Bronchoalveolar fluid and plasma inflammatory biomarkers in contemporary ARDS patients.

Purpose: Bronchoalveolar fluid (BALF) and plasma biomarkers are often endpoints in early phase randomized trials (RCTs) in acute respiratory distress syndrome (ARDS). With ARDS mortality decreasing, we analyzed baseline biomarkers in samples from contemporary ARDS patients participating in a prior RCT and compared these to historical controls. Materials and methods: Ninety ARDS adult patients enrolled in the parent trial. BALF and blood were collected at baseline, day 4 ± 1, and day 8 ± 1. Interleukins-8/-6/-1ß/-1 receptor antagonist/-10; granulocyte colony stimulating factor; monocyte chemotactic protein-1; tumour necrosis factor-α; surfactant protein-D; von Willebrand factor; leukotriene B4; receptor for advanced glycosylation end products; soluble Fas ligand; and neutrophil counts were measured. Results: Compared to historical measurements, our values were generally substantially lower, despite our participants being similar to historical controls. For example, our BALF IL-8 and plasma IL-6 were notably lower than in a 1999 RCT of low tidal volume ventilation and a 2007 biomarker study, respectively. Conclusions: Baseline biomarker levels in current ARDS patients are substantially lower than 6-20 years before collection of these samples. These findings, whether from ICU care changes resulting in less inflammation or from variation in assay techniques over time, have important implications for design of future RCTs with biomarkers as endpoints.

A phase II randomized placebo-controlled trial of omega-3 fatty acids for the treatment of acute lung injury.

OBJECTIVES: Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury. DESIGN: Phase II randomized controlled trial. SETTING: Five North American medical centers. PATIENTS: Mechanically ventilated patients with acute lung injury ≥18 yrs of age. INTERVENTIONS: Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days. MEASUREMENTS AND MAIN RESULTS: Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p < .0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups. CONCLUSIONS: Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Intraoperative adherence to a low tidal volume ventilation strategy in critically ill patients with preexisting acute lung injury.

PURPOSE: Low tidal volume (LTV) ventilation reduces mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). This study investigates adherence of intraoperative LTV and whether patient outcomes were different with or without continued intraoperative LTV ventilation in patients with previously established ALI or ARDS. MATERIALS AND METHODS: A retrospective analysis was performed of adults with ALI/ARDS over a 2-year period who underwent surgery between 24 hours and 14 days after the diagnosis of ALI/ARDS. The main outcome was intraoperative LTV use. Secondary outcomes included perioperative respiratory and clinical outcomes. RESULTS: Of the 249 patients who underwent surgery between 24 hours and 14 days after ALI/ARDS diagnosis, 101 (41%) received preoperative LTV ventilation. Fifty-four (53%) received intraoperative LTV ventilation, whereas 47 (47%) did not. Use of preoperative LTV ventilation was associated with use of intraoperative LTV ventilation (P < .01). No differences in respiratory or clinical outcomes between patients with or without intraoperative LTV ventilation were observed. CONCLUSIONS: Adherence to intraoperative LTV in surgical patients was low. Adherence of LTV intraoperatively was not associated with improved oxygenation, reductions in hospital length of stay, or in-hospital mortality. The importance of adhering to an intraoperative LTV strategy remains unclear.

Genetic variation in the FAS gene and associations with acute lung injury.

