Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group.

OBJECTIVES: To evaluate the safety and physiologic response of inhaled nitric oxide (NO) in patients with acute respiratory distress syndrome (ARDS). In addition, the effect of various doses of inhaled NO on clinical outcome parameters was assessed. DESIGN: Prospective, multicenter, randomized, double-blind, placebo-controlled study. SETTING: Intensive care units of 30 academic, teaching, and community hospitals in the United States. PATIENTS: Patients with ARDS, as defined by the American-European Consensus Conference, were enrolled into the study if the onset of disease was within 72 hrs of randomization. INTERVENTIONS: Patients were randomized to receive placebo (nitrogen gas) or inhaled NO at concentrations of 1.25, 5, 20, 40, or 80 ppm. MEASUREMENTS AND MAIN RESULTS: Acute increases in PaO2, decreases in mean pulmonary arterial pressure, intensity of mechanical ventilation, and oxygenation index were examined. Clinical outcomes examined were the dose effects of inhaled NO on mortality, the number of days alive and off mechanical ventilation, and the number of days alive after meeting oxygenation criteria for extubation. A total of 177 patients were enrolled over a 14-month period. An acute response to treatment gas, defined as a PaO2 increase > or =20%, was seen in 60% of the patients receiving inhaled NO with no significant differences between dose groups. Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs. The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment, as measured by the oxygenation index. There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate, the number of days alive and off mechanical ventilation, or the number of days alive after meeting oxygenation criteria for extubation. However, patients receiving 5 ppm inhaled NO showed an improvement in these parameters. In this dose group, the percentage of patients alive and off mechanical ventilation at day 28 (a post hoc analysis) was higher (62% vs. 44%) than the placebo group. There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo. Four patients had methemoglobin concentrations >5%. The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm. CONCLUSIONS: From this placebo-controlled study, inhaled NO appears to be well tolerated in the population of ARDS patients studied. With mechanical ventilation held constant, inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment. An improvement in oxygenation index was observed over the first 4 days. Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome.

Bovine surfactant therapy for patients with acute respiratory distress syndrome.

Lung surfactant is deficient in patients with acute respiratory distress syndrome (ARDS). We performed a randomized, prospective, controlled, open-label clinical study of administration of a bovine surfactant to patients with ARDS to obtain preliminary information about its safety and efficacy. Patients received either surfactant by endotracheal instillation in addition to standard therapy or standard therapy only. Three different groups of patients receiving surfactant were studied: patients receiving up to eight doses of 50 mg phospholipids/kg, those receiving up to eight doses of 100 mg phospholipids/kg, and those receiving up to four doses of 100 mg phospholipids/kg. Outcome measures included ventilatory support parameters, arterial blood gases, organ system failures, bronchoalveolar lavage (BAL) analyses, immunologic analyses, survival, and adverse events during the 28-d study period. Fifty-nine study patients were evaluable; 43 in the surfactant group and 16 in the control group. The FI(O2) at 120 h after treatment began was significantly decreased only for patients who received up to four doses of 100 mg phospholipids/kg surfactant as compared with control patients (p = 0.011). Mortality in the same group of patients was 18.8%, as compared with 43.8% in the control group (p = 0.075). The surfactant instillation was generally well tolerated, and no safety concerns were identified. This pilot study presents preliminary evidence that surfactant might have therapeutic benefit for patients with ARDS, and provides rationale for further clinical study of this agent.

Integrated management of venous thromboembolism.

Diagnostic methods for pulmonary embolism and deep vein thrombosis of the lower extremity are intertwined, since the latter nearly always precedes the former. Recent prospective studies show that an independent clinical estimate of disease probability helps to refine probability estimates of ventilation-perfusion lung scans and of ultrasonography with compression, reducing the need for pulmonary angiography and contrast venography. Repeated ultrasonography with compression can also be used to stratify patients into groups that are at high or low risk for subsequent pulmonary embolic events. I give algorithms and guidelines for the clinical use of these findings. Effective treatment of acute venous thromboembolism depends on achieving an antithrombotic state with heparin and warfarin. I give recommendations for dosing and monitoring heparin and warfarin that are based on knowledge of heparin blood levels and on use of the international normalized ratio with warfarin therapy. Use of low-molecular-weight heparin to prevent deep vein thrombosis is briefly described.

Tissue factor pathway inhibitor and von Willebrand factor antigen levels in adult respiratory distress syndrome and in a primate model of sepsis.

Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein primarily synthesized by the endothelium. A major fraction (approximately 85%) of TFPI remains associated with the endothelium, whereas a small fraction (approximately 15%) is secreted into the blood. In our attempts to search for a marker(s) of endothelial injury in the setting of adult respiratory distress syndrome (ARDS), we retrospectively measured plasma TFPI levels in patients at risk for and with ARDS caused by several etiologic factors. Plasma von Willebrand factor antigen (vWF-Ag), another endothelial-specific protein, was also measured in these patients. The mean plasma TFPI levels were slightly elevated (approximately 1.3-fold), whereas vWF-Ag levels were significantly elevated (approximately 3-fold) in the at-risk group as compared with those in the normal subjects. Both the TFPI (approximately 1.8-fold) and the vWF-Ag (approximately 4-fold) levels were further elevated in the ARDS group. Moreover, the sequential plasma samples from patients with ARDS had progressively increased levels of vWF-Ag and TFPI up to Days 4 and 8, respectively. Neither plasma vWF-Ag nor TFPI levels correlated with mortality in the at-risk group or the ARDS group. TFPI levels were also measured in bronchoalveolar lavage fluids (BALF). The levels (ng/ml) were: normal subjects, 0.05 +/- 0.02 SE; at-risk group, 0.35 +/- 0.16 SE; ARDS group, 0.99 +/- 0.28 SE. Thus, the BALF TFPI levels were increased approximately 7-fold in the at-risk group and approximately 20-fold in the ARDS group relative to the value in the normal subjects. These findings indicate increased local synthesis of TFPI in the alveolar space both in the at-risk patients and in those with ARDS. In additional studies in a primate model of sepsis, lethal doses (LD100) of E. coli administered to baboons resulted in a progressive increase in TFPI levels (approximately 2-fold at 6 h), whereas sublethal doses caused only minimal increase (approximately 1.2-fold). The vWF-Ag levels were elevated approximately 5-fold after infusion of LD100 concentrations of E. coli at 6 h and 4-fold after infusion of sublethal concentrations of E. coli at 24 h. Autopsies on animals in the LD100 group revealed pulmonary congestion, leukocyte infiltration, edema, and hemorrhage, all suggestive of acute lung injury. Thus, in the setting of acute lung injury plasma vWF-Ag appears to be considerably increased prior to significant damage to the endothelium, whereas increased plasma TFPI occurs only after severe injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Prediction of survival and mortality in patients with adult respiratory distress syndrome.

The adult or acute respiratory distress syndrome (ARDS) is an increased permeability pulmonary edema that occurs most often as a complication of bacterial sepsis, aspiration of gastric contents, or massive trauma. Clinically, the syndrome is recognized as acute respiratory failure with bilateral infiltrates on chest radiograph, a marked oxygenation defect, and normal or nearly normal cardiac function. Since its first comprehensive description > 25 yrs ago, the reported mortality rate of ARDS has remained high. Current series describe mortality rates in the range of 50% to 60%. The major cause of death in patients with ARDS seems to be bacterial sepsis and multiple organ dysfunction. Predictors of survival and mortality have been studied. Older patients (> or = 60 yrs) who develop bacterial sepsis and multiple organ dysfunction are at high risk to die. Younger patients who develop ARDS from trauma or other noninfectious causes have a better prognosis. Persistent metabolic acidosis on the first day of ARDS is a particularly poor prognostic sign.

IR-192, low dose rate endobronchial brachytherapy in the treatment of malignant airway obstruction.

PURPOSE: To assess the value of low-dose-rate endobronchial brachytherapy in the treatment of malignant airway obstruction. METHODS AND MATERIALS: Between September 1986 and April 1989, 39 patients with malignant airway obstruction had 49 catheter placements for an afterloading, low-dose-rate Ir-192 endobronchial brachytherapy. A flexible fiberoptic bronchoscope with fluoroscopic guidance was used for positioning. Thirty-eight of 39 (97%) patients completed the prescribed treatments. Ninety-seven percent had received previous external radiation in doses ranging from 36-60 Gy. One patient had metastatic renal cell carcinoma; the remainder had recurrent lung cancer. Endobronchial laser treatments were given to three patients 2-3 weeks prior to endobronchial brachytherapy. All patients were followed until death. The median dose delivered in 48 of the 49 placements was 20 Gy at 1 cm. RESULTS: Follow-up bronchoscopy was performed in 28 (72%) of 39 patients. Of these, 13 (46%) had a complete response, 12 (43%) had a partial response, and 3 (17%) had a minor response. Dyspnea improved in 30 of 37 patients (82%); hemoptysis in 17 of 19 patients (89%); cough in 31 of 39 patients (79%); and postobstructive pneumonia in 21 of 23 patients (92%). The median survival for the entire group was 5 months (range 1-31 months). CONCLUSION: This technique is simple, well-tolerated and offered significant palliation.

