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Biomedical subjects

P M Dorinsky

Publications and source records attributed to P M Dorinsky.

33 records · Page 2Linked to original sources
PubMed1991

Increased intestinal protein permeability in a model of lung injury induced by phorbol myristate acetate.

Multiple nonpulmonary organ failure is a frequent complication of the adult respiratory distress syndrome (ARDS), and contributes significantly to the high mortality rate associated with this disorder. Although previous studies suggest that systemic organ injury may be an integral component of ARDS, little is known about the specific functional alterations that occur in these target organs. The present study was designed, therefore, to test the hypothesis that endothelial damage, as assessed by microvascular permeability changes, develops in systemic organs in a model of acute lung injury. To test this postulate, the microvascular permeability for total protein was estimated using the steady-state relationship between the lymph (CL) to plasma (Cp) protein concentration ratio (i.e., CL/Cp) and lymph flow in autoperfused cat ileum preparations. Specifically, CL/Cp was measured in five cats, 2 h after acute lung injury was induced by intravenously administered phorbol myristate acetate (PMA), 15 micrograms/kg, and the results were compared with those of seven time-matched control animals. Prior to PMA infusion, the PaO2/FIO2 ratio was 451 +/- 28 in both groups and remained unchanged (486 +/- 26) in the control group. By contrast, the PaO2/FIO2 ratio fell to 275 +/- 95 after PMA infusion (p less than 0.05). In addition, whereas CL/Cp was 0.099 +/- 0.008 in the control animals, it increased to 0.36 +/- 0.06 in the PMA-injured animals (p less than 0.01). In summary, this study demonstrated that in this model of acute lung injury produced by PMA-induced activation of circulating inflammatory cells, both acute lung injury and systemic organ injury (i.e., morphologic and permeability alterations) occurred.

Acute Disease↗
PubMed1990

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↗
PubMed1990

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.

Bacterial Infections↗
PubMed1989

Neutrophil accumulation and structural changes in nonpulmonary organs after acute lung injury induced by phorbol myristate acetate.

Multiple nonpulmonary organ failure contributes significantly to the high mortality rate associated with the adult respiratory distress syndrome (ARDS). However, little is known about specific structural and/or functional alterations that occur in nonpulmonary organs in this syndrome. Therefore, the present study was designed to test the hypothesis that inflammatory cell infiltration and structural changes occur both in the lungs and in nonpulmonary organs in ARDS. To test this hypothesis, neutrophil accumulation and structural alterations were evaluated in nonpulmonary organs from dogs with acute lung injury produced by intravenous phorbol myristate acetate (PMA) (30 micrograms/kg; n = 5). As expected, morphologic changes were present in the lungs of the PMA-treated animals and included a diffuse neutrophilic pneumonitis with interstitial, vascular, and alveolar components. PMA-treated dogs had significant increases in neutrophils (expressed as PMN/mm2 tissue section area) compared with those in control animals in the following organs: heart, 14 +/- 3 versus 4 +/- 1; brain, 2.5 +/- 0.3 versus 0.7 +/- 0.3; duodenum, 34 +/- 7 versus 10 +/- 2; liver, 397 +/- 16 versus 103 +/- 12 (p less than 0.025, all comparisons). In addition, severe necrosis and inflammation of vessels, sinusoidal thrombosis, and hepatic necrosis were noted in the liver. Like the changes noted in the lung, hepatic lesions appeared to be vascular in origin and were consistent with lesions produced by the intravascular activation of neutrophils. No microscopic lesions were detected in the brain, kidney, duodenum, and heart. Taken together, the finding of concurrent lung injury, liver injury, and nonpulmonary organ neutrophil accumulation suggests the possibility of a common pathway of injury in this model of ARDS.

Animals↗
PubMed1989

Bronchiolitis in adults. A reversible cause of airway obstruction associated with airway neutrophils and neutrophil products.