RATIONALE: Fas (CD95) modulates apoptosis and inflammation and is believed to play an important role in lung injury. OBJECTIVES: To determine if common genetic variation in FAS is associated with acute lung injury (ALI) susceptibility, risk of death, and FAS gene expression. METHODS: We genotyped 14 single nucleotide polymorphisms (tagSNPS) in FAS in samples from healthy white volunteers (control subjects, n = 294) and patients with ALI (cases, n = 324) from the ARDSnet Fluid and Catheter Treatment Trial (FACTT). FAS genotypes associated with ALI in the discovery study were confirmed in a nested case-control validation study of critically ill patients at risk for ALI (n = 657). We also tested for associations between selected tagSNPS and FAS mRNA levels in whole blood from healthy control subjects exposed to media alone or LPS ex vivo. MEASUREMENTS AND MAIN RESULTS: We identified associations between four tagSNPs in FAS (FAS(-11341A>T) [rs17447140], FAS(9325G>A) [rs2147420], FAS(21541C>T) [rs2234978], and FAS(24484A>T) [rs1051070]) and ALI case status. Haplotype-based analyses suggested that three of the tagSNPs (FAS(9325G>A), FAS(21541C>T), and FAS(24484A>T)) function as a unit. The association with this haplotype and ALI was validated in a nested case-control study of at-risk subjects (P = 0.05). This haplotype was also associated with increased FAS mRNA levels in response to LPS stimulation. There was no association between FAS polymorphisms and risk of death among ALI cases. CONCLUSIONS: Common genetic variants in FAS are associated with ALI susceptibility. This is the first genetic evidence supporting a role for FAS in ALI.

Informed consent: what is it? Who can give it? How do we improve it?

The freedom to choose is integral to our daily lives, directs our interactions with patients, and is a key component of our conduct of human-subjects research. Most of the historical errors and atrocities in human experimentation had at their core a failure of consent. In response to those events, national and international law developed to direct researchers to a process of informed consent to participate in research. The application of this process, though, can be challenging. What does this process look like? Does it require written documentation, and if so what type? Who can give informed consent? Though researchers worldwide would agree on the concept of informed consent, the nuts and bolts of applying this ideal can create obstacles to researchers, confusion to subjects, and increasing regulations that may or may not help achieve the goal. I will review the current regulatory guidelines, summarize the types of consent, and consider options for improving the informed-consent process.

Institutional review board consideration of chart reviews, case reports, and observational studies.

Though the need for human-subjects review is readily apparent to investigators when conducting a randomized clinical trial, that same requirement is often less obvious when considering activities such as chart reviews, observational studies, or even case reports. In some cases all that is needed is notification of the institutional review board, which might then exempt the research. In other cases, waiver of consent and Health Insurance Portability and Accountability Act authorization may be granted, whereas in some situations risk to privacy may be considered too great and approval denied. In all cases, including case reviews, quality-improvement projects, and chart reviews, the most cautious approach for the investigator is to discuss regulatory requirements with the institutional review board official to ensure compliance. I will review what constitutes human-subjects research and how investigators may access protected health information, and consider some examples of observational research.

Cytomegalovirus reactivation in critically ill immunocompetent patients.

CONTEXT: Cytomegalovirus (CMV) infection is associated with adverse clinical outcomes in immunosuppressed persons, but the incidence and association of CMV reactivation with adverse outcomes in critically ill persons lacking evidence of immunosuppression have not been well defined. OBJECTIVE: To determine the association of CMV reactivation with intensive care unit (ICU) and hospital length of stay in critically ill immunocompetent persons. DESIGN, SETTING, AND PARTICIPANTS: We prospectively assessed CMV plasma DNAemia by thrice-weekly real-time polymerase chain reaction (PCR) and clinical outcomes in a cohort of 120 CMV-seropositive, immunocompetent adults admitted to 1 of 6 ICUs at 2 separate hospitals at a large US tertiary care academic medical center between 2004 and 2006. Clinical measurements were assessed by personnel blinded to CMV PCR results. Risk factors for CMV reactivation and association with hospital and ICU length of stay were assessed by multivariable logistic regression and proportional odds models. MAIN OUTCOME MEASURES: Association of CMV reactivation with prolonged hospital length of stay or death. RESULTS: The primary composite end point of continued hospitalization (n = 35) or death (n = 10) by 30 days occurred in 45 (35%) of the 120 patients. Cytomegalovirus viremia at any level occurred in 33% (39/120; 95% confidence interval [CI], 24%-41%) at a median of 12 days (range, 3-57 days) and CMV viremia greater than 1000 copies/mL occurred in 20% (24/120; 95% CI, 13%-28%) at a median of 26 days (range, 9-56 days). By logistic regression, CMV infection at any level (adjusted odds ratio [OR], 4.3; 95% CI, 1.6-11.9; P = .005) and at greater than 1000 copies/mL (adjusted OR, 13.9; 95% CI, 3.2-60; P < .001) and the average CMV area under the curve (AUC) in log(10) copies per milliliter (adjusted OR, 2.1; 95% CI, 1.3-3.2; P < .001) were independently associated with hospitalization or death by 30 days. In multivariable partial proportional odds models, both CMV 7-day moving average (OR, 5.1; 95% CI, 2.9-9.1; P < .001) and CMV AUC (OR, 3.2; 95% CI, 2.1-4.7; P < .001) were independently associated with a hospital length of stay of at least 14 days. CONCLUSIONS: These preliminary findings suggest that reactivation of CMV occurs frequently in critically ill immunocompetent patients and is associated with prolonged hospitalization or death. A controlled trial of CMV prophylaxis in this setting is warranted.

