Robert C. McIntyre

Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia Coli and Salmonella typhimurium endotoxemia

In addition to stimulating IFN-γ synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1β and the chemokines IL-8 and macrophage inflammatory protein-1α. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1β converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1β, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium. In contrast, both wild-type and IL-1β−/− mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-γ but not IL-1β in ICE−/− mice is responsible for this resistance. However, IFN-γ-deficient mice were not resistant to S. typhimurium LPS, suggesting an IFN-γ-independent role for IL-18. Anti-IL-18 Abs protected mice against a lethal injection of either LPS. Anti-IL-18 treatment also reduced neutrophil accumulation in liver and lungs. The increased survival was accompanied by decreased levels of IFN-γ and macrophage inflammatory protein-2 in anti-IL-18-treated animals challenged with E. coli LPS, whereas IFN-γ and TNF concentrations were decreased in treated mice challenged with S. typhimurium. In conclusion, neutralization of IL-18 during lethal endotoxemia protects mice against lethal effects of LPS. This protection is partly mediated through inhibition of IFN-γ production, but mechanisms involving decreased neutrophil-mediated tissue damage due to the reduction of either chemokines (E. coli LPS) or TNF (S. typhimurium LPS) synthesis by anti-IL-18 treatment may also be involved.

Randomized, placebo-controlled trial of lisofylline for early treatment of acute lung injury and acute respiratory distress syndrome

Objective To determine whether the administration of lisofylline (1-[5R-hydroxyhexyl]-3,7-dimethylxanthine) would decrease mortality in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Design A prospective, randomized, double-blind, placebo-controlled, multicenter study. Setting Intensive care units at 21 hospitals at the ten centers constituting the ARDS Clinical Trials Network. Patients A total of 235 patients who met eligibility criteria were enrolled in the study (116 into the lisofylline group, 119 into the placebo group). Interventions Patients were randomized to receive either lisofylline or placebo. The dose of lisofylline was 3 mg/kg with a maximum dose of 300 mg intravenously every 6 hrs. The intravenous solution of study drug was administered over 10 mins every 6 hrs. Dosing was continued for 20 days or until the patient achieved 48 hrs of unassisted breathing. Measurements and Main Results The trial was stopped by the Data Safety Monitoring Board for futility at the first scheduled interim analysis. The patient groups had similar characteristics at enrollment. No significant safety concerns were associated with lisofylline therapy. There was no significant difference between groups in the number of patients who had died at 28 days (31.9% lisofylline vs. 24.7% placebo, p = .215). There was no significant difference between the lisofylline and placebo groups in terms of resolution of organ failures, ventilator-free days, infection-related deaths, or development of serious infection during the 28-day study period. The median number of organ failure–free days for the five nonpulmonary organ failures examined (cardiovascular, central nervous system, coagulation, hepatic, and renal) was not different between the lisofylline and placebo groups. Although lisofylline has been reported to decrease circulating free fatty acid levels, we did not find any such treatment effect compared with placebo. Conclusions In this study, there was no evidence that lisofylline had beneficial effects in the treatment of established ALI/ARDS.

Thirty years of clinical trials in acute respiratory distress syndrome.

ObjectiveTo systematically review clinical trials in acute respiratory distress syndrome (ARDS). Data SourcesComputerized bibliographic search of published research and citation review of relevant articles. Study SelectionAll clinical trials of therapies for ARDS were reviewed. Therapies that have been compared in prospective, randomized trials were the focus of this analysis. Data ExtractionData on population, interventions, and outcomes were obtained by review. Studies were graded for quality of scientific evidence. Main ResultsLung protective ventilator strategy is supported by improved outcome in a single large, prospective trial and a second smaller trial. Other therapies for ARDS, including noninvasive positive pressure ventilation, inverse ratio ventilation, fluid restriction, inhaled nitric oxide, almitrine, prostacyclin, liquid ventilation, surfactant, and immune-modulating therapies, cannot be recommended at this time. Results of small trials using corticosteroids in late ARDS support the need for confirmatory large clinical trials. ConclusionsLung protective ventilator strategy is the first therapy found to improve outcome in ARDS. Trials of prone ventilation and fluid restriction in ARDS and corticosteroids in late ARDS support the need for large, prospective, randomized trials.

