Research Bronchoscopies in Critically Ill Research Participants: An Official American Thoracic Society Workshop Report.

Bronchoscopy for research purposes is a valuable tool to understand lung-specific biology in human participants. Despite published reports and active research protocols using this procedure in critically ill patients, no recent document encapsulates the important safety considerations and downstream applications of this procedure in this setting. The objectives were to identify safe practices for patient selection and protection of hospital staff, provide recommendations for sample procurement to standardize studies, and give guidance on sample preparation for novel research technologies. Seventeen international experts in the management of critically ill patients, bronchoscopy in clinical and research settings, and experience in patient-oriented clinical or translational research convened for a workshop. Review of relevant literature, expert presentations, and discussion generated the findings presented herein. The committee concludes that research bronchoscopy with bronchoalveolar lavage in critically ill patients on mechanical ventilation is valuable and safe in appropriately selected patients. This report includes recommendations on standardization of this procedure and prioritizes the reporting of sample management to produce more reproducible results between laboratories. This document serves as a resource to the community of researchers who endeavor to include bronchoscopy as part of their research protocols and highlights key considerations for the inclusion and safety of research participants.

25-Hydroxycholesterol exacerbates vascular leak during acute lung injury.

Cholesterol-25-hydroxylase (CH25H), the biosynthetic enzyme for 25-hydroxycholesterol (25HC), is most highly expressed in the lung, but its role in lung biology is poorly defined. Recently, we reported that Ch25h is induced in monocyte-derived macrophages recruited to the airspace during resolution of lung inflammation and that 25HC promotes liver X receptor-dependent (LXR-dependent) clearance of apoptotic neutrophils by these cells. Ch25h and 25HC are, however, also robustly induced by lung-resident cells during the early hours of lung inflammation, suggesting additional cellular sources and targets. Here, using Ch25h-/- mice and exogenous 25HC in lung injury models, we provide evidence that 25HC sustains proinflammatory cytokines in the airspace and augments lung injury, at least in part, by inducing LXR-independent endoplasmic reticulum stress and endothelial leak. Suggesting an autocrine effect in endothelium, inhaled LPS upregulates pulmonary endothelial Ch25h, and non-hematopoietic Ch25h deletion is sufficient to confer lung protection. In patients with acute respiratory distress syndrome, airspace 25HC and alveolar macrophage CH25H were associated with markers of microvascular leak, endothelial activation, endoplasmic reticulum stress, inflammation, and clinical severity. Taken together, our findings suggest that 25HC deriving from and acting on different cell types in the lung communicates distinct, temporal LXR-independent and -dependent signals to regulate inflammatory homeostasis.

Alveolar Biomarker Profiles in Subphenotypes of the Acute Respiratory Distress Syndrome.

OBJECTIVES: We sought to determine whether hyperinflammatory acute respiratory distress syndrome (ARDS) and hypoinflammatory ARDS, which have been associated with differences in plasma biomarkers and mortality risk, also display differences in bronchoalveolar lavage (BALF) biomarker profiles. We then described the relationship between hyperinflammatory ARDS and hypoinflammatory ARDS to novel subphenotypes derived using BALF biomarkers. DESIGN: Secondary analysis of a randomized control trial testing omega-3 fatty acids for the treatment of ARDS. SETTING: Five North American intensive care units. PATIENTS: Adults (n = 88) on invasive mechanical ventilation within 48 hours of ARDS onset. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We classified 57 patients as hypoinflammatory and 31 patients as hyperinflammatory using a previously validated logistic regression model. Of 14 BALF biomarkers analyzed, interleukin-6 and granulocyte colony stimulating factor were higher among patients with hyperinflammatory ARDS compared with hypoinflammatory ARDS, though the differences were not robust to multiple hypothesis testing. We then performed a de novo latent class analysis of the 14 BALF biomarkers to identify two classes well separated by alveolar profiles. Class 2 (n = 63) displayed significantly higher interleukin-6, von Willebrand factor, soluble programmed cell death receptor-1, % neutrophils, and other biomarkers of inflammation compared with class 1 (n = 25). These BALF-derived classes had minimal overlap with the plasma-derived hyperinflammatory and hypoinflammatory classes, and the majority of both plasma-derived classes were in BALF-derived class 2 and characterized by high BALF biomarkers. Additionally, the BALF-derived classes were associated with clinical severity of pulmonary disease, with class 2 exhibiting lower Pao2 to Fio2 and distinct ventilatory parameters, unlike the plasma-derived classes, which were only related to nonpulmonary organ dysfunction. CONCLUSIONS: Hyperinflammatory and hypoinflammatory ARDS subphenotypes did not display significant differences in alveolar biologic profiles. Identifying ARDS subgroups using BALF measurements is a unique approach that complements information obtained from plasma, with potential to inform enrichment strategies in trials of lung-targeted therapies.

