Inter-individual variability of plasma PAF-acetylhydrolase activity in ARDS patients and PAFAH genotype.

BACKGROUND: Platelet activating factor (PAF), a pro-inflammatory phospholipid, stimulates cytokine secretion from polymorphonuclear leukocytes expressing the transmembrane G-protein coupled PAF receptor. Elevated PAF levels are associated with acute respiratory distress syndrome (ARDS) and sepsis severity. The pro-inflammatory effects of PAF are terminated by PAF acetylhydrolase (PAF-AH). OBJECTIVE: We sought to determine whether allelic variants in the human PAFAH gene (Arg92His, Ile198Thr, and Ala379Val) contribute to variability in PAF-AH activity in patient plasma obtained within 72 h of ARDS diagnosis. RESULTS: Plasma PAF-AH activity (mean +/- SD) was higher in patients homozygous for the Arg92 allele compared to His92 allele carriers (2.21 +/- 0.77 vs. 1.64 +/- 0.68 U/min; P < 0.01; n = 31 and 21 respectively). Baseline plasma PAF-AH activity was higher among day 7 survivors vs. day 7 non-survivors (2.05 +/- 0.75 vs. 1.27 +/- 0.63, P = 0.05). CONCLUSION: These data demonstrate an association between PAF-AH allelic variation, plasma activity, and outcome in ARDS.

Pulmonary Kaposi's sarcoma in the acquired immune deficiency syndrome. Clinical, radiographic, and pathologic manifestations.

Pulmonary Kaposi's sarcoma related to the acquired immune deficiency syndrome (AIDS) has not been well characterized. To define the clinical, radiographic, and pathologic features of this entity, 11 autopsy-proved cases of pulmonary Kaposi's sarcoma were reviewed. The most common clinical symptoms were dyspnea and cough, but hemoptysis and stridor were also found. Nodular infiltrates and pleural effusions were the most commonly found radiographic abnormalities. Pulmonary function tests were sensitive in detecting the pulmonary abnormalities due to Kaposi's sarcoma. A low diffusion capacity, lack of arterial desaturation with exercise, and obstruction to airflow were suggestive of pulmonary involvement with this malignancy. Although endobronchial Kaposi's sarcoma was visualized at bronchoscopy as cherry-red, slightly raised lesions, bronchial biopsy specimens always showed no abnormalities. Transbronchial brushings and biopsy specimens and analysis of pleural fluid were also not helpful in establishing a diagnosis. In the seven subjects with extensive parenchymal Kaposi's sarcoma at autopsy, the pleura was always involved. Eight subjects had involvement of the tracheobronchial tree. In all of the subjects, pulmonary Kaposi's sarcoma was a significant cause of morbidity, and in three of 11 subjects (27 percent) it was the direct cause of death.

Infections and the inflammatory response in acute respiratory distress syndrome.

STUDY OBJECTIVE: Systemic inflammatory response syndrome (SIRS) and infections are frequently associated with the development and progression of acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS). We investigated, at onset and during the progression of ARDS, the relationships among (1) clinical variables and biological markers of SIRS, (2) infections defined by strict criteria, and (3) patient outcome. Biological markers of SIRS included serial measurements of inflammatory cytokines (IC)-tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8-in plasma and BAL fluid. METHODS: We prospectively studied two groups of ARDS patients: 34 patients treated conventionally (group 1) and nine patients who received glucocorticoid rescue treatment for unresolving ARDS (group 2). Individual SIRS criteria and SIRS composite score were recorded daily for all patients. Plasma IC levels were measured by enzyme-linked immunosorbent assay on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients received mechanical ventilation. Unless contraindicated, bilateral BAL was performed on day 1, weekly, and when ventilator-associated pneumonia was suspected. Patients were closely monitored for the development of nosocomial infections (NIs). RESULTS: ICU mortality was similar among patients with and without sepsis on admission (54% vs 40%; p < 0.45). Among patients with sepsis-induced ARDS, mortality was higher in those who subsequently developed NIs (71% vs 18%; p < 0.05). At the onset of ARDS, plasma TNF-alpha, IL-1 beta, IL-6, and IL-8 levels were significantly higher (p < 0.0001) in nonsurvivors (NS) and in those with sepsis (p < 0.0001). The NS group, contrary to survivors (S), had persistently elevated plasma IC levels over time. In 17 patients, 36 definitive NIs (17 in group 1 and 19 in group 2) were diagnosed by strict criteria. No definitive or presumed NIs caused an increase in plasma IC levels above patients' preinfection baseline. Daily SIRS components and SIRS composite scores were similar among S and NS and among patients with and without sepsis-induced ARDS, were unaffected by the development of NI, and did not correlate with plasma IC levels. CONCLUSIONS: Sepsis as a precipitating cause of ARDS was associated with higher plasma IC levels. However, NIs were not associated with an increase in SIRS composite scores, individual SIRS criteria, or plasma IC levels above patients' preinfection baseline. SIRS composite scores over time were similar in S and NS. SIRS criteria, including fever, were found to be nonspecific for NI. Irrespective of etiology of ARDS, plasma IC levels, but not clinical criteria, correlated with patient outcome. These findings suggest that final outcome in patients with ARDS is related to the magnitude and duration of the host inflammatory response and is independent of the precipitating cause of ARDS or the development of intercurrent NIs.

