Anti-endotoxin monoclonal antibodies.
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Antibodies, Monoclonal↗
Biomedical subjects
G R Bernard
Publications and source records attributed to G R Bernard.
An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.
BACKGROUND: Constriction of small pulmonary arteries and arterioles and focal vascular injury are features of pulmonary hypertension. Because thromboxane A2 is both a vasoconstrictor and a potent stimulus for platelet aggregation, it may be an important mediator of pulmonary hypertension. Its effects are antagonized by prostacyclin, which is released by vascular endothelial cells. We tested the hypothesis that there may be an imbalance between the release of thromboxane A2 and prostacyclin in pulmonary hypertension, reflecting platelet activation and an abnormal response of the pulmonary vascular endothelium. METHODS: We used radioimmunoassays to measure the 24-hour urinary excretion of two stable metabolites of thromboxane A2 and a metabolite of prostacyclin in 20 patients with primary pulmonary hypertension, 14 with secondary pulmonary hypertension, 9 with severe chronic obstructive pulmonary disease (COPD) but no clinical evidence of pulmonary hypertension, and 23 normal controls. RESULTS: The 24-hour excretion of 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) was increased in patients with primary pulmonary hypertension and patients with secondary pulmonary hypertension, as compared with normal controls (3224 +/- 482, 5392 +/- 1640, and 1145 +/- 221 pg per milligram of creatinine, respectively; P less than 0.05), whereas the 24-hour excretion of 2,3-dinor-6-keto-prostaglandin F1 alpha (a stable metabolite of prostacyclin) was decreased (369 +/- 106, 304 +/- 76, and 644 +/- 124 pg per milligram of creatinine, respectively; P less than 0.05). The rate of excretion of all metabolites in the patients with COPD but no clinical evidence of pulmonary hypertension was similar to that in the normal controls. CONCLUSIONS: An increase in the release of the vasoconstrictor thromboxane A2, suggesting the activation of platelets, occurs in both the primary and secondary forms of pulmonary hypertension. By contrast, the release of prostacyclin is depressed in these patients. Whether the imbalance in the release of these mediators is a cause or a result of pulmonary hypertension is unknown, but it may play a part in the development and maintenance of both forms of the disorder.
6-Ketoprostaglandin F1 alpha↗
Effect of cyclooxygenase inhibition on amphotericin B-induced lung injury in awake sheep.
Amphotericin therapy in humans has been reported to cause severe pulmonary dysfunction in some patients, and these abnormalities have been reproduced in unanesthetized sheep. To determine the role of cyclooxygenase products in this response, paired, random-order experiments in 11 sheep were done using the cyclooxygenase inhibitor ibuprofen. Ibuprofen blunted increases in pulmonary artery pressure (Ppa) after amphotericin (peak Ppa 38 +/- 3 cm H2O in amphotericin-alone group vs. 30 +/- 1 cm H2O in ibuprofen + amphotericin group, P less than .05) and reduced peak lung lymph flow to approximately 170% of baseline compared with 350% of baseline in amphotericin-alone group (P less than .05). In addition, the increase in airflow resistance across the lung and the decrease in partial pressure of oxygen seen after amphotericin was blocked by ibuprofen. Therefore, amphotericin-induced lung dysfunction is produced in part through the generation of cyclooxygenase products of arachidonic acid metabolism and can be ameliorated by pretreatment with the cyclooxygenase inhibitor ibuprofen.
6-Ketoprostaglandin F1 alpha↗
The role of cyclooxygenase products in lung injury induced by tumor necrosis factor in sheep.
