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Lactate and Pyruvate Cncentratins, and Acid-Base Balance f Cerebrspinal Fluid in Experimentally Induced Intracerebral and Subarachnid Hemrrhage in Dgs BY TOMEI SUGI, M.D., MASATOSHI FUJISHIMA, M.D., AND TERUO OMAE, M.

1 Lactate and Pyruvate Cncentratins, and Acid-Base Balance f Cerebrspinal Fluid in Experimentally Induced Intracerebral and Subarachnid Hemrrhage in Dgs BY TOMEI SUGI, M.D., MASATOSHI FUJISHIMA, M.D., AND TERUO OMAE, M.D. Abstract: Lactate and Pyruvate Cncentratins, and Acid-Base Balance f Cerebrspinal Fluid in Experimentally Induced Intracerebral and Subarachnid Hemrrhage in Dgs The effect f bld injected int either subarachnid space r subcrtical brain tissue upn lactate and pyruvate cncentratins as well as acid-base balance f cerebrspinal fluid (CSF) was studied in the anesthetized dg. CSF lactate and lactate/pyruvate rati (L/P rati) increased prgressively fllwing the intracranial injectin f bld and reached the maximum level at six hurs after injectin. These changes were significantly greater in animals with intracerebral hematma than in thse with subarachnid hemrrhage (SAH). An increase in CSF lactate and L/P rati in hemrrhagic CSF seems t be caused by tw different factrs. Shed bld cells per se prduce lactate and pyruvate, and bld in the subarachnid space and intracerebral hematmas cause secndary changes in brain tissue metablism by a prbable reductin f cerebral bld flw. Therefre, an increase in CSF lactate with a cncmitant rise in CSF L/P rati is a useful indicatr fr brain tissue hypxia, even when CSF is hemrrhagic. The assciatin f an increase in CSF lactate t a disprprtinate decrease in CSF HCO was als bserved in these animals. Additinal Key Wrds cerebral hypxia lactate/pyruvate rati anaerbic glyclysis Intrductin D In 1967, Frman and Smith 1 reprted that lactate cncentratin f cerebrspinal fluid (CSF) in patients with subarachnid hemrrhage (SAH) markedly increased, and it was cncluded that the increase was due t the glucse metablism f shed bld cells per se in the CSF space. In ur previus study in patients with cerebrvascular diseases, 2 we als fund that hemrrhagic CSF cntained a higher lactate level and lactate/pyruvate rati (L/P rati) than did clear CSF. An increase in lactate in CSF as well as in brain tissue has been reprted in a variety f diseases r circumstances causing hypxia in the brain. They include hypxemia, ' * hyperventilatin, 5-8 hyptensive shck, 7 circulatry arrest, 8 head injury, 9 and cerebrvascular diseases " In ur experience, 2 ' 12 an increase in CSF lactate and L/P rati was significantly greater in strke patients having disturbed cnsciusness r a pr prgnsis than in thse having nrmal cnsciusness r with a gd recvery. L/P rati f CSF reflects the redx state f the cytplasmic NADH/NAD + system when CSF is in Frm the Secnd Department f Internal Medicine, The Faculty f Medicine, Kyushu University, Maidashi -1-1, Higashi-Ku, Fukuka City 812, Japan. diffusin equilibrium with brain tissue. - 1> u These facts suggested that even in the presence f bld in CSF, anaerbic glyclysis f brain tissue, in additin t that f shed bld cells, culd be reflected in CSF lactate level r CSF L/P rati. The present study was undertaken t clarify whether an increase in lactate and L/P rati in hemrrhagic CSF represented the anaerbic state f the brain. Methds Twenty-three mngrel dgs, weighing 8 t 15 kg, were anesthetized with 0 mg per kilgram f intravenus pentbarbital sdium and paralyzed with 2 mg per kilgram f gallamine triethidide. Respiratin was artificially cntrlled, and Pac, was maintained between 0 and 50 mm Hg as cnstantly as pssible by adjusting respiratin rate r tidal vlume. Hypxic animals with P, belw 60 mm Hg were excluded frm the present study. One femral artery was cannulated fr recrding f bld pressure with a pressure transducer, and fr sampling f bld. A 21 -gauge needle was intrduced int the cisterna magna, and thrugh this needle CSF samples were btained, and intracranial pressure was recrded by cnnecting the needle t a pressure transducer specific fr lw grade pressures. Physilgical saline was cntinuusly infused int the cannulated femral vein thrughut the experiment, and pentbarbital and gallamine were supplemented every hur. Strke, Vl. 6, Nvember-December

