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K L Brigham

Publications and source records attributed to K L Brigham.

At least 145 records · Page 8Linked to original sources
PubMed1982

Effects of red cell exchange on calculated sheep lung vascular permeability to 14C-urea and 14C-thiourea.

We performed fourteen experiments on sheep to determine whether or not erythrocytes tracer transport alters the calculated value of capillary tracer permeability surface area. In each set of experiments 14C-urea or 14C-thiourea was equilibrated with: (1) a whole blood sample; (2) saline alone, and (3) packed erythrocytes alone. Aliquots of each of these samples were injected separately into the superior vena cava of sheep and multiple indicator data collected from the aorta. Lung urea or thiourea microvascular permeability surface area (PS) was calculated for each set of data using the integral extraction method. These results were compared to the predictions of a detailed theory of microvascular transport which included red cell effects. As predicted by the theory, only small differences were found between urea PS calculations based on pre-equilibrated blood or plasma injectates. When 14C-urea in the injectate was confined to red cells, the average PS calculation was approximately 60% of the average plasma-equilibrated value (also predicted by theory). This ratio was substantially lower (25%) when 14C-thiourea was used as an indicator, suggesting that the red cell membrane, rather than the microvascular barrier, limits thiourea exchange. We conclude that a finite red cel-plasma urea exchange rate does not significantly influence the calculation of lung vascular PS when the injected blood is equilibrated with urea prior to its introduction into the vascular system.

Animals↗
PubMed1982

Evidence for pulmonary release of 5-hydroxyeicosatetraenoic acid (5-hete) during endotoxemia in unanesthetized sheep.

Leukocyte trapping in the pulmonary circulation may be an important component of the lung vascular injury response to endotoxin, but mediators of the pulmonary leukostasis and increased lung vascular permeability are unknown. The leukocyte 5-lipoxygenation pathway of arachidonic acid metabolism yields highly biologically active products including leukotrienes C4 and D4 (formerly slow reacting substance of anaphylaxis) and the potent chemotaxin, leukotriene B4. A major product of 5-lipoxygenation is 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE), for which a sensitive, stable isotope dilution assay employing combined gas chromatography-mass spectrometry is available. This assay was used to test the hypothesis that 5-lipoxygenation products might participate in pulmonary vascular responses to endotoxin. We measured 5-HETE concentrations in lung lymph at three intervals during endotoxemia in unanesthetized sheep. Concentrations of 5-HETE in lung lymph exceeded those in aortic blood plasma. Lymph 5-HETE concentrations increased from 1.7 +/- 0.3 (mean +/- SEM, N = 7) ng/ml during baseline to peak values of 6.1 +/- 1.8 ng/ml (p less than 0.05) during the 2 1/2 hours after endotoxemia and preceeding the steady state increased lung vascular permeability response. During the increased permeability steady state from 240 to 270 minutes after endotoxin, lymph 5-HETE concentrations (1.4 +/- 0.3 ng/ml) and lymph 5-HETE flow (i.e., 5-HETE concentration x lung lymph flow rate) returned to baseline values. Although these observations are consistent with the hypothesis that 5-lipoxygenation products participate in the pulmonary vascular injury response to endotoxin, lymph 5-HETE concentrations did not correlate with any of the other experimental measurements. It may be only coincidence that the increase in lymph 5-HETE concentrations appeared contemporaneous with the onset of lung vascular injury.

Animals↗
PubMed1982

The exchange of small molecules as a measure of normal and abnormal lung microvascular function.

Evidence exists for the utility of measures of small-molecule exchange in assessing the normal and abnormal transport status of the lung vasculature. The evidence for the usefulness of PS for 14C-urea is: 1. PSu compares to other small molecules as would be expected from free-diffusion coefficients. 2. The extraction of 14C-urea decreases with increase flow as would be expected of a diffusion-limited indicator. 3. PSu is unaffected by moderate pressure increase, it increases when lymph protein flow indicated permeability increase, and it decreases when surface area is reduced. 4. Lung injuries such as E. coli endotoxemia in sheep and ARDS in patients can both reduce PSu, presumably through surface area reduction, and increase PSu, through increased permeability. Two events that accompany clinically important vascular injury complicate the interpretation of lung MT curves. These events are surface area loss and heterogeneity of flow and transport properties in the lung. Additional work is needed to precisely measure these variables and assess their importance.

