Humoral agent from calf lung producing pulmonary arterial vasoconstriction.

Saline washings obtained in vivo from the lung of young calves produce pulmonary hypertension upon intrayascular (systemic or pulmonary) injection into either the dog or the calf. This pulmonary hypertension is produced by vasoconstriction of small, precapillary pulmonary vessels. The active agent, pulmonary arterial constrictor substance, differs chemically and physiologically from other substances which have been investigated with respect to vasomotor activity in the pulmonary circulation. Although the chemical nature of the active agent is not known it appears to have a relatively large molecular weight. Whether this agent plays a role in the physiological regulation of the pulmonary circulation is not known.

Arterial constrictor response in a diving mammal.

Angiograms were obtained in the harbor seal, Phoca vitulina, in air and during diving. During diving there is arterial constriction of the vascular beds of muscle, skin, kidney, liver, spleen, and presumably of all vascular beds except those perfusing the brain and heart. There is sudden constriction and narrowing of muscular arteries close to their origin from the aorta. Constriction of small arterial branches is so intense that blood flow is essentially lost in all involved organs.

Dissociation of bradycardia and arterial constriction during diving in the seal Phoca vitulina.

Bradycardia associated with diving in the harbor seal has been dissociated from the arterial constrictor response by intracardiac pacing. Development of arterial constriction does not depend upon the development of bradycardia. During pacing, arterial constriction continues in the absence of bradycardia. Increases in heart rate to values greater than 120 beats per minute during a dive produce a progressive decrease in mean aortic pressure, which suggests that one major function of bradycardia is to reduce cardiac output, thus matching left ventricular output to the restricted vascular bed and decreased venous return associated with diving.

Pulmonary mechanics during pregnancy.

Previously reported changes in static lung volumes during pregnancy have been confirmed. Measurements of lung compliance (C(L)) and total pulmonary resistance (R(L)) were made in 10 women in the last trimester of pregnancy and 2 months postpartum, employing an esophageal balloon and recording spirometer. C(L) was unaffected by pregnancy, but R(L) was 50% below normal during pregnancy. Measurements of airway conductance (C(A)) were made, employing the constant pressure body plethysmograph on 14 nonpregnant and 13 pregnant women. Specific airway conductance was increased during pregnancy. Serial measurements of C(A) indicated a progressive increase beginning at about 6 months of gestation and a return to normal by 2 months postpartum. The mechanism of the increased C(A) during pregnancy is not known. It may be related to changes in bronchial smooth muscle tone and conceivably explains the tolerance of certain patients with lung resections to pregnancy.

Photochemical lesions in the primate retina under conditions of elevated blood oxygen.

Under conditions of nonthermal radiant exposure to blue light (440 nm) the primate retina can suffer photic injury by a mechanism that must be photochemical in nature. We have examined the effects of elevated blood oxygen (pO2 of 270 mmHg) on the retinal photosensitivity to blue light in two macaque monkeys by histologic analysis of 12 lesions at 1 to 57 days after irradiation. The retinal image diameter from a xenon arc lamp source was 1 mm, the duration of exposure was 100 sec, and the radiant exposures ranged from 11 to 36 J/cm2. When blood oxygenation is not elevated experimentally, the threshold radiant exposure for a blue light lesion to be visible funduscopically at 2 days postexposure is about 30 J/cm2. At a high blood pO2 level, a radiant exposure of only 11 J/cm2 gave a funduscopically visible lesion at 1-day postexposure. This large increase in retinal sensitivity to blue light damage appears to be due to photodynamic action. The only direct effect of elevated blood pO2 on the retina observed histologically was the presence of numerous granules in the cells of the retinal pigment epithelium (RPE). However, there was no apparent histopathology associated with the elevation of blood pO2 alone. Analysis of the various photic lesions showed only moderate damage to the neural retina, but a strong response was seen in the RPE. This is the histopathologic pattern of a typical blue light lesion shown in previous studies but more severe. So the effect of elevated blood O2 is to increase retinal sensitivity to photic damage, to lower the damage threshold, and to increase the severity of damage at a given radiant exposure. The status of lesions at 23 and 57 days postexposure suggests that such injuries are repairable.

Effects of acid aspiration on pulmonary alveolar epithelial membrane permeability.

