- Email: [email protected]
The effect of the administration of cortisol on the levels of cortisol and electrolytes in blood and cerebrospinal fluid in man
The Effect of the Administration of Cortisol on the Levels of Cortisol and Electrolytes in Blood and Cerebrospinal Fluid in Man By TETSUO UETE AND SHURO NISHIMURA In some patients with brain tumor, neurosurgery involving ventricular drainage and ventriculograpby resulted in au increase in the sodium level in cerebrospinal fluid without any modification of its level in blood. In these patients, the effects of the administration of cortisol on the levels of corticosteroids, sodium, and potassium in blood and cerebrospinal fluid were studied. After the administration of cortisol, the corticosteroid levels in blood and cerebrospinal fluid were markedly increased. When patients had normal levels of sodium in cerebrospinal
fluid, cortisol administration did not affect these sodium levels. However, when the sodium level in cerebrospinal fluid was high, the sodium level decreased 2 to 4 hr after the administration of cortisol. In all these patients, the sodium and potassium levels in blood were not influenced by cortisol administration. This finding may have bearing upon the apparent beneficial action of adrenal cortical hormones on cerebral edema following trauma or brain surgery. (Metabolism 20: No. 3, March, 319-326, 1971)
HE MARKED THERAPEUTIC EFFECT of glucocorticoids on cerebral edema is well known.14 The increase in the volume of the brain has been associated with an increase in its content of sodium and water. Glucocorticoids are thought to reestablish a normal extracellular sodium and intracellular distribution of potassium of the central nervous system. Although there is a blood-cerebrospinal fluid barrier for corticosteroids, cortisol enters the cerebrospinal fluid from the blood following the administration of cortisol to man.5-g This indicates that a direct effect of adrenal cortical hormones on the central nervous system plays an important role in its therapeutic effect on cerebral edema. However, the mode of action of adrenal cortical hormones with respect to this effect is not well understood. Therefore, the present investigation examined the effects of administration of cortisol on the levels of cortisol and electrolytes in blood and cerebrospinal fluid after various neurosurgical procedures.
T
From the Kitano Hospital Tazuke Kofukai City, Japan. Received for publication October 19, 1970.
Medical
Research
Institute,
Kita-ku,
Osaka
Supported by a grant from the Tazuke Kofukai Medical Research Foundation. TETSUO UETE, M.D.: Director, The Second Research Division, Kitano Hospital Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka City, Japan. SHURO NISHIMURA, M.D.: Professor of Neurosurgery, Osaka City University, Osaka City, Japan; formerly Neurosurgeon-in-Chief, Kitano Hospital Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka City, Japan. METABOLISM,VOL. 20, No. 3 (MARCH), 1971
319
320
UETE AND NISHIMURA
Table L-Effect of Administration of Cortisol on the Levels of Corticosteroids and Electrolytes in Blood and Cerebrospinal Fluid in Patients Who Had Normal Sodium Levels in Blood and Cerebrospinal Fluid Following Neurosurgery Cerebrospinal
Blood Corticosteroids kW100 ml
Case 1, male, 30 yr, 50 kg, cerebellar tumor Control 12.6 Cortisol injection, 100 mg i.v. 1 hour 122.0 2 66.5 3 47.0 4 36.4 5 28.7 Case 2, male, 25 yr, 55 kg, cerebellar tumor Control 23.1 Cortisol injection, 100 mg iv. 1 hour 143.0 2 71.5 3 42.5 4 42.5 5 29.1 Case 3, female, 57 yr, 50 kg, cerebral tumor 9.7 Control Cortisol injection, 75 mg i.v. 99.0 1 hour 73.0 2 50.3 3 38.8 4 22.7 5 Case 4, male, 23 yr, 60 kg, craniopharyngioma 8.3 Control Cortisol injection, 75 mg i.v. 128.0 1 hour 76.8 2 65.0 3 43.3 4 36.6 5
Na K meq/liter
Corticosteroids pg/lOO ml
Fluid Na K meq/liter
124
3.6
2.3
127
2.0
120 120 118 123 119
3.6 4.1 4.2 4.0 3.9
35.8 26.8 19.9 14.9 8.4
125 124 127 128 126
2.1 1.8 1.9 1.8 1.8
137
3.8
3.1
134
2.0
139 139 139 137 143
3.4 3.5 3.4 3.5 3.3
31.4 25.6 12.3 8.8 7.9
134 137 136 138 136
2.0 2.0 1.8 1.9 1.9
128
0.4
I33
127 127 127 126 123
19.5 21.9 18.3 14.1 9.7
136 137 142 134 141
138
2.9
136
138 137 137 134 133
9.1 11.9 10.5 10.5 7.6
135 134 136 136 138
MATERIALS AND METHODS The levels of corticosteroids in blood and cerebrospinal fluid were studied in the patients who consented to the investigation. Blood samples were obtained from the cubital vein. Cerebrospinal fluid was obtained from a ventricular drain, which had been previously in‘serted for either examination or treatment of the patient. Simultaneous determination of corticosteroids in blood and cerebrospinal fluid was carried out by the method described previously. 8,s Specimens of cerebrospinal fluid, 2-4 ml, and serum, 0.5-1.0 ml, were adjusted to pH 1.0 with sulfuric acid and extracted twice with 10 ml of chloroform or methylene chloride. The chloroform extract was evaporated to dryness at 40% under reduced pressure after dehydration with sodium sulfate. The residue was dissolved in 4 ml of H,O and extracted twice with 6 ml of petroleum ether. The water layer was further extracted with 6 ml of chloroform. The chloroform extract was dehydrated with sodium sulfate and treated with 2 ml of 70 per cent sulfuric acid diluted with 100 per cent ethanol. After 40 min at room temperature, fluorescence was determined using an Aminco-Bowman spectrofluorometer. The activation monochrometer was set at 470 nm