Animals↗
PubMed1982

Effect of changing lung mass on lung water and permeability-surface area in sheep.

The effects of changing cardiac output and lung mass on pulmonary capillary surface area, lung water, and hemodynamics were studied in eight sheep. 51Cr-erythrocytes, 125I-albumin, 3H2O, and [14C]urea were injected into the right atrium, and timed samples were collected from the aorta for the calculation of cardiac output (CO), extravascular lung water (EVLW), and permeability-surface area product (PS) for [14C]urea. CO was varied by opening and closing arteriovenous shunts, and lung mass was decreased by first tying off the left lung followed by tying off the right lower lobe. Pulmonary arterial pressure (r = -0.741) and pulmonary vascular resistance (r = -0.700) increased as lung mass was decreased. CO decreased slightly (r = -0.470 while left atrial pressure was not changed (r = -0.144) by decreasing lung mass. There was a close correlation between EVLW and lung mass (r = 0.944) and between [14C]urea PS and lung mass (r = 0.672). We were able to demonstrate that [14C]urea behaves as a diffusion-limited tracer in a single pass through the lungs, since [14C]urea extraction decreased as flow per unit mass increased. These results support the clinical use of multiple-tracer studies to measure EVLW and [14C]urea PS.

Animals↗
PubMed1982

Respiratory failure after endotoxin infusion in sheep: lung mechanics and lung fluid balance.

Infusion of Escherichia coli endotoxin (0.12-1.5 micrograms/kg) into unanesthetized sheep causes transient pulmonary hypertension and several hours of increased lung vascular permeability, after which sheep recover. To produce enough lung injury to result in pulmonary edema with respiratory failure, we infused larger doses of E. coli endotoxin (2.0-5.0 micrograms/kg) into 11 chronically instrumented unanesthetized sheep and continuously measured pulmonary arterial, left atrial and aortic pressures, dynamic lung compliance, lung resistance, and lung lymph flow. We intermittently measured arterial blood gas tensions and pH, made interval chest radiographs, and calculated postmortem extravascular bloodless lung water-to-dry lung weight ratio (EVLW/DLW). Of 11 sheep 8 developed respiratory failure; 7 died spontaneously 6.3 +/- 1.1 h, and one was killed 10 h after endotoxin infusion. All sheep that had a premortem room air alveolar-arterial gradient in partial pressure of O2 (PAo2-Pao2) greater than 42 Torr (58 +/- 5 (SE) Torr) died. Of eight sheep that had radiographs made, six developed radiographically evident interstitial or interstitial and alveolar edema. Pulmonary artery pressure rose from base line 22 +/- 2 to 73 +/- 3 cmH2O and remained elevated above baseline levels until death. There was an initial fourfold decrease in dynamic compliance and sixfold increase in pulmonary resistance; both variables remained abnormal until death. EVLW/DLW increased with increasing survival time after endotoxin infusion, suggesting that pulmonary edema accumulated at the same rate in all fatally injured sheep, regardless of other variables. The best predictor of death was a high PAo2-Pao2. The marked increase in pulmonary resistance and decrease in dynamic compliance occurred too early after endotoxin infusion (15-30 min) to be due to pulmonary edema. The response to high-dose endotoxin in sheep closely resembles acute respiratory failure in humans following gram-negative septicemia. Respiratory failure and death in this model were not due to pulmonary edema alone.

Animals↗
PubMed1982

Bronchomotor responses of isolated sheep airways to electrical field stimulation.

