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Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
CRITICAL CARE
R. Phillip Dellinger
Critical Care Medicine
Cooper University Hospital
Camden New Jersey
Five general topics related to critical care were discussed during this session: (1) the use of drotrecogin alfa (activated; DrotAA) for adults with severe sepsis and a low risk of death, (2) the utility of pulmonary artery catheters, (3) intensive insulin therapy in medical intensive care unit (ICU) patients, (4) the efficacy of medical emergency response teams, and (5) the optimal use of positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS).
After the approval of DrotAA for adults with severe sepsis and a high risk of death, the U.S. Food and Drug Administration required a second study to evaluate its efficacy in the presence of a low risk of death (1). In this second study, 2,640 patients were enrolled with a low risk of death defined as an Acute Physiology and Chronic Health Evaluation (APACHE) II score of less than 25 or the presence of single-organ failure. Because of the variability in accepted indications for DrotAA worldwide, patients could also be enrolled into this study if the investigator thought a patient was at low risk for death despite a high APACHE II score or the presence of multiorgan failure (2). This study was terminated early because of futility, as there was no significant difference in the 28-d mortality rate between the administration of DrotAA and placebo. However, there were increased serious bleeding complications in the patients who received DrotAA. On the basis of the results of these two trials, DrotAA should only be used in adults with severe sepsis and a high risk of death due to sepsis-induced organ dysfunction.
It has been a decade since Connors and colleagues demonstrated a possible increased mortality attributable to the use of pulmonary artery catheters in critically ill patients (3). Since that time, several randomized controlled trials have demonstrated no differences in mortality with the use of a pulmonary artery catheter (4–6). Recently, Harvey and colleagues enrolled 1,041 patients who the treating physician believed should be managed with a pulmonary artery catheter (7). The majority of patients enrolled into this study had multiorgan dysfunction, and the major reason for placing a pulmonary artery catheter was to guide inotropic or vasoactive medications. After randomization to either placement or no placement of a pulmonary artery catheter, all clinical management was left to the discretion of the treating physician. Noninvasive monitoring of cardiac output could be used in those patients without a pulmonary artery catheter and was obtained in 79% of these control patients. Similar to previous randomized trials, there was no difference in mortality for those critically ill patients managed with a pulmonary artery catheter. Based on the results of this trial and the more recently published Fluid and Catheter Treatment Trial (FACCT) trial by the ARDS Network (ARDSnet), pulmonary artery catheters should not be routinely used in the management of critically ill patients (8).
Previously, van den Berghe and colleagues demonstrated that intensive insulin therapy reduces morbidity and mortality in surgical ICU patients (9). However, it was unclear whether the results from this previous trial were applicable for medical ICU patients. Therefore, van den Berghe and colleagues conducted a prospective randomized trial of 1,200 adult medical ICU patients to examine the effects of tight glycemic control (80–110 mg/dl) (10). In contrast to their results for surgical ICU patients, intensive insulin therapy did not significantly reduce in-hospital mortality for medical ICU patients. However, morbidity was significantly improved, specifically by preventing newly acquired kidney injury, accelerating weaning from mechanical ventilation, and decreasing ICU and hospital length of stay. In a subgroup analysis of 767 patients with an ICU length of stay of 3 d or more, in-hospital mortality was significantly reduced in those patients randomized to tight glycemic control. However, this group of patients could not be prospectively identified. On the basis of these studies, glucose control is clearly important in critically ill patients in the presence of hyperglycemia. However, the specific target glucose concentration for critically ill patients remains controversial.