Skeletal muscle macrophage ablation in mice.

Macrophages are important mediators of skeletal muscle function in both healthy and diseased states. In vivo specific depletion of macrophages provides an experimental method to understand physiological and pathophysiological effects of macrophages. Systemic depletion of macrophages can deplete skeletal muscle macrophages but also alters systemic inflammatory responses and metabolism, which confounds the muscle specific effects of macrophage depletion. The primary aim of this manuscript is to evaluate two methods of murine intramuscular macrophage depletion in an acute lung injury-associated indirect skeletal muscle wasting mouse model. Adult C57BL/6 (WT) and Macrophage Fas-Induced Apoptosis (MaFIA, C57BL/6-Tg) mice received clodronate liposomes or the dimerization drug AP20187 through intramuscular injection of the tibialis anterior muscle compartment, respectively. Vehicle control was injected in the contralateral muscle. We demonstrate intramuscular AP20187 in the MaFIA mouse depletes macrophages but causes an infiltration of CD45 intermediate neutrophils. In contrast, intramuscular clodronate liposomes successfully depletes macrophages without an associated increase in CD45 intermediate cells. In conclusion, intramuscular clodronate is effective for selective depletion of muscle macrophages without eliciting acute inflammation seen with AP20187 in MaFIA mice. This technique is an important tool to study the functional roles of macrophages in skeletal muscle.

Evolution of Investigating Informed Assent Discussions about CPR in Seriously Ill Patients.

CONTEXT: Outcomes after cardiopulmonary resuscitation (CPR) remain poor. We have spent 10 years investigating an "informed assent" (IA) approach to discussing CPR with chronically ill patients/families. IA is a discussion framework whereby patients extremely unlikely to benefit from CPR are informed that unless they disagree, CPR will not be performed because it will not help achieve their goals, thus removing the burden of decision-making from the patient/family, while they retain an opportunity to disagree. OBJECTIVES: Determine the acceptability and efficacy of IA discussions about CPR with older chronically ill patients/families. METHODS: This multi-site research occurred in three stages. Stage I determined acceptability of the intervention through focus groups of patients with advanced COPD or malignancy, family members, and physicians. Stage II was an ambulatory pilot randomized controlled trial (RCT) of the IA discussion. Stage III is an ongoing phase 2 RCT of IA versus attention control in in patients with advanced chronic illness. RESULTS: Our qualitative work found the IA approach was acceptable to most patients, families, and physicians. The pilot RCT demonstrated feasibility and showed an increase in participants in the intervention group changing from "full code" to "do not resuscitate" within two weeks after the intervention. However, Stages I and II found that IA is best suited to inpatients. Our phase 2 RCT in older hospitalized seriously ill patients is ongoing; results are pending. CONCLUSIONS: IA is a feasible and reasonable approach to CPR discussions in selected patient populations.

Content of Tele-Palliative Care Consultations with Patients Receiving Dialysis.

