Neurogenic pulmonary edema. Pathogenesis, clinical picture and therapy

Neurogenic pulmonary edema (NPE) is a rare but always life-threatening complication in patients with central nervous system lesions. NPE is evident if patients shortly after cerebral lesions suddenly develop pulmonary edema and other causes of the symptoms, such as aspiration of gastric content, congestive heart failure and direct toxic exposure, are ruled out. METHODS: The current body of literature, partially obtained by computer-guided search (Winspirs) regarding epidemiology, pathophysiology and therapy of NPE was reviewed. Additionally, the case of a patient who developed a sudden pulmonary edema after an episode of tonic-clonic seizures is analyzed. We first provide information about history, definition, incidence and mortality of NPE. Second, a case report of a postictal NPE is presented to illustrate the clinical picture of NPE, and the applied therapeutic strategies are discussed. Third, recent pathophysiologic concepts about symptoms and possible therapeutic principles are reviewed. Fourth, a rational therapeutic plan for the prehospital emergency therapy of NPE is outlined. RESULTS: The different etiologies all have one characteristic feature: an acute emergency which causes increased intracerebral pressure (ICP). NPE is known in patients after cerebral trauma, intracranial hemorrhage, stroke, intracranial tumor or seizures. The incidence is estimated at around 1% after cerebral trauma, at 71% after cerebral hemorrhage and at 2% after seizures. Mortality is appraised to lie between 60 and 100%, independent of etiology. There is a definite pathophysiologic sequence leading to NPE: a central nervous system lesion causes a sudden increase in ICP which triggers an upregulation of sympathetic signal transduction to assure brain perfusion. Increased tonus of venous and arterial vessels and of myocardial function are the immediate consequences. However, if systemic vascular resistance (SVR) increases excessively, left ventricular failure and finally pulmonary edema (NPE) may result. Additionally, the protein-rich edema fluid points to an increased endothelial permeability within the pulmonary circuit. This is thought to be caused by the acute pressure increase and by neurohumoral mechanisms, possibly similar to those described for the systemic inflammatory response syndrome (SIRS). The most important central nervous system structures involved in NPE are the medulla oblongata and the hypothalamus. CONCLUSION: NPE is always a life-threatening symptom after increased ICP, where immediate therapeutic interventions are imperative. A rational therapeutic approach needs to be focused on decreasing ICP as primary goal. Additionally, attempts should be made to optimize body oxygenation, decrease pre- and afterload and increase myocardial contractility. Postictal patients suspicious for incipient ventilation problems must be admitted to hospital for further evaluation.     

Expression cloning and characterization of a renal electrogenic Na+/HCO3- cotransporter

Bicarbonate transporters are the principal regulators of pH in animal cells, and play a vital role in acid-base movement in the stomach, pancreas, intestine, kidney, reproductive system and central nervous system. The functional family of HCO3- transporters includes Cl- -HCO3- exchangers, three Na+/HCO3- cotransporters, a K+/HCO3- cotransporter, and a Na+-driven Cl- -HCO3- exchanger. Molecular information is sparse on HCO3- transporters, apart from Cl- -HCO3- exchangers ('anion exchangers'), whose complementary DNAs were cloned several years ago. Attempts to clone other HCO3- transporters, based on binding of inhibitors, protein purification or homology with anion exchangers, have so far been unsuccessful. Here we monitor the intracellular pH and membrane voltage in Xenopus oocytes to follow the expression of the most electrogenic transporter known: the renal 1:3 electrogenic Na+/HCO3- cotransporter from the salamander Ambystoma tigrinum. We now report the successful cloning and characterization of a cDNA encoding a cation-coupled HCO3- transporter. The encoded protein is 1,035 amino acids long with several potential membrane-spanning domains. We show that when it is expressed in Xenopus oocytes, this protein is electrogenic, Na+ and HCO3- dependent, and blocked by the anion-transport inhibitor DIDS, and conclude that it is the renal electrogenic sodium bicarbonate cotransporter (NBC).     

Myocardial function during hypoxia in the presence of different buffers

Electrically driven rabbit left atria were exposed to 20 min periods of either hypoxia or anoxia in the presence of a bicarbonate-phosphate buffer, a Tris buffer [tris (hydroxymethyl) aminomethane hydrochloride] or combination of both. The bicarbonate-phosphate buffer system was shown to be important for tissue survival during hypoxia or anoxia whereas recovery was diminished in the presence of Tris only. Stimulus threshold and arrhythmias were shown to increase for atria in Tris. Oxygen consumption determinations on both spontaneously beating right atria and quiescent left atria showed no difference between pre- and post-hypoxia or between different buffers. Tris was shown to elicit a positive inotropic effect without an increase in O2 consumption.     

