CSF leukotriene C4 following subarachnoid hemorrhage

Leukotrienes derive from arachidonic acid metabolism via the lipoxygenase pathway and modulate several cellular events. In the central nervous system, leukotrienes are mainly synthesized in the gray matter and in vascular tissues. Their production is enhanced in ischemic conditions and in experimental subarachnoid hemorrhage (SAH). Previous studies have indicated the ability of the leukotrienes C4 and D4 to constrict arterial vessels in vivo and in vitro and have suggested their involvement in the pathogenesis of cerebral arterial spasm. In the present study, the authors measured lumbar and cisternal cerebrospinal fluid (CSF) levels of leukotriene C4 in 48 patients who had suffered aneurysmal SAH. In 12 of the cases, symptomatic and radiological spasm was evident. The mean lumbar CSF level of immunoreactive-like activity of leukotriene C4 (i-LTC4) was significantly higher (p less than 0.005) than in control cases, while the cisternal CSF level was higher than the lumbar mean concentration (p less than 0.005). Patients presenting with vasospasm had significantly higher levels of i-LTC4 compared to patients without symptomatic vasospasm. This is the first report concerning monitoring of i-LTC4 levels in the CSF after SAH. The results of this study suggest that: 1) metabolism of arachidonic acid via the lipoxygenase pathway is enhanced after SAH; 2) the higher cisternal CSF levels of i-LTC4 may be part of the biological response in the perianeurysmal subarachnoid cisterns after the hemorrhage; and 3) the higher CSF levels of i-LTC4 in patients presenting with vasospasm suggest that a relationship exists between this compound and arterial spasm and/or reflect the development of cerebral ischemic damage.     

Disturbance of CSF absorption after experimental subarachnoid hemorrhage; correlation with subarachnoid fibrosis

Correlation between subarachnoid fibrosis and absorption resistance of cerebrospinal fluid (CSF) after experimental subarachnoid hemorrhage (SAH) was studied in dogs. Scanning electron microscope (SEM) was used along with steady-state infusion method. Experimental SAHs were produced by injecting 0.6-1.0 ml/kg of blood into the cisterna magna singly, twice and three times for 11, 7 and 8 dogs respectively. All dogs were sacrificed by perfusing their brain with 10% formaldehyde solution immediately after completion of the measurement of CSF absorption resistance. This was conducted at various periods ranging from 3 to 7 weeks after the first blood injection. Measurement of absorption resistance was performed by infusion of physiological saline solution into the spinal subarachnoid space at speeds of 0.1, 0.2 and 0.3 ml/min for 30, 15 and 10 minutes respectively. The measurement was also conducted in 9 dogs without producing SAH as a control study. Specimens collected from basal cistern, lateral cerebral fissures and parasagittal sulci were observed in their subarachnoid spaces under SEM, and the degree of subarachnoid fibrosis was expressed by one of 5 grades for comparison with the absorption resistance in each dog. The grade of subarachnoid fibrosis significantly correlated with the absorption resistance. The absorption disturbances tended to improve after about a month along with disappearance of subarachnoid fibrosis. The results in this study suggest that subarachnoid fibrosis might be involved in inducing CSF absorption disturbances by affecting both the major and the lesser pathways of CSF.     

Effect of experimental subarachnoid hemorrhage on CSF eicosanoids in the rat

A simple and inexpensive experimental model of subarachnoid hemorrhage (SAH) was developed in the rat. Based on accumulating data indicating the important role of arachidonic acid metabolites in the etiology of delayed cerebral vasospasm, we investigated changes induced by SAH on cerebrospinal fluid (CSF) levels of prostaglandin E2 (PGE2), F2 alpha (PGF2 alpha), and thromboxane B2 (TXB2). SAH was produced by the cisternal injection of blood via percutaneous suboccipital puncture. SAH rats (n = 200) were injected with 300 microliters of fresh autologous arterial blood; Control rats (n = 100) received the same volume of mock CSF. In 60 additional animals, no injections were made. To follow the changes induced by SAH on both the spectrum and time course of CSF eicosanoids, cisternal CSF samples were collected under basal conditions, 6, 12, and 36 after cisternal injection. PGE2, PGF2 alpha, and TXB2 were assayed in aliquots of CSF obtained by pooling samples from each experimental group. Eicosanoids were assayed using radioimmunoassay techniques. Arterial spasm was verified in parallel groups of SAH and control rats by comparison of the angiographic diameters of the basilar arteries (BA) and middle cerebral arteries (MCA) to that of the stapedial artery. CSF levels of all three eicosanoids were significantly higher in the SAH groups compared to both noninjected and mock-CSF injected control rats. These increases in concentrations of eicosanoids were accompanied by a decrease in the mean vascular diameter (77.5-82.0% of control) on day 2 following cisternal injection. We conclude that marked elevations of spasmogenic eicosanoids in the CSF are associated with experimental SAH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased levels of nitrite/nitrate in the cerebrospinal fluid of patients with subarachnoid hemorrhage

