**2. Microcirculation regulation**

In eukaryotes, transfer of oxygen and nutrition into the cell and removal of carbon dioxide and waste material occurs at the cell surface. In multicellular organisms, this event occurs in the interstitial area [3].

In humans, blood flow follows the path: left ventricle large- and medium-diameter arteries small arteries known as precapillary resistance arterioles and terminal arterioles capillary beds not containing contractile elements and where oxygen and solute exchange occurs postcapillary resistance venules and collecting veins capacitance veins and large veins right atrium.

Tissue oxygenation (DO2) is calculated as being equal to arterial oxygen saturation (SaO2 ) × blood haemoglobin level cHb × 1.39 × cardiac output (CO).

The result is that it takes 30–60 s for oxygen entering blood in the lungs to reach tissues. However, for oxygen to reach peripheral tissues, it is necessary for there to be sufficient airway opening, normal respiratory pattern, normal alveolar gas exchange, sufficient blood haemoglobin level, and sturdy and sufficient vein structure in addition to microcirculatory blood flow supplying metabolic requirements of the tissues [7].

For metabolism and sufficient adenosine triphosphate (ATP) production to occur, tissues need to have sufficient blood perfusion. In situations without sufficient oxygen supply, anaerobic glycolysis increases in tissues and lactic acid release occurs. Increased lactic acid causes metabolic acidosis. Acidosis reduces cardiac contractility and increases peripheral vascular resistance and, as a result, tissue hypoxia deepens. At the same time, increasing blood potassium levels linked to developing acidosis reduce cardiac contractility and cause a reduction in the presentation of oxygen to tissues.

Apart from true arteriovenous shunt areas of the body, blood perfusion passes through many capillary veins, and capillary blood flow is controlled by arteriole resistance. This situation is more pronounced especially in the heart, lungs, and skeletal muscles. In situations when reduced blood flow reduces in tissues, regional vasodilatation may ensure sufficient blood perfusion of tissues and sufficient oxygenation [8].

Moving away from the arteriolar areas, smooth muscle structure begins to appear in the adventitia layer of veins. This smooth muscle structure is contracted by adrenergic stimuli and is considered to increase capillary perfusion pressure [3].

As described by Bayliss, in situations with increased blood pressure, an attempt is made to keep blood flow to vital organs like the brain, heart, kidneys, liver, and carotid bodies fixed via developing vasocontraction [14]. This adaptation is processed in reverse in hypotensive situations. In this development, the tension-sensitive sodium and calcium channels play a

**Figure 3.** Local vasodilatation with tissue metabolites. KATP, ATP-dependent potassium ion channel; KIR, inwardrectifying potassium ion channel that gives rise to hyperpolarization; TRPV, transitory receptor-mediated potential;

Microcirculation and Hyperbaric Oxygen Treatment http://dx.doi.org/10.5772/intechopen.75609 53

• Autonomous nervous system (cholinergic, adrenergic, non-cholinergic, non-adrenergic

• Vasoactive humoral and tissue factors (angiotensin II, bradykinin, vasopressin, catechol-

• Local metabolic changes (partial oxygen pressure [PO2], partial carbon dioxide pressure [PCO2], pH, osmotic pressure [Posm], potassium [K+] concentration, metabolic material

In endothelial tissue, the friction caused by blood triggers nitric oxide (NO) release. In situations with vasodilatation in NO terminal arterioles, increasing NO release develops. Frictionlinked vasodilatation is responsible for mechanoconduction of the glycocalyx structure covering the endothelial surface and plays a role in blood flow regulation in inflammation,

Vasodilators like NO and prostaglandin I2 are found in the whole vascular system, especially the terminal arterioles. Other vasodilator effect agonists include serotonin, histamine, adenosine triphosphate (ATP), adenosine diphosphate (ADP), bradykinin, acetylcholine, thrombin,

role.

system)

like adenosine)

and endothelin.

**2.1. Factors affecting arteriole resistance**

cAMP, cyclic adenosine monophosphate.

amines, natriuretic peptides, etc.)

ischemia and other pathological situations [15].