To determine the functional innervation of sheep airway smooth muscle, we measured the isometric tension developed by sheep tracheal segments, bronchial rings, and lung parenchymal strips in response to electrical field stimulation (ES) in tissue chambers. The contractions caused by ES were abolished in trachea and bronchi by atropine 10(-6) M or tetrodotoxin 1.6 X 10(-6) M. The small contractions evoked in lung parenchymal strips were not affected by tetrodotoxin. Electrical stimulation in the presence of atropine 10(-6) M and phentolamine 10(-6) M caused a frequency-dependent reduction in serotonin-induced tension in tracheal segments and bronchial rings. Electrical stimulation had little or no effect on the tension evoked in lung parenchymal strips by acetylcholine 10(-5) M or to histamine 10(-6) M. Propranolol 10(-6) M or guanethidine 10(-5) M caused a shift to the right in the frequency-response curve of trachea and bronchi. These findings suggest the presence of cholinergic excitatory and adrenergic inhibitory innervation in larger sheep airways. A concomitant nonadrenergic inhibitory system may be present. The terminal bronchioles present in lung parenchymal strips do not appear to have an effective bronchomotor innervation.

Animals↗
PubMed1982

Effect of histamine on lung mechanics in sheep. Comparison of aerosol and parenteral administration.

The purpose of this study was to examine the effects of parenteral and aerosol histamine on lung mechanics in sheep. Eleven sheep were chronically prepared with pulmonary arterial (PA) and left atrial (LA) catheters, a tracheostomy, and a silastic envelope in the pleural space. Unanesthetized sheep were studied in a pressure-compensated integrated-flow whole-body plethysmograph, and measurements of dynamic lung compliance (Cdyn), resistance of the lung (RL), and functional residual capacity (FRC) were made. Histamine was infused through PA or LA catheters or given as an aerosol at increasing concentrations until Cdyn decreased by 35%, RL doubled, or FRC increased by 25%. Parenteral histamine caused a reproducible decrease in Cdyn, a variable increase in RL, and no change in FRC. There were no significant differences between the LA and PA infusions. Aerosol histamine had similar effects to parenteral histamine, except some sheep did show an increase in FRC. Repeat studies in 3 animals showed PA histamine infusions to be highly reproducible, whereas changes associated with aerosol histamine were slightly less reproducible. Among sheep there was a several hundredfold range in responsiveness to either aerosol or parenteral histamine. There was a significant correlation (r = 0.98, p less than 0.001) between the parenteral histamine dose required for a response and the aerosol dose. These data were interpreted as suggesting that airway responsiveness to histamine is an inherent physiologic property.

Aerosols↗
PubMed1982

Mechanisms of lung injury.

The adult respiratory distress syndrome is pulmonary edema with low heart pressures and hypoxemia. Based on experimental models of the human disease, it is likely that functional injury to the lung includes pulmonary vasoconstriction, a loss of hypoxic vasoconstriction, increases in resistance to airflow across the lungs, decreases in lung compliance (perhaps both resulting from airway constriction), and lung microvascular injury resulting in pulmonary edema. Data accumulated over the last several years strongly suggest an important role for both cyclo-oxygenase metabolites and lipoxygenase metabolites of arachidonic acid in mediating lung vascular injury in this syndrome. Likewise, more recent evidence suggests a causative role for granulocytes in mediating the lung injury. Based on what is known about the biological activity of products of granulocytes and metabolites of arachidonic acid, it is reasonable to hypothesize a sequence of events in which arachidonate metabolites and granulocytes interact to result in pulmonary vasoconstriction, loss of hypoxic vasoconstriction, airway responses and capillary injury. It remains possible, perhaps even likely, that other humoral mediators, platelets and perhaps even other cellular mediators (for example, mast cells or lymphocytes) participate in the pathogenic sequence of events in ARDS. Specific delineation of the mechanisms of lung injury in this syndrome must await further research.

Adult↗
PubMed1982

Effects of cyclooxygenase inhibitors on pulmonary vascular responses to endotoxin in unanesthetized sheep.

