**8. Physiological shunt and dead space**

The venous shunt reduces the PaO2 and SpO2 foreseeably, but severe hypoxemia develops when the accessible oxygen stores are exhausted. However, many patients with venous shunts also have a reduced FRC (e.g., pulmonary edema), which will accelerate the onset of hypoxia.

#### **8.1. Physiopathological responses to hypoxia**

Heart attacks, stroke, and cancer have become the most common causes of death in the twenty-first century, as the average age in many countries around the world is constantly increasing. The causes of these diseases are many and varied; it indicates genetic predisposition and environmental effects. But limited oxygen is a common feature that is contributing to the development of these pathological conditions all around. However, cells and organisms can trigger adaptive responses aimed at helping them cope with these threats to hypoxic conditions. Under this heading, the role of hypoxin in three pathological conditions consisting of myocardial, cerebral ischemia, and tumorigenesis will be briefly explained. The ability to sustain oxygen homeostasis is crucial for survival of all vertebrate species. For the O<sup>2</sup> presentation, correct forming of complex platform such as entry (lungs), transport vehicles (erythrocytes), motorways and secondary roads (vasculature), and repulsive force (heart) during development and regulations in organism entry form the basis for oxygen homeostasis.

#### **8.2. Physiological responses to hypoxia**

#### *8.2.1. Systemic responses*

hypoxemia that is currently developing. Moreover, after a while, it does not prevent continuous development of hypercapnia, which is life threatening and acidosis related to hypercapnia.

When airway obstruction is relieved during apnea, there is a flow of gas through the pres-

prolongation of the duration of the apnea. If airway obstruction is relieved with 100% oxygen, the patient is likely to have a temporary improvement in hemoglobin oxygen desaturation,

The prominence of hemoglobin is not that it is an oxygen storage but it is an efficient oxygen transport from the lungs to the tissues. Anemia causes a small decrease in the time of critical hypoxia; however, this effect will also be more pronounced in patients with reduced FRC.

Metabolic rate has a simple and predictable effect on the rate of oxygen uptake and hence the duration of critical hypoxia. Increasing the oxygen consumption from 250 to 400 mL/min

when the accessible oxygen stores are exhausted. However, many patients with venous shunts also have a reduced FRC (e.g., pulmonary edema), which will accelerate the onset of hypoxia.

Heart attacks, stroke, and cancer have become the most common causes of death in the twenty-first century, as the average age in many countries around the world is constantly increasing. The causes of these diseases are many and varied; it indicates genetic predisposition and environmental effects. But limited oxygen is a common feature that is contributing to the development of these pathological conditions all around. However, cells and organisms can trigger adaptive responses aimed at helping them cope with these threats to hypoxic conditions. Under this heading, the role of hypoxin in three pathological conditions consisting of myocardial, cerebral ischemia, and tumorigenesis will be briefly explained. The ability to

to increase from 40 to 50% [126].

and SpO2

even though the tidal volume is not maintained and inspired oxygen volume is small.

during this one passive inhalation saves time to save the

foreseeably, but severe hypoxemia develops

during this one-time passive inhalation may lead to a significant

**5. Reoxygenation**

38 Tracheal Intubation

**7. Metabolic rate**

reduces the time for SpO<sup>2</sup>

**8. Physiological shunt and dead space**

**8.1. Physiopathological responses to hypoxia**

The venous shunt reduces the PaO2

sureless thorax. Securing a high FiO<sup>2</sup>

**6. Hemoglobin concentration**

airway. Securing a high FiO<sup>2</sup>

Hypoxia and hyperoxia are detected by specialized chemoreceptor cells. In cases where the use of O<sup>2</sup> is impaired, chemoreceptor systems rapidly change blood circulation as well as pulmonary ventilation and perfusion to optimize O<sup>2</sup> delivery to tissues. This process is based on the direct response of the neuroepithelial bodies present in the airway to the specialized chemoreceptor cells, such as arterial circulation carotid bodies, and the hypoxia of vascular smooth muscle cells.

