Withdrawal Of Cerebrospinal Fluid Research Articles

Application of microdialysis to the pharmacokinetics of analgesics: Problems with reduction of dialysis efficiency in vivo

Microdialysis in freely moving rats coupled to high-performance liquid chromatography (HPLC) was used to measure the free concentration of acetaminophen (APAP) in blood and cerebrospinal fluid (CSF) after an intravenous bolus dose (25 mg/kg). In vitro calibration of two commercially available probe types was performed in 0.9% NaCl solution and blood. The influence of these media on recovery was tested by retrodialysis. This technique was also used for in vivo calibration and to monitor the dynamics of the performance of implanted probes. The results were compared with data obtained from conventional sampling techniques of direct withdrawal of blood and CSF, and also with the results obtained by correcting dialysate concentrations using in vitro recovery values. The data demonstrate that whole blood lowers recovery not only by reducing the free concentration of drug, but also by directly influencing dialysis efficiency (mean reduction of recovery: 50.1%). By contrast, low transport capacities of CSF surrounding the implanted probe lead to suboptimal conditions and, therefore, to a reduction of in vivo recovery (mean reduction of recovery: 65.5%). After correction of recovery values using in vivo retrodialysis prior to dosing the animal, we obtained similar data as compared to conventional sampling techniques. These results demonstrate that microdialysis may provide a minimally invasive method to monitor the free concentrations of drugs, such as acetaminophen, in different compartments, and allow a multitude of pharmacokinetic data to be obtained from freely moving animals.

Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: Phenytoin

The temporal pharmacokinetic (blood) and neurophannacokinetic (cerebrospinal fluid, CSF) interrelationship of phenytoin was studied after acute and during chronic (up to 5 days) intraperitoneal administration of phenytoin (30, 50 or 100 mg/kg) using a new freely behaving rat model. After administration, phenytoin rapidly appeared in both serum ( T max mean range 0.15–0.38 h) and CSF ( T max mean range 0.9–1.4 h), suggesting ready penetration of the blood-brain barrier. However, transport across the blood-brain barrier may be rate limiting since whilst phenytoin concentrations rose dose dependently in serum, CSF concentrations did not. Further, the divergence between the blood and CSF compartments increased with chronic dosing. C max , AUC and t 1 2 values for serum increased non-linearly, suggestive of accumulation kinetics. Based on these data, high initial phenytoin blood concentrations are essential if phenytoin entry into the brain is to be facilitated, and this may be important in studies of phenytoin in animal models of status epilepticus.

Effect of altering cerebrospinal fluid pressure on spinal cord blood flow

Removal of cerebrospinal fluid (CSF) has been proposed as a means of protecting the spinal cord Against ischemic injury during thoracoabdominal aneurysm operations. We investigated the effect of altering CSF pressure (CSFP) on lumbar spinal cord blood flow (SCBF) in an experiment using dogs. The SCBF was measured before and after withdrawal of CSF in settings with and without thoracic aortic clamping. Furthermore, SCBF was measured at the basal state and after elevation of CSFP to 20 mm Hg and to 40 mm Hg. The SCBF did not change significantly before and after removal of CSF in settings both with and without thoracic aortic clamping. Elevation of CSFP significantly reduced SCBF. Elevation of CSFP reduces SCBF, but lowering CSFP per se does not increase SCBF whether the thoracic aorta is occluded or not. This supports the notion that removal of CSF offers spinal cord protection only when CSFP is abnormally elevated.

Antiepileptic drug pharmacokinetics and neuropharmacokinetics in individual rats by repetitive withdrawal of blood and cerebrospinal fluid: milacemide