321
EFFECT OF CORTISOL
Table l.--Effect of Administration of Cortisol on the Levels of Corticosteroids and Electrolytes in Blood and Cerebrospinal Fluid in Patients Who Had Normal Sodium Levels in Blood and Cerebrospinal Fluid Following Neurosurgery (Coned) Cerebrospinal
Blood C;;Wiy&tei-$ds
Cortiti-~;~~p”
Na K meq/liter
Fluid Na K m&liter
20 yr, 61 kg, cerebral tumor
Case 5, male, Control Cortisol 1 hour 2 3 4 5 Case 6, male, Control Cortisol 1 hour 2 3 4 5 Case 7, male, Control Cortisol 1 hour 2 3 4 5
16.4
135
2.4
129
98.6 57.5 48.5 34.5 23.9
132 133 131 129 129
11.5 12.7 12.7 9.6 7.5
129 134 131 129 136
15.1
131
4.2
1.9
144
2.1
28.9 33.0 26.0 26.8 26.8
132 131 131 131 132
4.1 4.0 4.1 4.2 4.1
10.2 4.2 2.5 3.0 3.2
143 152 262 296 240
2.3 2.5 2.7 4.1 4.6
13.3
140
4.3
0.7
150
2.3
21.4 23.3 23.3 27.5 23.3
143 145 142 142 146
4.3 4.3 4.5 3.9 4.3
2.1 2.8 4.2 0.4 0.7
145 164 236 172 142
2.2 2.5 3.8 2.5 2.2
injection, 75 mg iv.
57 yr, 55 kg, meningoneuritis injection,
25 mg i.m.
22 yr, 64 kg, cerebellar tumor injection, 65 mg i.m.
and the fluorescence monochrometer at 520 nm. Distilled water which was treated similarly, served as a control. Cortisol, 0.5 to 1.0 pg, dissolved in distilled water, was similarly extracted and purified and the recovery of cortisol was determined. The levels of corticosteroids in blood and cerebrospinal fluid were adjusted bv this factor. The levels of electrolytes in blood and cerebrospinal fluid were determined by flame photometry using the Coleman flame photometer. RESULTS Patients
with brain
triculography.
tumors
were treated
normal
sodium levels in cerebrospinal
sodium
levels.
increased
However,
sodium
cerebrospinal
drainage
and ven-
most patients had fluid, but some of them showed increased
no significant
level in cerebrospinal
pressure,
relationship
and cerebrospinal
was observed
fluid and the prognosis
size or site of tumor,
the effect of the administration in blood
with ventricular
A few days to a week after this operation,
of cortisol
between
the
of their disease,
and so on. In this investigation,
on the levels of sodium and potassium
fluid was studied using these two groups of patients.
The results are shown in Tables
1 and 2.
Cases 1 to 5 These patients in the blood
showed normal levels of corticosteroids,
and cerebrospinal
fluid after
sodium,
the operation.
When
and potassium cortisol
was
322
UETE
AND NISHIMURA
Table Z.-Effect of Administration of Cortisol on the Levels of Corticosteroids and Electrolytes in Blood and Cerebrospinal Fluid in Patients Who Had Elevated Sodium Levels in Cerebrospinal Fluid Following Neurosurgery Blood Corticosteroids pg/lOO ml
Case 8, male, 43 yr, 52 kg, cerebellar tumor Control 11.0 Cortisol injection, 25 mg i.m. 1 hour 23.0 2 3 17.5 4 5 21.9 Case 9, male, 41 yr, 60 kg, cerebellar tumor Control 8.9 Cortisol injection, 25 mg i.m. 1 hour 18.4 2 18.8 3 14.2 4 13.1 5 13.2 Case 10, male, 13 yr, 33.5 kg, cerebral tumor 3.5 Control Cortisol injection, 100 mg i.v. 111.0 1 hour 61.4 2 39.0 3 26.0 4 23.6 5 Case 11, male, 21 yr, 50 kg, cerebral tumor 4.2 Control Cortisol injection, 100 mg i.v. 109.0 1 hour 77.0 2 49.4 3 27.3 4 5
Cerebrospinal Na K m&liter
__~
-
Corticosteroids pg/lOO ml
Fluid Na K m&liter
130
4.4
0.2
340
134 140 140 150 133
3.9 3.9 3.3 3.6
1.0 2.4 2.9 2.0 2.0
240 145 140 163 144
132
5.1
0.8
328
2.7
133 134 132 132
5.2 5.2
1.9 1.9 2.6 3.2 1.8
157 140 158 300 300
2.7
5.0
5.6
2.7
143
5.1
0.8
166
2.7
137 135 138 135 138
4.5 4.3 4.5 4.6 4.6
35.6 27.9 16.8 9.8 8.3
146 130 120 153 158
2.2 2.3 1.8 2.3 2.5
138
4.1
3.6
160
2.4
139 137 129 141
4.0 3.8 4.2 4.1 4.0
10.8 9.6 9.3 7.8 6.9
128 143 130 123 180
2.2 2.5 2.2 1.9 2.8
administered intravenously, the cortisol levels in blood and cerebrospinal fluid were markedly increased compared with the control levels, but the sodium levels in blood and cerebrospinal fluid were not significantly modified by cortisol, as is shown in Table 1. Cases 6 and 7 In these cases, the sodium levels in the blood and cerebrospinal fluid were within normal limits. After the administration of cortisol, the levels of cortisol in the blood and cerebrospinal fluid were elevated. The sodium level in the blood was not influenced by the cortisol administration, but the sodium levels in the cerebrospinal fluid were increased 3 to 5 hours after the administration of cortisol in these cases in contrast to cases 1-5. These results are also shown in Table 1.