In the past 4 yr, 16 adult patients were identified who had accelerated onset of a severe respiratory disorder (usually obstructive in nature) that was clinically distinct from the more commonly encountered chronic obstructive disorders (e.g., chronic bronchitis, emphysema, asthma, bronchiectasis, cystic fibrosis, and alpha 1-antitrypsin deficiency). These patients, termed patients with "bronchiolitis," underwent pulmonary function testing, bronchoscopy with bronchoalveolar lavage (BAL), and open lung biopsy. Although lung biopsy findings varied somewhat among the patients, each biopsy contained a prominent component of bronchiolitis. Pulmonary function testing and BAL were also repeated after 3 months of treatment with oral prednisone (1 mg/kg/day). Initial BAL neutrophil percentages were significantly higher in the bronchiolitis group (54 +/- 10%) than in smokers with chronic bronchitis (3.9 +/- 1.0%) or in normal nonsmoking volunteers (0.8 +/- 0.5%) (p less than 0.01, both comparisons). Eleven of 15 patients with bronchiolitis had significant improvement (greater than or equal to 15% increase in FEV1) in their lung function after prednisone treatment. Furthermore, this "responder" subgroup had a significant reduction in BAL neutrophil percentages after treatment with prednisone (46 +/- 15% to 6 +/- 3%, p less than 0.05). Finally, the neutrophil products collagenase and myeloperoxidase were detected in the BAL fluid of patients with bronchiolitis. These findings suggest a central role for the neutrophil in the pathogenesis of bronchiolitis and emphasize the utility of BAL in the identification of these patients.

Adolescent↗
PubMed1989

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.

Acute Disease↗
PubMed1988

Oxygen distribution and utilization after phorbol myristate acetate-induced lung injury.

There is considerable evidence suggesting that substrate (e.g., oxygen) distribution and utilization are abnormal in the setting of acute respiratory failure from the adult respiratory distress syndrome (ARDS). The mechanisms that may explain this anomalous relationship include: redistribution of cardiac output resulting in the nonuniform delivery of substrate to regional vascular beds; increases in flow through anatomic precapillary arteriovenous channels; increased organ metabolic demand; and direct injury to the regional microvasculature. To test these hypotheses, we used radiolabeled 15-mu microspheres to measure cardiac output, regional blood flow, total systemic shunt flow, oxygen uptake (VO2), and oxygen delivery (QO2) in dogs after phorbol myristate acetate (PMA: 30 micrograms/kg; n = 5)-induced neutrophil activation and acute lung injury. These studies demonstrated that neutrophil activation and acute lung injury was accompanied by an increase in the level of QO2 (e.g., 19.1 ml/min.kg) necessary to maintain a constant level of VO2. Although PMA-induced acute lung injury did not result in an increase in the fraction of cardiac output comprising total systemic shunt flow or in an increase in whole body metabolic demand compared to control animals (e.g., PMA = 0 micrograms/kg; n = 10), it did result in a significant decrease in cardiac output. In addition, there were significant reductions in blood flow to most organs after PMA-induced acute lung injury that were not reversible with intravascular volume expansion (80 ml isotonic saline/kg; n = 5). The exclusion of reversible volume depletion, anatomic shunts, and increased metabolic demand suggest a role for microvascular injury in the development of the regional blood flow abnormalities and the supply dependence of oxygen uptake observed in this study. In the context of the mechanisms of lung injury known to be operative in this model, these microcirculatory abnormalities may be mediated through the intravascular activation of circulating neutrophils.

Acute Disease↗
PubMed1988

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.

Hemodynamics↗
PubMed1987

Alterations in regional blood flow during positive end-expiratory pressure ventilation.