1. The kinetics and metabolism of milacemide have been studied in an animal model which allows the simultaneous investigation of the temporal inter-relationships of drugs and metabolites in blood (pharmacokinetics) and cerebrospinal fluid (CSF, neuropharmacokinetics) in individual freely moving rats. 2. Milacemide dose-dependently increased CSF glycine and glycinamide (intermediary metabolite) concentrations. This confirms that milacemide is a CNS glycine prodrug. 3. Pretreatment with L-deprenyl (2 mg kg-1), a specific inhibitor of monoamine oxidase type B (MAO-B), almost completely prevented the formation of glycinamide and increased milacemide accumulation in CSF. Tmax and t1/2 were significantly increased and Cmax and AUC values were decreased for glycinamide compared to controls. Pretreatment with clorgyline (5 mg kg-1), a specific inhibitor of MAO-type A, only moderately decreased glycinamide Cmax and AUC values. 4. After milacemide administration (100, 200 and 400 mg kg-1, i.p.) serum and CSF milacemide concentrations rose linearly and dose-dependently. Serum glycinamide concentrations exhibited small dose-dependent rises but these were not linearly related. In contrast, CSF glycinamide concentrations rose linearly and dose-dependently with Cmax values 2.5, 3.2 and 4.1 times greater than the corresponding values for serum glycinamide after giving 100, 200 and 400 mg kg-1 respectively of milacemide. 5. Serum glycine concentrations were unaffected but CSF concentrations increased dose-dependently and these were significant at the higher milacemide doses (200 and 400 mg kg-1). Animals given 400 mg kg-1 milacemide had glycine values which were still significantly elevated 7 h later. 6. In conclusion, serum milacemide rapidly enters and equilibrates with the CNS compartment where it is metabolised primarily by MAO-B to glycinamide and finally to glycine. Metabolism in the peripheral compartment is negligible.

Cerebrospinal fluid flow. III. Pathological cerebrospinal fluid pulsations.

Cardiac- and respiration-related movements of the cerebrospinal fluid (CSF) were investigated by MRI in 71 patients. In most patients with arteriosclerotic occlusive vascular disease CSF pulsations are normal. Decreased pulsatile flow is detectable in those with arteriovenous malformations, intracranial air and following lumbar puncture and withdrawal of CSF. Increased pulsatile flow in the cerebral aqueduct was found in 2 patients with large aneurysms, idiopathic communicating syringomyelia and in most cases of normal pressure hydrocephalus (NPH). CSF flow in the cervical spinal canal is, however, reduced or normal in NPH, indicating reduction of the unfolding ability of the surface of the brain and/or inhibition of rapid CSF movements in the subarachnoid space over its convexity.

Cerebral energy metabolism in experimental canine hydrocephalus

Cerebral energy metabolism, its relationship to the stage and extent of hydrocephalus, and the effect of cerebrospinal fluid (CSF) removal on it were studied in experimental canine hydrocephalus produced by intracisternal injection of kaolin by using phosphorus-31 (P-31) magnetic resonance (MR) spectroscopy and MR imaging. P-31 MR spectra were serially obtained before and after CSF removal, maximally on eight occasions over a period of nearly 5 h. There was a decrease in the ratio of creatine phosphate to inorganic phosphate, used as an indicator of the bioenergetic state, in acute and subacute stages of hydrocephalus as compared with the control. An animal in the subacute stage, when periventricular edema was most prominent, exhibited the most predominent decrease in this ratio at 14 days after hydrocephalic insult. The recovery of the ratio toward the control level was seen in the chronically hydrocephalic animal. There was no change in adenosine triphosphate (ATP) levels in any stage of hydrocephalus. Serial spectra obtained after the withdrawal of ventricular CSF showed no change in the bioenergetic state of the brain in any stage of hydrocephalus. There was no relationship between either the extent of hydrocephalus or the ventricular CSF pressure and the change in the bioenergetic state or the levels of any of the phosphorus compounds. These findings may indicate the alteration of the mitochondrial energy metabolism in hydrocephalus, which may explain the mechanism of hydrocephalic syndrome.

Effect of a brief hypoxic/hypotensive episode on the in vivo release of cerebral cortical γ-aminobutyric acid and glycine

γ-Aminobutyric acid (GABA) and glycine levels in rat cerebral cortical superfusates rose during a 10-min period to reach stable concentrations of ∼0.55 μM and ∼12.3 μM, respectively. In cerebrospinal fluid withdrawn from the fourth ventricle, the GABA concentration was 0.1 μM, and that of glycine, 10.55 μM. GABA, and to a lesser extent glycine, concentrations increased in the cortical superfusates during and immediately following exposure of the rats to a 5-min period of 5% oxygen in nitrogen inhalation.

