HYPOXIA

One of the fundamental conditions of life of both cells and the organism is a
continuous energy production and consumption. In animals and humans, the sole
and universal source of this energy is easily recyclable using ATPase energy of
phosphate bonds of high-energy compounds, among which is dominated by the
ATP. The ATP production occurs during redox reactions involving carbohydrates
and fats (less proteins), which are the major substrates for oxidation. Set of
oxidation - reduction reactions of nutrients called biological oxidation. It should be
emphasized that in all aerobic organisms overwhelming amount of all produced in
the process of biological oxidation ATP is formed in mitochondria, in which there
is a conjugate with phosphorylation oxidation of substrates with the obligatory
participation of oxygen.

Consequently, to a normal ensure the cells with energy are required:

1. The sufficient amount of substrates (mainly transformation products of

carbohydrates and fats) and oxygen are delivered into mitochondria.

2. There is efficient utilization of substrates and oxygen, continuously was formed

a sufficient amount of ATP. In case of violation of the processes, noted in claim 1
and / or 2, takes place hypoxia necessarily accompanied by an energy deficit.

Hypoxia.

Hypoxia is a typical pathological process characterized by the development

of oxygen starvation of tissues resulting from insufficient supply of tissues with
oxygen or violation of oxygen utilization by cells. In fact, hypoxia results from
failure and / or inefficiency of biological oxidation that accompanied by energy
deficits.
It should be noted that hypoxia, which is often called oxygen starvation,
does not mean in all cases the reduction of oxygen partial pressure (pO2) in the
tissues. There are some forms of hypoxia, in which the pO2 in the tissues is normal
or even increased, but due to violations of oxygen utilization and emerging energy
shortage for this reason such conditions relate to hypoxia. Clinical manifestations
of different origin hypoxia characterized by great similarity.
Hypoxia - the most common of all the typical pathological processes - is
very common in clinical practice and is a pathogenetic basis and an essential
component of most diseases.
 The classification of hypoxia.

It is currently used classification of hypoxia, proposed by I.R. Petrov.

According to this classification hypoxia are divided into two major groups: 1)
exogenous hypoxia; 2) endogenous hypoxia.
Exogenous hypoxia occurs as a result of lowering the oxygen partial pressure
in the inspired air. It is divided into 2 types: 1) hypobaric, which is accompanied
by a decrease of the atmospheric pressure; 2) normobaric, at which the atmospheric
pressure is normal.
Endogenous hypoxia occurs from violations of the structure and function of
individual organs and systems. According to the etiopathogenetical principle
endogenous hypoxia divided into several types: 1) respiratory; 2) circulatory
(cardiovascular); 3) hemic (blood); 4) tissue (histotoxic); 5) mixed. In recent
years, the classification of Petrov was supplemented by an additional 2 types of
endogenous hypoxia: 1) substrate; 2) overload.
On the course there are the following types of hypoxia: 1) lightning -
develops within tens of seconds; 2) acute - develops within tens of minutes; 3)
subacute - develops within a few hours; 4) chronic - lasts weeks, months, years.
On the severity there are the following types of hypoxia: 1) easy; 2)
reasonable; 3) heavy; 4) critical.
On the prevalence distinguished: 1) a general or systemic hypoxia; 2) local
hypoxia, accompanied by the development of the process in a single organ or part
of organ.
Common manifestations of hypoxia are: 1) hypoxemia - a decrease of
oxygen tension and the percentage of oxyhemoglobin in the blood; 2) hypercapnia
- increase in tension of carbon dioxide in the blood; 3) cyanosis;

Etiology and pathogenesis of certain types of hypoxia.

Exogenous hypoxia.

