Increased concentrations of the monoamine metabolities homovanillic acid and 5-hydroxyindoleacetic acid in lumbar and central CSF and of 3-methoxy-4-hydroxyphenylglycol in lumbar CSF after subarachnoid haemorrhage

Summary The concentrations of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MOPEG) were determined in cerebrospinal fluid (CSF) from patients with subarachnoid haemorrhage (SAH) using a mass fragmentographic method.In a first group of 24 patients lumbar CSF was collected during the first 10 days after SAH. The concentrations of HVA and 5-HIAA showed a several-fold increase in the majority of subjects while that for MOPEG was less pronounced in comparison to controls.In a second group of 12 SAH-patients, CSF was collected in 10 ml fractions during surgical clipping of aneurysms. The mean concentrations of HVA, 5-HIAA and MOPEG in lumbar CSF was 469,275 and 39 pmol/l, respectively, whereas central CSF concentrations were 1,212, 499 and 48 pmol/ml, respectively. Compared to healthy controls, both HVA and 5-HIAA showed increased levels (pl 0,01) but MOPEG was within the normal range.No correlation between the concentrations of the monoamine metabolites, the neurological condition or the cerebral vascular diameter was observed in neither of the two groups.It is suggested that the accumulation of HVA and 5-HIAA in SAH patients is explained by a disturbance of the active transport mechanism.This study was supported by grants from Karolinska Institutet.     

Monoamine acid metabolites in ventricular CSF of patients with brain tumours

Summary Homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in ventricular CSF were determined in 19 patients (12 female 7 male) with brain tumours. No relationship was found between ventricular fluid pressure (VFP) and levels of HVA and 5-HIAA. A relationship was observed between ventricular CSF, HVA concentrations and tumour induced alterations in CSF dynamics. HVA concentrations were very high in patients whose tumours involved the third ventricle, the aqueduct, or the fourth ventricle, producing marked alterations in CSF flow. HVA concentrations significantly lower than in controls were observed in cases where tumours involved the lateral ventricles. Concentrations of acid metabolites in patients with little or no alteration in CSF dynamics corresponded with those in patients with other neurosurgical disorders.     

Homovanillic acid and 5-hydroxyindoleacetic acid in the ventricular CSF of comatose patients with obstructive hydrocephalus

Ventricular cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were determined every 2 to 4 hours over a period of 1 to 4 days in 12 patients, consisting of seven cases of brain tumor, two cases of cerebrovascular disease, and three cases of head injury. The concentrations of HVA and 5-HIAA varied with time in all cases, and significant correlations were found between the two values in eight cases. However, the relationship between variations of HVA and 5-HIAA levels and rhythms of sleep and waking could not be clarified. Both HVA and 5-HIAA concentrations varied at high levels in two patients whose CSF flow was completely blocked by tumor at the site of the fourth ventricle and aqueduct, respectively. On the contrary, in a case with craniopharyngioma in the third ventricle which blocked the bilateral foramina of Monro, although the HVA values were high, the 5-HIAA values varied at low levels. Of five comatose patients, two had cerebrovascular lesions and three had sustained head injury, and, in four of the five, the values of either one or both of HVA and 5-HIAA were low, but in the fifth case the 5-HIAA value was high. Estimation of HVA and 5-HIAA concentrations in ventricular CSF may be a valuable tool in the investigation of brain monoamine metabolism. However, many factors must be considered in the interpretation of results of clinical studies.     

Determination of HVA and 5-HIAA in ventricular CSF of patients with brain tumors

Ventricular concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were evaluated in 17 patients suffering from brain tumor and 4 pseudo-tumor patients. Significant differences were observed in those patients in whom the tumor leads to a marked modified CSF dynamic. No relationship were on the contrary observed between VFP and HVA or 5-HIAA levels.     

The amount of blood in CSF and degree of hydrocephalus studied with CT as compared to clinical condition and concentrations of various substances in human CSF after subarachnoid haemorrhage

Thirty-nine (39) patients with subarachnoid haemorrhage (SAH) were studied with computed tomography (CT). The amount of blood in the cerebrospinal fluid (CSF) and the degree of hydrocephalus were evaluated. These two parameters were correlated with the clinical condition on admission and at discharge and against CSF concentration of a series of CSF substances. These included the major monoamine metabolites homovanillic acid (HVA), 5-hydroxyindole-acetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG) and in addition the concentrations of hypoxanthine, aspartate and somatomedins. The amount of blood and the degree of hydrocephalus on admission did not seem to influence the concentration of these substances over time. It was found that patients with large amounts of blood in the CSF had a worse clinical outcome (p less than 0.05) compared to patients with no or moderate amount of blood. In addition, patients with enlargement of the temporal horns showed a worse clinical condition on admission (p less than 0.01) than did patients without such enlargement. Despite a significant (p less than 0.01) vasoconstriction there was no correlation between vascular calibre and concentration of the substances in the CSF. It is speculated whether or not the increased levels of these substances were the result of cell lysis per se, a disturbance of the CSF circulation or to the toxic effect of blood resulting in deranged metabolism in both the CSF and brain tissue after SAH.     