Cerebral blood flow and metabolism in severely head-injured children

The literature suggests that in children with severe head injury, cerebral hyperemia is common and related to high intracranial pressure (ICP). However, there are very few data on cerebral blood flow (CBF) after severe head injury in children. This paper presents 72 measurements of cerebral blood flow ("CBF15"), using the 133Xe inhalation method, with multiple detectors over both hemispheres in 32 children aged 3 to 18 years (mean 13.6 years) with severe closed head injury (average Glasgow Coma Scale (GCS) score 5.4). In 25 of the children, these were combined with measurements of arteriojugular venous oxygen difference (AVDO2) and of cerebral metabolic rate of oxygen (CMRO2). In 30 patients, the first measurement was taken approximately 12 hours postinjury. In 18 patients, an indication of brain stiffness was obtained by withdrawal and injection of ventricular cerebrospinal fluid and calculation of the pressure-volume index (PVI) of Marmarou. The CBF and CMRO2 data were correlated with the GCS score, outcome, ICP, and PVI. Early after injury, CBF tended to be lower with lower GCS scores, but this was not statistically significant. This trend was reversed 24 hours postinjury, as significantly more hyperemic values were recorded the lower the GCS score, with the exception of the most severely injured patients (GCS score 3). In contrast, mean CMRO2 correlated positively with the GCS score and outcome throughout the course, but large standard deviations preclude making predictions based on CMRO2 measurements in individual patients. Early after injury, there was mild uncoupling between CBF and CMRO2 (CBF above metabolic demands, low AVDO2) and, after 24 hours, flow and metabolism were completely uncoupled with an extremely low AVDO2. Consistently reduced flow as found in only four patients; 28 patients (88%) showed hyperemia at some point in their course. This very high percentage of patients with hyperemia, combined with the lowest values of AVDO2 found in the literature, indicates that hyperemia or luxury perfusion is more prevalent in this group of patients. The three patients with consistently the highest CBF had consistently the lowest PVI: thus, the patients with the most severe hyperemia also had the stiffest brains. Nevertheless, and in contrast to previous reports, no correlation could be established between the course of ICP or PVI and the occurrence of hyperemia, nor was there a correlation between the levels of CBF and ICP at the time of the measurements. The authors argue that this lack of correlation is due to: 1) a definition of hyperemia that is too generous, and 2) the lack of a systematic relationship between CBF and cerebral blood volume

Positive end-expiratory pressure in supine and sitting positions: its effects on intrathoracic and intracranial pressures.

The effects of positive end-expiratory pressure (PEEP) on central venous and intracranial (ICP) pressures were evaluated in 10 patients with posterior fossa tumors, in both supine and sitting positions. With patients in the supine position, intrathoracic PEEP-dependent venous hypertension was clearly transmitted to the intracranial compartment but without intracranial hypertension. On the contrary, with patients in the sitting position PEEP had no influence in almost half of our patients. In patients with radiological or clinical signs of increased ICP, however, the combination of head flexion and rotation with institution of PEEP caused a dangerous increase in ICP, even when the patients were in the sitting position. The need for early withdrawal of cerebrospinal fluid in these patients is stressed.

The Carboxy‐Terminal Glycopeptide of the Vasopressin Precursor in the Guinea‐Pig: Release Studies Using a Specific and Sensitive Homologous Radioimmunoassay

Abstract The glycopeptide corresponding to the C-terminal portion of the vasopressin precursor (CPP)has been isolated from guinea-pig posterior pituitary glands and used to generate a specific and sensitive radioimmunoassay. The antiserum is directed to the peptide rather than sugar moieties, and detects two components in pituitary extracts: CPP itself, and a biosynthetic intermediate (NP-CPP) containing both neurophysin and CPP sequences. Release of CPP from neurointermediate lobes incubated in vitro was stimulated five-fold by high K(+) in a Ca(2+) dependent manner: in vivo studies suggest that CPP is released under conditions stimulating vasopressin release. Chronic dehydration depleted neural lobe stores of CPP in parallel with other vasopressin-related components, and plasma levels of CPP were raised from 68+/-18 to 320 + 89 fmol/ml (SEM, n = 6). In anaesthetized guinea-pigs, intraperitoneal injections of increasingamounts of hypertonic saline increased plasma levels of CPP in a graded manner compared with isotonic saline injections. Acute haemorrhage also stimulated CPP release into plasma, and the half-time of clearance of CPP after infusion to steady state levels in guinea-pig plasma was 24 min. Cerebrospinal fluid withdrawn from the cisterna magna also contained detectable amounts of CPP (390 + 25 fmol/ml) suggesting that CPP is released from both hypophysical and extra-hypophysical projections. This assay may now be used to study the biosynthesis, processing and release of endogenous CPP under different physiological conditions.