#### *8.2.2. Vascular smooth muscle cells*

While the peripheral vein are enlarged in response to low oxygen, the veins in the pulmonary vein narrows in order to achieve ventilation-perfusion matching by removing blood from areas where ventilation is worse [127]. Hypoxic pulmonary vasoconstriction is a rapid response in the pulmonary arteries and venules. It is abundant in small resistance arteries. Pulmonary vein is an intrinsic feature of the vein smooth muscles and begins with the inhibition of one or several of the various K<sup>+</sup> channels that regulate the membrane potential [128]. The resulting depolarization activates voltage-gated Ca+2 channels, and activation of the channels increases the systolic calcium level and leads to myocyte constriction (**Figure 5A**). While K<sup>+</sup> channels are the effects of hypoxic pulmonary vasoconstriction, it does not known that whether they are intrinsically O2 -sensitive or under the control of an actual O<sup>2</sup> receptor. Hypoxic vasodilatation is another rapid response that increases blood perfusion in O<sup>2</sup> -deprived tissues. This is especially indicated in coronary and cerebral vessels. Hypoxic vasodilation is mediated in part by K-ATP channels opened in response to hypoxia-induced ATP reduction in vascular smooth muscle cells (**Figure 5B**) [129].

**Figure 5.** Schematic representation of the response of vascular smooth muscle cells to hypoxia. (A) Pulmonary smooth muscle cells and (B) peripheral smooth muscle cells [129].

However, there are other O<sup>2</sup> -sensitive mechanisms that most likely function by regulating the entry of Ca+2 into the cell.

phosphate bonds in normal cells. Electron transport into O2

process is known as oxidative phosphorylation.

while phosphorylation is less affected [133, 134].

tory mechanisms at the level of translation initiation [139].

activation of phosphofructokinase enhances.

*8.2.6. Adaptation to hypoxia*

 is tightly bound by ATP synthesis. Electron transport is carried out via protein-bound redox centers to complex III then (Co-enzyme Q-cytochrome c reductase) and complex IV from complex I (NADH-coenzyme Q reductase) or II (succinate-coenzyme Q reductase) and forms an electrochemical H + gradient in the inner membrane of the mitochondria. This gradient is used for ATP synthesis by complex V (ATP synthase) after electrochemical gradient: this

Studies on isolated mitochondria have shown that the basic effect of decreasing O<sup>2</sup>

chondrial respiration is inhibition in the respiratory chain and increase in proton leakiness

Hypoxia adaptation at the cellular level is accomplished by increasing the efficiency of the energy-producing pathways in a basically increased anaerobic glycolysis activity, while reducing energy consuming processes [135]. Ion-motive ATPase and protein synthesis are predominant processes in energy consumption in cells at standard metabolic rate, producing over 90% of ATP consumption in mouse skeleton and 66% in mouse thyocytes [136]. Hepatocyte studies have shown that protein synthesis is largely inhibited in response to hypoxia [137]. Buttgereit and Brand [138] have shown that ATP-consuming processes are in fact organized in a hierarchy, protein synthesis and RNA/DNA synthesis are the first inhibitory processes when energy becomes limited, and Na/K pump and Ca cycle have the highest priority. This phenomenon, also known as oxygen adaptation, involves very precise regula-

Hypoxic cells turn to glycolysis to meet energy needs. Oxygen-dependent mitochondrial respiration from two pathways of ATP production lowers oxygenation than oxidative phosphorylation in oxygen-independent glycolytic ATP production. In the presence of sufficient glucose, glycolysis may continue to produce ATP, depending on the increased activity of glycolytic enzymes. Phosphofructokinase is the major regulator that controls carbon flux by glycolysis. It is allosterically activated by ADP and AMP and inhibited by ATP; in this way, the rate of glycolysis is regulated according to the energy requirement. However, the most potent allosteric activator is fructose-2, 6-biphosphate [140]. The synthesis and degradation of the fructose-2, 6-biphosphatase are dependent on a single enzyme (6-phosphofluoro-2-kinase/ fructose-2, 6-biphosphate [PFK-2]). This enzyme is regulated within minutes by phosphorylation via AMP-activated protein kinase (AMPK) [141], but the expression is also enhanced by transcriptional activation via hypoxia-induced factor-1 (HIF-1) [142]. AMPK phosphorylates PFK-2 in a single site resulting in an increase in the Vmax of kinase activity, thus the allosteric

The active kinase opens the ATP-producing catabolic pathways and closes the ATP-consuming anabolic pathways [143, 144]. This acute direct phosphorylation is chronically provided by gene expression. Phosphorylation of PFK-2 is an example of this. AMPK activation has been reported to transport glucose-transporter Glut-4 to the plasma membrane, resulting in glucose uptake. Glut-4 increases the expression of mitochondrial enzymes that play a role in the

FADH<sup>2</sup>

in the oxidation of NADH and

http://dx.doi.org/10.5772/intechopen.76851

Pathophysiology of Apnea, Hypoxia, and Preoxygenation

on mito-

41

#### *8.2.3. Carotid and neuroepithelial bodies*

Airway neuroepithelial bodies perceive changes in oxygen inspired, while carotid objects perceive arterial oxygen levels. Both of them respond to low O<sup>2</sup> presentation by initiating activity in efferent chemosensory fibers to form cardiorespiratory regimens in the event of low O<sup>2</sup> [130, 131].