323
EFFECT OF CORTISOL
Cases 8 to 1 I These patients had normal sodium and potassium levels in the blood, but the sodium level in cerebrospinal fluid was elevated after the operation. Following the administration of cortisol, the sodium level in the blood was not altered, but the increased sodium level in the cerebrospinal fluid decreased to normal values within 2 to 4 hr. However, some 4 to 5 hr later, the sodium level in the cerebrospinal fluid rose. DISCUSSION
In this study, after neurosurgery such as ventricular drainage and ventriculography, the sodium level in cerebrospinal fluid was increased in some patients with brain tumors. This increase in sodium level may be related to the development of cerebral edema following brain surgery. Therefore, the effect of adrenal cortical hormones on the sodium levels in cerebrospinal fluid and blood was studied in these patients. When the sodium level in cerebrospinal fluid was within normal limits, the majority of patients showed no alteration of sodium level after administration of cortisol, but some cases showed an increase. In contrast to those patients, all patients who had increased sodium levels in cerebrospinal fluid, over 160 meq/liter showed a decrease in the sodium level following the administration of cortisol. However, no significant effect of cortisol on the sodium level in blood was observed in these patients. It is of particular interest that patients responded to cortisol differently, depending upon the concentration of sodium in their cerebrospinal fluid. The steroid effect on the sodium level in cerebrospinal fluid is most likely a direct effect of hormones on the brain tissue. This observation may bear upon the apparent beneficial action of adrenal cortical hormones on cerebral edema. Decreased intracranial pressure induced by corticosteroids has been reported after head injuries, lo tuberculous meningitis,ll stroke,13J3 metastatic breast carcinoma to brain,14 and pseudotumor cerebri. l5 Corticosteroids seem to have a favorable effect on postoperative increases in intracranial pressure.l@Is It has also been reported that dexamethasone decreases the pressure of cerebrospinal fluid in d0gs.l” This effect is more marked and obvious in dogs with induced intracerebral hemorrhage compared with normal dogs. In addition, dexamethasone probably decreases the cerebrospinal fluid production rate in dogs.“O The present finding, that the increased sodium level in cerebrospinal fluid was reduced by the acute administration of large amounts of corticosteroids, may well support the observations of these workers. Previous studies21,22 also indicate that the acute administration of cortisol to rats resulted in an increase in the intracellular sodium concentration of the brain and a decrease in the ratio of extracellular to intracellular sodium concentration. The opposite results are observed with desoxycorticosterone and aldosterone.** Furthermore, the acute administration of dexamethasone produced an increase in the rate of sodium entry and the exchangeable sodium in normal rat brain.z3 CertainIy, the increased entry of sodium into the brain induced by acute administration of steroids would not be expected to help cerebral edema. Rather, one might expect it would further increase the pathologic accumulation of sodium in the brain. In this study, when increased sodium levels exist in cerebrospinal
324
UETE AND NISHIMURA
fluid, cortisol showed a beneficial therapeutic effect, decreasing the sodium level in the cerebrospinal fluid to normal. This effect of adrenal cortical hormones is not explained by the observations of previous workers using normal rats. However, on the basis of various studies it has been suggested that the beneficial effects of glucocorticoids reflect the prevention of the accumulation of water as well as sodium in brain tissue.3J-“F It has also been postulated that corticosteroids decrease sodium uptake by the brain cells.” In addition, dexamethasone decreases the uptake of radioactive iodinated serum albumin by brain lesions.28v2QThe correction of an increased sodium level in cerebrospinal fluid by glucocorticoids observed in this study may be due to the fact that the glucocorticoids decrease sodium uptake by the brain cells from the blood. Glucocorticoids may also enhance the extrusion of sodium from the cerebrospinal fluid into blood. Blinderman et a1.3 have postulated an anti-inflammatory role of the steroids at the level of the cell membrane as a basic action of steroids. The response may not be merely an anti-inflammatory one in the usual sense, since papilledema and elevated cerebrospinal fluid pressure have been described in Addison’s disease and these respond to cortisone therapy.30-3” REFERENCES 1. Galicich, J. H., and French, L. A.: Use of dexamethasone in the treatment of cerebral edema resulting from brain tumor and brain surgery. Amer. Practitioner 12: 169, 1961. 2. Galicich, J. H., French, L. A., and Melby, J. C.: Use of dexamethasone in treatment of cerebral edema associated with brain tumors. Lancet 81:46, 1961. 3. Blinderman, E. E., Graf, C. J., and Fitzpatrick, T.: Basic studies in cerebral edema: Its control by a corticosteroid (SoluMedrol). J. Neurol. 19:319, 1962. 4. French, L. A.: The use of steroids in the treatment of cerebral edema. Bull. N.Y. Acad. Med. 42:301, 1966. 5. Abelson, D., Barson, D. N., and Toakley, J. G.: Studies of cerebrospinal fluid following oral administration of cortisoneacetate or hydrocortisone. J. Endocr. 12:87, 1955. 6. Christy, N., and Fishman, B. A.: Studies of the blood-cerebrospinal fluid barrier to cortisol in dog. J. Clin. Invest. 40:1997, 1961. 7. Murphy, B. E. P., Cosgrove, J. B., McIlauham, M. C., and Pattee, C. J.: Adrenal corticoid levels in human cerebrospinal fluid. Canad. Med. Ass. J. 97:13, 1967. 8. Uete, T., Wasa, M., and Shimogami, A.: Corticosteroid determination in cerebrospinal fluid. Metabolism 16:608, 1967.