Exogenous hypoxia occurs due to the decrease of the oxygen partial pressure
in the inspired air. There are two types - normobaric and hypobaric.
Exogenous hypobaric hypoxia develops with a total decrease of barometric
pressure and observed during elevations to high mountains or flying in
unpressurized aircraft without oxygen support systems (for example, on balloons
or at airplanes with the open cockpit).
Exogenous normobaric hypoxia develops at normal atmospheric barometric
pressure, but the decreased partial pressure of oxygen in the inspired air. Such
situations may occur while being in closed, poorly ventilated areas, working in
mines, faults in the oxygen support systems in the cockpits of the aerial vehicles,
submarines, after improper rescue breathing.
This type of hypoxia characterized by an oxygen partial pressure drop in the
alveoli and therefore slows down the process of oxygenation of hemoglobin in the
lungs, leading to a lower percentage of oxyhemoglobin and oxygen tension in the
blood. That is, there is a condition of hypoxemia. At the same time, increases the
content of reduced hemoglobin in the blood, accompanied by development of
cyanosis.
Decreases the difference between the levels of oxygen tension in the blood
and tissues, that leads to a slowing it enters to tissues.
The lowest oxygen tension at which still can be carried out the tissue
respiration is called critical. For arterial blood the critical oxygen tension
corresponds to 27-33 mmHg, for venous blood - 19 mmHg. In these conditions
increases the affinity of hemoglobin to oxygen, which is characterized by a shift
oxyhemoglobin dissociation curve to the left and leads to even more difficulties the
supply of oxygen to the tissues, thus forming a vicious circle.
Exogenous hypobaric hypoxia is the main link in the pathogenesis of such
nosological forms as altitude sickness and mountain sickness.
Altitude sickness got its name due to the fact that people are faced with it
during the development of the stratosphere. Notable disorders (primarily from the
CNS - euphoria, loss of critical attitude to its actions) already observed with
decreasing pO2 to 100 mmHg (normally 158 mmHg), which corresponds to an
altitude of about 3500 m. at pO2 of 50 - 55 mmHg. (corresponds to an altitude of
8000 - 8500 m above sea level), there is a loss of consciousness and there are
severe disorders that are incompatible with life.
Mountain sickness develops in most untrained and asthenical people
permanently living on the plains and climbing in the mountains. As a rule,
mountain sickness occurs when the height of over 4,500 meters. The height of
6000 meters above sea level is critical, because noted in this hypoxemia and
decreased amount of oxyhemoglobin to 64% can not be fully offset by protective
and adaptive reactions. Leading pathogenetic mechanisms of altitude sickness are
not only partial pressure of oxygen, but also carbon dioxide in the arterial blood,
and caused by this disturbances of acid - base status and development of tissue
hypoxia due to violation of tissue oxygen utilization.

The respiratory hypoxia.

 The respiratory hypoxia develops in various forms of respiratory failure,
which is accompanied by a decrease in blood oxygenation in the alveoli. Causes of
the respiratory hypoxia are:

1) Violation of alveolar ventilation, which, in its turn, may develop as a

result of:
a. dysfunctions of the lungs for obstructive (foreign substances in the
lumen of the upper respiratory tract, swelling of the mucous membranes of
the upper respiratory tract, spasm of bronchial smooth muscle tumors) and
restrictive (inflammation and congestion in the lungs, atelectasis,
pneumosclerosis, deficiency of surfactant) types;
b. violations of the integrity of the chest and the pleural cavity
(pneumothorax);
c. mobility disorders of the thorax (deformation of the ribs and the
spinal column, ossification of costal cartilage, pleural adhesions, ascites,
flatulence);
d. dysfunctions of the neuromuscular apparatus (intercostal neuralgia,
myositis, myasthenia, lesion of the diaphragm);
e. dysfunctions of the motoneurons of the spinal cord (spinal cord
injury, poliomyelitis, syringomyelia);
f. dysfunctions of the respiratory center (intoxication, trauma,
hemorrhages, ischemia).
2) Violation of the gas diffusion through the alveolar membrane with a
decrease in the respiratory surface of the lungs due to the decrease in the number of
functioning alveoli, including pulmonary collapse at deficiency of surfactant.
3) Violation of the pulmonary tissue perfusion with decreasing blood supply
of the lungs, including increase shunting of the venous blood into the arterial in the
lungs or heart pathology.
At hypoventilation reduces the supply of oxygen in the blood, which causes
a drop of oxygen tension in arterial blood, that is, the development of hypoxemia.
Reduces the amount of oxyhemoglobin. At the same time, increases content of
reduced hemoglobin. Hypoventilation accompanied by the development of
hypercapnia, which reduces the affinity of hemoglobin to oxygen, what is
manifested by shift of the oxyhemoglobin dissociation curve to the right. Decrease
of affinity of oxyhemoglobin to oxygen leads to difficulty the blood oxygenation in
the lungs.