Nf-κb Regulatory Mechanisms In Alveolar Macrophages From Patients With Acute Respiratory Distress Syndrome

Activation of the nuclear regulatory factor NF-kappaB occurs in the lungs of patients with the acute respiratory distress syndrome (ARDS) and may contribute to the increased expression of immunoregulatory cytokines and other proinflammatory mediators in this setting. Because of the important role that NF-kappaB activation appears to play in the development of acute lung injury, we examined cytoplasmic and nuclear NF-kapppaB counterregulatory mechanisms, involving IkappaB proteins, in alveolar macrophages obtained from 7 control patients without lung injury and 11 patients with established ARDS. Cytoplasmic levels of the NF-kappaB subunits p50, p65, and c-Rel were significantly decreased in alveolar macrophages from patients with ARDS, consistent with enhanced migration of liberated NF-kappaB dimers from the cytoplasm to the nucleus. Cytoplasmic and nuclear levels of IkappaBalpha were not significantly altered in alveolar macrophages from patients with established ARDS, compared with controls. In contrast, nuclear levels of Bcl-3 were significantly decreased in patients with ARDS compared with controls (P = 0.02). No IkappaBgamma, IkappaBbeta, or p105 proteins were detected in the cytoplasm of alveolar macrophages from control patients or patients with ARDS. The presence of activated NF-kappaB in alveolar macrophages from patients with established ARDS implies the presence of an ongoing stimulus for NF-kappaB activation. In this setting, appropriate counterregulatory mechanisms to normalize nuclear levels of NF-kappaB and to suppress NF-kappaB-mediated transcription, such as increased cytoplasmic and nuclear IkappaBalpha levels or decreased Bcl-3 levels, appeared to be induced. Nevertheless, even though counterregulatory mechanisms to NF-kappaB activation are activated in lung macrophages of patients with ARDS, NF-kappaB remains activated. These results suggest that fundamental abnormalities in transcriptional mechanisms involving NF-kappaB and important in the inflammatory response occur in the lungs of patients with ARDS.

Western trauma association critical decisions in trauma: Screening for and treatment of blunt cerebrovascular injuries

This is a recommended management algorithm from the Western Trauma Association addressing the diagnostic evaluation and management of blunt cerebrovascular injuries (BCVI) in adult patients. Because there are no published prospective randomized clinical trials that have generated class I data, the recommendations herein are based on published observational studies and expert opinion of Western Trauma Association members. The algorithm (Fig. 1) and accompanying comments represent a safe and sensible approach that could be followed at most trauma centers. We recognize that there will be patient, personnel, institutional, and situational factors that may warrant or require deviation from the recommended algorithm. We encourage institutions to use this guideline to formulate their own local protocols. The algorithm contains letters at decision points; the corresponding paragraphs in the text elaborate on the thought process and cite the pertinent literature. The annotated algorithm is intended to (a) serve as a quick bedside reference for clinicians; (b) foster more detailed patient care protocols that will allow for prospective data collection and analysis to identify best practices; and (c) generate research projects to answer specific questions concerning decision making in the management of adults with BCVI.

Western Trauma Association critical decisions in trauma: resuscitative thoracotomy.