The induction activity of chemoreceptor cells by hypoxia/hypoxemia is dependent on the presence of membrane K<sup>+</sup> channels inhibited by low O2 . As a result, increased cytosolic calcium concentration causes activation of neurotransmitter release and efferent sensory fibers.

#### *8.2.4. Regulation of the cellular metabolism*

One of the most essential parameters that healthy cells have to maintain is high ATP content. Cell death occurs when the ATP production does not meet the energy required to sustain the ionic and osmotic balance. When ATP levels fall, ion-motivated ATPase regeneration occurs, leading to membrane depolarization, Ca+2 flow into the cell from voltage-gated Ca+2 channels, and subsequent activation of calcium-dependent phospholipases and proteases. These events result in uncontrolled cell swelling, hydrolysis of the major cell components, and eventual cell necrosis (**Figure 6**) [132].

#### *8.2.5. Effects of hypoxia on mitochondria*

Oxygen deprivation is generally considered mitochondrial respiratory failure in the case of hypoxia or ischemia. In fact, mitochondria are the main source of molecules with high-energy

**Figure 6.** Schematic representation of the cascade leading to cell death when cells are exposed to severe hypoxia [132].

phosphate bonds in normal cells. Electron transport into O2 in the oxidation of NADH and FADH<sup>2</sup> is tightly bound by ATP synthesis. Electron transport is carried out via protein-bound redox centers to complex III then (Co-enzyme Q-cytochrome c reductase) and complex IV from complex I (NADH-coenzyme Q reductase) or II (succinate-coenzyme Q reductase) and forms an electrochemical H + gradient in the inner membrane of the mitochondria. This gradient is used for ATP synthesis by complex V (ATP synthase) after electrochemical gradient: this process is known as oxidative phosphorylation.

Studies on isolated mitochondria have shown that the basic effect of decreasing O<sup>2</sup> on mitochondrial respiration is inhibition in the respiratory chain and increase in proton leakiness while phosphorylation is less affected [133, 134].

#### *8.2.6. Adaptation to hypoxia*

However, there are other O<sup>2</sup>

*8.2.3. Carotid and neuroepithelial bodies*

the presence of membrane K<sup>+</sup>

necrosis (**Figure 6**) [132].

*8.2.4. Regulation of the cellular metabolism*

*8.2.5. Effects of hypoxia on mitochondria*

ceive arterial oxygen levels. Both of them respond to low O<sup>2</sup>

entry of Ca+2 into the cell.

[130, 131].

40 Tracheal Intubation

sensory fibers.


presentation by initiating activity

. As a result, increased cyto-

Airway neuroepithelial bodies perceive changes in oxygen inspired, while carotid objects per-

in efferent chemosensory fibers to form cardiorespiratory regimens in the event of low O<sup>2</sup>

The induction activity of chemoreceptor cells by hypoxia/hypoxemia is dependent on

channels inhibited by low O2

solic calcium concentration causes activation of neurotransmitter release and efferent

One of the most essential parameters that healthy cells have to maintain is high ATP content. Cell death occurs when the ATP production does not meet the energy required to sustain the ionic and osmotic balance. When ATP levels fall, ion-motivated ATPase regeneration occurs, leading to membrane depolarization, Ca+2 flow into the cell from voltage-gated Ca+2 channels, and subsequent activation of calcium-dependent phospholipases and proteases. These events result in uncontrolled cell swelling, hydrolysis of the major cell components, and eventual cell

Oxygen deprivation is generally considered mitochondrial respiratory failure in the case of hypoxia or ischemia. In fact, mitochondria are the main source of molecules with high-energy

**Figure 6.** Schematic representation of the cascade leading to cell death when cells are exposed to severe hypoxia [132].

Hypoxia adaptation at the cellular level is accomplished by increasing the efficiency of the energy-producing pathways in a basically increased anaerobic glycolysis activity, while reducing energy consuming processes [135]. Ion-motive ATPase and protein synthesis are predominant processes in energy consumption in cells at standard metabolic rate, producing over 90% of ATP consumption in mouse skeleton and 66% in mouse thyocytes [136]. Hepatocyte studies have shown that protein synthesis is largely inhibited in response to hypoxia [137]. Buttgereit and Brand [138] have shown that ATP-consuming processes are in fact organized in a hierarchy, protein synthesis and RNA/DNA synthesis are the first inhibitory processes when energy becomes limited, and Na/K pump and Ca cycle have the highest priority. This phenomenon, also known as oxygen adaptation, involves very precise regulatory mechanisms at the level of translation initiation [139].