SUGI, FUJISHIMA, OMAE The animals were divided int three grups as fllws: SAH, intracerebral hemrrhage (ICH), and cntrls. In ten dgs f Grup 1 (SAH), 1 t 4 ml (2.6 ± 0.

2 SUGI, FUJISHIMA, OMAE The animals were divided int three grups as fllws: SAH, intracerebral hemrrhage (ICH), and cntrls. In ten dgs f Grup 1 (SAH), 1 t 4 ml (2.6 ± 0.9 ml, mean ± SD) f autlgus arterial bld were injected int the cisterna magna. In anther ten dgs f Grup 2 (ICH), a small burr hle was made in the parietal regin f the skull and a 21-gauge needle was carefully inserted t reach the subcrtical white matter ver the lateral ventricle by using a steretaxic apparatus. An intracerebral hematma was made by intrducing 2 t ml (2.4 ± 0. ml) f arterial bld int the brain tissue. A small amunt f injected bld leaked int the ventricles and subarachnid space, which was cnfirmed at autpsy. In each grup, 1 x h ml f CSF (1 ml fr metablite determinatin, 0.5 ml fr gas analysis) and 0.5 ml f arterial bld were withdrawn twice during the cntrl resting state, and every hur during the six-hur experimental perid fllwing the intracranial injectin f bld. There were three dgs in Grup ; CSF and arterial bld were btained in a similar manner as in Grups 1 and 2, withut the intracranial injectin f bld. Lactate and pyruvate cncentratins in CSF were determined enzymatically using Lactat-Test and Pyruvat- Test (Behringer Mannheim). CSF L/P rati was calculated frm the measured values f lactate and pyruvate cncentratins. In CSF and arterial bld, ph, Pc, and P, were determined at 7 C with IL-Meter Mdel 11. Bicarbnate (HCO ) was calculated by using Hendersn-Hasselbalch nmgram and Mitchell's crrectin fr CO 2 slubility and pk' fr CSF. 15 The animals were killed at the end f the experiment, and the brains were examined macrscpically fr the extent f bld in the subarachnid space and fr the lcatin and size f the hematma. Results In three cntrl animals (Grup ) there were n remarkable changes in lactate, pyruvate, L/P rati, ph and HCO f CSF during seven hurs, as shwn in table 1. Mean values fr each parameter during the cntrl resting perid f Grups 1 and 2 are tabulated in table 2. N significant differences in each parameter were nted between these tw grups. In Grups 1 and 2, serial changes in CSF lactate and pyruvate cncentratins, and L/P rati fllwing the intracranial injectin f bld are illustrated in figure 1. CSF lactate in bth grups increased prgressively after injectin f bld and reached the maximum level at six hurs. Mean values fr an increase in CSF lactate at six hurs frm the levels during the cntrl perid were TABLI 1 & CSF Lactate (mm/1) hurs FIGURE 1 Serial changes in laclate and pyruvale cncentratins and L/P rati in CSF fllwing the injectin f bld int either subcrtical brain tissue r subarachnid space. Mean values fr the change in lactate and pyruvale cncentratins and L/P rati are greater in ICH than in SAH. Each vertical bar indicates SEM. * = prbability f P < = />< mm per liter in Grup 2 (ICH) and 1.0 mm per liter in Grup 1 (SAH), respectively. The difference between the values f the tw grups was f statistical significance at tw, three and six hurs fllwing the injectin f bld. At fur and five hurs, hwever, Mean Values fr Lactate, Pyruvate and Bicarbnate Cncentratins, L/P Rati and ph in Repeated Sampling f CSF in Three Cntrl Animals Hurf a s 6 7 Lactate (mm/l) Pyruvate (mm/l) L/P rati HCOi (meq/l) ph Strke, Vl. 6, Nvember-December 1975