Noninvasive positive-pressure ventilation via face mask during bronchoscopy with BAL in high-risk hypoxemic patients.

STUDY OBJECTIVE: The aim of this study was to assess the feasibility and safety of noninvasive positive-pressure ventilation (NPPV) via a face mask to aid in performing fiberoptic bronchoscopy (FOB) with BAL in immunosuppressed patients with gas exchange abnormalities that contraindicate using conventional unassisted FOB. STUDY POPULATION: Eight consecutive immunosuppressed patients (40 +/- 14 years old) with suspected pneumonia entered the study. Entrance criteria included the following: (1) PaO2/fraction of inspired oxygen (FIo2) of 100 or less; pH of 7.35 or more; and (3) improvement in O2 saturation during NPPV before initiating FOB. INTERVENTION: Patients had routine application of topical anesthesia to the nasopharynx. A full face mask was connected to a ventilator (Servo 900C; Solna, Sweden) set to deliver continuous positive airway pressure (CPAP) of 4 cm H2O, pressure support ventilation of 17 cm H2O, and 1.0 FIo2. The mask was secured to the patient with head straps. NPPV began 10 min before starting FOB and continued for 90 min or more after the procedure was completed. The bronchoscope was passed through a T-adapter and advanced through the nose. BAL was obtained by sequential instillation and aspiration of 5 to 25 mL aliquots of sterile saline solution through a bronchoscope wedged in a radiographically involved subsegment. Oxygen saturation, heart rate, respiratory rate, and arterial blood gases were monitored during the study. RESULTS: NPPV significantly improved PaO2/FIo2 and O2 saturation. FOB with NPPV was well tolerated, and no patient required endotracheal intubation. A causative pathogen was identified by BAL in all patients. Six patients responded to treatment and survived hospital admission. Two patients died 5 to 7 days after FOB from unrelated complications of the underlying illness. CONCLUSIONS: NPPV should be considered during bronchoscopy of immunosuppressed patients with severe hypoxemia.

Noninvasive face mask ventilation in patients with acute respiratory failure.

Noninvasive face mask ventilation has been used successfully in patients with paralytic respiratory failure. This study evaluated whether noninvasive face mask ventilation can be used for patients with acute respiratory failure due to intrinsic lung disease. Six patients with hypercapnia and four with hypoxemic acute respiratory failure met clinical and objective criteria for mechanical ventilation, which was delivered with pressure control and pressure support via a tightly strapped, clear face mask. No patient terminated the study because of inability to deliver adequate ventilation or to improve oxygen exchange; three eventually required endotracheal intubation. The mask was generally well tolerated. All patients had a nasogastric tube placed on suction, and none vomited or aspirated. The mean duration of treatment was 33 h (range, 3 to 88). The physiologic response was considered similar to that which would have been achieved with conventionally delivered ventilation. Noninvasive face mask ventilation may have a role in managing respiratory failure.

Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time.

BACKGROUND: Inflammatory cytokines have been related to the development of adult respiratory distress syndrome (ARDS), shock, and multiple organ dysfunction syndrome (MODS). We tested the hypothesis that unfavorable outcome in patients with ARDS is related to the presence of a persistent inflammatory response. For this purpose, we evaluated the behavior of inflammatory cytokines during progression of ARDS and the relationship of plasma inflammatory cytokines with clinical variables and outcome. METHODS: We prospectively studied 27 consecutive patients with severe medical ARDS. Plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukins (ILs) 1 beta, 2, 4, 6, and 8 were measured (enzyme-linked immunosorbent assay [ELISA] method) on days 1, 2, 3, 5, 7, 10, and 12 of ARDS and every third day thereafter while patients were receiving mechanical ventilation. Subgroups of patients were identified based on outcome, cause of ARDS, presence or absence of sepsis, shock, and MODS at the time ARDS developed. Subgroups were compared for levels of plasma inflammatory cytokines on day 1 of ARDS and over time. RESULTS: Of the 27 patients, 13 survived ICU admission and 14 died (a mortality rate of 52%). Overall mortality was higher in patients with sepsis (86 vs 38%, p < 0.02). The mean initial plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 were significantly higher in nonsurvivors (p < 0.0001) and in those patients with sepsis (p < 0.0001). Plasma levels of IL-1 beta (p < 0.01) and IL-6 (p = 0.03) were more strongly associated with patient outcome than cause of ARDS (p = 0.8), lung injury score (LIS), APACHE II score, sepsis (p = 0.16), shock, or MODS score. Plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 remained significantly elevated over time (p < 0.0001) in those who died. Although it was the best early predictor of death (p < 0.001), plasma IL-2 > 200 pg/mL lost its usefulness after the first 48 h. A plasma IL-1 beta or IL-6 level > 400 pg/mL on any day in the first week of ARDS was associated with a low likelihood of survival. CONCLUSIONS: Our findings indicate that unfavorable outcome in acute lung injury is related to the degree of inflammatory response at the onset and during the course of ARDS. Patients with higher plasma levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 on day 1 of ARDS had persistent elevation of these inflammatory cytokines over time and died. Survivors had lesser elevations of plasma inflammatory cytokines on day 1 of ARDS and a rapid reduction over time. Plasma IL-1 beta and IL-6 levels were consistent and efficient predictors of outcome.