The Usefulness of Lumbar Epidural Pressure as an Index of Intracranial Pressure

The reliability of lumbar intraspinal epidural pressure (ISEDP) as an index of intracranial pressure was investigated in seven patients with high intracranial pressure following neurosurgery. ISEDP and intracranial epidural pressure (ICEDP) were measured simultaneously, the latter by the conventional method. ISEDP was measured with a Gaeltec catheter-tip pressure transducer placed percutaneously in the lumbar epidural space via Touhy's needle. In five of seven patients, the ISEDP value was consistently 70 to 100% of the ICEDP value. In all patients, ISEDP always fluctuated in parallel with ICEDP, and the time courses of both were quite similar in response not only to normal cardiac pulsation but also to various manipulations, such as neck compression, coughing, breath holding, mannitol administration, and compression at the cranial defect. In one patient with communicating hydrocephalus following subarachnoid hemorrhage, the relationship between ISEDP and cerebrospinal fluid (CSF) pressure was studied. Upon gradual withdrawal of CSF, ISEDP decreased in parallel with CSF pressure until the latter reached 8 mmHg. Below 8 mmHg CSF pressure, ISEDP did not correlate with CSF pressure. This phenomenon was attributed to slackness of the dural sac due to lowering of CSF pressure, which severed contact between the spinal dural theca and the sensor. Although the discrepancy between ISEDP and ICEDP was prominent in some patients, especially those with low intracranial pressure or blockage of the subarachnoid space, in this study ISEDP reliably reflected ICEDP. The results suggest that ISEDP measurement is useful in monitoring intracranial pressure in patients with increased intracranial pressure. Also, the procedure is simple and relatively noninvasive.

Auditory brain stem responses in infants with posthaemorrhagic ventricular dilatation.

Nineteen infants with posthaemorrhagic ventricular dilatation had auditory brain stem responses measured during the period of maximal ventricular dilatation. These showed various patterns ranging from normal, through various abnormalities, to complete absence of responses. When serial auditory brain stem responses were studied in parallel with the evolution of posthaemorrhagic ventricular dilatation it was seen that the abnormalities of auditory brain stem response usually resolved irrespective of the persistence or progression of ventricular dilatation. No correlation was found between cerebrospinal fluid pressure and prolonged interpeak intervals on the auditory brain stem response. In three patients with posthaemorrhagic ventricular dilatation improvement in the auditory brain stem response occurred when cerebrospinal fluid was withdrawn. Intermittent withdrawal of cerebrospinal fluid (by ventricular tap or lumbar puncture) in two of these infants was followed by improvement in the auditory brain stem response after a period of 24 hours (but not sooner). In one infant born at full term improvement in the auditory brain stem response was noted one week after shunting.

Concurrent monitoring of central carbamazepine and transmitter amine metabolism and motor activity in individual unrestrained rats using repetitive withdrawal of cerebrospinal fluid

A method for repeated withdrawal of cerebrospinal fluid (CSF) from the cisterna magna was used in a pharmacokinetic and behavioural study of conscious, freely-moving rats, given the antiepileptic drug carbamazepine (35 mg/kg i.p.). Pharmacokinetic constants (i.e. time to peak concentration, peak concentration, area under the curve and t 1 2 ) for the drug and its primary metabolite carbamazepine-10,11-epoxide and also concentrations of acidic metabolites of 5-hydroxytryptamine and dopamine were obtained for the CSF of individual rats. A pharmacodynamic constant, the effective concentration of drug in CSF for 50% inhibition of motor activity was also determined for each animal. The above data provides good indices of the corresponding values for carbamazepine and its metabolite in brain insofar as a separate experiment showed good correlations between CSF and brain for concentrations of both the drug and its metabolite. Carbamazepine appeared to be largely responsible for the depression of motor activity as the metabolite, at the levels attained, seemed to have little effect. The changes in motor activity were not associated with altered concentrations of the metabolites of 5-hydroxytryptamine or dopamine in the CSF. While the investigation did not reveal major advantages in monitoring the drug under study in CSF rather than in serum it illustrates the potential of the CSF method as a simple way to obtain neuropharmacokinetic and neuropharmacodynamic profiles of the action of drugs in individual rats.