Tumor necrosis factor-alpha (TNF alpha) has been proposed as a mediator of endotoxin-induced lung injury. When given to sheep, TNF alpha mimics endotoxin (LPS) causing hypoxemia, pulmonary hypertension, leukopenia, reduced dynamic compliance (Cdyn), increased resistance to airflow (RL), exudation of lung lymph, and enhanced airway reactivity. TNF alpha also induces rapid release of thromboxane A2 (TxA2), prostaglandin E2 (PGE2), and prostacyclin (PGI2). We hypothesized that the inflammatory effects of TNF alpha are due at least in part to cyclooxygenase products, and therefore cyclooxygenase inhibition would have similar effects on TNF alpha-induced lung injury as has previously been demonstrated for LPS-induced lung damage. Using awake sheep with chronic lung lymph fistulas, we measured Cdyn, RL, and FRC using a whole-body plethysmograph. Pulmonary artery (Ppa), left atrial (PLA), and systemic arterial (Psa) pressures were recorded continuously. Arterial blood gases (for calculating AaPO2), leukocyte counts, and lymph samples (for prostanoid levels) were collected every 30 min. Eleven animals underwent paired random-order experiments receiving ibuprofen (14 mg/kg) 1 h before human recombinant TNF alpha (10 micrograms/kg), or an identical dose of TNF alpha alone. Within 15 min of initiating TNF alpha, Ppa doubled and remained elevated for 4 h. Ibuprofen prevented the early rise in Ppa after TNF alpha. In the group receiving TNF alpha alone, increases in Ppa were accompanied by a 60% decline in leukocyte count and a 50% increase in AaPo2 within 30 min. Ibuprofen prevented increases in AaPo2, but it had no effect on leukopenia or late increases in lymph flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparison of elastin peptide concentrations in body fluids from healthy volunteers, smokers, and patients with chronic obstructive pulmonary disease.
Proteolysis of elastic fibers is central to the development of emphysema, and a simple, noninvasive assay of elastin degradation would be useful in diagnosis and in therapeutic monitoring. We have adapted an indirect enzyme-linked immunosorbent assay (ELISA) to determine plasma, urine, and bronchoalveolar lavage fluid (BALF) elastin peptide concentrations in nonsmokers, healthy smokers, and patients with chronic obstructive pulmonary disease (COPD). Plasma elastin peptide concentrations were significantly higher in subjects with COPD (66.8 +/- 5.8 ng/ml, n = 10) compared with nonsmokers (23.4 +/- 4.6 ng/ml, n = 12), and healthy smokers had intermediate values (36.0 +/- 6.8, n = 6), p less than 0.05. Urine values (both unadjusted and normalized to urine creatinine concentration) were approximately 10-fold higher than plasma in all subject groups, and the relative differences among groups were the same as for plasma with values of 910.8 +/- 105.6, 358.1 +/- 101.2, and 281.0 +/- 67.8 ng/ml for subjects with COPD (n = 10), healthy smokers (n = 6), and healthy nonsmokers (n = 12), respectively. Poor recovery of BALF in COPD subjects reduced differences in the BALF elastin peptide concentrations among subjects groups, although the healthy smokers and COPD subjects tended to have higher amounts. Assuming some dilution due to lavage technique, elastin peptide concentrations were estimated to be substantially higher in epithelial lining fluid than in plasma, suggesting lung as a significant source of elastin peptides in COPD. This is the first application of elastin peptide measurement to human urine or BALF, and we conclude that this assay in urine is useful in characterizing elastin turnover in patients with or at risk for emphysema.
Adult↗
N-acetylcysteine in experimental and clinical acute lung injury.
