I N the clinical situation it is not uncommon

Transcription

1 J Neurosurg 51:78-84, 1979 Influence of on the composition of isolated edema fluid in cold-induced brain edema K. GWAN GO, M.D., JURJEN GAZENDAM, M.D., AND ANNIE K. VAN ZANTEN, B.c. Department of Neurosurgery and Central Isotope Laboratory, University of Groningen, Groningen, The Netherlands v" The isolation of edema fluid from cats with cold-induced cerebral edema allowed the study of changes of Na + and K + content, lactate dehydrogenase and creatine phosphokinase activity, colloid osmotic pressure and the level of intravenously administered 9~mTc-albumin in the edema fluid during a period of. The changes consisted of an increase of all mentioned parameters, except Na+; and could be interpreted as a concentration of solutes (but for Na +) in the extracellular edema fluid, concomitant to a reduction of the extracellular space, as the oxygen deficiency caused improper functioning of the cellular Na+-K + pump, with a resulting shift of fluid (including Na into the cellular elements. KEY WORD 9 brain edema 9 9 chemistry 9 sodium pump I N the clinical situation it is not uncommon for patients suffering from brain edema to undergo episodes of deficient oxygenation in relation to respiratory complications. Apart from the deleterious influence the may have on brain tissue metabolism, already altered by the edematous condition, changes of tissue fluid balance may be considered to occur. Whereas in vasogenic edema the edema fluid is located in the extracellular space, tends to induce a water accumulation in the intracellular space on account of the energy deficit blocking the proper functioning of the Na+-K pump. Furthermore, during our earlier studies of isolated edema fluid, incidentally an excessive elevation of edema fluid colloid osmotic pressure was observed, suggesting a relation with a deficient tissue oxygenation occurring during the experiment? In this study was induced in a series of cats in which edema fluid was isolated for analysis following a cold injury, as described in a previous paper? Materials and Methods Cats were anesthetized with phenobarbital intramuscularly, and pentobarbital intraperitoneally, and anesthesia was maintained with nitrous oxideoxygen through endotracheal intubation as in the previous series? In addition, muscular relaxation was achieved by the intravenous injection of suc- cinylcholine (2.5 mg/kg body weight) every 30 minutes, and the animals were ventilated with a Loosco infant ventilator.* Cannulation of the right femoral artery and vein was performed for arterial blood pressure recording and intravenous injection of 99mTc-labeled albumin and Evans blue. Ventricular fluid pressure was monitored through a needle in the right cerebral ventricle. The cold injury was inflicted on the left cerebral cortex by applying a freezing probe at -30 ~ C for 5 minutes directly on the dura, followed by the insertion into the brain of needles connected to polyethylene tubes devised for the isolation of edema fluid, as in the previous series? Hypoxia was induced 100 minutes after the cold injury, by changing ventilation from 1 liter liters N~O before, to (0.15 to 0.5) liters O5 + (2.85 to 2.5) liters N~O, making 3 liters/min. Edema fluid and blood samples were collected every 30 minutes, and cerebrospinal fluid (CF) was obtained just before killing, that is, 5 hours after the cold injury. The samples were subjected to the same analysis as reported in the previous series, and those data are considered as controls for the present experiment? *Loosco infant ventilator manufactured by Hoekloos, chiedam, P.O.B. 78, The Netherlands. 78 J. Neurosurg. / Volume 51 / July, 1979

