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1 Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 2 Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee; and 3 Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Barry J . Make
Emphysema Center, Pulmonary Rehabilitation and Critical Care
National Jewish Medical and Research Center
Denver, Colorado
Chronic obstructive pulmonary disease (COPD) has been the topic of much interest and investigation over the past several years. This session focused on aspects of treatment as well as new insights into the incidence of pulmonary embolism in patients with COPD.
The National Emphysema Treatment Trial (NETT), a well-known randomized, controlled trial of 1,218 patients with emphysema, compared maximal medical therapy with lung volume reduction surgery (LVRS). Nauheim and colleagues (1) provided long-term follow-up of patients with severe emphysema who underwent LVRS in the NETT. The most important new finding was that LVRS improved survival in all patients, with a relative risk of death with surgery of 0.86 (P = 0.02). Improvements in exercise tolerance and quality of life assessed by the St. George's Respiratory Questionnaire (SGRQ) also persisted for 3 and 4 years, respectively. A subgroup of subjects with low exercise capacity and upper lobe predominant emphysema was again shown to have the greatest survival benefit over 5 years (relative risk of death, 0.57). LVRS is a viable option for selected patients with severe emphysema, but it remains difficult to predict outcomes from LVRS in individual patients.
The incidence of pulmonary embolism (PE), a potentially life-threatening entity, has not been well established in many patient populations, including those with COPD. In a single-center study, Tillie-Leblond and colleagues (2) evaluated 211 patients consecutively admitted for COPD exacerbation without obvious etiology, with spiral computed tomography (CT) pulmonary angiogram and lower extremity venous ultrasound. Of note, 29% of the patients had malignancy and 44% had mild COPD. The authors reported that 25% of these individuals had pulmonary emboli. Subjects with malignancy, prior thromboembolic disease, and at least a 5-mm Hg decrement in PaCO2 appeared to be at highest risk for PE. Interestingly, in another study of 123 patients with acute COPD exacerbation evaluated in the emergency department of two European academic centers (3), only 3.3% were shown to have PE. Differences in study populations make this discrepancy difficult to reconcile. Further evaluation for PE, however, should be considered in patients with COPD exacerbations of uncertain etiology, especially if they have mild disease and comorbidities, such as malignancy.
Statins, angiotensin-converting enzyme inhibitors (ACEI), and angiotensin receptor blockers (ARBs) are widely used to treat patients with cardiovascular disease. In a retrospective time-matched, nested case-control study, Mancini and coworkers (4) evaluated the impact of these medications in patients with COPD. The investigators compared outcomes, including hospitalization for COPD, myocardial infarction, and total mortality, between a COPD cohort with high cardiovascular risk and recent coronary revascularization and a low-risk group without myocardial infarction. The use of statins and either ACE inhibitors or ARBs was associated with decrements in COPD hospitalization (risk ratio, 0.66) and total mortality (risk ratio, 0.42) in both cohorts. In the high-risk cohort, the rate of myocardial infraction was also decreased (risk ratio, 0.39). The benefits were sustained even when patients treated with systemic corticosteroids were included. Although the study had significant limitations, including its retrospective design, it suggests that these medications may be useful for, and have specific biologic effects in, patients with COPD.
The TORCH (Towards a Revolution in COPD Health) trial (5) is among the largest clinical trials ever performed in patients with COPD. This international study used a prospective, randomized, double-blind, placebo-controlled design; 6,112 patients were included in the intention-to-treat group. Four groups were evaluated: those taking placebo versus salmeterol alone, versus fluticasone alone, and versus salmeterol/fluticasone combination (500/50 µg). The primary endpoint was all-cause mortality; secondary endpoints included rate of exacerbation, quality of life as assessed by the SGRQ, and FEV1. The average age and FEV1 were 65 years and 44% of predicted, respectively. The withdrawal rate from the study was 44% in the placebo arm. There was a 17.5% relative and 2.6% absolute reduction in risk of death in subjects receiving combination therapy. The P value, however, was 0.052. There was no difference in mortality in individuals receiving salmeterol alone compared with placebo. The combination of salmeterol and fluticasone was also associated with a reduction in annual rates of exacerbations (1.13 exacerbations per patient per year vs. 0.85 exacerbations per patient per year in the placebo group), improved quality of life, and reduction in the rate of decline in FEV1. There was a higher rate of pneumonia in the fluticasone-containing groups when compared with the others. Despite its large size and well-conceived study design, additional studies may be necessary to better establish the role of inhaled corticosteroids and long-acting bronchodilators in COPD. The substantial study withdrawal rate in the placebo group also illustrates the challenges inherent in large placebo-controlled trials in chronic disease states.