Pulmonary release of thromboxanes and prostaglandins occurs during the first hour after endotoxin infusion in sheep concomitant with transient, severe pulmonary hypertension (phase I) and followed by a prolonged period of increased lung vascular permeability (phase II) characterized by moderately elevated pulmonary artery pressure and high flow of protein-rich lung lymph. Indomethacin and meclofenamate both inhibited phase I pulmonary hypertension but did not prevent later increases in pulmonary artery pressure and lung lymph flow to levels seen with endotoxin alone in the same sheep. Indomethacin significantly exaggerated phase II lung lymph flow (endotoxin = 19 +/- ml/hr; indomethacin + endotoxin = 24 +/- 4 ml/hr, p less than 0.05), and meclofenamate enhanced phase II lymph protein clearance (endotoxin = 12.9 +/- 1.5 ml/hr; meclofenamate + endotoxin = 17.1 +/- 2.5 ml/hr, p less than 0.05). Hypoxemia seen with endotoxin alone was inhibited by meclofenamate. These data indicate that during endotoxemia cyclooxygenase products mediate phase I pulmonary hypertension. Inhibitors of cyclooxygenase prevent ventilation perfusion imbalance that results in endotoxin induced hypoxemia. Exaggeration of phase II lymph responses by cyclooxygenase inhibitors suggests that prostaglandin synthesis moderates phase II or that lipoxygenation products contribute to the phase II increased permeability response.

Animals↗
PubMed1981

Effects of graded increases in pulmonary vascular pressures on lung fluid balance in unanesthetized sheep.

Fourteen experiments were conducted on 12 chronically instrumented unanesthetized sheep in which we monitored pulmonary arterial, left atrial, and aortic pressures, lung lymph flow, and lymph-to-plasma ratios (L/P) of total proteins and four endogenous protein fractions during baseline and progressive elevations of left atrial pressure. We found that L/P for total proteins decreased as lung lymph flow increased until lymph flow exceeded four to five times baseline and thereafter remained nearly constant (filtration independent) at 0.26. The four protein fractions exhibited a filtration independent L/P that was related to the effective molecular radius of the protein fraction. The minimal L/P were 0.36, 0.28, 0.18, and 0.09 for the protein fractions that had effective molecular radii of 36, 38.5, 59, and 101 A, respectively. In addition, we found no evidence supporting a stretched pore phenomenon over the pressure range utilized in this investigation.

Anesthesia↗
PubMed1981

Methylprednisolone prevention of increased lung vascular permeability following endotoxemia in sheep.

To see whether methylprednisolone would affect the pulmonary vascular response to endotoxemia, we studied responses to endotoxemia in the presence and absence of methylprednisolone in the same chronically instrumented, unanesthetized sheep. Infusion of Escherichia coli endotoxin (0.70-1.33 mug/kg) caused an initial period of marked pulmonary hypertension followed several hours later by a long period of increased vascular permeability when pulmonary vascular pressures were near base line (base-line pulmonary artery pressure (PPa) = 21+/-1 cm H(2)O SE, left atrial pressure (Pla) = 1+/-3; experimental PPa = 20+/-3, Pla = 3+/-4; P = NS), lung lymph flow ( Qlym) was high (base-line Qlym = 7.2+/-0.2 ml/h; experimental Qlym = 23.2+/-1.0; P < 0.05) and lymph/plasma protein concentration (L/P) was high (base-line L/P = 0.65+/-0.04; experimental L/P = 0.79+/-0.05; P < 0.05). When methylprednisolone (1.0 g + 0.5 g/h i.v.) was begun 30 min before the same dose of endotoxin was infused, the initial pulmonary hypertension was less and the late phase increase in lung vascular permeability was prevented (experimental PPa = 24+/-1, Pla = 1+/-1, Qlym = 10.0+/-0.4; L/P = 0.56+/-0.03). Qlym and L/P were significantly (P < 0.05) lower than with endotoxin alone. Methylprednisolone began during the initial pulmonary hypertensive response to endotoxin also prevented the late phase increase in lung vascular permeability, but the drug had no effect once vascular permeability was increased. We conclude that large doses of methylprednisolone given before or soon after endotoxemia prevent the increase in lung vascular permeability that endotoxin causes, but do not reverse the abnormality once it occurs.

Animals↗
PubMed1981

Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia.