Circulatory hypoxia
 Circulatory hypoxia is observed when circulatory disorders which leads to
insufficient blood supply to the tissues and thus to insufficient intake of oxygen to
the tissues. Two types of circulatory hypoxia are distinguished: systemic and local.

The system circulator hypoxia is developed when: 1) heart failure; 2) sharp

and chronic decrease in a vascular tone (shock, collapse, faint, hypotonic illness);
3) reduction of volume of the circulating blood (blood loss, dehydration); 4) the
violation of rheological properties of blood which is shown a blood condensation
(in the first phase of the DVS-syndrome).
Local circulatory hypoxia is developed when: 1) thrombosis; 2) embolism,
and thromboembolism; 3) spasm or compression of blood vessels; 4) ischemia; 5)
venous congestion and stasis; 6) strengthening the shunting of blood through the
arterio-venous anastomosis.
Both forms of circulatory hypoxia are characterized by a decrease in the
volume of blood flowing to the organs and oxygen delivery due to the decrease in
the volume of blood circulation. The content of oxyhemoglobin, partial pressure
of oxygen in arterial blood can remain normal. Due to slowing speed of blood
circulation and increasing of oxyhemoglobin dissociation while the accumulation
of carbon dioxide in the tissues the utilization of oxygen in the tissues is increased
which is accompanied by a decrease in the content of oxyhemoglobin in venous
blood and an increase in arteriovenous oxygen difference. Often patients are also
suffered from acrocyanosis.
If the development of the circulatory hypoxia associated with the opening of
arteriovenous shunts then the gain of the inflowing oxygen utilization of blood
does not occur, the content of oxyhemoglobin in venous blood remain high, which
leads to a reduction of arteriovenous oxygen differences. The opening of
arteriovenous shunts observed in patients with expressed spasm of precapillary
sphincters, sludge of erythrocytes, the DVS-syndrome.

Hemic hypoxia

Hemic (blood) hypoxia is developed due to decrease in the effective oxygen

capacity of the blood as a result of decrease in hemoglobin and also due to
impaired ability of hemoglobin associated, transported and delivered oxygen to
tissues. The reasons of hemic hypoxia are: 1) anemia; 2) qualitative changes of
hemoglobin which are followed by violation of the oxygen-accompanied functions.
Such changes occur during the formation of carboxyhemoglobin or
methemoglobin. Carboxyhemoglobin appears in the blood with carbon monoxide
poisoning (CO) which has a high affinity for hemoglobin (250-350 times higher
than the oxygen). When the content of carbon dioxide in the air is more than 0.1%
the half of hemoglobin turns in carboxyhemoglobin. Carbon monoxide enters the
body through: 1) smoking; 2) inhalation of smoke during a fire; 3) inhalation of
products of incomplete combustion of fuel; 4) exposure to solvents and paints that
contain methylene chloride (a substance is metabolized in the liver to form CO).
Carboxyhemoglobin can not participate in the transport of oxygen. Partial
replacement of hemoglobin to carboxyhemoglobin not only reduces its amount that
can carry oxygen but also hinders the dissociation of oxyhemoglobin and returning
the remaining oxygen to the tissues. The curve of dissociation of an
oxyhemoglobin moves to the left. Weighting is also the fact that carbon monoxide
poisoning doesn't occur reflex stimulating breathing due to the partial pressure of
oxygen in the blood remains constant.
Methemoglobin is composed of trivalent iron and is not capable of carrying
oxygen. At home and at work a person is faced with substances that cause the
formation of methemoglobin in the body. These are: 1) Inorganic and organic
nitrogen-containing compounds (nitrite, nitrate, ammonium nitrate, organic
nitrogen-containing substances); 2) dyes (methylene blue); 3) oxidizing
(bertoletova salt, potassium permanganate, naphthalene, quinone); 4) drugs,
including Novocainum, aspirin, Citramonum, sulfonamides and others.).
Methemoglobin formers may have a direct inhibitory effect on tissue respiration,
divide oxidation and phosphorylation that can cause a tissues form of hypoxia.
Formation of methemoglobin not only reduces the oxygen capacity of the blood
but also greatly reduces the ability of the remaining hemoglobin to give oxygen to
the tissues. Because of this the arteriovenous difference in oxygen content is
reduced. The curve of dissociation of an oxygemoglobin moves to the left.
Thus, there are strong similarities in mechanisms of hypoxia during carbon
monoxide poisoning and methemoglobin formers.
Hemic hypoxia that occurs under the influence of various etiological factors
is characterized by features of the changes of selected indicators that have a crucial
in determining the severity and nature of hypoxia.
With anemia the total content of oxyhemoglobin in arterial and venous blood
is decreased although the partial pressure of oxygen and degree of oxygenation of
hemoglobin remain normal. Formation of carboxyhemoglobin leads to reduce the
amount of oxyhemoglobin and arteriovenous difference in oxygen content. The
latter circumstance is due to the fact that carboxyhemoglobin reduces the
oxyhemoglobin dissociation and cause displacement of the dissociation curve to
the left. Due to this supply of oxygen to the tissues is reduced, which further
increases the severity of hypoxia.

