Bulk Flow Of Cerebrospinal Fluid Research Articles

Brain ion and volume regulation during acute hypernatremia in Brattleboro rats

Regulation of brain ions and volume in response to 30 min of hypernatremia has been studied in two strains of anesthetized rats, the vasopressin-deficient Brattleboro and its vasopressin-competent parent strain, the Long-Evans. Plasma [Na] was increased by intraperitoneal injection of hyperosmolal NaCl. Brain volume was regulated during hypernatremia associated with tissue uptake of Na and Cl in both strains, but osmotically stimulated uptake of Na was 61% less in the Brattleboro. Blood-to-brain transfer constants for 22Na, measured as a function of plasma osmolality, were similar in the two strains. In contrast, bulk flow of cerebrospinal fluid (CSF) into brain, induced by osmotic dehydration of brain, was 55% less in the Brattleboro. CSF secretion in unstressed animals was also reduced, by 34%, in the Brattleboro compared with the Long-Evans. Reduced Na uptake by the brain of the Brattleboro rat during hypernatremia can be explained on the basis of a three-compartment model of brain volume regulation. Results support a function for vasopressin in brain ion homeostasis.

Effect of Alteration of Cerebrospinal Fluid Bulk Flow on Nicotine Cerebrospinal Fluid Exit Transfer Kinetics

AbstractThis study was undertaken to determine if a compound which alters the bulk flow of cerebrospinal fluid (CSF) alters the elimination kinetics of a compound in the CSF. Acetazolamide was chosen as the CSF bulk flow-altering agent. It produces a relatively large effect on the flow process, affecting both choroidal and extrachoroidal CSF production, and has been shown to affect CSF flow following iv administration. The compound monitored was nicotine. Acetazolamide was administered orally for one week before and intravenously during the experiment. Nicotine was administered by a bolus injection directly into the CSF via the cisterna magna. The results indicate that the introduction of acetazolamide into the general circulation increases the rate of removal of nicotine from the CSF. Subjects receiving acetazolamide had elevated CSF pressures. The increase in CSF pressure associated with the administration of acetazolamide suggests pressure as a possible factor in the observed increase in the rate of removal of nicotine.

Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality.

Brain volume is regulated during acute hyperosmolality based, in part, on the tissue gain of Na, Cl, and K. This study evaluates the contribution of bulk flow of cerebrospinal fluid (CSF) into brain to the volume regulatory gain of electrolytes. Artificial CSF containing radiolabeled albumin and diethylenetriamine penta-acetic acid (DTPA) was perfused for 60 min through the ventricles and/or subarachnoid space of anesthetized rats, and tracer clearances from CSF to brain were measured as a function of plasma osmolality. Osmolality was elevated after 30 min of perfusion by intraperitoneal injection of hypertonic NaCl or mannitol. Albumin and DTPA clearances increased with osmolality at the same rate, despite a sevenfold difference in diffusion coefficient, consistent with osmotic stimulation of a bulk flow component of tracer influx into brain. The volume shift estimated on the basis of this data is 114 microliters CSF/g dry wt brain for a 60-mosmol/kg increase in osmolality. Results indicate that CSF is a major source of the volume regulatory gain of Na and Cl, but not of K.

Cerebrospinal fluid anion transport

Perfusion of the ventriculocisternal system in unanesthetized sheep was used to quantify the pathways by which the pertechnetate anion (TcO4−) may leave the cerebrospinal fluid space. The largest fraction (about 89%) was removed from the fluid before it reached the cisterna magna; this extraction was significantly inhibited by iodide ion in the perfusion fluid. One-fifth of the extracted pertechnetate remained in the head of the animal for over 3 hours. Only about 3% of the infused pertechnetate was resorbed with the bulk flow of cerebrospinal fluid through the arachnoid villi. These results are consistent with the concept of a specific brain channel for removal of anions. As pertechnetate and iodide ion are thought to be transported by the same mechanisms, the physiological role of this channel may be maintenance of a very low iodide concentration in the extracellular fluid of the brain. (Neurosurgery 17:778-783, 1985)

Cerebrospinal fluid anion transport: studies of pertechnetate in unanesthetized sheep.