Background: Little is known about the content of communication in palliative care telehealth conversations in the dialysis population. Understanding the content and process of these conversations may lead to insights about how palliative care improves quality of life. Methods: We conducted a qualitative analysis of video recordings obtained during a pilot palliative teleconsultation program. We recruited patients receiving dialysis from five facilities affiliated with an academic medical center. Palliative care clinicians conducted teleconsultation using a wall-mounted screen with a camera mounted on a pole and positioned mid-screen in the line of sight to facilitate direct eye contact. Patients used an iPad that was attached to an IV pole positioned next to the dialysis chair. Conversations were coded using a preexisting framework of themes and content from the Serious Illness Conversation Guide (SICG) and revised Edmonton Symptom Assessment System-Renal. Results: We recruited 39 patients to undergo a telepalliative care consultation while receiving dialysis, 34 of whom completed the teleconsultation. Specialty palliative care clinicians (3 physicians and 1 nurse practitioner) conducted 35 visits with 34 patients. Median (interquartile range) duration of conversation was 42 (28-57) minutes. Most frequently discussed content included sources of strength (91%), critical abilities (88%), illness understanding (85%), fears and worries (85%), what family knows (85%), fatigue (77%), and pain (65%). Process features such as summarizing statements (85%) and making a recommendation (82%) were common, whereas connectional silence (56%), and emotion expression (21%) occurred less often. Conclusions: Unscripted palliative care conversations in outpatient dialysis units through telemedicine exhibited many domains recommended by the SICG, with less frequent discussion of symptoms. Emotion expression was uncommon for these conversations that occurred in an open setting.

Macrophages augment the skeletal muscle proinflammatory response through TNFα following LPS-induced acute lung injury.

Muscle may contribute to the systemic inflammatory environment during critical illness, but leukocyte interaction and cytokine influence on muscle and its response has not been fully explored in this context. Using an in vivo model of intratracheal lipopolysaccharide (IT LPS)-induced acute lung injury, we show that skeletal muscle rapidly responds with expression of proinflammatory genes, which may be explained by migration of LPS into the circulation. Treatment of mature C2C12 myotubes with LPS at a level achieved in the circulation following IT LPS elicited a proinflammatory cytokine expression profile similar to that of in vivo murine muscle following IT LPS. Stimulation with toll-like receptor (TLR) 2 and 3 agonists provoked comparable responses in C2C12 myotubes. Additionally, co-cultures of C2C12 myotubes and bone marrow-derived macrophages (BMDM) identified the capacity of macrophages to increase myotube proinflammatory gene expression, with tumor necrosis factor-α (TNFα) gene and protein expression largely attributable to BMDM. To investigate the contribution of TNFα in the synergy of the co-culture environment, C2C12 myotubes were treated with recombinant TNFα, co-cultures were established using TNF-deficient BMDM, and co-cultures were also depleted of TNFα using antibodies. To determine whether the in vitro observations were relevant in vivo, mice received intramuscular administration of LPS ± TNFα or TNFα-neutralizing antibodies and showed that TNFα is both sufficient and necessary to induce synergistic cytokine release from muscle. Taken together, these data demonstrate how skeletal muscle tissue may contribute proinflammatory cytokines following acute endotoxin injury and the potential of leukocytes to augment this response via TNFα secretion.

Feasibility and Acceptability of Telemedicine-Facilitated Palliative Care Consultations in Rural Dialysis Units.

Background: Patients receiving dialysis have unmet palliative care needs. Limited access to palliative care is a key barrier to its integration into routine dialysis care. Objective: To determine the feasibility and acceptability of telepalliative care in rural dialysis units. Methods: This was a single-arm pilot clinical trial. The target population was patients with kidney failure receiving outpatient dialysis in a rural U.S. state. Feasibility was measured by one-month completion rate. Acceptability was measured using an adapted telemedicine questionnaire. Results: We recruited 39 patients with mean age 71.2 years to undergo a telepalliative care consultation while receiving dialysis. Four specialty palliative care clinicians (three physicians and one nurse practitioner) conducted the visits. The recruitment rate was 40% (39/96), scheduling rate was 100% (39/39), and one-month completion rate was 77% (30/39). Thirty-six patient participants (14 women and 22 men) completed the baseline survey. Audiovisual aspects of the visit were rated highly. More than 80% reported the visit being at least as good as an in-person visit and 41% felt the teleconsult was better. Eighty-one percent of patients felt the appointment was relevant to them, 58% felt they learned new things about their condition, and 27% reported the appointment changed the way they think about dialysis. Discussion: Telepalliative care is acceptable to patients receiving dialysis and is a feasible approach to integrating palliative care in rural dialysis units. The study was registered with Clinicaltrials.gov (NCT03744117).

The role for high flow nasal cannula as a respiratory support strategy in adults: a clinical practice guideline.