Employing a modification of the in vivo model of a liquid-filled canine lung, we measured the movement of substances of specific sizes (albumin, 69,000 daltons with a molecular radius of 35 A; and dextran with a molecular weight of 150,000 to 170,000 and an approximate molecular radius of 100 A) from the pulmonary capillary blood to the liquid-filled lung. A solution with a specific pH (1.5 to 4.5) was instilled into the left lung of the animals at a dosage of 3 to 5 ml/kg of body weight. For both albumin and dextran with a molecular weight of 150,000 to 170,000, the time for 50 percent equilibration between the specific substance in the blood and the same substance in the pulmonary liquid decreased significantly with instillation of pulmonary liquid with a pH of 1.5 and 2.5 but did not with a pH of 3.5 or above (P less than 0.05). In addition, since histamine has been implicated as a possible humoral mediator leading to increased permeability of alveolar membranes, the levels of histamine were measured in pulmonary liquids and blood in all groups. Levels of histamine in the pulmonary liquid (but not blood) were significantly higher in animals with instillation of liquids with a pH of 1.5 and 2.5 compared to all other groups.

Pulmonary microvascular and alveolar epithelial permeability characteristics in N-nitroso-N-methylurethane-injected dogs.

The subcutaneous injection of 5 to 6 mg/kg of body weight of N-nitroso-N-methylurethane (NNNMU) has been reported to cause acute alveolar injury in animals. To determine the permeability characteristics of the alveolar epithelium, we employed the in vivo saline-filled dog lung model and determined the time to 50 percent equilibration in minutes of a specific tracer in the blood and the lung model and determined the time to 50 percent equilibration in minutes of a specific tracer in the blood and the lung liquid (T 1/2) for endogenous serum albumin (MW 69,000 daltons, molecular radius 35 A) and exogenously administered 500,000 MW polydispersed dextrans (molecular radius 200 A). Compared to control animals, T1/2 decreased (permeability increased) in NNNMU-injected dogs from 3,500 +/- 100 to 682 +/- 160 minutes for albumin and from 20,000 +/- 250 to 2,790 +/- 750 minutes for 500,000 MW dextran (P less than 0.001). To determine the permeability characteristics of the pulmonary microvasculature, we employed the right lymph duct cannulation dog model and measured lymph flow/30 minutes, lymph albumin and dextran concentration, and lymph/plasma albumin and dextran ratios in control and NNNMU-injected dogs. Compared to control animals, lymph flow was significantly greater in NNNMU dogs, 2.07 +/- 1.1 vs .71 +/- .50 ml/30 minutes (P less than 0.01), respectively. We conclude that NNNMU injection increases permeability in both the alveolar epithelium and the pulmonary microvasculature.

Continuous positive airway pressure without tracheal intubation in spontaneously breathing patients.

Indications for the use of therapy with continuous positive airway pressure (CPAP) in spontaneously breathing patients are increasing in number. The value of this technique without tracheal intubation was investigated in 14 patients with acute respiratory distress. In most patients (eight patients, or 57 percent) the technique was successful, as evidenced by avoidance of the necessity for tracheal intubation and improvements in clinical appearance, arterial oxygen pressure, and chest x-ray films. Complications were observed in three patients, but these necessitated discontinuation of therapy in only one. The use of this technique allows avoidance of endotracheal intubation and mechanical ventilation, with their attendant risks.

The role of leukocytes in ethchlorvynol-induced pulmonary edema.

Intravenous administration of ethchlorvynol (Placidyl) is known to produce noncardiogenic pulmonary edema in animals and humans. Since intrapulmonary sequestration of leukocytes has been observed to occur following injection of ethchlorvynol, we evaluated the role of these elements of the blood in producing pulmonary edema. In vivo studies in dogs showed intrapulmonary trapping of leukocytes, as evidenced by increasing leukocyte differences between blood from the pulmonary artery and arterial blood. In both animals with normal leukocyte counts and those depleted of leukocytes (less than 500 cells per millimeter), pulmonary edema occurred, as evidenced by increased pulmonary water after injection of ethchlorvynol. Preparations of isolated lung perfused with either whole blood or leukocyte-poor plasma had similar gains in weight following injection of ethchlorvynol, in spite of marked differences in leukocyte counts. We conclude that intrapulmonary sequestered leukocytes do not play a role in ethchlorvynol-induced pulmonary edema.

A comparison of physiological responses to percussive brain trauma in dogs and sheep.