Tissue hypoxia
 Tissue hypoxia occur due to violations of the cell's ability to dispose of
oxygen (under normal admission it in cells!) or due to a decrease in the
effectiveness of biological oxidation (reduction of ATP production) as a result of
separation of oxidation and phosphorylation. Utilization of oxygen by cells may be
disrupted as a result of various enzyme inhibitors of biological oxidation,
unfavorable changes in pH and ionic composition of the environment in which
they act violation of enzyme synthesis and disruption of biological membranes.
Hypoxia which occurs when dissociation of oxidation and phosphorylation
in the respiratory chain is a kind of tissue-type version of hypoxia. Tissue oxygen
consumption while usually increasing, but the share of energy derived from the
oxidation of substrates in the form of heat increases, and the share energy in form
of ATP - decreases. This leads to a depreciation biooxidation and relative
deficiency.
The consumption of oxygen by the tissues is normally increase but the share
of energy derived from substrates of the oxidation in the form of heat is increase,
and the share energy in form of ATP is decrease. This leads to a depreciation of
biooxidation and its relative deficiency.
The etiology of tissue hypoxia is: 1) inactivation of the enzyme tissue
respiration under the influence of toxic substances. For example, cyanide is destroy
the activity of cytochrome oxidase; alcohol, ether, barbiturates are cellular
dehydrogenases; ions of mercury, silver and copper are respiratory enzymes; 2)
violation of the synthesis of enzymes at deficiency of vitamins B1, B2, PP,
pantothenic acid; 3) disconnection of oxidative phosphorylation which occurs
when an excess of thyroid hormones, microbial toxins, nitrite poisoning; 4)
damage of the mitochondria; 5) swelling of tissues which increases the distance
between the capillaries and the cells, this leads to difficulty of oxygen diffusion.
The oxygen tension and the percentage of oxyhemoglobin in the arterial
blood are normal and in the venous are increased when tissue hypoxia.
Arteriovenous difference in oxygen content decreases due to the decrease of
oxygen absorption by tissues. Cyanosis in this type of hypoxia does not develop.