With the introduction of medical emergency teams (METs), care for critically ill patients by intensivists has extended beyond the walls of the ICU. Previous studies have demonstrated that the introduction of METs reduces the incidence of unplanned ICU admissions, cardiac arrests, and in-hospital mortality. However, these studies were limited by the use of historical control subjects or the lack of a randomized study design. The investigators performed a randomized trial comparing the use of METs to the usual standard of care in 23 Australian hospitals (11). The management and resuscitation teams at the control hospitals continued their standard practice procedures during the study period. For the study hospitals, specific calling criteria were established for METs, including alterations in respiratory, circulatory, and neurologic function. During the study period, the rate of calls for the cardiac arrests or MET criteria was increased at the hospitals randomized to METs. However, the number of cardiac arrests, unplanned ICU admissions, and unexpected deaths were not reduced in the hospitals randomized to METs. The reason for these negative results may be related to improvement in the delivery of care in the control hospitals, the criteria established to contact the MET, or other inadequacies in the implementation of the MET system. On the basis of these results, it is presently unclear whether METs should be routinely utilized in acute care hospitals.
Higher levels of PEEP improve oxygenation and decrease FIO2 requirements but do not improve outcome in patients with acute lung injury or ARDS (12). Targeting higher levels of PEEP in those patients who demonstrate improvement in physiologic measures may identify a subset of patients with ARDS who ultimately benefit in clinically relevant outcomes. Grasso and colleagues studied 19 patients with ARDS who were initially ventilated with lower levels of PEEP (average of 9 cm H2O) for 12 h and subsequently with the higher levels of PEEP (average of 16 cm H20) for 12 h (13). In nine of these patients, the higher end-expiratory pressure strategy resulted in significant alveolar recruitment, improvement in PaO2/FIO2 ratio, and reduction in static lung elastance. Future studies that randomize patients with ARDS to high or standard levels of PEEP only if they demonstrate a significant physiologic response to high levels of PEEP may further define the proper use of PEEP for patients with ARDS.
MECHANICAL VENTILATION
B. Taylor Thompson
Medical Intensive Care Unit
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
In this session, three general topics related to mechanical ventilation were reviewed: (1) the use of noninvasive ventilation to prevent extubation failure, (2) lung-protective strategies for both adults and children with acute lung injury, and (3) heterogeneity in pulmonary function during acute asthmatic exacerbations.
The use of noninvasive ventilation has been used to prevent reintubation in patients with postextubation respiratory failure. A previous multicenter study that enrolled 221 patients with postextubation respiratory failure concluded that noninvasive ventilation was not effective in preventing the need for reintubation and may be harmful (14). However, certain subsets of patients with postextubation respiratory failure may benefit from noninvasive ventilation. Ferrer and colleagues examined the use of noninvasive ventilation postextubation in a cohort of patients who were considered to be at high risk of reintubation (15). Patients were defined as being at high risk for reintubation if they were older than 65 yr, had cardiac failure as the cause of their respiratory failure, or had an APACHE II score of greater than 12 on the day of extubation. Patients with excessive amounts of secretions were excluded from this study. In total, 162 patients were randomized to noninvasive ventilation for 24 h after extubation or standard care with oxygen delivered by a Venturi mask. The use of noninvasive ventilation significantly reduced respiratory failure after extubation from 33 to 16%, and ICU mortality was significantly decreased from 12 to 3%. Almost all of the survival benefit was observed in those patients with hypercapnia during their spontaneous breathing trial. Similar results were identified in a study of 209 patients who developed hypoxemia after major abdominal surgery (16). The use of continuous positive airway pressure (CPAP) with 7.5 cm H2O significantly reduced the need for reintubation, ICU length of stay, and the development of pneumonia, infection, and sepsis. Therefore, the prophylactic use of noninvasive ventilation appears to be beneficial for patients considered to be at high risk of extubation failure. Future studies will be necessary to identify the specific characteristics that identify patients who are at high risk for the development of postextubation respiratory failure.
