**7. Microcirculation and disease**

### **7.1. Microcirculatory dysfunction**

Microcirculation plays a critical role in the physiological process such as oxygen supply to tissues and nutritional exchange and has a key role in modulation of inflammation and coagulation. These functions are mainly controlled by endothelial cells, which produce biologic signals to regulate local blood flow, cell adhesion, permeability, and coagulation activation. The most important function of the microcirculation is the regulation of flow within the different organs [43].

Microcirculation, in general, provides sufficient oxygen distribution to meet the oxygen demands of every cell within an organ. A regulatory mechanism with several signalling pathways allows microcirculatory flow to occur independently of changes in systemic blood pressure; this mechanism is called autoregulation. Perfusion of capillaries increases due to the vasodilation of terminal arterioles, which causes a decrease in the number of recruited capillaries. These capillaries are mainly under local control, which is possible because endothelial cells sense metabolic and physical signals, and respond to them by modulating arteriolar smooth muscle cell tone. In this process, nitric oxide (NO), which is produced by endothelial cells, is one of the components in the exertion of this process [44].

physiological regulatory mechanism of microcirculation. In that case, red blood cells become less deformable and more easily aggregate with endothelial cells during sepsis [47, 49].

Microcirculation and Hyperbaric Oxygen Treatment http://dx.doi.org/10.5772/intechopen.75609 59

During sepsis, the percentage of activated neutrophils with increased adhesion molecules generate reactive oxygen species and inflammatory soluble factors that directly disrupt microcirculatory structures, such as the endothelial glycocalyx. Oxidative stress causes changes in endothelial glycocalyx structure. Permanent glycocalyx degradation leads to loss of integrity of adherens junctions and increased paracellular permeability with the following break of endothelial barrier function, which results in fluid leakage from the intravascular space and causes tissue oedema. Afterwards, accumulation of water in tissues leads to tissue hypoxia. In sepsis, endothelial glycocalyx degradation is associated with sepsis-related clinical conditions such as acute lung injury and cardiovascular dysfunction as a consequence of microcirculation dysfunction. Also, glycocalyx degradation contributes to the enhanced expression of adhesion molecules with increased leukocyte trafficking and shift towards the procoagulant state. Prothrombotic effect further contributes the adhesion of red blood cells, leukocytes, and platelets to the vascular endothelium, which causes vascular microthrombosis. The activation of coagulation pathways results in capillary obstruction by fibrin clots secondary to dissemi-

The microcirculation is important for the normal delivery of oxygen to vital organs. The type and phase of critical illness define the degree of microcirculatory resuscitation required. It is important to recruit the microcirculation due to heterogeneous nature of the microvascular alterations. Fluid resuscitation and vasoactive agents are one of the main therapies for the hemodynamic resuscitation that aims to restore the circulating volume, and increasing the cardiac output and arterial blood pressure in shock patients and play a critical role with the goal of improving tissue perfusion. Individual responses to vasopressors may change, but the microvascular response to vasopressors appears to be dependent on the basal condition of the microcirculation [50]. Fluid resuscitation improves microcirculatory blood flow. The mechanisms by which fluids may improve the microcirculation are not well understood but may be related to restoring circulatory volume which increases perfusion pressure and causes local vasodilation, or modulates interactions between the endothelium and circulating

Hypertonic saline (HTS) is a potential solution to cure the microcirculation of traumatic haemorrhagic shock. HTS improves intestinal perfusion associated with arteriolar vasodilation of distal premucosal arterioles, decreases endothelial oedema and prevents leukocyte adhesion to postcapillary venules. To restore capillary density, a new approach to fluid resuscitation is based on the fluid with high viscosity to increase plasma viscosity and NO production causing microcirculatory vasodilation with resulting capillary recruitment. At the same time, vasopressor agents may maintain tissue perfusion in the presence of life-threatening hypotension in haemorrhagic shock, even if fluid dilatation is in progress and hypovolemia

nated intravascular coagulation [44, 47].

cells to decrease microvascular blood viscosity [46, 48, 49].

has not yet been corrected [49].

**7.2. Treatment**

In the pathophysiology of sepsis and septic shock, the microcirculation is the basic region of the circulatory system, in which main components are arterioles, venules, shunts, and capillaries. The structures in the microcirculation system are capable of contraction, except capillaries. Capillaries are made of endothelial cells alone, without contractile structures. Microcirculatory dysfunction may arise as a result of several factors such as endothelial dysfunction, leukocyte-endothelium interactions, coagulation and inflammatory disorders, and functional shunting that may occur during sepsis which can affect capillaries to change hemodynamics [43, 44].