To see whether circulating granulocytes are necessary for the lung vascular reaction to endotoxin, we measured the endotoxin response in chronically instrumented sheep before and after granulocyte depletion with hydroxyurea. Granulocyte depletion did not affect the pulmonary hypertension caused by endotoxin (peak mean pulmonary artery pressures = 38 +/- 2 cm H2O before depletion and 42 +/- 2 after depletion, P = NS). The late phase increase in lung lymph flow after endotoxin was significantly lower in the granulocytopenic animals as reflected by lung lymph flow (mean steady state lymph flow before depletion = 30.6 +/- 2.0 SE ml/h; mean steady state lymph flow after granulocyte depletion = 15.4 +/- 1.0; P less than 0.01) even though late phase pulmonary vascular pressures were similar before and after granulocyte depletion. Lung lymph protein clearance (lymph flow x lymph/plasma protein concentration) was also significantly lower after granulocyte depletion (mean steady state before depletion = 2.14 +/- 1.4 SE ml/h; and after depletion = 10.4 +/- 1.0; P less than 0.01). We conclude that circulating granulocytes are necessary for the development of increased lung vascular permeability to fluid and protein following endotoxin. The pulmonary vasopressor effects of endotoxin in sheep are independent of granulocytes.

Animals↗
PubMed1981

Studies on group B beta-hemolytic Streptococcus. II. Effects on pulmonary hemodynamics and vascular permeability in unanesthetized sheep.

To study the effects of Group B beta-hemolytic Streptococcus on the pulmonary circulation and lung fluid balance, live and heat-killed bacteria and their toxin were infused into an awake sheep lung-lymph preparation. In every case, the response was biphasic; there was an initial period of marked pulmonary hypertension and high flow of protein-poor lymph associated with tachypnea, chills, and fever. A second phase followed during which pulmonary vascular pressures returned to near baseline and remained stable, but lymph flow remained high. The changes seen in the initial phase resemble the previously reported response to mechanically increased pulmonary vascular pressure and suggest that the increase in fluid filtration is secondary to increased microvascular pressure. During the second phase after toxin infusion, the increase in lung lymph flow was paralleled by an increase in lymph protein clearance. This cannot be accounted for by the hemodynamic changes alone an suggests that the permeability of lung microvascular walls to protein was increased. It is concluded that group B beta-hemolytic streptococcal toxin in the sheep model causes pulmonary hypertension and increased pulmonary vascular permeability.

Animals↗
PubMed1981

Catamenial pneumothorax in sisters.

Two sisters had documented pelvic endometriosis and catamenial pneumothoraxes. Both were typical of the 54 reported cases of catamenial pneumothorax in that pneumothoraxes were always on the right and occurred only at menses with onset in the fourth decade. One patient was asymptomatic during 11 months of menstrual suppression with hormones but subsequently required surgery where diaphragmatic perforations were found. The other patient was treated with isoxazole ethisterone with no pneumothoraxes while under suppression. These patients are unlike any of the previously reported cases of familial pneumothoraxes. We have not found a previous report of a familial catamenial pneumothorax.

Adult↗
PubMed1981

Comparison of the effects of saline and homologous plasma infusion on lung fluid balance during endotoxemia in the unanesthetized sheep.

The effects of saline infusion (20 ml/kg/30 minutes) and homologous plasma infusion (20 ml/kg/30 minutes) on the lung fluid balance during increased pulmonary capillary permeability secondary to Escherichia coli endotoxin infusion (1 microgram/kg/15 minutes) were studied in unanesthetized sheep. Saline and homologous plasma infusion increased lung lymph flow by 10.6% and 10.8%, respectively. The bloodless wet-to-dry ratio was 5.1 +/- 0.2 in the saline group and 5.2 +/- 0.2 in the homologous plasma group. The saline infusion decreased the plasma oncotic pressure while the plasma infusion increased plasma oncotic pressure. However, the increase in plasma oncotic pressure was negated by concomitant changes in the lymph oncotic pressure and greater increases in pulmonary microvascular pressure during the plasma infusion. Changes in pulmonary microvascular pressure predominated over changes in the oncotic pressure gradient. Both saline and homologous plasma infusion increase fluid filtration into the interstitial space by the same magnitude. Therefore neither has a clear advantage in the treatment of pulmonary edema during increased permeability.

Animals↗