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.

Role of 5-HT2 receptor inhibition in pulmonary embolization.

We examined the role of serotonin at the 5-HT2 receptor site after pulmonary embolization for changes in hemodynamics, gas exchange, and lung water. Pulmonary embolization was induced using 0.75 gm/kg autologous clot in anesthetized artificially ventilated dogs. Pulmonary vascular resistance rose by 5 min from 3.4 +/- 1.5 to 14.2 +/- 2.1 mm Hg/liter/min (p less than 0.001), arterial oxygenation decreased from 91 +/- 5 to 68 +/- 5 mm Hg (p less than 0.01), platelet count decreased from 201 +/- 64 to 141 +/- 32 ml X 10(3), and the wet to dry weight lung ratio increased from 2.59 +/- 0.34 to 4.21 +/- 0.21 (p less than 0.001). Inhibition by ketanserin, a selective serotonergic inhibitor at the 5-HT2 receptor site substantially attenuated the increase in pulmonary vascular resistance from 3.6 +/- 1.4 to 8.0 +/- 2.5 mm Hg/liter/min, ablated the hypoxemia and platelet reduction and inhibited the formation of pulmonary edema. Infusion of serotonin simulated only some of the above changes as the pulmonary vascular resistance increased from 3.16 +/- 1.6 to 13.5 +/- 4.1 mm Hg/liter/min (P less than 0.01) and the oxygenation decreased from 96 +/- 5 to 57 +/- 4 mm Hg (P less than 0.01). Serotonin infusion, however, did not cause pulmonary edema. The administration of ketanserin ablated the increase in pulmonary vascular resistance and the hypoxemia following serotonin infusion. We conclude that following pulmonary embolization, serotonin at the 5-HT2 receptor is responsible for the fall in PaO2 and partially responsible for the increased pulmonary vascular resistance. Although ketanserin inhibits the formation of pulmonary edema following pulmonary embolization, serotonin does not seem to be directly responsible.

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.

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.

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.

Acute respiratory failure after sodium morrhuate esophageal sclerotherapy.

Two of 30 patients with esophageal varices had respiratory distress develop within 8-24 h of esophageal sclerotherapy. Evidence of aspiration and sepsis were absent in these two patients with the clinical picture of adult respiratory distress syndrome. To investigate the possible etiologic role of sodium morrhuate in this syndrome, a sheep model was established and pulmonary hemodynamics, lung lymph flow, and albumin concentration were measured before and after the intravenous injection of 2.5-15.0 cm3 of sodium morrhuate. In all 8 animals studied, mean pulmonary artery pressures increased from 11.6 +/- 2.8 to 32.8 +/- 4.9 mmHg (p less than 0.01) 30 s after injection. These pressures returned to baseline values over 120 min. Lymph flow increased from 0.91 +/- 0.89 to 2.8 +/- 1.5 ml/30 min at 90 min postinjection (p less than 0.05) and returned to baseline values in animals monitored for 6-8 h. The lymph/plasma albumin ratio decreased from 0.856 +/- 0.08 to 0.74 +/- 0.01 (p less than 0.05) 120 min postinjection. Pulmonary edema was not evident histologically or gravimetrically (wet/dry weight ratio was 3.65 +/- 0.3 and not different from normal). It was concluded that sodium morrhuate injection in sheep causes marked but transient pulmonary hypertension associated with an increased lymph flow of relatively protein-poor lymph. Sodium morrhuate esophageal sclerotherapy may affect pulmonary hemodynamics and contribute to respiratory difficulties in patients.

Indomethacin blunts ethchlorvynol-induced pulmonary hypertension but not pulmonary edema.

Ethchlorvynol (10 mg/kg) causes transient pulmonary hypertension and an increased permeability pulmonary edema in sheep. To determine the role of cyclooxygenase and its metabolites, histamine, and catecholamines in both phenomena, we studied five groups of sheep: group I, placebo; group II, ethchlorvynol; group III, indomethacin with ethchlorvynol; group IV, diphenhydramine with ethchlorvynol; group V, phentolamine with ethchlorvynol. Indomethacin, but not diphenhydramine or phentolamine, blunted the pulmonary hypertensive response seen immediately following the ethchlorvynol injection. However, none of the drugs had any effect on the increased permeability pulmonary edema. We conclude that cyclooxygenase or its metabolites partially mediates the hypertensive response but not the increased permeability pulmonary edema seen in sheep following ethchlorvynol injection.

