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Biomedical subjects

P M Dorinsky

Publications and source records attributed to P M Dorinsky.

At least 19 recordsLinked to original sources
PubMed1997

Endotoxin-induced ileal Vo2-Do2 alterations do not correlate with the severity of ileal injury.

PURPOSE: Altered Vo2-Do2 relationships are most often noted to occur in the setting of sepsis or endotoxin (LPS)-induced systemic organ microvascular injury and are generally thought to be causally linked to that injury. However, we have recently shown that ileal microvascular injury is not associated with altered ileal Vo2-Do2, relationships. Thus, we hypothesized that the severity of LPS-induced systemic organ microvascular injury would not correlate with the development of systemic organ Vo2-Do2 alterations. MATERIALS AND METHODS: To test this hypothesis, we used the in situ autoperfused feline ileal preparation to simultaneously examine microvascular permeability, reflected as the ileal lymph to plasma protein concentration ratio (CL/CP), and ileal Vo2-Do2 relationships 2 hours after intravenous LPS (0.75-2.0 mg/kg; n = 9) and in matching controls (n = 5). RESULTS: As expected, all LPS-treated animals were found to have extensive ileal histological damage and marked increases in the CL/CP compared with controls (0.308 +/- 0.019 v 0.097 +/- 0.009; P < .001). In addition, although the critical Do2 (Do2c) was elevated in the LPS-treated animals relative to controls (34.2 +/- 5.0 v 16.7 +/- 1.4 mL/min/kg; P < .03), there was no correlation between the Do2c and the CL/CP in the LPS-treated animals. Finally, ileal wet to dry weight ratios after LPS did not differ from controls. CONCLUSION: Taken together, these data suggest that factors other than organ injury, as assessed by morphological and permeability alterations, are important in the pathogenesis of altered systemic organ Vo2-Do2 relationships after LPS.

Animals↗
PubMed1997

Ischemia/reperfusion injury to the ileum does not account for the ileal VO2-DO2 alterations induced by endotoxin.

PURPOSE: Endotoxin (lipopolysaccharide [LPS])-induced systemic organ injury leads to disruption of normal systemic organ metabolic processes, which are manifest clinically by signs of accelerated anaerobic metabolism (e.g., tissue acidosis and hyperlactatemia) and altered VO2-DO2 relationships. The association of increased anaerobic metabolism with VO2-DO2 alterations has led to the notion that ischemia/ reperfusion (I/R) injury may be a prerequisite for the development of VO2-DO2 alterations during endotoxemia. However, in contrast to sepsis, in which oxygen consumption is often increased, oxygen consumption is severely decreased after I/R injury. Based on these observations, we hypothesized that I/R injury would result in systemic organ VO2-DO2 alterations, which are distinct from those that occur in sepsis. MATERIALS AND METHODS: We used the in situ autoperfused feline ileal preparation to simultaneously examine microvascular permeability, reflected as the ileal lymph to plasma protein concentration ratio (CL/CP), and ileal VO2-DO2 relationships after either intravenous LPS (2.0 mg/kg; n = 5) or I/R injury (n = 5), and in matching controls (n = 5). RESULTS: As expected, all LPS-treated and I/R-injured animals were found to have extensive ileal histological damage and marked increases in the CL/CP compared with controls (0.315 +/- 0.009 and 0.329 +/- 0.034, respectively, v 0.097 +/- 0.009; P < .001, both comparisons). In addition, the critical DO2 (DO2c) was elevated, and the critical oxygen extraction was decreased in both the I/R and LPS groups relative to controls. However, as initially hypothesized, the VO2 at the critical DO2 was markedly decreased in the I/R group compared with that of the LPS group. CONCLUSIONS: These data indicate that I/R injury is insufficient to account for the systemic organ VO2-DO2 alterations that occur with LPS injury.

Acidosis↗
PubMed1996

Metabolic consequences of sepsis. Correlation with altered intracellular calcium homeostasis.

The availability of adequate substrate for energy homeostasis is a minimal requirement for vital organ function that normally is provided through dietary intake. When dietary sources of nutrients are inadequate, the body relies on alternate sources of energy provided by gluconeogenesis, lipolysis, and ketogenesis. Sepsis is associated with disruption of virtually all these provisional sources of energy substrate (see Fig. 4). In addition, sepsis impairs the function of the glycolytic pathway, the integrity of which is necessary for glucose to be used effectively for energy production. These abnormalities, coupled with disruption of the intracellular energy-producing machinery (e.g., glycolytic and gluconeogenic enzymes, mitochondria) eventually lead to a reduction in intracellular ATP. Furthermore, a reduction in intracellular ATP can undermine virtually all the energy-consuming functions of the cell, including energy substrate formation (e.g., failed gluconeogenesis), antioxidant production, and calcium homeostasis. High levels of intracellular calcium, in turn, are known to activate many potentially destructive enzymatic pathways (e.g., proteases, phospholipases, endonucleases) that further diminish cell function and may result in cell death. In this context, iCa2+ accumulation may play an important role in the progression from early sepsis to MODS, the most common cause of mortality in the ICU.

