Cerebrospinal fluid lactate and lactate/pyruvate ratios in hydrocephalus JAMES E. RAISIS, M.D., GLENN W . KINDT, M . D . , JOHN E. MCGILLICUOI)V, M.D., AND CAROLE A. MILLER,M.D.
Department of Surgery, Section of Neurological Surgery, University of Michigan Medical Center, Ann Arbor, Michigan v' Cerebral metabolism in 21 hydrocephalic patients was studied. Preoperative and postoperative specimens of cerebrospinal fluid (CSF) were obtained and the cerebral perfusion pressure (CPP) was calculated in each instance. The specimens of CSF were analyzed for lactate and pyruvate and the lactate/pyruvate (L/P) ratio was calculated for each sample. The L/P ratio, which reflects the redox state of the cell, was used to determine the extent of anaerobic metabolism. An inverse relationship was noted between CPP and lactate as well as the L/P ratio. In general, the level of anaerobic metabolism was decreased after insertion of a shunt. KEy W o R o s 9 hydrocephalus 9 shunt 9 anaerobic metabolism lactate/pyruvate ratio 9 cerebral perfusion pressure
HE status of cerebral metabolism in hydrocephalus has not been thoroughly investigated. Previous experiments have demonstrated that a moderate increase in intracranial pressure (ICP) may significantly reduce cerebral blood flow due to a decrease in the cerebral perfusion pressure (CPP). 6,s,15 In the presence of a decreased CPP there is a shift from aerobic to anaerobic metabolism? ,7,1~ The anaerobic metabolism results in a rise in the lactate and lactate/pyruvate ( L / P ) ratio in brain tissue and the cerebrospinal fluid (CSF). ''~'~2'~8 Granholm and Siesj8 s noted that the lactate and the L / P ratio were elevated in the CSF of hydrocephalic patients, but the effects of CPP and the results of shunting on cerebral metabolism were not considered in their report. In this study the extent of anaerobic metabolism in hydrocephalic patients was deter-
T
J. Neurosurg. / Volume44 / March, 1976
9
mined by measuring the lactate and the L / P ratio in CSF before and after shunting procedures. The postshunt metabolic values were used as controls and compared with preshunt values. A correlation of metabolic parameters, that is, lactate and the L / P ratio, was made with the C P P of individual patients. Clinical Materials and Methods
A total of 21 patients with communicating and noncommunicating hydrocephalus were studied. Patients with disease processes such as posterior fossa tumors or active meningitis were excluded. Ventricular fluid was obtained either at the time of ventriculogram or intraoperatively prior to the placement of a ventriculoatrial shunt. Approximately 1 week after the operative procedure, additional 337
J. E. Raisis, et al. TABLE 1
Preoperative and postoperative data from hydrocephalic patients Preoperative Data Case Ventricular CPP Lactate Pyruvate L/P No. Pressure* (mm Hg) (rnM/1) (raM/l) (ram Hg) 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
16.1 36.8 22.0 36.8 19.9 13.2 33.0 15.4 18.4 17.6 18.4 22.1 20.6 22.0 29.0 29.4 18.4 22.8 51.4 9.5 25.7
80 56.2 54.7 56.2 56.8 57.5 58 74.6 78.3 86.4 109 64.6 54.0 45 63.6 67.2 68.3 70.2 67.9 48.3 57.6
1.7 2.3 1.4 2.3 1.7 3.7 2.6 1.9 1.7 2.9 2.2 1.8 2.3 2.4 3.5 2.5 1.9 1.5 2.1 2.4 3.6
.10 .10 .07 .I0 .10 .19 .12 .14 .19 .31 .21 .13 .16 .14 .19 .17 .10 .12 .13 .10 .28
17.0 23.0 20.0 23.0 17.0 19.4 21.6 13.6 8.9 9.4 10.4 13.8 14.4 17.1 18.4 14.7 19.0 12.1 15.9 24 12.9
Postoperative Data CPP Lactate (mm Hg) (raM/l)
Pyruvate (raM/l)
L/P
92 89
3.8 2.1
.17 .12
22.4 17.5
89 72.9 67
2.1 1.3 3.3
.16 .12 .27
13.1 10.8 12.2
86.2 92.9 100.2 123.6 80.1 61.4
1.3 1.7 2.0 2.5 1.5 2.0
.14 .11 .17 .18 .12 .15
9.2 15.5 11.8 13.9 12.5 13.3
* Postoperative ventricular pressures were 3.8 mm Hg or less.