PURPOSE: High flow nasal cannula (HFNC) is a relatively recent respiratory support technique which delivers high flow, heated and humidified controlled concentration of oxygen via the nasal route. Recently, its use has increased for a variety of clinical indications. To guide clinical practice, we developed evidence-based recommendations regarding use of HFNC in various clinical settings. METHODS: We formed a guideline panel composed of clinicians, methodologists and experts in respiratory medicine. Using GRADE, the panel developed recommendations for four actionable questions. RESULTS: The guideline panel made a strong recommendation for HFNC in hypoxemic respiratory failure compared to conventional oxygen therapy (COT) (moderate certainty), a conditional recommendation for HFNC following extubation (moderate certainty), no recommendation regarding HFNC in the peri-intubation period (moderate certainty), and a conditional recommendation for postoperative HFNC in high risk and/or obese patients following cardiac or thoracic surgery (moderate certainty). CONCLUSIONS: This clinical practice guideline synthesizes current best-evidence into four recommendations for HFNC use in patients with hypoxemic respiratory failure, following extubation, in the peri-intubation period, and postoperatively for bedside clinicians.

Alveolar CCN1 is associated with mechanical stretch and acute respiratory distress syndrome severity.

The cellular communication network factor 1 (CCN1) is a matricellular protein that can modulate multiple tissue responses, including inflammation and repair. We have previously shown that adenoviral overexpression of Ccn1 is sufficient to cause acute lung injury in mice. We hypothesized that CCN1 is present in the airspaces of lungs during the acute phase of lung injury, and higher concentrations are associated with acute respiratory distress syndrome (ARDS) severity. We tested this hypothesis by measuring 1) CCN1 in bronchoalveolar lavage fluid (BALF) and lung homogenates from mice subjected to ventilation-induced lung injury (VILI), 2) Ccn1 gene expression and protein levels in MLE-12 cells (alveolar epithelial cell line) subjected to mechanical stretch, and 3) CCN1 in BALF from mechanically ventilated humans with and without ARDS. BALF CCN1 concentrations and whole lung CCN1 protein levels were significantly increased in mice with VILI (n = 6) versus noninjured controls (n = 6). Ccn1 gene expression and CCN1 protein levels were increased in MLE-12 cells cultured under stretch conditions. Subjects with ARDS (n = 77) had higher BALF CCN1 levels compared with mechanically ventilated subjects without ARDS (n = 45) (P < 0.05). In subjects with ARDS, BALF CCN1 concentrations were associated with higher total protein, sRAGE, and worse [Formula: see text]/[Formula: see text] ratios (all P < 0.05). CCN1 is present in the lungs of mice and humans during the acute inflammatory phase of lung injury, and concentrations are higher in patients with increased markers of severity. Alveolar epithelial cells may be an important source of CCN1 under mechanical stretch conditions.

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.

Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial.

Importance: The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown. Objective: To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill. Design, Setting, and Participants: Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States. Interventions: Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76). Main Outcomes and Measures: The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days. Results: Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was -0.79 log10 units (-2.06 to 0.48) in the ganciclovir group and -0.79 log10 units (-2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, -0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, -27 (95% CI, -40 to -14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54). Conclusions and Relevance: Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting. Trial Registration: clinicaltrials.gov Identifier: NCT01335932.

Telemedicine as a tool to provide family conferences and palliative care consultations in critically ill patients at rural health care institutions: a pilot study.

BACKGROUND: Many critically ill patients who transfer from rural hospitals to tertiary care centers (TCCs) have poor prognoses, and family members are unable to discuss patient prognosis and goals of care with TCC providers until after transfer. AIM: Our TCC conducted teleconferences prior to transfer to facilitate early family discussions. DESIGN/SETTING: We conducted a retrospective review of these telemedicine family conferences among critically ill patients requested for transfer which occurred from December 2008 to December 2009 at our TCC. Outcomes for each patient and detailed descriptions of the conference content were obtained. We also assessed limitations and attitudes and satisfaction with this intervention among clinicians. RESULTS: During the 12-month period, 12 telemedicine consultations were performed. Of these patients, 10 (83%) died in the 30 days following the request for transfer. After the telemedicine consultation, 8 (67%) patients were transferred to our TCC from their respective hospitals, while 4 (33%) patients continued care at their regional hospital and did not transfer. Of the patients who transferred to TCC, 7 (88% of those transferred) returned to their community after a stay at the TCC. CONCLUSION: This study demonstrates that palliative care consultations can be provided via telemedicine for critically ill patients and that adequate preparation and technical expertise are essential. Although this study is limited by the nature of the retrospective review, it is evident that more research is needed to further assess its applicability, utility, and acceptability.

