Clinical Medicine Midterm Notes PDF

The cardiovascular system Basic science underpins clinical medicine The cardiovascular system, also known as the circulatory system, is a complex network of organs and vessels responsible for transporting blood, oxygen, nutrients, and hormones throughout the body. The t...

The cardiovascular system Basic science underpins clinical medicine The cardiovascular system, also known as the circulatory system, is a complex network of organs and vessels responsible for transporting blood, oxygen, nutrients, and hormones throughout the body. The three principal components that comprise the circulatory system are: - The heart (the pump), - The blood vessels or vascular system (set of interconnected tubes) - The blood (a fluid connective tissue containing water, solutes, and cells that fills the tubes). BLOOD is composed of formed elements (cells and cell fragments) suspended in a liquid called plasma. More than 90% of PLASMA is water, but dissolved in it there are also a large number of proteins, nutrients, metabolic wastes, and other molecules being transported between organ systems. The plasma proteins constitute most of the plasma solutes by weight and can be classified in 3 major groups: The albumins and the globulins which have many overlapping functions, and Fibrinogen which play an important role in clotting (when fibrinogen and other clotting proteins are removed from the plasma, serum is obtained) The BLOOD CELLS are: - The leukocytes (white blood cells) which are involved in immune defenses and include neutrophils (engulf microbes by phagocytosis), eosinophils (fight off invasions by eukaryotic parasites releasing toxic chemicals), monocytes (circulate in the blood and develop into macrophages), macrophages (engulf virus and bacteria), basophils (secrete the anticlotting factors heparin at the site of infection to help the circulation flushing out the infected site and lymphocytes (T cells and B cells which protect against specific pathogens by directly killing them or by secreting antibodies into the circulation) - Platelets which are circulating cell fragments involved in maintaining homeostasis and blood  - The erythrocytes (red blood cells), which are produced by the bone marrow, are involved in gas transport, carrying oxygen taken in by the lungs and carbon dioxide produced by the cells. They contain large amounts of the protein hemoglobin to which oxygen and carbon dioxide reversibly combine (oxygen binds to iron atoms in the hemoglobin molecules). The hematocrit is defined as the percentage of blood volume that is erythrocytes. It is measured by centrifugation (spinning at high speed) of a sample of blood. The erythrocytes are forced to the bottom of the centrifuge tube, the plasma remains on top, and the leukocytes and platelets form a very thin layer between them called the buffy coat. The hematocrit is normally about 45% in men and 42% in women. The HEART plays a central and vital role in the circulatory system, ensuring the continuous flow of blood through the body. It consist of: - 4 chambers: 2 atria (upper chambers) and 2 ventricles (lower chambers) that work in coordination to ensure efficient blood circulation - 4 valves: Semilunar valves that prevent backflow of blood from arteries to ventricles during ventricular diastole (relaxation). → Aortic valve: located between left ventricle and aorta → Pulmonary valve: located between right ventricle and the pulmunary artery (trunk) Atrioventricular (AV) valves that prevent backflow of blood from ventricles to atria during ventricular systole (contraction) but do not control valve opening and closing → Tricuspid valve: located between right atrium and right ventricle → Bicuspid (or mitral) valve: located between left atrium and left ventricle Both are anchored by chordae tendinae - Walls: Endocardium: Is the innermost layer of the heart that lines chambers and valves. It is composed of endothelial cells (or endothelium), which rest on a thin layer of connective tissue. It is continuous with the lining of the blood vessels entering and leaving the heart. Myocardium: Is the middle and thickest layer and it is composed of cardiac muscle tissue (striated with sarcomeres) with cells containing numerous mitochondria, forming the bulk of the heart mass Is responsible for the contraction of the heart, generating the force needed to pump blood throughout the circulatory system. The gap junctions between cells allows action potential to spread rapidly from cell to cell Epicardium: Is the outermost fibrous layer, directly covering the surface of the heart and surrounding the myocardium Pericardium: Protective layer (fibrous sac) that surround the entire heart. The loosely fitting superficial part of this sac is the fibrous pericardium, while the tough, dense connective tissue layer protects the heart, anchors it to surrounding structures, and prevents overfilling of the heart with blood. Between the epicardium and the pericardium there is the pericardial cavity, which contains the pericardial fluid that reduces friction as the heart moves - Cells: Cardiac cells: Make up the cardiac tissue and work to keep the heart pumping