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Physiopathology of Cerebral Compensation

Centro Diagnostico ,*Neurochirurgia, Osp. civ. Caserta

There is a great impair between the neurophysiopathology knowledge and the one used to approach clinically the cerebroascular patient, a strict link lacking in practice between physiopatology and clinics.
 

The importance of the cerebral circulation is clear considering that brain is only 2% in weight of human body, while cerebral blood flow (CBF) is in mean 800 ml/min. i.e. almost 15% of cardiac output. Regional flow is almost 40-60 ml/min, where a region is almost a cerebral lobe.
Ischemia is a condition in which oxygen input to a tissue is less than its metabolic needs. Clinicians however are interested also in the conditions preparing ischemia, as on these ones they can act to avoid the onset of pathologic event.
So the analysis of compensation must include also risk conditions, asymptomatic and not ischemic ones, where also if there is an obstacle in a main vascular path, anyway collateral circulation feeds efficiently the parenchyma.
To develop a good collateral circulation intracranial anastomoses, described in the previous chapter on diagnostics of compensation, must be fully functioning. In particular, Willis Circle and orbitay plexus anastomoses. Very often Willis Circle is uncomplete and this causes the onset of more dramatics ischemic events, when there is an obstruction of one of the main vessels going into the skull.
The first kind of compensation is flow change inside the anastomoses. Flow has a direction determined by energy gradients. When these change, i.e. after obstruction or high degree stenosis of a vessel, also flow direction becomes aware of that, with effects of increase, invariance, reduction, zero-flow, inversion.
Previously described diagnostic tests for compensation recognition are based on these responses and on compression manoeuvres.
A quite general model of collateral circulation is shown in Fig.1, where the electric scheme of the WheatStone Bridge can be recognized.
If the A branch resistance is notably increased or if the loop is open eliminating the A branch, the downstream bed receives blood from B trough the anastomosis. But also for less strong changes of A resistance, blood in the anastomosis flows from B towards A.
Bridge equilibrium, i.e. the zero-flow anastomosis condition, is reached when V₂/V₁ = B/A while if V₂/V₁ > B/A flow goes from B towards A. On the contrary if V₂/V₁ < B/A
flow goes from A towards B.
These relations hold in the arterious system, while in the venous one disequations must be inversed.
Applying to the circuit the loop method, An flow (computation is omitted) is given by:
f
i_An = i₁ - i₂ = - (f/D)(AV₂ - BV₁);

where the determinant is positive, because it is sum of all positive terms (resistances and products between resistances) and f changes its sign whether it is directed towards arterial or venous district, so that:
iAn <=> 0 if V₂/V₁ <=> B/A.

In the case that A and B are the two internal carotid arteries (CI), An the anterior communicating artery (CA), V₁ and V₂ the two intracranic downstream vascular beds, the ratio between resistances of V₂ and V₁ must be greater than the ratio between resistances of the two carotids.
If V₁ and V₂ are patent, without Wills malformations, (V₁ = V₂ and V₁/V₂ ~ 1), then B must be more patent than A, i.e. A has a minor caliber or is a stenotic vessel.(Fig. 2)
In the case V₁ and V₂ are instead very different, i.e. distal emboly on V₂ with high resistance, while the two carotids are comparable, then part of B flow is deviated towards V₁ instead of towards V₂. In practice, healthy districts steal blood from occluded ones. (Fig. 3).
A final remark is that emoderivation (or steal) takes place only when there are anastomose upstream to occluded zones, while downstream anastomoses are in an ideal working condition.
Practically, CA in upstream position to a medium cerebral artery, which has some of its terminal branches occluded, steals blood from it, while compensation comes from pial anastomoses in downstream position.
 

If regional flow falls below 10 ml/100 gr tissue/min, neuronal death onsets in almost 6 minutes. This means that nothing can be tried to restore this zone. Necrotic area is however surrounded by an inschemic area, inside which neurons are only subjected to a decreased circulation, nevertheless sufficient to mantain them in an evident limited functional status of life.
This area is called the ischemic penumbra or penumbra. The last aim of every actual therapy is therefore to restore the penumbra to a normal functional status.
In the focus HCT and eritrocyte aggregation should decrease, while in the penumbra area these values should increase. Necrosis and penumbra extensions are due to the vascular obstruction site and to the terminal or not character of the excluded vascular beds. (last fields)
If the district circulation is dependent on several vessels, compensation comes generally from distal anastomoses with pial and precortical arteries.
Still lasts the problem of the regulation of pial anastomoses, why they are more or less wide, so making it possible to restore revascularized areas in different ways.
 

Cerebral circulation takes place in a constant volume compartment, the cranial box, so that any sub-compartimental volume change involves an opposite change in other sections. The overall volume of these sections is therefore constant. No other organ is in the same condition, becoming quite similar only those organs which have a rigid capsule.
Another analogue is the anterior tibial muscle lodge in the leg and its compression pathology in the revascularization syndrome.

Volume changes of several compartiments onset in cerebral edema, as a citotoxic (intracellular) or vasogenic (extracellular) edema. In the latter water and ions transfer trough the blood-brain barrier happens crossing the so called endoletial "tie junctions".
Endotelium itself is only a transfer zone and does not increase in volume. The brain lacks in parenchymal lymphatic vessels. Perivascular spaces are functional analogues of lymphatic vessels.
 