Noninvasive positive pressure ventilation via face mask. First-line intervention in patients with acute hypercapnic and hypoxemic respiratory failure.

OBJECTIVES: We have previously reported our experience with noninvasive positive pressure ventilation (NPPV) via face mask in a small group of selected patients with acute respiratory failure (ARF). NPPV was frequently effective (70% success rate) in correcting gas exchange abnormalities and in avoiding endotracheal intubation (ETI); NPPV also had a low rate of complications. We have evaluated the clinical application of NPPV as first-line intervention in patients with hypercapnic and short-term hypoxemic ARF. A dedicated respiratory therapist conducted an educational program with physicians-in-training rotating through the medical ICUs of a university medical center and supervised implementation of a simplified management protocol. Over 24 months, 164 patients with heterogeneous forms of ARF received NPPV. We report on the effectiveness of NPPV in correcting gas exchange abnormalities, in avoiding ETI, and associated complications, in different conditions precipitating ARF. PATIENT POPULATION: One hundred fifty-eight patients completed the study. Forty-one had hypoxemic ARF, 52 had hypercapnic ARF, 22 had hypercapnic acute respiratory insufficiency (ARI), 17 had other forms of ARF, and 26 with advanced illness had ARF and refused intubation. Twenty-five percent of the patients developed ARF after extubation. INTERVENTION: Mechanical ventilation was delivered via a face mask. Initial ventilatory settings were continuous positive airway pressure (CPAP) mode, 5 cm H2O, with pressure support ventilation of 10 to 20 cm H2O titrated to achieve a respiratory rate less than 25 breaths/min and an exhaled tidal volume of 7 mL/kg or more. Ventilator settings were adjusted following arterial blood gases (ABG) results. RESULTS: The mean duration of NPPV was 25 +/- 24 h. When the 26 patients with advanced illness are excluded, NPPV was effective in improving or correcting gas exchange abnormalities in 105 patients (80%) and avoiding ETI in 86 (65%). Failure to improve ABG values was the reason for ETI in 20 of 46 (43%). The overall average predicted and actual mortality were 32% and 16%, respectively. Survival was 93% in non-intubated patients and 79% in intubated patients. NPPV was effective in lessening dyspnea throughout treatment in all but seven patients. Complications developed in 24 patients (16%). In patients with hypercapnic ARF, nonresponders had a higher PaCO2 at entrance (91.5 +/- 4.2 vs 80 +/- 1.5; p < 0.01). In patients with hypercapnic ARF and ARI, arterial blood gases response (pH and PaCO2) within 2 h of NPPV predicted success (p < 0.0001). None of the entrance parameters predicted need for ETI. CONCLUSIONS: We conclude that application of NPPV in clinical practice is an effective and safe alternative to ETI in many hemodynamically stable patients with hypercapnic ARF and in those with hypoxemic ARF in whom the clinical condition can be readily reversed in 48 to 72 h. An educational and supervision program is essential to successfully implement this form of therapy.

Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome.

BACKGROUND: Inflammatory cytokines (ICs) are important modulators of injury and repair. ICs have been found to be elevated in the BAL of patients with both early and late ARDS. We tested the hypothesis that recurrent injury to the alveolocapillary barrier and amplification of intra-alveolar fibroproliferation observed in nonresolving ARDS is related to a persistent inflammatory response. For this purpose, we obtained serial measurements of BAL IC and correlated these levels with lung injury score (LIS), BAL indexes of endothelial permeability (albumin, total protein [TP]), and outcome. METHODS: We prospectively studied 27 consecutive patients with severe medical ARDS. Using enzyme-linked immunosorbent assay methods, levels of tumor necrosis factor-alpha (TNF-alpha) and interleukins (IL) 1 beta, 2, 4, 6, and 8 were measured at frequent intervals in both plasma and BAL. In 22 patients, bilateral BAL was obtained on day 1 of ARDS and at weekly intervals when possible. Right and left BALs were analyzed separately for IC levels, total cell count and differential, albumin, TP, and quantitative bacterial cultures. RESULTS: On day 1 of ARDS, the 10 nonsurvivors had significantly higher (p = 0.0002) BAL TNF-alpha, IL-1 beta, IL-6, and IL-8 levels, which remained persistently elevated over time, indicating a continuous injury process. In contrast, the 12 survivors had a lesser elevation and a rapid reduction over time. Initial BAL IL-2 and IL-4 levels were significantly higher in patients with sepsis (p = 0.006); both increased over time in survivors and nonsurvivors. BAL levels of TNF-alpha, IL-1 beta, IL-6, and IL-8 correlated with BAL albumin and TP concentrations but not with LIS or ratio of arterial oxygen tension to inspired oxygen concentration. BAL: plasma ratios were elevated for all measured cytokines, suggesting a pulmonary origin. On day 1 of ARDS, nonsurvivors had significantly higher (p = 0.04) BAL: plasma ratios for TNF-alpha, IL-1 beta, IL-6, and IL-8. Over time, BAL:plasma ratios for TNF-alpha, IL-1 beta and IL-6 remained elevated in nonsurvivors and decreased in survivors. CONCLUSIONS: Our findings indicate that an unfavorable outcome in ARDS is associated with an initial, exaggerated, pulmonary inflammatory response that persists unabated over time. Plasma IC levels parallel changes in BAL IC levels. The BAL:plasma ratio results suggest, but do not prove, a pulmonary origin for IC production. BAL TNF-alpha, IL-1 beta, and IL-8 levels correlated with BAL indices of endothelial permeability. In survivors, reduction in BAL IC levels over time was associated with a decline in BAL albumin and TP levels, suggesting effective repair of the endothelial surface. These findings support a causal relationship between degree and duration of lung inflammation and progression of fibroproliferation in ARDS.

