The effect of dexamethasone phosphate on the production rate of cerebrospinal fluid in the spinal subarachnoid space of dogs

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1 The effect of dexamethasone phosphate on the production rate of cerebrospinal fluid in the spinal subarachnoid space of dogs OSAMU SATO, M.D., MAKOTO HARA, M.D., TAKEHIKO ASAI, M.D., RYUICHI TSUGANE, M.D., AND NAOKI KAGEYAMA, M.D. Department of Neurosurgery, Nagoya University School o[ Medicine, Nagoya, Yapwi The effect of intravenous dexamethasone on cerebrospinal fluid (CSF) production was studied in dogs by a method of caudocephalad perfusion of the spinal subarachnoid space with an inulin-containing buffer. The CSF production rate began to reduce immediately after the injection of 0.15 mg/kg and attained a maximal reduction of 50% in 50 minutes. KEY WORDS production dexamethasone phosphate spinal subaraehnoid space cerebrospinal fluid intracranial space INCE the classical experiments of Dandy and Blackfan, 5,e the choroid plexus has been considered to be a main source of cerebrospinal fluid (CSF). The suggestion of extraventricular fluid formation was reviewed by Weed 34 and substantiated by many others; 2,4,1~ however, no one has accurately measured the rate quantitatively. Various techniques have been used to study the rate of CSF formation, the most satisfactory being the perfusion of the cerebrospinal fluid system developed by Pappenheimer, et al. 21 They performed ventriculocisternal perfusion in the goat with artificial CSF containing inulin as a tracer and showed that only very small amounts of inulin leave the ventricles by either diffusion or active transport into the brain or blood. Rail, et al., 2~ also confirmed this and concluded that decrease in the inulin concentration occurring during perfusion was almost exclusively related to the volume of newly formed CSF in the system. Applying this technique to kaolin-induced hydrocephalic dogs, Sato and Bering 29 measured the formation rate of CSF in the intracranial subarachnoid space at ml/min. Sato, et al., 28 reported a production rate of ml/min in the spinal subarachnoid space using the same technique. Since the work of Prados, et al., 28 which showed that adrenal cortical and anterior pituitary extracts reduced cerebral edema, much attention has been paid to the value of steroids in the treatment of cerebral edema and intracranial hypertension. However, there have been only a few papers reporting the effect of steroids in the production and absorption of CSF. a,9,2n'a5 Sato 26 has reported that the CSF production rate of ml/min in the whole intracranial space can be reduced by about 50% with the use of 0.15 mg/kg of intravenous dexamethasone. It is the purpose of this paper to clarify whether or not there is any difference in the 480 J. Neurosurg. / Volume 39 / October, 1973

2 Effect of dexamethasone phosphate on CSF production effect of dexamethasone on the production rate in the whole intracranial space including the choroid plexus and ependymal layer, and the spinal subarachnoid space that does not contain these structures. Materials and Methods For this study we used 26 adult mongrel dogs, weighing between 10 and 15 kg. The whole perfusion system followed the method described by Pappenheimer, et al., 13,21,22 and the technique of spinal subarachnoid space perfusion has been stated in detail previously. 27 Perfusions of artificial CSF containing 25 mg% of inulin solution as a tracer were carried out in a caudocephalad direction for about 3 hours without changing the perfusion pressure, which ranged from 70 to 180 mm H20. After a stable state was reached, two 10-minute samples were taken; the dogs were then given 0.15 mg/kg of dexamethasone phosphate intravenously. After the injection, samples were taken every 10 minutes in the first 30 minutes and every 20 minutes thereafter for 2 hours. Inulin determination was carried out on these samples by means of resorcinol. 31 Figure 1 illustrated the experimental set-up. Results The net rate of CSF formation was calculated by the means of Heisey, et al. a'~ The rate of formation was equal to inulin clearance plus the difference between outflow and inflow rates. According to Sato, et al., '2r,2s the formation rate of CSF in the spinal subarachnoid space of dogs is expressed as: Vf = ( ) CSFP ml/min. CSFP was the CSF pressure when zero pressure was taken at the level of the spinal cord. Inulin was removed from the subarachnoid space by bulk absorption at a rate that varied linearly with the hydrostatic pressure. However, pressure was proved to have only a little effect on the CSF production in the spinal subarachnoid space. In the present series, perfusions were carried out in 26 dogs; only in 10 dogs were the data considered satisfactory from the technical point of view (Table 1). The reduction in the CSF production rate was estimated at about 50%, and began 10 to 20 minutes after the dexamethasone was administered; it reached its maximum decrease in approximately 30 to 50 minutes. Although Table 1 indicates that CSF production in the space examined was FIG. 1. Diagram of the perfusion system. J. Neurosurg. / Volume 39 / October,