9. -, Nishimura, S., Ohya, H., Shimomura, T., and Tatebayashi, Y.: Corticosteroid levels in blood and cerebrospinal fluid in various diseases. J. Clin. Endocr. 30: 208, 1970. 10. Gurdjian, E. S., and Webster, J. E.: Head Injuries, Mechanism, Diagnosis, and Management. Boston, Little, Brown, 1958, p. 482. 11. Barnard, C.: Tuberculous meningitis, cortisone treatment as an adjunct to the antibiotics. The effect on the clinical features and the cerebrospinal fluid. S. Afr. Med. J. 27:219, 1953. 12. Roberts, H. J.: Supportive adrenocortical steroid therapy in acute and subacute cerebrovascular accidents, with particular reference to brain-stem involvement. J. Amer. Geriat. Sot. 6:686, 1958. 13. Russek, H. I., Russek, A. S., and Zohman, B. L.: Cortisone in immediate therapy of apoplectic stroke. J.A.M.A. 159: 102, 1955. 14. Kofman, S., Garvin, J. S., Nagamani, D., and Taylor, S. G. III.: Treatment of cerebral metastases from breast carcinoma with prednisolone. J.A.M.A. 163:1473, 1957. 15. Paterson, R., DePasquale, N., and Mann, S.: Pseudotumor cerebri. Medicine 40:85, 1961. 16. Ingraham, F. D., Matson, D. D., and McLaurin, R. L.: Cortisone and ACTH as
EFFECT
OF CORTISOL
an adjunct to the surgery of craniopharyngiomas. New Eng. J. Med. 246:568, 1952. 17. Raaf, J., Stainsby, D. L., and Larson, W. L. E.: The use of ACTH in conjunction with surgery for neoplasms in the parasellar area. 3. Neurol. 11:463, 1954. 18. Tytus, J. S., Seltzer, H. S., and Kahn, E. A.: Cortisone as an aid in the surgical treatment of craniopharyngiomas. J. Neurosurg. 12:555, 1955. 19. Hooshmand, H., Dove, J., Houff, S., and Suter, C.: Effects of diuretics and steroids on CSF pressure. Arch. Neurol. 21:499, 1969. 20. Sato, 0.: The effect of dexamethasone on cerebrospinal fluid production rate in the dog. Brain Nerve 19:485, 1967. 21. Timiras, P. S., Woodbury, D. M., and Goodman, L. S.: Effect of adrenalectomy, hydrocortisone acetate and desoxycorticosterone acetate on brain stability and electrolyte distribution in mice. J. Pharmacol. Exp. Ther. 112:80, 1954. 22. Woodbury, D. M., and Vanadakis, A.: Effect of steroids on the central nerve system. In Dorfman, R. I. (Ed.): Methods in Hormone Research, Vol. V. New York, Academic, 1966, p. 1. 23. Fishman, R. T.: Factors influencing sodium exchange in brain: Effects of dexamethasone. Zn Caveness, W. F., and Walker, A. E. (Eds.) : Head Injury. Philadelphia, Lippincott, 1966. p. 490.
325 24. Elliott, K. A. C., and Jasper, H. H.: Measurement of experimentally induced brain swelling and shrinkage. Amer. J. Physiol. 157:122, 1949. 25. -, and Yrarrazaval, S.: Effect of adrenalectomy and cortisone on tissue permeability in vitro. Nature 169:416, 1952. 26. Taylor, J. M., Levy, W. A., Herzog, I., and Scheinberg, L. C.: Prevention of experimental cerebral edema by corticosteroids: biochemical and ultrastructural studies. Neurology 15:667, 1965. 27. Fox, J. L.: Development of recent thoughts on intracranial pressure and the blood-brain barrier. J. Neurol. 21:909, 1964. 28. Pappius, H. M., and McCann, W. P.: Effects of steroids on cerebral edema in cats. Arch. Neurol. 20:207, 1967. 29. Rovit, R. L., and Magen, R.: Steroids and cerebral edema: the effects of glucocorticoids on abnormal capillary permeability following cerebral injury in cats. J. Neuropath. Exp. Neurol. 27:277, 1968. 30. Forsham, P. H., and Thorn, G. W.: The adrenals. In Williams, R. H. (Ed.): Textbook of Endocrinology. Philadelphia, Saunders, 1955, p. 776. 31. Jefferson, A.: A clinical correIation between encephalopathy and papilledema in Addison’s disease. J. Neurol. Neurosurg. Psychiat. 19:21, 1956. 32. Walsh, F. B.: Papilledema associated with increased intracranial pressure in Addison’s disease. Arch. Ophthal. 47:86, 1952.