Hypoxic cells turn to glycolysis to meet energy needs. Oxygen-dependent mitochondrial respiration from two pathways of ATP production lowers oxygenation than oxidative phosphorylation in oxygen-independent glycolytic ATP production. In the presence of sufficient glucose, glycolysis may continue to produce ATP, depending on the increased activity of glycolytic enzymes. Phosphofructokinase is the major regulator that controls carbon flux by glycolysis. It is allosterically activated by ADP and AMP and inhibited by ATP; in this way, the rate of glycolysis is regulated according to the energy requirement. However, the most potent allosteric activator is fructose-2, 6-biphosphate [140]. The synthesis and degradation of the fructose-2, 6-biphosphatase are dependent on a single enzyme (6-phosphofluoro-2-kinase/ fructose-2, 6-biphosphate [PFK-2]). This enzyme is regulated within minutes by phosphorylation via AMP-activated protein kinase (AMPK) [141], but the expression is also enhanced by transcriptional activation via hypoxia-induced factor-1 (HIF-1) [142]. AMPK phosphorylates PFK-2 in a single site resulting in an increase in the Vmax of kinase activity, thus the allosteric activation of phosphofructokinase enhances.

The active kinase opens the ATP-producing catabolic pathways and closes the ATP-consuming anabolic pathways [143, 144]. This acute direct phosphorylation is chronically provided by gene expression. Phosphorylation of PFK-2 is an example of this. AMPK activation has been reported to transport glucose-transporter Glut-4 to the plasma membrane, resulting in glucose uptake. Glut-4 increases the expression of mitochondrial enzymes that play a role in the long-term hexokinase and tricarboxylic acid cycle and in the respiratory chain. On the other hand, AMPK directly inhibits the expression of fatty acid, triglyceride, and sterol synthase and the expression of fatty acid synthase and gluconeogenesis enzymes [145].

by continuous VEGF synthesis. The interaction between HIF-1α and pVHL is regulated via the hydroxylation of two proline residues of HIF-1α with the prolyl hydroxylase enzyme. In the absence of oxygen, this enzyme is no longer active: unmodified prolyl-HIF-1α does not interact with pVHL and accumulates [148, 149]. The absolute oxygen requirement of this prolyl hydroxylase suggests that this enzyme may function as a direct oxygen sensor. Other pathways indicate that HIF-1α stabilization and/or synthesis is also dependent on the PI-3 kinase/Akt pathway in the case of hypoxia. The usage of PI-3 K inhibitors prevents accumulation of HIF-1 [150]. The increase in HIF-1α synthesis is also dependent on the PI-3 K/Akt pathway [151].

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43

HIF-1α stabilization is the first step in HIF-1 activation: For complete transcriptional activity, sufficient redox conditions, separation from chaperone HSP90, phosphorylation as well as coactivators such as CBP/p300 or SRC-1 are required [152, 153]. Hypoxia directly regulates the association of HIF-1α with the coactivator CBP/p300. Similarly to prolyl hydroxylase, it hydroxylates the HIF-1α carboxy-terminal transactivation site on Asn 803 of asparagyl hydroxylase, whose activity is tightly bound to the oxygen. This modification prevents the

HIF-1α is not only essential for a variety of physiological responses in chronic hypoxia but also for embryonic survival and cardiac and vascular development. Hif1a−/− mice are not viable: development of Hif1a−/− embryos arrests by day E9.0 and mice die by E10.5 [155, 156]. There is a marked regression of blood vessels in the cephalic region and replacement by a smaller number of enlarged vascular structures. Loss of pericyte support of the endothelium leading to vascular regression is probably responsible for these defects. Massive cell death in cephalic mesothelium was observed concurrent with the deterioration of the vessel development. Heart development in HIF-1α−/− embryos is also abnormal. In ARNT−/− mice, embryonic death probably occurs due to insufficiency of the embryonic component required for vascularization of placenta [157]. Observation of similar vascular abnormalities in HIF-1α and VGEF-deficient embryos suggests hypoxia-induced overexpression in VEGF for the develop-

Hypoxia due to deteriorated blood flow has detrimental effect on organ structure and function. This is especially true in prolapse (cerebral ischemia) and heart infarction (myocardial ischemia). Hypoxia also plays an important role in the regulation of tumor growth and metas-

High energy requirements compared to low energy reserves make the brain particularly susceptible to hypoxic conditions. Although the brain produces a small fraction of total

increase in cerebral blood flow. However, hypoxemia and ischemia in children suffering from severe asphyxia and in prolapse sufferers result in brain damage. Longer periods of

requirement in physiological conditions is met by a rapid and satisfactory

consumption.

tasis. Here, we describe the role of hypoxin in these three pathological conditions.

body weight (2%), it proportionally accounts for a large percentage of O<sup>2</sup>

association with CBP/p300 in the case of normoxia [154].

ment of the vascular system.