2 Influence of on cold-induced edema Na+ meq/liter JL A I ~ gray 4 5 hours Fro. 1. Mean sodium content of and edema fluid in the (A) and gray (B) before and after the induction of at 100 minutes after cold injury (with standard deviation). I Blood Gases Results During the arterial oxygen tension decreased to mm Hg compared to mm Hg before, while oxygen saturation diminished to % from the value of % before. During the hypoxic period the arterial CO2 tension decreased from to mm Hg, while ph changed from to Location of Needles As in the previous series, the tips of the needles measuring 4, 5, 8, 9, 10, 11, and 12 mm were situated in the underlying the lesion; the tips of those measuring 6 and 7 mm were in the uninjured wedge of cortex underneath the lesion and the needle 13 mm in length had its tip in the gray of the claustrum. Electrolytes Plasma sodium remained at the same level (mean meq/liter) throughout the experiment. Nor did edema fluid Na + change during the experiment, even during, both in and in gray (mean and meq/liter, respectively). Plasma potassium was elevated during the hypoxic period, particularly at the end ( meq/liter) compared to the value before ( meq/liter). Edema fluid K + showed a decrease during the 100 minutes before. After the start of the hypoxic episode, edema fluid K + rose to a maximum at 4 hours after cold injury of meq/liter for gray and meq/liter for (Figs. 1 and 2). Technetium-99m-Labeled Albumin Plasma 9Wc-albumin radioactivity showed the same declining course as in the control series. Before, edema fluid 99mTc-albumin activity showed the same course as in the control series, that is, downward for and upward for cortex. After the induction of, however, edema fluid samples from both and gray showed an elevation of 99mTc-albumin activity (significant with respect to controls) to maximum values of % and %, respectively, at 3 hours after cold injury (Fig. 3). Colloid Osmotic Pressure Colloid osmotic pressure of showed the same decrease during the experiment as in the control series. Before, colloid osmotic pressure of edema fluid showed the same inclination as in the control series, in which that of decreased from an initial high value, and that of gray increased from an initial low value. During the period of the colloid osmotic pressure of edema fluid in both and gray rose to maximum values of and mm Hg, respectively, at 4 hours after cold injury. Notably the colloid osmotic pressure of the edema fluid samples exceeded that of from 80 minutes after induction of onward (Fig. 4). J. Neurosurg. / Volume 51 / July,

3 K. G, Go, J. Gazendam and A. K. van Zanten K + m Eq/liter I / ~ 12 A 12 \ 8 I "f ~ ~ nnlmnm mm ~t; \l \ gray ~ ~ 4 5 hours FIG. 2. Mean potassium content of edema fluid in the (A) and gray (B) as compared to, before and after the induction of (100 minutes following cold injury). refers to significant difference (p < 0.05) between gray and. Asterisk refers to significant difference (p < 0.05) with respect to controls at the same time. B % ~ gray t) is hours FIG. 3. Meang~mTc-albumin radioactivity(as percentage ofinitialradioactivity) of and edemafluid ~om andgray, be~reandahertheinductionof. DefinitionsasinFig J. Neurosurg. / Volume 51 / July, 1979

4 Influence of on cold-induced edema cop mmhg 24 2o - ~ ~ ~ 16 ~~ 12 /. =/' 8 / $ gray hours FIG. 4. Mean colloid osmotic pressure (COP) of, and edema fluid from gray and, be~re and during. Definitions asin Fig. 2. LDH 12 U/liter xl03 10 s?- /..11 -% gray hours FIG. 5. Mean lactate dehydrogenase (LDH) activity in, and edema fluid from gray and, before and during. Definitions as in Fig. 2. Enzymes Plasma lactate dehydrogenase (LDH) activity showed no changes during the experiment. Edema fluid LDH activity showed the same course in the first 100 minutes before as in the control series, that is, declining for and rising for gray. At the induction of both and gray activities started to rise to a maximum of 9745 i 949 U/liter for and U/liter for gray at 240 minutes after freezing (Fig. 5). Creatine phosphokinase (CPK) activity of was slightly elevated at the beginning of the experiment but decreased gradually. In - edema fluid, CPK activity started high and decreased steeply during the period before J. Neurosurg. / Volume51 /July,

