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U konzervativnom liječenju povišenog intrakranijskog tlaka već dugo se koriste hiperosmolarne otopine (najviše manitol) koje se daju intravenski, ali točan mehanizam njihovog djelovanja na snižavanja intrakranijskog tlaka nije u potpunosti razjašnjen. Stoga je u ovom radu eksperimentalno, na mačkama proučavan utjecaj promjene osmolarnosti krvi i cerebrospinalnog likvora na volumen cerebrospinalnog likvora, te povezanost tih promjena volumena likvora s intrakranijskim tlakom. U tu svrhu korišteni su modeli direktne ventrikulo-akveduktalne i ventrikulo-cisternalne perfuzije s izoosmolarnom i hiperosmolarnom otopinom umjetnog likvora, spontanog istjecanja likvora iz cisterne magne i mjerenja tlaka likvora u lateralnoj moždanoj komori. Promjene osmolarnosti krvi vršene su intravenskim davanjem 20% manitola, te intraperitonealnim davanjem destilirane vode. Dobiveni rezultati pokazali su da promjene osmotskih sila u likvorskom sustavu dovode do promjena ukupnog volumena cerebrospinalnog likvora i da su promjene tlaka likvora (intrakranijskog tlaka) direktno povezane s tim promjenama volumena likvora. Veličina promjene volumena likvora ovisi o površini likvorskog sustava koja je izložena promjenama osmotskih sila. Također je pokazano da pri fiziološkom tlaku likvora, bez promjena osmotskih sila nema „čistog“ stvaranja niti apsorpcije likvora. Svi dobiveni rezultati nisu u skladu s klasičnom hipotezom o sekreciji, cirkulaciji i apsorpciji likvora, ali su u skladu s predloženom novom hipotezom o dinamici cerebrospinalnog likvora., Hyperosmolar solutions (mostly mannitol) have long been used in clinical practice to reduce intracranial pressure, but the exact mechanism by which this effect occurs is still unclear. So, in this study we wanted to investigate experimentally, on cats, the effect of changes in serum and CSF osmolarity on CSF volume and how this changes of CSF volume influence on intracranial pressure. For this purpose we used experimental models of direct ventriculo-aqueductal and ventriculo-cisternal perfusion with both isoosmolar and hyperosmolar aCSF, the free drainage of CSF from a cannula put into the cisterna magna and the measuring of CSF pressure by the cannula put into the lateral ventricle of the brain. Serum osmolarity was changed by intravenous application of 20% mannitol or intraperitoneal administration of distilled water. Obtained result showed that the changes of osmotic forces in CSF compartments leads to changes of total CSF volume and that changes of CSF pressure are directly connected with this changes of CSF volume. The extent of CSF volume changes depends on the size of contact area of CSF system that was exposed to the changes of osmotic forces. It was also shown that with physiological intracranial pressure, without changes of osmotic forces, there was no “net” CSF formation or absorption. All obtained results contradict the classic hypothesis of secretion, circulation and absorption of CSF, but support proposed new hypothesis of CSF hydrodynamics.

The classic hypothesis presents the cerebrospinal fluid (CSF) as the “third circulation, ” which flows from the brain ventricles through the entire CSF system to the cortical subarachnoid space to eventually be passively absorbed into the superior sagittal sinus through arachnoid granulations. The choroid plexus represents a key organ in the classic CSF physiology and a powerful biological pump, which exclusively secretes CSF. Thereby, the CP is considered to be responsible for CSF pressure regulation and hydrocephalus development. The role of the CP in the CSF dynamics has been thoroughly analyzed by presenting arguments in favor of the thesis that the CPs are neither biological pumps nor the main site of CSF secretion ; that they do not participate in regulation of ICP/CSF pressure ; are not the reason for the existence of hydrostatic pressure gradient in the CSF system and that this gradient is not permanent (disappeared in the horizontal position) ; and that they do not generate imagined unidirectional CSF circulation, hydrocephalus development and increased ICP/CSF pressure. The classic hypothesis cannot provide an explanation for these controversies but the recently formulated Bulat-Klarica-Orešković hypothesis can. According to this hypothesis, CSF production and absorption (CSF exchange) are constant and present everywhere in the CSF system, and although the CSF is partially produced by the CP, it is mainly formed as a consequence of water filtration between the capillaries and interstitial fluid.