Microcirculatory changes during sepsis include various mechanisms such as redistribution of blood flow from the skin and the splanchnic area to brain or heart, or with endothelial activation and injury which results with the loss of the glycocalyx around endothelium. Increased microvascular permeability with capillary damage then causes oedema formation and hypovolemia. And also, secondary capillary plugging comes out with decreased RBC deformability and increased leukocyte adhesion to the endothelial surface. On the other hand, production of reactive oxygen species (ROS) disturbs microcirculatory structures, cellular interactions, and haemostasis. Overall, these alterations contribute to a reduction in decreased functional capillary density, the progress of various abnormalities in microcirculatory blood flow, and the loss of main vasoregulation in most vascular beds. These alterations terminate with a disrupted regulation of local oxygen delivery, which turns into the fast initiation of tissue hypoxia [44, 47].

Proinflammatory cytokines become dominant in the early stages of sepsis to eliminate the pathogen. However, proinflammatory responses in sepsis generate an intense response that impairs the microcirculation. In this stage, most of the cellular components of the microcirculation, such as endothelial cells, smooth muscle cells, platelets, leukocytes, and red blood cells are affected. Increased number of interrupted capillaries results with microcirculatory dysfunction which appears to have prognostic significance in sepsis, as the severity of initial microcirculatory imbalance in the early resuscitation phase of therapy [45, 46].

In sepsis, NO synthase (iNOS) which heterogeneously expressed in various vascular beds, causes pathological shunts. Therefore, iNOS-deficient areas become hypoperfused. Furthermore, increased production of reactive oxygen species interferes with NO formation by endothelial NOS and with formed NO, reducing its concentration. Also, during sepsis, red blood cells lose their ability to release vasodilators in the presence of hypoxia that impairs physiological regulatory mechanism of microcirculation. In that case, red blood cells become less deformable and more easily aggregate with endothelial cells during sepsis [47, 49].

During sepsis, the percentage of activated neutrophils with increased adhesion molecules generate reactive oxygen species and inflammatory soluble factors that directly disrupt microcirculatory structures, such as the endothelial glycocalyx. Oxidative stress causes changes in endothelial glycocalyx structure. Permanent glycocalyx degradation leads to loss of integrity of adherens junctions and increased paracellular permeability with the following break of endothelial barrier function, which results in fluid leakage from the intravascular space and causes tissue oedema. Afterwards, accumulation of water in tissues leads to tissue hypoxia.

In sepsis, endothelial glycocalyx degradation is associated with sepsis-related clinical conditions such as acute lung injury and cardiovascular dysfunction as a consequence of microcirculation dysfunction. Also, glycocalyx degradation contributes to the enhanced expression of adhesion molecules with increased leukocyte trafficking and shift towards the procoagulant state. Prothrombotic effect further contributes the adhesion of red blood cells, leukocytes, and platelets to the vascular endothelium, which causes vascular microthrombosis. The activation of coagulation pathways results in capillary obstruction by fibrin clots secondary to disseminated intravascular coagulation [44, 47].

### **7.2. Treatment**

Microcirculation, in general, provides sufficient oxygen distribution to meet the oxygen demands of every cell within an organ. A regulatory mechanism with several signalling pathways allows microcirculatory flow to occur independently of changes in systemic blood pressure; this mechanism is called autoregulation. Perfusion of capillaries increases due to the vasodilation of terminal arterioles, which causes a decrease in the number of recruited capillaries. These capillaries are mainly under local control, which is possible because endothelial cells sense metabolic and physical signals, and respond to them by modulating arteriolar smooth muscle cell tone. In this process, nitric oxide (NO), which is produced by endothelial

In the pathophysiology of sepsis and septic shock, the microcirculation is the basic region of the circulatory system, in which main components are arterioles, venules, shunts, and capillaries. The structures in the microcirculation system are capable of contraction, except capillaries. Capillaries are made of endothelial cells alone, without contractile structures. Microcirculatory dysfunction may arise as a result of several factors such as endothelial dysfunction, leukocyte-endothelium interactions, coagulation and inflammatory disorders, and functional shunting that may occur during sepsis which can affect capillaries to change hemo-

Microcirculatory changes during sepsis include various mechanisms such as redistribution of blood flow from the skin and the splanchnic area to brain or heart, or with endothelial activation and injury which results with the loss of the glycocalyx around endothelium. Increased microvascular permeability with capillary damage then causes oedema formation and hypovolemia. And also, secondary capillary plugging comes out with decreased RBC deformability and increased leukocyte adhesion to the endothelial surface. On the other hand, production of reactive oxygen species (ROS) disturbs microcirculatory structures, cellular interactions, and haemostasis. Overall, these alterations contribute to a reduction in decreased functional capillary density, the progress of various abnormalities in microcirculatory blood flow, and the loss of main vasoregulation in most vascular beds. These alterations terminate with a disrupted regulation of local oxygen delivery, which turns into the fast initiation of tissue