Monoamines in the brain cerebrospinal fluid of facial pain patients.

The purpose of the study was to assay monoamines in cerebrospinal fluid (CSF) obtained from the trigeminal cistern of 64 patients with intractable facial pain. The CSF was analyzed for homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), end-product markers of activity for the dopamine, serotonin, and norepinephrine systems, respectively. HVA averaged 121 ng/mL in these facial pain patients, compared to 150 to 550 ng/mL in 10 studies of ventricular brain CSF in assorted psychiatric and pain patients. 5-HIAA averaged 29 to ng/mL in our facial pain patients compared to 60 to 120 ng/mL in nine studies of ventricular brain CSF in assorted psychiatric and neurological patients. Trigeminal cistern CSF MHPG averaged 9 ng/mL, similar to the range of 13 studies of lumbar CSF of assorted psychiatric and pain diagnoses. These results indicate that (1) the electrochemical detection method provides a unique way of accurately measuring nanogram concentrations of multiple monoamines in a little as 0.25 mL of CSF; (2) trigeminal cistern and posterior fossa brain CSF monoamine metabolites reflect a different profile of dopaminergic and serotonergic functioning in these facial pain patients from that previously reported with lumbar CSF measurements of other patients; and (3) trigeminal sensory ganglion or brain dopamine and serotonin systems may be concomitantly dysfunctional in intractable facial pain.     

On the nature of brain stem disorders in severe head injured patients

Summary In head injured patients changes were found in the CSF levels of metabolites of the dopaminergic and the serotonergic neurotransmission (HVA and 5-HIAA). After the fifth, day following trauma a significant derease of the HVA levels in the lumbar CSF after probenecid treatment was found. The intensity of this decrease was found to be related to the severity of the trauma (period of unconsciousness), but not to the state of consciousness.Also the probenecid-induced 5-HIAA levels in conscious patients were decreased after the fifth post-traumatic day. In unconscious patients, however, an increased turnover of serotonin was found to be also related to the period of unconsciousness, particularly in the period of 5–20 days after trauma. Between 21 and 60 days after trauma the 5-HIAA concentrations in unconscious patients decreased remarkably, but they were still significantly higher than in the conscious patients. It can be concluded that during unconsciousness serotonergic neurons have a high rate of turnover, but that both neurotransmitter systems are damaged by the direct or indirect consequences of the injury.     

Increased concentration of hypoxanthine in human central cerebrospinal fluid after subarachnoid haemorrhage

Summary The adenine nucleotide metabolites hypoxanthine, xanthine and uric acid were determined by high performance liquid chromatography in cerebrospinal fluid (CSF) from 25 patients with subarachnoid haemorrhage (SAH) and from 26 control subjects. In addition, the haemoglobin and protein levels in the CSF of the patients were determined.In 13 subjects, from which lumbar CSF was collected three, six and nine days after SAH, there was a gradual increase in 8 patients for hypoxanthine and in 3 of the 13 patients for xanthine and uric acid. The mean concentrations were not significantly higher than the controls. In 12 SAH patients, consecutive CSF fractions of 10 ml were collected peroperatively during surgical clipping of aneurysms. The hypoxanthine concentrations increased continously from lumbar to central CSF samples. Hypoxanthine levels were 6.5±1.0 M in lumbar CSF compared to 11.8±2.3 M in central CSF (p<0.001), while xanthine, uric acid, haemoglobin and protein levels were equally distributed. Furthermore, the SAH patients showed about 3 times higher concentrations of central CSF hypoxanthine (p<0.01) and xanthine (p<0.05) while that for uric acid was similar compared to all control subjects. Also, an in vitro study showed that the increased concentrations of the adenine nucleotide metabolites could not be caused by degradation of blood components in the subarachnoid space.It is presumed that the increased central CSF concentrations of hypoxanthine that were demonstrated in patients after SAH could be a sensitive marker for brain tissue ischaemia. However, since there was no correlation between the hypoxanthine levels, clinical condition or cerebral vascular diameter, other factors have to be excluded before ischaemia alone could explain the elevated central hypoxanthine levels in patients without major clinical dysfunction after SAH.This study was supported by grants from Karolinska Institutet, the Swedish National Society against Heart and Chest disease, The Swedish Society of Medical Sciences, Wibergs Foundation, Boehringer Ingelheim and the Swedish Medical Research Council (proj. no. 7485).     