Calcium↗
PubMed1996

Diagnosis and therapy of acute respiratory distress syndrome in adults: an international survey.

In an attempt to identify the range of opinions influencing the diagnosis and therapy of patients with the adult respiratory distress syndrome (ARDS), a postal survey was mailed to 3,164 physician members of the American Thoracic Society Critical Care Assembly. The questionnaire asked opinions regarding the factors important in the diagnosis of ARDS and its treatment. Thirty-one percent of physicians surveyed responded within 4 weeks, the vast majority of which were board certified or eligible in Internal Medicine, Pulmonary Disease, and/or Critical Care Medicine. A known predisposing cause, measure of oxygenation efficiency, and a chest radiograph depicting pulmonary edema were reported to be the most important criteria for a clinical and research diagnosis of ARDS. Lung compliance and bronchoalveolar lavage neutrophil or protein content were reportedly less important. The initial treatment of patients with ARDS was reported to be most commonly accomplished using volume-cycled ventilation in the assist/control mode. Nearly half the responders reported using lower tidal volumes (5 to 9 mL/kg) than the traditionally recommended 10 to 15 mL/kg. Most respondents indicated they have intentionally allowed CO2 retention. On average, oxygen toxicity was thought to begin at an FIO2 between 0.5 and 0.6. It was reported that modest levels of positive end-expiratory pressure (PEEP) were used in incremental fashion as FiO2 requirements increased. Perceived indications for insertion of pulmonary artery catheters and compensation of the effects of PEEP on the pulmonary artery occlusion pressure varied widely among the responders. We conclude that reported practice patterns regarding the care of ARDS patients vary widely even within a relatively homogenous group of critical care practitioners.

Adult↗
PubMed1996

Acid aspiration results in ileal injury without altering ileal V(O2)-D(O2) relationships.

Systemic organ endothelial injury and V(O2)-D(O2) relationship alterations occur frequently in the setting of acute lung injury, and they are believed to play an important role in the pathogenesis of the multiple organ dysfunction syndrome (MODS). However, the relationship, if any, between systemic organ endothelial injury and V(O2)-D(O2) relationship alterations remains unknown. We hypothesized that microvascular endothelial injury and attendant interstitial edema would result in increased diffusion distances for oxygen and altered systemic organ V(O2)-D(O2) relationships. To test this hypothesis, we utilized the in situ autoperfused feline ileal preparation to evaluate ileal V(O2)-D(O2) relationships in control animals (n = 5) and in animals with HCl-induced acute lung and systemic organ injury (n = 5). As expected, ileal endothelial protein permeability (CL/CP) was increased in HCl-injured animals compared to control animals (0.187 +/- 0.024 versus 0.097 +/- 0.009; p < 0.01). However, contrary to our original hypothesis and despite marked morphologic and endothelial protein permeability alterations, ileal V(O2)-D(O2) relationships were not altered in the HCl-injured animals. Moreover, V(O2)-D(O2) relationships in the ileum remained unchanged even when ileal venous pressures were increased to 15 mm Hg. Taken together, these findings do not support an important role for oxygen diffusion limitation in the pathogenesis of altered systemic organ V(O2)-D(O2) relationships.

Animals↗
PubMed1995

Anti-CD18 antibody does not block ileal injury induced by phorbol myristate acetate.

Acute lung injury (ALI) is frequently complicated by systemic microvascular injury. In previous studies, ALI from acid aspiration resulted in ileal microvascular injury. This was due to systemic inflammation and was prevented by MoAb 60.3, an antibody against the CD18 antigen that mediates leukocyte adherence. The present study was designed to test the hypothesis that ileal microvascular injury during phorbol myristate acetate (PMA)-induced systemic inflammation is also blocked by MoAB 60.3. We assessed the injury by measuring the concentration ratios of lymph protein to plasma protein (i.e., CL/CP) at steady-state lymph flows in autoperfused cat ileum preparations. As expected, the CL/CP increased in the ilea of animals given PMA (15 micrograms/kg; n = 5) compared with the ilea of control animals (n = 5) (0.202 +/- 0.024 versus 0.106 +/- 0.010; p = 0.006) and was accompanied by widespread morphologic alterations. Intravenously administering MoAb 60.3 (2 mg/kg) to animals before the PMA infusion (n = 5) yielded a CL/CP value indistinguishable from that of the PMA group (0.222 +/- 0.024 versus 0.202 +/- 0.024; p = NS). These results suggest that CD18-mediated leukocyte adherence is not important in the mechanism of PMA-induced ileal microvascular injury.