through involuntary movements thanks to their ability to generate electricity Pacemaker cells: Comprise a small population that spontaneously fire to trigger each heartbeat. BLOOD VESSELS play a major function in reglating blood pressure and in distributing blood flow to the various tissue. They can be divided into arteries, arterioles, capillaries, venules, and veins. The main blood vessels in the cardiovascular system are: the superior/inferior vena cava, the pulmunary artery and vein, and the aorta The walls of all blood vessels, except the very smallest, have three distinct layers, or tunics (“coverings”), that surround a central blood-containing space, the vessel lumen. - The innermost tunic is the tunica intima which contains the endothelium, the simple squamous epithelium that lines the lumen of all vessels. The endothelium is continuous with the endocardial lining of the heart, and its flat cells fit closely together, forming a slick surface that minimizes friction as blood moves through the lumen. In vessels larger than 1 mm in diameter, a subendothelial layer, consisting of a basement membrane and loose connective tissue, supports the endothelium. - The tunica media (in the middle), is made of smooth muscle cells and sheets of elastin arranged circularly. The activity of the smooth muscle is regulated by sympathetic vasomotor nerve fibers of the autonomic nervous system and a different chemicals. Depending on the body’s needs at any given moment, regulation causes either vasoconstriction (lumen diameter decreases as the smooth muscle contracts) or vasodilation (lumen diameter increases as the smooth muscle relaxes). The activities of the tunica media are critical in regulating circulatory dynamics because small changes in vessel diameter greatly influence blood flow and blood pressure. Generally, the tunica media is the bulkiest layer in arteries, which bear the chief responsibility for maintaining blood pressure and circulation. - The outermost layer of a blood vessel wall, the tunica externa (also called the tunica adventitia), is composed largely of loosely woven collagen fibers that protect and reinforce the vessel, and anchor it to surrounding structures. The tunica externa is infiltrated with nerve fibers, lymphatic vessels, and, in larger veins, a network of elastic fibers. - ARTERIES carry oxygenated blood away from the heart under high pressure The exception to this is the pulmonary arteries, which carry deoxygenated blood to the lungs to get oxygenated Their second major function, related to their elasticity, is to act as a “pressure reservoir” for maintaining blood flow through the tissues during diastole. The major coronary vessels that perfuse the heart are the Right Coronary Artery, the Left Coronary Artery, the Left Anterior Descending Artery and the Left Circumflex Artery If one of these vessel gets occluded, the blood flow to the heart stops and a heart attck occurs As they branch out, they become smaller and form ARTERIOLES, which have smooth muscle that enables them to regulate blood flow to specific tissues by controlling the diameter of their lumens, a process known as vasoconstriction (narrowing) or vasodilation (widening). Arterioles then deliver blood to capillaries - CAPILLARIES are the smallest but most numerous blood vessels. They connect arterioles to venules and play a crucial role in the exchange of oxygen, nutrients, and waste products between the blood and tissues (have intimate contact with tissue cells). This exchanges occur primarily through the thin capillary walls. Lipid soluble substances such as CO2, O2 and steroid hormones, easily diffuse across the plasma membrane and pass through the endothelial cells. On the other hand, substances insoluble in lipids such as glucose, amino acids and electrolytes, have to pass through fluid-filled pores within and between the endothelial cells. Large, non-lipid molecules such as plasma protein are excluded from passage. They are endothelial cells with no smooth muscle therefore they cannot regulate their own blood flow. Because of this they have what are called precapillary sphincters, small rings of smooth muscle located at the entrance of capillary beds. They play a crucial role in regulating blood flow into capillaries and, consequently, controlling the distribution of blood within tissues  The contraction or relaxation of these sphincters is a dynamic process that allows the body to adjust blood flow based on metabolic needs The lymphatic system recovers fluids that leak from the blood vessels VENULES are small veins connected to capillaries that then branch out to form bigger VEINS which are responsible for returning the deoxygenated blood back to the heart from the periphery (venous return) under lower pressure. The pulmonary vein is the only exception since it carries oxygenated blood to the heart to get delivered to the rest of the body. Are composed of the same 3 layers as the arteries, but they have thinner walls, less elastic tissue and less smooth muscle. They are capacitance vessels sincethey have a larger internal diameter (less rigid so can hold more blood) Veins are able to carry out their functions thanks to 3 