Perfusion of the ventriculocisternal system in unanesthetized sheep was used to quantify the pathways by which the pertechnetate anion (TcO4-) may leave the cerebrospinal fluid space. The largest fraction (about 89%) was removed from the fluid before it reached the cisterna magna; this extraction was significantly inhibited by iodide ion in the perfusion fluid. One-fifth of the extracted pertechnetate remained in the head of the animal for over 3 hours. Only about 3% of the infused pertechnetate was resorbed with the bulk flow of cerebrospinal fluid through the arachnoid villi. These results are consistent with the concept of a specific brain channel for removal of anions. As pertechnetate and iodide ion are thought to be transported by the same mechanisms, the physiological role of this channel may be maintenance of a very low iodide concentration in the extracellular fluid of the brain.

Compartmental analysis of cerebrospinal fluid transfer and absorption in simulated hydrocephalus

A mathematical model of the cerebrospinal fluid (CSF) flow dynamics found in hydrocephalic infants with myelomeningocele lesions was constructed using criteria obtained from analogous clinical situations where 125I-labelled and 131I-labelled ortho-iodo-benzoyl-amino-acetic acid (hippuran) had been employed to measure CSF flow dynamics. The quantitative results from this study allowed clinical data to be assessed and the importance of various CSF transfer mechanisms to be discussed. The mathematical model indicates that the majority of radiopharmaceutical passes from the cerebral reservoir (the ventricles) into the blood. Experimental evidence indicates that the principal mechanism responsible for this movement is the bulk flow of CSF between its sites of production in the choroid plexus and absorption by the arachnoid villi.

CSF distribution of morphine, methadone and sucrose after intrathecal injection

The lumbar to cisternal CSF distribution of morphine and methadone were compared to C-14 sucrose, a standard marker of CSF bulk flow, after lumbar subarachnoid injections in a sheep preparation. Morphine appeared and peaked simultaneously with C-14 sucrose in cisternal CSF at 90 to 190 minutes. The mean peak cisternal CSF morphine concentrations were sustained for 30–40 minutes, and averaged 148 ng/ml, representing 0.3% of the administered dose. Methadone was not detectable in cisternal CSF up to 240–300 minutes after lumbar subarachnoid administration. The C-14 sucrose/morphine ratio was increased an average of 6.7 times in cisternal CSF as compared to the ratio wf the two compounds injected into the lumbar subarachnoid space. These studies demonstrate that morphine, a hydrophilic oploid, given intrathecally moves rostrally and appears in cisternal CSF by bulk flow. Furthermore the rostral redistribution of morphine is associated with the clearance of morphine from CSF. Methadone, a lipophilic opioid, appears to be completely cleared from CSF before it reaches the cisterna magna. These pharmacokinetic studies support a contribution of supraspinal sites to the analgesic and adverse effects produced by morphine given by spinal routes of administration. In contrast methadone appears to exert its effects predominantly at spinal sites.

Cytosine arabinoside cerebrospinal fluid kinetics.

To better characterize the disposition of cytosine arabinoside (Ara-C) in cerebrospinal fluid (CSF), its kinetics were studied in seven patients with meningeal leukemia in complete remission. After intraventricular injection of 30 mg Ara-C, CSF and plasma samples were obtained over a 24-hr period. Ara-C levels were measured by a reverse-phase HPLC assay (with a sensitivity of 0.5 microM in CSF and 1.0 microM in plasma) that readily separated Ara-C from its major metabolite uracil arabinoside (Ara-U). Elimination of Ara-C from CSF followed a biphasic pattern, with an initial t1/2 of 1 hr and a terminal t1/2 of 3.4 hr. Ara-C clearance from CSF was 0.42 ml/min, suggesting that drug elimination was primarily by CSF bulk flow. The ratio of the AUC of Ara-U to the AUC of Ara-C was 0.08, indicating only minor metabolism of Ara-C to Ara-U in CSF, in contrast to that after systemic Ara-C. Despite initial CSF Ara-C concentrations exceeding 2 mM, Ara-C was not detectable in plasma in any patient. Intraventricular Ara-C results in very high levels in CSF, but systemic tissues are relatively spared from exposure to Ara-C.

Pharmacokinetics of intraventricular administration.

