Immunologic therapy for ARDS, septic shock, and multiple-organ failure.

Advances in cytokine biology and molecular biology have led to the development of novel immunologic approaches to the treatment of septic shock, ARDS, and MOF. These advances are necessary since improvements in supportive care clearly fall short of the hoped-for reductions in mortality associated with these disorders. As noted in this review, these new therapies are directed at three distinct levels of the inflammatory cascade: (1) the inciting event or insult (eg, endotoxin); (2) the mediators (eg, TNF, IL-1); and (3) the effector cells (eg, neutrophils). The current status of these treatments has been reviewed; and while each individual therapy has shown potential, it is likely that combinations of these agents may be necessary to substantially impact on survival. That is, due to the complexity and redundancy of the inflammatory network, it is doubtful that a "magic bullet" will be found. However, it is also clear that advances in our understanding of the pathogenesis of ARDS, septic shock, and MOF at the molecular level have provided clinicians with powerful weapons with which to do battle. It remains to be seen which ones will work the best.

Relationships of oxygen uptake and oxygen delivery in respiratory failure not due to the adult respiratory distress syndrome.

Previous studies have suggested that oxygen uptake (VO2) may be dependent on oxygen delivery (QO2) at most levels of QO2 in patients with the adult respiratory distress syndrome (ARDS); however, the adequacy of substrate delivery in patients with non-ARDS respiratory failure is unclear. The purpose of the present study was to examine the relationship between VO2 and QO2 in a group of critically ill patients (n = 10) with non-ARDS respiratory failure (ie, cardiac pulmonary edema, chronic obstructive pulmonary disease [COPD], or pneumonia). For comparison, these relationships were also examined in a group of patients (n = 6) with ARDS. The data indicate that VO2 is dependent on QO2 in both patients with ARDS and non-ARDS respiratory failure. In contrast, regional venous oxygen tension differences varied considerably between the two groups of patients, indicating differences in local adaptations to critical reductions in QO2. Finally, over a similar range of QO2, oxygen extraction was greater in patients with ARDS compared to patients with non-ARDS respiratory failure (r = -0.67 and slope = -0.62 vs r = -0.45 and slope = -0.35; p less than 0.05). These data suggest that a linear relationship between VO2 and QO2 is not unique to patients with ARDS and may not predict regional adaptations to critical reductions in substrate availability.

Analysis of airflow obstruction by bronchoalveolar lavage following bone marrow transplantation. Implications for pathogenesis and treatment.

The development of airflow obstruction, most often due to bronchiolitis, is a significant cause of morbidity and mortality in recipients of allogeneic BMT. Current consensus holds that this airways disease is the result of chronic GVHD and/or CMV infection. However, recent studies of idiopathic forms of BRO have demonstrated a striking influx of neutrophils into the lungs of affected individuals. Reasoning that the immune cell populations involved in tissue injury associated with either CGVHD or CMV infection would consist predominantly of lymphocytes, we tested this hypothesis by performing BAL in 12 adults with minimal or absent smoking histories who developed significant airflow obstruction (FEV1/FVC = 80.7 +/- 1 percent preBMT and 56.8 +/- 2.4 percent postBMT; p less than 0.001) following allogeneic BMT. Eleven of 12 patients had evidence of chronic, stable GVHD at the time of the study. In contrast to non-BMT patients with BRO, BAL defined two distinct patterns of lung inflammation in the BMT patients with airflow obstruction: (a) neutrophil predominance (five patients; neutrophil percentage = 20.2 +/- 6.6 percent); and (b) lymphocyte predominance (three patients; lymphocyte percentage = 35.9 +/- 12.1 percent). These data suggest that the pattern of inflammation in the lungs of BMT patients with BRO is not uniform and is not associated with active microbial infection. From these results, it is inferred that the airways injury in BMT patients may reflect diverse pathogenetic mechanisms initiated in the context of CGVHD and cytotoxic drug therapy.

Adult bronchiolitis. Evaluation by bronchoalveolar lavage and response to prednisone therapy.