specimens were obtained by tapping the shunt reservoir. Care was taken to obtain enough fluid to ensure a fresh ventricular sample by discarding the first 0.5 to 1.0 cc. The C S F was immediately placed in 6% perchloric acid, mixed thoroughly, and stored in ice. I f a precipitate formed the specimen was centrifuged. The s u p e r n a t a n t was decanted and frozen for later analysis. Duplicate aliquots of these specimens were then analyzed by enzymatic technique for lactate and pyruvate. 1,1~ The L / P ratio was calculated from these values. Some specimens of C S F were obtained under anaerobic conditions for determination of p H and pCO~. Mean ventricular pressure and mean systemic arterial pressure were recorded when the C S F sample was obtained, and the C P P was calculated.
operative values were not obtained on 10 patients either because of difficulty with fluid aspiration from the shunt or because the C S F was bloody or xanthochromic. The problem encountered when aspirating postoperative samples was most likely due to collapse of the ventricle around the ventricular catheter. Postoperative blood-tinged or xanthochromic samples were discarded since they would falsely elevate lactate values. The p H and pCO2 values obtained on the specimens collected under anaerobic conditions were within normal ranges, 7.32 to 7.45 p H and 28 to 40 m m Hg respectively. No complications occurred because of the C S F aspirations. The results suggest an inverse relationship between the C P P and the L / P ratio, as well as between C P P and the lactate. When the lactate and the L / P ratios were correlated with the C P P values as shown in Table 2, three categories of C P P were used: low (45-59 m m Results Hg); marginal (60-69 m m Hg); and normal Data were collected from 21 patients (70 m m Hg and higher). The lactate values before shunting and from 11 of these patients and the L / P ratios were averaged for each of after shunting. The values for these individual these ranges. Low C P P was associated with a patients are recorded in Table 1. Post- high lactate and L / P ratio, and conversely, a
338
J. Neurosurg. / Volume 44 / March, 1976
CSF lactate/pyruvate ratios in hydrocephalus TABLE 2
Correlation of preoperative CSF lactate and L/P ratios with cerebral perfusion pressure ( CPP) Average No. of Lactate Average Cases (mM/1) L/P
Cerebral Perfusion Pressure low (45 - 59 m m Hg) marginal (60 - 69 m m Hg) normal (70 - 100 m m Hg)
10 6 5
2.5 2.2 2.1
19.2 15.6 11.8
TABLE 3
Comparison of pre- and postoperative lactate and L/P ratios in five hydrocephalic patients with low preoperative CPP
Preoperative Data PostoperativeData Case CPP Lactate CPP Lactate No. (mm Hg) (mM/1) L/P (ram Hg) (raM/l) L/P 2 4 5 6 13
56.2 56.2 56.8 57.5 54.0
2.3 2.3 1.7 3.7 2.3
23.0 23.0 17.0 19.4 14.4
89 89 72.9 67 61.4
2.1 2.1 1.3 3.3 2.0
17.5 13.1 10.8 12.1 13.3
low lactate and L / P ratio was noted with a normal CPP (Table 2). In general, a decrease in the CSF lactate and the L / P ratio occurred following insertion of a shunt. For Table 3, the data are taken from the five patients with low CPP (less than 60 mm Hg) who had both preoperative and postoperative specimens sampled. All of these patients showed a reduction in both lactate and the L/P ratio following a shunting procedure. Discussion
The exact etiology of "brain damage" in hydrocephalus is not known. Most likely it is a combination of mechanical distortion that results from ventricular dilatation and metabolic changes induced by increased pressure. Marked ventricular dilatation in congenital hydrocephalus is, in many instances, associated with permanent brain dysfunction. However, there has not been a good correlation between the thickness of the cortical mantle and the neurological state of the patient? ~ Elevated ICP may also result in J. Neurosurg. / Volume44 / March, 1976