The widespread use of neurosurgical devices for intraventricular drug delivery has led to an escalation in the number of CSF pharmacokinetic studies. When experimental data for ventricular CSF concentration vs. time are normalized for dose and plotted for drugs with a wide range of physical properties, there is a remarkably narrow range. Simulations from a distributed model for the central nervous system suggest that the narrow range of observed CSF half-times following bolus administration is a consequence of physiologic limits upon rate of drug removal from CSF. Whereas bulk flow of CSF establishes minimum rate of drug washout, diffusion through brain tissue and subsequent removal by capillaries establishes a maximum rate of drug egress which is only seven times the minimum rate. Predictions of CSF concentration vs. time can be made based upon the capillary exchange rate for a particular drug, which could be estimated or calculated from CSF concentration measurements following systemic administration. Simulations are also presented of steady-state CSF concentrations during continuous ventricular infusions.

Clearance of albumin from mouse subarachnoid space: a measure of CSF bulk flow

A method is described for percutaneous lumbar cerebrospinal fluid (CSF) cannulation and intrathecal infusion in the laboratory mouse. The clearance from CSF of infused [ 125I]albumin was measured in a group of awake 2-month-old normal female mice as a measure of CSF bulk flow. Between 30 and 60 min following infusion, 125I activity in CSF declined linearly at a rate of 0.888 ± 0.185 percent/min corresponding to a CSF bulk flow rate of 325.27 ± 67.76 nl/min. This rate of CSF bulk flow correlates well with CSF bulk flow rates measured in larger species by the ventriculocisternal perfusion method. This method for intrathecal infusion and subsequent CSF sampling should be useful for measuring various aspects of CSF physiology in the laboratory mouse under normal and pathologic conditions.

Effect of Pressure on Cerebrospinal Fluid Absorption in Cats, Baboons, and Humans

To circumvent time constraints inherent in indicator clearance measurements of cerebrospinal fluid absorption, investigators have used the relationship between CSF pressure at steady state and the rate of infusion of mock CSF, in both patients and experimental animals, to evaluate the bulk absorption rate of CSF. This latter approach required mathematical model of the effect of CSF pressure on CSF bulk flow. Two such models--a fixed resistance and a variable resistance model of CSF flow through arachnoid villi--have been used in both clinical and laboratory settings. In this study, the relationship between steady state CSF pressure and mock CSF infusion rate was assessed using both mathematical models. We studied two patients, three cats, and seven baboons. Values of CSF outflow resistance calculated according to both models as well as other parameters of CSF bulk flow estimated on the basis of both models were all in the range expected from other studies. The data from these experiments do not provide justification for preferring one model over the other. Depending on the experimental or clinical situation, some of the assumptions behind both models may not be valid. Multiple direct measurements of the rates of CSF absorption and formation over a wide range of CSF pressures in individual subjects will be necessary to validate either the variable or the fixed resistance model or to suggest a more appropriate model. Until such information is available, it is probably reasonable to use both approaches for the analysis of mock CSF infusion data. CSF bulk flow parameters calculated on the basis of either the variable or the fixed resistance model should never be taken as absolute, but should be evaluated critically in the context of the clinical or experimental situation.

Effect of Pressure on Cerebrospinal Fluid Absorption in Cats, Baboons, and Humans

To circumvent time constraints inherent in indicator clearance measurements of cerebrospinal fluid absorption, investigators have used the relationship between CSF pressure at steady state and the rate of infusion of mock CSF, in both patients and experimental animals, to evaluate the bulk absorption rate of CSF. This latter approach required mathematical model of the effect of CSF pressure on CSF bulk flow. Two such models--a fixed resistance and a variable resistance model of CSF flow through arachnoid villi--have been used in both clinical and laboratory settings. In this study, the relationship between steady state CSF pressure and mock CSF infusion rate was assessed using both mathematical models. We studied two patients, three cats, and seven baboons. Values of CSF outflow resistance calculated according to both models as well as other parameters of CSF bulk flow estimated on the basis of both models were all in the range expected from other studies. The data from these experiments do not provide justification for preferring one model over the other. Depending on the experimental or clinical situation, some of the assumptions behind both models may not be valid. Multiple direct measurements of the rates of CSF absorption and formation over a wide range of CSF pressures in individual subjects will be necessary to validate either the variable or the fixed resistance model or to suggest a more appropriate model. Until such information is available, it is probably reasonable to use both approaches for the analysis of mock CSF infusion data. CSF bulk flow parameters calculated on the basis of either the variable or the fixed resistance model should never be taken as absolute, but should be evaluated critically in the context of the clinical or experimental situation.

