Hypoxia - Riga Stradins University Pathology Lecture PDF

Riga Stradins University Department of Pathology 2022 / 2023 Hypoxia Prof. Ilze Strumfa Dr. Agnese Ūdre  Definition Hypoxia is low level of oxygen in body tissues Additional te...

Riga Stradins University Department of Pathology 2022 / 2023 Hypoxia Prof. Ilze Strumfa Dr. Agnese Ūdre  Definition Hypoxia is low level of oxygen in body tissues Additional terminology: Hypoxemia – low level of O2 in arterial blood Hypercapnia – increased partial pressure of CO2 in arterial blood Hypocapnia – decreased level of CO2 in arterial blood  Clinical significance ◼ Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology. ◼ Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.  Clinical significance II ◼ Severity of hypoxia is determined by:  Onset – sudden or gradual;  Duration;  Severity;  Type of hypoxia;  Tissue sensitivity to hypoxia. ◼ Compensatory capacity is lower if hypoxia develops abruptly, lasts longer and is severe.  Classification of hypoxia by onset Acute hypoxia – rapid onset, < 6h Chronic hypoxia – lasting more than 90 days Fulminant hypoxia – lightning-fast Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Acute hypoxia ◼ Rapid onset ◼ Less frequent compared to chronic hypoxia ◼ Examples:  Mountain sickness  Suffocation  Airway obstruction with foreign body  Sudden suppresion of respiratory centre  Acute cardiac failure  Shock – acute circulatory failure Underwood's Pathology: a Clinical Approach, 7th edition, 2019  Chronic hypoxia ◼ Chronic course ◼ Examples:  Chronic heart failure/ Congestive heart failure  Chronic respiratory failure  Chronic anaemia Underwood's Pathology: a Clinical Approach, 7th edition, 2019  Fulminant hypoxia Catastrophe medicine, also known as disaster medicine, is a specialized field of medical practice focused on the management and treatment of ◼ Rare, occurs mostly in catastrophe medicine injuries and illnesses that occur during large-scale disasters or catastrophic events ◼ Example: an explosive decompression of airplane cabin at high altitude (10 km above sea level) ◼ Oxygen is forced out from the lungs due to the rapid expansion of gas during a rapid decompression ◼ Severe fatal barotrauma – rapid confusion, drowsiness, death due to respiratory center failure Underwood's Pathology: a Clinical Approach, 7th edition, 2019  Types of hypoxia ◼ Hypoxic hypoxia ◼ Respiratory hypoxia ◼ Hemic hypoxia ◼ Circulatory hypoxia ◼ Histotoxic hypoxia Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Hypoxic hypoxia ◼ Oxygen pressure (SpO2) in the blood is too low to saturate the hemoglobin ◼ Clasification by atmospheric pressure:  Hypobaric hypoxic hypoxia – low atmospheric pressure induces altitude sickness.  Normobaric hypoxic hypoxia – staying in inadequately ventilated room or a place with high CO2 levels. Underwood's Pathology: a Clinical Approach, 7th edition, 2019  Altitude sickness (I)  Hypoxic symptoms in previously healthy mountain climbers.  Pathogenesis: hypobaric hypoxic hypoxia  Symptoms include: ◼ Headache ◼ Nausea, vomiting ◼ Dyspnoea ◼ Sleeping disorders  Typically begins at ~2500 m elevation  3000 m elevation – pulmonary oedema is possible – due to constricted pulmonary arteries  3500 m elevation – cerebral oedema may occur – due to dilated cerebral arteries Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Altitude sickness (II) When you go to very high altitudes, some people feel overly happy or excited. ◼ High altitude euphoria is possible. This can lead to poor decision-making because they don't realize their limits. The reason: Low oxygen (hypoxia) affects the brain,  Poor judgement of one’s capacity especially the part that helps with self-control—kind of like how alcohol works. Depression and Apathy:  Mechanism: during hypoxia, cerebral cortical inhibitory functions are diminished, similarly as in alcohol intoxication ◼ Subsequently, severe depression and apathy occurs ◼ Reaching 5000 – 6000 m altitude, sensory, motor and mental functions deteriorate, leading to reduced awareness of the current situation, coordination difficulties, decreased muscle function After the euphoria, people can feel very down or uninterested in things. At Extremely High Altitudes (5000–6000 m): Your thinking, movements, and reactions slow down. It becomes harder to understand what's happening around you. You may also lose coordination and feel weaker as Underwood's Pathology: a Clinical Approach, 7th edition, 2019; your muscles don’t work well. Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Hypoxic hypoxia: Hypoxic hypoxia happens when there’s not enough oxygen in the blood due to low oxygen levels in the air compensatory mechanisms (I) ◼ Hyperventilation when air has low level of CO2:  Can lower hypoxia but can also cause hypocapnia When Air Has Low CO2: (decreased level of CO2 in blood); Breathing faster helps bring in more oxygen. But it can also reduce the amount of CO2 in the blood (hypocapnia)  Hypocapnia can lead to respiratory alcalosis (blood. Low CO2 can cause respiratory alkalosis (the pH deviation to alkalinity); blood becomes too alkaline). Alkalinity can reduce the drive to breathe, making the situation worse.  Hypocapnia lowers activity of respiratory center. ◼ Hyperventilation in circumstances when CO2 in air is elevated. The body may hyperventilate even more to try to get rid of excess CO2. ◼ Circulatory response The heart may beat faster or pump more blood to get more oxygen to the tissues ◼ Secondary polycytemia Over time, the body may produce more red blood cells to carry more oxygen, which is known as secondary polycythemia Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Hypoxic hypoxia compensatory mechanisms (II) ◼ Hyperventilation in circumstances when CO2 in air is elevated  Can lower hypoxia but lead to hypercapnia (higher blood level of CO2);  Hypercapnia can lead to respiratory acidosis (blood pH decreases);  Hypercapnia increases activity of respiratory center. ◼ Circulatory response ◼ Secondary polycythemia Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Respiratory hypoxia ◼ Caused by decline in respiratory functions in any level:  Hypoventilation;  Impairment of gas diffusion via alveolo-capillary membrane; When air doesn't reach all parts of the lungs or blood doesn't flow  Ventilation-perfusion mismatch.properly through the lungs, leading to poor oxygen exchange. ◼ Respiratory hypoxia leads to:  Hypercapnia: elevated CO2 in blood, because CO2 cannot be exchanged via lungs;  Hypercapnia can lead to respiratory acidosis (blood pH decreases). Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Oxyhemoglobin dissociation curve Low CO2 Higher pH (alkaline blood) Lower temperature Fetal hemoglobin (found in babies) Normal P50 is around 27 mmHg P50= the oxygen pressure at which hemoglobin is 50% saturated. Left shift: P50 decreases (oxygen binds more tightly) Right shift: P50 increases (oxygen is released more easily High CO2 Low pH (acidic blood) Higher temperature 2,3-DPG (a molecule that helps release oxygen) Hemoglobin lets go of oxygen more easily, making it easier for tissues to get oxygen. Hemoglobin holds onto oxygen more tightly, meaning less oxygen is released to tissues. https://rk.md/2017/oxyhemoglobin-dissociation-curve/  Causes of respiratory hypoxia 1. Hypoventilation ◼ Airway obstruction:  Foreign body  Tumor contraction in the airway that can make it hard to breath  Inflammatory oedema (bronchitis)  Bronchospasms during bronchial asthma attack ◼ Paralysis of respiratory muscles ◼ Skeletal deformations Abnormal chest shapes can make breathing difficult. ◼ Respiratory center suppression (medications, narcotic abuse, hypocapnia) ◼ Superficial breathing due to pain: thoracic trauma, pleuritis, intercostal neuralgia Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Causes of respiratory hypoxia 2. Impairment of gas diffusion via alveolo-capillary membrane ◼ Reduction of surface area for gas exchange:  Lung emphysema damage to air sacs reduces the area for oxygen exchange ◼ Decline of functioning alveoli:  Pneumonia; infection fills alveoli with fluid or pus  Lung oedema. fluid buildup in lungs reduces oxygen absorption ◼ Pneumofibrosis: increased thickness of connective tissue in alveolar septum:  Cryptogenic fibrosing alveolitis. lung scarring that thickens the walls of air sacs Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Causes of respiratory hypoxia 3. Ventilation/perfusion missmatch ◼ Normal ventilation, no blood supply: increased «dead space». Air Without Blood  Pulmonary embolus;  Lung emphysema (lots of enlarged alveoli with less surface area and fewer alveolar capillaries); enlarged air sacs with less blood supply  Cardiovascular shock (blood flow to lungs is decreased). ◼ Pulmonary shunt – opposite of dead space. Consists of alveoli that are perfused, but not ventilated: Blood Without Air  Pneumonia and pulmonary oedema;  Tissue trauma – alveolar wall swelling;  Atelectasis – collapse of alveoli from failure to expand;  Mucous plugging;  Pulmonary arteriovenous fistula. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; https://www.osmosis.org/learn/Ventilation-perfusion_ratios_and_VQ_mismatch Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Hemic hypoxia ◼ Lack of oxygen in the blood flowing to the tissues because of decreased haemoglobin level  Anemia – low count of erythrocytes in blood leads to low hemoglobin levels.  Functional hemoglobin defects: inability to transport oxygen molecules: ◼ CO intoxication; ◼ Fe oxidation from Fe2+ to Fe3+: methemoglobinemia; severe oxidative stress (smoking etc.). ◼ Increased hemoglobin affinity to oxygen: thalassemia; inherited hemoglobinopathies Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Oxyhemoglobin dissociation curve https://rk.md/2017/oxyhemoglobin-dissociation-curve/  Circulatory hypoxia oxygen can’t be delivered to tissues because of poor blood circulation, even if there’s enough oxygen in the lungs and blood. ◼ Decreased cardiac output leads to prolonged systemic transit time The body heart isn’t pumping enough blood, causing slower circulation through the Even though blood oxygen (PaO2) may ◼ The PaO2 in blood can be initially normal. start off normal, tissues won’t get enough oxygen because of sluggish blood flow.  Cardiovascular failure. heart’s pumping action is weak or failing (e.g., heart failure).  Shock (any etiology). A critical condition (e.g., from blood loss, infection, or heart failure) where blood flow to tissues drops too low. ◼ Can rapidly progress to mixed hypoxia: circulatory + hemic; circulatory + respiratory hypoxia. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Histotoxic hypoxia ◼ Histotoxic hypoxia refers to a reduction in ATP production by the mitochondria due to a defect in the cellular usage of oxygen.  Cyanide poisoning: cessation of aerobic cell metabolism. Cyanide binds to the enzyme cytochrome C oxidase and blocks the mitochondrial transport chain.  Monobromides, tetrachloromethane: blocks Krebs cycle enzymes.  Anesthetic substance overdose: dehydrogenase blockage. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Symptoms of hypoxia ◼ Cyanosis ◼ Dyspnea – subjective and objective difficulty of breathing (shortness of breath; breathlessness). ◼ Hypotension ◼ Other symptoms:  Fatigue  Malaise  Anxiety, confusion, insomnia ◼ Symptoms caused by compensatory mechanisms Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Symptoms of hypoxia: cyanosis (I) ◼ Cyanosis is characterized by a blueish discoloration of the skin or mucous membranes. ◼ Central cyanosis occurs when the level of deoxygenated hemoglobin in the arteries is above 50 g/L with oxygen saturation below 85%. ◼ Cyanosis might not be clinically evident in a patient with severe anemia due to inability to obtain high enough level of reduced hemoglobin. Anemia means less hemoglobin overall: There’s not enough hemoglobin in the blood to produce the high levels of reduced hemoglobin needed to cause cyanosis, even if oxygen levels are very low. Reduced hemoglobin is the key: Cyanosis= high level of reduced hemoglobin hence less oxygen Cyanosis becomes noticeable only when there’s a high concentration of deoxygenated hemoglobin (around 5g/dL or more), which may not be possible in someone with very low total hemoglobin levels. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Symptoms of hypoxia: cyanosis (II) ◼ Types of cyanosis:  Central/ arterial cyanosis: arterial blood are not enough oxydated and contains reduced hemoglobin: ◼ Tetralogy of Fallot (a type of congenital heart pathologies). ◼ Lung diseases.  Peripheral/ acral/ venous cyanosis: seen in the upper and lower extremities where the blood flow is less rapid. ◼ Low cardiac output; ◼ Venous stasis; ◼ Exposure to extreme cold. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Symptoms of hypoxia: cyanosis (III) ◼ The arterial blood gas shows the partial pressure of dissolved oxygen in the blood as well as the saturation of hemoglobin. ◼ The pulse oximeter measures the absorption of light at only two wavelengths which correspond to that of oxyhemoglobin and deoxyhemoglobin. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; https://www.ncbi.nlm.nih.gov/books/NBK482247  Hypoxia without cyanosis ◼ Hemic hypoxia – due to anemia with total hemoglobin 60 – 90 g/L (normal level 120 – 150 g/L) ◼ CO intoxication: carboxyhemoglobin is lightly red ◼ Histotoxic hypoxia Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Consequences of hypoxia ◼ Target organs:  Brain!!  