| Abstract | Povišen intrakranijski tlak ili povišeni tlak cerebrospinalnog likvora još uvijek
predstavlja vrlo težak klinički i terapijski problem, čak i u razvijenim zemljama, a
liječenje dodatno otežavaju stanja koja dovode do opstrukcije kraniospinalnog prostora.
U konzervativnom liječenju intrakranijske hipertenzije hiperosmolarna otopina manitola
predstavlja „zlatni standard“, premda mehanizam njenog djelovanja nije do kraja
razjašnjen. Postavili smo hipotezu kako do pada intrakranijskog tlaka pri intravenskoj
primjeni manitola dolazi zbog smanjenja volumena likvora, a ne zbog smanjenja
volumena mozgovine i/ili cerebralne krvi kako se to do sada vjerovalo.
Kako bismo to ispitali na novom modelu intrakranijske hipertenzije u svinja (n=6)
izazivali smo porast intrakranijskog tlaka postavljanjem Foleyevog katetera parijetalno
epiduralno i pratili promjene likvorskog tlaka u kraniju (IKT) i lumbalno (LT) prije, za
vrijeme i 60 minuta nakon intravenske primjene 10% otopine manitola (1 g/kg/15 min)
pri normalnoj i prekinutoj kraniospinalnoj komunikaciji (izazvanoj zatezanjem kirurške
niti cirkularno epiduralno u razini C2). U kontrolnoj fazi, nakon intravenske primjene
manitola uočeni su tipični učinci na vitalne (brzina otkucaja srca, srednji arterijski tlak,
diureza) i biokemijske pokazatelje (hematokrit, koncentracija elektolita u plazmi) te tlak
cerebrospinalnog likvora (blago sniženje). U drugoj fazi u svih jedinki je uspješno
izazvana intrakranijska hipertenzija punjenjem balona (volumen 3 mL) Foleyevog
katetera (porast IKT-a s kontrolnih 12,3 ± 2,7 mm Hg na 47,8 ± 21,1 mm Hg). Primjena
otopine manitola u ovoj fazi je dovela do značajnog pada tlaka cerebrospinalnog likvora
lumbalno i u kraniju natrag prema kontrolnim vrijednostima. Međutim, nakon izazivanja
kraniocervikalne opstrukcije u trećoj fazi pokusa, primjena otopine manitola dovela je do
razdvajanja tlakova likvora. Naime, tlak likvora u kraniju je porastao (32 ± 4,06 mm Hg),
dok je tlak likvora lumbalno postupno padao (8,6 ± 2,4 mm Hg).
Rezultati dodatno potvrđuju hipotezu prema kojoj povećana osmolarnost plazme,
uzrokovana primjenom otopine manitola, dovodi do osmotskog izvlačenja vode iz
likvorskog sustava, te smanjenja volumena likvora i to dominantno iz spinalnog prostora koji je promjenjivog volumena. To se uklapa u novi koncept fiziologije cerebrospinalnog
likvora prema kojem je volumen likvora (nastajanje i nestajanje likvora i intersticijske
tekućine) reguliran međuodnosom osmotskih i hidrostatskih sila na razini kapilara
središnjeg živčanog sustava. U translacijskim istraživanjima veliki životinjski modeli,
poglavito svinje, zbog sličnosti njihovog središnjeg živčanog sustava s ljudskim
omogućuju korištenje suvremenog neuromonitoringa, istovjetnog kao i u ljudi, te
olakšavaju prijenos eksperimentalnih saznanja u kliničku primjenu. Ovi rezultati
objašnjavaju zbog čega se u slučaju sumnje na patološko stanje koje prekida
kraniospinalnu komunikaciju bolesnicima ne smiju intravenski primjenjivati
hiperosmolarne otopine. |
| Abstract (english) | 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. |