3 Sato, Hara, Asai, Tsugane and Kageyama TABLE 1 Effect of intravenous dexamethasone on CSF production rate Before Dexamethasone Alter Dexamethasone (ml/min) Dog (ml/min) No min min rain min min min min min rain min DSP DSP DSP DSP DSP DSP DSP DSP DSP DSP abolished, or virtually so, at the end of the experiments in four of the animals, no definite conclusion was reached as to whether this indicated actual cessation of CSF production or deterioration of the preparation after a 5-hour period of perfusion. Discussion There are many theories to explain the efficacy of glucosteroids in the treatment of cerebral edema of intracranial hypertension. Among these are such postulations as the possibility that steroids reduce the cerebral edema, 3,~,s,12,15,17,18,25,3~ inhibit the growth of tumor cells, 16,'~r reduce the production of CSF, ~6,36 or act on some extracerebral site. g0 Actually, satisfactory explanations of the basic mechanism of steroid therapy are fragmentary; little attention has been paid to the influence of steroids on production and absorption of CSF. Garcia-Bengochea 9 administered cortisone acetate 20 mg/kg/day to non-castrated cats for 2 weeks and found a significant reduction of CSF as measured by spinal catheterization; he ascribed the reduction to augmented diuresis. However, others 26 believed this was not an exact measurement of CSF production. Using a ventriculocisternal perfusion method with artificial CSF containing inulin as an indicator, Sato ~6 measured the CSF production rate quantitatively after administration of dexamethasone in dogs; he reported that the CSF production rate was reduced by 50% in 30 minutes with rapid administration of the doses of 0.15 mg/kg dexamethasone, and suggested that dexamethasone works closely on the water-ion transport system. It is important to notice that Garcia-Bengochea used large doses of cortisone for 2 weeks while Sato's experiments involved a single injection. Amano I also studied the influence of dexamethasone on the CSF production rate in the edematous brains of dogs. Brain edema, produced by shaking the dog's head, resulted in a significant fall of CSF production after administration of dexamethasone 0.15 mg/kg within 60 minutes. Weiss and Nulsen z5 made dogs hydrocephalic by the intracisternal injection of a suspension of kaolin and compared these to normal dogs with regard to the influence of dexamethasone on CSF production. Ventricular drainage of hydrocephalic dogs and cisternal drainage of normal dogs were used for the evaluation of measurement 30 cm below the level of the right atrium. They found a reduction of 40% in hydrocephalic dogs and 50% in normal dogs compared to control groups within 30 minutes after the administration of 0.25 mg/kg of dexamethasone. This corresponds well with Sato's result. No difference between these two groups was noted. They further analyzed the CSF and serum osmolality, electrolytes, and chemical constituents that would influence the flow of CSF, and found no significant differences between controls and animals 482 J. Neurosurg. / Volume 39 / October, 1973

4 Effect of dexamethasone phosphate on CSF production treated with dexamethasone. They suggested alteration of some undefined active cellular process as the underlying mechanism; they could not show any significant change in the parameters that would establish a passive diffusional gradient between the subarachnoid and vascular compartments. Recently, Schwartz, et al., 32 claimed that normal brain, and especially the choroid plexus, shows a rapid uptake of radioactive hydrocortisone; this may indicate a direct and specifically located action that reduces CSF production. Using mice of strain C57BL and autoradiography, they found penetration into normal brain tissue, especially the choroid plexus, within 2 minutes, and clearance by 60 minutes. No comment was made on the reason for this significant uptake by the choroid plexus. The choroid plexus was conventionally considered the site of CSF production. However, more recently it has been generaliy accepted that CSF is also produced in extraventricular cerebrospinal subarachnoid spaces. Choroid plexus was proven to form 30% to 40% of the CSF produced in the ventricular system rostral to the fourth ventricle of the rhesus monkey, 19,2~ and CSF formation in the ventrieular system amounted to 42% in dogs. ~s Our results were similar to those of our previous study; 26 that is, the CSF production rate began to reduce within 10 minutes and reached about 50% reduction within 50 to 60 minutes after intravenous dexamethasone administration. This means that Schwartz's findings may only indicate its accumulation in the blood vessels of the choroid plexus and that a steroid does not exert its action on the choroid plexus selectively. Since the actual mechanism of CSF production is still not clearly defined, the reason why steroid reduces the CSF production remains obscure. However, our present study shows the effect of steroid on the intracranial CSF system to be similar to its effect on the spinal subarachnoid space. We can only agree with Weiss's comment that alteration of some undefined active cellular process is the underlying mechanism in the production of CSF. References 1. Amano Y: The cerebrospinal fluid production rate in the experimentally induced edamatous brain and influences of dexamethasone upon it. Nagoya J Med Sci 31: , Bering EA Jr, Sato O: Hydrocephalus: changes in formation and absorption of cerebrospinal fluid within the cerebral ventricles. J Neurosurg 20: , Blinderrnan EE, Graf CJ, Fitzpatrick T: Basic studies in cerebral edema. Its control by a corticosteroid (Solu-Medrol). J Neurosurg 19: , Boldrey EB, Low-Beer BVA, Stern WE, et al: Formation and absorption of fluid in the spinal subarachnoid space in man. Report of ease. Bull Los Angeles Neurol Soc 16: , Dandy WE: Experimental hydrocephalus. Ann Surg 70: , Dandy WE, Blackfan KD: Internal hydrocephalus: an experimental, clinical and pathological study. Am.I Dis Child 8: , Galicich JH, French LA: Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am Praetit 12: , Galicich JH, French LA, Belby JC: Use of dexamethasone in the treatment of cerebral edema associated brain tumors. Lancet 81:46-53, Garcia-Bengochea F: Cortisone and the cerebrospinal fluid of non-castrated cats. Am Surg 31: , Hassin GB: Notes on the nature and origin of the cerebrospinal fluid. J Nerv Merit Dis 59: , Hassin GB: Cerebrospinal fluid: its origin, nature and function..i Neuropath Exp Neurol 7: , Hatanaka H, Sano K, Kitamura K, et al: (Steroids and cerebral edema.) Brain Nerve (Tokyol 15: , 1963 (Jap) 13. Heisey SR, Held D, Pappenheimer JR: Bulk flow and diffusion in the cerebrospinal fluid system of the goat. Am J Physiol 203: , Katzenelbegen S: The Cerebrospinal Fluid and its Relation to the Blood. A Physiological and CHnieal Study, Vol 19. Baltimore, Johns Hopkins Press, 1935, p Kofman S, Garvin JS, Nagamani D, et al: Treatment of cerebral metastases from breast carcinoma with prednisolone. JAMA 163: , Kotsilimbas DG, Meyer L, Berson M, et al: Corticosteroid effect on intracerebral melanomata and associated cerebral edema. Neurology 17: , Lippert RG, Svien HJ, Grindlay JH, et al: The effect of cortisone on experimental cerebral edema. J Neurosurg 17: , 1960 J. Neurosurg. / Volume 39 / October,