Increased levels of somatomedins in human lumbar and central cerebrospinal fluid after subarachnoid haemorrhage

Summary The somatomedins, multitargit growth-promoting peptide hormones, were measured with radio receptor assay in cerebrospinal fluid (CSF) after subarachnoid haemorrhage (SAH) in 21 patients and after head injury in 2 patients.In the first group of 10 patients, lumbar (n=8) or central (n=2) CSF was collected on days three, six and nine after SAH. 6 of the 8 patients with SAH showed an increase in somatomedin concentrations ranging between 0.52–1.26 U/ml while 2 patients fell within the normal range between 0.19–0.48 U/ml. In the 2 patients with head injury, the somatomedin concentrations were scarcely detectable.In the second group of 13 patients with SAH, CSF was collected peroperatively during surgical clipping of an aneurysm. These patients fell into two groups: 6 patients who had CSF somatomedin levels within the normal range and 7 patients with pathologically increased somatomedin concentrations ranging between 0.38–1.26 U/ml. Neither the neurological condition nor the cerebral vascular diameter correlated with the somatomedin concentrations. It is suggested that the increased somatomedin levels in CSF after SAH could be a compensatory response in order to stimulate cerebral anabolism after injury.This work was supported by grants from Karolinska Institutet, the Swedish Medical Research Council, Sävstaholmsföreningen, and Loo and Hans Osterman Research Fund.     

S-100 protein in cerebrospinal fluid of patients with subarachnoid haemorrhage: A potential marker of brain damage

Summary Concentrations of S-100 protein in cerebrospinal fluid (CSF) were measured by a recently developed radioimmunoassay (RIA) in 45 patients with subarachnoid haemorrhage (SAH), 44 with verified ruptured aneurysm. In each of 43 patients 2–15 serial CSF samples were analysed, and in the remainder 1 sample was examined. The concentrations of S-100 protein proved to be related to the brain damage caused by the SAH, indexed as outcome (Glasgow Outcome Scale). The S-100 concentrations were related to the severity of the haemorrhage and to the development of delayed ischaemic deterioration. Delayed ischaemic deterioration (vasospasm) was usually accompanied by an increase in CSF S-100 concentration after 4 days. Patients in whom no S-100 value exceeded 20 ng S-100 per ml during the course of the disease had a favourable outcome, whereas patients in whom one or several CSF samples contained more than 100 ng/ ml became severely disabled or vegetative or died. The present study suggests that CSF S-100 analysis may be used as an objective and early measure of the degree of brain damage sustained by the SAH patient.     

CSF Neurotransmitter metabolites in comatose head injury patients during changes in their clinical state

Summary The main metabolites of noradrenaline, serotonin, and dopanine, methoxyhydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5HIAA), and homovanillic acid (HVA), respectively, were assessed in CSF samples of patients in coma after severe head injury, the first days after the accident and again after an improvement (13 patients) or deterioration (7 patients) in their clinical state, evaluated by the score on the Glasgow Coma Scale.Improvement was accompanied by significant decreases in HVA and 5HIAA. In the patients who deteriorated, the levels of the three metabolites remained high.The results show that the increased turnover of CNS neurotransmitters in severe head injury normalizes during recovery. The use of noradrenaline, dopamine, and serotonin antagonists in brain injury experimental models may clarify the role of the increased biogenic amine turnover in the processes that lead to recovery. We propose relevant pharmacological intervention influencing neurotransmission in severe head injury.     

Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage

OBJECT: The aim of this study was to explore whether levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are elevated in the cerebrospinal fluid (CSF) and serum of patients after aneurysmal subarachnoid hemorrhage (SAH). METHODS: This prospective clinical study focused on 21 patients who had recently suffered an SAH due to aneurysmal rupture and 15 control patients with hydrocephalus who had no other central nervous system disease. Cerebrospinal fluid and serum samples obtained within the first 3 days and on the 5th and 7th days of SAH were assayed for ICAM-1 and VCAM-1 by using quantitative enzyme-linked immunosorbent assays. Levels of soluble forms of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.009) in the patients' CSF and those of ICAM-1 (p = 0.00001) and VCAM-1 (p = 0.00001) in their serum were found to be elevated after SAH compared with levels in the CSF and serum of control patients with hydrocephalus. In addition, when the authors compared the increased levels of adhesion molecules in the CSF and serum of patients after SAH, the only statistically insignificant difference that they found was between the levels of VCAM-1 in serum obtained on Days 5 and 7 after SAH (p = 0.27). CONCLUSIONS: Adhesion molecules are a group of macromolecules that may participate in the inflammatory process, a common pathway leading to vasospasm after SAH. Leukocyte adherence to the vascular endothelium, which is induced by adhesion molecules, has been believed to be the initial signal of the development of vasospasm. The authors have demonstrated the synchronized elevation of two adhesion molecules in both CSF and serum following aneurysmal SAH. Blocking of ICAM-1 as well as VCAM-1 by monoclonal antibodies post-SAH may provide a beneficial effect on vasospasm.     