Physiological variables were monitored in dogs and sheep after exposure of the brain to a pressure wave produced by a fluid-percussion device. Mean systemic arterial pressure (SAP), mean pulmonary arterial pressure (PAP), and pulmonary wedge pressure (PWP) were recorded prior to and following trauma. Lung lymph flows (QLYM) were measured prior to and for 2 hours after trauma. Plasma catecholamine levels were quantitated prior to and at 30 seconds following trauma. In 16 dogs, SAP increased from 123 +/- 14.6 to 254 +/- 60.8 mm Hg (p less than 0.0001), PAP increased from 17 +/- 4.4 to 27 +/- 10.8 mm Hg (p less than 0.05), and PWP increased from 4 +/- 2.4 to 15 +/- 8.8 mm Hg (p less than 0.0001), all at 30 seconds posttrauma. All pressures returned to near baseline values within 6 minutes. The QLYM from the right lymph duct in 12 dogs increased from 0.82 +/- 0.77 to 2.7 +/- 2.1 and 1.88 +/- 1.82 ml/30 min, respectively, at 30 and 120 minutes. In five dogs the plasma concentrations of dopamine, epinephrine, and norepinephrine increased from 234 +/- 98 to 1906 +/- 1384, 609 +/- 641 to 19,813 +/- 10,234, and 388 +/- 194 to 3223 +/- 992 pg/ml, respectively (all p less than 0.01). In sheep there were no changes in SAP, PAP, PWP, QLYM, or catecholamine levels in response to percussive wave trauma up to 10 atm. Ratios of lung tissue water to dry weight were not significantly different from control animals in either species. The authors conclude that in dogs there is a profound sympathetic discharge resulting in dramatic elevations in plasma catecholamines, systemic and pulmonary artery hypertension, and an increase in pulmonary lymph flow. Sheep fail to demonstrate changes in any of these variables after severe percussive wave brain trauma.

Indomethacin and ketanserin block ethchlorvynol-induced hypoxemia in dogs.

Intravenous injection of ethchlorvynol (ECV) leads to hypoxemia and a permeability pulmonary edema. Whether the hypoxemia is directly attributable to the pulmonary edema or caused by release of mediators has not been explored. Three groups of dogs were studied: (1) ECV, (2) indomethacin--ECV, and (3) ketanserin--ECV. In group 1, 25 to 30 mg/kg of ECV caused a significant fall in PaO2 at 4 min (92 +/- 12.6 to 77 +/- 21 mm Hg, p less than 0.05), which persisted throughout the experiment. The P(A-a)O2 gradient widened significantly at 3 min (22 +/- 11 to 31 +/- 16.8 mm Hg, p less than 0.05) and remained abnormal for the remainder of the experiment. There was no significant fall in PaO2 in groups 2 and 3. Lung tissue water to dry weight ratio increased significantly in all groups at 60 min. Lung tissue water to dry weight ratios were normal at 10 min after ECV injection in additional groups. It was concluded that ECV causes hypoxemia, which is mediated by cyclooxygenase products and 5 hydroxytryptamine. This hypoxemia can be prevented by the administration of drugs that block these products.

Basic mechanisms underlying the production of photochemical lesions in the mammalian retina.

Extended exposure (100s) of the macaque retina to blue light (400-500nm) produces a photochemical type or types of lesion. The basic mechanisms responsible for such photic damage are unknown but the toxic combination of light and oxygen leading to the free radicals O-.2, H2O2, OH., and O2(1 delta) have been suggested as a possible source of the phototoxicity. To test this hypothesis, the radiant exposure (J. cm-2) to short wavelength light (435-445nm) required for minimal damage in the macaque retina is under investigation as a function of oxygenation and after administration of substances known to either inhibit/scavenge radicals or act as anti-inflammatory/anti-oxidant agents. Substances under study include beta-carotene, steroids, catalase and SOD. Here we report radiant exposure in J.cm-2 needed to produce a minimal lesion vs oxygenation as measured by partial pressure of O2 in arterial blood (Po2). There is a sharp drop in the radiant exposure threshold with increase in the partial pressure of O2 in arterial blood, e.g. 30 J.cm-2 at 75 torr to 10 J.cm-2 at 271 torr, a factor of 3. Methylprednisolone injected intravenously one hour before exposure (125 mg) has been shown to raise the threshold for retinal damage in two macaques by a factor of approximately 2. Another animal fed beta-carotene (7.5 mg daily) over a period of 3 months has been exposed to blue light at several levels of oxygenation. The results suggest a protective effect.

The effects of endogenous and exogenous histamine on pulmonary alveolar membrane permeability.

The effects of exogenously administered histamine phosphate (0.1 microgram per kg of body weight per min, or 90 microgram per hour) and endogenous histamine released by intravenous injection of 0.5 mg of Compound 48/80 on alveolar membrane permeability to substances of differing molecular weight (60 to 20,000 daltons) were studied using the in vivo saline-filled dog lung model. The half-time, i.e., the time required for 50 per cent equilibration between tracer substances in the blood compared to the saline-filled lung, was measured at baseline for urea, sucrose, and dextrans of varying molecular weight. The half-time decreased significantly for substances as large as 10,000 daltons after histamine infusion, and 20,000 daltons after injection of Compound 48/80. We conclude that histamine can increase alveolar epithelial permeability for substances of low molecular weight.