BACKGROUND In the past three decades, there has been a significant clinical shift in the performance of resuscitative thoracotomy (RT), from a nearly obligatory procedure before declaring any trauma patient deceased to a more selective application of RT. We have sought to formulate an evidence-based guideline for the current indications for RT after injury in the patient. METHODS The Western Trauma Association Critical Decisions Committee queried the literature for studies defining the appropriate role of RT in the trauma patient. When good data were not available, the Committee relied on expert opinion. RESULTS There are no published PRCT and it is not likely that there will be; recommendations are based on published prospective observational and retrospective studies, as well as expert opinion of Western Trauma Association members. Patients undergoing cardiopulmonary resuscitation (CPR) on arrival to the hospital should be stratified based on injury and transport time. Indications for RT include the following: blunt trauma patients with less than 10 minutes of prehospital CPR, penetrating torso trauma patients with less than 15 minutes of CPR, patients with penetrating trauma to the neck or extremity with less than 5 minutes of prehospital CPR, and patients in profound refractory shock. After RT, the patient’s intrinsic cardiac activity is evaluated; patients in asystole without cardiac tamponade are declared dead. Patients with a cardiac wound, tamponade, and associated asystole are aggressively treated. Patients with an intrinsic rhythm following RT should be treated according to underlying primary pathology. Following several minutes of such treatment as well as generalized resuscitation, salvageability is reassessed; we define this as the patient’s ability to generate a systolic blood pressure of greater than 70 mm Hg with an aortic cross-clamp if necessary. CONCLUSION The success of RT approximates 35% for the patient arriving in shock with a penetrating cardiac wound and 15% for all patients with penetrating wounds. Conversely, patient outcome is relatively poor when RT is performed for blunt trauma, 2% survival for patients in shock and less than 1% survival for patients with no vital signs. Patients undergoing CPR on arrival to the hospital should be stratified based on injury and transport time to determine the utility of RT. This algorithm represents a rational approach that could be followed at trauma centers with the appropriate resources; it may not be applicable at all hospitals caring for the injured. There will be patient, personnel, institutional, and situational factors that may warrant deviation from the recommended guideline. The annotated algorithm is intended to serve as a quick bedside reference for clinicians.

Western trauma association/critical decisions in trauma: Operative management of adult blunt hepatic trauma

This is a recommended algorithm of the Western Trauma Association for the operative management of blunt hepatic injuries. Because there are few published prospective randomized trials, the recommendations are based on available published prospective, observational, and retrospective data and expert

IL-1 regulates in vivo C—X—C chemokine induction and neutrophil sequestration following endotoxemia

The influx of neutrophils into tissues in response to inflammatory stimuli involves C—X—C chemokines. Interleukin-1 (IL-1) stimulates chemokine production in vitro , but its role in vivo on chemokine production is not as clearly understood. We hypothesized that IL-1 mediates in vivo tissue C—X—C chemokine production induced by systemic lipopolysaccharide (LPS). IL-1 activity was blockedbyIL-1 receptor antagonist (IL-1Ra). Rats were injected with Salmonella typhi LPS (0.5 mg/kg) with and without prior administration of IL-1Ra. Cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-2 (MIP-2) protein and mRNA levels, tissue neutrophil accumulation, and indices of organ injury were measured. LPS administration resulted in increased plasma, lung, and liver IL-1β that was decreased by IL-1Ra. LPS also induced an increase in plasma, lung, and liver CINC-1 and MIP-2 protein and mRNA. However, IL-1Ra had no effect on LPS-induced plasma or lung tissue CINC-1 levels. In contrast, IL-1Ra pretreatment did significantly decrease CINC-1 protein expression in the liver (45% decrease) and MIP-2 protein expression in plasma (100% decrease), lung (72% decrease) and liver (100% decrease) compared to LPS-treated controls. Steady-state mRNA levels by Northern blot analysis of both CINC-1 and MIP-2 in lung and liver were similar to the protein findings. Pretreatment with IL-1Ra also resulted in a 47% and 59% decrease in lung and liver neutrophil accumulation, respectively, following LPS. In addition, indices of both lung and liver injury were decreased in animals pretreated with IL-1Ra. In summary, LPS induces IL-1β and MIP-2 expression in the lung and liver, both of which are IL-1 dependent. Although lung neutrophil accumulation in both lung and liver after LPS is also IL-1 mediated, lung CINC-1 levels were unaffected by IL-1Ra. These data suggest that IL-1 regulates tissue chemokine expression and neutrophil accumulation after LPS.

Inhaled nitric oxide variably improves oxygenation and pulmonary hypertension in patients with acute respiratory distress syndrome.