EXPERIMENTALLY INDUCED INTRACEREBRAL AND SUBARACHNOID HEMORRHAGE IN DOCS TABLE 1 Mean Values fr Lactate, Pyruvate and Bicarbnate Cncentratins, L/P Rati and ph f CSF, and Pc* f Arterial Bld During

3 EXPERIMENTALLY INDUCED INTRACEREBRAL AND SUBARACHNOID HEMORRHAGE IN DOCS TABLE 1 Mean Values fr Lactate, Pyruvate and Bicarbnate Cncentratins, L/P Rati and ph f CSF, and Pc* f Arterial Bld During Cntrl Resting State Prir t the Intracranial Injectin f Bld SAH ICH (n = (n = 10) 10) Lactate (mm/l) 1.95 ± ± 0.6 Pjrruvate (mm/l) 0.29 ± ± CSF L/P rati 8.47 * = = = 1.08 ph 7.72 ± 7.9 =t HCOi (meq/l) 25.9 =t 27.2 ± Pact (mm Hg) 41.5 ± ±.4 Mean ± SD. the difference was nt significant because f the small number f dgs available fr statistical analysis. CSF L/P rati remained unchanged fr the first three hurs after injectin, and thereafter started t rise and reached the maximum level at six hurs. The increase in CSF L/P rati in ICH at three hurs r later was always greater than in SAH. Mean values fr an increase in L/P rati at six hurs was 4.04 in ICH, significantly higher than 1.71 in SAH. A maximum change in CSF lactate and L/P rati f individual dg is shwn infigure2. Accrding t the size f the hematma prduced, Grup 2 was divided int three subgrups: small (S), mderate (M), and large (L) hematmas. There was a tendency fr a greater increase in lactate r L/P rati in dgs with large hematmas than small nes. The changes in CSF ph and HCOj are shwn in figure. CSF ph in Grups 1 and 2 tended t fall at the late stage f the experiment, althugh it was nt significantly different frm the cntrl resting state prir t injectin. In spite f a prgressive decrease in CSF HCO at fur hurs r later fllwing the hematma prduced in Grup 2, the variatin f the individual values was t great t reach statistical significance. In Grup 1, there were n cnsistent I changes in CSF HCO during the perid f bservatin. Figure 4 shws the crrelatin f changes in CSF lactate with CSF HCO btained at the varius intervals during the experimental perid. There was an inverse relatin between the tw values, i.e., an increase in lactate was accmpanied by a decrease in CSF HCO. The amunt f HCO decrease was greater than the lactate increase, and the rati f the frmer t the latter was rughly 1.5 t 1. There were, hwever, sme dgs shwing an ppsite relatin with an increase in HCO assciated with an increase in lactate. N significant relatinship was btained between the amunt f bld injected and the maximal increase in either CSF lactate r L/P rati as depicted in figure 5. Intracranial pressure rse slightly fr a shrt perid f time fllwing the intracranial injectin f bld, and then fell and remained belw the cntrl level because f repeated withdrawal f CSF samples. The maximum CSF pressure in mst A CSF HC r' (meq/l) T M SAH SAH S M L ICH FIGURE! I C H Maximum changes in CSF laclate (left) and L/P rati (right) in individual dgs. ICH was divided int three subgrups by the size f hematma as small (S), mderate (M). and large (L) hematmas. CSF lactate as well as L/P rati increased mre markedly in dgs with a large hematma than in thse with a small hematma. -i FIGURE hurs Serial changes in CSFpH and bicarbnate cncentratin fllwing intracranial injectin f bld. CSF ph remained unchanged in bth grups. CSF HC0 tended t fall in ICH, althugh the change was nt statistically significant frm the cntrl resting perid. Strke, Vl. 6, Nvember-December