NONPULMONARY CRITICAL CARE
Margaret S. Herridge
Interdepartmental Division of Critical Care Medicine
University of Toronto
Toronto, Ontario, Canada
End-of-Life Care in the Intensive Care Unit
Communication at the end of life is an important measure of quality of care and is directly linked to family satisfaction (6). In light of recent work demonstrating a high risk of post-traumatic stress disorder (PTSD) in family members of patients who die in the intensive care unit (ICU) (7), a study was conducted to determine if the content and structure of the end-of-life family conference, with the addition of a brochure on bereavement, would decrease adverse psychological outcomes in family members after the patient's death (8). In this prospective, multicenter, randomized controlled trial, family members of 126 dying ICU patients were randomized to a protocolized family conference with a bereavement brochure or a customary end-of-life family conference. The intervention group family conference had five objectives: Value and appreciate things family said; Acknowledge emotions; Listen; ask questions that allow you to Understand who the patient is as a person; and Elicit questions from the family (VALUE) (9, 10). Family members in the intervention arm had longer conferences, spent more time talking during the conference, were better able to express guilt, and had fewer symptoms of depression, anxiety, and PTSD compared with the control group at 90 days after the family member's death. The authors conclude that a proactive VALUE-based communication strategy for end-of-life family conferences may lessen the adverse psychological consequences and burden of bereavement associated with the death of a family member in the ICU. Limitations include the short duration of follow-up and the inability to assess the independent contribution of the bereavement brochure. This study reinforces the importance of family-centered care in the ICU and validates the importance of the family conference, not just as a means of communication but as a therapeutic intervention with measurable impact on family outcome.
Sustainability of Human Resources in the ICU
As the population ages and more patients require ICU care, the sustainability of ICU human resources is a major concern. Burnout syndrome in ICU nurses has been identified as a contributor to compromised well-being, decreased quality of care, absenteeism, and high turnover rates (11). French investigators administered the Maslach Burnout Inventory questionnaire to 2,392 ICU nurses in 165 French ICUs (12). Severe burnout syndrome symptoms were present in one-third of respondents and were related to age, organizational factors in the ICU, participation in a research group, quality of working relationships with nurse manager or physicians, and perceived conflict with patients and care of dying patients or patients in whom support was withdrawn. This study suggests that a significant proportion of ICU nurses had severe burnout syndrome. Attention to conflict resolution, the process of end-of-life care, and participation in ICU research groups may be important ways to ameliorate symptoms of burnout. This study is one of several in the past year to evaluate stress among members of the ICU multidisciplinary team. Additional publications have examined the prevalence of PTSD in ICU nurses (13), the impact of organizational factors on ICU nurse retention (14), burnout syndrome in intensivists (15), and moral distress in respiratory therapists/practitioners (16). Further studies are needed to test future interventions to determine how to best sustain ICU human resources, a fragile and precious resource.
Renal Replacement Therapy and Safety
Intermittent hemodialysis has been believed to contribute to hemodynamic instability in critically ill patients. It remains uncertain whether continuous renal replacement therapy offers advantages over intermittent hemodialysis (17). In a prospective, unblinded, randomized, multicenter study in 21 ICUs in France (18), 360 critically ill patients with acute renal failure and multiorgan dysfunction were randomized to either intermittent hemodialysis or continuous venovenous hemofiltration. Explicit guidelines were provided in both groups to help improve tolerance of renal replacement therapy and metabolic control; there was no explicit standardization of the frequency or duration of renal replacement therapy. There were no significant differences in 28-, 60-, or 90-day survival rates, or in the incidence or time to renal recovery between treatment groups. There were no significant differences in adverse events between groups, with the exception of hypothermia, which was more common in the continuous renal replacement therapy group. Specifically, intermittent hemodialysis appeared to be well tolerated from a hemodynamic standpoint. Information on the delivered dose of dialysis was not provided. These data suggest that most patients will safely tolerate intermittent hemodialysis without compromising renal recovery or mortality outcomes and that dialysis modality alone may not be a determinant of ICU outcomes.