Clinically, lung injury is characterized by one or more of the following: altered gas exchange, dyspnea, decreased static compliance, and nonhydrostatic pulmonary edema. Although many antioxidants have been investigated in in vitro systems and in animal models, only some are at the developmental stage, or safe for clinical trials. Considerable evidence has recently accumulated supporting the hypothesis that leukocyte activation involves release of large quantities of highly reactive oxygen radicals, and hydrogen peroxide is partially responsible for diffuse microvascular and tissue injury in septic patients. Granulocyte depletion in animal models reduces the degree of fall in dynamic lung compliance and the increase in airflow resistance, lymph flow, and hypoxemia secondary to endotoxin administration. We hypothesized that the partial benefit derived from granulocyte depletion was due to the effective removal of a major source of oxygen radicals. Among the list of free radical scavengers, N-acetylcysteine stands out, because of its established usefulness in at least one human disease thought to be secondary to free radical organ damage (acetaminophen or paracetamol overdose). It is an extremely safe agent with a wide toxic-therapeutic window. An increasing number of animal studies indicate efficacy for this agent in the prevention and therapy of lung injury involving toxic oxygen species. We developed a randomized, double-blind protocol for the study of intravenous N-acetylcysteine in patients with established adult respiratory distress syndrome (ADRS). Results of this trial are preliminary. Nevertheless, they indicate that plasma and red cell glutathione levels are decreased in ADRS patients, and that N-acetylcysteine increases plasma cysteine as well as plasma and red cell glutathione. There are also indications that cardiopulmonary physiology is favorably affected by such therapy including improvements in chest radiograph edema scores, pulmonary vascular resistance, static compliance, oxygen delivery, and oxygen consumption.
Acetylcysteine↗
Effects of ritodrine infusion on hemodynamics and lung lymph in awake sheep.
The effect of the beta-agonist, ritodrine HCl, was studied on cardiac output (CO) and pulmonary lymph flow (QL) in sheep. Increased CO is associated with an increase in pulmonary QL in sheep during exercise. Isoproterenol increases CO but has not been shown to increase pulmonary QL. Ritodrine HCl was chosen because of its association with pulmonary edema when used to halt premature labor in pregnant women. Unanesthetized sheep received an intravenous infusion of ritodrine in increasing doses over 4 h up to a maximum of 6.3 micrograms/kg/min. Pulmonary pressure increased 2 mmHg after 1 h and returned to baseline by hours 3 and 4 with no change in left atrial pressure or lymph to plasma protein ratio. Pulmonary QL increased by 61% and CO by 80% at hour 3 of infusion (ritodrine dose 5.4 micrograms/kg/min) and remained at this level. Pulmonary QL and CO (normalized to baseline) correlated, r = 0.72, p less than 0.001, but there was no correlation between pulmonary QL and calculated microvascular pressure. Although an increase in pulmonary microvascular endothelium permeability with concurrent pulmonary vasodilation can not be completely ruled out, it appears from this study that beta-agonist therapy with ritodrine increases pulmonary QL by a CO related recruitment of microvessels.
Animals↗
Adult respiratory distress syndrome. Strategies to provide support and enhance oxygen delivery.
Respiratory failure itself is rarely the cause of death in patients with adult respiratory distress syndrome (ARDS). The multiple-organ failure that often accompanies the syndrome or the underlying disease or trauma that leads to ARDS is more frequently the cause. Thus, care of these patients consists of providing life-sustaining support until they respond to therapy. The authors explain what happens in respiratory failure and how gas exchange can be enhanced in these critically ill patients.
Humans↗
Direct vasodilator effect of hyperventilation-induced hypocarbia in autonomic failure patients.
Hyperventilation produces small decreases in blood pressure in normal subjects and larger decreases in patients with autonomic failure. The authors studied the mechanism for this observation by measuring mean arterial pressure (MAP) and arterial blood gas (ABG) changes in eight patients with severe primary autonomic failure after various maneuvers designed to alter PaCO2, PaO2, and pH. Maneuvers included voluntary hyperventilation, breathing a 5% CO2/95% O2 mixture, breathing 12% O2, breathing through a 1 meter tube to increase dead space, breathing 100% O2, and infusion of 120 mEq NaHCO3 over 30 minutes. All maneuvers led to expected changes in ABGs. Voluntary hyperventilation lowered MAP by 23 +/- 4 (p less than 0.01) mmHg but MAP was raised 11 +/- 3 and 7 +/- 1 mmHg by hyperventilation resulting from increasing breathing dead space or from breathing 5% CO2, respectively. Breathing 100% O2 or 12% O2 had no significant effect on MAP, and NaHCO3 infusion raised MAP by 8 +/- 4 (p less than 0.05) mmHg. With all maneuvers, change in MAP correlated with change in PaCO2 (r = 0.72, p less than 0.001) and change in pH (r = -0.57, p less than 0.01) but not with PaO2. Multiple regression analysis showed that only changes in PaCO2 predicted the change in MAP for all maneuvers. The authors conclude that a decrease in PaCO2 causes the observed decreases in MAP with hyperventilation. This most likely represents a direct peripheral vasodilator effect of hypocarbia rather than a reflex or centrally-mediated mechanism since our patient population is characterized by inadequate or absent autonomic cardiovascular reflex responses.