Plasma and BAL cytokine response to corticosteroid rescue treatment in late ARDS.

BACKGROUND: In late ARDS, a persistent and exaggerated inflammatory response causes recurrent injury to the alveolocapillary barrier and amplification of intra-alveolar fibroproliferation. When ARDS patients fail to improve, corticosteroid (CS) rescue treatment frequently leads to rapid improvements in lung function. We tested the hypothesis that response to CS treatment is related to suppressing the inflammatory response by comparing changes in lung function to inflammatory cytokine (IC) levels in the plasma and BAL. METHODS: Blood samples were obtained on days 1, 3, 5, and 7 of ARDS, and on days -5, -3, 0 (initiation of treatment), +3, +5, +7, +10, and +14 of CS treatment. Bilateral BAL was obtained on day 1 of ARDS, before administration of CS treatment, and at weekly intervals. We analyzed changes in IC levels during CS treatment in relation to improvements in lung injury score (LIS), indices of endothelial permeability, and final outcome. We also analyzed data to identify timing to a significant reduction in plasma IC levels and predictors of response. RESULTS: Nine patients entered the study. CS treatment was initiated 15 +/- 9 days into ARDS. Improvement in LIS (> 1-point reduction) was rapid (< 7 days) in five, delayed (< 14 days) in two, and absent in two. Baseline plasma and BAL IC levels in study patients were similar to a previously reported comparison group of 12 ARDS nonsurvivors. No significant changes in plasma and BAL IC levels were observed before CS administration. Following initiation of CS treatment, significant reductions in plasma tumor necrosis factor-alpha and interleukin 6 (IL-6) levels were seen by day 7 in both rapid and delayed responders (p = 0.03). IL-1 beta was significantly reduced by day 5 (p = 0.04) in rapid responders and by day 10 (p = 0.03) in delayed responders. In responders, improvement in LIS and BAL albumin paralleled reduction in plasma and BAL IC levels. At initiation of treatment, rapid responders had significantly lower tumor necrosis factor-alpha and IL-6 levels. Nonresponders had a significantly higher plasma IL-6 level on days 1 to 3 of ARDS (p = 0.004) and lower ratio of arteriolar oxygen tension to inspired oxygen concentration at initiation of treatment (p < 0.01). CONCLUSIONS: In patients with late ARDS and a low likelihood of survival, prolonged corticosteroid rescue treatment was associated with a reduction in plasma and BAL IC levels and parallel improvements in indices of endothelial permeability and LIS.

Management of bacterial pneumonia in ventilated patients. Protected bronchoalveolar lavage as a diagnostic tool.

We conducted a prospective study to determine the effectiveness of protected bronchoalveolar lavage (PBAL) in diagnosing pneumonia in ventilated patients and the usefulness of bronchoscopic data in treating ventilated patients. Entrance criteria were (1) fever and a new or progressive infiltrate on chest roentgenogram with either leukocytosis or a macroscopically purulent tracheal aspirate, and (2) no antibiotic therapy for at least 48 h before bronchoscopy. Twenty-five ventilated patients met entrance criteria for the study and completed the protocol. PBAL was effective in retrieving distal airway secretions with a minimal degree of contamination as indicated by a specificity and a negative predictive value of 100 percent. Bacterial isolates grew in all patients with pneumonia at a concentration greater than or equal to 100,000 cfu/ml, with a median growth of 500,000 cfu/ml. The presence of a two-log difference between the highest quantitative culture count in patients without pneumonia and the lowest quantitative culture count in patients with pneumonia allowed a clearer determination of a patient's status, with regard to pneumonia, compared with the significant overlap in unprotected BAL. Gram and Giemsa stains of the PBAL were positive in all patients with pneumonia and negative in those without pneumonia. All but one patient with pneumonia received narrow-spectrum antibiotic therapy. All patients without infection had no antibiotic administered. Clinical and roentgenographic criteria could not discriminate between patients with and without pneumonia, confirming the findings of previous investigations. The results of microscopic and culture analyses of the PBAL effluent proved useful in directing antibiotic treatment in patients with pneumonia and in avoiding unnecessary antibiotic use in those patients without pneumonia.