mechanisms: - Skeletal muscle pump: When muscles contract during activities such as walking or exercising, they squeeze the nearby veins, pushing blood back toward the heart. This action helps propel blood against gravity and assists in venous return. - Respiratory pump: During inhalation, the diaphragm contracts, and the thoracic cavity expands, causing a decrease in thoracic pressure. This decrease in pressure helps draw blood into the thoracic veins, including the vena cava, aiding venous return to the heart. - Venous valves: Medium and large veins also have one-way valves that prevent the backflow of blood. These valves ensure that blood moves unidirectionally toward the heart. The rapid flow of blood throughout the body is produced by pressures created by the pumping action of the heart. This type of flow is known as BULK FLOW because all constituents of the blood move together. Cardiovascular system function is impacted by the endocrine, nervous, and urinary systems. The circulatory system forms a closed loop, so that blood pumped out of the heart through one set of vessels returns to the heart by a different set. Therefore the CIRCULATION in the cardiovascular system can be broadly categorized into two main circuits: - The left side of the heart is the pump for systemic circulation, which carries oxygen-rich blood from the left ventricle through all the organs and tissues of the body (except the lungs) and then to the right atrium. - On the other hand, the right side of the heart is the pump for pulmonary circulation, which carries oxygen-poor blood from the right ventricle to the lungs and then to the left atrium. More particularly the pathway of blood through the heart is a carefully coordinated flow: In booth circuits, blood vessels carry the blood and are collectively termed microcirculation  HEARTBEAT COORDINATION Lecture 4 The heart is a dual pump in that the left and right sides of the heart pump blood separately, but simultaneously, into the systemic and pulmonary vessels. Efficient pumping of blood requires that the atria contract first, followed almost immediately by the ventricles. Contraction of cardiac muscle, like that of skeletal and many smooth muscle, is triggered by depolarization of the plasma membrane. Gap junctions interconnect myocardial cells and allow action potentials to spread from one cell to another. This initial depolarization normally arises in a small group of conducting-system cells (that determine the heart rate) called the sinoatrial (SA) node, located in the right atrium near the entrance of the superior vena cava. The action potential then spreads from the SA node throughout the atria and then into and throughout the ventricles. SEQUENCE OF EXCITATION The SA node is normally the pacemaker for the entire heart. Its depolarization generates the action potential that leads to depolarization of all other cardiac muscle cells. Electrical excitation of the heart is coupled with contraction of cardiac muscle, therefore, the discharge rate of the SA node determines the heart rate, the number of times the heart contracts per minute. The action potential initiated in the SA node spreads throughout the myocardium, passing from cell to cell by way of gap junctions. Depolarization first spreads through the muscle cells of the atria, with conduction rapid enough that the right and left atria contract at essentially the same time. The spread of the action potential to the ventricles involves a more complicated conducting system, which consists of modified cardiac cells that have lost contractile capability but that conduct action potentials with low electrical resistance. The link between atrial depolarization and ventricular depolarization is a portion of the conducting system called the atrioventricular (AV) node, located at the base of the right atrium. The action potential is conducted relatively rapidly from the SA node to the AV node through internodal pathways. The propagation of action potentials through the AV node is relatively slow (requiring approximately 0.1 sec), a delay that allows atrial contraction to be completed before After the AV node has become excited, the action potential propagates down the interventricular septum. This pathway has conducting-system fibers called the bundle of His, or atrioventricular bundle. The AV node and the bundle of His constitute the only electrical connection between the atria and the ventricles. Except for this pathway, the atria are separated from the ventricles by a layer of nonconducting connective tissue known as the interventricular septum. Within the interventricular septum, the bundle of His divides into right and left bundle branches, which separate at the bottom (apex) of the heart and enter the walls of both ventricles. These pathways are composed of Purkinje fibers, which are large-diameter, rapidly conducting cells connected by low-resistance gap junctions. The branching network of Purkinje fibers conducts the action potential rapidly to myocytes throughout the ventricles. The rapid conduction along the Purkinje fibers and the diffuse distribution of these fibers cause depolarization of right and left ventricular cells to