Autonomic Nervous System↗
Persistent generation of peptido leukotrienes in patients with the adult respiratory distress syndrome.
The time course of leukotriene generation in the adult respiratory distress syndrome (ARDS) was investigated by measurement of urinary leukotriene E4 (LTE4) excretion, the major urinary LT metabolite in humans. Sequential measurements were made in nine subjects entered into the study within 48 h of the onset of ARDS, defined by an arterial/alveolar PO2 ratio of less than 0.3 and radiographic evidence of diffuse bilateral pulmonary edema. Initial urinary LTE4 excretion was significantly elevated (1.250 +/- 0.050 ng/mg creatinine sulphate; n = 7) compared with a non-ARDS postoperative group (0.254 +/- 0.114 ng/mg; n = 5) and normal control subjects (0.035 +/- 0.010 ng/mg; n = 12). LTE4 excretion in the first 24 h was estimated to be 6.9 micrograms, representing a release of 0.1 micrograms/kg/h of peptido leukotrienes into the bloodstream. These values were physiologically important based on a comparison with the increased urinary LTE4 excretion observed after antigen-induced bronchoconstriction in allergic asthmatics (baseline LTE4, 0.06 +/- 0.04 ng/mg; postantigen, 0.56 +/- 0.14 ng/mg; 0.17 micrograms LTE4/24 h; n = 8). In subjects with ARDS, this pathologic LTE4 excretion persisted during a subsequent 5-day study period. Leukotriene E4 excretion was associated with persistent abnormalities in gas exchange, pulmonary edema, and lung compliance, suggesting an important role for peptido leukotrienes in the pathophysiology of ARDS.
Adult↗
Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition.
Arachidonic acid metabolites, especially thromboxane-A2 and prostacyclin, have been shown to be increased in experimental models of sepsis and the adult respiratory distress syndrome (ARDS) and play a major pathophysiologic role. This study was designed to determine if these metabolites are increased in human sepsis syndrome and if inhibition of fatty acid cyclooxygenase affects their formation and their pathophysiologic sequelae. We conducted a double-blind, placebo-controlled trial of ibuprofen (800 mg given rectally every 4 h for three doses) in 30 patients with sepsis syndrome defined by abnormal vital signs, the appearance of serious infection, and at least one major organ failure. Urinary concentrations of the metabolite of thromboxane-A2, 2,3-dinor-TxB2, and prostacyclin, 2,3-dinor-6-keto-prostaglandin F2 alpha, were elevated 10 to 20 times normal and declined to four to five times normal by 12 h after entry in the ibuprofen-treated group and remained elevated in the placebo-treated patients. The urinary concentration of TxB2 and 6-keto-prostaglandin F1 alpha, which reflect renal production of TxA2 and prostacyclin, respectively, were also increased approximately 10-fold over normal and were subsequently decreased by ibuprofen. Coincident with the reduction in metabolite levels, the ibuprofen-treated group, but not the placebo-treated group, experienced a significant decline in temperature, heart rate, and peak airway pressure, and a trend towards more rapid reversal of shock (p = 0.12).(ABSTRACT TRUNCATED AT 250 WORDS)
Cyclooxygenase Inhibitors↗
Effects of intravenous amphotericin B infusion on hemodynamics and airway mechanics in awake sheep.