Noninvasive positive pressure ventilation in status asthmaticus.

OBJECTIVE: In asthmatic patients with acute respiratory failure (ARF), placing an endotracheal tube is associated with a high rate of complications and results in increased airway resistance. In acute asthma, mask-continuous positive airway pressure (CPAP) decreases airway resistance and the work of breathing (WOB), but does not improve gas exchange. In COPD with ARF, adding intermittent positive pressure ventilation to mask-CPAP results in an additional improvement in WOB and is highly effective in correcting gas exchange abnormalities. In our medical ICU, noninvasive positive pressure ventilation (NPPV) is used as first-line interventional therapy in eligible patients with hypercapnic ARF. We report our experience with NPPV in 17 episodes of asthma and ARF over a 3-year period. METHODS: A face mask was secured with head straps, avoiding a tight fit, and connected to a ventilator (PB-7200). Initial ventilatory settings included CPAP at 4 +/- 2 cm H2O to offset intrinsic positive end-expiratory pressure and pressure support ventilation (PSV) at 14 +/- 5 cm H2O aiming at a respiratory rate less than 25 breaths/min and an exhaled tidal volume of 7 mL/kg or more. PSV was then adjusted following arterial blood gas results. RESULTS: Mean age was 35.4 +/- 11.3 years; 10 patients were female. The mean (+/- SE) for different physiologic values are reported at initiation, less than 2 h, 2 to 6 h, and 12 to 24 h into NPPV. pH was 7.25 +/- 0.01, 7.32 +/- 0.02 (p = 0.0012), 7.36 +/- 0.02 (p < 0.0001), and 7.38 +/- 0.02; PaCO2 was 65 +/- 2, 52 +/- 3(p = 0.002), 45 +/- 3(p < 0.0001), and 45 +/- 4; PaO2 fraction of inspired oxygen was 315 +/- 41, 403 +/- 47, 367 +/- 47, and 472 +/- 67 (p = 0.06); and respiratory rate was: 29.1 +/- 1, 22 +/- 1 (p < 0.0001), 20 +/- 1, and 17 +/- 1. NPPV was well tolerated, and only two patients required sedation. Initial delivered minute ventilation was 16 +/- 4 L/min. The mean (+/- SD) peak inspiratory pressure to ventilate in the NPPV-treated patients was 18 +/- 5 cm H2O and always less than 25 cm H2O. There was no complication or problem with expectorating of secretions. Oral intake (liquid diet) was preserved. Two patients required intubation (35 min and 89 h into NPPV) for worsening PaCO2. Duration of NPPV was 16 +/- 21 h. All patients survived. Length of hospital stay was 5 +/- 4 days. CONCLUSIONS: In asthmatic patients with ARF, NPPV via a face mask appears highly effective in correcting gas exchange abnormalities using a low inspiratory pressure (< 25 cm H2O). A randomized study is in progress to assess fully the role of NPPV in status asthmaticus.

Bilateral bronchoalveolar lavage in the diagnosis of opportunistic pulmonary infections.

To further improve the diagnostic value of bronchoscopy in the immunosuppressed population presenting with diffuse pulmonary infiltrates, we prospectively investigated the utility of bilateral bronchoalveolar lavage (BAL). We performed 62 bronchoscopies on 52 immunosuppressed patients. Of the 52 patients, 33 had pulmonary infections. The yield for Pneumocystis carinii pneumonia on bilateral BAL was 94 percent (31/33), compared to the 84 percent (51/61) previously obtained with unilateral BAL in our institution. The recovery of P carinii was unilateral in four of five patients without AIDS and in four of 26 patients with AIDS. Transbronchial biopsy gave a yield of 85 percent (11/13). In ten patients with definitive cytomegalovirus (CMV) pneumonia, recovery of CMV by combined culture and cytology was 100 percent. Of nine bronchoscopies with positive cytology for CMV, five showed cytopathologic changes in the BAL from both sides and four in the BAL from one side only. No complications were seen in the 14 patients with thrombocytopenia or the five patients receiving mechanical ventilation. Our findings indicate that bilateral BAL significantly increases the yield for recovery of P carinii (p less than 0.02) and CMV (p less than 0.001) in immunosuppressed patients.

Causes of fever and pulmonary densities in patients with clinical manifestations of ventilator-associated pneumonia.