The acute management of intrathecal methotrexate overdose: Pharmacologic rationale and guidelines

INTRATHECAL METHOTREXATE TtlERAPY is now used widely for the prevention and treatment of meningeal leukemia and lymphoma. During the past year we have been consulted on more cases Of intrathecal methotrexate overdosage then in any previous year. In the study reported here we used a modified one-compartment pharmacologic model to suggest guidelines for the acute management of intrathecal methotrexate poisoning, and illustrate how the approach was applied to two patients. METHODS AND PHARMACOLOGIC RATIONALE A modified Single compartment model was used to predict the efficacy of cerebrospinal fluid withdrawal for removal of intrathecally administered drug. The compartment was takefi to represent the volume of drug distribution within the CSF (Vi,Cs~). As such, VJ s~ was not held constant but expressed as a function of time (t) after administration. This modification incorporates the ascent of drug in the subarachnoid space after intralumbar administration. The initial VD csF was taken as the volume of drug injected (Vo). The rate of V~ csF expansion during the initial phase or distribution was assumed tO be governed by CSF bulk flow. The latter was approximated by the rate of CSF production which in the model was assumed to be 30 ml/hour? Hence,

The response of brain to transient elevations in intraventricular pressure

A mathematical theory has been developed to evaluate the change in size of the cerebral ventricles in response to a square-wave pressure pulse within the ventricles. Specifically, the theory utilizes a lumped compartment viscoelastic spherical shell model of the brain and takes into account available creep compliance data. The pressure change in the cortical subarachnoid space plays a critical role in determining the net displacement of the brain. The rise in cortical subarachnoid pressure is governed by a rate constant γ which is nearly proportional to the absorption coefficient when absorption is rate-limiting, inversely proportional to the compliance of the spinal subarachnoid space, and also depends upon the resistance to flow through CSF pathways. A rapid rise in pressure within the cortical subarachnoid space results in an inward displacement of the ventricles immediately after the ventricular pressure pulse has ceased. Thereafter, the ventricles return toward their initial size as the pressure in the cortical subarachnoid space decays. A slow rise, on the other hand, favors permanent ventricular enlargement. Decreased absorption of CSF, long duration pulses, and bulk flow of CSF into brain, which are observed in hydrocephalus, all favor the development of ventricular enlargement.

Cerebrospinal fluid bulk flow study

Eight normal dogs were studied and then made hydrocephalic (kaolin induced) to demonstrate and compare the use of R131ISA and 99mTcDTPA in cerebrospinal fluid (CSF) bulk flow studies. The radioisotopes were simultaneously injected into the CSF space in the cisterna magna of normal dogs and into the lateral ventricles of hydrocephalic dogs after an equal volume of CSF had been removed. The average dose of RISA was 100 μCi, and for TcDTPA it was 7 mCi. A bag of lactated Ringer's solution (500 ml) was used as a control phantom after being injected with the same dose of isotope as used in the animals. Brain scans were obtained with the gamma ray camera at 4 and 24 hours after injection. We used four criteria to evaluate results: clinical state of the animal, CSF ventricular pressures with challenges, percentage of retained isotope in counts per minute, and ventricular size at postmortem examination. The results demonstrate that the amount of isotope retention over 20 hours and the clinical state of the dog are better correlated when RISA is used than when TcDTPA is used. The study indicates that RISA is more reliable than TcDTPA as an indicator of CSF bulk flow in both normal and hydrocephalic dogs.

