Daniel P. Schuster

The acute respiratory distress syndrome.

The acute respiratory distress syndrome (ARDS) is a serious and complex clinical problem that often threatens the lives of patients. Emerging clinical data suggest that the survival of patients with this disorder may have improved during the last two decades, presumably because of advances in supportive medical care. Among the supportive therapies used to treat patients with ARDS, none is more complex than mechanical ventilation. New strategies for administering mechanical ventilation to patients with ARDS may reduce the occurrence of iatrogenic volotrauma and oxygen toxicity, accounting in part for the recently observed improvements in patient survival. Prevention and cure of ARDS have remained elusive goals because of the lack of specific therapies directed against the known pathogenic factors. Ongoing investigations are aimed at identifying specific therapies to interrupt the mechanisms of inflammation and lung injury responsible for this syndrome. Until such therapies become available, clinicians caring for patients with ARDS should attempt to minimize additional morbidity and mortality resulting from nosocomial infections and iatrogenic injuries.

Clinical evaluation compared to pulmonary artery catheterization in the hemodynamic assessment of critically ill patients

Although pulmonary artery (PA) catheterization is frequently employed in the management of critically ill patients, there is little documentation that the information obtained alters patient management. This study evaluated prospectively this question in 103 PA catheterizations. Before catheterization, physicians were asked to predict the range of several hemodynamic variables, the presumed diagnosis, and their plan for therapy. After catheterization, each chart was reviewed. The hemodynamics at the time of catheterization and therapy within 8 h of catheterization were noted. Pulmonary artery occlusive (wedge) pressure (WP) was correctly predicted 30% of the time. Cardiac output, systemic vascular resistance (SVR), and right atrial pressure (RAP) were correctly predicted approximately 50% of the time. There was no significant difference in the ability to predict hemodynamics of subgroups with either hypotension or impaired oxygenation. After catheterization, planned therapy was altered in 58% of the cases. Unanticipated therapy was added in 30% of the cases. This study documents the difficulty of predicting accurately hemodynamics based solely on clinical evaluation. Thus, the information obtained by catheterization often leads to alterations in the therapeutic plan. We suggest that PA catheterization is both indicated and useful in the management of critically ill patients.

Prophylactic Therapy for Stress Ulcer Bleeding: A Reappraisal

The combined data from 16 prospective trials (2133 patients) appear to suggest that antacids prevent stress ulcer bleeding more effectively than does cimetidine. However, the use of occult blood detection methods to diagnose stress ulcer bleeding may have led to the recognition of clinically insignificant bleeding. When the data from these trials are categorized according to the criteria used for the diagnoses of bleeding (either occult blood detection or clinically overt bleeding), there was no significant difference between antacids and cimetidine in the prevention of overt bleeding (3.3% of 458 compared with 2.7% of 402 patients who bled, respectively; p = 0.69). In addition, both agents were more effective (p less than 0.001) than placebo (15% of 720 patients who bled) in the prevention of overt bleeding. Cimetidine and antacids are equal in preventing significant stress ulcer bleeding.

Precedents for Meaningful Recovery during Treatment in a Medical Intensive Care Unit Outcome in Patients with Hematologic Malignancy

The medical records of 77 patients with hematologic malignancy who were admitted to a medical intensive care unit over a 21-month period were reviewed. The overall hospital mortality rate was 80 percent. Sixteen patients (21 percent) were discharged from the intensive care unit but eventually died in the hospital. The cause of death was the result of a new problem in only three of these 16 patients. Hypotension (shock) and acute respiratory failure were the reasons prompting admission to the intensive care unit in 75 percent, but death in the intensive care unit was almost always the result of intractable hypotension rather than refractory hypoxemia. Only four of 52 patients who required mechanical ventilation left the hospital. In all four, the duration of ventilatory support was less than five days and the cause of respiratory failure was noninfectious in nature. Factors such as congestive heart failure, leukopenia, and abnormalities in mental status modified the hospital course, but did not alter outcome once prolonged mechanical ventilation became necessary. The data suggest that once acute respiratory failure develops in patients with lymphoma or leukemia, presumably as a result of infection, and mechanical ventilation for more than a relatively brief period is required, the prognosis is uniformly grim. Decisions to limit aggressive therapies is subsets of intensive care patients such as these should be aided by data that show a lack of precedent for meaningful recovery.