Multiparametric analysis of cerebral substrates and nitric oxide delivery in cerebrospinal fluid in patients with intracerebral haemorrhage: correlation with hemodynamics and outcome

Summary Background. There is no information regarding the possible role of cerebral substrates in the pathogenesis of neuronal injury in intracerebral haemorrhages (ICHs). Purposes of this prospective study were to clarify whether changes in substrates are the consequence of the initial brain damage in ICH and to elucidate the relationship among the biochemical mechanisms and clinical course of patients with ICH. Method. During a period of two years, patients (GCS ≤8) who had ICH secondary to an aneurysm (SAH), stroke (sICH), or trauma (tICH) and underwent ventriculostomy with ICP monitoring and/or underwent cranial surgery were randomly enrolled in this study. Extracellular concentrations of glutamate, aspartate, glycine, GABA, lactate, lactate/pyruvate ratio, and glucose in the CSF were measured by use of high-performance liquid chromatography (HPLC). The nitric oxide (NO) concentration in the CSF was analyzed by chemiluminescence. Findings. There were 75 patients (38 women and 37 men) with ICH included in this study. Twenty-one patients had SAH, 28 sICH, and 26 tICH. In tICH patients, there was a 30-fold increase in glutamate and a 10-fold in aspartate over reference values. The levels of glutamate, aspirate, GABA, lactate, glucose, and NO differed significantly among the three groups (p<0.001). There were no significant differences in glycine and L/P ratio among the groups. The initial GCS, the mean CPP and outcome six months after the insult were all significantly correlated with the concentration of substrates (p<0.01), both within groups and among the total sample. The CSF levels of glutamate lactate, NO and glucose correlated significantly with outcome (p<0.005). Conclusions. This study confirms the correlation between the level of EAAs and the outcome of ICHs, suggesting that neurochemical monitoring of these substances may have a role in caring for patients.     

Free fatty acids in human cerebrospinal fluid following subarachnoid hemorrhage and their potential role in vasospasm: a preliminary observation

OBJECT: The mechanisms leading to vasospasm following subarachnoid hemorrhage (SAH) remain unclear. Accumulation in cerebrospinal fluid (CSF) of free fatty acids (FFAs) may play a role in the development of vasospasm; however, in no previous study have concentrations of FFAs in CSF been examined after SAH. METHODS: We collected samples of CSF from 20 patients with SAH (18 cases of aneurysmal SAH and two cases of spontaneous cryptogenic SAH) and used a high-performance liquid chromatography assay to determine the FFA concentrations in these samples. We then compared these findings with FFA concentrations in the CSF of control patients. All FFA concentrations measured 24 hours after SAH were significantly greater than control concentrations (p < 0.01 for palmitic acid and < 0.001 for all other FFAs). All measured FFAs remained elevated for the first 48 hours after SAH (p < 0.05 for linoleic acid, p < 0.01 for palmitic acid, and p < 0.001 for the other FFAs). After 7 days, a second elevation in all FFAs was observed (p < 0.05 for linoleic acid, p < 0.01 for palmitic acid, and p < 0.001 for the other FFAs). Samples of CSF collected within 48 hours after SAH from patients in whom angiography and clinical examination confirmed the development of vasospasm after SAH were found to have significantly higher concentrations of arachidonic, linoleic, and palmitic acids than samples collected from patients in whom vasospasm did not develop (p < 0.05). CONCLUSIONS: Following SAH, all FFAs are initially elevated. A secondary elevation occurs between 8 and 10 days after SAH. This study provides preliminary evidence of FFA elevation following SAH and of a potential role for FFAs in SAH-induced vasospasm. A prospective study is warranted to determine if CSF concentrations of FFAs are predictive of vasospasm.     

