Intensive care unit drug use and subsequent quality of life in acute lung injury patients.

OBJECTIVE: To examine the relationship between the use of sedative and neuromuscular blocking agents during a patient's intensive care unit (ICU) stay and subsequent measures of health-related quality of life. DESIGN: Cross-sectional mail survey and retrospective medical record abstraction of a prospectively identified cohort of lung injury patients. SETTING: ICUs in three teaching hospitals in a major metropolitan area. PATIENTS: Patients with acute lung injury (n = 24). INTERVENTIONS: None--observational study. MEASUREMENTS AND MAIN RESULTS: Patients' charts were reviewed for those patients returning postdischarge quality-of-life questionnaires. Duration, daily dose, and route of administration for sedatives and neuromuscular blocking agents were abstracted from ICU flow sheets. Relationships among ICU variables (days of sedation, days of neuromuscular blockade, and severity of illness as measured by Acute Physiology and Chronic Health Evaluation III score) and outcomes (symptoms of depression and symptoms of posttraumatic stress disorder) were assessed. Depressive symptoms at follow-up were correlated with days of sedation (p = .007), but not with days of neuromuscular blockade or initial severity of illness. The composite posttraumatic stress disorder symptom impact score was correlated with days of sedation (p = .006) and days of neuromuscular blockade (p = .035), but not with initial severity of illness. There were no significant differences between the frequency of patients reporting a specific posttraumatic stress disorder symptom in the high sedation group and the low sedation group, and there were no significant differences in specific posttraumatic stress disorder symptoms between the group that had received neuromuscular blockade and those who had not. CONCLUSIONS: The use of sedatives and neuromuscular blocking agents in the ICU is positively associated with subsequent measures of depression and posttraumatic stress disorder symptoms 6-41 months after ICU treatment for acute lung injury.

Right heart catheterization in acute lung injury: an observational study.

Right heart catheterization (RHC) is commonly used in the diagnosis and management of acute lung injury (ALI). However, controversy exists regarding RHC. We examined RHC use during the first 3 d of ALI in an observational study of 135 patients defined by American-European Consensus Conference criteria. Study parameters examined for association with RHC included the Acute Physiology and Chronic Health Evaluation (APACHE) III score, lung injury score (LIS), and 20 additional epidemiologic, clinical, and laboratory parameters. RHC was performed in 70 patients (52%) within the first 3 d of ALI. RHC was positively associated (p < 0.05) with a diagnosis of sepsis, APACHE III score, blood urea nitrogen (BUN), creatinine, net fluid balance, and positive end-expiratory pressure. RHC was negatively associated (p < 0.05) with mean arterial pressure (Pa) and PaO2/FIO2. Logistic regression identified four predictors for RHC placement: sepsis, PaO2/FIO2, BUN, and Pa. Initial right atrial and pulmonary artery occlusion pressure measurements demonstrated a moderately strong correlation (r = 0.72). Use of RHC was associated with a change in one or more therapeutic interventions (intravascular fluids, vasopressors, diuretics) in 78% of patients. In summary, patients receiving RHC during the first 3 d of ALI were more severely ill than those who did not receive RHC, and RHC was associated with a change in therapy in most patients.

Health-related quality of life after acute lung injury.

Our study objective was to assess health-related quality of life in survivors of acute lung injury (ALI) and to supplement generic and disease-specific questionnaires with findings from a focus group of ALI survivors. Six patients participated in the focus group, which revealed patient concerns with amnesia, depressed mood, avoidance behaviors, and a prolonged recovery period. Using a cross-sectional study design, 24 patients completed a questionnaire 6 to 41 mo after their lung injury. A total of 43% of the patients with ALI met criteria for depression; 43% had self-reported significant functional limitations, although 39% had minimal or no limitations. Significant respiratory and psychologic symptoms were reported in a quarter to a third of patients. There were large decrements in all domains of the SF-36 (a generic health-related quality-of-life instrument) in our sample compared with norms previously established for the general population. In addition, our patients had similar physical difficulties compared with previously studied patients with chronic medical illnesses but had more deficits in the social functioning and mental health domains. We conclude that long after lung injury, survivors have significantly lower health-related quality of life than the general population and are likely to have pulmonary and psychologic symptoms.

Diagnosis and management of acute lung injury.