BACKGROUND: Ventilator-associated pneumonia, a leading cause of sepsis in patients with acute respiratory failure, is difficult to distinguish clinically from other processes affecting patients receiving mechanical ventilation. We conducted a prospective study of patients with suspected ventilator-associated pneumonia to identify the causes of fever and densities on chest radiographs and to evaluate the diagnostic yield and efficiency of tests used alone and in combination. METHODS: The 50 patients entered into the study underwent a systematic diagnostic protocol designed to identify all potential causes of fever and pulmonary densities. Diagnoses responsible for fever were established by strict diagnostic criteria for 45 of the 50 patients. The prevalence of specific conditions and diagnostic yield of individual tests were used to formulate a simplified diagnostic protocol. RESULTS: The diagnostic protocol identified 78 causes of fever (median 2 per patient). Infections were the leading causes of fever and pulmonary densities. Of the 45 patients with fever, 37 had one or more infections identified (67 sources). Most infections (84 percent) were one of four types:pneumonia, sinusitis, catheter-related infection, or urinary tract infection. Ventilator-associated pneumonia occurred in only 42 percent. All but nine infections (87 percent) were directly or indirectly related to insertion of a catheter or a tube. Concomitant infections were frequent (62 percent), particularly in patients with sinusitis (100 percent), catheter-related infections (93 percent), and pneumonia (74 percent). Of concomitant infections, 60 percent were caused by a different pathogen. Noninfectious causes of fever were more common in the 22 patients with adult respiratory distress syndrome. Histologically proved pulmonary fibroproliferation was the only cause of fever in 25 percent of patients with adult respiratory distress syndrome. Radiographic densities were caused by an infection in only 20 patients (19 pneumonia, 1 empyema). In more than 50 percent of the 25 patients without adult respiratory distress syndrome, congestive heart failure, and atelectasis were the sole causes of pulmonary densities, and fever always originated from an extrapulmonary site of infection. Used in combination, bronchoscopy with protected sampling, computed tomographic scan of the sinuses, and cultures of maxillary sinus aspirate, central intravenous or arterial lines, urine, and blood identified 58 of the 78 sources of fever (74 percent). CONCLUSIONS: The observations in this study document the complex nature of acute respiratory failure and fever and underscore the need for accuracy in diagnosis. The frequent occurrence of multiple infectious and noninfectious processes justifies a systematic search for source of fever, using a comprehensive diagnostic protocol. A simplified diagnostic protocol was devised based on the diagnostic value of individual tests.

Fibroproliferative phase of ARDS. Clinical findings and effects of corticosteroids.

Most patients with adult respiratory distress syndrome (ARDS) survive the initial insult which caused respiratory failure only to succumb later to sepsis caused by nosocomial pneumonia or to pulmonary fibrosis. Clinical criteria and analysis of the tracheal aspirate are notoriously inadequate for establishing a diagnosis of ventilator-associated pneumonia. We implemented a comprehensive diagnostic protocol to determine the cause of sepsis in ARDS patients who had been ventilated for more than three days and who had no bronchoscopic evidence of pneumonia. Nine patients with late ARDS who had fever (89 percent), leukocytosis (89 percent), a new localized infiltrate (78 percent), purulent tracheal secretions (89 percent), low systemic vascular resistance (50 percent), and marked uptake of gallium in the lungs (100 percent) had no source of infection identified. Open-lung biopsy specimens from seven patients showed the fibroproliferative phase of diffuse alveolar damage and confirmed absence of pneumonia. Treatment with prolonged high doses of corticosteroids was associated with a marked and rapid improvement in lung injury score (p less than 0.003 at five days). Our findings indicate that the fibroproliferative process occurring in the lungs of patients with late ARDS gives rise to clinical manifestations identical to those of pneumonia and is potentially responsive to steroid treatment.

Noninvasive face mask mechanical ventilation in patients with acute hypercapnic respiratory failure.

Mechanically assisted intermittent positive-pressure ventilation effectively provides ventilatory support in patients with respiratory failure but it requires placing an artificial airway. We have previously reported our successful experience delivering mechanical ventilation via a face mask (FMMV) rather than with an endotracheal tube in a pilot study of patients with acute respiratory failure. The present investigation evaluated an additional 18 patients with hypercapnic respiratory failure to determine the efficacy of FMMV in a more homogeneous group and to determine factors predicting its success. FMMV was successful in avoiding intubation in 13 of the 18 patients. A significant initial improvement in PCO2 (greater than 16 percent decrease) and in pH (from less than 7.30 to greater than 7.30) predicted success. The five patients who failed on FMMV required endotracheal intubation because of inability to improve gas exchange (three patients), apnea due to sedatives (one patient), and management of secretions (one patient). FMMV was generally well accepted with only two patients withdrawn because of intolerance of the mask. The mean duration of FMMV was 25 h. Complications were seen in only two patients (11 percent): aspiration (one patient) and mild skin necrosis (one patient). Seven patients entered the study by meeting entrance criteria after an unsuccessful extubation attempt and therefore received both forms of mechanical ventilation. All but one patient avoided reintubation, and the face mask proved to be as effective as the endotracheal tube as a conduit for delivering the mechanical tidal volume and improving gas exchange. Our findings indicate that FMMV is a viable option for short-term (one to four days) ventilatory support of patients with hypercapnic respiratory failure and insufficiency.

Corticosteroid rescue treatment of progressive fibroproliferation in late ARDS. Patterns of response and predictors of outcome.