Four adult patients with biopsy-proven bronchiolitis were identified and prospectively evaluated. Each patient presented with the rapid onset (weeks to months) of severe respiratory disease that was clinically distinct from asthma, chronic bronchitis, bronchiectasis, cystic fibrosis, and emphysema. Bronchiolitis patients were evaluated by pulmonary function testing and bronchoalveolar lavage (BAL) before and after two months of treatment with 1 mg/kg/day of prednisone. Initial BAL results of bronchiolitis patients were compared to those of cigarette smokers with chronic bronchitis (n = 4), asymptomatic cigarette smokers (n = 5), and normal nonsmoking volunteers (n = 5). Neutrophils comprised 53 +/- 13 percent of the cells recovered by BAL in bronchiolitis patients but only 3 +/- 2 percent of the cells in chronic bronchitis patients, 1.5 +/- 0.6 percent of the cells in asymptomatic smokers, and 0.3 +/- 0.3 percent of the cells in normal volunteers (p less than 0.01, all comparisons). Moreover, prednisone produced a striking decrease in lower respiratory tract neutrophils (53 +/- 13 percent to 8 +/- 3 percent, p less than 0.05) in all bronchiolitis patients while lung function either improved (two patients) or remained unchanged (two patients). These findings suggest a central role for the neutrophil in bronchiolitis and argue that BAL may be clinically useful in the diagnosis and management of these patients.

The combination of ipratropium and albuterol optimizes pulmonary function reversibility testing in patients with COPD.

STUDY OBJECTIVES: To determine whether the combination of ipratropium bromide and albuterol results in greater and more consistent pulmonary function test (PFT) response rates than ipratropium bromide or albuterol alone in patients with COPD. DESIGN: Retrospective review of two recently completed 3-month, randomized, double-blind, parallel, multicenter, phase III trials. SETTING: Outpatient. PATIENTS: A total of 1,067 stable patients with COPD. INTERVENTIONS: Ipratropium bromide (36 microg qid), albuterol base (180 microg qid), or an equivalent combination of ipratropium bromide and albuterol sulfate (42 microg and 240 microg qid, respectively). MEASUREMENTS AND RESULTS: PFT response rates were analyzed using 12% and 15% increases in FEV1 compared with baseline values and were measured in the various treatment groups on days 1, 29, 57, and 85 in these trials. Regardless of whether a 12% or a 15% increase in FEV1 was used to define a positive response, an equivalent combination of ipratropium bromide and albuterol sulfate was superior to the individual agents (p < 0.05; all comparisons within 30 min). In addition, a 15% or more increase in FEV1 was seen in > 80% of patients who received the combination of ipratropium and albuterol sulfate during the initial PFT and continued to be observed 3 months after initial testing. CONCLUSIONS: Use of a combination of ipratropium bromide and albuterol sulfate is superior to the individual agents in identifying PFT reversibility in patients with COPD.

Acid aspiration-induced acute lung injury causes leukocyte-dependent systemic organ injury.

The adult respiratory distress syndrome is a form of acute lung injury (ALI) that is frequently associated with systemic organ injury and often occurs in the setting of wide-spread inflammatory cell activation. However, whether conditions that lead to ALI result in systemic organ injury is unclear. This study was designed to test the hypothesis that ALI induced by acid aspiration will not result in systemic organ injury. Morphological alterations and lymph-to-plasma protein ratios were measured in autoperfused cat ileum preparations of four control animals and five animals with ALI produced by the endobronchial instillation of 0.1 N HCl (0.5 ml.kg-1.lung-1). After 2 h, the lymph-to-plasma protein ratio (a measure of microvascular permeability) was increased in the ilea of HCl-injured animals compared with control animals (0.234 +/- 0.03 vs. 0.121 +/- 0.005; P = 0.012) and was accompanied by extensive morphological alterations. Four additional HCl-injured animals were pretreated with an antileukocyte adherence antibody (anti-CD18, 2 mg/kg) that blocked the HCl-induced alterations in the ileum. This study provides evidence for significant systemic organ injury after acid aspiration-induced ALI and suggests that the neutrophil may be a key mediator.

Use of changes in symptoms to predict changes in lung function in assessing the response to asthma therapy.