Severe acute lung injury, also known as the adult respiratory distress syndrome (ARDS), is a dynamic and explosive clinical syndrome which exacts a mortality of approximately 50%. The criteria for the diagnosis of severe acute lung injury include five principal elements: hypoxemia despite high concentrations of supplemental oxygen, diffuse pulmonary infiltrates on chest radiographs, decreased lung compliance, appropriate antecedent history, and the absence of congestive heart failure. Identifying an appropriate antecedent history requires consideration of a diverse group of etiologies which may injure alveolar structures via either the air-lung or blood-lung interface. The management of patients with acute lung injury should be approached with four principal goals: (1) cardiopulmonary resuscitation and stabilization; (2) rapid identification and elimination of the cause of lung injury; (3) achieving adequate tissue oxygen delivery and support of other end-organs; and (4) prevention, recognition, and aggressive treatment of any complications that develop during the course of therapy. Recent observations have suggested that conventional methods of positive-pressure ventilation may indirectly injure alveolar tissue, thereby perpetuating lung injury. Furthermore, the optimal use of fluid and hemodynamic support remains controversial. Thus, controlled clinical trials are necessary to develop oxygenation, ventilatory, and hemodynamic support strategies which optimize recovery and minimize further injury and to define the role of newer pharmacologic agents in the prevention and treatment of acute lung injury.

Pathogenesis of pulmonary fibrosis: platelet-derived growth factor precedes structural alterations in the Hermansky-Pudlak syndrome.

Peptides that modulate mesenchymal cell function have been detected in the fibrotic lung disorders once physiologic dysfunction is present. Despite this close association with manifest disease, their role in initiating alveolar remodeling remains unknown. We examined the hypothesis that one potent peptide, platelet-derived growth factor (PDGF), would be present at the alveolar surface before the onset of physiologic dysfunction in patients in whom pulmonary fibrosis subsequently develops. Bronchoalveolar lavage and physiologic assessment were performed in asymptomatic patients with the Hermansky-Pudlak syndrome (n = 30), obligate heterozygous (n = 9), and normal volunteers (control group). Lavage cell number and profile were normal, but alveolar macrophages demonstrated characteristic autofluorescence and ultrastructural features of ceroid. Lavage fluid from physiologically normal patients with Hermansky-Pudlak syndrome and from those with occult restrictive disease demonstrated two PDGF-related peptides (14 kd and 38 kd). Radioligand binding and fibroblast proliferation assay demonstrated that the peptides were functional. By immunoassay the concentration of PDGF in lavage fluid was six times greater than control values (p < 0.01). In situ hybridization together with bioassay indicated that alveolar macrophages were one cellular source of PDGF. Similar results were obtained for heterozygotes. These data identify macrophage-derived PDGF peptides as important candidate molecules in the initiation of alveolar remodeling in the fibrotic lung disorders.

Obliterative bronchiolitis after lung transplantation: a fibroproliferative disorder associated with platelet-derived growth factor.

Fibroproliferative disorders are characterized by accumulations of mesenchymal cells and connective tissue in critical locations, leading to organ dysfunction. We examined the role of platelet-derived growth factor (PDGF) in the pathogenesis of obliterative bronchiolitis, a fibroproliferative process that occurs after lung transplantation and results in small airway occlusion. Bronchoalveolar lavage fluid from obliterative bronchiolitis patients significantly stimulated fibroblast migration, whereas fluid from patient controls did not. Quantitation by radioligand binding assay demonstrated increased concentrations of PDGF in lavage fluid from obliterative bronchiolitis patients (patients, 104 +/- 26.9 pM; controls, 8.4 +/- 6.9 pM; P < 0.01). Heparin affinity, gel filtration, and Western blot analysis confirmed the presence of PDGF in lavage fluid. Immunohistochemical and in situ hybridization studies of histologic sections and bronchoalveolar lavage cells suggest that alveolar macrophages are one cellular source. Prospective evaluation of sequential bronchoalveolar lavage samples from a patient who developed obliterative bronchiolitis demonstrated markedly increased PDGF concentrations before the onset of irreversible airflow obstruction. These findings are consistent with a role for PDGF in the fibroproliferative changes observed in obliterative bronchiolitis.

Single lung transplantation for severe emphysema.

