# Internal Medicine/Hypoxia and Cyanosis
## Hypoxia

* Purpose of the Cardiorespiratory System
** The primary function of the cardiorespiratory system is to ensure the delivery of oxygen (O2) and nutrients to cells while removing carbon dioxide (CO2) and metabolic waste products from them. This vital process relies not only on the integrity of the cardiovascular and respiratory systems but also on factors like red blood cell count, hemoglobin levels, and the availability of inspired air with sufficient oxygen content.
* Responses to Hypoxia
** Hypoxia, which signifies decreased O2 availability to cells, leads to significant metabolic changes. It typically results in the inhibition of oxidative phosphorylation and an increase in anaerobic glycolysis. This shift from aerobic to anaerobic metabolism, known as the Pasteur effect, reduces the rate of adenosine 5'-triphosphate (ATP) production.
** In severe hypoxia, when ATP production falls short of meeting cellular energy demands, it triggers cell membrane depolarization, uncontrolled calcium ion (Ca2+) influx, and the activation of Ca2+-dependent enzymes, ultimately leading to cell swelling, activation of apoptotic pathways, and cell death.
** The body adapts to hypoxia by upregulating genes that encode various proteins, including glycolytic enzymes like phosphoglycerate kinase and phosphofructokinase, as well as glucose transporters (Glut-1 and Glut-2). Growth factors such as vascular endothelial growth factor (VEGF) and erythropoietin enhance red blood cell production. Hypoxia-induced gene expression is largely governed by the hypoxia-sensitive transcription factor, hypoxia-inducible factor-1 (HIF-1).
** Hypoxia also induces systemic arteriolar dilation by opening KATP channels in vascular smooth muscle cells, due to a decrease in ATP concentration. In contrast, in pulmonary vascular smooth muscle cells, inhibition of potassium (K+) channels leads to depolarization, activating voltage-gated Ca2+ channels, raising cytosolic Ca2+ levels, and causing smooth muscle contraction. While this hypoxia-induced pulmonary arterial constriction diverts blood from poorly ventilated lung areas to better-ventilated ones, it increases pulmonary vascular resistance and right ventricular afterload.
** Hypoxia's effects on the Central Nervous System (CNS) are significant. Acute hypoxia results in impaired judgment, motor coordination, and symptoms resembling acute alcohol intoxication. High-altitude illness includes symptoms like headaches, gastrointestinal distress, dizziness, insomnia, and fatigue. Severe hypoxia can lead to high-altitude pulmonary edema (HAPE) or, rarely, high-altitude cerebral edema (HACE), which can cause severe headaches, papilledema, and coma. In the later stages of severe hypoxia, brainstem regulatory centers are affected, typically leading to respiratory failure and death.
** In the Cardiovascular System, acute hypoxia triggers the chemoreceptor reflex, causing venoconstriction and systemic arterial vasodilation. This initial response is accompanied by a transient increase in myocardial contractility, followed by decreased contractility with prolonged hypoxia.
* Causes of Hypoxia
** Respiratory Hypoxia: It occurs due to respiratory failure, causing a decline in arterial oxygen partial pressure (Pao2). In cases of persistent respiratory failure, the hemoglobin-oxygen (Hb-O2) dissociation curve shifts to the right, leading to arterial hypoxemia, especially when caused by pulmonary diseases.
** Hypoxia Secondary to High Altitude: As individuals ascend to high altitudes, the reduced oxygen content in inspired air (Fio2) decreases alveolar oxygen partial pressure (Pao2). This leads to high-altitude illness, characterized by symptoms like headache, gastrointestinal issues, and more severe hypoxemia at higher altitudes.
** Hypoxia Secondary to Right-to-Left Extrapulmonary Shunting: This type of hypoxia is similar to intrapulmonary right-to-left shunting but is due to congenital cardiac malformations, such as tetralogy of Fallot or atrial septal defects.
** Anemic Hypoxia: It results from reduced hemoglobin concentration in the blood, leading to decreased oxygen-carrying capacity. Even though Pao2 may be normal, the absolute amount of O2 transported per unit of blood volume is reduced.
** Carbon Monoxide (CO) Intoxication: Hemoglobin binding with CO (carboxy-hemoglobin [COHb]) limits O2 transport, and COHb shifts the Hb-O2 dissociation curve to the left, reducing O2 unloading, further contributing to tissue hypoxia.
** Circulatory Hypoxia: Occurs due to reduced tissue perfusion and increased tissue O2 extraction, leading to an increased arterial-mixed venous O2 difference (a-v-O2 difference). It is common in heart failure and various forms of shock.
** Specific Organ Hypoxia: Localized circulatory hypoxia can result from arterial obstruction, vasoconstriction, venous obstruction, or edema. Different organs can experience localized hypoxia for various reasons.
** Increased O2 Requirements: Elevated tissue O2 consumption without a corresponding increase in perfusion leads to tissue hypoxia and a decline in venous Po2.
** Improper Oxygen Utilization: Certain toxins, like cyanide, impair cellular O2 utilization by interfering with mitochondrial electron transport and oxidative phosphorylation, leading to histotoxic hypoxia.
* Adaptation to Hypoxia
** The body responds to chronic hypoxia by increasing hemoglobin concentration and red blood cell production in the bloodstream, known as polycythemia. Chronic mountain sickness is a condition that can develop in individuals exposed to prolonged high-altitude hypoxemia, characterized by a blunted respiratory drive, reduced ventilation, erythrocytosis, and other symptoms.

## Cyanosis

* Definition and Types of Cyanosis
** Central Cyanosis: Occurs when arterial oxygen saturation (Sao2) decreases significantly, usually due to reduced oxygen partial pressure (Pao2). It is often associated with respiratory or cardiovascular problems.
** Peripheral Cyanosis: Typically caused by normal vasoconstriction in response to cold exposure. It may also result from reduced cardiac output, arterial obstruction, venous obstruction, or other circulatory issues.
* Differential Diagnosis of Central Cyanosis: Various factors can cause central cyanosis, including low Pao2 due to reduced atmospheric pressure, impaired pulmonary function (e.g., pneumonia or pulmonary edema), anatomic shunts (e.g., certain congenital heart diseases), and more.
* Approach to the Patient with Cyanosis:
** Evaluating the time of onset, differentiating central from peripheral cyanosis, checking for clubbing of the digits, measuring Pao2 and Sao2, and conducting spectroscopic examination of blood when the cause of cyanosis is unclear.
* Clubbing:
** Clubbing is the bulbous enlargement of distal finger and toe segments due to connective tissue proliferation. It can be hereditary, idiopathic, or associated with various medical conditions, including congenital heart disease, lung diseases (e.g., lung cancer, bronchiectasis), gastrointestinal diseases (e.g., inflammatory bowel disease, hepatic cirrhosis), and certain occupational exposures.