U konzervativnom liječenju povišenog intrakranijskog tlaka već dugo se koriste hiperosmolarne otopine (najviše manitol) koje se daju intravenski, ali točan mehanizam njihovog djelovanja na snižavanja intrakranijskog tlaka nije u potpunosti razjašnjen. Stoga je u ovom radu eksperimentalno, na mačkama proučavan utjecaj promjene osmolarnosti krvi i cerebrospinalnog likvora na volumen cerebrospinalnog likvora, te povezanost tih promjena volumena likvora s intrakranijskim tlakom. U tu svrhu korišteni su modeli direktne ventrikulo-akveduktalne i ventrikulo-cisternalne perfuzije s izoosmolarnom i hiperosmolarnom otopinom umjetnog likvora, spontanog istjecanja likvora iz cisterne magne i mjerenja tlaka likvora u lateralnoj moždanoj komori. Promjene osmolarnosti krvi vršene su intravenskim davanjem 20% manitola, te intraperitonealnim davanjem destilirane vode. Dobiveni rezultati pokazali su da promjene osmotskih sila u likvorskom sustavu dovode do promjena ukupnog volumena cerebrospinalnog likvora i da su promjene tlaka likvora (intrakranijskog tlaka) direktno povezane s tim promjenama volumena likvora. Veličina promjene volumena likvora ovisi o površini likvorskog sustava koja je izložena promjenama osmotskih sila. Također je pokazano da pri fiziološkom tlaku likvora, bez promjena osmotskih sila nema „čistog“ stvaranja niti apsorpcije likvora. Svi dobiveni rezultati nisu u skladu s klasičnom hipotezom o sekreciji, cirkulaciji i apsorpciji likvora, ali su u skladu s predloženom novom hipotezom o dinamici cerebrospinalnog likvora.

Objectives were to study the effect of blood osmolarity on cerebrospinal fluid (CSF) volume and CSF pressure in cats. Three types of methods were used on anesthetized cats. The first, ventriculo-cisternal perfusion (12.96 m L/ min) before and after i.v. application of 20% mannitol ; the second, measuring the outflow of CSF by cisternal free drainage ; and the third, measuring CSF pressure in the ventricles of an intact CSF system, with the second and third method being performed before and after the i.p. application of a hypo-osmolar substance (distilled water). n the first group, the application of 20% mannitol led to a significantly reduced ( p < 0.005) outflow volume (from 12.60 ± 0.29 to 0.94 ± 0.09 m L/min). In the second group, the outflow CSF volume significantly increased ( p < 0.001) after the application of distilled water (from 18.8 ± 0.3 to 28.2 ± 0.7 m L/min). In the third group, after the application of distilled water, the CSF pressure also significantly increased ( p < 0.05 ; from 8.3 ± 0.8 to 16.1 ± 0.14 cm H 2 O). We conclude that changes in serum osmolarity change the CSF volume because of the osmotic gradient between the blood and all of the CSF compartments, and also that the change in CSF pressure is closely associated with changes in CSF volume.

The cerebrospinal fluid (CSF) formation rate (Vf) has been extensively studied by the ventriculocisternal perfusion, a method still regarded as the most precise one. This method as well as the equation for the calculation of the CSF formation rate (Vf) was established by Heisey et al4 on indicator dilution in perfusate. They assumed that the dilution of the indicator substance in perfusion is a consequence of newly formed CSF i.e. a higher CSF formation rate would result in a higher degree of dilution of the indicator substance. Therefore, such method is indirect and any mistake in the interpretation of the degree of indicator dilution would lead to questionable and often contradictory results regarding CSF formation rates. According to Heisey’s equation, Vf shoud not depend on the rate of ventriculocisternal perfusion. However it has been shown that Vf is perfusion dependt value10, and also that during perfusion the indicator substance is partially absorbed into surrounding tissue. It is possible that obtained Vf dependence on perfusion rate was caused by observed absorption of indicator substances. For that reason, in anaesthetised cats ventriculocisternal perfusion was performed at higher (252.0 mL/min) and at lower perfusion rate (65.5 mL/min) and Vf was calculated at both experimental and corrected (just for absorbed amount) values of indicator substance. Since (inspite of the correction) the difference of 12.4 mL/min between lower (15.0 mL/min) and higher perfusion rate (27.4 mL/min) was obtained, it is obvious that ventriculocisternal perfusion method cannot be considered reliable for measuring CSF formation rate.

The cerebrospinal fluid (CSF)formation rate (Vf) has been extensively studied by the ventriculo-cisternal perfusion technique, which is still regarded as the most precise method.