brain damage independent of mechanical distortion. When the ICP rises significantly, the CPP is decreased and ischemia occurs. If the ischemia is marked, there is a decrease in high-energy phosphorylated compounds such as phosphocreatine and ATP. ls'15 A marked decrease in these compounds is ultimately associated with permanent brain damage. The early effect of a reduced CPP is a mild ischemia resulting in a shift toward anaerobic metabolism. 15 This shift may be detected by the elevation of the CSF lactate and the L / P ratio. The L / P ratio conveniently reflects the oxidation-reduction state ( N A D H / N A D +) of the tissue, provided the pH is within relatively normal limits. ~'4'1~'13 The N A D H / N A D + ratio within the cytoplasm of the cell is in near equilibrium with the L/P ratio of brain tissue. Lactate and pyruvate differ quantitatively across the cell membrane but their ratio remains similar? The intracellular lactate and pyruvate are therefore reflected in the CSF values? '7 Zwetnow and Siesj5, ~8'~5 in a series of animal experiments, showed the close relationship of cerebral metabolism with CPP. More specifically, they demonstrated that it was necessary to reduce the CPP to approximately 30 mm Hg before a decrease in tissue high-energy compounds such as phosphocreatine and ATP occurred. However, with a small reduction in CPP there was a rise in the lactate and L/P ratio in brain. Their results indicate that elevated lactate values and L / P ratios in brain tissue are earlier and more sensitive indicators of tissue hypoxia than are changes in tissue highenergy phosphorylated compounds. We have attempted to correlate the CPP with the metabolic state of brain tissue in a clinical situation. The CPP was determined and the CSF analyzed for lactate and pyruvate in hydrocephalic patients with elevations in their ICP. Correlation between metabolic parameters representing anaerobic metabolism (lactate and L/P ratio) and the CPP was made before and after the placement of a ventricular shunt (Table 1). A graphic illustration of the preoperative data is shown in Fig. 1, which plots the L / P ratio against the CPP. The line that best fits these values was determined by standard linear regression techniques. Previously reported animal experiments demonstrated a similar 339
J. E. Raisis, et al.
FIG. 1. Graph illustrating preoperative data correlating CPP with L/P ratios. A hne best fitting the points was determined by linear regression techniques.
obtain postoperative specimens of CSF for comparison with preoperative values. In each of these patients there was a reduction in the lactate and the L/P ratio following the placement of a shunt with restoration of a higher CPP. When the paired t test was used this reduction was significant at the 0.001 level for both lactate and the L/P ratio. These results indicate that shunting hydrocephalic patients with significantly decreased CPP restores and maintains cellular oxidative metabolism. The status of cellular metabolism in brain tissue, as reflected by the lactate and the L / P ratio in CSF, might be used to aid in the diagnosis of clinical problems. Measurements of these metabolic parameters may be useful in the evaluation of various CSF shunting devices and may possibly aid in the detection of intermittently malfunctioning valves. In addition, the CSF lactate and L/P ratio could be of assistance in the evaluation of patients who have arrested hydrocephalus. Caution should be used in correlating metabolic changes with neurological deficits until more information is available. The presence of anaerobic metabolism, however, is indicative of cellular hypoxia and, if it is longstanding or severe, may ultimately result in cellular damage.