BACKGROUND: The majority of adult patients with asthma are managed by primary care providers. Although there is no generally accepted gold standard for the assessment of asthma severity in general practice, treatment decisions and modifications to therapy are strongly influenced by patients' symptoms and history of asthma medication use. OBJECTIVES: The primary goal of this study was to determine whether there is a correlation between changes in asthma symptoms during treatment and changes in lung function, as measured by peak expiratory flow (PEF). A secondary goal was to compare the relative efficacy (in terms of improvement in asthma symptoms and lung function) of 3 commonly used asthma treatments: inhaled fluticasone propionate, inhaled salmeterol xinafoate, and oral zafirlukast. METHODS: This was a retrospective comparison employing regression analyses of asthma symptom and lung function data from 2890 male and female adolescent and adult patients with persistent asthma who were enrolled in 8 randomized, double-blind, double-dummy, parallel-group studies. Data on patients' self-rated symptoms, PEF, supplemental albuterol use, nighttime awakenings, and frequency of asthma exacerbations were used to ascertain whether there was a correlation between changes in asthma symptoms and changes in pulmonary function, and to compare treatment effects. RESULTS: Changes in patients' ratings of asthma symptoms after treatment with study medications showed a strong correlation with changes in lung function. Similarly, changes in lung function were strongly correlated with changes in supplemental beta-agonist use and quality of life. In addition, fluticasone or salmeterol treatment resulted in significantly greater increases in mean morning PEF (P < 0.001), significantly greater decreases in symptom scores (P < or = 0.004), significantly fewer nights with awakenings due to symptoms (P < or = 0.017), and significantly greater reductions in supplemental beta-agonist use (P < 0.001) compared with zafirlukast treatment or placebo. Patients treated with fluticasone or salmeterol also experienced significantly lower rates of asthma exacerbation (3%) during treatment than did those receiving zafirlukast (7%) or placebo (12%) (P < 0.001 and P = 0.015, fluticasone and salmeterol, respectively). CONCLUSION: These findings support the validity of primary care practitioners' basing asthma-management decisions on patients' symptoms.

Multiple organ failure.

Diagnostic criteria for individual organ system failure are imprecise, a factor that adds a considerable amount of ambiguity to this area of clinical research. Nonetheless, multiple organ failure is a common sequela of ARDS and other catastrophic medical and surgical illnesses that continues to limit patient survival. The cumulative weight of investigative evidence currently supports the premise that concepts of acute respiratory failure must encompass the abnormal gas exchange in the systemic as well as the pulmonary microvasculature. In this context, we need not dispense with the term ARDS, as respiratory distress applies equally to the nonpulmonary organs as well as the lungs.

Metabolic consequences of sepsis. Correlation with altered intracellular calcium homeostasis.

The availability of adequate substrate for energy homeostasis is a minimal requirement for vital organ function that normally is provided through dietary intake. When dietary sources of nutrients are inadequate, the body relies on alternate sources of energy provided by gluconeogenesis, lipolysis, and ketogenesis. Sepsis is associated with disruption of virtually all these provisional sources of energy substrate (see Fig. 4). In addition, sepsis impairs the function of the glycolytic pathway, the integrity of which is necessary for glucose to be used effectively for energy production. These abnormalities, coupled with disruption of the intracellular energy-producing machinery (e.g., glycolytic and gluconeogenic enzymes, mitochondria) eventually lead to a reduction in intracellular ATP. Furthermore, a reduction in intracellular ATP can undermine virtually all the energy-consuming functions of the cell, including energy substrate formation (e.g., failed gluconeogenesis), antioxidant production, and calcium homeostasis. High levels of intracellular calcium, in turn, are known to activate many potentially destructive enzymatic pathways (e.g., proteases, phospholipases, endonucleases) that further diminish cell function and may result in cell death. In this context, iCa2+ accumulation may play an important role in the progression from early sepsis to MODS, the most common cause of mortality in the ICU.

Cryptogenic bronchiolitis.

Cryptogenic bronchiolitis is a unique clinical disorder that causes rapidly progressive, chronic airflow obstruction. In this article, we reviewed the pathology, clinical characteristics, and proposed pathogenesis of cryptogenic bronchiolitis. It is evident that cryptogenic bronchiolitis represents the result of a disordered inflammatory response in the small airways of the lung. The clinical characteristics of cryptogenic bronchiolitis, in most instances, should allow this disorder to be distinguished from other causes of chronic airflow obstruction, as well as from BOOP. In this regard, a high clinical suspicion and an awareness of its unique clinical features are the keys to the diagnosis of cryptogenic bronchiolitis.

Validity of bronchoalveolar lavage in acute lung injury: recovered cells accurately reflect changes in the lung parenchyma.

Bronchoalveolar lavage (BAL) has come into widespread use as a tool to diagnose and manage various lung diseases. However, the usefulness of BAL is based on the assumption that the cells recovered in BAL fluid accurately reflect cellular populations in the lung parenchyma. To test this hypothesis, random source (n = 16) dogs were given intravenous phorbol myristate acetate (PMA) to produce acute, diffuse lung inflammation. Dogs were divided into three groups. Group I animals (n = 2) underwent BAL and open lung biopsy at time zero. Group II (n = 7) animals underwent hourly BAL after PMA with open lung biopsy at 3 h. Group III (n = 7) animals underwent hourly BAL after PMA with open lung biopsy at 6 h. When BAL cell populations were compared with the corresponding biopsies, there was a direct correlation (r = 0.67) between BAL neutrophil percentages and neutrophils present in histologic sections. These findings suggest BAL accurately reflects changes in the lung parenchyma in acute lung disease.