Vasoconstriction in hyperoxic situations is an attempt to keep tissue oxygenization stable and, in addition, to reduce the risk of tissue hyperoxygenization [9]. The 2.5 atmosphere pressure applied during hyperbaric oxygen treatment increases 4–5 times partial oxygen pressure in subdermal healthy and infected tissues by [10]. In a study, hyperbaric oxygen administration had reduced local blood circulation about 76.5% in pancreatitis patients, while this rate was identified as 37% with normobaric hyperoxygenization [11]. Hyperoxic situations increase oxygen amount, which dissolves in plasma. The free oxygen amount is an important point in the development of oxygen diffusion. There is a moderate level of oxygen saturation values measured in the postcapillary section of microcirculation. This effect may be explained by the vasoconstriction which occurs with the hyperbaric oxygen administration.

During inflammation increased leukocyte adhesion occurring in venules and resistance increase to venous blood flow develops and venous pressure increases. At the same time, an increase occurs in the length of venules. An attempt is made to increase oxygen presentation to tissues [12, 13]. Also during inflammation, mediators like vascular endothelial growth factor (VEGF) are released to the environment and have a venodilatatory effect.

Arterioles and terminal arterioles cause changes in local blood perfusion resistance and may directly change the blood flow amount to tissues. In situations with vasodilatation of arterioles and terminal arterioles, there is an opening of closed capillaries and lengthening of capillaries. This situation causes an increase in the surface necessary for material transfer. However, in situations with venular contraction, there is a hydrostatic pressure increase in capillary beds and diffusion pressure increases. Capacitance and large veins change cardiac output above the heart's full volume and affect microcirculation (**Figure 3**).

**Figure 3.** Local vasodilatation with tissue metabolites. KATP, ATP-dependent potassium ion channel; KIR, inwardrectifying potassium ion channel that gives rise to hyperpolarization; TRPV, transitory receptor-mediated potential; cAMP, cyclic adenosine monophosphate.

As described by Bayliss, in situations with increased blood pressure, an attempt is made to keep blood flow to vital organs like the brain, heart, kidneys, liver, and carotid bodies fixed via developing vasocontraction [14]. This adaptation is processed in reverse in hypotensive situations. In this development, the tension-sensitive sodium and calcium channels play a role.

#### **2.1. Factors affecting arteriole resistance**

airway opening, normal respiratory pattern, normal alveolar gas exchange, sufficient blood haemoglobin level, and sturdy and sufficient vein structure in addition to microcirculatory

For metabolism and sufficient adenosine triphosphate (ATP) production to occur, tissues need to have sufficient blood perfusion. In situations without sufficient oxygen supply, anaerobic glycolysis increases in tissues and lactic acid release occurs. Increased lactic acid causes metabolic acidosis. Acidosis reduces cardiac contractility and increases peripheral vascular resistance and, as a result, tissue hypoxia deepens. At the same time, increasing blood potassium levels linked to developing acidosis reduce cardiac contractility and cause a reduction in the

Apart from true arteriovenous shunt areas of the body, blood perfusion passes through many capillary veins, and capillary blood flow is controlled by arteriole resistance. This situation is more pronounced especially in the heart, lungs, and skeletal muscles. In situations when reduced blood flow reduces in tissues, regional vasodilatation may ensure sufficient blood

Moving away from the arteriolar areas, smooth muscle structure begins to appear in the adventitia layer of veins. This smooth muscle structure is contracted by adrenergic stimuli

Vasoconstriction in hyperoxic situations is an attempt to keep tissue oxygenization stable and, in addition, to reduce the risk of tissue hyperoxygenization [9]. The 2.5 atmosphere pressure applied during hyperbaric oxygen treatment increases 4–5 times partial oxygen pressure in subdermal healthy and infected tissues by [10]. In a study, hyperbaric oxygen administration had reduced local blood circulation about 76.5% in pancreatitis patients, while this rate was identified as 37% with normobaric hyperoxygenization [11]. Hyperoxic situations increase oxygen amount, which dissolves in plasma. The free oxygen amount is an important point in the development of oxygen diffusion. There is a moderate level of oxygen saturation values measured in the postcapillary section of microcirculation. This effect may be explained by the vasoconstriction which occurs with the hyperbaric oxygen