relationship between a CPP of 40 and 110 mm Hg. TM The patients were placed into three categories based on the ranges of CPP as demonstrated in Table 2. When the CPP was low, the lactate and L / P ratios were elevated. When the CPP was marginal, these metabolic parameters were somewhat lower. This pressure range (60 to 69 mm Hg) probably included cases in which the CPP was adequate to maintain oxidative metabolism, and some in which the CPP was inadequate and Acknowledgment resulted in a shift toward anaerobic metabThe authors wish to express their appreciation to olism. In the final category, the CPP was normal and the lactate and L / P ratios were their Dr. George W. Williams for his help with the statistical analysis of the data. lowest. Statistical analysis that used the Pearson correlation coefficient demonstrated a References significant inverse relationship between CPP 1. Bergmeyer H: Methods of Enzymatic and the L / P ratio (r = - 0 . 6 6 , p < 0.005). Analysis, ed 2. Williams DH, translator. New With the same test there was a trend toward a York: Academic Press, 1965, pp 266-270 similar relationship between CPP and the lactate values, but this was not statistically 2. Granholm L, Siesj~ BK: The effects of hypercapnia and hypocapnia upon the cerebrosignificant (r = -0.17, p > 0.10). The data spinal fluid lactate and pyruvate concendemonstrate the dependence of cellular oxtrations and upon the lactate; pyruvate, ATP, idative metabolism upon the maintenance of ADP, phosphocreatine and creatine concenan adequate CPP in patients with increased trations of cat brain tissue. Acta Physiol Stand ICP. 75:257-266, 1969 The level of anaerobic metabolism was 3. Granholm L, Siesj~ BK: Signs of tissue hypoxia in infantile hydrocephalus. Dev Med Child decreased after the placement of a ventricular Neuroi [Suppl] 22:73-77, 1970 shunt as shown by a decrease in L / P ratio in 64% of the patients (Table 1). This resump- 4. Huckabee WE: Relationship of pyruvate and lactate during anaerobic metabolism. 1. tion of aerobic metabolism coincided well Effects of infusion of pyruvate or glucose and with the reduction of ICP and the restoration of hyperventilation. J Clin Invest 37:244-254, of a higher CPP. The data from five patients 1958 with low preoperative CPP values are given in 5. Kaasik AE, Nilsson L, Siesj~ BK: The effects Table 3. In these five patients we were able to of arterial hypotension upon the lactate, 340
J. Neurosurg. / Volume 44 / March, 1976
CSF lactate/pyruvate ratios in hydrocephalus
6.
7.
8. 9.
10.
l l. 12. 13.
pyruvate and bicarbonate concentrations of brain tissue and cisternal CSF, and upon the tissue concentrations of phosphocreatine and adenine nucleotides in anaesthetised rats. Acta Physiol Scand 78:448-458, 1970 Kety SS, Shenkin HA, Schmidt CF: The effects of increased intracranial pressure on cerebral circulatory functions in man. J Clin Invest 27:493-499, 1948 Kj~illquist A, Siesj~5 BK, Zwetnow N: Effects of increased intracranial pressure on cerebral blood flow and on cerebrospinal fluid HCOa, pH, lactate and pyruvate in dogs. Acta Physiol Scand 75:345-352, 1969 Langfitt TW: Increased intracranial pressure. Clin Neurosurg 16:436-471, 1968 Lowry OH, Passonneau JV, Hasselberger FX, et al: Effects of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J Biol Chem 239:18-30, 1969 Marbach EP, Well MH: Rapid enzymatic measurement of blood lactate and pyruvate. Use and significance of metaphosphoric acid as a common precipitant. Clin Chem 13: 314-325, 1967 McIlwain H: Biochemistry and the Central Nervous System, ed 3. Boston: Little-Brown, 1966 Siesj5 BK, Kj[illquist A., Zwetnow N: The CSF lactate/pyruvate ratio in cerebral hypoxia. Life Sci [1I] 7:45-52, 1968 Siesj~5 BK, Zwetnow N: Effects of increased cerebrospinal fluid pressure upon adenine
J. Neurosurg. / Volume44 / March, 1976
nucleotides and upon lactate and pyruvate in rat brain tissue. Acta Neurol Scand 46: 187-202, 1970 14. Yashon D, Jane JA, Sugar O: The course of severe untreated infantile hydrocephalus. Prognostic significance of the cerebral mantle. J Neurosurg 23:509-516, 1965 15. Zwetnow NN: Effects of increased cerebrospinal fluid pressure on the blood flow and on the energy metabolism of the brain. An experimental study. Acta Physiol Scand [Suppl] 339:1-31, 1970 16. Zwetnow N, Kj~illquist A, Siesj/5 BK: Cerebral blood flow during intracranial hypertension related to tissue hypoxia and to acidosis in cerebral extracellular fluids. Prog Brain Res 30:87-92, 1968
This paper was presented at the annual meeting of the American Association of Neurological Surgeons, at St. Louis, Missouri, April 20-25, 1974, and in part at the Second International Symposium on Intracranial Pressure at Lund, Sweden, in June, 1974. This work was supported in part by NINCDS, PHS, Grant NS 11103-02. Address reprint requests to: James E. Raisis, M.D., Section of Neurosurgery, University of Michigan Medical Center, Ann Arbor, Michigan 48104.