*8.2.9. Cerebral ischemia*

The increased O2

*8.2.8. Pathological responses to hypoxia*

#### *8.2.7. Regulation of the gene expression*

When faced with hypoxic difficulties, various responses are developed by cells and tissues:


Most of these processes take place very early with the onset of hypoxia and are caused by the activation of existing proteins; but in the long run, all of these responses are mediated by the upregulation of genes encoding key actors, for example:


HIF-1 is a heterodimeric factor consisting of HIF-1α and HIF-1β/ARNT. Both subunits belong to the Per-ARNT/Ahr-Sim family of bHLH transcription factors. While the HLH and PAS motifs play a role in dimerization, the main coil is the DNA-binding site. The HIF-1 [alpha] protein contains two transactivation regions at the C-terminus. ARNT is structurally expressed and is located in the nucleus. On the other hand, hypoxia accumulates when HIF-1α mRNA levels are constant in normoxia and hypoxia, and normoxide protein is rapidly destroyed. Normoxide targets the HIF-1α polyubiquitin and destroys the protozoa. In addition to the reduction of hypoxic synthesis of all proteins, ARNT and HIF-1α proteins are translocated efficiently due to the presence of the internal ribosome entry in the mRNA corresponding to the normoxia and hypoxia and normoxside [147].

HIF-1α contains an oxygen-dependent degradation site in which a highly conserved binding site for the tumor suppressor von Hippel Lindau protein (pVHL) is present. The pVHL targets a HIF-1α degradation to form a complex that activates the E3 ubiquitin ligase that ubiquitinates HIF-1α. Inactivation of pVHL is associated with von Hippel Lindau cancer syndrome. It prevents the binding of pVHL mutations to HIF-1α, leading to structural expression of this transcription factor and target genes. Such mutations probably increase angiogenesis potential by continuous VEGF synthesis. The interaction between HIF-1α and pVHL is regulated via the hydroxylation of two proline residues of HIF-1α with the prolyl hydroxylase enzyme. In the absence of oxygen, this enzyme is no longer active: unmodified prolyl-HIF-1α does not interact with pVHL and accumulates [148, 149]. The absolute oxygen requirement of this prolyl hydroxylase suggests that this enzyme may function as a direct oxygen sensor. Other pathways indicate that HIF-1α stabilization and/or synthesis is also dependent on the PI-3 kinase/Akt pathway in the case of hypoxia. The usage of PI-3 K inhibitors prevents accumulation of HIF-1 [150]. The increase in HIF-1α synthesis is also dependent on the PI-3 K/Akt pathway [151].

HIF-1α stabilization is the first step in HIF-1 activation: For complete transcriptional activity, sufficient redox conditions, separation from chaperone HSP90, phosphorylation as well as coactivators such as CBP/p300 or SRC-1 are required [152, 153]. Hypoxia directly regulates the association of HIF-1α with the coactivator CBP/p300. Similarly to prolyl hydroxylase, it hydroxylates the HIF-1α carboxy-terminal transactivation site on Asn 803 of asparagyl hydroxylase, whose activity is tightly bound to the oxygen. This modification prevents the association with CBP/p300 in the case of normoxia [154].

HIF-1α is not only essential for a variety of physiological responses in chronic hypoxia but also for embryonic survival and cardiac and vascular development. Hif1a−/− mice are not viable: development of Hif1a−/− embryos arrests by day E9.0 and mice die by E10.5 [155, 156]. There is a marked regression of blood vessels in the cephalic region and replacement by a smaller number of enlarged vascular structures. Loss of pericyte support of the endothelium leading to vascular regression is probably responsible for these defects. Massive cell death in cephalic mesothelium was observed concurrent with the deterioration of the vessel development. Heart development in HIF-1α−/− embryos is also abnormal. In ARNT−/− mice, embryonic death probably occurs due to insufficiency of the embryonic component required for vascularization of placenta [157]. Observation of similar vascular abnormalities in HIF-1α and VGEF-deficient embryos suggests hypoxia-induced overexpression in VEGF for the development of the vascular system.

