XI. Oxygen transport to tissue, its disorders and types of hypoxia

1 Terms

2, 3 DPG 2,3, diphosphoglycerate is a molecule present in erythrocytes that facilitates oxygen release from hemoglobin. During chronic hypoxia of tissues (high altitudes, anemia, etc) the concentration of 2,3DPG is increased.
affinity of hemoglobin to oxygen affinity describes how easily oxygen binds to hemoglobin (released from hemoglobin). It is affected by blood properties such as pH, temperature, pCO2 and concentration of 2,3 DPG. The affinity of hemoglobin to oxygen increases in low temperature, low pH, low 2,3 DPG concentration.
arteriovenous oxygen difference a difference between partial pressure of oxygen in the arteries and in the veins. It depends on activity of particular tissue and its perfusion.
CO carbon monoxide: a poisonous gas, its affinity to hemoglobin is 200x higher than the affinity of oxygen to hemoglobin. Healthy adults have 2% of Hb bound to CO, smokers have 10% of HbCO (carboxyhemoglobin). The binding of CO to hemoglobin increases the affinity of hemoglobin to oxygen and makes it impossible to release oxygen in tissues. CO poisoning leads to tissue hypoxia.
cyanosis blue coloration of the skin and mucosas occurring when more than 50g/1l of deoxyhemoglobin is present in the blood
deoxyhemoglobin hemoglobin that released oxygen (deoxygenated hemoglobin)
oxygen dissociation curve a sigmoid curve describing the percentage of saturated hemoglobin at a particular partial pressure of oxygen
hematocrit a volume ratio of red blood cell in blood. It is different for men and women.
hypercapnia increased partial pressure of  CO2 in tissues
hypoxemia insufficient amount of oxygen in blood
hypoxia insufficient amount of oxygen in tissues
ischemia decreased supply of oxygen and nutrients and inablity to remove products of metabolism from tissues due to perfusion disorder. Ischemie is also called ischemic hypoxia.
carbaminohemoglobin a transport form of CO2, that is bound to aminooacids of hemoglobin and is easily released in the lungs (due to decreased pCO2)
carboanhydrase  (carbonate dehydrogenase) – an enzyme present in almost all tissue that catalysis reaction of CO2 and water that produces H+ and HCO3
carboxyhemoglobin CO bound to Hb
curare “an arrow poison” , an alkaloid mixture found in plants, that binds to acetylcholine receptors on neuromuscular junction and blocks signal transmission
myoglobin an endogenous pigment, its molecule is similar to hemoglobin in the muscles. One molecule of myoglobin binds one molecule of oxygen (hemoglobin binds 4 oxygen molecules)
oxyhemoglobin hemoglobin saturated with oxygen (oxygenated hemoglobin Hb)
pCO2 partial pressure of carbon dioxide. A pressure of dissociated CO2, depends on pCO2 in the inhaled air, ventilation, perfusion and activity of the tissues  
paO2 partial pressure of oxygen in arterial blood
PAO2 partial pressure of oxygen in the alveoli
pressure unit conversion  1kPa = 7,5 torr, 1 torr = 0,133 kPa, 1 torr = 1mmHg (100mmHg = 13,3 kPa, 40mmHg = 5,32 kPa)
hemoglobin saturation formation of bonds between oxygen and iron molecule during oxygenation
bonding capacity of hemoglobin 1g of hemoglobin binds 1,34ml of oxygen. A healthy adults that has 15g of hemoglobin in 100ml of blood, but has capacity to carry 20,1 ml oxygen per 100 ml of blood.

2 Introduction

A human body needs 250 ml of oxygen per minute, that means 360l per 24 hours. Oxygen is necessary for aerobic metabolism to produce energy. 80 to 95 percent of energy is used to maintain ion gradients, physical activity and metabolism.