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.

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.

Histamine receptor and prostaglandin synthetase blockers in ethchlorvynol-induced pulmonary edema in canines.

The injection of ethchlorvynol intravenously in humans and animals causes an increased permeability form of pulmonary edema. The proximate cause for this increased alveolar capillary membrane permeability is unknown but humoral mediators such as histamine and prostaglandins could play a role. To determine whether these agents were a factor in the altered permeability, we employed the saline-filled dog lung model and measured the flux of albumin across the alveolar capillary membrane. Following the intravenous injection of ethchlorvynol, there was a marked increase in permeability which was not altered by treatment with H1 and H2 receptor blockers or a prostaglandin synthetase inhibitor. We conclude that histamine and prostaglandins play no role in the increased permeability associated with ethchlorvynol injection.

Pulmonary alveolar epithelial permeability in surgically induced hemorrhagic pancreatitis in dogs.

The adult respiratory distress syndrome has been associated with acute pancreatitis in 5-8% of patients. to determine, in a quantitative manner, the effects of acute, hemorrhagic pancreatitis on alveolar epithelial permeability, we studied two groups of dogs (group 1 - sham-operated, 7 dogs; group 2 - surgically induced pancreatitis, 7 dogs) and measured the flux of 10,000-20,000 molecular weight dextran and albumin (69,000 molecular weight), from the blood to the saline-filled lung. Following the surgical procedure (day 1), serum amylase levels increased significantly (397 +/- 70-1,268 +/- 95 dye units) in group 2 but not in group 1. Alveolar epithelial permeability (expressed as T1/2 time in minutes to 50% equilibration between blood and lung liquid) did not increase in either group for dextrans or albumin. We conclude that experimental acute pancreatitis does not cause an increase in alveolar epithelial permeability for molecular weight substances up to 69,000 daltons.

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.

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.

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.

The effect of salicylate infusion on the alveolar epithelial membrane in the isolated perfused lung.

We observed two patients with aspirin (ASA) ingestion (blood levels of 87 and 56.5 mg/100 ml) who presented with noncardiogenic pulmonary edema (adult respiratory distress syndrome. To determine if ASA had a direct effect on the alveolar epithelial membrane, we established an in vitro isolated lung model and perfused it with platelet free plasma. T1/2 (in minutes), the time for 50% equilibration between the plasma and the saline filled lung, was determined before and after 500 mg salicylate infusion for various molecular weight dextrans. T1/2 decreased significantly (p less than 0.05) as follows: 3000 MW dextran, 2273 +/- 932 to 961 +/- 375; 40,000 MW dextran, 4059 +/- 1550 to 733 +/- 275; 70,000 MW dextran, 11,730 +/- 2750 to 7700 +/- 2230. Histamine levels in plasma and lung liquid did not change significantly with ASA infusion. We conclude that ASA directly increases alveolar epithelial permeability to dextrans less than 70,000 MW.

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.

The pulmonary alveolar capillary membrane during hemorrhagic hypotension in dogs.

Hemorrhagic hypotension is associated with increased lung water accumulation, secondary to loss of integrity of the alveolar capillary membrane. Whether this increased permeability of the alveolar capillary membrane occurs during hypotension or after resuscitation with intravenously administered fluids remains controversial. In an attempt to answer this question, we measured the movement of various molecular weight substances from pulmonary capillaries to the fluid filled alveolus using an in vivo saline solution filled dog lung model. During hemorrhage, T1/2--time to 50 per cent equilibration between blood and alveolar liquid--decreased for urea and dextrans of 3,000 and 10,400 molecular weight. There was no change compared with the base line figures for dextran 20,000 molecular weight and albumin, 69,000 molecular weight. In addition, during hemorrhage, lung liquid--but not blood--histamine levels increased significantly. We conclude that hemorrhagic hypotension leads to increased permeability of the alveolar capillary membrane to molecular weight substances less than 20,000 molecular weight. This increased permeability may be mediated by histamine.

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.