Long-term outcomes after in-hospital CPR in older adults with chronic illness.

BACKGROUND: Outcomes after in-hospital CPR in older adults with chronic illness are unclear. METHODS: We examined inpatient Medicare data from 1994 through 2005 to identify CPR recipients. We grouped beneficiaries aged ≥ 67 years by severity of six chronic diseases-COPD, congestive heart failure (CHF), chronic kidney disease (CKD), malignancy, diabetes, and cirrhosis-and investigated survival to discharge, discharge destination, rehospitalizations, and long-term survival. RESULTS: We identified 358,682 CPR recipients. Most patients with chronic disease were less likely to survive to discharge (eg, 14.8% in the advanced COPD group [P < .001] and 11.3% in the advanced malignancy group [P < .001]) than patients without chronic illness (17.3%). Among discharge survivors, the median long-term survival was shorter in patients with chronic illness (eg, 5.0, 3.5, and 2.8 months in the advanced COPD, malignancy, and cirrhosis groups, respectively; P < .001 for all) than without (26.7 months). Although 7.2% of CPR recipients without chronic disease were discharged home and survived at least 6 months without readmission, ≤ 2.0% of recipients with advanced COPD, CHF, malignancy, and cirrhosis (P < .001 for all) met these criteria. Adjusted analyses confirmed that most subgroups with chronic illness had lower hospital discharge survival, and among discharge survivors, most were discharged home less often, experienced more hospital readmissions, and had worse long-term survival. CONCLUSIONS: Older CPR recipients with any of the six underlying chronic diseases investigated generally have much worse outcomes than CPR recipients without chronic disease. These findings may substantially affect decisions about CPR in patients with chronic illness.

Parenteral fish oil lipid emulsions in the critically ill: a systematic review and meta-analysis.

INTRODUCTION: ω-3 Polyunsaturated fatty acids contained in fish oils (FO) possess major anti-inflammatory, antioxidant, and immunologic properties that could be beneficial during critical illness. We hypothesized that parenteral FO-containing emulsions may improve clinical outcomes in the critically ill. METHODS: We searched computerized databases from 1980-2012. We included randomized controlled trials (RCTs) conducted in critically ill adult patients that evaluated FO-containing emulsions, either in the context of parenteral nutrition (PN) or enteral nutrition (EN). RESULTS: A total of 6 RCTs (n = 390 patients) were included; the mean methodological score of all trials was 10 (range, 6-13). When the results of these studies were aggregated, FO-containing emulsions were associated with a trend toward a reduction in mortality (risk ratio [RR], 0.71; 95% confidence interval [CI], 0.49-1.04; P = .08; heterogeneity I (2) = 0%) and a reduction in the duration of mechanical ventilation (weighted mean difference in days [WMD], -1.41; 95% CI, -3.43 to 0.61; P = .17). However, this strategy had no effect on infections (RR, 0.76; 95% CI, 0.42-1.36; P = .35) and intensive care unit length of stay (WMD, -0.46; 95% CI, -4.87 to 3.95; P = .84, heterogeneity I (2) = 75%). CONCLUSION: FO-containing lipid emulsions may be able to decrease mortality and ventilation days in the critically ill. However, because of the paucity of clinical data, there is inadequate evidence to recommend the routine use of parenteral FO. Large, rigorously designed RCTs are required to elucidate the efficacy of parenteral FO in the critically ill.

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.

Fish oil in critical illness: mechanisms and clinical applications.

Fish oil is rich in omega-3 fatty acids, which have been shown to be beneficial in multiple disease states that involve an inflammatory process. It is now hypothesized that omega-3 fatty acids may decrease the inflammatory response and be beneficial in critical illness. After a review of the mechanisms of omega-3 fatty acids in inflammation, research using enteral nutrition formulas and parenteral nutrition lipid emulsions fortified with fish oil were examined. The results of this research to date are inconclusive for both enteral and parenteral omega-3 fatty acid administration. More research is required before definitive recommendations can be made on fish oil supplementation in critical illness.