fluid, cortisol administration did not affect these sodium levels. However, when the sodium level in cerebrospinal fluid was high, the sodium level decreased 2 to 4 hr after the administration of cortisol. In all these patients, the sodium and potassium levels in blood were not influenced by cortisol administration. This finding may have bearing upon the apparent beneficial action of adrenal cortical hormones on cerebral edema following trauma or brain surgery. (Metabolism 20: No. 3, March, 319-326, 1971)
HE MARKED THERAPEUTIC EFFECT of glucocorticoids on cerebral edema is well known.14 The increase in the volume of the brain has been associated with an increase in its content of sodium and water. Glucocorticoids are thought to reestablish a normal extracellular sodium and intracellular distribution of potassium of the central nervous system. Although there is a blood-cerebrospinal fluid barrier for corticosteroids, cortisol enters the cerebrospinal fluid from the blood following the administration of cortisol to man.5-g This indicates that a direct effect of adrenal cortical hormones on the central nervous system plays an important role in its therapeutic effect on cerebral edema. However, the mode of action of adrenal cortical hormones with respect to this effect is not well understood. Therefore, the present investigation examined the effects of administration of cortisol on the levels of cortisol and electrolytes in blood and cerebrospinal fluid after various neurosurgical procedures.
T
From the Kitano Hospital Tazuke Kofukai City, Japan. Received for publication October 19, 1970.
Medical
Research
Institute,
Kita-ku,
Osaka
Supported by a grant from the Tazuke Kofukai Medical Research Foundation. TETSUO UETE, M.D.: Director, The Second Research Division, Kitano Hospital Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka City, Japan. SHURO NISHIMURA, M.D.: Professor of Neurosurgery, Osaka City University, Osaka City, Japan; formerly Neurosurgeon-in-Chief, Kitano Hospital Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka City, Japan. METABOLISM,VOL. 20, No. 3 (MARCH), 1971
319
320
UETE AND NISHIMURA
Table L-Effect of Administration of Cortisol on the Levels of Corticosteroids and Electrolytes in Blood and Cerebrospinal Fluid in Patients Who Had Normal Sodium Levels in Blood and Cerebrospinal Fluid Following Neurosurgery Cerebrospinal
Blood Corticosteroids kW100 ml
Case 1, male, 30 yr, 50 kg, cerebellar tumor Control 12.6 Cortisol injection, 100 mg i.v. 1 hour 122.0 2 66.5 3 47.0 4 36.4 5 28.7 Case 2, male, 25 yr, 55 kg, cerebellar tumor Control 23.1 Cortisol injection, 100 mg iv. 1 hour 143.0 2 71.5 3 42.5 4 42.5 5 29.1 Case 3, female, 57 yr, 50 kg, cerebral tumor 9.7 Control Cortisol injection, 75 mg i.v. 99.0 1 hour 73.0 2 50.3 3 38.8 4 22.7 5 Case 4, male, 23 yr, 60 kg, craniopharyngioma 8.3 Control Cortisol injection, 75 mg i.v. 128.0 1 hour 76.8 2 65.0 3 43.3 4 36.6 5
Na K meq/liter
Corticosteroids pg/lOO ml
Fluid Na K meq/liter
124
3.6
2.3
127
2.0
120 120 118 123 119
3.6 4.1 4.2 4.0 3.9
35.8 26.8 19.9 14.9 8.4
125 124 127 128 126
2.1 1.8 1.9 1.8 1.8
137
3.8
3.1
134
2.0
139 139 139 137 143
3.4 3.5 3.4 3.5 3.3
31.4 25.6 12.3 8.8 7.9
134 137 136 138 136
2.0 2.0 1.8 1.9 1.9
128
0.4
I33
127 127 127 126 123
19.5 21.9 18.3 14.1 9.7
136 137 142 134 141
138
2.9
136
138 137 137 134 133
9.1 11.9 10.5 10.5 7.6
135 134 136 136 138
MATERIALS AND METHODS The levels of corticosteroids in blood and cerebrospinal fluid were studied in the patients who consented to the investigation. Blood samples were obtained from the cubital vein. Cerebrospinal fluid was obtained from a ventricular drain, which had been previously in‘serted for either examination or treatment of the patient. Simultaneous determination of corticosteroids in blood and cerebrospinal fluid was carried out by the method described previously. 8,s Specimens of cerebrospinal fluid, 2-4 ml, and serum, 0.5-1.0 ml, were adjusted to pH 1.0 with sulfuric acid and extracted twice with 10 ml of chloroform or methylene chloride. The chloroform extract was evaporated to dryness at 40% under reduced pressure after dehydration with sodium sulfate. The residue was dissolved in 4 ml of H,O and extracted twice with 6 ml of petroleum ether. The water layer was further extracted with 6 ml of chloroform. The chloroform extract was dehydrated with sodium sulfate and treated with 2 ml of 70 per cent sulfuric acid diluted with 100 per cent ethanol. After 40 min at room temperature, fluorescence was determined using an Aminco-Bowman spectrofluorometer. The activation monochrometer was set at 470 nm