Proinflammatory cytokines become dominant in the early stages of sepsis to eliminate the pathogen. However, proinflammatory responses in sepsis generate an intense response that impairs the microcirculation. In this stage, most of the cellular components of the microcirculation, such as endothelial cells, smooth muscle cells, platelets, leukocytes, and red blood cells are affected. Increased number of interrupted capillaries results with microcirculatory dysfunction which appears to have prognostic significance in sepsis, as the severity of

In sepsis, NO synthase (iNOS) which heterogeneously expressed in various vascular beds, causes pathological shunts. Therefore, iNOS-deficient areas become hypoperfused. Furthermore, increased production of reactive oxygen species interferes with NO formation by endothelial NOS and with formed NO, reducing its concentration. Also, during sepsis, red blood cells lose their ability to release vasodilators in the presence of hypoxia that impairs

initial microcirculatory imbalance in the early resuscitation phase of therapy [45, 46].

cells, is one of the components in the exertion of this process [44].

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

dynamics [43, 44].

hypoxia [44, 47].

The microcirculation is important for the normal delivery of oxygen to vital organs. The type and phase of critical illness define the degree of microcirculatory resuscitation required. It is important to recruit the microcirculation due to heterogeneous nature of the microvascular alterations. Fluid resuscitation and vasoactive agents are one of the main therapies for the hemodynamic resuscitation that aims to restore the circulating volume, and increasing the cardiac output and arterial blood pressure in shock patients and play a critical role with the goal of improving tissue perfusion. Individual responses to vasopressors may change, but the microvascular response to vasopressors appears to be dependent on the basal condition of the microcirculation [50]. Fluid resuscitation improves microcirculatory blood flow. The mechanisms by which fluids may improve the microcirculation are not well understood but may be related to restoring circulatory volume which increases perfusion pressure and causes local vasodilation, or modulates interactions between the endothelium and circulating cells to decrease microvascular blood viscosity [46, 48, 49].

Hypertonic saline (HTS) is a potential solution to cure the microcirculation of traumatic haemorrhagic shock. HTS improves intestinal perfusion associated with arteriolar vasodilation of distal premucosal arterioles, decreases endothelial oedema and prevents leukocyte adhesion to postcapillary venules. To restore capillary density, a new approach to fluid resuscitation is based on the fluid with high viscosity to increase plasma viscosity and NO production causing microcirculatory vasodilation with resulting capillary recruitment. At the same time, vasopressor agents may maintain tissue perfusion in the presence of life-threatening hypotension in haemorrhagic shock, even if fluid dilatation is in progress and hypovolemia has not yet been corrected [49].

The effects of red blood cell transfusions also seem to be quite variable. One of the other commonly used therapy is transfusions of red blood cells (RBC), which is used in critically ill patients to restore oxygen-carrying capacity. But, transfusion decisions are based on serum haemoglobin levels, and it is difficult to notice because normal microvascular haematocrit is much lower than systemic values. Although the beneficial effect of RBC transfusions over microcirculatory parameters in septic patients is still not clear, RBC transfusions are effective in improving tissue oxygen transport by promoting RBC delivery to the microcirculation [50].

microcirculation independently from systemic hemodynamic parameters which is a key therapeutic target in septic shock patients. [57]. Some of well-documented HBOT mechanisms in sepsis treatment are attenuation of inflammatory mediators and free radicals, reduction of bacterial proliferation, inhibition of lipopolysaccharide-induced acute lung injury and enabling neutrophils to kill bacteria with oxygen dependent mechanisms. It was also proposed that HBOT can delay onset of sepsis and may boost the effect of antibiotics [58].

Microcirculation and Hyperbaric Oxygen Treatment http://dx.doi.org/10.5772/intechopen.75609 61

Meningococcal sepsis can cause purpura fulminans which occurs by the formation of thrombi haemorrhages and occlusion of dermal vessels and often a life-threatening condition [59].. Clinically, it was shown that HBOT is effective in meningococcal sepsis which is complicated with the necrotic tissue [60]. HBOT with its immunostimulatory, neovascularity, and bacteri-