The role of nitric oxide (NO) in the mechanism of delayed cerebral vasospasm (VS) after subarachnoid hemorrhage (SAH) was investigated by analyzing the stable metabolites of NO, nitrite and nitrate, by the Griess method in the cerebrospinal fluid (CSF) and venous blood of 29 patients with SAH, the CSF of 22 control patients, and venous blood from eight normal subjects. VS was defined as diffuse and severe angiographical vasospasm detected by angiography performed around days 7–9 after the onset. Six of the 29 patients had VS. The nitrite/nitrate levels in the blood of patients with SAH were almost within the range of those in normal subjects, but the levels in the CSF of patients with SAH were significantly higher than those of the control group. Patients with VS after SAH had significantly lower levels in the CSF than patients without VS on days 7–9, when VS is most likely to occur. These observations suggest that NO production in the CSF environment occurs following SAH, but possibly may not provoke VS. Received: 2 June 1998 / Accepted: 15 April 1999     

CSF dynamics in patients with subarachnoid and/or intraventricular hemorrhage

The purpose of this study was to examine the extent to which reduction of cerebrospinal fluid (CSF) absorption contributes to raised intracranial pressure (ICP) in patients with acute subarachnoid hemorrhage (SAH). Seventeen patients suffering from SAH and/or intraventricular hemorrhage were studied; all were admitted in Grades II to V according to Hunt and Hess. Eleven patients had a proven aneurysm. The ICP, monitored via an intraventricular catheter, was above 15 mm Hg (2 kPa) during part of the monitoring period in all patients. B-waves at 1/min were noted in all patients. Resistance to outflow of CSF was determined by the following techniques: 1) bolus injection; 2) constant-rate steady-state infusion; or 3) controlled withdrawal ("inverse infusion"). Resistance to outflow of CSF was increased in all patients, ranging from 11.5 to 85 mm Hg/ml/min. The ICP was linearly correlated with outflow resistance. Four (50%) of the eight survivors required a shunt. Neither the presence of hydrocephalus on admission, nor the level of ICP, nor the magnitude of resistance to outflow of CSF was clearly related to the requirement of a permanent CSF diversion.     

Serum neuron-specific enolase levels after subarachnoid hemorrhage

We examined serum levels of neuron-specific enolase by enzyme immunoassay in 29 patients with subarachnoid hemorrhage due to ruptured cerebral aneurysm. Serum neuron-specific enolase levels were significantly higher in patients with a poor neurological status than in patients with a good neurological status on admission, and the greater the amount of subarachnoid blood, the higher the serum neuron-specific enolase level. Patients with a good outcome had low serum neuron-specific enolase levels throughout their courses. Serum neuron-specific enolase levels increased with development of delayed ischemic neurological deficits and, especially in poor outcome patients, high levels persisted until 3 weeks after the subarachnoid hemorrhage.     