S-100 Protein in cerebrospinal fluid after aneurysmal subarachnoid haemorrhage

Summary The concentration of S-100 protein measured in ventricular cerebrospinal fluid (CSF) from 32 patients with subarachnoid haemorrhage (SAH) during the acute phase was related to features on admission such as the Hunt and Hess neurological scale and the amount of blood at the first computed tomography (CT). The S-100 values were also related to functional outcome assessed by the Glasgow outcome scale (GOS) at 12 months. Twenty-two patients were re-examined more than 2 years after the SAH, and the initial S-100 values were related to signs of structural brain damage at CT and single photon emission computed tomography (SPECT) and to the results of neuropsychological evaluation (NPE). NPE included standardized tests for memory functions, intellectual functions, visuo-spatial abilities, sensory-motor functions, and concept formation. Life-adjustment was assessed by two separate questionnaires. Tests for agnostic dysfunction and the Western aphasia battery test (WABT) were also performed.Patients who were functionally disabled or ultimately died had significantly higher initial CSF concentrations of S-100 protein than patients showing good recovery. Patients with low-attenuated regions and/or increased ventricular size at CT and/or regionally decreased tracer uptake on SPECT had higher S-100 levels during days 2–8 than had patients showing no such changes. Logistic and multiple regression analysis of all characteristics assessed during the acute phase after SAH showed that the CSF S-100 concentration during days 2–8 was the factor best correlated to GOS and findings on CT and/or SPECT.All patients showed varying degrees of cognitive impairment at follow-up. The results of NPE and the WABT were related to outcome assessed by GOS and to increased ventricular size on CT. Women had a stronger feeling of maladjustment, but the scores for life adjustment were otherwise not related to other outcome criteria.It is concluded that the ventricular CSF S-100 concentration during the acute phase after SAH is related not only to the functional outcome as assessed by GOS but also to signs of brain damage seen on late CT and SPECT.     

Positron emission tomography with 68-Ga-EDTA and computed tomography in patients with subarachnoid haemorrhage

Summary 26 patients with subarachnoid haemorrhage (SAH) were investigated with 68-Ga-EDTA and positron emission tomography (PET) in order to evaluate the presence of a blood brain barrier (BBB) disturbance. Only one patient showed a BBB disruption. It is suggested that increased levels of substances with higher molecular weight than 68-Ga-EDTA in the cerebrospinal fluid (CSF) are the result of a change in the metabolism of the CSF and the brain tissue caused by a SAH.     

Induction of cytosolic free calcium elevation in rat vascular smooth-muscle cells by cerebrospinal fluid from patients after subarachnoid hemorrhage

The purpose of this study was to determine the effects of cerebrospinal fluid (CSF) from patients with subarachnoid hemorrhage (SAH) on cytosolic free calcium in cultured rat vascular smooth-muscle cells using the fluorescent intracellular calcium indicator fura-2/AM. Samples of CSF were collected from 12 patients (seven with and five without vasospasm) on Days 2, 6, 11, and 16 after SAH. Control CSF samples were obtained from five patients 6 to 9 months after they had undergone successful aneurysm surgery following an SAH. All CSF samples in both the non-vasospasm and vasospasm groups, regardless of the day of sampling after the SAH, induced significantly higher transient intracellular calcium elevations when compared to levels induced by control CSF. Furthermore, the addition of 2 mM ethyleneglycol-bis (beta-aminoethylether)-N,N'-tetra-acetic acid (EGTA) caused a slight reduction in the peak height in the CSF-induced intracellular calcium rise which declined more rapidly to basal levels than those studied without EGTA. In the non-vasospasm group, the intracellular calcium concentration remained stable after SAH throughout the study period. In contrast, in the vasospasm group, this concentration was highest on Day 2 post-SAH, but sharply decreased on Day 6 and rose again on Day 11. This result correlated with the clinical signs of vasospasm in these patients. These findings indicated that the intracellular calcium elevations induced by CSF obtained after SAH were due to the combination of the influx of extracellular calcium and the mobilization of intracellular calcium from storage sites. The changes in intracellular calcium concentrations in vascular smooth-muscle cells induced by CSF obtained from patients on successive days following SAH suggest that the substances that induce this repeat calcium elevation on Day 11 post-SAH may be the key spasmogens for vasospasm after SAH.     

Concentrations of 5-Hydroxyindoleacetic Acid and Homovanillic Acid in the Cerebrospinal Fluid of Chronic Therapy-Resistant Schizophrenics Before and After Hemodialysis Therapy

The concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) have been determined by high-performance liquid chromatography in samples of lumbar cerebrospinal fluid from chronic therapy-resistant schizophrenics, both before and after either inactive or active hemodialysis for 10 weeks. A reasonable test-retest reliability was found for 5-HIAA during the inactive dialysis, but this was not found during active dialysis.     

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     

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.