In conclusion, microcirculation plays a critical role in the physiological process such as oxygen supply to vital organs, nutritional exchange and modulation of inflammation. The most important function of the microcirculation is the regulation of flow within the different organs. Microcirculatory changes include various mechanisms such as redistribution of blood flow from the skin and the splanchnic area to brain or heart, or with endothelial activation and injury which results with the loss of the glycocalyx around endothelium. The assessment of the microcirculation enables us for the early detection of possible deterioration and potential organ dysfunctions. Microcirculatory blood flow can be detected at the bedside by different techniques which are simple and gives quantitative data. Fluid resuscitation and vasoactive agents are one of the main therapies for the hemodynamic resuscitation that aims to restore the circulating volume, and increasing the cardiac output and arterial blood pressure and play a critical role with the goal of improving tissue perfusion. HBOT inhibits replicating, spreading of anaerobic and some other bacteria and is a clinical treatment adjunct to traditional surgery and antibiotic therapy for the deadly serious necrotizing infection. Also, HBOT applied in acute ischemic stroke, femoral head necrosis and carbon monoxide intoxication aim to increase oxygen supply to the ischemic tissue and to reduce the extent of irreversible tissue damage.

and Reyhan Arslantas3

1 Marmara University, Department of Anesthesiology and Reanimation, Istanbul, Turkey

3 Health Sciences University, Kartal Dr. Lutfi Kırdar Training and Research Hospital,

2 Sutcu Imam University, Department of Anestehesiology and Reanimation,

cidal effect can be adjunct treatment for non-healing ulcers and problematic wounds.

**8. Conclusion**

**Author details**

Kahramanmaras, Turkey

\*, Omer Faruk Boran<sup>2</sup>

\*Address all correspondence to: gulfethi@gmail.com

Anesthesiology and Reanimation Clinics, Istanbul, Turkey

Fethi Gul<sup>1</sup>

Fluid resuscitation in combination with vasoactive and inotropic support is effective in improving the microcirculation. Recruitment of the microcirculation can be achieved with combination therapies. An anti-inflammatory agent or specific iNOS inhibitor can reduce pathological shunting and improve blood flow to recruit weak microcirculatory units. The effects can be seen in the early phase of sepsis, within 24 h of diagnosis, but if cardiac output is increased, no improvement will be made after 48 h [51].

The use of steroids in sepsis may provide a clinical benefit in modulating the systemic inflammatory response. It can preserve the endothelial glycocalyx and attenuate rolling of leucocytes to the endothelium, may improve endothelial function and thereby ameliorate the distributive defect [52].

Statins, which are cholesterol-lowering agents also have pleiotropic effects and have an antiinflammatory and anti-oxidant activity during sepsis. They increase levels of eNOS, with the down-regulation of iNOS, so this regulation of NOS increases NO levels, restoring the autoregulatory functions [53].

Vasodilator substances may have a role to restore the microcirculation and decrease the effect of excessive vasoconstriction which causes decreased vascular density and stopped-flow capillaries. In a research, it was reported that nitroglycerin administration rapidly improved the microcirculation [54].

In haemorrhagic shock, reducing the blood flow to the microvascular units may prevent hypoxia. This downregulation of cellular metabolism is called conformance or hibernation. However, increase in lactate level during the acute phase of haemorrhagic shock indicates the limits of this adaptative metabolic downregulation. The critical factor in microvascular regulation to meet oxygen supply is the local regulation of arteriolar tone. Many mechanisms contribute to the local regulation of arteriolar tone, which includes response to myogenic response, shear-dependent response, and tissue metabolic response. During haemorrhagic shock, the decrease in DO2 reduces the generation of adenosine 5′ triphosphate (ATP) and adenosine 5′ diphosphate (ADP) which results in the accumulation of ADP and its degradation products. CO2 is a strong vasodilator, which accumulates when there is an increase in cellular metabolism or reduced clearance of CO2 during tissue hypoperfusion. In haemorrhagic shock, the therapeutic precedence is to stop the bleeding and to prevent the increase of bleeding. Fluid resuscitation may promote coagulopathy by diluting coagulation factors [55, 56].

Reduced microvascular perfusion is a characteristic feature of sepsis and implicated in organ dysfunction with multiple organ failure. Hyperbaric oxygen (HBO) has potentially beneficial effects for the microcirculation improvement in sepsis . It was shown that HBOT improves microcirculation independently from systemic hemodynamic parameters which is a key therapeutic target in septic shock patients. [57]. Some of well-documented HBOT mechanisms in sepsis treatment are attenuation of inflammatory mediators and free radicals, reduction of bacterial proliferation, inhibition of lipopolysaccharide-induced acute lung injury and enabling neutrophils to kill bacteria with oxygen dependent mechanisms. It was also proposed that HBOT can delay onset of sepsis and may boost the effect of antibiotics [58].

Meningococcal sepsis can cause purpura fulminans which occurs by the formation of thrombi haemorrhages and occlusion of dermal vessels and often a life-threatening condition [59].. Clinically, it was shown that HBOT is effective in meningococcal sepsis which is complicated with the necrotic tissue [60]. HBOT with its immunostimulatory, neovascularity, and bactericidal effect can be adjunct treatment for non-healing ulcers and problematic wounds.