In Vivo Imaging of 64Cu-Labeled Polymer Nanoparticles Targeted to the Lung Endothelium

Nanoparticles (NPs) targeting the intercellular adhesion molecule 1 (ICAM-1) hold promise as a mean of delivering therapeutics to the pulmonary endothelium in patients with acute and chronic respiratory diseases. As these new materials become available, strategies are needed to understand their behavior in vivo. We have evaluated the use of 64Cu and PET to noninvasively image the lung uptake and distribution of NPs coated with an anti-ICAM antibody. Methods: Model fluorescent NPs were coated with a mixture of an anti-ICAM antibody (or nonspecific IgG) and 64Cu-DOTA-IgG (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Biodistribution and small-animal PET and CT studies were performed in healthy mice and in mice pretreated with lipopolysaccharides (LPSs). Metabolism studies were also performed to evaluate the stability of 64Cu-labeled NPs in lungs in vivo. Results: The lungs of mice administered anti-ICAM NPs labeled with 64Cu were clearly imaged by small-animal PET 1, 4, and 24 h after administration. Both biodistribution and small-animal imaging showed a 3- to 4-fold higher uptake in the lungs of mice injected with ICAM-targeted NPs relative to that of the control group. Lung uptake was further enhanced by pretreating the mice with LPS, presumably because of ICAM-1 upregulation. However, an approximately 2-fold decrease in lung signal was observed in each experimental group over 24 h. Metabolism studies in lung tissues harvested from mice injected with 64Cu-labeled anti-ICAM NPs showed considerable release of a small 64Cu-radiometabolite from the NPs beginning as early as 1 h after injection. A decrease in lung fluorescence was also observed, most likely reflecting partial release of NPs from the lungs in vivo. Conclusion: The use of small-animal PET to track 64Cu-labeled nanostructures in vivo shows potential as a strategy for the preclinical screening of new NP drug delivery agents targeting the lung endothelium and other tissues. Future design optimization to prolong the stability of the radiolabel in vivo will further improve this promising approach.

The measurement of lung water

IntroductionIn this review, we compare the spectrum of currently availablemethods for quantifying pulmonary edema in patients.ReviewImaging and indicator dilution techniques comprise the most commonstrategies for measuring lung water at the bedside. The most accurate (within10% of the gravimetric gold standard) and most reproducible (< 5%between-test variation) are also, unfortunately, the most expensive and mostdifficult to implement for purposes of large-scale clinical trials or forroutine clinical practice.ConclusionThe standard chest radiograph remains the best screening test forthe detection of pulmonary edema. Indicator-dilution techniques are probablythe best available method at present for quantitation in patient groups.

Recombinant platelet-activating factor acetylhydrolase to prevent acute respiratory distress syndrome and mortality in severe sepsis: Phase IIb, multicenter, randomized, placebo-controlled, clinical trial.

OBJECTIVE Platelet-activating factor (PAF) is a potent proinflammatory mediator implicated in the pathogenesis of both severe sepsis and acute respiratory distress syndrome. One of the regulatory pathways for PAF involves degradation to the inactive metabolite lyso-PAF by the enzyme PAF acetylhydrolase (PAF-AH). Because reduced concentrations of the natural form of PAF-AH have been reported in septic patients, the present study was conducted to determine whether treatment with recombinant human PAF-AH (rPAF-AH, Pafase) was safe when administered after the onset of severe sepsis and whether it decreases the prevalence of acute respiratory distress syndrome and 28-day all-cause mortality. DESIGN A prospective, randomized, double-blind, placebo-controlled, multicenter trial. SETTING Thirty-three medical and surgical intensive care units located in the United States. PATIENTS A total of 127 patients with severe sepsis, but without established acute respiratory distress syndrome, were enrolled in the study. Randomization occurred within 12 hrs of the onset of severe sepsis. Patients then received 1.0 mg/kg rPAF-AH (n = 45), 5.0 mg/kg rPAF-AH (n = 39), or placebo (n = 43) administered intravenously, once daily, for five consecutive days. MEASUREMENTS AND MAIN RESULTS Demographic and baseline clinical characteristics of the three treatment groups were similar, except for a significantly higher prevalence of respiratory tract infections as the cause of severe sepsis in patients treated with 1.0 mg/kg rPAF-AH. There were no treatment-related deaths, and the overall prevalence of adverse events was similar among rPAF-AH-treated and placebo-treated patients. There were no significant differences in the prevalence of acute respiratory distress syndrome among the three treatment groups. However, 28-day all-cause mortality was 21% in the 1.0 mg/kg rPAF-AH group, 28% in the 5.0 mg/kg rPAF-AH group, and 44% in the placebo group (overall chi-square p =.07; 1.0 mg/kg rPAF-AH vs. placebo, p =.03). A trend toward reduced multiple organ dysfunction also was observed in the 1.0 mg/kg rPAF-AH group compared with the placebo group (p =.11). CONCLUSION The results from this study indicate that rPAF-AH was well tolerated and should be pursued as a potential new treatment to decrease mortality in patients with severe sepsis.