Regional blood flow distribution in endotoxin-treated dogs: modification by ibuprofen.

PURPOSE: The aim of this study was to determine whether the improved hemodynamic profiles reported with cyclooxygenase inhibition during sepsis include improvements in tissue perfusion is unknown. Our hypothesis was that cyclooxygenase inhibition with ibuprofen will prevent the endotoxin-induced alterations in regional blood flow distribution from developing and/or restore the endotoxin-induced loss of responsiveness to intravascular volume expansion. METHODS: We measured cardiac output, regional blood flow, and total systemic shunt flow in dogs using radiolabeled 15-microns microspheres. These parameters were assessed in control (N = 10) and endotoxin-treated animals (N = 7). Additional endotoxin-treated animals (N = 7) were also pretreated with ibuprofen. RESULTS: Compared with controls, endotoxin-treated animals exhibited marked reductions in blood flow to most systemic organs that were not reversed with large, intravenous saline infusions (ie, isotonic saline; 40 mL/kg; N = 4). By contrast, although ibuprofen pretreatment (12.5 mg/kg; N = 7) completely prevented the reductions in mean arterial pressure caused by endotoxin from occurring, it did little to prevent the development of endotoxin-induced alterations in regional blood flow distribution. Nonetheless, in contrast to the endotoxin-treated animals, there were significant increases in cardiac output and blood flow to several organs after saline infusion in the ibuprofen-pretreated animals. CONCLUSIONS: Cyclooxygenase inhibition with ibuprofen has few direct effects on regional blood flow distribution after endotoxin. However, cyclooxygenase inhibition with ibuprofen does attenuate the endotoxin-induced decrease in vascular responsiveness to intravenous saline infusion.

Ischemia/reperfusion injury to the ileum does not account for the ileal VO2-DO2 alterations induced by endotoxin.

PURPOSE: Endotoxin (lipopolysaccharide [LPS])-induced systemic organ injury leads to disruption of normal systemic organ metabolic processes, which are manifest clinically by signs of accelerated anaerobic metabolism (e.g., tissue acidosis and hyperlactatemia) and altered VO2-DO2 relationships. The association of increased anaerobic metabolism with VO2-DO2 alterations has led to the notion that ischemia/ reperfusion (I/R) injury may be a prerequisite for the development of VO2-DO2 alterations during endotoxemia. However, in contrast to sepsis, in which oxygen consumption is often increased, oxygen consumption is severely decreased after I/R injury. Based on these observations, we hypothesized that I/R injury would result in systemic organ VO2-DO2 alterations, which are distinct from those that occur in sepsis. MATERIALS AND METHODS: We used the in situ autoperfused feline ileal preparation to simultaneously examine microvascular permeability, reflected as the ileal lymph to plasma protein concentration ratio (CL/CP), and ileal VO2-DO2 relationships after either intravenous LPS (2.0 mg/kg; n = 5) or I/R injury (n = 5), and in matching controls (n = 5). RESULTS: As expected, all LPS-treated and I/R-injured animals were found to have extensive ileal histological damage and marked increases in the CL/CP compared with controls (0.315 +/- 0.009 and 0.329 +/- 0.034, respectively, v 0.097 +/- 0.009; P < .001, both comparisons). In addition, the critical DO2 (DO2c) was elevated, and the critical oxygen extraction was decreased in both the I/R and LPS groups relative to controls. However, as initially hypothesized, the VO2 at the critical DO2 was markedly decreased in the I/R group compared with that of the LPS group. CONCLUSIONS: These data indicate that I/R injury is insufficient to account for the systemic organ VO2-DO2 alterations that occur with LPS injury.

Endotoxin-induced ileal Vo2-Do2 alterations do not correlate with the severity of ileal injury.