occur nearly simultaneously and ensure a single coordinated contraction. Actually, though, depolarization and contraction do begin slightly earlier in the apex of the ventricles and then spread upward. The result is an efficient contraction that moves blood toward the exit valves. CARDIAC ACTION POTENTIAL AND EXCITATION OF THE SA NODE The mechanism by which action potentials are conducted along the membranes of heart cells is similar to that of other excitable tissues like neurons and skeletal muscle cells. It involves the controlled exchange of materials (ions) across cellular membranes, however, different types of heart cells express unique combinations of ion channels that produce different action potential shapes. In this way, they are specialized for particular roles in the spread of excitation through the heart MYOCARDIAL CELL ACTION POTENTIAL As in skeletal muscle cells and neurons, the resting membrane is much more permeable to K+ than to Na+, therefore, the resting membrane potential is much closer to the K+ equilibrium potential than to the Na+ equilibrium potential. 1) Because of this, the depolarizing phase of the action potential is due mainly to the opening of voltage-gated Na+ channels, resulting in the entry of sodium ions that depolarize the cell and sustains the opening of more Na+ channels in positive feedback fashion. 2) However, unlike other excitable tissues, the reduction in Na+ permeability in cardiac muscle is not accompanied by immediate repolarization of the membrane to resting levels. Rather, there is a partial repolarization caused by a special class of transiently open K+ channels, and then the membrane remains depolarized at plateau for a prolonged period. This continued depolarization occurs because K+ permeability declines below the resting value due to the closure of the K+ channels that were open in the resting state, and because there is a large increase in the cell membrane permeability to Ca2+. 3) In myocardial cells, membrane depolarization causes voltage-gated Ca2+ channels in the plasma membrane to open, which results in a flow of Ca2+ ions down their electrochemical gradient into the cell. These channels open much more slowly than do Na+ channels, and, because they remain open for a prolonged period, they are often referred to as L-type Ca2+ channels (L = long lasting). The flow of positive Ca ions into the cell just balances the flow of K ions out of the cell keeps the membrane depolarized at the plateau value (200-300 milliseconds) 4) Ultimately, repolarization does occur as potassium moves out. This is due to the inactivation of the L-type Ca2+ channels and the opening of another subtype of K+ channels, which open in response to depolarization (but after a delay) and  NODAL CELL ACTION POTENTIAL There are important differences between action potentials of cardiac muscle cells and those in nodal cells of the conducting system. The SA node cell does not have a steady resting potential but, instead, undergoes a slow depolarization known as pacemaker potential which brings the membrane potential to threshold, at which point an action potential occurs. Three ion channel mechanisms contribute to the pacemaker potential. - The first is a progressive reduction in K+ permeability. The K+ channels that opened during the repolarization phase of the previous action potential gradually close due to the membrane’s return to negative potentials. - Second, pacemaker cells have a unique set of channels that, unlike most voltage-gated ion channels, open when the membrane potential is at negative values. These nonspecific cation channels known as F-type conduct mainly an inward, depolarizing Na+ current - The third pacemaker channel is a type of Ca2+ channel known as T-type that opens only briefly but contributes inward Ca2+ current and an important final depolarizing boost to the pacemaker potential. Although SA node and AV node action potentials are basically similar in shape, the pacemaker currents of SA node cells bring them to threshold more rapidly than AV node cells, which is why SA node cells normally initiate action potentials and determine the pace of the heart. 1) The depolarizing phase is caused not by Na+ but rather by Ca2+ influx through L-type Ca2+ channels. These Ca2+ currents depolarize the membrane more slowly than voltage-gated Na+ channels, and one result is that action potentials propagate more slowly along nodal-cell membranes than in other cardiac cells. 