Do plicních sklípků přichází ventilací vzduch (směs plynů) včetně kyslíku, který difuzí přestupuje po koncentračním gradientu do krve (z krve do alveolů po koncentračním gradientu difunduje oxid uhličitý). V krvi se větší část kyslíku naváže na hemoglobin (oxygenace hemoglobinu – asi 98% transportovaného kyslíku) a část se rozpouští v plazmě jako paO2 (2%). Perfuze plic zajišťuje transport oxygenované krve do levého srdce a odtud do celého těla. V periferních kapilárách difunduje na základě gradientu rozpuštěný kyslík do intersticia a jeho parciální tlak v plazmě je udržován uvolňováním ze zásob vázaných na hemoglobinu. Ve tkáních je kyslík spotřebováván podle její metabolické aktivity. Vzniká při tom oxid uhličitý, který difunduje na venózním konci kapiláry do krve a je krví odváděn do plic, kde se vydýchá.

Air (including oxygen)  gets to alveoli in the process of ventilation, oxygen then follows concentration gradient to the blood (carbon dioxide diffuses in opposite direction to be exhaled). In the blood most of the oxygen is bound to hemoglobin (oxygenation of hemoglobin – approximately 98% of transported oxygen) and a small part is dissociated in the blood plasma as paO2 (2%).

Blood from the lungs (lung perfusion) transports oxygenated blood to the left heart and then to the whole body. In the peripheral capillaries dissociated oxygen diffuses to the interstitium according to the concentration gradient. Its partial pressure in the blood plasma is maintained by release from hemoglobin. Oxygen in the tissues is used according to the metabolic activity of the tissue. Carbon dioxide is produced in the tissues and diffuses to the venous end of the capillary to the blood. Blood transports carbon dioxide to the lungs, where it is exhaled.

Obr. 11.1: Oxygen transport

pIO2  partial pressure of oxygen in inhaled air, pICO2  partial pressure of carbon dioxide in inhaled air pEO2,  pECO2 partial pressures in exhaled air.

Deficiency of oxygen in the tissues is called hypoxia. There are several mechanism that result in hypoxia.

Hypoxiaand its types

Hypoxia, types of hypoxia.

Hypoxia is defined as an oxygen deficiency in tissues. There are several types of hypoxia. Hypoxemic hypoxia is caused by inadequate supply of oxygen due to low amount of oxygen in inhaled air or due to respiratory defects. Anemic hypoxia is caused by small amount of hemoglobin or defected types of hemoglobin. Stagnant type of hypoxia can be a result of a  heart failure or a thrombus causing insufficient supply of blood to the tissues. Histotoxic hypoxia arises when a tissue itself is unable  to use the oxygen due to blockage of electron transport chain by certain drugs or poisons (cyanide, high concentration of lactic acid in blood plasma).

Types of hypoxia differ by their causes, partial pressure of oxygen in arterial and venous blood, oxygen consumption in the tissue and presence of cyanosis. Oxygen consumption in the tissues can be determined by arterio-venous difference (a-v difference). In healthy tissue it is 60 mmHg  (paO2 – pvO2 = 100 – 40 = 60 (mmHg)). Cyanosis is blue colouring of skin and mucosas due to increased concentration of deoxyhemoglobin. (Higher than 50g of hemoglobin per 1l of blood.)

Hypoxemic hypoxia is defined by low partial pressure of oxygen in arterial blood. Tissues are using the same amount of oxygen therefore the leftover amount of oxygen in venous blood is lower. (In hypoxemic hypoxia: paO2 80 mmHg, tissues use 60 mmHg there will be 20 mmHg left in the venous blood.) This type of hypoxia leads to central cyanosis. The cause of hypoxia is “before the heart” (lower pO2 in the inhaled air or in the lungs) and hemoglobin is not sufficiently saturated.

Anemic hypoxia is caused by hemoglobin deficiency due to low amount of erythrocytes or defects of hemoglobin – inability to bind or release sufficient amount of oxygen. Partial pressures paO2   and  pvO2 will be normal, pvO2 will decrease during strong physical exercise. This type of hypoxia does not lead to cyanosis. Even though there is hemoglobin deficiency, hemoglobin saturation is normal.