PEEP improves the gas-exchange abnormalities that accompany adult respiratory distress syndrome (ARDS). However, since PEEP decreases cardiac output, it may also alter regional blood flow and therefore, substrate delivery to specific organs. To test this hypothesis, radiolabeled 15-mu microspheres were used to directly quantify the effects of mechanical ventilation with PEEP on regional blood flow to individual organs in animals. Mechanical ventilation alone produced a -21.2 +/- 3.6% and a -28.1 +/- 5.2% decrease in cardiac output at 30 and 60 min, respectively. The addition of 14 cm H2O PEEP resulted in little further reduction in cardiac output at 30 and 60 min (-28 +/- 2.3% and -36.4 +/- 4.9%, respectively). However, 25 cm H2O PEEP reduced markedly (p less than .01) cardiac output (-59.2 +/- 6.1% at 30 min and -55.1 +/- 4.0% at 60 min). Although blood flows to the kidney and brain were maintained, decreases in cardiac output were invariably accompanied by proportional decreases in blood flow to the heart. Intravascular volume expansion with saline (20 ml/kg) during 14 cm H2O PEEP significantly improved cardiac output (3.23 +/- 0.34 to 4.22 +/- 0.13 L/min; p less than .01) and proportionately increased blood flow to several regional vascular beds, including the heart. These data suggest that PEEP decreases cardiac output to produce reversible alterations in blood flow to a number of regional vascular beds. These PEEP-induced alterations in regional blood flow may have important implications for the development of multiple-organ failure in ARDS patients.

Animals↗
PubMed1986

Lung neutrophils in the adult respiratory distress syndrome. Clinical and pathophysiologic significance.

Although neutrophils are of pathogenetic importance in various animal models of acute lung injury, their role in the adult respiratory distress syndrome (ARDS) is unclear. To study the significance of lung neutrophils in this disorder, patients with ARDS (n = 11) were evaluated by bronchoalveolar lavage within 24 h of admission to the intensive care unit. Patients with non-ARDS respiratory failure requiring mechanical ventilation (n = 4) and normal volunteers (n = 12) were also studied. Neutrophils constituted 67.6 +/- 9.8% of recovered lavage cells in patients with ARDS compared with only 4.0 +/- 2.4% of cells in mechanically ventilated control patients and 0.8 +/- 0.2% in normal volunteers (p less than 0.005, both comparisons). Furthermore, in patients with ARDS (n = 6) evaluated serially by bronchoalveolar lavage at 72-h intervals, neutrophil percentages decreased from 91 +/- 3.2% (initial lavage) to 42.8 +/- 12% (final lavage) (p less than 0.005). Lung neutrophils also predicted the severity of abnormalities in gas exchange and lung protein permeability. That is, the percentage of neutrophils correlated directly with the alveolar-arterial Po2 difference (r = 0.69, p less than 0.01) and lavage fluid total protein concentrations (r = 0.62, p less than 0.01). Because large numbers of lung neutrophils were present in these patients, ARDS lavage fluid was assayed for neutrophil mediators relevant to the pathogenesis of acute lung injury. Neutrophil elastase activity was not detected in any ARDS lavages, although elastase was antigenically present in most samples and appeared to be complexed to alpha-1-antitrypsin. In contrast to elastase, neutrophil collagenase was readily detectable in ARDS fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1985

Hypoxia results in an increase in total systemic shunt flow in dogs.

There is considerable evidence to indicate that blood flow to many organs changes in response to hypoxia. However, since blood may traverse nutrient capillaries or be shunted through precapillary arteriovenous channels, measurements of total organ blood flow alone may not accurately reflect microcirculatory adaptations to hypoxia. To test this hypothesis, we determined the effect of controlled normoxic ventilation (PO2 = 86.4 +/- 2.8 Torr; N = 10) and controlled hypoxic ventilation (PO2 = 45.9 +/- 1.0 Torr; N = 5) on cardiac output, nutrient blood flow and total systemic shunt flow in dogs using radiolabelled 15 micrometers microspheres. The microspheres were injected from left heart catheters in each animal and total systemic shunt flow was estimated from the radioactivity present in pulmonary artery reference samples. Cardiac output, as well as nutrient blood flow to the heart and brain, was similar in both hypoxic animals and normoxic controls. Although we could detect no significant changes in nutrient blood flow to the remaining organs in response to hypoxia, total systemic shunt flow increased from a baseline value of 4.4% of cardiac output to a maximum value of 7.9% of cardiac output in hypoxic animals compared to 2.3% of cardiac output in normoxic animals at a similar time point (P less than 0.01). This hypoxia-induced increase in total systemic shunt flow may contribute to the overall decline in organ function often observed in this setting.

Animals↗
PubMed1985

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.

Adult↗