Catheter-related Infections in the ICU
Catheter-related bloodstream infections are common and consequential. Several interventional studies have shown reductions in catheter-related infections using evidence-based guidelines (19). Pronovost and colleagues reported the results of a cohort study of 103 ICUs in Michigan (20). They evaluated the effect of an intervention to reduce catheter-related bloodstream infections that was based on five Centers for Disease Control and Prevention–recommended, evidence-based procedures shown to have the greatest effect on reducing catheter-related bloodstream infections: hand washing, use of full barrier precautions during central line insertion, cleaning skin with chlorhexidine, avoidance of femoral line insertion, and surveillance removal of all unnecessary catheters. There was a 66% reduction in catheter-related bloodstream infections after implementation of this intervention and the benefit was sustained through 18 months of follow-up. The median rate of catheter-related bloodstream infections decreased from 2.7 infections per 1,000 catheter-days at baseline to 0 at 0 to 3 months after implementation of the intervention, and 0 during 18 months of follow-up. Compliance with the intervention was not monitored, and data on bloodstream organisms were not collected. This impressive study demonstrates the feasibility of a large-scale project to evaluate the effect of interventions to enhance patient safety.
DIAGNOSTIC IMAGING
David Lynch
Department of Radiology
National Jewish Medical and Research Center
Denver, Colorado
Two general topics related to diagnostic imaging were discussed in this session: (1) the use CT scanning to improve the detection of lung cancer and (2) the use of magnetic resonance imaging (MRI) to identify early smoking-related ventilation defects.
CT scanning has been extensively studied as a sensitive screening test to detect early lung cancers. The first study discussed in this session reported the survival results for patients with stage I lung cancer detected on CT screening (21). The patients had been enrolled in a large international screening consortium from 37 countries. Overall 31,567 individuals underwent low-dose CT screening. A total of 83% of these individuals were current or former smokers. A total of 27,456 repeated screenings were performed 7 to 18 months after the previous screening. Of these patients, 484 were diagnosed with lung cancer, and 412 of them had a clinical stage I tumor. The median duration of follow-up was 40 months, with a range of 1 to 123 months. The estimated 10-year survival for these 412 patients was 88% (95% confidence interval [CI], 84–91). Among the 302 participants with clinical stage I cancer who underwent surgical resection within 1 month after diagnosis, the survival rate was 92% (95% CI, 88–95%). The results of this study indicate that annual spiral CT screening can detect lung cancer that is curable. However, because of the absence of a control arm, this study is subject to a variety of biases, including lead time bias. In addition, the relatively short median follow-up of 40 months makes a true estimate of 10-year survival potentially inaccurate.
A second study by Bach and colleagues has four primary objectives: to determine whether CT screening (1) increases the frequency of lung cancer diagnosis, (2) increases the frequency of lung cancer resection, (3) reduces the risk of a diagnosis of advanced lung cancer, and (4) reduces the risk of death from lung cancer (22). This article was a joint analysis of three large longitudinal studies. A total of 3,246 patients were examined with a median follow-up time of 3.9 years. The rates of lung cancer diagnosis, patients treated with resection, advanced disease at the time of presentation, and lung cancer deaths were compared with previously developed prediction models. Overall, there were 144 detected cases of lung cancer with 38 deaths. A total of 96 of the 144 screen-detected cancers had stage I or II disease. The survival for these early-stage cancers was 88% at 2 years. Of importance, 27 of the patients in this study presented with stage III or IV cancer with a 2-year survival of 47%, and 15 patients had small cell cancer with a 2-year survival of only 50%. CT scanning did increase the detection and number of lung cancer resections but did not decrease the number of advanced lung cancer diagnoses at the time of presentation or the number of deaths from lung cancer. Therefore, there is still controversy whether CT scanning for high-risk individuals improves mortality in patients who are diagnosed with lung cancer. The results of an ongoing study randomizing patients to screening with either conventional chest radiography or CT scanning may further define the role of radiographic lung cancer screening in high-risk individuals.
Lung cancers that are detected on screening CT scans have been previously reported to be slower growing, to have a lower metabolic activity on positron emission tomography scanning, and a higher rate of epidermal growth factor receptors (EGFR). The purpose of the next study was to further evaluate the growth rate of cancers identified during a CT screening study (23). The authors reviewed 61 cancers diagnosed in 59 patients during a CT screening study of 1,520 individuals older than 50 years with a more than 20 pack-year history of cigarette smoking. A total of 48 cancers were visible on more than one CT examination and were used to calculate a volume doubling time. The mean volume doubling time was 518 days. However, there was a wide range of volume doubling times in this study. Thirteen of the 48 tumors had a volume doubling time of greater than 400 days, a threshold that had previously been used to define an indolent cancer that might not be clinically relevant. There were also sex differences in the overall mean tumor volume doubling time: 688 days in women and 234 in men. This finding may be due in part to a higher prevalence of bronchoalveolar cell carcinoma and adenocarcinoma in women. This study suggests that there is a wide range of cancer growth rates and that a substantial proportion of screen-detected cancers may be tumors that are so slow growing that it is more likely that the individual may die of another medical condition.