Animals↗
PubMed1994

Regional blood flow distribution in endotoxin-treated dogs: modification by ibuprofen.

PURPOSE: The aim of this study was to determine whether the improved hemodynamic profiles reported with cyclooxygenase inhibition during sepsis include improvements in tissue perfusion is unknown. Our hypothesis was that cyclooxygenase inhibition with ibuprofen will prevent the endotoxin-induced alterations in regional blood flow distribution from developing and/or restore the endotoxin-induced loss of responsiveness to intravascular volume expansion. METHODS: We measured cardiac output, regional blood flow, and total systemic shunt flow in dogs using radiolabeled 15-microns microspheres. These parameters were assessed in control (N = 10) and endotoxin-treated animals (N = 7). Additional endotoxin-treated animals (N = 7) were also pretreated with ibuprofen. RESULTS: Compared with controls, endotoxin-treated animals exhibited marked reductions in blood flow to most systemic organs that were not reversed with large, intravenous saline infusions (ie, isotonic saline; 40 mL/kg; N = 4). By contrast, although ibuprofen pretreatment (12.5 mg/kg; N = 7) completely prevented the reductions in mean arterial pressure caused by endotoxin from occurring, it did little to prevent the development of endotoxin-induced alterations in regional blood flow distribution. Nonetheless, in contrast to the endotoxin-treated animals, there were significant increases in cardiac output and blood flow to several organs after saline infusion in the ibuprofen-pretreated animals. CONCLUSIONS: Cyclooxygenase inhibition with ibuprofen has few direct effects on regional blood flow distribution after endotoxin. However, cyclooxygenase inhibition with ibuprofen does attenuate the endotoxin-induced decrease in vascular responsiveness to intravenous saline infusion.

Animals↗
PubMed1994

Paraaminosalicylate blocks that ileal injury induced by phorbol myristate acetate.

Activation of neutrophils with the release of oxidant radicals has been implicated in the pathogenesis of gut injury in inflammatory bowel disease (IBD). The pathogenesis of gut injury in the multiple organ dysfunction syndrome associated with acute lung injury, although less focal, appears to be similar. Paraaminosalicylate (PAS) has been shown to be effective in treating IBD, most likely because of its ability to scavenge oxidant radicals. The present study was therefore designed to test the hypothesis that PAS attenuates the gut injury typically seen during systemic neutrophil activation by phorbol myristate acetate (PMA). We assessed gut injury by measuring the concentration ratio of lymph to plasma protein (CL/CP) at steady-state lymph flows in autoperfused cat ileum preparations. As expected, the CL/CP increased in animals given PMA (15 micrograms/kb; n = 6) compared with control animals (n = 5) (0.205 +/- 0.033 versus 0.118 +/- 0.004; p = 0.04) 0.04) and were accompanied by morphologic alterations. In contrast, the intravenous administration of PAS (100 mg/kg) to animals prior to PMA infusion (n = 5) yielded a CL/CP value indistinguishable from that in control animals (0.113 +/- 0.017 versus 0.118 +/- 0.004). Additional in vitro studies suggested that the protective effects of PAS were not the result of altered neutrophil margination, chemotaxis, or oxidant burst. Although PAS appeared to protect the ileum from PMA-induced microvascular injury, it had no protective effects on the lungs.

Acute Disease↗
PubMed1994

Gastrointestinal tract dysfunction in critical illness: pathophysiology and interaction with acute lung injury in adult respiratory distress syndrome/multiple organ dysfunction syndrome.

The adult respiratory distress syndrome (ARDS), a common complication of critical illness, is associated with a > 50% mortality rate. Refractory respiratory failure is, however, an uncommon cause of mortality in these patients. Most deaths are due to a syndrome of relentless organ dysfunction accompanied by abnormal organ system interactions, collectively referred to as the multiple organ dysfunction syndrome (MODS). MODS is associated with two chief pathophysiologic derangements: a) the unregulated activation of systemic inflammatory cascades; and b) alterations of oxygen uptake (VO2)-oxygen delivery (DO2) relationships. Current concepts regarding the pathophysiology of MODS, specifically its relationship to unregulated systemic inflammation and alterations in VO2-DO2 alterations, are discussed. Within this framework, current and future areas for investigation that may result in mechanism-specific innovations with the potential to interrupt events mediated by gastrointestinal dysfunction that lead to MODS are presented.