5 K. G. Go, J. Gazendam and A. K. van Zanten CPK U/liter 3 xlo 12 i0 4/ 6 gray hours FIo. 6. Mean creatine phosphokinase (CPK) enzyme-activity in, and edema fluid from gray and, be~re and during. Definitions as in Fig. 2., whereas in the gray, edema fluid showed an increasing CPK activity before ; both courses were similar to the control series. During the period of deficient oxygenation, CPK activity in both - and gray- edema fluid rose to maximum values of 11, and 12, U/liter, respectively (Fig. 6). Cerebrospinal Fluid Of the 10 animals in the present series, CF could be obtained at the end of the experiment from four. In these, Na + content was meq/liter; K + content meq/liter; 9~Tc-albumin radioactivity % of activity; colloid osmotic pressure mm Hg; LDH activity U/liter; and CPK activity U/liter. Ventricular Fluid Pressure Ventricular fluid pressure became elevated to a mean maximum value of mm H~O, which was higher than in the control series, as an additional pressure rise occurred after induction of the. Discussion In the first period of the experiment in which oxygenation was adequate, the results of analysis of the edema fluid showed a similar pattern to that in the control series: a decreasing K level after a high initial value in both and gray, a declining 99~Tc-albumin radioactivity, colloid osmotic pres- sure, and enzyme content after high starting values in - edema fluid. Edema fluid in the gray showed a rising course for the same parameters. The high initial values in edema fluid in represent the breakdown of the blood-brain barrier (causing ggmtc-albumin passage and elevation of colloid osmotic pressure) or cellular damage by the freezing (with consequent release of K and enzymes), whereas the low but subsequently rising values in edema fluid in gray reflect the delayed migration of the high-molecular components of the exudate into the gray. 4 The induced was of a moderate degree, as judged by the decrease of arterial oxygen tension and of oxygen saturation. A more severe grade of proved not to be compatible with the times of survival in which the changes were studied in this series. Due to slight hyperventilation of the animals there was a concomitant hypocapnia. Nevertheless, there remained some degree of metabolic acidosis, presumably related to the general lack of oxygen in the entire organism. The period of was characterized by an elevation of colloid osmotic pressure, a~mtc-albumin radioactivity, LDH and CPK content, and K concentration of the edema fluid from both and gray. Typically the Na content of edema fluid remained unchanged. It was considered whether these changes could be explained by the release of cellular contents due to alterations of permeability of the cellular membranes induced by the. However, a change of membrane permeability that would allow the massive 82 J. Neurosurg. / Volume 51 / July, 1979

6 Influence of on cold-induced edema 9 OD [] peote~n 9 Ila + O II+ o,, ~ -,,, 'DoX- ~,,~ J ~ v Io o%~_ \" /0 \,, ----'. \ o / 9 I."Do. o 0/ o 9 vasogenic brain edema vasogenic brain edema + FIG. 7. Diagram representing the distribution of protein, sodium, and potassium in the cellular elements and the distended extracellular spaces of brain tissue with vasogenic edema (left) and when is also present {right). passage of large protein molecules was difficult to conceive. Moreover, it would not account for the elevation of edema fluid a~r~tc-albumin activity, as this exogenous protein was not present within the cells. Therefore, the increase of all the estimated parameters (except Na +) in edema fluid during was interpreted as the result of concentration of the solutes in the extracellular edema fluid and the reduction of the extracellular space due to the shift of water, accompanied by Na +, into the cells (Fig. 7). Hypoxia is known to create a shift of fluid into the cellular elements of the brain, causing their swelling, as demonstrated by electron microscopy, n.12 The shift of fluid may be explained by the improper functioning of the Na+-K + pump, resulting from the energy deficit during, as has been reported to decrease the tissue adenosine triphosphate: adenosine diphosphate (ATP/ADP) ratio and the tissue creatine phosphate content, and to raise the tissue lactate:pyruvate ratio. 2,s,9 imilar changes of edema fluid composition were observed after the intracerebral injection of ouabain, 5 relating them to the functioning of the cellular Na+-K + adenosine triphosphatase, as ouabain is known to block the enzyme by binding. The shift of fluid during oxygen deficiency comprises the entry of Na +, water, and CI- into the cellsj ~ and the loss of K + from them.' The release of K + into the extracellular edema fluid during was obvious from the elevation of its concentration in edema fluid; this increase was excessively high presumably because of the concomitant concentration of the edema fluid. The K outflow was also evident, as an additional rise of K + content in the CF samples, in accordance with earlier reports. 7 Although Na + was shifted into the cells from the extracellular edema fluid during the period of deficient oxygenation, the Na + level in edema fluid did not decrease, suggesting a proportional diminution of the extracellular space (previously distended by the edema). This reduction of the extracellular space was also indicated by the increase of electrical impedance measured during in a comparable series of animals? On comparing the increases of the various parameters during, the increases of LDH and CPK activities (4.5 and 6 times the control values, respectively) far exceed the increases of colloid osmotic pressure and 99mTc-albumin radioactivity (1.9 and 1.1 times the control values, respectively). This finding suggests some release of the enzymes from the cellular elements during as an explanation of the excessive augmentation of enzyme activities. It still remains to be clarified, however, how large these increases would be, expressed in molar concentration, that is, to what extent they would contribute to the total protein concentration in the edema fluid. In the light of the tarling hypothesis of transcapillary fluid exchange, it may be considered whether during the elevated colloid osmotic pressure of edema fluid, which even exceeds that of, may result not only in a fluid balance favoring retention of the edema fluid, but eventually in a shift of fluid into the tissue, causing aggravation of the edema. The additional elevation of ventricular fluid pressure, which occurred within a relatively short time on induction of the, may probably be ascribed to vasodilatation rather than to the additional development of edema. J. Neurosurg. / Volume 51 / July,