4 SUGI, FUJISHIMA, OMAE 2 ^ 1 I I m 8" 1 X p. "2 M _ -4-5 FIGURE 4 A CSF Lactate (inm/1) -6 The crrelatin f changes between CSF lactate and CSF HCO at varius lime intervals after intracranial injectin f bld. An inverse relatinship is btained, althugh sme shwed an increase in HCO in spite f a rise in lactale. The amunt f decrease in HCO is greater than the lactate increase. animals was recrded tw hurs after beginning the experiments. The mean CSF pressures were 16. ± 8.4 mm Hg in SAH and 12.7 ± 4. mm Hg in ICH. There was n bvius relatinship between a maximum rise in CSF pressure and a maximum increase in either CSF lactate r L/P rati during the experimental perid. Discussin The present study shwed that when bld was intrduced int either the subarachnid space r the 4 ml u FIGURE 8 4 ml The relatinship between the amunt f bld injected and the change in CSF lactate (left) r in CSF L/P rati (right). The changes in lactate r L/P rati are independent f the amunt f injected bld. brain tissue, CSF lactate and the L/P rati increased prgressively in each experimental mdel. There have been bservatins suggesting that ne f the causes f increased CSF lactate in SAH culd be due t the glyclytic prcess in the shed bld cells. In an in vitr study, Frman and Smith 1 bserved a prgressive increase in lactate with a cncmitant fall in ph and HCOj in the mixture f bld and mck CSF tnmetered fr 12 hurs. Similar bservatins shwing a rise in lactate in the hemrrhagic CSF have been reprted by Shannn et al. 16 and Granhlm. 17 The latter nted the CSF L/P rati t be unchanged despite an increase in bth lactate and pyruvate. The increase in CSF lactate and L/P rati was significantly greater in dgs with ICH than in dgs with SAH in the present study. As the experimental cnditins were the same in the tw grups except fr hematma frmatin in ICH, the circulatry and the metablic disturbances f the brain are assumed t be mre severe in ICH than in SAH. These facts suggest that, in additin t a rise in lactate derived frm shed bld cells, an increase in CSF L/P rati as well as lactate in hemrrhagic CSF seems t reflect the anaerbic state f the brain. These parameters culd be used as indicatrs fr the severity f the cerebral hypxia r the prgnsis f patients with ICH. In his in viv study, Granhlm 17 als fund an increase in CSF lactate and pyruvate, but n change in L/P rati during the ne t three hurs fllwing the intracisternal injectin f bld in cats. In cntrast, the present study shwed that CSF lactate and L/P rati increased prgressively and reached their maximum level at six hurs. This increase in CSF L/P rati may indicate the anaerbic state f the brain tissue. This anaerbic glyclysis in the experimental SAH, as frequently seen in patients with SAH, was cnsidered due t decreased cerebral bld flw resulting frm cerebral vasspasm r frm the increased intracranial pressure. Althugh we have n direct data t prve that a gradual decrease in cerebral circulatin fllwed induced SAH, a delayed but cnsistent rise in CSF L/P rati suggests that the intracranial bld injectin might cause a reductin f bld supply t the brain r derangement f brain metablism which results in brain hypxia. The relatinship f changes in CSF lactate with CSF HCO varies with the different experimental cnditins. In hypxia, MacMillan and Siesj 18 bserved a ne-t-ne relatinship between an increase in CSF lactate and a decrease in CSF HCO. In the present study, a larger decrease in CSF HCO relative t the increase in CSF lactate was shwn, and the rati was 1.5 t 1, i.e., 1 mm per liter f lactate prduced was cupled with 1.5 meq per liter f HCO. Similarly, a 1: relatinship was reprted by Mines and S^rensen 19 in hypxic dgs. Shannn et al. 16 studied the acid-base changes in hemrrhagic CSF fllwing the intracisternal injectin f red bld cells in dgs and fund the rise in CSF lactate and pyruvate accunted fr nly 718 Strke, Vl. 6, Nvember-December 1975

