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.

Effects of antihistamines on the lung vascular response to histamine in unanesthetized sheep. Diphenhydramine prevention of pulmonary edema and increased permeability.

To see whether antihistamines could prevent and reverse histamine-induced pulmonary edema and increased lung vascular permeability, we compared the effects of a 4-h intravenous infusion of 4 mug/kg per min histamine phosphate on pulmonary hemodynamics, lung lymph flow, lymph and plasma protein content, arterial blood gases, hematocrit, and lung water with the effects of an identical histamine infusion given during an infusion of diphenhydramine or metiamide on the same variables in unanesthetized sheep. Histamine caused lymph flow to increase from 6.0+/-0.5 to 27.0+/-5.5 (SEM) ml/h (P less than 0.05), lymph; plasma globulin concentration ratio to increase from 0.62+/-0.01 to 0.67+/-0.02 (P less than 0.05), left atrial pressure to fall from 1+/-1 to -3+/-1 cm H2O (P less than 0.05), and lung lymph clearance of eight protein fractions ranging from 36 to 96 A molecular radius to increase significantly. Histamine also caused increases in lung water, pulmonary vascular resistance, arterial PCO2, pH, and hematocrit, and decreases in cardiac output and arterial PO2. Diphenhydramine (3 mg/kg before histamine followed by 1.5 mg/kg per h intravenous infusion) completely prevented the histamine effect on hematocrit, lung lymph flow, lymph protein clearance, and lung water content, and reduced histamine effects on arterial blood gases and pH. 6 mg/kg diphenhydramine given at the peak histamine response caused lymph flow and lymph: plasma protein concentration ratios to fall. Metiamide (10 mg/kg per h) did not affect the histamine lymph response. We conclude that diphenhydramine can prevent histamine-induced pulmonary edema and can prevent and reverse increased lung vascular permeability caused by histamine, and that histamine effects on lung vascular permeability are H1 actions.

Pulmonary vascular effects of fat emulsion infusion in unanesthetized sheep. Prevention by indomethacin.

Pulmonary diffusing capacity and arterial blood Po(2) decrease in humans when 10% fat emulsion is infused. To study its effects on the pulmonary circulation and lung fluid balance, we infused 0.25 g/kg x h of a 10% fat emulsion (Intralipid, Cutter Laboratories, Inc., Berkeley, Calif.) into an awake sheep lung lymph preparation. The emulsion caused a sustained increase in pulmonary artery pressure to approximately twice base line with little change in left atrial pressure. Pa(O2) decreased an average 13 torr and lung lymph flow increased two- to threefold. Lymph/plasma total protein concentration fell as lymph flow increased; the magnitude of the lymph/plasma protein decrease was similar to that reported previously when lung vascular pressures were mechanically elevated. Heparin infusion (loading dose = 4,000 U, maintenance dose = 2,000 U/h) cleared the serum of triglycerides but did not alter the response to fat emulsion. Indomethacin infusion (loading dose = 5 mg/kg, maintenance dose = 3 mg/kg x h) blocked the rise in pulmonary artery pressure, the increase in lung lymph flow, and the fall in Pa(O2). Neither extravascular lung water nor [(14)C]urea lung vascular permeability surface area products were altered by fat emulsion infusion. We conclude that fat emulsion infusion in sheep increases lung microvascular filtration by increasing vascular pressures, but has no effect on vascular permeability. Since the effects are blocked by indomethacin, they may be prostaglandin mediated.

Effects of prostaglandin cyclic endoperoxides on the lung circulation of unanesthetized sheep.

Although prostaglandins E(2) and F(2alpha) have been suggested as mediators of the pulmonary hypertension seen after endotoxin infusion or during alveolar hypoxia, their precursors, the endoperoxides (prostaglandins G(2) and H(2)) are much more potent vasoconstrictors in vitro. In this study we compared the effects of prostaglandin (PG)H(2), a stable 9-methylene ether analogue of PGH(2) (PGH(2)-A), PGE(2), and PGF(2alpha) on pulmonary hemodynamics in awake sheep. The animals were prepared to allow for measurement of (a) lung lymph flow; (b) plasma and lymph protein concentration; (c) systemic and pulmonary vascular pressures; and (d) cardiac output. We also determined the effect of prolonged PGH(2)-A infusions on lung fluid balance and vascular permeability by indicator dilution methods, and by assessing the response of lung lymph. Both PGH(2) and PGH(2)-A caused a dose-related increase in pulmonary artery pressure: 0.25 mug/kg x min tripled pulmonary vascular resistance without substantially affecting systemic pressures. Both were 100 times more potent than PGE(2) or PGF(2alpha) in this preparation. PGH(2)-A, as our analysis of lung lymph and indicator dilution measurements show, does not increase the permeability of exchanging vessels in the lung to fluid and protein. It does, however, augment lung fluid transport by increasing hydrostatic pressure in the pulmonary circulation. We conclude: (a) that PGH(2) is likely to be an important mediator of pulmonary vasoconstriction; (b) its effects are probably not a result of its metabolites PGE(2) or PGF(2alpha).

Atypical multicentric reticulohistiocytosis with paraproteinemia.

Two women had multiple subcutaneous nodules that showed features of multicentric reticulohistiocytosis (MR). Neither had joint symptoms. Both had a raised erythrocyte sedimentation rate, an immunoglobulin G paraproteinemia, and raised levels of nonhepatic serum alkaline phosphatase. The skin lesions have been followed up, using light and electron microscopy, immunoperoxidase, and histochemical methods. The material in the giant cells stained positively for gamma heavy chain determinants: the light chain type in each case was that of the paraprotein. An attempt to reproduce the skin lesions in one patient by intradermal injection of her paraprotein failed.