Nitrogenase activity and respiration of cultures of Rhizobium spp. with special reference to concentrations of dissolved oxygen

Studies of nitrogenase in cultures of the cowpea rhizobia (Rhizobium spp.) strains 32H1 and CB756 are reported. Preliminary experiments established that, even when agar cultures were grown in air, suspensions of bacteria prepared anaerobically from them were most active at low concentrations of free dissolved O2. Consequently, assays for activity used low concentrations of O2, stabilized by adding the nodule pigment leghaemoglobin. In continuous, glutamine-limited cultures of 32H1, nitrogenase activity appeared only when the concentration of dissolved O2 in the cultures approached 1 muM. Lowering the glutamine concentration in the medium supplied to the culture from 2 to 1 mM halved the cell yield and nitrogenase activity was also diminished. Omitting succinate from the medium caused the concentration of dissolved O2 to rise and nitrogenase activity was lost. Upon restoration of the succinate supply, the O2 concentration immediately fell and nitrogenase was restored. The activity doubled in about 8 h, whereas the doubling time of this culture was 14 h. Sonic extracts of 32H1 cells from continuous cultures with active nitrogenase contained components reacting with antiserum against nitrogenase Mo-Fe protein from soybean bacteroids. Continuous cultures grown at higher O2 concentration, with only a trace of active nitrogenase, contained less of these antigens and they were not detected in highly aerobic cultures. Nitrogenase activity of a continuous culture was repressed by NH+4; the apparent half-life was about 90 min. Cells of 32H1 from a continuous culture growing at between 30 and 100 muM dissolved O2 possessed a protective mechanism which permitted respiration to increase following exposure to a rapid increase in O2 concentration from low levels (O2 shock). This effect disappeared as the O2 concentration for growth was reduced towards 1 muM.     

In-vitro metabolism of etomidate by rat liver fractions

(R)-(+)-etomidate and (S)-(-)-etomidate were found to be metabolized in-vitro by various rat liver homogenization fractions: the 16,000 g supernatant fraction caused a more intensive metabolic breakdown than the microsomal fraction; the 100,000 g supernatant fraction was only slightly active. The metabolism was somewhat more rapid and more extensive for the (R)-(+)-etomidate than for the (S)-(-)-isomer. For both isomers, a dose-dependence was observed: the smaller the substrate concentration, the smaller the relative amount of unmetabolized drug, and the more the rate of metabolic breakdown after a certain incubation time slowed down. Only minor qualitative differences between the metabolic pathways of the two isomers were observed. The main metabolic pathway for the in-vitro metabolism was the hydrolysis of the ethyl ester. Decarboxylation and oxidative N-dealkylation were also observed.     

Impact of protein deprivation on protein and DNA synthesis in the developing rat pancreas

The metabolic effects of protein malnutrition on growth and development of the exocrine pancreas are largely unknown. The aim of the present study was to evaluate the effects of protein malnutrition on pancreatic protein and DNA synthesis during postnatal development. Rat dams and their offspring were fed a protein-deficient diet (6% casein) or a control diet (25% casein) during gestation, lactation and after weaning. Pancreatic protein and DNA synthesis were measured in vitro at postnatal ages 1, 3, 10, 23, 36 and 60 days, by assessing [3H]leucine and [3H]thymidine incorporation in freshly isolated acini. Different patterns of protein synthesis were seen in the two groups. At birth, pancreatic protein synthesis was low in both control and malnourished animals. At day 3, protein synthesis in the control acini increased 10-fold while synthesis in acini of the malnourished animal group was only 50% of age-matched control values. No differences in protein synthesis were detected between the control and malnourished groups between 10 and 36 days of age. At 60 days (adulthood), acinar protein synthesis declined in the control-fed rats, but a significant increase was observed in the malnourished animals (p < 0. 0005). At birth, DNA synthesis was high in the acini from both control and malnourished animals. The low-protein diet induced a slight reduction in DNA synthesis at day 3, without altering the general pattern during later stages of development. In conclusion, protein deprivation has variable effects on pancreatic protein and DNA synthesis at different stages of postnatal development. Furthermore, the mechanisms of control within acini appear to be intrinsically regulated.     

Human and clinical perspectives on leptin

The neurochemical coding of neurones located in ganglia of the nerve trunk accompanying the chicken ureter was analysed and quantified using NADPH-diaphorase reactivity and immunohistochemistry against tyrosine hydroxylase (TH), nitric oxide synthase (NOS), calbindin (CAL), vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), somatostatin (SOM), substance P (SP) and calcitonin gene-related peptide (CGRP) in untreated or colchicine-treated preparation. Almost all neurones were either positive for TH (38%) or for SOM (60%). Only 4% of the neurones were both TH- and SOM-positive and 3% of the neurones exhibited neither TH nor SOM immunoreactivity. The relative numbers of NPY-, NOS-, CAL- and VIP-positive neurones were 57%, 28%, 14% and 7%, respectively. No SP- or CGRP-positive neurones were observed. All NADPH-diaphorase-positive neurones expressed NOS immunoreactivity. Only in some TH-positive neurones was NPY and/or NOS found. Four major subpopulations were found in the ureteric ganglia. The SOM-positive neurones were subdivided into SOM/NPY/NOS- (28% of all neurones), SOM/NPY- (18%) and SOM/CAL/NPY-positive neurones (14%). A subpopulation of these peptid- ergic neurones also contained VIP. About 35% of the neurones contained TH only. Neurones of all subpopulations (72% of the neurones), except most of the CAL-positive neurones, were encircled by dense plexus of varicose SP/CGRP-positive, presumably sensory nerve fibres. Dense plexus of VIP-positive fibres were observed around 89% of the neurones. The chemical coding of the neuronal subpopulations identified in the ganglia accompanying the chicken ureter resembled that observed in the ganglia of Remak's nerve but was remarkably different from that of the autonomic neurones described in mammalian species.