Pulmonary fibroproliferation (PFP) is directly or indirectly the leading cause of death in patients with late ARDS. We previously reported our experience using intravenous corticosteroids (IVC) in 8 patients with late ARDS and now have expanded our observation to a total of 25 patients with severe fibroproliferation (mean lung injury score [LIS] 3) and progressive respiratory failure (RF). Thirteen patients had open-lung biopsy before treatment. Patients were started on IVC treatment (IVCT) an average of 15 +/- 7.5 days into mechanical ventilation (MV). Significant physiologic improvement (SPI) to IVCT was defined as a reduction in LIS of greater than 1 point or an increase in PaO2:FIO2 ratio of greater than 100. We observed three patterns of response: rapid responders (RR) had an SPI by day 7 (n = 15); delayed responders (DR) had an SPI by day 14 (n = 6); nonresponders (NR) were without SPI by day 14 (n = 4). Overall the following significant mean changes were seen within 7 days of IVCT: LIS from 3 to 2 (p = 0.001), PaO2:FIO2 from 162 to 234 (p = 0.0004), PEEP from 11 to 6.8 cm H2O (p = 0.001), chest radiograph score from 3.8 to 3.0 (p = 0.009), and VE from 16 to 13.6 L/min (p = 0.01). Development of pneumonia was related to the pattern of response. Surveillance bronchoscopy was effective in identifying pneumonia in eight afebrile patients. Nineteen of 25 (76 percent) patients survived the ICU admission. Comparisons were made between survivors (S) and nonsurvivors (NS) and among the three groups of responders. At the time ARDS developed, no physiologic or demographic variable could discriminate between S and NS. At the time of IVCT, only liver failure was more frequent in nonsurvivors (p = 0.035). Histologic findings at open-lung biopsy and pattern of physiologic response clearly predicted outcome. The presence of preserved alveolar architecture (p = 0.045), myxoid type fibrosis (p = 0.045), coexistent intraluminal bronchiolar fibrosis (p = 0.0045), and lack of arteriolar subintimal fibroproliferation (p = 0.045) separated S from NS. ICU survival rate was 86 percent in responders and 25 percent in nonresponders (p = 0.03). Only one death resulted from refractory respiratory failure.

The pathogenesis of ventilator-associated pneumonia: I. Mechanisms of bacterial transcolonization and airway inoculation.

Ventilator-associated pneumonia (VAP) is an infection of the lung parenchyma developing in patients on mechanical ventilation for more than 48 h. VAP is associated with a remarkably constant spectrum of pathogenic bacteria, most of which are aerobic Gram-negative bacilli (AGNB) and, to a lesser extent Staphyloccus aureus. Most authorities agree that VAP develops as a result of aspiration of secretions contaminated with pathogenic organisms, which appear to be endogenously acquired. These pathogens gain access to the distal airways by mechanical reflux and aspiration of contaminated gastric contents and also by repetitive inoculation of contaminated upper airway secretions into the distal tracheobronchial tree. Persistence of these organisms in the upper airways involves their successful colonization of available surfaces. Although exogenous acquisition can occur from the environment, the rapidity at which critically ill patients acquire AGNB in the upper airways in conjunction with the low rate of AGNB colonization of health-care workers exposed to the same environment favors the presence of endogenous proximate sources of AGNB and altered upper airway surfaces that are rendered receptive. Proximate sources of AGNB remain unclear, but potential sites harboring AGNB prior to illness include the upper gastrointestinal tract, subgingival dental plaque, and the periodontal spaces. Following illness or antibiotic therapy, competitive pressures within the oropharynx favor AGNB adherence to epithelial cells, which lead to oropharyngeal colonization. Similar dynamic changes in contiguous structures (oropharynx, trachea, sinuses, and the upper gastrointestinal tract) lead to the transcolonization of these structures with pathogenic bacteria. Following local colonization or infection, these structures serve as reservoirs of AGNB capable of inoculating the lower airways. As the oropharynx becomes colonized with AGNB, contaminated oropharyngeal secretions reach the trachea, endotracheal tube, and ventilator circuit. Contaminated secretions pooled above the endotracheal tube cuff gain access to the trachea and inner lumen of the endotracheal tube by traversing endotracheal tube cuff folds. Amorphic particulate deposits containing AGNB form along the endotracheal tube and are capable of being propelled into the distal airways by ventilator-generated airflow or by tubing manipulation. Bacteria embedded within this type of amorphous matrix are particularly difficult for the host to clear. If host defenses fail to clear the inoculum, then bacterial proliferation occurs, and the host inflammatory response progresses to bronchopneumonia.(ABSTRACT TRUNCATED AT 400 WORDS)

The role of gallium-67 scintigraphy in diagnosing sources of fever in ventilated patients.