The clinical pulmonary infection score poorly predicts pneumonia in patients with burns.

The Clinical Pulmonary Infection Score (CPIS) has been reported to be a useful tool in the diagnosis of ventilator-associated pneumonia (VAP) in the critical care setting. However, the systemic inflammation associated with injury may limit the utility of CPIS in patients with burns. The purpose of this study was to determine the potential utility of CPIS in the management of burn patients. A retrospective review was performed on all burn patients who underwent quantitative culture to diagnose VAP from 2003 to 2005. CPIS was retrospectively calculated for each patient on the day of the procedure. The sensitivity, specificity, and predictive values of a CPIS greater than 6 for VAP diagnosis were calculated. In addition, CPIS scores of patients with and without pneumonia were compared using the Mann-Whitney U test. A total of 46 quantitative cultures were obtained in 28 patients during the study period. Average patient age was 45 +/- 19 years, average TBSA was 33 +/- 18%, and the average APACHE II score on admission was 16 +/- 6. Sixty-eight percent of patients had inhalation injury. Twenty-six quantitative cultures were positive, and 20 were negative. Mean CPIS was 5.7 for patients with negative quantitative cultures and 5.5 for patients with positive cultures (P = .41). The sensitivity of CPIS scoring was 0.3, and its specificity was 0.8. CPIS had a positive predictive value of 0.7 and negative predictive value of 0.5. CPIS--a reported reliable indicator of VAP in critically ill patients--did not accurately predict the presence of pneumonia in burn patients. VAP diagnosis in burn patients should still rely on clinical suspicion verified by quantitative culture.

Low tidal volume ventilation does not increase sedation use in patients with acute lung injury.

OBJECTIVE: Low tidal volume ventilation is associated with reduced mortality in patients with acute lung injury, yet concerns exist about patient comfort and the levels of sedation and analgesia required during its use. We compared the doses and duration of sedatives and opioid analgesics in patients receiving low vs. traditional tidal volumes at our institution. DESIGN: Secondary analysis of a randomized clinical trial. SETTING: University-affiliated county hospital in Seattle, WA. PATIENTS: Sixty-one patients with acute lung injury enrolled in the National Heart, Lung and Blood Institute's ARDS Network tidal volume trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-three patients were randomized to the lower tidal volume arm (6 mL/kg of predicted body weight) and 28 patients were randomized to the higher tidal volume arm (12 mL/kg of predicted body weight). There were no significant differences in the percentage of study days patients received sedatives, opioids, or neuromuscular blockade. When specific study days were examined, there were no significant differences in the proportion of patients receiving benzodiazepines, propofol, haloperidol, and opioids on days 1, 2, 3, and 7 of mechanical ventilation, nor were there differences in the doses of benzodiazepines and opioids on those days. CONCLUSIONS: At our institution, low tidal volume ventilation was not associated with increased dose or duration of sedatives in patients with acute lung injury. Sedation administration should not be considered a barrier to implementing a lung-protective ventilation strategy.

The epidemiology and definition of the acute respiratory distress syndrome.