Stagnant hypoxia (ischemic) is caused by defect of perfusion. paO2 is normal, but the tissues are taking more oxygen from slowly flowing blood, therefore venous pO2 is low. The arterio-venous difference is increased for the same reason. The tissues take more oxygen, therefore the will be more deoxyhemoglobin in blood which will lead to peripheral cyanosis. (This type of hypoxia is also referred to as circulatory hypoxia)

Histotoxic hypoxia develops due to inability of tissues to accept and use oxygen. Partial pressure of arterial blood will be normal, partial pressure of venous blood will be higher. Arterio-venous difference will decrease, because tissues use less oxygen. There will be no cyanosis. The cause of this hypoxia might be cyanide poisoning that blocks oxidative phosphorylation in mitochondria or high concentration of lactate in blood plasma.

Tab. 11.1: Table comparing different types of hypoxia

4 Causes of hypoxemic hypoxia

Hypoxemic hypoxia is caused by low partial pressure of oxygen in inhaled air or lung traumas – disorders that appear “before the heart”.

4.1 Inhaled air

Inhaled air contains 21% oxygen, 78% nitrogen and the rest consist of noble gases (helium, argon), carbon dioxide (CO2<0,03%) and other gases. In zero altitude the pressure is 760mmHg. Altitude has no effect on composition of air, however the atmospheric pressure decreases with increasing altitude and so decrease partial pressure of individual gases.

Altitude

(m/ nm)

atmosferic pressure(mmHg) FIO2

(%)

pIO2

(mmHg)

pAO2

(mmHg)

paO2

(mmHg)

paCO2

(mmHg)

0 760 0,21 150 105 100 40
2000 610 0,21 120 90 80
8848 253 0,21 43 35 28 7,5

Tab. 11.2: Partial pressure of air in different altitudes.FIO2 = inhaled air fraction (21%), pIO2 = partial pressure of oxygen in  trachea, paCO2 = partial pressure of carbon dioxide in arteries (we assume it is the same as in alevoli), pAO2 = partial pressure of oxygen in alveoli (calculated value), paO2 = partial pressure of oxygen in arteries.

Increased partial pressure of one of the components of inhaled air means that partial pressure of other components has to decrease so that overall atmospheric pressure remains constant. If partial pressure of pCO2  in the inhaled air increases, partial pressure of oxygen and other gasses decreases.

4.2 Ventilation

Ventilation is exchange of air between alveoli and the environment. It depends on various factors:

-respiratory control (nervous and humoral)

-ascending and descending pathways, neuromuscular junction (curare poisoning)

– respiratory tract quality

-quality of respiratory muscles and thoracic cavity

-quality of lung tissue

Decreased rate of respiration always leads to increased partial pressure of carbon dioxide in alveoli. If the partial pressure of alveolar oxygen decreases, so does the gradient that drives the oxygen diffusion from the alveoli and the blood passing through the lungs – that leads to hypoxia because less oxygen passes to the blood. Hypercapnia may also develop (as the  partial pressure CO2 builds up in the venous blood, because it cannot be effectively exhaled, it disturbs the gradient between tissues and venous blood).

4.3    Ventilation – perfusion ratio (V/Q)

The most common cause of hypoxemic hypoxia is the defect of ventilation-perfusion ratio in the lungs. For the lungs to work normally the lung have to be ventilated and perfused. Ideally the process of ventilation and perfusion should be balanced out ( ventilated air has to be distributes to perfused parts of the lungs and the other way around). However the lungs are divided into areas with various ventilation-perfusion ratios.

In normal healthy lungs, the bottom part of the lungs is perfused better then  the upper part and the upper part is better ventilated than the bottom part. Average ratio is V/Q=0,8. Increased perfusion in the upper parts and increased ventilation of the bottom parts activates  sympathicus. (occurs due to increased physical activity)

-the bottom third of the lungs is better perfused due to gravity: normal ventilation/ increased perfusion= decreased ventilation/perfusion ratio  (V/Q< 1)

– the upper third of lungs is less perfused (due to gravity) and the most ventilated: normal ventilation/ decreased perfusion= increased ventilation perfusion ratio (V/Q>1)

-the middle third of the lungs is equally ventilated and perfused – ideal ratio (V/Q=1)

Pic. 11.2:

The blood coming to the left heart will have normal values of partial pressure of oxygen (PAO2 = parcial pressure of oxygen in alveoli, PaO2 = v arterial blood)

he body has regulatory mechanism that is able to compensate local changes of ventilation and perfusion. Under pathological circumstances the normal ventilation/perfusion ratio is disturbed.