UNLABELLED: Lung transplantation is effective therapy for patients with severe obstructive lung disease. We reviewed seven patients with severe emphysema (age, 48 +/- 5 years; forced expiratory volume in 1 second [FEV1] 0.76 +/- 0.26 liters) who received single-lung transplants (SLT) at our institution between August 1989 and September 1990. Studies to assess the adequacy of cardiac function before transplantation showed moderately reduced right ventricular function (by multiple gated acquisition, 34 +/- 6%), moderately elevated pulmonary artery pressure (25 +/- 3 mm Hg), and normal left ventricular function (by multiple gated acquisition 65% +/- 12%) and coronary arteriograms. Time on the waiting list before transplantation was reduced compared with heart-lung transplant (HLT) recipients (waiting time, 2.9 +/- 1.5 months for SLT, 9.6 +/- 10.2 months for HLT). Six of the SLT recipients are currently alive (after transplantation interval, 17 +/- 5 months); the remaining recipient died of pulmonary embolism 21 days after SLT. Number of ventilator days, intensive care unit days, and days to hospital discharge after transplantation did not differ significantly from HLT recipients. Cardiopulmonary bypass was necessary in four SLT recipients. Pulmonary function was markedly improved after SLT (FEV1, 1.78 +/- 0.73 L/min after SLT versus 0.75 +/- 0.3 L/min before SLT; p less than 0.01), and functional status is correspondingly improved. CONCLUSIONS: SLT constitutes effective therapy for patients with severe emphysema, including those with moderate reduction of right ventricular function; and SLT offers distinct advantages over HLT, including decreased waiting time before transplantation, improved donor organ utilization, and less frequent need for cardiopulmonary bypass.

Acute lung injury. Pathogenesis of intraalveolar fibrosis.

In patients dying with acute lung injury, interstitial mesenchymal cells migrate into the airspace where they replicate and deposit connective tissue. We therefore hypothesized that peptides capable of promoting mesenchymal cell migration and replication would be present in the alveolar airspace. To examine this hypothesis, patients with severe acute diffuse lung injury (n = 26) underwent bronchoalveolar lavage. Acutely ill patients without lung injury served as controls (n = 12). Recovered effluent was examined for mesenchymal cell growth-promoting and migration-promoting activity. Lavage cell supernates from both patients and controls were devoid of bioactivity. However, substantial growth-promoting and migration-promoting activity was present in lavage fluid from nearly every patient, whereas little or none was present in fluid from controls. Characterization of the bioactivity indicated a significant proportion consisted of three peptides related to PDGF: (a) a 14-kD peptide that shared with PDGF several biophysical, biochemical, receptor-binding, and antigenic properties; (b) a 29-kD peptide that appeared identical to PDGF of platelet origin; and (c) a 38-kD peptide that was biophysically and antigenically similar to PDGF. These data indicate that peptide moieties are present in the airspace of patients after acute lung injury that can signal mesenchymal cell migration and replication.

Mechanisms of alveolar fibrosis after acute lung injury.

In patients who die after severe acute lung injury, a dramatic fibroproliferative response occurs within the alveolar air space, interstitium, and microvessels. Profound shunt physiology, dead space ventilation, and pulmonary hypertension are the physiologic consequences of this fibroproliferative response. The anatomic pattern of the response is unique within each alveolar compartment. For example, the air space is obliterated by granulation tissue, with replicating mesenchymal cells, their connective tissue products, and an expanding network of intra-alveolar capillaries. In contrast, the vascular fibroproliferative response is dominated by mesenchymal cell replication and connective tissue deposition within the walls of microvessels. Despite the unique anatomic features of these fibroproliferative processes, the regulatory signals involved are likely to be similar. Although our current understanding of the signals regulating the fibroproliferative response to acute lung injury is limited, inferences can be made from in vitro studies of mesenchymal cell behavior and several better understood fibroproliferative processes, including wound healing and chronic fibrotic lung diseases. As clinicians, our future ability to enhance effective lung repair will likely utilize therapeutic strategies specifically targeted to the signals that regulate the fibroproliferative process within the alveolar microenvironment.

Granulomatous diseases of the lung that mimic respiratory infections.

Granulomatous diseases of the lung may have clinical, roentgenographic, and pathological features that closely mimic respiratory tract infections. The protean manifestations of sarcoidosis allow confusion with a wide variety of infectious diseases. Acute hypersensitivity pneumonitis closely mimics an infectious illness; even subacute or chronic presentations may be mistaken for infections. Less commonly, the manifestations of intravenous talc granulomatous disease may also mimic infection.