During inflammation increased leukocyte adhesion occurring in venules and resistance increase to venous blood flow develops and venous pressure increases. At the same time, an increase occurs in the length of venules. An attempt is made to increase oxygen presentation to tissues [12, 13]. Also during inflammation, mediators like vascular endothelial growth fac-

Arterioles and terminal arterioles cause changes in local blood perfusion resistance and may directly change the blood flow amount to tissues. In situations with vasodilatation of arterioles and terminal arterioles, there is an opening of closed capillaries and lengthening of capillaries. This situation causes an increase in the surface necessary for material transfer. However, in situations with venular contraction, there is a hydrostatic pressure increase in capillary beds and diffusion pressure increases. Capacitance and large veins change cardiac

tor (VEGF) are released to the environment and have a venodilatatory effect.

output above the heart's full volume and affect microcirculation (**Figure 3**).

blood flow supplying metabolic requirements of the tissues [7].

52 Hyperbaric Oxygen Treatment in Research and Clinical Practice - Mechanisms of Action in Focus

presentation of oxygen to tissues.

administration.

perfusion of tissues and sufficient oxygenation [8].

and is considered to increase capillary perfusion pressure [3].


In endothelial tissue, the friction caused by blood triggers nitric oxide (NO) release. In situations with vasodilatation in NO terminal arterioles, increasing NO release develops. Frictionlinked vasodilatation is responsible for mechanoconduction of the glycocalyx structure covering the endothelial surface and plays a role in blood flow regulation in inflammation, ischemia and other pathological situations [15].

Vasodilators like NO and prostaglandin I2 are found in the whole vascular system, especially the terminal arterioles. Other vasodilator effect agonists include serotonin, histamine, adenosine triphosphate (ATP), adenosine diphosphate (ADP), bradykinin, acetylcholine, thrombin, and endothelin.

NO formed by the nitric oxide synthase enzyme found within endothelial cells is effective through paracrine routes. NO within the cell commonly shows the effect by ensuring calcium entry into the cell via guanosine monophosphate and protein kinase activation. In addition to vasodilatation, NO has anti-thrombogenic effects by reducing tissue factor expression, platelet aggregation, and adhesion molecule expression like VCAM. At the same time, proliferation in venous smooth muscles is reduced and it limits neointimal hyperplasia development in vein walls [16].

In situations with low oxygen levels or pH, ATP molecules released from erythrocytes found in microcirculation cause vasodilatation while haemoglobin molecules occurring with erythrocyte fragmentation bind to NO causing the development of NO-dependent vasodilatation. During hyperoxia the reactive oxygen radicals prevent nitric oxide-mediated vasodilatation; on the other hand, vascoconstrictor effect results in low tissue blood flow [27]. In addition, synthesis of the vasodilator prostaglandin is reduced while synthesis of the vasoconstrictor

Microcirculation and Hyperbaric Oxygen Treatment http://dx.doi.org/10.5772/intechopen.75609 55

The microcirculation performs the necessary oxygen distribution to meet the basic metabolic requirements of the tissues. Anatomically, it consists of arterioles, capillaries and venules. In situations where physiological or pathological stress develops, the balance between oxygen delivery and demand becomes very important. This delicate balance can play an important role in the progression of critical illnesses. In daily clinical practice, monitoring the microcirculation is essential for detection of potential organ dysfunctions. The ideal technique would allow quantification of vascular recruitment and the magnitude, heterogeneity, responsiveness, and efficiency of oxygen transfer to the tissues. There are a variety of methods and

The assessment of these factors can be analysed in five parameters: (i) total microvascular density (TVD), (ii) perfused microvascular density (PVD), (iii) proportion of perfused microvessels (PPV), (iv) microvascular flow index (MFI) and (v) heterogeneity of microvascular flow index. The first two reflect density, (iii) and (iv) reflect the flow, and (v) represents the heterogeneity of flow. Microcirculatory blood flow can be detected at the bedside by videomicroscopic techniques, and by laser Doppler flowmetry, near-infrared spectroscopy (NIRS), tissue reflectance spectrophotometry, or by tonometry. These techniques provide simple and quantitative data. Biochemical parameters that show microcirculation are reliable and include

Video microscopic techniques involve highly sensitive video microscopes that allow direct measurement of capillary density, perfusion and flow dynamics. Video microscopic techniques have shown a correlation between increased mortality in ICU patients [29]. These techniques, which included orthogonal polarisation spectral (OPS), sidestream dark-field (SDF)

prostaglandin (and endothelin-1) is increased [28].