321
EFFECT OF CORTISOL
Table l.--Effect of Administration of Cortisol on the Levels of Corticosteroids and Electrolytes in Blood and Cerebrospinal Fluid in Patients Who Had Normal Sodium Levels in Blood and Cerebrospinal Fluid Following Neurosurgery (Coned) Cerebrospinal
Blood C;;Wiy&tei-$ds
Cortiti-~;~~p”
Na K meq/liter
Fluid Na K m&liter
20 yr, 61 kg, cerebral tumor
Case 5, male, Control Cortisol 1 hour 2 3 4 5 Case 6, male, Control Cortisol 1 hour 2 3 4 5 Case 7, male, Control Cortisol 1 hour 2 3 4 5
16.4
135
2.4
129
98.6 57.5 48.5 34.5 23.9
132 133 131 129 129
11.5 12.7 12.7 9.6 7.5
129 134 131 129 136
15.1
131
4.2
1.9
144
2.1
28.9 33.0 26.0 26.8 26.8
132 131 131 131 132
4.1 4.0 4.1 4.2 4.1
10.2 4.2 2.5 3.0 3.2
143 152 262 296 240
2.3 2.5 2.7 4.1 4.6
13.3
140
4.3
0.7
150
2.3
21.4 23.3 23.3 27.5 23.3
143 145 142 142 146
4.3 4.3 4.5 3.9 4.3
2.1 2.8 4.2 0.4 0.7
145 164 236 172 142
2.2 2.5 3.8 2.5 2.2
injection, 75 mg iv.
57 yr, 55 kg, meningoneuritis injection,
25 mg i.m.
22 yr, 64 kg, cerebellar tumor injection, 65 mg i.m.
and the fluorescence monochrometer at 520 nm. Distilled water which was treated similarly, served as a control. Cortisol, 0.5 to 1.0 pg, dissolved in distilled water, was similarly extracted and purified and the recovery of cortisol was determined. The levels of corticosteroids in blood and cerebrospinal fluid were adjusted bv this factor. The levels of electrolytes in blood and cerebrospinal fluid were determined by flame photometry using the Coleman flame photometer. RESULTS Patients
with brain
triculography.
tumors
were treated
normal
sodium levels in cerebrospinal
sodium
levels.
increased
However,
sodium
cerebrospinal
drainage
and ven-
most patients had fluid, but some of them showed increased
no significant
level in cerebrospinal
pressure,
relationship
and cerebrospinal
was observed
fluid and the prognosis
size or site of tumor,
the effect of the administration in blood
with ventricular
A few days to a week after this operation,
of cortisol
between
the
of their disease,
and so on. In this investigation,
on the levels of sodium and potassium
fluid was studied using these two groups of patients.
The results are shown in Tables
1 and 2.
Cases 1 to 5 These patients in the blood
showed normal levels of corticosteroids,
and cerebrospinal
fluid after
sodium,
the operation.
When
and potassium cortisol
was
322
UETE
AND NISHIMURA
Table Z.-Effect of Administration of Cortisol on the Levels of Corticosteroids and Electrolytes in Blood and Cerebrospinal Fluid in Patients Who Had Elevated Sodium Levels in Cerebrospinal Fluid Following Neurosurgery Blood Corticosteroids pg/lOO ml
Case 8, male, 43 yr, 52 kg, cerebellar tumor Control 11.0 Cortisol injection, 25 mg i.m. 1 hour 23.0 2 3 17.5 4 5 21.9 Case 9, male, 41 yr, 60 kg, cerebellar tumor Control 8.9 Cortisol injection, 25 mg i.m. 1 hour 18.4 2 18.8 3 14.2 4 13.1 5 13.2 Case 10, male, 13 yr, 33.5 kg, cerebral tumor 3.5 Control Cortisol injection, 100 mg i.v. 111.0 1 hour 61.4 2 39.0 3 26.0 4 23.6 5 Case 11, male, 21 yr, 50 kg, cerebral tumor 4.2 Control Cortisol injection, 100 mg i.v. 109.0 1 hour 77.0 2 49.4 3 27.3 4 5
Cerebrospinal Na K m&liter
__~
-
Corticosteroids pg/lOO ml
Fluid Na K m&liter
130
4.4
0.2
340
134 140 140 150 133
3.9 3.9 3.3 3.6
1.0 2.4 2.9 2.0 2.0
240 145 140 163 144
132
5.1
0.8
328
2.7
133 134 132 132
5.2 5.2
1.9 1.9 2.6 3.2 1.8
157 140 158 300 300
2.7
5.0
5.6
2.7
143
5.1
0.8
166
2.7
137 135 138 135 138
4.5 4.3 4.5 4.6 4.6
35.6 27.9 16.8 9.8 8.3
146 130 120 153 158
2.2 2.3 1.8 2.3 2.5
138
4.1
3.6
160
2.4
139 137 129 141
4.0 3.8 4.2 4.1 4.0
10.8 9.6 9.3 7.8 6.9
128 143 130 123 180
2.2 2.5 2.2 1.9 2.8
administered intravenously, the cortisol levels in blood and cerebrospinal fluid were markedly increased compared with the control levels, but the sodium levels in blood and cerebrospinal fluid were not significantly modified by cortisol, as is shown in Table 1. Cases 6 and 7 In these cases, the sodium levels in the blood and cerebrospinal fluid were within normal limits. After the administration of cortisol, the levels of cortisol in the blood and cerebrospinal fluid were elevated. The sodium level in the blood was not influenced by the cortisol administration, but the sodium levels in the cerebrospinal fluid were increased 3 to 5 hours after the administration of cortisol in these cases in contrast to cases 1-5. These results are also shown in Table 1.