PURPOSE: Altered Vo2-Do2 relationships are most often noted to occur in the setting of sepsis or endotoxin (LPS)-induced systemic organ microvascular injury and are generally thought to be causally linked to that injury. However, we have recently shown that ileal microvascular injury is not associated with altered ileal Vo2-Do2, relationships. Thus, we hypothesized that the severity of LPS-induced systemic organ microvascular injury would not correlate with the development of systemic organ Vo2-Do2 alterations. MATERIALS AND METHODS: To test this hypothesis, we used the in situ autoperfused feline ileal preparation to simultaneously examine microvascular permeability, reflected as the ileal lymph to plasma protein concentration ratio (CL/CP), and ileal Vo2-Do2 relationships 2 hours after intravenous LPS (0.75-2.0 mg/kg; n = 9) and in matching controls (n = 5). RESULTS: As expected, all LPS-treated animals were found to have extensive ileal histological damage and marked increases in the CL/CP compared with controls (0.308 +/- 0.019 v 0.097 +/- 0.009; P < .001). In addition, although the critical Do2 (Do2c) was elevated in the LPS-treated animals relative to controls (34.2 +/- 5.0 v 16.7 +/- 1.4 mL/min/kg; P < .03), there was no correlation between the Do2c and the CL/CP in the LPS-treated animals. Finally, ileal wet to dry weight ratios after LPS did not differ from controls. CONCLUSION: Taken together, these data suggest that factors other than organ injury, as assessed by morphological and permeability alterations, are important in the pathogenesis of altered systemic organ Vo2-Do2 relationships after LPS.

Oxygen uptake-oxygen delivery alterations in the isolated liver after hydrogen peroxide challenge.

Acute, diffuse lung injury is frequently complicated by systemic organ injury and alterations in the relationship between oxygen uptake (VO2) and oxygen delivery (QO2). In this regard, systemic organ neutrophil accumulation and morphologic alterations consistent with systemic organ injury often occur in nonpulmonary organs in these settings. However, whether VO2-QO2 matching is also altered in these injured systemic organs remains unproven. Thus, the present study was designed to test the hypothesis that hydrogen peroxide (H2O2), a product of neutrophil oxidative metabolism, will cause systemic organ structural abnormalities and alter VO2-QO2 matching. To test this hypothesis, VO2-QO2 relationships, morphologic changes, and organ water content were evaluated in both uninjured, isolated perfused rabbit livers and in isolated perfused rabbit livers after injury with 5 mmol/L H2O2. Following H2O2 injury, peak VO2 fell from 1.36 +/- 0.35 mL/min/100 g to 0.79 +/- 0.16 mL/min/100 g (P < .05) and peak O2 extraction fell from 0.83 +/- 0.09 to 0.66 +/- 0.04 (P < .05). In addition, VO2 was lower for any given level of QO2 in the H2O2-injured livers compared with the control livers (P < .01). Finally, liver extravascular water content was increased in H2O2-injured livers compared with the control livers (0.79 +/- 0.02 v 0.71 +/- 0.05; P < .05). These observations indicate that H2O2, a product of neutrophil oxidative metabolism, is capable of producing both morphologic changes as well as gas exchange alterations in the isolated, perfused liver.

Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey.

In an attempt to identify the range of opinions influencing the diagnosis and therapy of patients with the adult respiratory distress syndrome (ARDS), a postal survey was mailed to 3,164 physician members of the American Thoracic Society Critical Care Assembly. The questionnaire asked opinions regarding the factors important in the diagnosis of ARDS and its treatment. Thirty-one percent of physicians surveyed responded within 4 weeks, the vast majority of which were board certified or eligible in Internal Medicine, Pulmonary Disease, and/or Critical Care Medicine. A known predisposing cause, measure of oxygenation efficiency, and a chest radiograph depicting pulmonary edema were reported to be the most important criteria for a clinical and research diagnosis of ARDS. Lung compliance and bronchoalveolar lavage neutrophil or protein content were reportedly less important. The initial treatment of patients with ARDS was reported to be most commonly accomplished using volume-cycled ventilation in the assist/control mode. Nearly half the responders reported using lower tidal volumes (5 to 9 mL/kg) than the traditionally recommended 10 to 15 mL/kg. Most respondents indicated they have intentionally allowed CO2 retention. On average, oxygen toxicity was thought to begin at an FIO2 between 0.5 and 0.6. It was reported that modest levels of positive end-expiratory pressure (PEEP) were used in incremental fashion as FiO2 requirements increased. Perceived indications for insertion of pulmonary artery catheters and compensation of the effects of PEEP on the pulmonary artery occlusion pressure varied widely among the responders. We conclude that reported practice patterns regarding the care of ARDS patients vary widely even within a relatively homogenous group of critical care practitioners.