#### *8.2.8. Pathological responses to hypoxia*

Hypoxia due to deteriorated blood flow has detrimental effect on organ structure and function. This is especially true in prolapse (cerebral ischemia) and heart infarction (myocardial ischemia). Hypoxia also plays an important role in the regulation of tumor growth and metastasis. Here, we describe the role of hypoxin in these three pathological conditions.

#### *8.2.9. Cerebral ischemia*

long-term hexokinase and tricarboxylic acid cycle and in the respiratory chain. On the other hand, AMPK directly inhibits the expression of fatty acid, triglyceride, and sterol synthase

When faced with hypoxic difficulties, various responses are developed by cells and tissues:

Most of these processes take place very early with the onset of hypoxia and are caused by the activation of existing proteins; but in the long run, all of these responses are mediated by the

• Tyrosine hydroxylase, which plays a role in dopamine synthesis in carotid body type I cells. • Glycolytic enzymes phosphoglycerate kinase 1, pyruvate kinase m, phosphofructokinase, aldolase A, glyceraldehyde 3-phosphate dehydrogenase enolase 1, and glucose carriers

• VEGF and PDGF to induce angiogenesis and NO synthase that increases vasodilatation • Transferrin receptors supporting erythrocyte production [146]. The transcriptional side is

HIF-1 is a heterodimeric factor consisting of HIF-1α and HIF-1β/ARNT. Both subunits belong to the Per-ARNT/Ahr-Sim family of bHLH transcription factors. While the HLH and PAS motifs play a role in dimerization, the main coil is the DNA-binding site. The HIF-1 [alpha] protein contains two transactivation regions at the C-terminus. ARNT is structurally expressed and is located in the nucleus. On the other hand, hypoxia accumulates when HIF-1α mRNA levels are constant in normoxia and hypoxia, and normoxide protein is rapidly destroyed. Normoxide targets the HIF-1α polyubiquitin and destroys the protozoa. In addition to the reduction of hypoxic synthesis of all proteins, ARNT and HIF-1α proteins are translocated efficiently due to the presence of the internal ribosome entry in the mRNA corresponding to

HIF-1α contains an oxygen-dependent degradation site in which a highly conserved binding site for the tumor suppressor von Hippel Lindau protein (pVHL) is present. The pVHL targets a HIF-1α degradation to form a complex that activates the E3 ubiquitin ligase that ubiquitinates HIF-1α. Inactivation of pVHL is associated with von Hippel Lindau cancer syndrome. It prevents the binding of pVHL mutations to HIF-1α, leading to structural expression of this transcription factor and target genes. Such mutations probably increase angiogenesis potential

and the expression of fatty acid synthase and gluconeogenesis enzymes [145].

transport capacity of blood.

*8.2.7. Regulation of the gene expression*

• Increased ventilation and heart rate

• Promotion of increased vascularization

largely mediated by the HIF-1 activity.

the normoxia and hypoxia and normoxside [147].

• Strengthening the O2

42 Tracheal Intubation

Glut-1 and Glut-4.

• Return from aerobic metabolism to anaerobic metabolism

upregulation of genes encoding key actors, for example:

High energy requirements compared to low energy reserves make the brain particularly susceptible to hypoxic conditions. Although the brain produces a small fraction of total body weight (2%), it proportionally accounts for a large percentage of O<sup>2</sup> consumption. The increased O2 requirement in physiological conditions is met by a rapid and satisfactory increase in cerebral blood flow. However, hypoxemia and ischemia in children suffering from severe asphyxia and in prolapse sufferers result in brain damage. Longer periods of hypoxia/ischemia lead to greater effects in the brain. The most sensitive areas appear to be the brain stem, hippocampus, and cerebral cortex. If the damage processes and eventually oxygenation is not restored, it becomes irreversible. Acute cell death is primarily caused by necrosis, but hypoxia also causes by late apoptosis. Although it is the only way to protect tissue, it should be noted that mainly reactive oxygen species reperfusion induces cell death through production and inflammatory cell infiltration. If the decrease in pO<sup>2</sup> is not too severe, it suppresses some of the cell functions; for example, proton synthesis and spontaneous electrical activity are suppressed and this condition is called penumbra, which is characterized with return when O2 is provided [158, 159].

*8.2.12. Determination of hypoxemia*

**Author details**

**References**

1994;**72**:3-4

1996;**51**:733-737

Ilknur Hatice Akbudak\* and Asli Mete

Pamukkale University, Denizli, Turkey

that they need to be administered from a tissue sample.