2) As in cardiac muscle cells, the long-lasting L-type Ca2+ channels prolong the nodal action potential, but eventually they close and K+ channels open and the membrane is repolarized. The return to negative potentials activates the pacemaker mechanisms once again, and the cycle repeats. Thus, the pacemaker potential provides the SA node with automaticity, the capacity for spontaneous, rhythmic self-excitation (independent of the nervous system) The slope of the pacemaker potential (how quickly the membrane potential changes per unit THE ELECTROCARDIOGRAM The electrocardiogram (ECG, also abbreviated EKG) is a tool for evaluating the electrical events within the heart. When action potentials occur simultaneously in many individual (contractile) myocardial cells, negative and positive currents (depolarization an repolarization events) are conducted through the body fluids around the heart and can be detected by recording electrodes at the surface of the skin. 12 different leads look at different aspects of the heart, however, usually 3 lead can accurately monitor heart rate and regularity. They are placed in what is known as the Einthoven Triangle, where - Lead I measures the electrical difference between the right arm (negative electrode) and the left arm (positive electrode). - Lead II measures the electrical difference between the right arm (negative electrode) and the left leg (positive electrode). - Lead III measures the electrical difference between the left arm (negative electrode) and the left leg (positive electrode). The triangle is formed by connecting these three leads, creating an equilateral triangle where the heart lies in the center. The electrical activity of the heart is projected along these axes, and the sum of the potentials in each lead (I + III = II) follows Einthoven's law. The triangle helps interpret the frontal plane of heart electrical activity, providing essential information in diagnosing heart conditions The ECG paper is broken into different sized boxes and squares to represent time (horizonally) and voltage (vertically). This is vital when determining if an ECG is normal or abnormal In a ECG the first deflection, the P wave, corresponds to current flow during atrial depolarization. The second deflection, the QRS complex, occurring approximately 0.15 sec later, is the result of ventricular depolarization. The final deflection, the T wave, is the result of ventricular repolarization. Atrial repolarization is usually not evident on the ECG because it occurs at the same time as the QRS complex. More particularly the PR Interval goes from the start of Atrial Depolarisation to the Start of Ventricular Depolarisation (0.12–0.20 seconds which means 3–5 squares) The ST Segment is the period at which both ventricles are completelydepolarised and ready to depolarised. If there is a delay, the voltage goes up and the R peak will result much more higher than usual, meaning that a massive heart attck will occur) The QT Interval is the time for both ventricular depolarization and repolarization to occur (0.33–0.42 seconds which means approx. 8-10 squares) In conclusion the ECG is not a direct record of the changes in membrane potential across individual cardiac muscle cells, but is a measure of the currents generated in the extracellular fluid by the changes occurring simultaneously in many cardiac cells. By using these methods, you To accurately determine the heart rate and assess the regularity of the heart rhythm, which helps in diagnosing cardiac conditions, differnt methods can be used. Each method is based on measuring the R-R interval, which is the distance between consecutive R-waves, representing ventricular contraction. - Six-Second Method: Count the number of R-waves in a 6-second interval (30 large boxes) and multiply by 10 to get the heart rate in bpm. In this case 4 x 10 = 40 bpm (person has bradichardia) - Heart Rate Calculator Rulers: Specialized rulers designed to measure heart rate based on the distance between R-waves. You have to match the QRS complex with the number and will get the reading - R-R Method: The number of large squares (5mm boxes) between two R waves is measured. The heart rate is calculated by dividing 300 by the number of large squares between the R-waves. In this case there are 5 boxes between the R waves, therefore 300/5 = 60 bpm - Digital Method: Many modern ECG machines have a built-in heart rate calculator that automatically detects the R-R intervals and In ECG analysis, different are the aspects that have to be checked: - P waves: Are they presents? Are they regular? Is there one P wave for each QRS complex? Are the P waves upright or inverted? (depends if there are issues with SA node) Do all the P waves look alike? (if not, there is a conduction issue) Is the P– R Interval >0.12 and < 0.20 seconds? - QRS complex: Do all the QRS complexes look alike? What is the QRS duration? Are there any ST segment changes? Is it normal, elevated (heart attack) or depressed (usually because of previous damages) ? The regularity of the heart rhythm is an important aspect that can help identify underlying cardiac conditions. Here’s how regularity is classified: - Regular: The time between consecutive R-waves (R-R intervals) is consistent. Seen in normal sinus rhythm, where the electrical impulses originate from the sinoatrial (SA) node at regular intervals. Another example is sinus bradychardia, where the electrical impulse still originates from the sinoatrial (SA) node, which keeps the time interval between each beat (R-R interval) the same, resulting in a regular rhythm, even though it is slower (below 60 beats per minute because of a delay between the Sa node and the AV node) Sinus tachycardia is a regular rhythm as well. It is characterized by a heart rate that is faster than normal (above 100 beats per minute), but the rhythm remains consistent, meaning that the R-R intervals