The use of smaller tidal volumes and reduced ventilatory pressures for patients with acute lung injury has been reported to improve clinical outcomes. Whether there is a safe plateau below which there is no benefit in further reducing tidal volumes and pressure is unclear. In a secondary analysis of the ARDSnet low tidal volume ventilation study, Hager and colleagues examined the absolute risk reduction in mortality of lower tidal volumes across four groups of plateau pressures from the first day patients were enrolled into the study (17). Even in the patients with the lowest plateau pressures (range of 10–20 cm H2O in the low tidal volume group and 16–26 cm H2O in the higher tidal volume group), mortality was reduced from 34 to 23%. On the basis of these results, it appears that there is not a safe plateau pressure below which low tidal volume ventilation is ineffective. Therefore, low tidal volume ventilation should be considered for all patients with acute lung injury regardless of their initial ventilatory pressures.
Regarding ventilatory strategies for acute lung injury, the results of the prone ventilation study for children, defined as patients between the ages of 2 wk to 18 yr, were also discussed (18). Patients were randomized to prone positioning for 20 h/d during the acute phase of lung injury for a maximum of 27 d. Similar to prior studies of prone positioning in adults with acute lung injury, there was no difference in ventilator-free days, mortality, organ failure–free days, or functional outcome with the use of prone positioning in children (19). Much of the care in this pediatric study was effectively protocolized, including ventilatory strategy, weaning, sedation, hemodynamic monitoring, nutritional therapy, and skin care, thereby setting a new standard for pediatric critical care research.
Finally, using positron emission tomography imaging, the effects of bronchoconstriction on regional ventilation were studied in patients with mild to moderate asthma (20). Bronchoconstriction, induced with methacholine, resulted in large clustered regions of poorly ventilated lung. The heterogeneity in ventilation was not exclusively consistent with constriction of the large airways. Using a computer model of airway constriction in the lung, the investigators demonstrated that, even for uniform smooth muscle activation of a symmetric bronchial tree, the presence of minimal heterogeneity alters symmetry and results in large clusters of poorly ventilated lungs. The results of this study have potential implications for future strategies of targeting of pulmonary aerosol deposition and mechanical ventilation during asthma exacerbations.
SLEEP MEDICINE
Atul Malhotra
Division of Sleep Medicine and Pulmonary and Critical Care Medicine
Brigham and Women's Hospital
Harvard Medical School
Boston, Massachusetts
During the Clinical Year in Review session for sleep medicine, three major topics were discussed: (1) the deleterious effects of sleep deprivation, (2) the epidemiology and efficacy of therapy for obstructive sleep apnea, and (3) the use of nasal CPAP to prevent Cheyne-Stokes respiration in patients with congestive heart failure.
Several prospective studies have suggested that short sleep duration may be a causally related to subsequent weight gain (21, 22). Over a 10-yr period, individuals who sleep on average less than 5 h/night have significant increases in their body mass index. The increase in body weight appears to be independent of reported diet and physical activity. Spiegel and colleagues identified some of the potential mechanisms by which sleep deprivation could lead to weight gain (23). Twelve healthy volunteers participated in a crossover design study in which they slept for either 10 h or 4 h a night for 2 consecutive nights. Reductions in the satiety hormone leptin, increases in the hunger hormone ghrelin, and increases in the perception of hunger were noted in study participants during the period of sleep deprivation compared with sleeping 10 h/night. These results suggest that sleep deprivation could lead to changes in the expression of hormones that regulate satiety and hunger, thereby resulting in excessive eating and subsequent weight gain.
Advanced age is associated with an increased prevalence of obstructive sleep apnea. A study by Malhotra and colleagues provides insight into the mechanism by which advanced age predisposes to the development of obstructive sleep apnea (24). Thirty-nine normal individuals underwent a formal sleep study, upper airway physiology during wakefulness, and volumetric magnetic resonance imaging. In these normal study patients, activation of the upper airway dilator muscles in response to a negative pressure was impaired with increasing age. In addition, there was preferential deposition of parapharyngeal fat around the upper airway with increasing age that was independent of systemic changes in fat deposition. These changes may contribute to the increase in collapsibility of the upper airway and increased risk of obstructive sleep apnea in elderly patients.