The identification of very early smoking-related pulmonary changes may be useful for both screening and the initiation of preventative therapies. In the final study, the authors performed MRI using hyperpolarized helium in 8 nonsmoking control subjects and 11 healthy smokers with normal FEV1 and physical examination (24). Hyperpolarized helium imaging is produced by the optical pumping of helium into the airways of the lung. Diffusion-weighted images were obtained to calculate the apparent diffusion coefficient of helium, which is a previously documented measure of the size of the airspaces. In larger, damaged emphysematous alveoli, the apparent diffusion coefficient of helium is increased as the larger alveolar spaces allow greater temporal distribution of the helium. Peripheral ventilation defects were identified in nine individuals, without any significant differences between smokers and nonsmokers. However, the appearance of the apparent diffusion coefficient of helium was very different in the smokers and nonsmokers. Nonsmokers had a very homogenous distribution of hyperpolarized helium. Smokers without emphysematous changes on CT scanning demonstrated a more heterogeneous distribution, consistent with larger alveolar spaces. The mean apparent diffusion coefficient of helium also had a strong correlation with FEV1/FVC ratio, DLCO (diffusion capacity of carbon monoxide), age, and pack-years of smoking. These results indicated that this novel technique may be useful in detecting very early emphysema in the lung.
MYCOBACTERIAL DISEASE
Richard Wallace
Department of Microbiology
University of Texas Health Center at Tyler
Tyler, Texas
This session reviewed publications that made a difference in tuberculosis (TB) and nontuberculous mycobacterial (NTM) disease in 2006–2007.
Tuberculosis
There is an interest in reassessing the treatment of TB, particularly in shortening duration and in evaluating new drugs. The newer quinolone antibiotics have shown particular promise. Burman and colleagues (25) performed a randomized, factorial design trial in adults with smear-positive TB, comparing moxifloxacin (400 mg daily) versus ethambutol, both given in combination with isoniazid, rifampin, and pyrazinamide. The subjects were treated with daily therapy for 2 weeks, and then either 5 days or thrice weekly. Of the 336 patients enrolled, 227 were evaluable; 22% had HIV infection, and 74% had cavitary disease as shown by chest X-ray. Patients in the moxifloxacin group more often had negative cultures after 4 (37 vs. 26%, P = 0.05) and 6 (54 vs. 42%, P = 0.06) weeks of therapy, but no differences were observed at 8 weeks (71% in each group). The dosing frequency had no effect on sputum conversion. There was a higher incidence of nausea (22 vs. 9%, P = 0.002) in the moxifloxacin group, but no difference in withdrawal from the study. The role of moxifloxacin in the treatment of TB requires additional study.
The R20979120 diarylquinoline is a new drug with activity against mycobacterial pathogens. In particular, it has activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. Its target is the atpE gene encoding the subunit c of the ATP synthase of M. tuberculosis. Two single-copy mutations in the ATP synthase gene conferring resistance to the drug have been identified. Petrella and coworkers (26) studied 13 mycobacterial species. They found that the region involved in drug resistance is conserved, except in Mycobacteriam xenopi, a species which is believed to be naturally resistant to the drug.
Extensively drug resistant (XDR) TB remains a major cause of death in sub-Saharan Africa, especially in patients coinfected with HIV. Gandhi and coworkers (27) evaluated sputum samples from 1,539 patients in a single study site in KwaZulu Natal, South Africa. A total of 542 patients were culture positive; of these, 221 (41%) were multidrug resistant (resistant to isoniazid and rifampin), and 53 (10%) were XDR (resistant to isoniazid, rifampin, quinolones, aminoglycosides, and capreomycin). Twenty-six (50%) of the XDR patients had no prior history of TB, whereas another 30% had previously been successfully treated for TB. Of the 44 patients tested for HIV, all were infected with the virus. Genotyping revealed that the XDR isolates were genetically similar in 39 of the 46 isolates tested. The mortality rate in patients with XDR TB was 98%, with a median survival time from specimen collection to death of 16 days. Two-thirds had been hospitalized in the district hospital in the preceding 2 years, suggesting nosocomial transmission. This study not only underscores the highly lethal nature of XDR TB but also points ominously to the fact that transmission likely occurred between individuals rather than as a consequence of unsuccessful therapy.