are equal, and the pattern is uniform, with each P wave followed by a QRS complex. Supraventricular Tachycardia (SVT) is also generally regular. In SVT, the heart rate is very fast, usually over 150 beats per minute, but the rhythm itself is regular, meaning that the time interval between each heartbeat remains constant. SVT originates above the ventricles, however, instead of spreading, it goes back to the Bundle of His, creating a loop. Ventricular Tachycardia (VT) is also classified as regular. This arrhythmia is characterized by a rapid heart rate originating from the ventricles, with a consistent rhythm. VT can be stable (with a pulse) or unstable (without a pulse) If the patient is not responsive, immediate intervention is often required to try and reset the heart: SHOCKABLE - Regularly Irregular: There is an irregularity in the rhythm, but it follows a pattern. - Irregularly Irregular: No consistent pattern to the R-R intervals. This is characteristic of atrial fibrillation (AFib), where the atria contract in a completely uncoordinated manner, leading to an irregular ventricular response. As a result, the R-R intervals on the ECG are uneven, and P waves are absent or replaced by erratic fibrillatory waves. It is usually solved using medications Premature Ventricular Complexes (PVCs) are also considered irregularly irregular. PVCs occur when there is an early contraction of the ventricles, followed by a compensatory pause which disrupts the normal rhythm of the heart. The R-R intervals become uneven, indicating the irregular nature of the rhythm. Ventricular fibrillation is also irregularly irregular. In VF, the ventricles quiver ineffectively rather than contracting in a coordinated manner, leading to a chaotic and disorganized electrical activity. VF is a life-threatening condition that can result in cardiac arrest, and immediate medical intervention is required: SHOCKABLE.  Asystole (unusual) is characterized by a complete absence of electrical activity in the heart, resulting in no contractions of the heart muscle, therefore leading to a flatline on the electrocardiogram (ECG). The ECG will show a straight line, indicating the absence of P waves, QRS complexes, or any other heart activity. As such, it is classified as irregularly irregular, but more accurately, it represents no rhythm at all: NOT SHOCKABLE Pulseless Electrical Activity (PEA) is a condition where there is organized electrical activity on the ECG, but the heart does not produce a pulse or adequate blood pressure (usually followin ga trauma) It is considered irregularly irregular in nature because, while there may be some electrical patterns, they do not correspond to effective cardiac contractions: NOT SHOCKABLE EXCITATION-CONTRACTION COUPLING The small amount of extracellular Ca2+ entering through L-type Ca2+ channels during the plateau of the action potential triggers the release of a larger quantity of Ca2+ from the sarcoplasmic reticulum through the ryanodine receptor channels. Ca2+ activation of thin filaments and cross-bridge cycling then lead to generation of force, just as in skeletal muscle. Contraction ends when Ca2+ is returned to the sarcoplasmic reticulum and extracellular fluid. Since the amount of Ca2+ released from the sarcoplasmic reticulum in cardiac muscle during a resting heartbeat is not usually sufficient to saturate all troponin sites, the number of active cross-bridges (and thus the strength of contraction) can be increased if more Ca2+ is released from the sarcoplasmic reticulum (as would occur, for example, during exercise). REFRACTORY PERIOD OF THE HEART Cardiac muscle is incapable of undergoing summation of contractions like that occurring in skeletal muscle This inability is the result of the long absolute refractory period of cardiac muscle, defined as the period during and following an action potential when an excitable membrane cannot be re-excited. Because of the prolonged, depolarized plateau in the cardiac muscle action potential, the absolute refractory period of cardiac muscle lasts almost as long as the contraction (approximately 250 msec), and the muscle cannot be re-excited multiple times during an ongoing contraction THE CARDIAC CYCLE The orderly process of depolarization triggers a recurring cardiac cycle of atrial and ventricular contractions and relaxations that take place during one complete heartbeat (0.8 sec at rest). It consists of two periods, both named for events occurring in the ventricles: - The phase of ventricular contraction and blood ejection called systole (0.3 secs) and - The alternating period of ventricular relaxation and blood filling, known as diastole (0.5 secs) Audible noises, also known as heart sounds, generated by the functioning of the heart occur during the cardiac cycle. 1) It starts with ATRIAL SYSTOLE where the atria contract. Blood is forced through the AV valves (semilunar aew closed) into the ventricles, which are relaxed at this point. Atrial contraction tops off the blood in the ventricles, adding to the End-Diastolic Volume (EDV), the maximum volume of blood in the ventricles during the cardiac cycle. 