341
Department of Surgery, Section of Neurological Surgery, University of Michigan Medical Center, Ann Arbor, Michigan v' Cerebral metabolism in 21 hydrocephalic patients was studied. Preoperative and postoperative specimens of cerebrospinal fluid (CSF) were obtained and the cerebral perfusion pressure (CPP) was calculated in each instance. The specimens of CSF were analyzed for lactate and pyruvate and the lactate/pyruvate (L/P) ratio was calculated for each sample. The L/P ratio, which reflects the redox state of the cell, was used to determine the extent of anaerobic metabolism. An inverse relationship was noted between CPP and lactate as well as the L/P ratio. In general, the level of anaerobic metabolism was decreased after insertion of a shunt. KEy W o R o s 9 hydrocephalus 9 shunt 9 anaerobic metabolism lactate/pyruvate ratio 9 cerebral perfusion pressure
HE status of cerebral metabolism in hydrocephalus has not been thoroughly investigated. Previous experiments have demonstrated that a moderate increase in intracranial pressure (ICP) may significantly reduce cerebral blood flow due to a decrease in the cerebral perfusion pressure (CPP). 6,s,15 In the presence of a decreased CPP there is a shift from aerobic to anaerobic metabolism? ,7,1~ The anaerobic metabolism results in a rise in the lactate and lactate/pyruvate ( L / P ) ratio in brain tissue and the cerebrospinal fluid (CSF). ''~'~2'~8 Granholm and Siesj8 s noted that the lactate and the L / P ratio were elevated in the CSF of hydrocephalic patients, but the effects of CPP and the results of shunting on cerebral metabolism were not considered in their report. In this study the extent of anaerobic metabolism in hydrocephalic patients was deter-
T
J. Neurosurg. / Volume44 / March, 1976
9
mined by measuring the lactate and the L / P ratio in CSF before and after shunting procedures. The postshunt metabolic values were used as controls and compared with preshunt values. A correlation of metabolic parameters, that is, lactate and the L / P ratio, was made with the C P P of individual patients. Clinical Materials and Methods
A total of 21 patients with communicating and noncommunicating hydrocephalus were studied. Patients with disease processes such as posterior fossa tumors or active meningitis were excluded. Ventricular fluid was obtained either at the time of ventriculogram or intraoperatively prior to the placement of a ventriculoatrial shunt. Approximately 1 week after the operative procedure, additional 337
J. E. Raisis, et al. TABLE 1
Preoperative and postoperative data from hydrocephalic patients Preoperative Data Case Ventricular CPP Lactate Pyruvate L/P No. Pressure* (mm Hg) (rnM/1) (raM/l) (ram Hg) 1
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
16.1 36.8 22.0 36.8 19.9 13.2 33.0 15.4 18.4 17.6 18.4 22.1 20.6 22.0 29.0 29.4 18.4 22.8 51.4 9.5 25.7
80 56.2 54.7 56.2 56.8 57.5 58 74.6 78.3 86.4 109 64.6 54.0 45 63.6 67.2 68.3 70.2 67.9 48.3 57.6
1.7 2.3 1.4 2.3 1.7 3.7 2.6 1.9 1.7 2.9 2.2 1.8 2.3 2.4 3.5 2.5 1.9 1.5 2.1 2.4 3.6
.10 .10 .07 .I0 .10 .19 .12 .14 .19 .31 .21 .13 .16 .14 .19 .17 .10 .12 .13 .10 .28
17.0 23.0 20.0 23.0 17.0 19.4 21.6 13.6 8.9 9.4 10.4 13.8 14.4 17.1 18.4 14.7 19.0 12.1 15.9 24 12.9
Postoperative Data CPP Lactate (mm Hg) (raM/l)
Pyruvate (raM/l)
L/P
92 89
3.8 2.1
.17 .12
22.4 17.5
89 72.9 67
2.1 1.3 3.3
.16 .12 .27
13.1 10.8 12.2
86.2 92.9 100.2 123.6 80.1 61.4
1.3 1.7 2.0 2.5 1.5 2.0
.14 .11 .17 .18 .12 .15
9.2 15.5 11.8 13.9 12.5 13.3
* Postoperative ventricular pressures were 3.8 mm Hg or less.