Fiberoptic bronchoscopic balloon occlusion and reexpansion of refractory unilateral atelectasis.

A new method using the flexible fiberoptic bronchoscope is described for the reexpansion of refractory unilateral lung or lobar atelectasis. The technique is well adapted for the critically ill ICU patient.

Physiological effects of controlled concussive brain trauma.

Utilizing a fluid percussion device, we measured the physiological effects of brain trauma in cats exposed to controlled levels of injury. Concussive brain injury at 3-4 atm of intensity led to profound elevations of the mean systemic arterial blood pressure from 128 +/- 26 to 229 +/- 33 mmHg, left ventricular end-diastolic pressure from 4 +/- 2 to 24 +/- 15 mmHg, and pulmonary wedge pressures (PWP) from 5 +/- 3 to 27 +/- 17 mmHg and a relatively moderate increase in intracranial pressure (ICP) from 6 +/- 3 to 38 +/- 31 mmHg (all P < 0.001). Pulmonary edema was evidenced by a significant increase in lung tissue wet-to-dry weight ratios to 3.74 +/- 0.81 as compared with a control group of 2.29 +/- 0.23 (P < 0.001). There was poor correlation between wet-to-dry weight ratios and PWP. Approximately 60% of all spontaneously breathing animals become permanently apneic within 6 min after injury, while the remaining 40% developed transient apnea. Arterial O2 or CO2 pressure alterations, in contrast to pretreatment with phentolamine did not affect the hemodynamic or edemogenic response to trauma. Phentolamine did not block the apneic response or increase in ICP. Comparative studies using intravenous levarterenol without trauma produced responses similar to trauma. Concussive brain injury of 3-4 atm results in pulmonary edema, apnea, sympathetically mediated peripheral vasoconstriction and left ventricular failure effect.

Increased alveolar epithelial permeability with acid aspiration: the effects of high-dose steroids.

Using the in vivo, liquid-filled dog lung model, we found that aspriation of acid with a pH of 2.5 or less led to increased alveolar epithelial permeability for albumin (molecular weight, 69,000 daltons; molecular radius, 35 a) and exogenously administered, polydispersed dextrans (molecular weight, 150,000 to 170,000 daltons: approximately molecular radius, 100 a). This increased permeability occurred with a large-volume (3 to 5 ml/kg) or small-volume (1 to 1.5 ml/kg) aspirate and with acid nebulization (1 to 1.5 ml/kg). When animals were either pretreated (30 min before aspiration) or post-treated (30 min after aspiration) with 30 mg of methylprednisolone/kg of body weight, there was no improvement in the increased permeability associated with acid aspiration. We conclude that, acutely, steroids have no effect on the increased alveolar epithelial permeability associated with acid aspiration.

Endotoxin-induced increased alveolar capillary membrane permeability.

In an attempt to define the effects of endotoxin on the permeability of the pulmonary alveolar capillary membrane (ACM) to a variety of substances [molecular weight (MW) varying from 60 to 69,000], we studied the movement of specific molecular species from the pulmonary capillary blood to the saline-filled "alveolus," employing an in vivo dog lung model. Following endotoxin injection (2-2.5 mg/kg) baseline T1/2 values (time, in minutes, for 50% equilibration of the specific solute between the blood and the saline-filled lung) decreased as follows (compared to baseline values): urea (MW 60) - 42.5 +/- 24 to 21.3 +/- 18; sucrose (MW 360) - 201 +/- 72 to 76 +/- 53; 3,000 MW dextran - 1,275 +/- 746 to 686 +/- 433; 10,400 MW dextran - 1,871 +/- 845 to 1,052 +/- 630 (all p less than 0.05). Neither 20,000 MW dextran nor albumin (MW 69,000) showed an increased permeability following endotoxin injection. Histamine analysis revealed a significant increase in all lung liquid samples post-endotoxin injection without a significant increase in blood histamine values. We conclude that, acutely (within 4 hr of injection), endotoxin causes an increase in permeability of the ACM for substances up to 10,400 MW. The role of histamine in this increased permeability remains controversial.

Bloody pericardial fluid. The value of blood gas measurements.

Clinically notable pericardial effusions developed in three patients with renal failure. Pericardiocentesis showed hemorrhagic fluid, the source of which was not apparent. Simultaneous determinations of PCO2, PO2, and pH values showed a substantial increase in PCO2 levels and decrease in PO2, pH, and bicarbonate levels in the pericardial compared with the intracardial aspirates. This was true when pericardial fluid PCO2, PO2, and pH values were compared with mixed venous samples. Determination of PO2, PCO2, pH, and bicarbonate values in pericardial aspirates may determine the source of the fluid.