Comparison of high frequency jet ventilation to conventional ventilation during severe acute respiratory failure in humans

High frequency jet ventilation (HFJV) was compared to conventional (high tidal volume, low frequency) ventilation in 9 patients with acute respiratory failure (ARF). Alveolar ventilation was comparable or lower with HFJV in all but one case. When comparisons were made at the same concentration of ox

Importance of hypoxic vasoconstriction in maintaining oxygenation during acute lung injury

Objective To investigate the role of hypoxic pulmonary vasoconstriction in the intrapulmonary blood flow redistribution and gas exchange protection during oleic acid acute lung injury. Design Prospective, controlled animal study. Setting Research laboratory of an academic institution. Subjects Three groups of five mongrel dogs. Interventions Induction of acute lung injury by 0.08 mL/kg oleic acid intravenously. Hypoxic pulmonary vasoconstriction inhibition by Escherichia coli endotoxin microdose (15 &mgr;g/kg) pretreatment or by metabolic alkalosis (pH 7.60). Measurements and Main Results Pulmonary arterial and venous resistances were determined by flow-pressure curves and by capillary pressure estimation. Regional lung water and pulmonary blood flow were assessed by positron emission tomography. Oleic acid alone increased the arterial and venous resistances, redistributed blood flow away from edematous areas, and decreased the Pao2 from 507 ± 16 to 373 ± 60 torr on Fio2 1.0 and positive end-expiratory pressure 5 cm H2O. Endotoxin pretreatment inhibited the increase in arterial resistance, suppressed the redistribution, and decreased the Pao2 to 105 ± 22 torr. Alkalosis inhibited the increase in arterial and venous resistances, suppressed the redistribution, and decreased the Pao2 to 63 ± 12 torr. Reversal of the alkalosis increased the arterial and venous resistances, restored the perfusion redistribution, and improved the Pao2 to 372 ± 63 torr. Changes in blood gases conformed to predictions of a computer lung model in which hypoxic pulmonary vasoconstriction was suppressed by endotoxin and alkalosis. Conclusions We conclude that in oleic acid-induced lung injury, a) pulmonary hypertension results from increases in both arterial and venous resistances; b) the increase in arterial resistance is the primary mechanism responsible for the perfusion redistribution and the gas exchange protection; and c) the increase in arterial resistance is most consistent with hypoxic pulmonary vasoconstriction.

Molecular imaging of host-pathogen interactions in intact small animals.

Characterization and non‐invasive measurement of host–pathogen interactions in living cells, animal models and humans at the cellular and molecular levels is now possible using remote imaging detectors. Positron emission tomography scanners, highly sensitive cooled charge‐coupled device cameras for bioluminescence and fluorescence imaging as well as high‐magnetic‐field magnetic resonance imaging scanners can be used to study such diverse processes as pathogen tropism, pathogen life cycle, signal transduction, host response, cell trafficking and gene transfer. In many cases, images from more than one modality can be fused, allowing structure–function and multifunction relationships to be studied on a tissue‐restricted or regional basis. These new instruments, when used in conjunction with targeted contrast agents, reporter substrates and radiopharmaceuticals, enable ‘molecular imaging’ with enormous potential for elucidating host–pathogen interactions in intact animal models.