5 Sato, Hara, Asai, Tsugane and Kageyama 18. Long DM, Hartmann JF, French LA: The response of experimental cerebral edema to glucosteroid administration. J Neurosurg 24: , Milhorat TH: Choroid plexus and cerebrospinal fluid production. Science 166: , Milhorat TH, Hammock MK, Fenstermacher JD, et al: Cerebrospinal fluid production by the choroid plexus and brain. Science 173: , Pappenheimer JR, Heisey SR, Jordan EF: Active transport of Diodrast and Phenolsulfophthalein from cerebrospinal fluid to blood. Am J Physiol 200:1-10, Pappenheimer JR, Heisey SR, Jordan EF, et al: Perfusion of the cerebral ventricular system in unanesthetized goats, hart J Physiol 203: , Prados M, Strowger B, Feindel W: Studies on cerebral edema. II. Reaction of the brain to exposure to air: physiologic change. Arch Neurol Psyehiat 54: , Rail DP, Oppelt WW, Patlak CS: Extracellular space of brain as determined by diffusion of inulin from the ventricular system. Life Sci 2:43-48, Rasmussen T, Gulati DR: Cortisone in the treatment of postoperative cerebral edema. J Neurosurg 19: , Sato O: The effect of dexamethasone on cerebrospinal fluid production rate in the dog. Brain Nerve (Tokyo) 19: , Sato O, Asai T, Amano Y, et al: Extraventricular origin of the cerebrospinal fluid: formation rate quantitatively measured in the spinal subarachnoid space of dogs. J Neurosurg 36: , Sato O, Asai T, Amano Y, et al: Formation of cerebrospinal fluid in spinal subarachnoid space. Nature 233: , Sato O, Bering EA Jr: Extraventricular formation of cerebrospinal fluid. Brain Nerve (Tokyo) 19:31-33, Shenkin HA, Gutterman P: The analysis of body water compartments in postoperative craniotomy patients. Part 3: The effects of dexamethasone. J Neurosnrg 31: , Schreiner GE: Determination of inulin by means of resorcinol. Proc Soe Exp Biol Med 74: , Schwartz ML, Tator CH, Hoffman HJ: The uptake of hydrocortisone in mouse brain and ependymoblastoma. $ Neurosurg 36: , Taylor JM, Levy WA, Herzog I, et al: Prevention of experimental cerebral edema by corticosteroids. Neurology 15: , Weed LH: Studies on cerebro-spinal fluid. No. IV. The dural source of cerebro-spinal fluid. J Meal Res 31:93-117, Weiss MH, Nulsen FE: The effect of glucocorticoids on CSF flow in dogs. J Neurosurg 32: , Weissmann G, Thomas L: Studies on lysosomes. II. The effect of cortisone on the release of acid hydrolases from a large granule fraction of rabbit liver induced by an excess of vitamin A. J Clin Invest 42: , Wright RL, Shaumba B, Keller J: The effect of glucocorticosteroids on growth and metabolism of experimental glial tumors. J Neurosurg 30: , 1969 Address reprint requests to: Osamu Sato, M.D., Nagoya University School of Medicine, 65 Tsurumai, Showa, Nagoya, Japan. 484 J. Neurosurg. / Volume 39 / October, 1973