specimens were obtained by tapping the shunt reservoir. Care was taken to obtain enough fluid to ensure a fresh ventricular sample by discarding the first 0.5 to 1.0 cc. The C S F was immediately placed in 6% perchloric acid, mixed thoroughly, and stored in ice. I f a precipitate formed the specimen was centrifuged. The s u p e r n a t a n t was decanted and frozen for later analysis. Duplicate aliquots of these specimens were then analyzed by enzymatic technique for lactate and pyruvate. 1,1~ The L / P ratio was calculated from these values. Some specimens of C S F were obtained under anaerobic conditions for determination of p H and pCO~. Mean ventricular pressure and mean systemic arterial pressure were recorded when the C S F sample was obtained, and the C P P was calculated.
operative values were not obtained on 10 patients either because of difficulty with fluid aspiration from the shunt or because the C S F was bloody or xanthochromic. The problem encountered when aspirating postoperative samples was most likely due to collapse of the ventricle around the ventricular catheter. Postoperative blood-tinged or xanthochromic samples were discarded since they would falsely elevate lactate values. The p H and pCO2 values obtained on the specimens collected under anaerobic conditions were within normal ranges, 7.32 to 7.45 p H and 28 to 40 m m Hg respectively. No complications occurred because of the C S F aspirations. The results suggest an inverse relationship between the C P P and the L / P ratio, as well as between C P P and the lactate. When the lactate and the L / P ratios were correlated with the C P P values as shown in Table 2, three categories of C P P were used: low (45-59 m m Results Hg); marginal (60-69 m m Hg); and normal Data were collected from 21 patients (70 m m Hg and higher). The lactate values before shunting and from 11 of these patients and the L / P ratios were averaged for each of after shunting. The values for these individual these ranges. Low C P P was associated with a patients are recorded in Table 1. Post- high lactate and L / P ratio, and conversely, a
338
J. Neurosurg. / Volume 44 / March, 1976
CSF lactate/pyruvate ratios in hydrocephalus TABLE 2
Correlation of preoperative CSF lactate and L/P ratios with cerebral perfusion pressure ( CPP) Average No. of Lactate Average Cases (mM/1) L/P
Cerebral Perfusion Pressure low (45 - 59 m m Hg) marginal (60 - 69 m m Hg) normal (70 - 100 m m Hg)
10 6 5
2.5 2.2 2.1
19.2 15.6 11.8
TABLE 3
Comparison of pre- and postoperative lactate and L/P ratios in five hydrocephalic patients with low preoperative CPP
Preoperative Data PostoperativeData Case CPP Lactate CPP Lactate No. (mm Hg) (mM/1) L/P (ram Hg) (raM/l) L/P 2 4 5 6 13
56.2 56.2 56.8 57.5 54.0
2.3 2.3 1.7 3.7 2.3
23.0 23.0 17.0 19.4 14.4
89 89 72.9 67 61.4
2.1 2.1 1.3 3.3 2.0
17.5 13.1 10.8 12.1 13.3
low lactate and L / P ratio was noted with a normal CPP (Table 2). In general, a decrease in the CSF lactate and the L / P ratio occurred following insertion of a shunt. For Table 3, the data are taken from the five patients with low CPP (less than 60 mm Hg) who had both preoperative and postoperative specimens sampled. All of these patients showed a reduction in both lactate and the L/P ratio following a shunting procedure. Discussion
The exact etiology of "brain damage" in hydrocephalus is not known. Most likely it is a combination of mechanical distortion that results from ventricular dilatation and metabolic changes induced by increased pressure. Marked ventricular dilatation in congenital hydrocephalus is, in many instances, associated with permanent brain dysfunction. However, there has not been a good correlation between the thickness of the cortical mantle and the neurological state of the patient? ~ Elevated ICP may also result in J. Neurosurg. / Volume44 / March, 1976