Animals↗
PubMed1993

Oxygen uptake-oxygen delivery alterations in the isolated liver after hydrogen peroxide challenge.

Acute, diffuse lung injury is frequently complicated by systemic organ injury and alterations in the relationship between oxygen uptake (VO2) and oxygen delivery (QO2). In this regard, systemic organ neutrophil accumulation and morphologic alterations consistent with systemic organ injury often occur in nonpulmonary organs in these settings. However, whether VO2-QO2 matching is also altered in these injured systemic organs remains unproven. Thus, the present study was designed to test the hypothesis that hydrogen peroxide (H2O2), a product of neutrophil oxidative metabolism, will cause systemic organ structural abnormalities and alter VO2-QO2 matching. To test this hypothesis, VO2-QO2 relationships, morphologic changes, and organ water content were evaluated in both uninjured, isolated perfused rabbit livers and in isolated perfused rabbit livers after injury with 5 mmol/L H2O2. Following H2O2 injury, peak VO2 fell from 1.36 +/- 0.35 mL/min/100 g to 0.79 +/- 0.16 mL/min/100 g (P < .05) and peak O2 extraction fell from 0.83 +/- 0.09 to 0.66 +/- 0.04 (P < .05). In addition, VO2 was lower for any given level of QO2 in the H2O2-injured livers compared with the control livers (P < .01). Finally, liver extravascular water content was increased in H2O2-injured livers compared with the control livers (0.79 +/- 0.02 v 0.71 +/- 0.05; P < .05). These observations indicate that H2O2, a product of neutrophil oxidative metabolism, is capable of producing both morphologic changes as well as gas exchange alterations in the isolated, perfused liver.

Animals↗
PubMed1993

Acid aspiration-induced acute lung injury causes leukocyte-dependent systemic organ injury.

The adult respiratory distress syndrome is a form of acute lung injury (ALI) that is frequently associated with systemic organ injury and often occurs in the setting of wide-spread inflammatory cell activation. However, whether conditions that lead to ALI result in systemic organ injury is unclear. This study was designed to test the hypothesis that ALI induced by acid aspiration will not result in systemic organ injury. Morphological alterations and lymph-to-plasma protein ratios were measured in autoperfused cat ileum preparations of four control animals and five animals with ALI produced by the endobronchial instillation of 0.1 N HCl (0.5 ml.kg-1.lung-1). After 2 h, the lymph-to-plasma protein ratio (a measure of microvascular permeability) was increased in the ilea of HCl-injured animals compared with control animals (0.234 +/- 0.03 vs. 0.121 +/- 0.005; P = 0.012) and was accompanied by extensive morphological alterations. Four additional HCl-injured animals were pretreated with an antileukocyte adherence antibody (anti-CD18, 2 mg/kg) that blocked the HCl-induced alterations in the ileum. This study provides evidence for significant systemic organ injury after acid aspiration-induced ALI and suggests that the neutrophil may be a key mediator.

Animals↗
PubMed1993

Immunologic therapy for ARDS, septic shock, and multiple-organ failure.

Advances in cytokine biology and molecular biology have led to the development of novel immunologic approaches to the treatment of septic shock, ARDS, and MOF. These advances are necessary since improvements in supportive care clearly fall short of the hoped-for reductions in mortality associated with these disorders. As noted in this review, these new therapies are directed at three distinct levels of the inflammatory cascade: (1) the inciting event or insult (eg, endotoxin); (2) the mediators (eg, TNF, IL-1); and (3) the effector cells (eg, neutrophils). The current status of these treatments has been reviewed; and while each individual therapy has shown potential, it is likely that combinations of these agents may be necessary to substantially impact on survival. That is, due to the complexity and redundancy of the inflammatory network, it is doubtful that a "magic bullet" will be found. However, it is also clear that advances in our understanding of the pathogenesis of ARDS, septic shock, and MOF at the molecular level have provided clinicians with powerful weapons with which to do battle. It remains to be seen which ones will work the best.

Antibodies, Bacterial↗
PubMed1993

Cryptogenic bronchiolitis.

Cryptogenic bronchiolitis is a unique clinical disorder that causes rapidly progressive, chronic airflow obstruction. In this article, we reviewed the pathology, clinical characteristics, and proposed pathogenesis of cryptogenic bronchiolitis. It is evident that cryptogenic bronchiolitis represents the result of a disordered inflammatory response in the small airways of the lung. The clinical characteristics of cryptogenic bronchiolitis, in most instances, should allow this disorder to be distinguished from other causes of chronic airflow obstruction, as well as from BOOP. In this regard, a high clinical suspicion and an awareness of its unique clinical features are the keys to the diagnosis of cryptogenic bronchiolitis.

Biopsy↗
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↗