323
EFFECT OF CORTISOL
Cases 8 to 1 I These patients had normal sodium and potassium levels in the blood, but the sodium level in cerebrospinal fluid was elevated after the operation. Following the administration of cortisol, the sodium level in the blood was not altered, but the increased sodium level in the cerebrospinal fluid decreased to normal values within 2 to 4 hr. However, some 4 to 5 hr later, the sodium level in the cerebrospinal fluid rose. DISCUSSION
In this study, after neurosurgery such as ventricular drainage and ventriculography, the sodium level in cerebrospinal fluid was increased in some patients with brain tumors. This increase in sodium level may be related to the development of cerebral edema following brain surgery. Therefore, the effect of adrenal cortical hormones on the sodium levels in cerebrospinal fluid and blood was studied in these patients. When the sodium level in cerebrospinal fluid was within normal limits, the majority of patients showed no alteration of sodium level after administration of cortisol, but some cases showed an increase. In contrast to those patients, all patients who had increased sodium levels in cerebrospinal fluid, over 160 meq/liter showed a decrease in the sodium level following the administration of cortisol. However, no significant effect of cortisol on the sodium level in blood was observed in these patients. It is of particular interest that patients responded to cortisol differently, depending upon the concentration of sodium in their cerebrospinal fluid. The steroid effect on the sodium level in cerebrospinal fluid is most likely a direct effect of hormones on the brain tissue. This observation may bear upon the apparent beneficial action of adrenal cortical hormones on cerebral edema. Decreased intracranial pressure induced by corticosteroids has been reported after head injuries, lo tuberculous meningitis,ll stroke,13J3 metastatic breast carcinoma to brain,14 and pseudotumor cerebri. l5 Corticosteroids seem to have a favorable effect on postoperative increases in intracranial pressure.l@Is It has also been reported that dexamethasone decreases the pressure of cerebrospinal fluid in d0gs.l” This effect is more marked and obvious in dogs with induced intracerebral hemorrhage compared with normal dogs. In addition, dexamethasone probably decreases the cerebrospinal fluid production rate in dogs.“O The present finding, that the increased sodium level in cerebrospinal fluid was reduced by the acute administration of large amounts of corticosteroids, may well support the observations of these workers. Previous studies21,22 also indicate that the acute administration of cortisol to rats resulted in an increase in the intracellular sodium concentration of the brain and a decrease in the ratio of extracellular to intracellular sodium concentration. The opposite results are observed with desoxycorticosterone and aldosterone.** Furthermore, the acute administration of dexamethasone produced an increase in the rate of sodium entry and the exchangeable sodium in normal rat brain.z3 CertainIy, the increased entry of sodium into the brain induced by acute administration of steroids would not be expected to help cerebral edema. Rather, one might expect it would further increase the pathologic accumulation of sodium in the brain. In this study, when increased sodium levels exist in cerebrospinal
324
UETE AND NISHIMURA
fluid, cortisol showed a beneficial therapeutic effect, decreasing the sodium level in the cerebrospinal fluid to normal. This effect of adrenal cortical hormones is not explained by the observations of previous workers using normal rats. However, on the basis of various studies it has been suggested that the beneficial effects of glucocorticoids reflect the prevention of the accumulation of water as well as sodium in brain tissue.3J-“F It has also been postulated that corticosteroids decrease sodium uptake by the brain cells.” In addition, dexamethasone decreases the uptake of radioactive iodinated serum albumin by brain lesions.28v2QThe correction of an increased sodium level in cerebrospinal fluid by glucocorticoids observed in this study may be due to the fact that the glucocorticoids decrease sodium uptake by the brain cells from the blood. Glucocorticoids may also enhance the extrusion of sodium from the cerebrospinal fluid into blood. Blinderman et a1.3 have postulated an anti-inflammatory role of the steroids at the level of the cell membrane as a basic action of steroids. The response may not be merely an anti-inflammatory one in the usual sense, since papilledema and elevated cerebrospinal fluid pressure have been described in Addison’s disease and these respond to cortisone therapy.30-3” REFERENCES 1. Galicich, J. H., and French, L. A.: Use of dexamethasone in the treatment of cerebral edema resulting from brain tumor and brain surgery. Amer. Practitioner 12: 169, 1961. 2. Galicich, J. H., French, L. A., and Melby, J. C.: Use of dexamethasone in treatment of cerebral edema associated with brain tumors. Lancet 81:46, 1961. 3. Blinderman, E. E., Graf, C. J., and Fitzpatrick, T.: Basic studies in cerebral edema: Its control by a corticosteroid (SoluMedrol). J. Neurol. 19:319, 1962. 4. French, L. A.: The use of steroids in the treatment of cerebral edema. Bull. N.Y. Acad. Med. 42:301, 1966. 5. Abelson, D., Barson, D. N., and Toakley, J. G.: Studies of cerebrospinal fluid following oral administration of cortisoneacetate or hydrocortisone. J. Endocr. 12:87, 1955. 6. Christy, N., and Fishman, B. A.: Studies of the blood-cerebrospinal fluid barrier to cortisol in dog. J. Clin. Invest. 40:1997, 1961. 7. Murphy, B. E. P., Cosgrove, J. B., McIlauham, M. C., and Pattee, C. J.: Adrenal corticoid levels in human cerebrospinal fluid. Canad. Med. Ass. J. 97:13, 1967. 8. Uete, T., Wasa, M., and Shimogami, A.: Corticosteroid determination in cerebrospinal fluid. Metabolism 16:608, 1967.