Resistance of the foramen of Monro.

A greyhound dog model was used to study the importance of the foramen of Monro as a resistance element to the flow of cerebrospinal fluid (CSF). Normal dogs had no pressure differential discernible despite the infusion of artificial CSF into one lateral ventricle. When CSF was withdrawn from one lateral ventricle, however, 7 of 10 dogs showed intraventricular pressure differentials at a steady state of 3.28-5.37 mm Hg. All normal dogs undergoing rapid bolus withdrawal of CSF from the ventricles developed pressure differentials. When these experiments were performed on hydrocephalic dogs, no pressure differential could be recorded. The foramen of Monro acts as a valve mechanisms that usually closes in response to CSF withdrawals.

A reservoir model for repeated CSF access in the rabbit

A simple, reliable and inexpensive subcutaneously implanted reservoir-catheter system method was developed for repeated sterile access to the rabbit brain ventricular system. The system provides an avenue for the repeated intrathecal administration of drugs and for the withdrawal of cerebrospinal fluid (CSF). Reservoirs were subcutaneously implanted under the scalp and connected to tubing inserted into the cisterna magna or the lateral ventricle. The systems successfully functioned in 38 of 41 animals (12 with cisternal magna catheters and 29 with lateral ventricle catheters), for up to 12 weeks following implantation. Patency of the systems were documented with X-rays and radiopaque injected contrast medium.

Cerebrospinal fluid from morphine-dependent rats precipitates opiate abstinence syndrome

Cerebrospinal fluid (CSF) was withdrawn from opiate-dependent rats following six hours of abstinence. It was infused into the third ventricle of opiate-dependent rats, precipitating immediate abstinence signs. The effect was similar to that of infusing the opiate antagonist naloxone, suggesting that opiate-dependent organisms may secrete an endogenous opiate antagonist substance. CSF withdrawn from non-dependent rats failed to precipitate an abstinence syndrome in morphine-dependent recipients. Conversely, CSF withdrawn from opiate-dependent rats following six hours of abstinence failed to precipitate an abstinence syndrome in non-dependent recipients. The active factor in the CSF is probably a peptide since it is filterable through a 10,000 MW filter and its activity is destroyed by three different proteolytic enzymes.

Motor Activity Increases Tryptophan, 5‐Hydroxyindoleacetic Acid, and Homovanillic Acid in Ventricular Cerebrospinal Fluid of the Conscious Rat

An investigation was made into the effects of running (1 h at 20 m/min) on central serotonergic and dopaminergic metabolism in trained rats. Methodology involved continuous withdrawal of cerebrospinal fluid (CSF) from the third ventricle of conscious rats and measurements of tryptophan (TRP), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels during a 2 h post-exercise period. All three compounds were increased during the hour following exercise and returned to their basal values within an hour later. CSF flow rate was stable when metabolite levels were elevated. Brain determinations indicated that CSF metabolite variations only qualitatively paralleled brain changes. Indeed, post-exercise TRP, 5-HIAA, and HVA levels were increased to a greater extent in brain when compared to CSF. It is suggested that increased serotonergic and dopaminergic metabolism, caused by motor activity, may be involved in the behavioral effects of exercise.

Acute head injury: pressure-volume relations and cerebrospinal fluid dynamics.

The main purposes of this study were to evaluate pressure-volume relations and cerebrospinal fluid (CSF) dynamics in patients with head injury and to evaluate the pressure-volume index (PVI) in that context. Sixteen head-injured patients underwent continuous intracranial (intraventricular) pressure (ICP) monitoring, studies of the PVI and the width of the pulse amplitude, and studies of CSF dynamics determined by the PVI technique or controlled withdrawal and expressed as resistance to the outflow of CSF (Rout). In this study, the PVI technique proved safe and relatively simple. The PVI based on bolus injections was significantly greater than the PVI based on CSF withdrawal. The PVI varied independently of clinical course, outcome, and ICP. The ICP pulse amplitude increased linearly with the ICP. It was not possible to establish any clinically useful correlation between pulsatile ICP changes and intracranial compliance (PVI). There was a linear correlation between ICP and Rout.