Heart  Lungs  Kidneys  Liver  Skeletal muscle Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Compensatory mechanisms (I) ◼ Organs responsible for blood oxygenation and possible compensation are:  Cardiovascular system  Respiratory system  Erythrocytes  Tissue metabolism Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Compensatory mechanisms (II) ◼ Hyperventilation (tachypnoea, hyperpnea):  Hypoxic stimulation leads to hyperventilation in an attempt to correct hypoxia at the expense of a CO2 loss  Hyperventilation can lead to respiratory alkalosis  Hyperventilation is the fastest compensatory mechanism for respiratory acidosis Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Compensatory mechanisms (III) ◼ Tachycardia:  Develops in hypoxic, respiratory, hemic hypoxia  Tachycardia raises myocardial need for oxygen, thus leading to myocardial hypoxic injury  Can result in circulatory hypoxia - Tachycardia: = Develops in hypoxic, respiratory, hemic hypoxia = Tachycardia raises myocardial need for oxygen, thus leading to myocardial hypoxic injury = Can result in circulatory hypoxia leading to circulatory hypoxia (poor circulation of oxygenated blood). Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Compensatory mechanisms (IV) ◼ Centralization of blood circulation When the body faces a shortage of blood or oxygen, it prioritizes sending blood to vital organs (like the heart and brain) and reduces blood flow to less essential areas (like the skin or muscles). This system gets triggered ◼ Renin-angiotensin-aldosterone system activation: when there’s a drop in blood volume, such as after blood loss.  Activated by hypovolemia, for example, after blood loss  Positive effect, if hypoxia is due to blood loss  Can have negative impact in case of circulatory hypoxia if heart pathology is due to arterial hypertension ◼ Increased erythropoietin synthesis in kidneys: it then forms RBC  Secondary polycythemia increase in the number of red blood cells  Positive effect, if hypoxia is due to blood loss  Negative effect: blood viscosity increases leading to elevated risk for thrombosis Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023  Oxyhemoglobin dissociation curve ◼ Describes the relationship between the saturation of hemoglobin and the partial pressure of arterial oxygen. ◼ In healthy adults, a PO2 of ~27 mmHg corresponds to ~50% hemoglobin saturation (red curve). This is known as the P50 of hemoglobin. There are many physiologic stressors which can shift the curve rightward or leftward and therefore change hemoglobin’s P50. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; Gould’s Pathophysiology for the Health Professions, 7th edition, 2023 Oxyhemoglobin dissociation curve (ODC) https://rk.md/2017/oxyhemoglobin-dissociation-curve/  Rightward shift of ODC ◼ Rightward shift is caused by:  increased temperature,  increased CO2 production (and therefore decreased pH leading to an acidosis) and increased 2,3-diphosphoglycerate (DPG),  Hypoxia,  Anaemia. ◼ In these situations, it is important for hemoglobin to unload oxygen to the starved tissues. ◼ Additionally, sickle cell hemoglobin (HbSS) and sulfhemoglobin are unable to readily bind oxygen (low affinity) and therefore are right-shifted. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; https://rk.md/2017/oxyhemoglobin-dissociation-curve  Leftward shift of ODC ◼ A leftward shift less PO2 can achieve a higher hemoglobin saturation compared to the baseline. Hemoglobin has a higher affinity for oxygen and is less «willing» to give up oxygen molecules to peripheral tissues. Many of the factors which create left shifts are the opposite of those creating right shifts. ◼ Additionally, methemoglobinemia (metHb), is unable to accept oxygen like the typical 2+ oxidation state, creates a leftward shift. ◼ Carbon monoxide binds hemoglobin ~250x more rapidly than oxygen, so binding spots are reduced and the curve shifts leftward. ◼ Fetal hemoglobin is structurally different than adult hemoglobin and adapted to have high affinity for oxygen since the uteroplacental circulation has relatively low partial pressures of oxygen. Underwood's Pathology: a Clinical Approach, 7th edition, 2019; https://rk.md/2017/oxyhemoglobin-dissociation-curve  GOOD LUCK IN YOUR STUDIES!