7 K. G. Go, J. Gazendam and A. K. van Zanten Acknowledgments We are indebted to Mr. F. Zuiderveen, Mrs. T. de Vries- Visscher, and Miss D. Woidendorp for technical assistance, and to Prof. W. chaafsma for statistical advice. References 1. Blank WF Jr, Kirshner H: The kinetics of extracellular potassium changes during and anoxia in the cat cerebral cortex. Bruin Res 123: , Broniszewska-Ardelt B, Jongkind JF: Effect of on substrate levels in the brain of the adult mouse. J Neurochem 18: , Gazendam J, Go KG, Van der Meer J J, et al: Changes of electrical impedance in edematous cat brain during and after intracerebral ouabain injection. In preparation 4. Gazendam J, Go KG, van Zanten A: Composition of isolated edema fluid in cold-induced brain edema. J Neurosurg 51:70-77, Gazendam J, Go KG, van Zanten AK: The effect of intracerebral ouabain administration on the composition of edema fluid isolated from cats with cold-induced brain edema. Brain Res (In press) 6. Go KG, Patberg WR, Teelken AW, et al: The tarling hypothesis of capillary fluid exchange in relation to brain edema, in Pappius HM, Feindel W (eds): Dynamics of Brain Edema. Berlin/Heidelberg/New York: pringer-verlag, 1976, pp Kirshner H, Blank WF Jr, Meyers RE: Changes in cortical subarachnoid fluid potassium concentrations during. Arch Neurol 33:84-90, Lippmann HG: Energiereiche Phosphate, Glukose, Laktat und Pyruvat im Hirn der Ratte unter )~nderung des po2 der Inspirationsluft. Acta Biol Mefl Ger 27: , alford LG, Plum F, iesj6 BK: Graded oligemia in rat brain. I. Biochemical alterations and their implications. Arch Neurol 29: , Van Harreveld A, chad6 JP: On the distribution and movements of water and electrolytes in the cerebral cortex, in Tower DB, chade JP: tructures and Function of the Cerebral Cortex. New York: American Elsevier, 1960, pp Webster HdeF, Ames A III: Reversible and irreversible changes in the fine structure of nervous tissue during oxygen and glucose deprivation. J Cell Biol 26: , Yu MC, Bakay L, Lee JC: Ultrastructure of the central nervous system after prolonged. I. Neuronal alterations. Acta Neuropathol 22: , 1972 Address reprint requests to: K. Gwan Go, M.D., Department of Neurosurgery, University Hospital, Groningen, The Netherlands. 84 J. Neurosurg. / Volume 51 / July, 1979