4.3.1 Compensation of disbalances of ventilation-perfusion ratio

If the perfusion is normal and ventilation is increased, alveolar pACO2 decreases(alveolar hypocapnia)  –  the lungs respond by bronchoconstriction. Bronchoconstriction during hypocapnia: increased ventilation-perfusion ratio is changed to normal because ventilation decreases so does V/Q ratio.

When alveolar pAO2 is  decreased in certain part of the lungs blood supply to this particular area decreases (reflex vasoconstriction). Reflex vasoconstriction: decreased V/Q ratio return to normal due to decreased perfusion (NOTE: hypoxia causes vasoconstrition only in the lungs, anywhere else in the body hypoxia leads to vasodilatation)

When compensatory mechanism are not able to compensate the disbalance of ventilation perfusion ratio, ratio stays disbalanced. However V/Q is the most important factor that affects the partial pressure of oxygen in arterial blood. The amount of oxygenated blood coming from both lobes to the heart is the deciding factor..

Disturbed ventilation perfusion ratio is the most common reason of hypoxemia and hypoxia of tissues

Obr. 11.3: Ventilation-perfusion ratio disbalance

mixture of less oxygenated blood with normally oxygenated blood decreases overall partial pressure of oxygen in arterial blood.

4.3.2 Types of ventilation/perfusion disorders

If a particular part of lungs is normally perfused, but not ventilated it is a pulmonary shunt. Ventilation/perfusion ratio is close to zero. Partial pressure of gases in alveoli are the same as the partial pressure of the gases in venous blood.(pAO2 = 40 mm Hg, pACO2 = 46 mm Hg). This blood mixes up with oxygenated blood from other parts of lungs. The resulting blood has lower partial pressure of oxygen and normal partial pressure of carbon dioxide. (Other parts of lungs hyperventilate)

If a particular part of the lungs is normally ventilated, but perfusion is decreased or stopped, there is a dead space. The blood flows through other vessels faster and under higher pressure. Hemoglobin does not manage to get fully saturated and the ventilation/perfusion ratio is increased. Partial pressure of gases in alveoli are similar to partial pressure of gases in inhaled air (pAO2 = 150 mm Hg, pACO2 = 0 mm Hg). Blood from this part of the lungs mixes up with the blood from the other parts and results in hypoxemia.

Pic. 11.5: Ventilation – perfusion disorders can be described using Fehn-Rahn diagram – individual points are defined by partial pressure of respiratory gases of A) arterial blood B)venous blood C)inhaled air.

4.4  Diffusion

Diffusion is a process of gas transport through alveolocapillary membrane. It is composed of pneumocytes lining the alveoli, basal membrane and endothelium. Gases also have to pass through a layer of surfactant, however that is insignificant.

The process of diffusion can be disturbed by many factors:

  • increased diffusion distance due to lung edema  (postcapillary lung hypertension due to left heart failure) or inflammation (edema and infiltration of immunocompetent cells) etc.

decreased diffusion area (due to emphysema – destruction of alveolar septi)

The quality of diffusion is described by alveolocapillary difference pAO2 minus paO2:

Partial pressure of oxygen in the arteries can be measured, partial pressure of oxygen in alveoli can be calculated using an equation of alveolar gasses. It depends on a fraction of inhaled oxygen, atmospheric pressure in trachea (atmospheric pressure in a particular altitude minus steam pressure) and partial pressure of CO2 in alveoli.

Simplified version of the equation used in hospitals: 

pAO2 = FIO2 (P- 47)  -  1,2 (paCO2)
pAO2  … partial pressure of oxygen in alveoli
FIO2 …  inhaled fraction of oxygen (0,21)
PB   …atmospheric pressure at a particular altitude
47 …   pressure of steam in nasopharynx , body temperature 37°C (the pressure depends only on body temperature
1,2 …  a constant taking into an account respiratory quotient (production CO2 in the body is dependent on metabolism of the nutrients)
paCO2….. partial pressure of carbon dioxide in arterial blood (the same as in alveoli)
pAO2 = PIO2  -  1,2 (paCO2)
PIO2 ......partial pressure of oxygen in the inhaled air ( in zero altitude the partial pressure of oxygen is 150 mmHg)

The normal difference of partial pressure of oxygen on alveolo-capillary membrane is dependent on age:

pAO2 – paO2  =  (age + 10) / 4

The comparison  of calculated alveolo-capillary difference and standard one determines whether the diffusion in the lungs is defected or not. If the calculated difference between  pAO2 – paO2  is higher than standard value, it means that the process of diffusion is disturbed or that there is disbalance of ventilation/perfusion ratio.