Nature of the vasoactive substance in CSF from patients with subarachnoid hemorrhage

The purpose of this experiment was to study the nature of vasoactive substance in cerebrospinal fluid (CSF) from patients with aneurysmal subarachnoid hemorrhage. The authors have examined the effects of disulfide bond-reducing agents, a sulfhydryl group oxidizing agent, and specific antagonists of so-called "classical" neurotransmitters on the in vitro isometric contraction of canine basilar arterial strips induced by bloody human CSF. The disulfide bond-reducing agents dithiothreitol (10(-4) M) and dithioerythritol (10(-4) M) suppressed the contraction induced by bloody CSF by an average of 40.3% and 61.2%, respectively. This suppression was achieved under conditions that did not alter KCl-induced contraction. The sulfhydryl group oxidizing agent, 5,5'-dithiobis-(2-nitrobenzoic acid), 10(-4) M, reversed the inhibitory effect of dithioerythritol on the contractile response to bloody CSF. No significant suppression of any response in any preparation was observed with methysergide (10(-7) M), mepyramine (10(-7) M), phenoxybenzamine (10(-5) M), propranolol (10(-6) M), or atropine (10(-6) M). These results indicate that disulfide bonds in the arterial smooth-muscle cells are involved in the contractile responses of canine basilar artery to bloody CSF. Prostaglandins, hemoglobin, and lipid hydroperoxides may all be spasmogens in bloody CSF, while serotonin, histamine, norepinephrine, and acetylcholine are probably not involved.     

Source of fibrin/fibrinogen degradation products in the CSF after subarachnoid hemorrhage

In 48 patients with a subarachnoid hemorrhage, levels of fibrin/fibrinogen degradation products (FDP's), total protein, and plasminogen were measured in the cerebrospinal fluid (CSF) between Days 9 and 15 after the bleed. Of these 48 patients, 22 received tranexamic acid. Despite a significant reduction in the incidence of rebleeding in patients taking tranexamic acid, no difference in FDP levels was found between patients receiving tranexamic acid and a control group of patients who were not; nor was any relationship evident between FDP levels and rebleeding. In patients with detectable levels of FDP's, CSF protein and plasminogen values were also increased, and FDP's were found more frequently in the CSF of patients with an impaired level of consciousness or with a neurological deficit. These findings suggest that in the 2nd week after subarachnoid hemorrhage, the presence of FDP's in the CSF reflects a damaged blood-CSF barrier rather than ongoing local fibrinolysis in the subarachnoid space. A finding of FDP's in the CSF is, therefore, an unreliable monitor of antifibrinolytic treatment in subarachnoid hemorrhage and cannot be used for selecting patients at high risk of rebleeding.     

The effect of subarachnoid hemorrhage on blood and CSF atrial natriuretic factor

Atrial natriuretic factor (ANF) is a diuretic natriuretic peptide hormone produced by both the heart and brain which has been postulated to play a role in the hemodynamic and sodium instability that frequently follows subarachnoid hemorrhage (SAH). Levels of ANF were measured in 12 patients with nontraumatic SAH and nine control patients with unruptured cerebral aneurysms. At surgery, the mean plasma ANF level (+/- standard deviation) of the SAH group was significantly higher than that of the control group (158.1 +/- 83.8 vs. 57.8 +/- 45.3 pg/ml, respectively; p = 0.01). There was no significant difference in serum sodium concentration, blood pressure, or central venous pressure between these groups. Nine patients with SAH due to aneurysm rupture had plasma ANF levels similar to those in three patients with SAH due to other causes. Four patients with moderate to severe SAH had significantly higher mean cerebrospinal fluid (CSF) ANF values (17.7 +/- 12.8 pg/ml) than five patients with minimal SAH (0.6 +/- 0.9 pg/ml) or the control group of nine patients (3.7 +/- 1.3 pg/ml) (p less than 0.05). Five patients with moderate to severe SAH had significantly higher plasma ANF values (202.6 +/- 72.2 pg/ml) than five with minimal SAH (86.8 +/- 29.2 pg/ml) or the control group (57.8 +/- 45.3 pg/ml) (p less than 0.05). Plasma ANF values were substantially higher than CSF ANF content in the SAH group (p less than 0.01) and in the control group (p = 0.05). From these data it is concluded that: 1) plasma ANF is elevated significantly after SAH; 2) this rise appears unrelated to the cause of hemorrhage, serum sodium concentration, blood pressure, or central venous pressure, but is related to the extent of the hemorrhage; 3) ANF concentrations in the CSF are significantly lower than in plasma, and are elevated after moderate to severe SAH; and 4) the source of CSF ANF is probably the plasma, and the source of plasma ANF is likely the heart.     