Several other important observational studies have further defined the mortality risk associated with a diagnosis of obstructive sleep apnea. In an observational study of 1,022 patients referred for polysomnography, obstructive sleep apnea was associated with an increased risk of stroke and death, with an odds ratio of 2 after adjustment for potential confounding variables (25). The risk correlated with the severity of the obstructive apnea as measured by the apnea–hypopnea index. Gami and colleagues reviewed death certificates of 112 decedents who died suddenly of cardiac causes and had also undergone polysomnography (26). The goal of this study was to examine the relationship between obstructive sleep apnea and the time of death. As compared with sudden death in the general population, which is most likely to occur at 10:00 A.M., patients with a history of obstructive sleep apnea are more likely die suddenly during the middle of the night. Sudden death from cardiac causes occurred in 46% of decedents with obstructive sleep apnea between the hours of midnight and 6:00 A.M., as compared with only 21% in decedents without a history of obstructive sleep apnea. This study was not able to assess an association between sleep apnea and an absolute increase in the risk of sudden death nor did it examine the efficacy of treatment with CPAP. In an attempt to determine whether the use of CPAP is associated with an improvement in long-term cardiovascular outcome, Marin and colleagues performed an observational study of healthy men, simple snorers, individuals with untreated sleep apnea, and patients treated with CPAP (27). Patients with untreated, severe obstructive sleep apnea had a higher incidence of fatal cardiovascular events than did those with untreated mild to moderate disease. In addition, the use of CPAP was associated with a reduction in fatal cardiovascular events. However, this observational study was unable to determine whether the use of CPAP was the cause of the reduction in cardiovascular death or simply a marker of lower cardiovascular risk. Future large multicenter randomized clinical trials will be necessary to determine whether CPAP can reduce the risk of cardiovascular death in patients with obstructive sleep apnea.
The final topic discussed in this session was the use of nasal CPAP for central sleep apnea in patients with congestive heart failure and left ventricular systolic dysfunction. Previous studies have suggested a benefit of nasal CPAP therapy related to an improvement in left ventricular function and reduction in circulating levels of catecholamines (28). Bradley and colleagues performed a multicenter randomized trial to examine the treatment of Cheyne-Stokes respiration in 258 patients with congestive heart failure (29). Although the episodes of apneas and hypopneas were reduced and left ventricular ejection fraction increased in those patients who received nasal CPAP, there was no survival improvement in the treated subjects. Of concern, there was a suggestion of an increase in early mortality in the CPAP-treated patients. These negative results may have been related to the following factors: the study may not have had sufficient power to detect a clinically significant difference in mortality, the apnea–hypopnea index may not have been adequately reduced in the treated subjects, or the volume status of the patients may have been critical to their response to nasal CPAP therapy.
LUNG CANCER
Rex C. W. Yung
Department of Pulmonary and Critical Care
Johns Hopkins School of Medicine
Baltimore, Maryland
The Clinical Year in Review for lung cancer discussed several major topics, including new insights in the epidemiology and prognosis of lung cancer, the role of adjuvant therapy after surgical resection of lung cancer, and the role of novel targeted therapies.
The incidence and mortality rates of lung cancer are both highest among African-American males, although these racial disparities have diminished slightly over the last decade. Using a multiethnic cohort of 215,000 individuals living in California and Hawaii, the racial disparities in the incidence of lung cancer were re-examined (30). Individuals aged between 45 and 75 yr were monitored over 8 yr for the development of lung cancer. The patients were then stratified according to their cigarette consumption. The risk of lung cancer among racial and ethnic groups was modified by the average number of cigarettes smoked per day. The greatest increase in risk in African Americans and Native Hawaiians was in those individuals who smoked no more than 30 cigarettes per day. There were no significant racial or ethnic disparities in the risk of lung cancer in those individuals who smoked more than 30 cigarettes per day. This study demonstrates that there may be racial and ethnic differences in susceptibility to developing lung cancer. Two possible mechanisms that could contribute to these racial disparities are differences in the metabolism of nicotine and dysfunction at critical cell cycle checkpoints (31, 32).