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

Minerva Anestesiologica. 2013;**79**:643-651

Tumor hypoxia is the strongest prognostic factor in various cancers. Hypoxic cells contribute to intrinsic radiation resistance. Apoptosis resistance and increased metastasis capacity are other contributing factors to this negative outcome. Therefore, the factors that aim to determine tumor oxygenation have serious clinical safety. A number of studies aim to identify a good hypoxia marker that can be used in immunomicroscopy studies [166]. The use of 2-nitromidazole specifically binding to hypoxic cells has been suggested; pimonidazole and EF5 are the best known of these. Reduction enzymes metabolize these drugs in the presence of oxygen, but when there is no oxygen they are converted to highly reactive free radical molecules that are covalently bound to protein and DNA. Subsequently, drug-protein binding may be detected by specific antibodies. Studies similar to the work of Evans and his colleagues showed the suitability of this method. However, these drugs have the disadvantage

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45

The discovery that HIF-1α specifically undergoes hypoxic upregulation and is rapidly destroyed in the presence of oxygen suggests that this protein may be an endogenous marker of this kind. Several studies examining HIF-1α as an endogenous hypoxia marker have confirmed the spatial association of HIF-1α with EF5 and pimonidazole [167]. It should be noted that the use of HIF-1α as a hypoxia marker is not easy because the level of HIF-1α is also

[1] Bourgain JL, Chastre J, Combes X, Orliaguet G. Oxygen arterial desaturation and upholding the oxygenation during intubation: Question 2. Societe Francaise d'Anesthesie et de

[2] Campbell IT, Beatty PC. Monitoring preoxygenation. British Journal of Anaesthesia.

[3] Lauscher P, Mirakaj V, Koenig K, Meier J. Why hyperoxia matters during acute anemia.

[4] Reber A, Engberg G, Wegenius G, Hedenstierna G. Lung aeration. The effect of preoxygenation and hyperoxygenation during total intravenous anaesthesia. Anaesthesia.

reanimation. Annales Françaises d'Anesthèsie et de Rèanimation. 2008;**27**:15-25

regulated by factors other than hypoxia, such as oncogenic mutations [168].

#### *8.2.10. Myocardial ischemia*

Acute coronary syndromes resulting from occlusion of one of the coronaries expose heart to ischemic conditions. If reperfusion is achieved after short ischemic periods (<20 minutes), it is reversible and not associated with necrosis development, but results in stunning phenomena. If the coronary occlusion duration goes beyond this point, a necrosis wave propagates from the subendocardium towards the subepicardium. After a few hours, reperfusion does not diminish the size of myocardial infarction.

Within seconds of cessation of blood flow energy metabolism shifts from mitochondrial respiration to anaerobic glycolysis. Concurrent active contractions are reduced and then terminated. Accumulation of lactate and protons in cardiomyocytes induces acidosis and osmotic load and subsequent cell edema. In addition, intracellular Ca+2 increases, probably due to the combined effect of Na<sup>+</sup> /Ca+2 modulators activated by cellular acidosis. If this happens, it will lead to cell necrosis [160]. To restore aerobic metabolism and to protect ischemic myocytes, it is necessary to restore the arterial flow. However, this situation itself increases the damage. This process is called ischemia-reperfusion injury. In the first few minutes of reperfusion, a large amount of released reactive oxygen radicals is a possible cause of this contractile failure.

#### *8.2.11. Tumor angiogenesis*

The onset of new vascularization in many primary tumors is defined as the angiogenic switch. Several key signaling events have been identified that involve immune/inflammatory responses and genetic mutations, but metabolic stress (hypoxia) is probably the most important of these factors [161, 162]. Tumor cells survive in the fluctuations of HIF-1 activation in oxygen tension. Various studies using HIF-1 mutant cells have shown that HIF-1 has profound effects on tumor biology. For example, tumors arising from embryonic stem cells with HIF-1α defect show abnormal vascularity and low growth rate [39]. Furthermore, HIF-1 is upregulated in a wide range of tumors, and there are important links between tumor grade, vascularization, and HIF-1α overexpression [163, 164]. This expression pattern suggests that tumor cells respond to hypoxia caused by HIF-1–mediated angiogenic protein expression. The VEGF is the strongest of these and its expression is regulated by HIF-1. In addition to promoting VEGF secretion, HIF-1 is also important for hypoxia adaptation of tumor cells [165].