Acute lung injury and ARDS have been clinically recognized syndromes for nearly 30 years. During that time, the understanding of the risks, pathophysiology, and outcomes has changed and improved. The definition for this disease has evolved in an attempt to identify more accurately and reliably a more homogeneous patient population that could be expected to have similar responses to the disease and therapies. The most widely accepted definition is that developed by the AECC in 1994 and now commonly used in epidemiologic studies and clinical trials. Estimates of the incidence of the disease and of mortality are significantly affected by variability in definitions used. Current estimates of the incidence of ALI, however, range from 3 to 75 cases/100,000 population/year. Mortality estimates range from 30% to 40%. Although mortality has improved from more than 60% 20 years ago, ALI survivors are still faced with an increased risk of death as well as significant decrements in physical function and quality of life through the first 12 months after hospital discharge. A great deal of progress has been made in the understanding and management of ALI patients. Now, as the search for new therapeutic options continues, equal attention must be focused on studying and improving qualitative outcomes for this group of patients.

Mitogen-activated protein kinases in the intensive care unit: prognostic potential.

OBJECTIVE: To evaluate the prognostic significance of the activational status of p38, specifically progression to multiple organ dysfunction syndrome (MODS), in a group of severely injured trauma patients. SUMMARY BACKGROUND DATA: To date, therapeutic manipulation of the host immunoinflammatory response has not affected the outcome of patients with MODS. A major concern is the inability to identify the patient most at risk so as to enable early intervention. METHODS: Nineteen trauma patients underwent bronchoalveolar lavage (BAL). Cells obtained were plated, stimulated with lipopolysaccharide (LPS), and then harvested at varying time points after stimulation. p38 was evaluated by Western blot. RESULTS: Nineteen patients were categorized into two groups according to baseline and LPS-stimulated p38 activation in cells obtained by BAL. Group 1 demonstrated a 10-fold increase in p38 activation with LPS treatment over unstimulated controls. Group 2 had high baseline levels of p38 that were unresponsive to subsequent LPS stimulation. Both groups were similar with respect to age, gender, shock (systolic blood pressure < 90), Injury Severity Score, APACHE II, lactate levels, base deficit, blood transfusions, and the cell differential of BAL fluid. However, patients in group 2 had a greater incidence of progression to MODS as defined by the Marshall MOD score, a longer duration of mechanical ventilation, a longer stay in the intensive care unit, and a longer overall hospital stay than group 1. CONCLUSIONS: These results demonstrate the prognostic significance of p38 activation in predicting outcome in critically ill trauma patients. Furthermore, these results demonstrate that trauma populations identical by current scoring systems contain a mixture of patients with markedly different outcomes as identified by p38 activation. Measurement of p38 may enable early identification of a subgroup of patients at increased risk for MODS to permit effective therapeutic intervention.

Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients.

OBJECTIVE: To determine the effectiveness of early, routine antioxidant supplementation using alpha-tocopherol and ascorbic acid in reducing the rate of pulmonary morbidity and organ dysfunction in critically ill surgical patients. SUMMARY BACKGROUND DATA: Oxidative stress has been associated with the development of the acute respiratory distress syndrome (ARDS) and organ failure through direct tissue injury and activation of genes integral to the inflammatory response. In addition, depletion of endogenous antioxidants has been associated with an increased risk of nosocomial infections. The authors postulated that antioxidant supplementation in critically ill surgical patients may reduce the incidence of ARDS, pneumonia, and organ dysfunction. METHODS: This randomized, prospective study was conducted to compare outcomes in patients receiving antioxidant supplementation (alpha-tocopherol and ascorbate) versus those receiving standard care. The primary endpoint for analysis was pulmonary morbidity (a composite measure of ARDS and nosocomial pneumonia). Secondary endpoints included the development of multiple organ failure, duration of mechanical ventilation, length of ICU stay, and mortality. RESULTS: Five hundred ninety-five patients were enrolled and analyzed, 91% of whom were victims of trauma. The relative risk of pulmonary morbidity was 0.81 (95% confidence interval 0.60-1.1) in patients receiving antioxidant supplementation. Multiple organ failure was significantly less likely to occur in patients receiving antioxidants than in patients receiving standard care, with a relative risk of 0.43 (95% confidence interval 0.19-0.96). Patients randomized to antioxidant supplementation also had a shorter duration of mechanical ventilation and length of ICU stay. CONCLUSIONS: The early administration of antioxidant supplementation using alpha-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of critically ill surgical patients.