Anemic anemia

Under physiological circumstances, there is 150g of hemoglobin in 1 liter of blood. Arterial hemoglobin is 100% saturated, venous hemoglobin is 75% saturated. Hemoglobin is composed of 4 subunits and each of them carries 1 molecule of oxygen. That is 1,33 ml of oxygen per 1 g of hemoglobin.

The most common cause of anemic hypoxia is insufficient amount of hemoglobin due to  insufficient formation (anemia due to shortage of substrates to form erytrocytes, due to damage of bone marrow or jejím útlakem při leukocytózách)), accelerated hemolysis (hemolytic anemia), compensatory dilution of blood volume by water due to massive bleeding. Decreased ability of hemoglobin to bind oxygen might be another cause of anemic anemia:

carboxyhemoglobin – CO is bound to hemoglobin, carbon monoxide has higher affinity to hemoglobin than oxygen and occupies all the oxygen binding sites. Even if there are some unoccupied binding sites, the affinity of hemoglobin to oxygen is decreased due to CO and CO is rarely released from its binding sites in tissues.

methemoglobin – it is a hemoglobin with Fe (III) instead of Fe (II). Fe(III) is formed by oxidation due to free radicals present in the blood. Methemoglobin reductase converts methemoglobin to hemoglobin.  However if there is overproduction of methemoglobin the conversion rate is insufficient. Methemoglobinemia can be acquired (due to smoking, taking certain medication or chemicals such as nitrates in drinking water) or congenital – methemoglobin reductase deficiency. (All nursing babies have methemoglobin reductase deficiency, because the baby food is made using drinking water containing nitrates instead of using distilled water)

6 Stagnant hypoxia (ischemic, circulatory)

6.1 Regulation of tissue perfusion

According to Hagen – Poiseuill law, the blood flow in vessels is determined by the diameter of the vessel at a constant pressure. Vasoconstriction decreases blood flow, vasodilatation increases the blood flow. The heart pumps against peripheral resistance that is determined by the diameter of arterioles (the most import vessels in terms of peripheral resistance).  Peripheral resistance and cardiac output are the most important factors to determine the blood pressure. Diameter of arterioles in the tissues and organs therefore regulate the organ perfusion as well as the blood pressure.

Under physiological circumstances the smooth muscle of the arterioles is regulated by the activity of the sympathetic nervous system. Smooth muscle of vessels is usually contracted. The muscle tonus might also be affected by other local and external mechanisms.

6.1.1 Local mechanisms allow

Tissues to regulate their perfusion depending on local factors. Local mechanisms are active hyperemia, autoregulation of blood flow and reactive hyperemia. All of these mechanism are affected by the local metabolism that changes according to the organ activity.

 

Active hyperemia:  under physiological circumstances, increased metabolic activity increases the blood flow through the tissues. The reason for increased blood flow are local factors leading to vasodilatation of arterioles such as decreased pO2,  increased pCO2 or increased concentration of catabolites: ADP, potassium, decrease of pH. This mechanism is well developed in tissues with high metabolic activity (brain).

 

Ø  Autoregulace průtoku krve se uplatňuje při změnách průměrného arteriálního tlaku (např. v ledvinách nebo mozku), kdy je potřeba udržet relativně stálý průtok. Podílí se na tom dva odlišné mechanizmy:

Autoregulation of blood flow occurs in tissues that require a constant blood flow but may experience fluctuation of blood pressure  (the kidneys and brain). There are two factors that affect autoregulation:

  • metabolic factors: decreased blood pressure decreases perfusion of tissues, which changes metabolic circumstances, such as decrease of pO2, increase of pCO2, or increased concentration of catabolites (e.g. lactate, potassium ion, adenosine) which leads to vasodilatation
  • myogenic mechanism (Bayliss reflex) – increased blood pressure mechanically stimulated myocytes of the smooth muscle in the vessels, they depolarize and contract resulting in vasoconstriction

If increased activity of smooth muscle lasts a few weeks the smooth muscle undergoes hypertrophy. The new hypertrophic muscle wall is more sensitive to nervous stimulation and contracts. (This mechanism is involved in development of hypertension.)