The results from a large single series of patients with resected non–small cell lung cancer were also discussed (33). This 1-yr study enrolled 6,644 patients from 303 institutions, all of whom had clinical and pathologic data for a minimum follow-up period of 5 yr. Using either clinical or pathologic staging, there were no significant differences in 5-yr survival between patients with stage IB and IIA disease. Similarly, there was no difference in 5-yr survival between patients with stage IIIA and IV disease. Of note, patients in this series with stage IV disease had a much better 5-yr survival (20%) when compared with previous 5-yr survival data of approximately 5 to 7%. Further information regarding lung cancer prognosis and staging will be available soon from the 11th International Association for the Study of Lung Cancer project. To date, 109,000 cases have been enrolled from North America, Europe, Asia, and Australia. Data from this large series of lung cancer cases will be used to revise the TNM staging system for lung cancer. Importantly, the results of this ongoing series will also be able to determine the prognosis of smaller primary lesions identified with high-resolution screening computed tomography scanners.
Recently, the results of several important studies have been published examining the role of adjuvant chemotherapy for resected non–small cell lung cancer. The International Adjuvant Lung Cancer Trial Collaborative Group studied a total of 1,867 patients who were randomized to three or four cycles of a cisplatin-based chemotherapy or observation after complete resection of non–small cell lung cancer (34). Varying doses of cisplatin were used in this study, with a variety of second agents. Thirty-one percent of patients also received radiation therapy. In this study, overall and disease-free survival was significantly improved in the patients who received adjuvant chemotherapy compared with control subjects. More recently, Winton and colleagues studied 482 patients who were randomized to vinorelbine and cisplatin or observation after resection for lung cancer (35). The randomization was stratified according to nodal status and presence of the ras mutation. There were improvements in both overall survival and relapse-free survival for the entire cohort. When patients were examined according to staging, there was a clear survival benefit for patients with stage II disease. The survival benefit was equivocal in patients with stage IB disease. The presence of the ras mutation was not a prognostic marker in this series of patients. On the basis of the results of these two studies, there are growing data to support the use of chemotherapy for various stages of lung cancer after complete resection of the tumor. Whether the outcome is improved when chemotherapy is given as induction or adjuvant postoperative therapy will require further studies. In addition, the role of sequential or concurrent radiation therapy and specific dosing of radiation will also require additional clinical trials.
Patients with advanced-stage lung cancer (III and IV) benefit from combinational chemotherapy with two agents. Because the overall mortality is extremely high in these patients and there is minimal improvement in clinical response when more than two chemotherapeutic agents are given, the use of targeted biological therapies has been examined in these patients. Epidermal growth factor receptors (EGFRs) are often present in non–small cell lung cancer cells, and up-regulated during tumor proliferation. Erlotinib inhibits tyrosine kinase activity of EGFR and previous clinical trials have demonstrated response rates of 10 to 20%. In a multicenter trial of 731 patients with stage IIIB or IV lung cancer, patients were randomized in a 2:1 fashion to receive oral erlotinib or placebo (36). Nearly 50% of the patients had received two prior regimens of chemotherapy, and 93% had received platinum-based chemotherapy. The response rate was 9% in the erlotinib group and less than 1% in the placebo group. Overall, the survival was significantly improved by 2 mo in those patients who received erlotinib from 4.7 mo to 6.7 mo. Patients who had no prior history of smoking, had tumors with high EGFR gene copy numbers, or positive EGFR protein expression were more likely to have a survival advantage with erlotinib therapy. Rash and diarrhea were the most common side effects associated with erlotinib, resulting in discontinuation of the study drug in 1% of patients, respectively. Other studies have also reported similar advantageous results with targeted biological therapy as first-line therapy when used in combination with conventional chemotherapy (37, 38). Due to their high cost, the present challenge is to develop guidelines for the use of targeted biological therapies for patients with advanced non–small lung cancer.
FOOTNOTES
Conflict of Interest Statement: M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
REFERENCES
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