OBJECTIVE: To evaluate the diagnostic value of gallium-67 scintigraphy in febrile ventilated patients by correlating the findings of 67Ga scintigraphy to sources of fever and pulmonary density, as determined by a comprehensive protocolized diagnostic evaluation. DESIGN: Prospective observational study. PATIENTS: Thirty-two intubated patients on mechanical ventilation for > or = 3 days with fever (> or = 38.3 degrees C) and a new or progressive density on chest radiograph. Twenty patients (21 tests) had adult respiratory distress syndrome (ARDS). INTERVENTION: Diagnostic evaluation for fever included bronchoscopy with protected specimen brushing and (protected) bronchoalveolar lavage (BAL); computed tomography (CT) of sinuses; cultures of blood, urine, and central lines; and CT of the abdomen in high-risk patients. MEASUREMENTS AND RESULTS: Uptake of 67Ga was reported as either focal or diffuse pulmonary uptake and extrapulmonary uptake. The combined causes of fever were pneumonia (9), fibroproliferation of late ARDS (7), abdominal process (4), sinusitis (4), urinary tract infection (3), and others (6). Causes of the pulmonary densities were pneumonia (9), ARDS (13), atelectasis (7), congestive heart failure (3), and empyema (1). Marked and diffuse pulmonary uptake was found only in patients with ARDS; however, it was not useful in discriminating those patients with pulmonary fibroproliferation as the sole cause of fever (p = 0.167) from those with infection. 67Ga scintigraphy was inadequate for detecting pneumonia but valuable in identifying extrapulmonary sites of infection in patients with ARDS (p = 0.021). CONCLUSIONS: 67Ga scintigraphy should be considered only as an adjunct diagnostic test in the febrile, ventilated patient who has no obvious source of fever, despite a negative evaluation that includes testing for pneumonia, sinusitis, and urinary tract infection, conditions that are rarely detected by 67Ga scintigraphy.

Noninvasive vs. conventional mechanical ventilation in patients with chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial.

OBJECTIVE: We conducted a randomized prospective study comparing noninvasive positive pressure ventilation (NPPV) with conventional mechanical ventilation via endotracheal intubation (ETI) in a group of patients with chronic obstructive pulmonary disease who failed standard medical treatment in the emergency ward after initial improvement and met predetermined criteria for ventilatory support. DESIGN AND SETTING: Prospective randomized study in a university hospital 13-bed general ICU. PATIENTS: Forty-nine patients were randomly assigned to receive NPPV (n=23) or conventional ventilation (n=26). RESULTS: both NPPV and conventional ventilation significantly improved gas exchanges. The two groups had similar length of ICU stay, number of days on mechanical ventilation, overall complications, ICU mortality, and hospital mortality. In the NPPV group 11 (48%) patients avoided intubation, survived, and had a shorter duration of ICU stay than intubated patients. One year following hospital discharge the NPPV group had fewer patients readmitted to the hospital (65% vs. 100%) or requiring de novo permanent oxygen supplementation (0% vs. 36%). CONCLUSIONS: The use of NPPV in patients with chronic obstructive pulmonary disease and acute respiratory failure requiring ventilatory support after failure of medical treatment avoided ETI in 48% of the patients, had the same ICU mortality as conventional treatment and, at 1-year follow-up was associated with fewer patients readmitted to the hospital or requiring for long-term oxygen supplementation. An editorial regarding this article can be found in the same issue (http://dx.doi.org/10.1007/s00134-002-1503-3).

Predictors of failure of noninvasive positive pressure ventilation in patients with acute hypoxemic respiratory failure: a multi-center study.

CONTEXT: In patients with hypoxemic acute respiratory failure (ARF), randomized studies have shown noninvasive positive pressure ventilation (NPPV) to be associated with lower rates of endotracheal intubation. In these patients, predictors of NPPV failure are not well characterized. OBJECTIVE: To investigate variables predictive of NPPV failure in patients with hypoxemic ARF. DESIGN: Prospective, multicenter cohort study. SETTING: Eight Intensive Care Units (ICU) in Europe and USA. PATIENTS: Of 5,847 patients admitted between October 1996 and December 1998, 2,770 met criteria for hypoxemic ARF. Of these, 2,416 were already intubated and 354 were eligible for the study. RESULTS: NPPV failed in 30% (108/354) of patients. The highest intubation rate was observed in patients with ARDS (51%) or community-acquired pneumonia (50%). The lowest intubation rate was observed in patients with cardiogenic pulmonary edema (10%) and pulmonary contusion (18%). Multivariate analysis identified age > 40 years (OR 1.72, 95% CI 0.92-3.23), a simplified acute physiologic score (SAPS II) > or = 35 (OR 1.81, 95% CI 1.07-3.06), the presence of ARDS or community-acquired pneumonia (OR 3.75, 95% CI 2.25-6.24), and a PaO2:FiO2 < or = 146 after 1 h of NPPV (OR 2.51, 95% CI 1.45-4.35) as factors independently associated with failure of NPPV. Patients requiring intubation had a longer duration of ICU stay ( P < 0.001), higher rates of ventilator-associated pneumonia and septic complications ( P < 0.001), and a higher ICU mortality ( P < 0.001). CONCLUSIONS: In hypoxemic ARF, NPPV can be successful in selected populations. When patients have a higher severity score, an older age, ARDS or pneumonia, or fail to improve after 1 h of treatment, the risk of failure is higher.