To gain a better understanding of the adverse pulmonary response to amphotericin B administration reported in humans, we examined the effects of this agent in the chronically instrumented awake sheep. We measured pulmonary artery and left atrial pressures (Ppa and Pla), lung lymph flow (Qlymph), dynamic lung compliance (Cdyn), resistance to airflow across the lung (RL), lymph thromboxane B2 (TxB2), lymph 6-keto-PGF1 alpha, peripheral leukocyte counts, and arterial blood gases. After at least one hour of stable baseline (BL) observation, amphotericin B (Fungizone, Squibb, 1 mg/kg) was infused intravenously over 1 h. Measurements were continued for 3 h after the start of infusion. Amphotericin caused an immediate decrease in Cdyn nadiring at 55 percent of BL and an increase in Ppa from 21 +/- 1 mm Hg at BL to 44 +/- 4 at 30 minutes. RL increased to 5.5-fold over BL by 30 minutes into infusion, and lung lymph TxB2 concentrations were increased tenfold compared with BL by the end of the 1-h infusion (p less than 0.05). In this same time interval, there were increases in Qlymph (1.5 ml/15 min at BL to 4.9 +/- 0.8), but 6-keto-PGF1 alpha concentrations did not reach maximum until 2 h after the start of infusion. There was a decrease in peripheral leukocyte count and PaO2 (80 +/- 3 mm Hg at BL to 69 +/- 4 at 1 h) that returned to BL over the remaining 2 h. The temporal relationship of the TxB2 peak with these pathophysiologic changes and previous data describing the effects of thromboxane in the sheep lung suggest that a component of these alterations is due to thromboxane release. We conclude that several pulmonary system abnormalities occur following amphotericin infusion in sheep and that these findings provide a better physiologic basis for explaining the human pulmonary response to amphotericin.
6-Ketoprostaglandin F1 alpha↗
A graphical ICU workstation.
A workstation designed to facilitate electronic charting in the intensive care unit is described. The system design incorporates a graphical, windows-based user interface. The system captures all data formerly recorded on the paper flowsheet including direct patient measurements, nursing assessment, patient care procedures, and nursing notes. It has the ability to represent charted data in a variety of graphical formats, thereby providing additional insights to facilitate the management of the critically ill patient. Initial nursing evaluation is described.
Attitude of Health Personnel↗
Lung microvascular transport properties measured by multiple indicator dilution methods in patients with adult respiratory distress syndrome. A comparison between patients reversing respiratory failure and those failing to reverse.
We conducted indicator dilution studies on the lungs of patients in the early phases of adult respiratory distress syndrome (ARDS) to test the hypothesis that capillary permeability was increased in patients with respiratory failure. Indicator dilution studies were performed using 51Cr-erythrocytes, 125I-albumin, 14C-urea, and 3H-water as tracers. The injectate was infused as a bolus into a central venous line. Peripheral arterial blood was collected and counted for radioactivity. Mathematical analysis of the indicator curves yielded cardiac output, measures of the product of capillary permeability and surface area for urea (PS and D1/2S), the intravascular lung volume (Vv), and the extravascular lung water volume (Ve). Permeability was separated from surface area by normalizing PS and D1/2S to Vv. Patients could be divided into 16 in whom blood gas determinations and radiologic criteria for ARDS were reversed and 23 in whom they were not. We examined indicator dilution and other measures of lung function in the two groups to determine whether significant differences in microvascular function existed. PS and PS/Vv were significantly higher in the nonreversal patients. Ve was above normal, but not different between groups. Linear regression analysis showed significant correlations for all of the following in the nonreversal group: Ve and all measures of permeability, pulmonary vascular resistance (PVR), and the inverse of permeability-surface area measures and AaDO2 and PVR. Only measures of Ve and PS correlated in the reversal group. These results support the hypothesis that capillary permeability is increased in patients with early ARDS and continuing respiratory failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Biological Transport↗
Cellular and humoral mediators of sepsis syndrome.