Bolus versus steady‐state infusion for determination of CSF outflow resistance

For rapid changes in cerebrospinal fluid volume an exponential relationship was demonstrated between CSF pressure and CSF volume in 15 cats. This relationship was valid over a CSF pressure range from 7 to 50 mm Hg and for acute increases of up to 9% to total CSF volume (approximately 13 ml for humans). Our data agree well with previous reports for the cat. A similar relationship has been shown in the dog and in humans. It has been claimed that, given the equations for CSF bulk flow and the exponential relationship between CSF pressure and CSF volume, one can calculate CSF outflow resistance by observing the decay of CSF pressure after a bolus injection into the CSF space. This claim was evaluated in an additional 18 cats. In these animals CSF outflow resistance calculated by the bolus method was compared with resistance calculated by a steady-state infusion method over the CSF outflow resistance range of 74 to 293 mm Hg/ml min-1. Resistance calculated by the bolus method underestimated resistance calculated by the steady-state method, and this underestimate grew larger with increasing resistance. The bolus technique is therefore not a valid method for determining CSF outflow resistance. The explanation offered for these results is that the decay of CSF pressure after a bolus injection into the CSF space occurs not only because of runoff of the injected volume of CSF but also because of "pressure relaxation" of the brain parenchyma around the CSF space. The phenomenon of pressure relaxation was not considered in developing the equation for calculation of CSF outflow resistance by the bolus technique. The time dependency of pressure relaxation allows for a fundamental element of hysteresis within the CSF space. A method of quantifying this element of hysteresis is suggested.

Pressure-dependent bulk flow of cerebrospinal fluid into brain

Cerebrospinal fluid (CSF) absorption was studied at the cortical surface in the acutely prepared, nonhydrocephalic animal. Cerebrospinal fluid containing radioactively labeled sucrose was infused into the cisterna magna at various rates for several hours to maintain elevated cerebrospinal fluid pressures. The equilibration of sucrose in the CSF was determined by periodic supracallosal cistern sampling. The cortical sucrose distribution space was 14.2% for low infusion rates and increased to 33.9% at the high infusion rates. Apparent diffusion coefficients based on the equilibration of sucrose in the CSF were significantly higher for the intermediate and high infusion rates than for the low infusion rate group, which was the same as a supracallosal-cisternal perfusion control group. The data suggest that bulk flow of CSF across the cortical surface occurs at elevated pressures.

Bulk flow of cerebrospinal fluid through a lumbo-omental pedicle graft in the dog.

Perfusion tests were performed in dogs with a pedicle graft of the greater omentum implanted in the lumbar subarachnoid space to measure its capacity to drain CSF. The CSF pressure was set at different levels in the range 0--50 mmHg and the outflow from a complete CSF space and then from the isolated dural sac was recorded in the same dog with an electronic drop recorder. It was shown that the omental graft could transport as much as 30% of the CSF normally carried by the physiological pathways. The spinal outflow in the controls was virtually non-existent. It is concluded that a bulk flow of CSF occurs through the graft. The results suggest that a lumbo-omental pedicle graft could possibly be used as a biological shunt in the treatment of hydrocephalus.

Metrizamide washout as a measure of CSF bulk flow

Metrizamide was injected into the ventricular system of three adults and five children with indwelling ventricular catheters and subcutaneous CSF reservoirs. A first-order rate constant, k, for metrizamide washout from one lateral ventricle was determined with reference to ventricular metrizamide concentration on serial (up to six) postinjection CT scans. Lateral ventricular volume, Vv, was estimated after metrizamide injection by a planimetric method and by partial volume analysis, an interactive computerized technique. The rate of lateral ventricular CSF formation, If, was calculated as k X Vv and ranged from 0.0622 to 0.103 ml/min. Precise measurements of lateral ventricular CSF bulk flow depend upon adequate mixing of the injected contrast material with ventricular CSF and accurate measurements of lateral ventricular volume.

The rate of CSF formation in man: Preliminary observations on metrizamide washout as a measure of CSF bulk flow

Metrizamide, a nonionic, water-soluble contrast agent, was injected into the ventricular system of 3 patients with indwelling ventricular catheters and subcutaneous cerebrospinal fluid reservoirs. A first-order rate constant, k, for metrizamide washout from the right lateral ventricle was determined with reference to mean ventricular metrizamide concentration on serial CAT scans; right ventricular volume, V, was estimated after metrizamide injection by multiplying the appropriate ventricular area on consecutive CAT slices by the nominal slice thickness. The rate of right lateral ventricular CSF formation, If, in our 3 patients was calculated as k X V and ranged from 0.083 to 0.103 ml per minute.