Procalcitonin has been proposed as a potentially valuable biomarker for diagnosing and guiding treatment of infections. Although procalcitonin levels may help reduce exposure to antibiotics, they are not useful to guide escalation of antibiotic therapy for critically ill patients.

Intravenous β2-Agonists Did Not Decrease Mortality in Patients With ARDS

Gao Smith FPerkins GDGates Set alBALTI-2 study investigators. Effect of intravenous β-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial. Lancet. 2012;379:229-35. []
Background: The acute respiratory distress syndrome accounts for substantial ICU morbidity and mortality, but the only therapeutic intervention that has significantly decreased mortality is low tidal volume ventilation. The syndrome is characterized by intense inflammation and alveolar edema. Therapy with β2-agonists has been shown to decrease inflammation and to increase sodium transport and the reabsorption of alveolar fluid in animal models. In a small human study, intravenous β2-agonist administration reduced fluid accumulation in the lungs. These data suggest that β2-agonists might be an important new therapy for ARDS. This randomized, placebo-controlled trial of intravenous salbutamol was designed to enroll 1334 patients with ARDS in clinical sites across the United Kingdom.
Findings: The primary outcome was 28-day mortality. Secondary outcomes included ICU and hospital mortality; ventilator-free days; organ failure–free days; ICU and hospital lengths of stay; and side effects, including tachycardia and arrhythmias. It was recommended that all patients be ventilated by using a lung-protective strategy with appropriate positive end-expiratory pressure and that a conservative fluid strategy be used.
A total of 324 patients were enrolled. The study was stopped after the second interim analysis showed significantly higher mortality in the salbutamol group than in the control group (34% vs. 23%), with a relative risk for death of 1.47. Compared with patients in the control group, patients in the salbutamol group had fewer ventilator-free days (8.5 vs. 11.1 days) and organ failure–free days (16.2 vs 18.5 days). Salbutamol was also associated with arrhythmias, tachycardia, and lactic acidosis.
Cautions: Mortality was lower than expected in the placebo group. In addition, there were no rigid requirements for the supportive care of patients, and salbutamol was used at a single predefined dose. However, the results are similar to those of another recent trial that evaluated the effect of inhaled β2-agonists in acute lung injury.
Implications: β2-Agonists should not be used as routine treatment of ARDS.

Survivors of Acute Lung Injury Have Long-Term Sequelae

Herridge MSTansey CMMatté Aet alCanadian Critical Care Trials Group. Functional disability 5 years after acute respiratory distress syndrome. N Engl J Med. 2011;364:1293-304. []
Background: Over the past decade, focus on the physical and emotional sequelae of critical illness has increased. Most studies have focused on the first months to 1 year after ICU discharge. Little was known about the long-term progression or duration of disability. In this study, 109 survivors of ARDS were evaluated for physical, mental, and quality-of-life impairment in a 5-year prospective, longitudinal cohort study.
Findings: At 3, 6, and 12 months and then at 2, 3, 4, and 5 years after ICU discharge, the patients had an interview; physical examination; and testing, including pulmonary function, a 6-minute walk, chest radiography, and the Short Form-36 Health Survey. Data were also collected to determine health care use and cost. Lung function was nearly normal in the patients at 1 year after ICU discharge and did not deteriorate over the 5-year study interval. However, the median distance walked in 6 minutes was significantly lower (76% of predicted) than in matched control patients, even at 5 years. The physical component scores on the Short Form-36 Health Survey were similarly lower than normal at 5 years. Although the mental component scores were nearly normal at 5 years, 51% of patients had at least 1 episode of depression. Seventy-seven percent of patients were ultimately able to return to work (94% to their original workplace). Interviews demonstrated that the recovery from ARDS resulted in a substantial burden on the caregivers or family members.
Cautions: Although this is, to our knowledge, the largest and most comprehensive study of survivors of ARDS, only 83 of the original 109 patients were available for follow-up at 1 year and only 64 at 5 years. The median age of the patients was 45 years at 1 year and 44 at 5 years. The patients were highly functional before developing ARDS; only 8% had preexisting pulmonary disease, 41% had no coexisting illnesses, and 77% worked full-time.
Implications: Even young, previously healthy persons who survive ARDS have persistent limitations 5 years after discharge from the ICU. Understanding those limitations may enable the development of strategies to prevent or ameliorate some of those sequelae. Current efforts at early mobilization, careful analysis of the risks and benefits of corticosteroids and paralytics, and strategies to decrease psychological stress in the ICU might contribute to improved long-term outcomes.


Celli BDecramer MLeimer IVogel UKesten STashkin DP. Cardiovascular safety of tiotropium in patients with COPD. Chest. 2010;137:20-30. [PMID: 19592475]


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Information & Authors


Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 156Number 1015 May 2012
Pages: 736 - 742


Published online: 15 May 2012
Published in issue: 15 May 2012




C. Gregory Elliott, MD
From Intermountain Medical Center, Murray, Utah, and University of Vermont, Burlington, Vermont.
Polly E. Parsons, MD
From Intermountain Medical Center, Murray, Utah, and University of Vermont, Burlington, Vermont.
Acknowledgment: The authors acknowledge the contribution of Jana Johnson, who obtained consent for slides and lecture and assisted with formatting and transmittal of the article.
Corresponding Author: C. Gregory Elliott, MD, Intermountain Medical Center, Department of Medicine, 5121 South Cottonwood Street, Suite 307, Murray, UT 84107; e-mail, [email protected].
Current Author Addresses: Dr. Elliott: Intermountain Medical Center, Department of Medicine, 5121 South Cottonwood Street, Suite 307, Murray, UT 84107.
Dr. Parsons: University of Vermont, Fletcher 311, 111 Colchester Avenue, Burlington, VT 05401.
Author Contributions: Conception and design: C.G. Elliott, P.E. Parsons.
Analysis and interpretation of the data: C.G. Elliott, P.E. Parsons.
Drafting of the article: C.G. Elliott, P.E. Parsons.
Critical revision of the article for important intellectual content: C.G. Elliott, P.E. Parsons.
Final approval of the article: C.G. Elliott, P.E. Parsons.
Collection and assembly of data: C.G. Elliott, P.E. Parsons.

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C. Gregory Elliott, Polly E. Parsons. Update in Pulmonary and Critical Care Medicine: Evidence Published in 2011. Ann Intern Med.2012;156:736-742. [Epub 15 May 2012]. doi:10.7326/0003-4819-156-10-201205150-00414

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