9. -, Nishimura, S., Ohya, H., Shimomura, T., and Tatebayashi, Y.: Corticosteroid levels in blood and cerebrospinal fluid in various diseases. J. Clin. Endocr. 30: 208, 1970. 10. Gurdjian, E. S., and Webster, J. E.: Head Injuries, Mechanism, Diagnosis, and Management. Boston, Little, Brown, 1958, p. 482. 11. Barnard, C.: Tuberculous meningitis, cortisone treatment as an adjunct to the antibiotics. The effect on the clinical features and the cerebrospinal fluid. S. Afr. Med. J. 27:219, 1953. 12. Roberts, H. J.: Supportive adrenocortical steroid therapy in acute and subacute cerebrovascular accidents, with particular reference to brain-stem involvement. J. Amer. Geriat. Sot. 6:686, 1958. 13. Russek, H. I., Russek, A. S., and Zohman, B. L.: Cortisone in immediate therapy of apoplectic stroke. J.A.M.A. 159: 102, 1955. 14. Kofman, S., Garvin, J. S., Nagamani, D., and Taylor, S. G. III.: Treatment of cerebral metastases from breast carcinoma with prednisolone. J.A.M.A. 163:1473, 1957. 15. Paterson, R., DePasquale, N., and Mann, S.: Pseudotumor cerebri. Medicine 40:85, 1961. 16. Ingraham, F. D., Matson, D. D., and McLaurin, R. L.: Cortisone and ACTH as
EFFECT
OF CORTISOL
an adjunct to the surgery of craniopharyngiomas. New Eng. J. Med. 246:568, 1952. 17. Raaf, J., Stainsby, D. L., and Larson, W. L. E.: The use of ACTH in conjunction with surgery for neoplasms in the parasellar area. 3. Neurol. 11:463, 1954. 18. Tytus, J. S., Seltzer, H. S., and Kahn, E. A.: Cortisone as an aid in the surgical treatment of craniopharyngiomas. J. Neurosurg. 12:555, 1955. 19. Hooshmand, H., Dove, J., Houff, S., and Suter, C.: Effects of diuretics and steroids on CSF pressure. Arch. Neurol. 21:499, 1969. 20. Sato, 0.: The effect of dexamethasone on cerebrospinal fluid production rate in the dog. Brain Nerve 19:485, 1967. 21. Timiras, P. S., Woodbury, D. M., and Goodman, L. S.: Effect of adrenalectomy, hydrocortisone acetate and desoxycorticosterone acetate on brain stability and electrolyte distribution in mice. J. Pharmacol. Exp. Ther. 112:80, 1954. 22. Woodbury, D. M., and Vanadakis, A.: Effect of steroids on the central nerve system. In Dorfman, R. I. (Ed.): Methods in Hormone Research, Vol. V. New York, Academic, 1966, p. 1. 23. Fishman, R. T.: Factors influencing sodium exchange in brain: Effects of dexamethasone. Zn Caveness, W. F., and Walker, A. E. (Eds.) : Head Injury. Philadelphia, Lippincott, 1966. p. 490.
325 24. Elliott, K. A. C., and Jasper, H. H.: Measurement of experimentally induced brain swelling and shrinkage. Amer. J. Physiol. 157:122, 1949. 25. -, and Yrarrazaval, S.: Effect of adrenalectomy and cortisone on tissue permeability in vitro. Nature 169:416, 1952. 26. Taylor, J. M., Levy, W. A., Herzog, I., and Scheinberg, L. C.: Prevention of experimental cerebral edema by corticosteroids: biochemical and ultrastructural studies. Neurology 15:667, 1965. 27. Fox, J. L.: Development of recent thoughts on intracranial pressure and the blood-brain barrier. J. Neurol. 21:909, 1964. 28. Pappius, H. M., and McCann, W. P.: Effects of steroids on cerebral edema in cats. Arch. Neurol. 20:207, 1967. 29. Rovit, R. L., and Magen, R.: Steroids and cerebral edema: the effects of glucocorticoids on abnormal capillary permeability following cerebral injury in cats. J. Neuropath. Exp. Neurol. 27:277, 1968. 30. Forsham, P. H., and Thorn, G. W.: The adrenals. In Williams, R. H. (Ed.): Textbook of Endocrinology. Philadelphia, Saunders, 1955, p. 776. 31. Jefferson, A.: A clinical correIation between encephalopathy and papilledema in Addison’s disease. J. Neurol. Neurosurg. Psychiat. 19:21, 1956. 32. Walsh, F. B.: Papilledema associated with increased intracranial pressure in Addison’s disease. Arch. Ophthal. 47:86, 1952.