The association between BMI and plasma cytokine levels in patients with acute lung injury.

BACKGROUND: Obesity is associated with poor outcomes in many diseases, although recent data suggest that acute lung injury (ALI) is an exception. This is particularly interesting because obesity is marked by increased levels of proinflammatory mediators associated with increased morbidity and mortality in ALI. We hypothesized that cytokine response might be attenuated in patients who are obese and critically ill or that obesity might modify the relationship between plasma cytokines and clinical outcomes in ALI. METHODS: We analyzed plasma biomarker levels (interleukin [IL]-6, IL-8, tumor necrosis factor-alpha receptor 1, surfactant protein D [SP-D], soluble intracellular adhesion molecule, von Willebrand factor (vWF), protein C, and plasminogen activator inhibitor-1) collected at baseline and day 3 in 1,409 participants in prior National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Network (ARDSNet) trials. BMI was calculated for each patient, and associations with cytokine levels and ventilator-free days (VFDs), organ failure-free days (OFDs), and mortality were investigated in regression models adjusting for confounders. RESULTS: In adjusted analyses, plasma IL-6 (P = .052), IL-8 (P = .001), and SP-D (P < .001) were inversely related to BMI, whereas vWF (P = .001) and WBC count (P = .042) increased proportionally with BMI. BMI was not associated with increased morbidity or mortality and did not modify the association between baseline biomarker levels and mortality, VFDs, or OFDs. CONCLUSIONS: Patients who are obese and have ALI have lower levels of several proinflammatory cytokines, suggesting that the inflammatory response may be altered in patients with ALI and a high BMI. Lower SP-D but higher vWF suggests decreased epithelial and increased endothelial injury in the lung of patients who are obese. Mechanisms by which obesity may modulate innate immunity in critical illness are unclear, and future studies should elucidate such mechanisms.

Management of the critically ill patient with severe acute pancreatitis.

OBJECTIVE: Acute pancreatitis represents a spectrum of disease ranging from a mild, self-limited course requiring only brief hospitalization to a rapidly progressive, fulminant illness resulting in the multiple organ dysfunction syndrome (MODS), with or without accompanying sepsis. The goal of this consensus statement is to provide recommendations regarding the management of the critically ill patient with severe acute pancreatitis (SAP). DATA SOURCES AND METHODS: An international consensus conference was held in April 2004 to develop recommendations for the management of the critically ill patient with SAP. Evidence-based recommendations were developed by a jury of ten persons representing surgery, internal medicine, and critical care after conferring with experts and reviewing the pertinent literature to address specific questions concerning the management of patients with severe acute pancreatitis. DATA SYNTHESIS: There were a total of 23 recommendations developed to provide guidance to critical care clinicians caring for the patient with SAP. Topics addressed were as follows. 1) When should the patient admitted with acute pancreatitis be monitored in an ICU or stepdown unit? 2) Should patients with severe acute pancreatitis receive prophylactic antibiotics? 3) What is the optimal mode and timing of nutritional support for the patient with SAP? 4) What are the indications for surgery in acute pancreatitis, what is the optimal timing for intervention, and what are the roles for less invasive approaches including percutaneous drainage and laparoscopy? 5) Under what circumstances should patients with gallstone pancreatitis undergo interventions for clearance of the bile duct? 6) Is there a role for therapy targeting the inflammatory response in the patient with SAP? Some of the recommendations included a recommendation against the routine use of prophylactic systemic antibacterial or antifungal agents in patients with necrotizing pancreatitis. The jury also recommended against pancreatic debridement or drainage for sterile necrosis, limiting debridement or drainage to those with infected pancreatic necrosis and/or abscess confirmed by radiologic evidence of gas or results or fine needle aspirate. Furthermore, the jury recommended that whenever possible, operative necrosectomy and/or drainage be delayed at least 2-3 wk to allow for demarcation of the necrotic pancreas. CONCLUSIONS: This consensus statement provides 23 different recommendations concerning the management of patients with SAP. These recommendations differ in several ways from previous recommendations because of the release of recent data concerning the management of these patients and also because of the focus on the critically ill patient. There are a number of important questions that could not be answered using an evidence-based approach, and areas in need of further research were identified.