#### *8.2.12. Determination of hypoxemia*

hypoxia/ischemia lead to greater effects in the brain. The most sensitive areas appear to be the brain stem, hippocampus, and cerebral cortex. If the damage processes and eventually oxygenation is not restored, it becomes irreversible. Acute cell death is primarily caused by necrosis, but hypoxia also causes by late apoptosis. Although it is the only way to protect tissue, it should be noted that mainly reactive oxygen species reperfusion induces cell

severe, it suppresses some of the cell functions; for example, proton synthesis and spontaneous electrical activity are suppressed and this condition is called penumbra, which is charac-

Acute coronary syndromes resulting from occlusion of one of the coronaries expose heart to ischemic conditions. If reperfusion is achieved after short ischemic periods (<20 minutes), it is reversible and not associated with necrosis development, but results in stunning phenomena. If the coronary occlusion duration goes beyond this point, a necrosis wave propagates from the subendocardium towards the subepicardium. After a few hours, reperfusion does not

Within seconds of cessation of blood flow energy metabolism shifts from mitochondrial respiration to anaerobic glycolysis. Concurrent active contractions are reduced and then terminated. Accumulation of lactate and protons in cardiomyocytes induces acidosis and osmotic load and subsequent cell edema. In addition, intracellular Ca+2 increases, probably

happens, it will lead to cell necrosis [160]. To restore aerobic metabolism and to protect ischemic myocytes, it is necessary to restore the arterial flow. However, this situation itself increases the damage. This process is called ischemia-reperfusion injury. In the first few minutes of reperfusion, a large amount of released reactive oxygen radicals is a possible

The onset of new vascularization in many primary tumors is defined as the angiogenic switch. Several key signaling events have been identified that involve immune/inflammatory responses and genetic mutations, but metabolic stress (hypoxia) is probably the most important of these factors [161, 162]. Tumor cells survive in the fluctuations of HIF-1 activation in oxygen tension. Various studies using HIF-1 mutant cells have shown that HIF-1 has profound effects on tumor biology. For example, tumors arising from embryonic stem cells with HIF-1α defect show abnormal vascularity and low growth rate [39]. Furthermore, HIF-1 is upregulated in a wide range of tumors, and there are important links between tumor grade, vascularization, and HIF-1α overexpression [163, 164]. This expression pattern suggests that tumor cells respond to hypoxia caused by HIF-1–mediated angiogenic protein expression. The VEGF is the strongest of these and its expression is regulated by HIF-1. In addition to promoting VEGF secretion, HIF-1 is also important for hypoxia adap-

/Ca+2 modulators activated by cellular acidosis. If this

is not too

death through production and inflammatory cell infiltration. If the decrease in pO<sup>2</sup>

is provided [158, 159].

terized with return when O2

diminish the size of myocardial infarction.

due to the combined effect of Na<sup>+</sup>

cause of this contractile failure.

*8.2.11. Tumor angiogenesis*

tation of tumor cells [165].

*8.2.10. Myocardial ischemia*

44 Tracheal Intubation

Tumor hypoxia is the strongest prognostic factor in various cancers. Hypoxic cells contribute to intrinsic radiation resistance. Apoptosis resistance and increased metastasis capacity are other contributing factors to this negative outcome. Therefore, the factors that aim to determine tumor oxygenation have serious clinical safety. A number of studies aim to identify a good hypoxia marker that can be used in immunomicroscopy studies [166]. The use of 2-nitromidazole specifically binding to hypoxic cells has been suggested; pimonidazole and EF5 are the best known of these. Reduction enzymes metabolize these drugs in the presence of oxygen, but when there is no oxygen they are converted to highly reactive free radical molecules that are covalently bound to protein and DNA. Subsequently, drug-protein binding may be detected by specific antibodies. Studies similar to the work of Evans and his colleagues showed the suitability of this method. However, these drugs have the disadvantage that they need to be administered from a tissue sample.

The discovery that HIF-1α specifically undergoes hypoxic upregulation and is rapidly destroyed in the presence of oxygen suggests that this protein may be an endogenous marker of this kind. Several studies examining HIF-1α as an endogenous hypoxia marker have confirmed the spatial association of HIF-1α with EF5 and pimonidazole [167]. It should be noted that the use of HIF-1α as a hypoxia marker is not easy because the level of HIF-1α is also regulated by factors other than hypoxia, such as oncogenic mutations [168].

## **Author details**

Ilknur Hatice Akbudak\* and Asli Mete \*Address all correspondence to: ilhakbudak@gmail.com Pamukkale University, Denizli, Turkey

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**Section 2**

**Endotracheal Intubation**