Nontuberculous Mycobacteria
NTM infections are increasingly common and challenging clinical entities. In a multicenter, randomized, controlled trial, Lindeboom and colleagues (28) compared surgical excision to antimicrobial therapy with clarithromycin and rifabutin (for at least 12 wk) for the treatment of microbiologically proven, NTM cervicofacial lymphadenitis in 100 children. There were 50 children in each group. The median age was 45 months; the most commonly involved lymph nodes were submandibular, and Mycobacterium avium was the most frequent isolate. The primary endpoint was cure at 6 months; secondary endpoints included surgical complications and adverse effects of antibiotics. Surgery had a higher cure rate compared with medical therapy (96 vs. 66%, respectively). The success rate was not affected by lymph node stage or mycobacterial species. Surgical complications occurred in 14 of 50 patients (28%), whereas 39 of 50 children (78%) in the antibiotic group had adverse effects resulting in discontinuation of antibiotics in four subjects. In addition to establishing the role of surgery in pediatric cervicofacial lymphadenitis, this study was notable for being the first randomized trial of this disease.
The role of parenteral aminoglycosides in the treatment of pulmonary M. avium complex (MAC) disease was studied by Kobashi and colleagues (29). In a multicenter trail in Japan from April 1998 to December 2004, 73 patients were randomized to receive treatment with a three-drug regimen of rifampicin, ethambutol, and clarithromycin plus intramuscular streptomycin (15 mg/kg) thrice weekly for 24 months after sputum conversion. Another 73 patients received the three-drug regimen without streptomycin. All patients were HIV negative; the study populations were comparable with respect to clinical, microbiologic, and radiographic parameters. The mean duration of therapy was similar between the groups. The sputum conversion rate at the completion of therapy was higher in the streptomycin group (71 vs. 51%, P = 0.05). However, there were no differences in sputum relapse rates, clinical symptoms, radiographic findings, laboratory data, or adverse effects. In conclusion, the role of streptomycin in the treatment of pulmonary MAC infection remains to be established.
Aerosolized aminoglycosides are also used to treat NTM infections in clinical practice but have been poorly studied. Davis and coworkers (30) reported their experience with aerosolized amikacin in six HIV-negative women with MAC pulmonary infection. All patients were symptomatic and had either failed or were unable to tolerate standard therapy. In a noncontrolled trial, they were treated with aerosolized amikacin at 15 mg/kg daily, in addition to other macrolide-containing drug regimens. Five of the six patients had symptomatic improvement; four were sputum culture negative at 6 months. One patient was unable to tolerate aerosolized amikacin and discontinued it after 4 months; this patient subsequently died of respiratory failure. No nephrotoxicity, ototoxicity, or vestibular toxicity was reported. As with other aspects of NTM therapy, additional larger studies are needed.
The emergence of macrolide resistance and its impact on clinical outcomes in MAC lung disease are crucial issues. Griffith and colleagues (31) retrospectively identified 51 patients in their center in Texas with clarithromycin-resistant MAC. Patients were divided into four groups based on whether they had received surgery and/or injectable aminoglycoside antibiotics for their treatment. Risk factors for development of resistance included therapy with macrolide alone or with macrolide–quinoline combination. Interestingly, macrolide resistance only developed in 4% of the 303 patients seen at their center who were treated with a standard three-drug regimen that included a macrolide. There was no risk difference between azithromycin or clarithromycin, or daily versus intermittent therapy. Twenty-four (47%) patients with macrolide resistance had nodular disease; the rest, most of whom were men, had upper lobe cavitary disease. In macrolide-resistant MAC, sputum conversion occurred in 11 of 14 patients (79%) who were also treated with 6 months of injectable aminoglycosides and lung resection, but only in 2 of 37 (5) who were not. In patients who remained culture positive, the 1-year mortality was 34%; none of the 13 patients who were culture negative died. This study is the first to address a number of important aspects on macrolide-resistant MAC lung disease, including its poor clinical outcome.
Perhaps the most significant publication in the area of NTM diseases is the American Thoracic Society and Infectious Diseases Society of America official statement (32). This comprehensive document, which includes 451 references, addresses salient topics in the epidemiology, pathogenesis, diagnosis, and treatment of MAC as well as 19 other NTM species. It also delineates a research agenda for NTM diseases. Although a comprehensive review is not feasible here, review of this statement is strongly recommended to clinicians who treat patients with NTM infections.
FOOTNOTES
Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
Related articles in Proceedings of the American Thoracic Society:
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