Diagnosis and treatment of fluctuant hearing loss.

Fluctuant hearing loss, a very real and common cause of sensorineural hearing loss, is probably due to cochlear hydrops resulting from an anatomically inadequate endolymphatic sac, poor circulation, and one or more metabolic disorders. In the early stages at least, it often responds to treatment.

Lung vascular permeability: inferences from measurements of plasma to lung lymph protein transport.

In chronically instrumented unanesthetized sheep, we measured steady-state hemodynamic and lung lymph responses to mechanically increased pressure and to intravenous infusions of histamine, Pseudomonas bacteria and E. coli endotoxin. Histamine, Pseudomonas bacteria and E. coli endotoxin caused exchanging vessel permeability to increase, as evidenced by high flows of protein rich lung lymph. This contrasts to the effects of increased pressure where lymph protein concentration falls as lymph flow increases. Microvascular sieving of proteins less than 100 Angstrom radius persisted in all increased permeability states, but with endotoxin, lymph clearance of larger proteins increased much more than with histamine or Pseudomonas. We compared several approaches to quantitative interpretations of lymph data and found that direct methods for calculating permeability-surface area products and reflection coefficients for proteins produced values which were difficult to interpret, probably because fundamental assumptions of the methods were violated in our experiments. A mathematical model based on multiple pore theory produced more plausible coefficients.

Infection of the respiratory tract with Mammomanogamus (Syngamus) laryngeus: a new case in Largo, Florida, and a summary of previously reported cases.

We present an unusual cause for chronic cough. Infection in a man by the nematode Mammomanogamus laryngeus is described along with a review of other reported human cases. High index of suspicion is urged, especially in world travelers.

Salicylate pulmonary edema: the mechanism in sheep and review of the clinical literature.

Several clinical reports of salicylate-induced pulmonary edema led us to investigate the mechanism in a chronic unanesthetized sheep preparation. We infused an aspirin-buffer solution intravenously at rates up to 1,200 mg of aspirin per hour and compared effects on lung lymph flow and lymph protein concentration to those seen after mechanical elevation of pulmonary vascular pressures. Aspirin had little effect on lung vascular pressures but caused lung lymph flow to increase an average of greater than twice baseline. Because lymph protein concentrations were higher for a given lymph flow with aspirin than during mechanical pressure elevation, lymph protein (lymph flow X lymph to plasma protein concentration) increased much more with aspirin. Thus, aspirin appears to cause increased permeability to fluid and protein in the pulmonary vascular bed. Aspirin caused arterial PO2 to decrease from 83 +/- 3 SE mm Hg to 74 +/- 3 mm Hg (P less than 0.05) and caused postmortem extravascular lung water to increase. These findings are supported by a review of the clinical literature, indicating that salicylate pulmonary edema in humans is noncardiac in origin and may occur at doses considered therapeutic for some diseases as well as after overdose.

Diphenhydramine reduces endotoxin effects on lung vascular permeability in sheep.

Because, in sheep, histamine-induced increased lung vascular permeability is prevented by diphenhydramine, we tested the effects of diphenhydramine on the sheep lung vascular response to endotoxin. We infused E. coli endotoxin (0.40-1.00 micrograms/kg) with and without diphenhydramine (3.0 mg/kg bolus + 1.5 mg . kg-1 . h-1) in the same unanesthetized sheep while measuring pulmonary arterial (Ppa) and left atrial (Pla) pressures, lung lymph flow (Qlym) and lymph (L) and plasma (P) protein concentrations. Endotoxin caused pulmonary hypertension soon after infusion (base-line Ppa = 22 +/- 3 (SE) cmH2O; after endotoxin Ppa = 40 +/- 2; P less than 0.05, n = 6) and after several hours an increase in permeability reflected in high flow of protein-rich lymph (base-line; Qlym = 7.5 +/- 1.4 (SE) ml/h, L/P protein concentration = 0.60 +/- 0.02: after endotoxin; Qlym = 21.4 +/- 3.1, P less than 0.05; L/P = 0.66 +/- 0.03, P less than 0.05). In the presence of diphenhydramine, endotoxin caused identical pressure changes but Qlym was lower during the period of increased permeability (16.7 +/- 3.0 (SE) ml/h, P less than 0.05 compared to endotoxin alone) and L/P protein concentration was similar (0.68 +/- 0.04, P = NS). We conclude that endogenous histamine may be partly responsible for the increase in lung vascular permeability after endotoxemia, but that histamine probably is not the sole mediator of the permeability change.

Increased pulmonary vascular permeability follows intracranial hypertension in sheep.

After reviewing the characteristics of neurogenic pulmonary edema, Theodore and Robin suggested that it was probably due to rupture of lung vessels by marked but transitory pulmonary hypertension. In this study, we have determined the effects of increased intracranial pressure in a sheep model in which we could measure the flow rate and protein content of lung lymph, and thus detect changes in pulmonary vascular permeability. We found that increasing intracranial pressure to amounts near systemic arterial pressure produced a 3-fold increase in the flow of protein-rich lymph, which indicates increased lung vascular permeability. The high permeability often developed, and always persisted, without extraordinary increases in pulmonary vascular pressure. We conclude that increased lung vascular permeability may follow intracranial hypertension and that extreme pulmonary hypertension is not a prerequisite. Our data do not permit us to exclude barotrauma to exchanging vessels as a cause of capillary damage, but do suggest that other factors, perhaps local release of permeability mediators, may be involved.