Clinical management and treatment of elevated intracranial pressure (ICP) still represents a challenge, even in developed countries. Some of the most common causes of elevated ICP include traumatic brain injury, cerebral oedema, meningitis, central nervous system neoplasia, hydrocephalus, and various metabolic disorders. Management of elevated ICP is additionally complicated by conditions that lead to the obstruction of flow of cerebrospinal fluid (CSF), as can be seen with spinal neoplasia, hematomas, bone deformations and trauma, Arnold-Chiari malformation type 1 and 2, brain herniation of various causes, etc. Intracranial pressure represents the pressure of CSF inside the cranium. The relationship of the three volumes inside the cranium (volume of blood, brain parenchyma and CSF) was described about 200 years ago and is known as the “Monro-Kellie doctrine”. It states that the total intracranial volume is constant, therefore an increase in one of the volumes results in a compensatory decrease in one or both of the remaining volumes, with the goal of preserving the ICP within physiological values. Once the ICP surpasses 15 mm Hg, intracranial hypertension (ICH) develops. The entire neurophysiology of CSF, and therefore all therapeutic methods for the treatment of ICH, are based on a 100-year-old hypothesis formed by Weed, Dandy and Cushing. This “classical hypothesis” on secretion, circulation, and absorption of CSF states that the CSF is actively secreted from the choroid plexuses in brain ventricles; it then circulates in a unidirectional manner from the point of its secretion to the point of its passive absorption into the venous sinuses of the dura, through the arachnoid granulations. Due to the growing number of clinical observations of failure of some of the established methods used in the treatment of elevated ICP, certain groups of researchers began to question this classical hypothesis, creating a different viewpoint on CSF secretion, circulation and absorption. This new hypothesis is also known as “Bulat – Orešković – Klarica hypothesis”. It defies all the basic principles of the classical hypothesis, stating that therethrough arachnoid granulations, but rather a constant water exchange in all the capillaries of the central nervous system (CNS), and that CSF is moved by the pulsation of blood vessels, in a “to-and-fro” manner. However, methods for treatment of ICH are still largely based on the classical hypothesis. These methods can be divided into basic prophylactic measures, conservative treatment, and surgical treatment. Hyperosmolar therapy represents the mainstay of conservative treatment, where mannitol remains “the gold standard” of therapy, even though the exact mechanisms of its effect are not fully understood. We hypothesized that intravenous administration of mannitol solution will cause a decrease in ICP by decreasing the volume of CSF, rather than the volume of brain parenchyma and/or blood volume, as is currently thought. To test our hypothesis, we created a new model of ICH in swine (n=6). After general anaesthesia induction, we performed four surgical procedures on each animal. The first procedure consisted of craniotomy (7 mm lateral and 10 mm posterior to bregma) through which a measuring cannula was placed into the left lateral ventricle of the brain. The second procedure included hemilaminectomy of the 4th lumbar vertebra to allow for measuring cannula introduction into the lumbar spinal subarachnoid space. We then performed another craniotomy on the contralateral side (using the same coordinates), through which a Foley catheter was introduced parietally epidurally. This catheter was used to induce ICH by balloon inflation (3 mL of saline manually applied over 2 minutes). Finally, a dorsal cervical laminectomy at the level of 2nd cervical vertebra was performed in order to place a surgical thread epidurally around the spinal cord, and by tightening of the thread, a craniospinal obstruction was created (creating an interruption of flow of the CSF from the cranium to the spinal canal). The experiment was divided into three phases, during which we monitored the ICP, the pressure of CSF in the lumbar subarachnoid space, along with the vital parameters of the animal (via an anaesthesiology multiparametric monitor), as well as biochemical parameters through serial arterial blood sampling enabled by cannulation of the medial saphenous artery. In each phase, an initial period of stabilization was allowed for 15 minutes, followed by intravenous administration of 10% mannitol solution (1 g/kg) over 15 minutes, after which we observed the CSF pressure dynamics for another 60 minutes. The first phase was the control phase in which we monitored the effect of mannitol on CSF dynamics as well as its effects on vital and biochemical parameters in intact animals. In the second phase, we observed the effect of mannitol in the setting of ICH and free craniospinal communication. Finally, the third phase consisted of induction of cerebrospinal obstruction, which allowed us to simulate a model of ICH with an obstruction of the flow of the CSF, providing insight into the effect of mannitol in such a state. At the end of the experiment, all animals were euthanised under a deep plane of anaesthesia. Necropsy was performed to additionally verify correct cannula placement in the brain ventricle, while samples of brain parenchyma were taken for histopathology to confirm brain lesion formation as a consequence of Foley catheter balloon inflation. In the first phase of the experiment, we noticed some of the typical effects of mannitol administration on both vital parameters (changes in heart rate, mean arterial pressure, diuresis) and biochemical parameters (decrease of haematocrit and electrolyte concentration), as well as its effect on CSF pressure (a mild decrease in intracranial and spinal CSF pressure). In the second phase, we successfully created ICH by Foley catheter balloon inflation in all animals. Intracranial pressure increased from 12,3 ± 2,7 mm Hg in the control phase, to 47,8 ± 21,1 mm Hg after balloon inflation. Administration of mannitol solution in this phase led to a significant decrease in CSF pressure in both measurement points (intracranial and spinal), approaching the values of the control phase. This demonstrated the efficacy of intravenously administered mannitol to decrease the ICP despite the increase of the intracranial volume (inflated balloon of the Foley catheter). However, when mannitol was administered after creation of craniospinal obstruction in the third phase, we observed a separation of the CSF pressures in the two compartments. The ICP increased (32 ± 4,06 mm Hg), while the spinal CSF pressure continuously decreased over time (8,6 ± 2,4 mm Hg). Therefore, we have set a reproducible experimental model of ICH in swine by creating a focal lesion via Foley catheter balloon inflation, which can be used for further research into CSF dynamics as well as to observe the effects of various drugs and procedures used for ICH treatment. We have also demonstrated the role of the spinal CSF compartment in ICP regulation. Furthermore, our results confirm the hypothesis according to which an increase in serum osmolarity caused by the administration of mannitol leads to osmotic extraction of water from the CSF system, and subsequently to a decrease in the volume of CSF, predominantly in the spinal compartment, owing to the elasticity of the dural sac. This finding fits into the new hypothesis of CSF physiology, according to which the volume of CSF (production and removal of CSF and interstitial fluid) is regulated by the interaction of osmotic and hydrostatic forces throughout the entire capillary net of the CNS. Large animal models, especially swine, are used more and more often in translational research, thanks to the similarities of their CNS with humans. Moreover, large animal models permit the use of the same modern neuromonitoring as is used in people in clinical setting, making it easier to transfer experimental data into clinical application. Our results clarify that the use of hyperosmolar solutions in patients with a suspected or confirmed craniospinal obstruction is contraindicated, as it leads to an increase of the ICP.