2) In VENTRICULAR SYSTOLE the ventricles contract while the atria relax. It is also termed ISOVOLUMETRIC VENTRICULAR CONTRACTION, because even if the pressure in the ventricles rises to a value greater than the atrial pressure, the ventricular volume remains contastant because all valves (both AV and semilunar) are closed. This prevent backflow into the atria, ando also causes the production of the first heart sound (S1), a soft, low-pitched lub. 3) The pressure in the ventricles however keeps increasing and arrives at a point where exceeds that in the aorta and pulmunary trunk, leading to the opening of the pulmonary valve (right side) and aortic valve (left side). In this pahse maximum arterial pressure, also known as systolic pressure (SP) is reached As a result, blood is ejected from the heart in what is known as the VENTRICULAR EJECTION PERIOD. The right ventricle pumps deoxygenated blood into the pulmonary artery, sending it to the lungs, while the left ventricle pumps oxygenated blood into the aorta, sending it to the rest of the body. The volume of blood ejected from each ventricle is called the STROKE VOLUME (SV), while the amount of blood remaining in the ventricle after the ejection is called the end-systolic volume (ESV). Frank-Starling Law states that the stroke volume of the left ventricle will increase as the left ventricular volume increases due to the myocyte stretch causing a more forceful systolic contraction (Cardiac contractility) 4) In VENTRICULAR DIASTOLE (EARLY) after the blood is ejected, the ventricles relax. As the pressure in the ventricles drops, the semilunar valves close to prevent backflow from the arteries into the ventricles, producing the second heart sound (S2), a louder dup. At this time, the AV valves are also closed, therefore, no blood is entering or leaving the ventricles (ventricular volume is not changing) hence the name ISOVOLUMETRIC VENTRICULAR RELAXATION The closing of the aortic valve causes a temporary increase in pressure in the aorta, which results in a brief upward deflection in the arterial pressure also known as dirotic notch However this effect ends rapidly since the ventricular pressure falls lower than atrial pressure. 5) This change in pressure gradient then results in the opening of the AV valves, and VENTRICULAR FILLING occurs as blood starts to flow passively in from the atria, in what is called the VENTRICULAR DIASTOLE (LATE). Here the minimum arterial pressure, also called diastolic pressure (DP) is reached. Atrial systole will then follow again to complete the filling of the ventricles (EDV) Preload: The amount of stretch experienced by cardiac muscle, at the end of ventricular filling during diastole. Afterload: Resistance that the L ventricle must overcome to pump blood. The volume of blood each ventricle pumps as a function of time, usually expressed in liters per minute, is called the CARDIAC OUTPUT (CO). In the steady state, the cardiac output flowing through the systemic and the pulmonary circuits is the same. The cardiac output can be calculated by multiplying the heart rate (the number of beats per minute) and the stroke volume (the blood volume ejected by each ventricle with each beat). Therefore: CO = HR x SV BLOOD PRESSURE REGULATION involves a complex set of mechanisms that maintain the balance between blood flow and vascular resistance to ensure adequate oxygen and nutrient supply to tissues. It operates through short-term and long-term processes involving the nervous system, hormones, and the kidneys. SHORT-TERM REGULATION It involves the nervous system and responds quickly to changes in blood pressure, such as when you stand up suddenly. - Baroreceptor Reflex: Is a key mechanism for maintaining short-term blood pressure homeostasis. Baroreceptors are stretch-sensitive receptors located in the carotid sinus and aortic arch. They detect changes in blood pressure based on how much the vessel walls are stretched With high blood pressure, an increased stretching of baroreceptors occurs, which sends signals to the brainstem (medulla oblongata). This leads to an increased parasympathetic activity (via the vagus nerve) and a decreased sympathetic activity, which ultimately results in the slowing of heart rate (bradycardia), dilation of blood vessels (vasodilation), and reduction of cardiac output (amount of blood pumped by the heart). With low blood pressure a decreased stretch in baroreceptors happens leading to a reduced signaling to the brainstem. This increases the sympathetic activity as well as the heart rate (tachycardia), the force of contraction, and vasoconstriction (narrowing of blood vessels), resulting in the increase of blood pressure to restore normal levels. - Chemoreceptor Reflex: Chemoreceptors located in the carotid and aortic bodies respond to changes in blood oxygen, carbon dioxide, and pH levels. Low oxygen (hypoxia) or high CO2 stimulate the chemoreceptors. At this point, signals are sent to the brainstem, which activates the sympathetic nervous system, causing increased heart rate, vasoconstriction, and elevated blood pressure to improve oxygen delivery. - Sympathetic Nervous System: It increases heart rate, as well as cardiac contractility (force of contraction) and