Reactive hyperemia is a special form of autoregulation of blood flow under pathological circumstances: In tissues that are lacking blood perfusion due to ischemia, after the release of obstruction the blood flow is greatly increased.

6.1.2 External mechanisms 

They are mediated by nervous and humoral stimuli.

 

Nervous stimuli: it is usually the activity of sympathicus that changes the basal tone of arterioles (via increased or decreased secretion of noradrenaline on sympathetic synapses) which leads to vasoconstriction or vasodilatation. Parasympathicus does not have a direct effect on arterioles.

Humoral factors:

noradrenaline – noradrenaline causes vasoconstriction in most of the tissues (leading to blood perfusion of vital organs due to stress). However in striated muscle, sympathicus causes vasodilatation. The effect depends on type and number of receptors.

angiotensin II – total vasoconstriction, vas efferens in glomeruli is the most sensitive

vasopressin (ADH) – vasoconstriction 

6.1.4 Endothelium

Endothelium has an important role in blood flow regulation – many substances (such as bradykinin) stimulate endothelium to secrete vasoactive paracrine substances. These substances affect smooth muscle of the vessels and cause vasodilatation (NO) or vasoconstriction (endothelin)

 6.1.4 Calcium

The extend of smooth muscle contraction depends on the amount of calcium in cell cytoplasm. The transfer of calcium to the smooth muscle cells is affected by many factor: it is facilitated by increased concentration of calcium in extracellular space (increased calcemia due to hyperparathyroidism)  or depolarization of the cell opens the calcium channels (due to mechanical stimulation due to increased blood pressure in the tissues, or activation of a1 receptors by noradrenaline)

IMPORTANT:

a) decresed pO2 (hypoxia) in the alveoli of the lungs leads to vasoconstriction, but the ventilation/perfusion ratio remains constant

b) under all circumstances metabolic regulation is more important than nervous regulation

6.2 Regulation of blood flow through specific tissues

The blood flow regulation is specific for different tissues.

Skin – the skin perfusion is mainly regulated by sympathetic nervous system. Under stressful circumstances, sympathicus supports the transfer of blood from the periphery to the vital organs. The perfusion of the skins also depends on temperature. Local decrease of temperature leads to vasoconstriction and local temperature increase leads to vasodilatation. (also mediated by sympathicus)

The striated muscle – the perfusion depends on its activity : when the activity is low sympathicus maintains vasoconstriction, when the activity is high the increased concentration of catabolites lead to active hyperemia. The stress reaction leads to vasodilation due to noradrenaline, that increases the blood supply of oxygenated blood to the muscles and they are ready for “fight or flight”. Shock (compensated phase) leads to increased concentration of adrenaline in the blood plasma, activation of α receptors, contraction of muscles and vasocontraction. Blood is transferred to the vital organs.

Heart (coronary arteries) – the perfusion is regulated mainly by local metabolic factors, as the heart is constantly active. The regulation is also affected by sympathicus but not by much.

The brain – the perfusion is regulated by autoregulation (in the range 60-189 mmHg of systolic pressure) and local factors. In comparison to other tissues, the brain is more sensitive to the change of the pCO2 than to pO2.  (increased pCO2 leads to vasodilatation and allows faster blood flow). The local distribution of blood in the brain is regulated by active hyperemia. Nervous regulation is negligible.