It should be emphasized the fundamental difference between the same at

first glance terms "tissue hypoxia" and " hypoxia of tissue". The first accurately
describes one type of hypoxia and the second only shows that some of tissue is in a
state of hypoxia (oxygen and energy starvation) without specifying its type.
 Substrate hypoxia

Substrate hypoxia in most cases is associated with impaired of delivery and

utilization of substrates of basic biological oxidation during normal delivery of O2.
The normal is that supply of substrates is large enough and far exceeds the reserves
of oxygen. However in some cases in the normal metabolism of oxygen, normal
intact membranes and enzyme systems may be the primary deficit of substrates
leading to disruption of all parts of the biological oxidation. The tissue of the brain
is most sensitive to such violations. Cessation of glucose in the brain after 5-8
minutes leads to the death of the most sensitive nerve cells. This form of hypoxia
may develop at deficiency of other substrates oxidation such as fatty acids in the
myocardium, severe general starvation. Oxygen consumption during hypoxia
substrate is usually reduced due to lack of substrate oxidation.

Overload hypoxia

Overload hypoxia develops due to the high oxygen need of tissues. This
condition can occur even in healthy people with severe physical activity when the
functional reserves of transport and utilization of oxygen and substrates, even
without the presence of pathological changes are insufficient to ensure sharply
increased need. The partial pressure of oxygen and content of oxyhemoglobin in
this form of hypoxia are normal and content of gas in venous blood is decrease due
to increasing consumption of tissues (oxygen consumption rate can be increased to
90%, and normally it is 25%). As a consequence of this process the arteriovenous
oxygen difference is increased. Strengthening oxyhemoglobin dissociation
metabolic acidosis is promote also arises. The metabolic acidosis which occurs
after this prosesses enhances the dissociation of oxyhemoglobin.

Mixed forms of hypoxia are the most frequent. They are characterized by a
combination of two or more basic types of hypoxia. For example, the respiratory
form of hypoxia along with circulatory hypoxia can be developed due to violation
of microcirculation in the lungs (shock lung) when traumatic shock.
Nitrate poisoning causes the hematic and tissue hypoxia forms because
under the action of these poisons not only the formation of methemoglobin occurs
but also dissociation of oxidation and phosphorylation.
The suppressing of oxidative processes in cells and also depression of the
respiratory center with violation of pulmonary ventilation occur in cases of
poisoning by barbiturates. This is cause the development of respiratory and at the
same time tissue hypoxia.
 Circulatory hypoxia (because of the defeat of the cardiovascular system) and
tissue (because of the blockade of respiratory chain of enzymes of acetaldehyde)
hypoxia are developed at the same time when alcohol intoxication.
Mixed forms of hypoxia also arise under the simultaneous action on the
organism of several different on points applications hypoxic factors.
The mechanism of mixed forms of hypoxia is often connected with the fact
that a primary arising hypoxia of any type which have reached a certain extent
causes a secondary violations in other organs and systems which involved in the
provision of biological oxidation. Every serious hypoxia is mixed.
Mixed forms of hypoxia are always have a more pronounced damaging
effect than any one type of hypoxia due to they are leaded to the disruption of
protective-adaptive reactions.

Mechanisms of damaging action of hypoxia

In the basis of hypoxia damaging action is lay a violation of formation of

high-energy phosphate compounds which create a deficit of cell energy supply and
leads to strictly restriction of the ability of cells to perform its functions and often
to cells' death independently of causes of hypoxia. The anaerobic mechanisms of
energy production can compensate the deficiency of oxidation processes not much.
Moreover lactic acid is accumulating in cells and metabolic acidosis which
exacerbates the disorder of metabolism caused by lack of oxygen in the tissue is
developing when turn on the anaerobic mechanisms.
The deficiency of energy supply of cells which is arising as a result of
hypoxia leads to the following consequences:
1. Violation in function of energy-dependent diaphragm pumps. This leads
to disruption of active transport of ions across membranes. As a result the
accumulation of sodium and the lose of potassium ions are occur in the cells due
to moving of ions through the membrane along the concentration gradient →
violation of the formation of the membrane potential → disordering in functions of
excitable tissues: nerve, muscle, myocardium.
2. Damage of mitochondria and infringement of functions of energy-
dependent calcium pump leads to the accumulation of intracellular calcium →
chaotic activation of various enzyme systems inside the cell → disorder of cellular
metabolism.
3. The increase in reactive oxygen formation → activation of free radical
oxidation and lipid peroxidation → damaging of external and internal membranes
of cell organelles (mitochondria, lysosomes, endoplasmic reticulum, nucleus).
4. Formation of a vicious circle:
1) secondary damage of mitochondria → greater violation of cellular
respiration and the growth of energy deficit;
2) damage of lysosomal membranes → output of lysosomal enzymes
of cytoplasm, their activation in conditions of acidosis → autolysis of intracellular
structures down to cells' death;
3) damage of the nucleus and endoplasmic reticulum → impossibility
of carrying out the processes of biosynthesis and recovering corrupted structures
what are exacerbated by energy deficit and a violation of functional activity of
enzyme systems.