Heparin therapy. Regimens and treatment considerations.

Heparin is a parenteral antithrombotic agent with efficacy in the treatment and prevention of venous thromboembolic disease and in preinfarctional angina. Accumulating evidence also suggests that heparin is useful in the prevention of coronary artery reocclusion after thrombolytic therapy for acute myocardial infarction, and in the prevention of left ventricular mural thrombosis after anterior wall myocardial infarction. Heparin appears to offer only marginal benefit in reducing mortality when given in combination with thrombolytic therapy and aspirin for acute myocardial infarction. When used for prevention of venous thromboembolism in moderate risk patients, heparin should be given subcutaneously in a dose of 5000 U every 12 hours for 5 to 7 days or until the patient is ambulatory. In higher risk patients, such as those undergoing total hip replacement, heparin should be given subcutaneously every 12 hours in a dose to prolong the activated partial thromboplastin time (aPTT) by 4 to 5 seconds into the upper normal range. When used to treat active venous thromboembolism or the peri-infarctional state, heparin should be given by intravenous infusion with loading and maintenance doses to consistently prolong the aPTT to between 1.5- and 2.5-fold the control value (mean of laboratory's normal range). If constant intravenous infusion is not possible, the drug should be given subcutaneously every 12 hours to consistently prolong the aPTT between 1.5 and 2.5 times control. This regimen is also recommended in pregnant women with venous thromboembolic disease or mechanical heart valves.

Achieving consensus on withdrawing or withholding care for critically ill patients.

OBJECTIVE: To examine the decision-making process to withhold or stop life support. DESIGN: Survey. SETTING: Medical intensive care unit of a tertiary care center. PARTICIPANTS: Physicians and families of 15 critically ill patients; in seven cases patients also participated. MEASUREMENTS: Meetings between physicians and family members concerning a decision to withhold or stop treatment of a critically ill family member were tape-recorded. Transcriptions of the meetings were analyzed for 1) process: how the physician introduced the need for a decision, framed the likely outcomes of options, and closed on a decision; 2) what decision was made; and 3) the outcome; died, discharged home, or discharged to another institution. RESULTS: The concept of "patient's wishes" was a central orientation point for the negotiation of consensus regarding withholding or withdrawing therapy even when the patient was not a participant. Physicians tended to provide a direct and unambiguous introduction, give equal weights to options during decision framing, but narrow the options during decision closure to correspond to their judgments. Not every decision was consistent with the physician's judgment. CONCLUSIONS: Decision making to withhold or withdraw life-support therapy from critically ill persons involves complex, difficult processes. Successful management of the tension among life extension, quality of life, patient autonomy, and social justice requires better understanding of these processes.

Priming of human neutrophil functions by tumor necrosis factor: enhancement of superoxide anion generation, degranulation, and chemotaxis to chemoattractants C5a and F-Met-Leu-Phe.

Recombinant human tumor necrosis factor-alpha (rTNF) stimulated increased generation of superoxide anion (O2-) by human neutrophils in a concentration-dependent fashion. Preincubation of human neutrophils with rTNF (2.2-2200 units/ml) for 10 min enhanced the subsequent generation of O2- in response to C5a and f-Met-Leu-Phe (FMLP). Recombinant TNF did not enhance O2- generation by neutrophils stimulated with phorbol myristate acetate (PMA). Recombinant TNF alone failed to induce release of myeloperoxidase (MPO) and lysozyme by neutrophils. However, it did enhance the release of MPO and lysozyme by neutrophils stimulated with C5a and FMLP, but not with PMA. Although rTNF alone (0.001-50,000 units/ml) was not chemotactic for neutrophils, preincubation of neutrophils with rTNF (0.001-0.1 units/ml) enhanced the chemotactic activity of suboptimal concentrations of C5a (0.1 nM) and FMLP (5 nM). Neutrophils treated with high concentrations of rTNF (100-10,000 units/ml) showed inhibition of random movement and of chemotaxis induced by C5a or FMLP. We conclude from these studies that rTNF primes neutrophils for enhanced responses to subsequent stimuli and thus may augment the inflammatory response by increased oxidant production and lysosomal enzyme release and promote down-regulation of chemotactic movement.