brain damage independent of mechanical distortion. When the ICP rises significantly, the CPP is decreased and ischemia occurs. If the ischemia is marked, there is a decrease in high-energy phosphorylated compounds such as phosphocreatine and ATP. ls'15 A marked decrease in these compounds is ultimately associated with permanent brain damage. The early effect of a reduced CPP is a mild ischemia resulting in a shift toward anaerobic metabolism. 15 This shift may be detected by the elevation of the CSF lactate and the L / P ratio. The L / P ratio conveniently reflects the oxidation-reduction state ( N A D H / N A D +) of the tissue, provided the pH is within relatively normal limits. ~'4'1~'13 The N A D H / N A D + ratio within the cytoplasm of the cell is in near equilibrium with the L/P ratio of brain tissue. Lactate and pyruvate differ quantitatively across the cell membrane but their ratio remains similar? The intracellular lactate and pyruvate are therefore reflected in the CSF values? '7 Zwetnow and Siesj5, ~8'~5 in a series of animal experiments, showed the close relationship of cerebral metabolism with CPP. More specifically, they demonstrated that it was necessary to reduce the CPP to approximately 30 mm Hg before a decrease in tissue high-energy compounds such as phosphocreatine and ATP occurred. However, with a small reduction in CPP there was a rise in the lactate and L/P ratio in brain. Their results indicate that elevated lactate values and L / P ratios in brain tissue are earlier and more sensitive indicators of tissue hypoxia than are changes in tissue highenergy phosphorylated compounds. We have attempted to correlate the CPP with the metabolic state of brain tissue in a clinical situation. The CPP was determined and the CSF analyzed for lactate and pyruvate in hydrocephalic patients with elevations in their ICP. Correlation between metabolic parameters representing anaerobic metabolism (lactate and L/P ratio) and the CPP was made before and after the placement of a ventricular shunt (Table 1). A graphic illustration of the preoperative data is shown in Fig. 1, which plots the L / P ratio against the CPP. The line that best fits these values was determined by standard linear regression techniques. Previously reported animal experiments demonstrated a similar 339
J. E. Raisis, et al.
FIG. 1. Graph illustrating preoperative data correlating CPP with L/P ratios. A hne best fitting the points was determined by linear regression techniques.
obtain postoperative specimens of CSF for comparison with preoperative values. In each of these patients there was a reduction in the lactate and the L/P ratio following the placement of a shunt with restoration of a higher CPP. When the paired t test was used this reduction was significant at the 0.001 level for both lactate and the L/P ratio. These results indicate that shunting hydrocephalic patients with significantly decreased CPP restores and maintains cellular oxidative metabolism. The status of cellular metabolism in brain tissue, as reflected by the lactate and the L / P ratio in CSF, might be used to aid in the diagnosis of clinical problems. Measurements of these metabolic parameters may be useful in the evaluation of various CSF shunting devices and may possibly aid in the detection of intermittently malfunctioning valves. In addition, the CSF lactate and L/P ratio could be of assistance in the evaluation of patients who have arrested hydrocephalus. Caution should be used in correlating metabolic changes with neurological deficits until more information is available. The presence of anaerobic metabolism, however, is indicative of cellular hypoxia and, if it is longstanding or severe, may ultimately result in cellular damage.