According to our new hypothesis, based on experimental data, the cerebrospinal fluid (CSF) is not formed at one site (inside brain ventricles) and absorbed at another (dural venous sinuses, perineural sheets of cranial nerves), but it might be formed and absorbed through capillary walls inside brain and spinal tissue, depending on hydrostatic and osmotic forces gradient between blood on one side and CSF and interstitial fluid on the other side. If our hypothesis is correct, the exchange of CSF between CSF system and surrounding tissue would depend on size of the contact area and on difference in blood and CSF osmolarity. This was tested on chloralose (100 mg/kg ; i.p.) anaesthetized cats at normal CSF pressure by collecting outflow sample after ventriculo-aqueductal (smaller contact area) or ventriculo-cisternal (larger contact area) perfusion by isoosmolar or hyperosmolar perfusate. At isoosmolar perfusion, the outflow volume (13.10 ± 2.01 µ L/min) was the same as the infused one in both the ventriculo-aqueductal and ventriculo-cisternal perfusion methods. At hyperosmolar perfusion, significantly higher outflow volume (34.12 ± 3.30 µ L/min) was obtained by ventriculo-cisternal perfusion than by ventriculo-aqueductal perfusion (22.09 ± 2.90 µ L/min) (p). These results clearly show that the CSF volume depends on osmolarity and size of contact area through which osmotic arrival of fluid takes place. Such results strongly support our new hypothesis on CSF hydrodynamics, but don't fit into classical hypothesis of CSF secretion, unidirectional flow and absorption.

The aim of the study was to evaluate whether or not cerebrospinal fluid formation rate (Vf) calculated according to the equation of Heisey et al., truly show the produced cerebrospinal fluid. For this reason Vf was simulated (40.6 microL/min) by an infusion pump in a plastic cylinder and the evaluation was done by comparing the results obtained between the calculated Vf and the simulated one. In both cases the result should be the same (40.6 micro/min). Other types of experiments were carried out by ventriculocisternal perfusion (92.4 microL/min) on anaesthetized and sacrificed cats. If the equation is correct, the calculated Vf for sacrificed animals should be zero, because there is no Vf in dead animals. The fact that the calculated Vf (46.5 microL/min) in the plastic cylinder was different (p < 0.0001) from the simulated one (40.6 microL/min) and that Vf was calculated even for dead animals (3-5 microL/min) clearly shows the that perfusion method may not be an accurate method for determination of Vf.

Introduction: The aim of the study was to evaluate is cerebrospinal fluid (CSF) formation rate (Vf) calculated according to the equation of Heisey et al., truly showing the secreted cerebrospinal fluid. Material and Methods: For this reason Vf was simulated by infusion of mock CSF (40.6 µ l/min) in a plastic cylinder and the evaluation was done by comparing the results obtained between the calculated Vf and the simulated one. In both cases the result should be the same (40.6 µ l/min). Other types of experiments were carried out by ventriculocisternal perfusion (92.4 µ l/min) on anaesthetized and sacrificed cats. If the equation is correct, the calculated Vf for sacrificed animals should be zero, because there is no secretion of CSF in dead animals. Results and Conclusion: The fact that the calculated Vf in the plastic cylinder (46.5 µ l/min, n = 4) was different from the simulated one (40.6 µ l/min, n = 4, p

Introduction: The aim of the study was to evaluate whether the cerebrospinal fluid (CSF) formation rate (Vf) calculated according to the equation of Heisey et al. corresponded to the CSF actually produced. Two experimental approaches were used: one involved a plastic cylinder and the other used cats before and after sacrifice with anesthetic overdose. In the plastic cylinder, CSF formation was simulated by the infusion of mock CSF at a rate 40.0 µ L/min. If the Heisey method were accurate, the Vf should be the same (40.0 µ L/min). In sacrificed cats, there was obviously no Vf (0 µ L/min), so according to the Heisey method Vf should not have been detected. Material and Methods: Ventriculocisternal perfusion was performed (92.4 µ L/min) with an indicator substance (dextran blue) dissolved in mock CSF (1 mg/mL) using the method of Heisey et al. A needle was introduced into the left lateral ventricle until free communication with the CSF was obtained. The needle was connected to a perfusion pump via polyethylene tubing and the perfusion solution was infused at a desired rate. From a second needle, which punctured the cisterna magna, 20-min samples of the perfusate were collected into glass tubes. The perfusion was allowed to proceed for 60 min and to stabilize prior to collecting the first sample. The animals were sacrificed by an anesthetic overdose and the samples were collected at 20-min intervals after 30 min of perfusion under the same conditions as in anesthetized cats. Perfusion in the plastic cylinder was performed in a 2-mL plastic syringe. Two plastic cannulas (O.D. 1.2 mm) connected with perfusion pumps were introduced from the back of the syringe. The simulation of the CSF secretion was performed (40.0 µ L/min ; mock CSF) through the upper cannula by the first pump, and the plastic cylinder was perfused (dextran blue dissolved in mock CSF ; 1 mg/mL ; 250.0 µ L/min) through the lower cannula by the second pump. The specimens were collected through the cannula connected to the front syringe orifice. All connections on the syringe were hermetically closed. The CSF Vf was calculated by the equation derived from Heisey et al.: Vf = Vi (Ci - Co)/Co, where Vi is the inflow perfusate rate, Ci is the concentration of the indicator substance in the inflow perfusate, and Co is the concentration of the indicator substance in the outflow perfusate. Results: During the experiments in the plastic chamber, the calculated CSF formation (46.2 µ L/min) presented statistically higher values (p