The story of mediators in sepsis syndrome is developing extremely rapidly and continues to unfold. This discussion has focused on those areas most studied and those that have the greatest clinical implications in the context of current knowledge. There are a number of mediators under active investigation that have not been reviewed here because their discussion is beyond the scope of this article. Just how all the pieces of the intricate cascade of events ultimately fit together is yet to be seen. However, the availability of important probes, such as cyclooxygenase inhibitors, TNF, anti-TNF, IL1, anti-IL1, anti-proteases, antioxidants, and antiendotoxin, is allowing major progress to be made in a short period of time. Transferring this knowledge to the bedside and everyday clinical practice is a slower process, but the prospects are bright for innovative new therapies for sepsis syndrome, septic shock, and the multiple organ failure associated with these clinical entities.
Antibody Formation↗
The adult respiratory distress syndrome.
The adult respiratory distress syndrome remains an enigmatic disorder with a high mortality rate, although it can sometimes be managed effectively. Recognizing the conditions with which it is associated is the first step in preventing its occurrence. Decreasing the risk factors of developing ARDS remains the fundamental goal of initial management. Once the syndrome has developed in a particular patient, the clinician's goals in management are to stabilize the patient, avoid further insults, maximize the support therapies available, and be cognizant of and avoid the potential adverse effects of these supportive therapies.
Humans↗
Potential of N-acetylcysteine as treatment for the adult respiratory distress syndrome.
The adult respiratory distress syndrome (ARDS), often referred to as non-cardiac pulmonary oedema, is now regarded as a very complicated inflammatory process with oedema being only one facet. In recognition of this, pharmacologic therapy with anti-inflammatory corticosteroids was used widely until the completion of randomized clinical trials. Unfortunately, corticosteroids have not been proved to be useful in preventing ARDS in septic patients nor in patients with established ARDS and this has led to investigations with pharmacologic agents which are safer and more specifically targeted to certain parts of the inflammatory process. We have examined the role of the glutathione anti-oxidant system in the sheep model of ARDS as well as in patients with established ARDS through use of intravenous N-acetylcysteine (NAC). We have found that the response to endotoxin is markedly blunted in sheep treated with NAC. In our controlled clinical trials with NAC we found that patients with ARDS have depressed plasma and red cell glutathione concentrations, that these levels are substantially increased by therapy with intravenous NAC and there are measurable clinical responses to treatment with regard to increased oxygen delivery, improved lung compliance and resolution of pulmonary oedema.
Acetylcysteine↗
The role of airflow resistance in patients with the adult respiratory distress syndrome.
Although reduced lung compliance is a hallmark of the adult respiratory distress syndrome (ARDS), the role of increased airflow resistance in this disorder has not been well studied. Because animal models of ARDS show marked increases in airflow resistance and because mediators known to participate in lung parenchymal injury have also been implicated in models of increased airway reactivity, we hypothesized that increased airflow resistance is a major contributor to altered lung mechanics in human ARDS. We studied 10 mechanically ventilated patients with ARDS (criteria: PaO2 less than or equal to 70 mm Hg breathing FIO2 greater than or equal to 0.4; bilateral pulmonary roentgenographic infiltrates; Ppaw less than or equal to 18 mm Hg) measuring dynamic (Cdyn) and static (Cstat) compliance, airflow resistance across the lungs (RL), shunt fraction (QS/QT breathing FIO2 = 1.0), minute ventilation (VE), (a/A)PO2, dead space to tidal volume ratio (VD/VT), airflow (pneumotachograph), transpulmonary pressure (intratracheal pressure minus esophageal pressure) and volume (integrated from flow) at 50 L/min peak flow rate. Airflow resistance was uniformly elevated and averaged six times normal (5.32 +/- 0.92 cm H2O/L/s versus 0.88 +/- 0.08) (p less than 0.05). Cdyn correlated directly with (a/A)PO2. RL correlated with peak pressure, but did not correlate with VE, shunt, (a/A)PO2, or VD/VT. We conclude that increased pulmonary airflow resistance contributes significantly to the altered lung mechanics in ARDS. These data are consistent with studies of animal models of ARDS and long-term survivors of ARDS and may be secondary to tissue factors, airway hyperreactivity, or airway inflammation.
Airway Resistance↗