5 EXPERIMENTALLY INDUCED INTRACEREBRAL AND SUBARACHNOID HEMORRHAGE IN DOGS 57% f the ttal fall in CSF HCOj. The discrepancy between changes in CSF lactate and HCOl is nt fully understd. It has been speculated that acid metablites ther than lactate exist r that an additinal mechanism f acidifying CSF is perative in hypxia r intracranial hemrrhages. Acknwledgment The authrs wish t thank Miss Y. Snda fr technical assistance. References 1. Frman C, Smith AC: Metablic acidsis f the cerebrspinal fluid assciated with subarachnid haemrrhage. Lancet 1: , Sugi T, Fujishima M, Yamaguchi T, et al: Lactate and pyruvate cncentratins and acid-base balance f cerebrspinal fluid and arterial bld in patients with cerebrvascular diseases. Clin Neurl 15:5-14, 1975 (in Japanese). SiesjS BK, Nilssn L: The influence f arterial hypxemia upn labile phsphates and upn extracellular and intracellular lactate and pyruvate cncentratins in the rat brain. Scand J Clin Lab Invest 27:8-96, Gurdjian ES, Stne WE, Webster JE: Cerebral metablism in hypxia. Arch Neurl Psychiat 51: , Plum F, Psner JB: Bld and cerebrspinal fluid lactate during hyperventilatin. Amer J Physil 212: , Kazemi H, Valenca LM, Shannn DC: Brain and cerebrspinal fluid lactate cncentratin in respiratry acidsis and alkalsis. Resp Physil 6: , Feldman RA, Yashn D, Lcke GE, et al: Cerebral tissue lactate in experimental ligemic shck. J Neursurg 4: , Yashn D, Paulsn G, Lcke GE, et al: Cerebral and spinal fluid anaerbism during circulatry arrest. Neurlgy 22: , King LR, McLaurin RL, Knwles HC Jr: Acid-base balance and arterial and CSF lactate levels fllwing human head injury. J Neursurg 4Q: , Zupping R, Kaasik AE, Raudam E: Cerebrspinal fluid metablic acidsis and brain xygen supply. Studies in patients with brain infarctin. Arch Neurl 25:-8, Sambrk MA, Hutchinsn EC, Aber GM: Metablic studies in subarachnid haemrrhage and strkes. I. Serial changes in acid-base values in bld and cerebrspinal fluid. Brain 96: , Fujishima M, Sugi T, Chki J, et al: Cerebrspinal fluid and arterial lactate, pyruvate and acid-base balance in patients with intracranial hemrrhages. Strke 6: (Nv-Dec) Siesj BK, Kjallquist A, Zwetnw N: The CSF lactate/pyruvate rati in cerebral hypxia. Life Sci 7:45-52, Granhlm L, Siesj BK: The effects f hypercapnia and hypcapnia upn the cerebrspinal fluid lactate and pyruvate cncentratins and upn the lactate, pyruvate, ATP, ADP, phsphcreatine and creatine cncentratins f cat brain tissue. Acta Physil Scand 75: , Mitchell RA, Herbert DA, Carman CT: Acid-base cnstants and temperature cefficients fr cerebrspinal fluid. J Appl Physil 20:27-0, Shannn DC, Shre N, Kazemi H: Acid-base balance in hemrrhagic cerebrspinal fluid. Neurlgy 22: , Granhlm L: The effect f bld in the CSF n the CSF lactate, pyruvate and bicarbnate cncentratins. Scand J Clin Lab Invest 2:61-66, MacMillan V, Siesj BK: The effect f arterial hypxemia upn acid-base parameters in arterial bld and cisternal cerebrspinal fluid f the rat. Acta Physil Scand 8: , Mines AH, S^rensen SG Changes in the electrchemical ptential difference fr HCO between bld and cerebrspinal fluid and in cerebrspinal fluid lactate cncentratin during iscarbic hypxia. Acta Physil Scand 81:225-2, 1971 Strke, Vl. 6, Nvember-December

A Plasma Humoral Factor of Extrarenal Origin Causing Release of Reninlike Activity in Hypotensive Dogs

A Plasma Humoral Factor of Extrarenal Origin Causing Release of Reninlike Activity in Hypotensive Dogs A Plasma Humral Factr f Extrarenal Origin Causing Release f Reninlike Activity in Hyptensive Dgs By E. De Vit, C. Wilsn, R. E. Shipley, R. P. Miller, and B. L. Mrtx ABSTRACT Plasma reninlike activity significantly