Gonadotropin-Releasing Hormone Pulses in Third Ventricular Cerebrospinal Fluid of Ovariectomized Rhesus Monkeys: Correlation with Luteinizing Hormone Pulses*

Morphological evidence suggests that GnRH may be released into cerebrospinal fluid (CSF) of the third ventricle. Therefore, a method of cannulating the third ventricle of monkey brains was developed for the purpose of examining GnRH secretion in primates. A stainless steel guide cannula was stereotaxically implanted into the third ventricle of 14 ovariectomized rhesus monkeys. A Silastic cannula for collecting CSF was inserted via the guide cannula into the ventral portion of the ventricle, permitting repeated CSF sampling for long time periods from the same animal. One week to 6 months after cannulation, CSF was collected continuously for periods of 5-10 h at 2 different rates (480 and 120 microliter/h) from conscious monkeys seated in chairs. Samples were divided into 15-min fractions, and the GnRH concentration in each was determined by RIA. In contrast to most previous studies, third ventricular CSF was found to contain significant concentrations of GnRH. GnRH was detected in 40 of 50 collections. Concentrations ranged from less than 8 to greater than 800 pg/ml, a range similar to that observed in hypophyseal portal blood. Furthermore, fluctuations within individual collections indicated that GnRH was released in pulses. The mean GnRH pulse frequency during the higher rate of CSF withdrawal was 0.43 +/- 0.06 pulses/h (n = 31), while the mean pulse amplitude was 91 +/- 7 pg/ml (n = 64). Neither parameter was influenced by the rate of CSF removal, as frequency was 0.52 +/- 0.08 pulses/h (n = 19) and amplitude was 94 +/- 11 pg/ml (n = 82) during the lower collection rate. However, the CSF withdrawal rate had a profound influence on LH secretion. In 12 of 17 collections at the higher rate, LH levels plummeted to undetectable concentrations during the first 2 h of CSF exfusion and remained low throughout the collection period. Pituitary responsiveness was not reduced, as a GnRH bolus (0.25 or 2.5 micrograms) after 6 h of CSF removal elicited a dose-dependent stimulation of LH secretion. In contrast, a higher incidence of normal pulsatile LH secretion (12 of 19 collections) was observed when the CSF withdrawal rate was reduced. During these 12 collections, LH and GnRH pulses occurred at regular intervals and exhibited similar pulse frequencies (mean +/- SE, 0.76 +/- 0.07 and 0.67 +/- 0.09 pulses/h for LH and GnRH, respectively). Most GnRH and LH pulses were synchronized, as 86% of all GnRH pulses (43 of 50) were accompanied by a LH pulse.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuronal responses in subfornical organ and other regions to Angiotensin II applied by various routes

Effects of Angiotensin II (AII) and of signals of hydromineral deficiencies on neuronal firing in the subfornical organ (SFO) and the surrounding regions of the rat were examined. AII was applied in three ways: electrophoresis, intracarotid injection, or intracerebroventricular injection. Seventeen SFO neurons (52%) were facilitated by electrophoretic AII and one (3%) was inhibited (AII-responding neurons). Neurons in other regions (cerebral cortex, nucleus triangularis septi, hippocampus, nucleus periventricularis) were also facilitated (23%) or inhibited (14%). Prostaglandin (PG)F 2, a universal vasoconstrictor, produced an effect similar to that by AII on neuronal activity of the SFO and surrounding regions, and this effect was antagonized by (NO 2 −), a vasoplegic agent. Intracarotid injection of AH caused biphasic facilitation of SFO activity. The second increase correlates with changes in blood pressure. Intraventricular injection of AII caused drastic and long lasting excitation of SFO activity. Simultaneous intraventricular application of NO 2 − blocked the AII effect on SFO neurons but not on blood pressure. Hypovolemia or cerebrospinal fluid withdrawal that might cause mechanical stimulation of circumventricular organs increased SFO neuronal activity. These results are compatible with the vasoconstriction hypothesis of an indirect effect of All through change in diameter of the vasa that surround neurons.