Kidneys – autoregulation in kidneys is a little bit more complicated. Autoregulation is necessary for maintaining glomerular filtration and to protect nephrons from high blood pressure. The kidneys are able to maintain stable blood flow and glomerular filtration pressure if the blood pressure is in the range of 80 – 180 mmHg. Increased blood perfusion in kidneys activates myogenic reflex in vas afferens causing vasoconstriction. Decreased blood perfusion stimulates mesangium of glomeruli to produce prostaglandins causing vas afferens to dilate. Angiotensin II mainly regulates the vas efferens (vasoconstriction) increasing the glomerular filtration pressure. If the circulatory volume is increased , angiotensin II causes pressure polyurea (if the circulatory volume is decreased there is decreased reabsorption in the distal tubules). Decreased perfusion actives RAAS (renin-angiotensin-aldosterone) and increases the sodium and water retention in the distal tubule. (If the perfusion is greatly decreased, the tubular function might be damaged. The portal system starting in vas efferens supplies tubules with oxygen and nutrients will not have enough blood. The proximal tubules are going to be more damaged than distal tubules because they have higher metabolism. Acute renal failure might develop – acute tubular necrosis due to shock (shock kidney).

6.3 The causes of ischemic hypoxia

Hypoxic ischemia develops due to decreased blood flow: The causes might be:

  • decrease of cardiac output due to heart failure or cardiogenic shock
  • decrease of systemic pressure (hypovolemic and distributive shock)
  • local tissue ischemia due to obstruction (thrombosis, embolia)
  • local diffusion disorder due to edema or microcirculation disorder

7 The consequences of hypoxia

Insufficient supply of oxygen in tissues is very common pathological situation and the body has developed certain mechanism to prevent further tissue damage.

7.1 Compensation of hypoxemia and hypoxia

Acute hypoxemia activates stress response – increased heart rate, increased blood pressure, increased rate of ventilation. That leads to increased oxygen supply to tissues. Apart from that the cells in the tissues have a sensor (transcription factor HIF1) that is activated by hypoxia and activates gene expression of genes neccessary for production of special proteins. These proteins are enzyme that increase rate of glycolysis, anaerobic ATP production, vascularisation of tissues (angiogenic factors), increase erythropoiesis (erythropoietin) and increase sympathicus activity.

However if the hypoxia is too severe or lasts too long, it might lead to death of cells by necrosis or apoptosis.

7.2 Ischemia

Ischemia is a consequence of ischemic hypoxia: decreased perfusion decreases supply of oxygen and nutrients and decreases the rate of transfer of metabolites away from the tissues. In the beginning this is compensated by vasodilatation (increased concentration catabolites pCO2, K+, ADP and increased pH). The decrease of pH facilitates the release of oxygen from hemoglobin (decreases the afinity of hemoglobin to oxygen). However if the compensatory mechanisms are not sufficient, the ischemia leads to change of function and metabolism of the cells and in the end results in morphological change and irreversible damage of tissues.

Some changes develop over time – in the beginning the energetic metabolism is disturbed, ATP is not formed, Na/K pump stops workink, Na accumulates in the intracellular space. Intracellular osmotic pressure increases and water is retained. The cell swell. Potassium is accumulated in extracellular space (in myocardial ischemia it might cause a local change in ECG). The dels develop swelling of the organelles, intracellular concentration of calcium is increased and enzymes are activated (such as caspases) that impact cell metabolism and may cause damage.  

Anaerobic metabolism is activated due to lack of oxygen in the extracellular fluid, acidosis is developed and lactate is formed. Vasodilation in ischemic tissues is developed due to decreased pO2 and pH, increased pCO2, increased concentration of K+ and ADP in. ECT), that leads to slow perfusion and increased capillary pressure. In the capillary hydrostatic pressure is greater than any other pressure and fluid is filtered to interstitium. That causes edema, increases diffusion lenghts, increases blood viscosity and makes ischemia even worse.

Ischemia has some specific consequences in certain tissues. In the lungs edema stops diffusion of gasses, in the brain increased intracellular concentration of calcium increases neurotransmitter release (mainly glutamate) and because it is an excitatory mediator it increases activity of neurons, increases their energy demand and damages them. Apart from that the function of brain changes. Ischemia in the heart impacts the conductivity and contractility (leads to arrhythmia) and impacts the ion distribution on membranes (change of ECG). In the intestines there is an increased risk of infection of peritoneum by the bacterias from the gut (due to vasogenic ileus) and rupture.