**3. Methods to assess microcirculation flow**

**4. Assessment of microcirculation**

**5.1. Measuring microcirculatory perfusion**

lactate, tissue CO2

**5. Direct methods**

parameters available to evaluate the microcirculatory state of a patient.

content and venous oxygen saturation.

As a result of material like adrenalin, thrombin, and angiotensin II binding to receptors found in abluminal vascular smooth muscle cells, calcium entry into the cell is activated and due to the inositol triphosphate (IP3) pathway, endothelin released into the subendothelial interstitial areas causes the better-known vasoconstriction effect [17]. In situations where vasodilator materials pass through endothelial cells with increased permeability outside of the vein, the vasodilator effect reverses and may cause vasoconstriction.

Specific receptor expression available in endothelial and smooth muscle tissue found in the vein structures of organs affect agonist concentration and provide vasoactive material to luminal and abluminal vein structures affecting the concentration or dilatation response [3].

In 1922, August Krogh et al. first defined vasodilatation occurring due to the chemical stimulus. In 1971, Siggins and Weitsen showed that vasodilatation was caused by cholinergic stimulation. Khayutin et al. in 1991 showed that vasodilatation occurred due to myelin nerve stimulus. In 1959, Hilton showed that communication present between the smooth muscle cells found in the vascular walls was effective on vasodilatation.

Gap junctions are structures formed by two half channels completing each other with nearly 9 nm size, allowing transfer between cells of ions and molecules with weight lower than 1 kDa isolated from the extracellular environment and linking two neighbouring cells. Just as gap junctions form between the same type of cells (endothelium-endothelium, smooth muscle-smooth muscle, etc.), they may also form between different cells (myoendothelial gap junctions). The channels allow transfer between cells of electrical stimuli and calcium [18].

Each half of gap junctions found in vein structures contain six connexins (Cx) proteins (Cx39, Cx40, Cx43, Cx45) [19]. Each connexin protein has effects with different clinical results [20].

In development-linked vasodilatation, each agonist has a different effect mechanism, with the best-described effect mechanism belonging to the agonist acetylcholine. When acetylcholine binds to a G protein-dependent muscarinic receptor, inositol triphosphate phosphorylation develops causing calcium release from endothelial endoplasmic reticulum [21, 22]. Simultaneously, calcium-dependent potassium channels open leading to hyperpolarization development in the cell [23]. After this flow, vasodilatation develops causing closure of voltage-dependent calcium channels within endothelial and vein smooth muscle cells [24]. At the same time, ion flows are communicated between cells via gap junctions with vasodilatation spreading distal and proximal to the point of acetylcholine binding [2].

Pericytes found in venules have regulatory effects on proliferation, differentiation and contractility of endothelial cells. During new vein creation, in situations where the endothelial layer is developing with tube shape contacts pericytes, endothelial growth and proliferation are suppressed, and maturation of the endothelial basal membrane structure is ensured [25, 26].

In situations with low oxygen levels or pH, ATP molecules released from erythrocytes found in microcirculation cause vasodilatation while haemoglobin molecules occurring with erythrocyte fragmentation bind to NO causing the development of NO-dependent vasodilatation.

During hyperoxia the reactive oxygen radicals prevent nitric oxide-mediated vasodilatation; on the other hand, vascoconstrictor effect results in low tissue blood flow [27]. In addition, synthesis of the vasodilator prostaglandin is reduced while synthesis of the vasoconstrictor prostaglandin (and endothelin-1) is increased [28].