Increased levels of lipid peroxides as predictive of symptomatic vasospasm and poor outcome after aneurysmal subarachnoid hemorrhage

OBJECT: Cerebral vasospasm remains a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). Reactive oxygen species and subsequent lipid peroxidation are reported to participate in the causes of cerebral vasospasm. This clinical study was performed to investigate the relationships between levels of lipid peroxides in cerebrospinal fluid (CSF) and both delayed cerebral vasospasm and clinical outcome after SAH. METHODS: Levels of phosphatidylcholine hydroperoxide (PCOOH) and cholesteryl ester hydroperoxide (CEOOH) in the CSF were measured in 20 patients with aneurysmal SAH. The patients' CSF was collected within 48 hours of hemorrhage onset and on Day 6 or 7 post-SAH. On Day 7, angiography was performed to verify the degree and extent of the vasospasm. The relationship between the patients' clinical profiles and the levels of lipid peroxides in the CSF were investigated. Both PCOOH and CEOOH were detectable in CSF, and their levels decreased within 7 days after onset of SAH. The levels of CEOOH within 48 hours after onset of hemorrhage were significantly higher in patients in whom symptomatic vasospasm later developed than in patients in whom symptomatic vasospasm did not develop (p = 0.002). Levels of PCOOH measured within 48 hours after onset of hemorrhage were significantly higher in patients with poor outcomes than in patients with good outcomes (p = 0.043). CONCLUSIONS: Increased levels of lipid peroxides measured in the CSF during the acute stage of SAH were predictive of both symptomatic vasospasm and poor outcome. Measurements of lipid peroxides in the CSF may be useful prognostically for patient outcomes as well as for predicting symptomatic vasospasm.     

S-100 protein and calmodulin levels in cerebrospinal fluid after subarachnoid hemorrhage

The levels of two calcium-binding proteins, S-100 protein and calmodulin, were measured serially in the cerebrospinal fluid (CSF) of patients after subarachnoid hemorrhage (SAH) and aneurysm surgery. These two proteins have a similar molecular structure and are highly concentrated in the central nervous system (CNS). The levels of S-100 protein found in the earliest postoperative CSF samples correlated with the preoperative SAH grades. High S-100 protein levels in the CSF were found in patients with poor SAH grades. Moreover, the prognosis of the patients correlated with the S-100 protein levels in the CSF samples taken during the immediate postoperative period and with the daily changes of the S-100 protein levels. Severe diffuse cerebral vasospasm was followed by a sharp S-100 protein increase. These results suggest that S-100 protein levels in the CSF provide a useful index of organic damage in the CNS, and furthermore that S-100 protein levels and their changes may have prognostic value for patients after SAH. On the other hand, there was a lack of correlation between the calmodulin levels and the preoperative grade or outcome. It would be inappropriate, however, to speculate from the results of this study that these calcium-binding proteins in the CSF play any causative role in pathological processes such as cerebral vasospasm or brain ischemia after SAH, since changes in the levels of these proteins followed the onset of clinical signs of deterioration.     

Long-term monitoring of CSF lactate levels and lactate/pyruvate ratios following subarachnoid haemorrhage

Summary Ventricular cerebrospinal fluid (CSF) lactate concentrations and lactate/pyruvate (L/P) ratios were measured daily in 20 patients from day 1 to day 12 after subarachnoid haemorrhage due to ruptured aneurysms. Patients without symptomatic vasospasm were classified in Group 1, patients with symptomatic vasospasm were classified in Group 2, and patients who were Hunt and Kosnik grade 4 on admission clinically were classified in Group 3. Patients in all three groups had high CSF lactate concentrations on day 1, and, especially in Group 3, the high lactate was accompanied by an increased L/P ratio and a decreased CSF bicarbonate. Lactate concentrations in Group 1 decreased throughout the observation period. Lactate concentrations in Group 2 also decreased but then began to increase again on days 5 to 7, correlating well with the onset of cerebral vasospasm. The delayed increase of CSF lactate in Group 2 was also accompanied by increases in the CSF pyruvate level and the CSF L/P ratio. Daily monitoring of CSF lactate may thus serve as a chemical marker for cerebral vasospasm.