Aim To demonstrate that changes in the cerebrospinal fluid (CSF) pressure in the cranial cavity and spinal canal after head elevation from the horizontal level occur primarily due to the biophysical characteristics of the CSF system, ie, distensibility of the spinal dura. Methods Experiments in vivo were performed on cats and a new artificial model of the CSF system with dimensions similar to the CSF system in cats, consisting of non-distensible cranial and distensible spinal part. Measurements of the CSF pressure in the cranial and spinal spaces were performed in chloralose-anesthetized cats (n = 10) in the horizontal position on the base of a stereotaxic apparatus (reference zero point) and in the position in which the head was elevated to 5 cm and 10 cm above that horizontal position. Changes in the CSF pressure in the cranial and spinal part of the model were measured in the cranial part positioned in the same way as the head in cats (n = 5). Results When the cat was in the horizontal position, the values of the CSF pressure in the cranial (11.9 +/- 1.1 cm, H2O) and spinal (11.8 +/- 0.6 cm H2O) space were not significantly different. When the head was elevated 5 cm, or 10 cm above the reference zero point, the CSF pressure in the cranium significantly decreased to 7.7 +/- 0.6 cm H2O and 4.7 +/- 0.7 cm, H2O, respectively, while the CSF pressure in the spinal space significantly increased to 13.8 +/- 0.7 cm H2O and 18.5 +/- 1.6 cm, H2O, respectively (P < 0.001 for both). When the artificial CSF model was positioned in the horizontal level and its cranial part elevated by 5 cm and 10 cm, the changes in the pressure were the same as those in the cats when in the same hydrostatic position. Conclusions The new model of the CSF system used in our study faithfully mimicked the changes in the CSF pressure in cats during head elevation in relation to the body. Changes in the pressure in the model were not accompanied by the changes in fluid volume in the non-distensible cranial part of the model. Thus, it seems that the changes in the CSF pressure occur due to the biophysical characteristics of the CSF system rather than the displacement of the blood and CSF volumes from the cranium to the lower part of body.

Is suggested that the key factors involved in regulation of CSF volume are osmolality differences between CSF, blood and extracelular fluid.

Aim. To evaluate ventriculo-cisternal perfusion as a method for measuring cerebrospinal fluid formation rate, calculated by means of thr Heisey et al equation. Method. All experiments were carried out on anesthetized cats fixed in the sphinx position in a stereotaxic frame. Ventriculo-cisternal perfusion was used at an intracranial pressure of -10 cm H2O at different perfusion rates (32, 0, 65.5, 125.0 and 252.0 uL/min). Dextran blue was applied as an indicator substance and the concentration of the indicator was measured with a spectrophotometer at a wavelength of 635 nm. Cerebrospinal fluid formation rate was calculated with the equation of Heisea et al. Results. The indicator substance was less diluted at a higher perfusion rate, and the calculated cerebrospinal fluid formation rate was lower. Theincrease in perfusion rate from 65.5 to 125.0 to 252.0 uL/min increased the concentration of indicaaator substance from 0.75 to 0.89 to 0.97 mg/mL and decreased calculated cerebrospinal fluid formation raate from 21.8 to 15.4 to 7.8 uL/min. This reduction was linear and increase in the perfusion rate by 1 uL/min decreased the cerebrospinal fluid formation rate by 0.05 uL/min. Conclusion. The calculated cerebrospinal fluid formation rate depends of different perfusion rate. The increase in the perfusion rate diminishes the calculated formation rate. Ventriculo-cisternal perfusion may not be a suitable method to calculate the cerebrospinal fluid formation rate according to the equation of the Heisey et al.