Compensatory and adaptive processes at a hypoxia

The primary importance in the immediately emergency of adaptation of

organism to hypoxia have the activation of oxygen transport which includes the
respiratory, circulatory and blood systems.
The system of external respiration is respond of increasing of alveolar
ventilation at the expense of deepening and increasing of breathing and
mobilization of reserve alveoli.
The reactions of cardio - vascular system are expressed by tachycardia,
increasing of impact and minute volume cardiac output, increasing in masses of
circulating blood (due to ejection of blood from depot) and the redistribution of
blood flow with the predominant blood supply to brain and the heart.
The properties of hemoglobin which are allowing to give the tissues an
additional amount of oxygen in the reduction of its dissolved fractions in plasma
have the important role in adaptation of hypoxia .
The increasing of oxygen capacity of blood by the ejection of erythrocytes
from the bone marrow are the fast reactions of system of blood .
The emergency adaptive reactions at the level of systems of utilization of
oxygen involve in limiting the functional (and therefore metabolic) activity of
organs and tissues which are not participating directly in providing the organism
with oxygen, strengthening the coupling of oxidation and phosphorylation and
activation of glycolysis.
The long-term adaptation mechanisms which are usually developed when
repetitive moderate in intensity hypoxia are the basis of increasing resistance to the
action of hypoxic factor. Mechanisms of long-term adaptation are characterized by
persistent metabolic, morphological and functional rearrangement and also
associated with certain rearrangement neuroendocrine regulation of such that they
provide economical expenditure energy of organs and tissues during reactions an
organism on different irritants.
 Phenomena hypertrophies and hyperplasia are developed in the systems
which are responsible of the transport of oxygen:
• increases the respiratory muscle mass;
• increases the number of pulmonary alveoli;
• increases the permeability of the pulmonary-capillary membrane, which
improves the diffusion of oxygen from the alveolar air in the blood;
• function of neurons of the respiratory center is activated;
• develops myocardial hypertrophy;
• improves blood flow to organs and tissues by increasing the number of
functioning capillaries;
• enhance hematopoiesis in the red bone marrow.

At the level of organs and tissues occur the adaptive changes in the system
of oxygen utilization.
• Improving the ability of tissue enzymes to recycle oxygen, to maintain a
sufficient level of oxidative processes and to carry out the normal synthesis of
ATP.
• More effective use of oxidation processes energy due to more efficiency
coupling of oxidation and phosphorylation.
• Strengthening the processes of anoxic energy release due to glycolysis.

In different types of hypoxia relation between developing protective and

adaptive reactions may be different. It is caused by a primary lesion. At exogenous
hypoxia the compensation includes equally all mechanisms. At respiratory hypoxia
due to the primary damage of the respiratory system are turned off respiratory
protective and adaptive mechanisms, at circulatory - weakened protective and
adaptive mechanisms of the circulatory system, at hemic - are not included
compensatory effects in the system of oxygen transport. Accordingly, with the
weakening of any kind of protective-adaptive mechanisms, increased strain falls on
the other. At tissue hypoxia adaptive effects are not effective in the system of
oxygen utilization, which in its turn leads to all other inefficiencies.
Violations typical for hypoxia develop in failure or exhaustion of protective-
adaptive mechanisms. However, hypoxia, like any other disease process, is closely
intertwined proper pathological and protective-adaptive effects, and if they do not
cover the damages develops oxygen starvation.