relationship between a CPP of 40 and 110 mm Hg. TM The patients were placed into three categories based on the ranges of CPP as demonstrated in Table 2. When the CPP was low, the lactate and L / P ratios were elevated. When the CPP was marginal, these metabolic parameters were somewhat lower. This pressure range (60 to 69 mm Hg) probably included cases in which the CPP was adequate to maintain oxidative metabolism, and some in which the CPP was inadequate and Acknowledgment resulted in a shift toward anaerobic metabThe authors wish to express their appreciation to olism. In the final category, the CPP was normal and the lactate and L / P ratios were their Dr. George W. Williams for his help with the statistical analysis of the data. lowest. Statistical analysis that used the Pearson correlation coefficient demonstrated a References significant inverse relationship between CPP 1. Bergmeyer H: Methods of Enzymatic and the L / P ratio (r = - 0 . 6 6 , p < 0.005). Analysis, ed 2. Williams DH, translator. New With the same test there was a trend toward a York: Academic Press, 1965, pp 266-270 similar relationship between CPP and the lactate values, but this was not statistically 2. Granholm L, Siesj~ BK: The effects of hypercapnia and hypocapnia upon the cerebrosignificant (r = -0.17, p > 0.10). The data spinal fluid lactate and pyruvate concendemonstrate the dependence of cellular oxtrations and upon the lactate; pyruvate, ATP, idative metabolism upon the maintenance of ADP, phosphocreatine and creatine concenan adequate CPP in patients with increased trations of cat brain tissue. Acta Physiol Stand ICP. 75:257-266, 1969 The level of anaerobic metabolism was 3. Granholm L, Siesj~ BK: Signs of tissue hypoxia in infantile hydrocephalus. Dev Med Child decreased after the placement of a ventricular Neuroi [Suppl] 22:73-77, 1970 shunt as shown by a decrease in L / P ratio in 64% of the patients (Table 1). This resump- 4. Huckabee WE: Relationship of pyruvate and lactate during anaerobic metabolism. 1. tion of aerobic metabolism coincided well Effects of infusion of pyruvate or glucose and with the reduction of ICP and the restoration of hyperventilation. J Clin Invest 37:244-254, of a higher CPP. The data from five patients 1958 with low preoperative CPP values are given in 5. Kaasik AE, Nilsson L, Siesj~ BK: The effects Table 3. In these five patients we were able to of arterial hypotension upon the lactate, 340
J. Neurosurg. / Volume 44 / March, 1976
CSF lactate/pyruvate ratios in hydrocephalus
6.
7.
8. 9.
10.
l l. 12. 13.
pyruvate and bicarbonate concentrations of brain tissue and cisternal CSF, and upon the tissue concentrations of phosphocreatine and adenine nucleotides in anaesthetised rats. Acta Physiol Scand 78:448-458, 1970 Kety SS, Shenkin HA, Schmidt CF: The effects of increased intracranial pressure on cerebral circulatory functions in man. J Clin Invest 27:493-499, 1948 Kj~illquist A, Siesj~5 BK, Zwetnow N: Effects of increased intracranial pressure on cerebral blood flow and on cerebrospinal fluid HCOa, pH, lactate and pyruvate in dogs. Acta Physiol Scand 75:345-352, 1969 Langfitt TW: Increased intracranial pressure. Clin Neurosurg 16:436-471, 1968 Lowry OH, Passonneau JV, Hasselberger FX, et al: Effects of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J Biol Chem 239:18-30, 1969 Marbach EP, Well MH: Rapid enzymatic measurement of blood lactate and pyruvate. Use and significance of metaphosphoric acid as a common precipitant. Clin Chem 13: 314-325, 1967 McIlwain H: Biochemistry and the Central Nervous System, ed 3. Boston: Little-Brown, 1966 Siesj5 BK, Kj[illquist A., Zwetnow N: The CSF lactate/pyruvate ratio in cerebral hypoxia. Life Sci [1I] 7:45-52, 1968 Siesj~5 BK, Zwetnow N: Effects of increased cerebrospinal fluid pressure upon adenine
J. Neurosurg. / Volume44 / March, 1976
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This paper was presented at the annual meeting of the American Association of Neurological Surgeons, at St. Louis, Missouri, April 20-25, 1974, and in part at the Second International Symposium on Intracranial Pressure at Lund, Sweden, in June, 1974. This work was supported in part by NINCDS, PHS, Grant NS 11103-02. Address reprint requests to: James E. Raisis, M.D., Section of Neurosurgery, University of Michigan Medical Center, Ann Arbor, Michigan 48104.
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