OBJECTIVE The purpose of this study was to determine the effect of inhaled nitric oxide (NO) on oxygenation, hemodynamics, and ventilation in patients with adult respiratory distress syndrome (ARDS). METHODS Sixteen trials of inhaled NO were performed in 14 ARDS patients (age 42.9 +/- 6) who had significant pulmonary hypertension (mean pulmonary artery pressure > 30 mm Hg). Patients were monitored with arterial and pulmonary artery catheters. Volume ventilation was performed by a strict protocol. Data were collected at baseline and 30 minutes after 20 and 40 ppm NO. RESULTS Overall, the Pao2/FIO2 ratio increased from 69.5 +/- 3.9 to 100.8 +/- 9.5 at 20 ppm, a 42.9 +/- 8.7% increase, and to 97.7 +/- 13.1 at 40 ppm, a 44.1 +/- 14.2% increase over baseline (p = 0.001). However, 5/16 trials demonstrated minimal improvement (Pao2/FIO2 ratio increase < 20%), 5 moderate improvement (20-50%), and 6 marked improvement (> 50%). Overall the mean pulmonary artery pressure (MPAP) decreased from 41.1 +/- 1.8 mm Hg to 34.3 +/- 1.3 at 20 ppm and 33.5 +/- 1.8 mm Hg at 40 ppm, a 15.0 +/- 3.7% decrease, p = 0.002. However, 5/16 trials demonstrated minimal improvement (MPAP decrease < 10%), 7 moderate improvement (10-20%), and 4 marked improvement (> 20%). At 40 ppm NO, 4 patients with moderate improvement in MPAP at 20 ppm NO had marked improvement. There were no changes in systemic oxygen delivery and consumption, intrapulmonary shunt, or lung compliance at 20 or 40 ppm (p > 0.05). Following collection of these data, prolonged NO inhalation (2-20 ppm) was done in 10 of 14 patients for 4.5 +/- 0.7 days (range 1-10 days). Overall, there were 7 deaths (mortality 50%). In patients receiving prolonged NO, there were 3 deaths (mortality 30%). All 4 patients who failed to respond to inhaled NO subsequently died (mortality 100%). CONCLUSIONS Inhaled NO improves oxygenation and pulmonary hemodynamics in patients with ARDS. However, the improvement to NO is variable.

Less Is More: Improved Outcomes in Surgical Patients with Conservative Fluid Administration and Central Venous Catheter Monitoring

BACKGROUND The ARDS Clinical Trials Network Fluid and Catheter Treatment Trial (FACTT) addressed fluid management and central monitoring of patients with acute respiratory distress syndrome/acute lung injury (ARDS/ALI). Because surgical patients may have been fundamentally different from the overall FACTT cohort, we set out to separately analyze the surgery patients in the trial. STUDY DESIGN We performed a posthoc, surgical subgroup analysis of 1,000 patients enrolled in the FACTT. Patients were randomized using a 2x2 factorial design comparing a conservative (CON) versus a liberal (LIB) strategy of fluid management and the use of a pulmonary artery catheter (PAC) or a central venous catheter (CVC). The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days, ICU-free days, and dialysis-free days until hospital discharge up to day 90. We defined surgical patients as those admitted to a surgical ICU, burn ICU, or cardiac surgical ICU; trauma patients; or those with an APACHE III surgical admission type. RESULTS There were 244 surgical patients. Risk of death within 60 days of randomization did not vary with catheter or fluid management, and a corresponding lack of effect was evident with regard to dialysis-free days. Ventilator-free days were increased in the fluid-conservative group (LIB, 13+/-1 days; CON, 15+/-1 days; p=0.04) at 28 days. CVC patients had more ventilator-free days at 28 and 90 days (28 days: CVC, 16+/-1 days; PAC, 13+/-1 days; p=0.03; 90 days: CVC, 64+/-3 days; PAC, 57+/-4 days; p=0.03). CVC patients had more ICU-free days at 90 days (90 days: CVC, 63+/-3 days; PAC, 55+/-3 days; p=0.04). CONCLUSIONS The risk of death did not vary with fluid management or catheter. A conservative fluid-administration strategy and central venous catheter monitoring resulted in more ventilator-free and ICU-free days in surgical patients with acute lung injury, and conservative fluid administration did not result in more renal failure.