Also if systemic pressure (SABP) is very variable, there are not definitively known mechanism which set the CBF to a constant or autoregulation.
Autoregulation is present in each organ, but it is more pronounced in the brain and the kidney. If CBF is almost constant, then there is between the means a linear dependence between the pressure drop (P) and the resistance ( R ) of the cerebral vascular bed.
P = R * CBF;
So that when autoregulation works well, vasodilation occurs in hypotension while vasoconstriction in hypertension, in order to reduce to a minimum CBF changes. Autoregulation factors are pH, heamatocrit, pCO₂, pO₂, Oxygen Haemoglobin Saturation (SaO₂), carotid to jugular arteriovenous oxygen difference (D_avO₂), the neural control and the intracranial pressure (ICP). There is no evidence instead of correlation between metabolic activity and CBF. A carotid stenosis causes a malfunction of autoregulation: CBF drops when % stenosis is greater of 94% in area and 75% in diameter with a significant reduction of downstream pressure. Autoregulation is specific of arteriolar site and not of the venular one.
 

In 1902 Bayliss formulated the hypothesis of the myogenic effect, which then took his name.
A vessel submitted to an increased transmural pressure contracts, on the contrary it dilates for a decreased one.
So the vessel smooth muscle cell could behave as a Folkow lenght receptor or a Johnson tension receptor.
The constriction of proximal arteries under myogenic control as an answer to a pressure increase causes a downstream pressure drop, so preventing with a protective effect the myogenic constriction of distal arteries. Following several authors, autoregulation is mainly myogenic. Myoepitelial junctions behave like the tension receptors of the kidney.
 

The behavior of the haematocrit (HCT) in ischemic zones is controverse: increase or decrease ? HCT reduction causes the onset of plasmatic microvessels, i.e. without cellular content, where the oxygen transfer reduces only to oxygen solute content, with a further worsening of ischemia.
Capillary blood flow is unstable and changes in an unpredictable manner and not synchronous with cardiac activity. When caliber becomes comparable to red blood cell diameter, cellular flow becomes a "bolus flow", i.e. blood cells cross speedly the microvessel, which for the greater part of time is only filled with plasma. Il the vessel diameter is less then 2.8m, then it is not physically possible that a red blood cell can cross it. Of course this value increases in conditions of reduced eritrocyte deformability. HCT instability is partially due to capillary velocity instability.
There are experimental data and mathematical models which support the fractioning of blood cellular content in a branching node as a function of flow velocity in the branch. Below a definite caliber, branching angle is not important. The cellular component would transfer into the branch with greater flow velocity. (Fig. 4) A riequilibrium element could be given by the parallel reduction of viscosity in the plasmatic branch, exiting into an increased flow velocity.
There is a problem of HCT definition, which in this case is an "in vivo" measure compared to common laboratory "in vitro" measures. In both cases however, time parameter is present also if hidden.
HCT is definied as the volume fraction of whole blood given by red blood cell. In this definition time is not present, but laboratory measures, given by cellular component sedimentation, tell us that time is important as the measure depends on it with an almost negative exponential behavior. This charachter is more evident from centrifugation measures, where observation time is further reduced.
In vivo, time has instead a fundamental importance. If HCT is measured on a microphotograph, then it is most probable to find the vessel in a full plasmatic phase, while serial observations could allow us to view the cellular content.
A HCT measuring technique consists of measuring the red blood cells surface, compared to that covered by capillaries.
 

Cerebral resistance vessels below 0.4 mm react essentially to local control factors. These ones are of different kind: chemical, neural, humoral. The physiology of this control is difficult and variable with animal species, while results often depend on preparation methods.
I.e., studying the effects of muscolar tone, it can be mechanically or pharmacologically simulated and often results of tested substances are different.
Furthermore, vessels can be studied isolated from their context "in vitro" or "in situ", leaving intact all their local connections. There is no rule to predict the "in situ" behavior from the "in vitro" one.
Blood-brain barrier integrity causes no action of several substances, which instead have a strong action if injected locally in the perivascular space.
These different behaviors are summarized in Table 1, where details can be seen, while several specific elements are underlined in text. All local chemical factors do not act on autoregulation, as their perivascular concentration does not change during pressural changes. Autoregulation is evident for pressure values in the range 50-150 mmHg. Below the lower limit, vasodilating response seems to be mediated by adenosine, while the upper limit of autoregulation can be shifted towards higher values by sympathetical stimulation. The latter exerts also a protection on the blood-brain barrier during hypertension. (Fig. 5)
Acetilcholine has an endotelium dependent action, while hystamine is endotelium independent. This means that intra-arterious infusion causes no response. Furthermore, cholinergic fibers are involved in vasodilation anticipation, as an analogy to the lower limbs behavior in the moments before muscle exercise. Small veins can contract also if there are no smooth muscle cells, as their vessel wall contains contractable elements.
Furthermore, though several observations, it has never been possible to visualize fibers connected to parenchymal vessels. There is then no neural control of autoregulation in parenchymal vessels, contrasting to results of meningeal observations.
 

The following formula holds: Metabolic Consumption of O₂ = CmRO₂ = CBF * D_avO₂.
When autoregulation works, CmRO₂ is a linear function of D_avO₂, which then can be used to estimate metabolic rate.
In cranial trauma or ischemic coma instead, when CmRO₂ is assumed low and constant, D_avO₂ increase is a clinical index of a sudden fall of CBF.
 
 

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