constrict blood vessels, which raises LONG-TERM REGULATION It involves the kidneys and hormones. These mechanisms control blood volume and systemic vascular resistance. - RAAS system: The Renin-Angiotensin-Aldosterone System is a critical hormonal system that regulates blood pressure over time, particularly in response to low blood volume or low blood pressure. Angiotensinogen (produced by the liver) is converted by renin (secreted by the kidneys when blood pressure is low or when there's reduced blood flow to the kidneys) into angiotensin I, which in turn is converted into angiotensin II, a potent vasoconstrictor, by the angiotensin-converting enzyme (ACE) in the lungs. The angiotensin II has different effects: It increases peripheral resistance (vasoconstriction), raising blood pressure. Stimulates aldosterone release from the adrenal glands, which in turn increases sodium and water reabsorption by the kidneys, increasing blood volume and blood pressure. Stimulates ADH (antidiuretic hormone) that promotes water reabsorption in the kidneys, also increasing blood volume. - Aldosterone: Is produced by the adrenal cortex in response to angiotensin II or high potassium levels. It increases sodium reabsorption in the kidneys, which leads to water retention and increased blood volume, raising blood pressure. - Antidiuretic Hormone/ Vasopressin: ADH is released by the posterior pituitary gland in response to low blood volume or high plasma concentration. It increases water reabsorption in the kidneys, which raises blood volume and it has also a mild vasoconstrictor effect, increasing blood pressure. - Atrial Natriuretic Peptide: ANP is a hormone released by the atria of the heart when blood volume or pressure is too high. It promotes excretion of sodium and water by the kidneys, reducing blood volume. It also inhibits the RAAS and the release of renin, aldosterone, and ADH Causes vasodilation, reducing blood pressure. CLINICAL APLLICATION In CORONARY ARTERY DISEASE, changes in one or more of the coronary arteries cause insufficient blood flow (ischemia) to the heart. The result may be myocardial damage in the affected region, or even death of that portion of the heart (a myocardial infarction, or heart attack) Sudden cardiac deaths during myocardial infarction are due mainly to ventricular fibrillation, an abnormality in impulse conduction triggered by the damaged myocardial cells. A small fraction of individuals with ventricular fibrillation can be saved if emergency resuscitation procedures are applied immediately after the attack. This includes cardiopulmonary resuscitation (CPR) and defibrillation MEASUREMENT OF CARDIAC FUNCTION Human cardiac output and heart function can be measured by a variety of methods. - Echocardiography is a noninvasive technique that uses ultrasonic waves. It can detect the abnormal functioning of cardiac valves or contractions of the cardiac walls, and it can also be used to measure ejection fraction. - Cardiac angiography, also called angiogram, is usually performed for evaluating cardiac function and for identifying narrowed coronary arteries or blockages It requires the temporary threading of a thin, flexible tube called a catheter through an artery or vein into the heart. A liquid containing radio-opaque contrast dye is then injected through the catheter during high-speed x-ray videography. - The electrocardiogram  The respiratory system Lecture 3 The respiratory system is responsible for taking in air (oxygen) through inspiration and blowing out the used air (Carbon Dioxide) through expiration It is divided in the Upper and Lower Breathing Passage The UPPER BREATHING PASSAGE includes: - The NOSE (nasal cavity and mouth) which is divided in: External nose: The visible part made of bone and cartilage for support Internal nose which has 4 functions: Warming, moistening and filtering air Detecting olfactory stimuli (through sensory receptors in olfactory Epithelium) Modifying speech vibrations Producing mucus - Air inspired from the nose or mouth goes into the PHARYNX, a passageway for air and food that connects the nasal cavity to the larynx (part of the airways) and the oral cavity to the esophagus (through which food passes to the stomach). It has 3 subdivisions: nasopharynx, oropharynx, and laryngopharynx. - The LARYNX, also known as the voice box, houses vocal folds (vocal cords). Has framework of cartilage and dense connective tissue. When food is swallowed, the larynx moves upward and tips the Epiglottis over the opening of the trachea. The rest of the time, the air passage in the pharynx is open for breathing During expiration the outgoing air rushes by a pair of vocal cords and we can produce sounds by voluntarily tensing muscles that stretch the cords so that they vibrate. The LOWER BREATHING PASSAGE includes: - The TRACHEA, also known as the windpipe, is a flexible tube running from the larynx and dividing inferiorly (at about vertebrae T5) into two main bronchi. Its walls contain C-shaped cartilages that are incomplete posteriorly where connected by trachealis. Is anterior to oesophagus and it is an air passageway that cleans warms, and moistens - The LUNGS, like the heart, lungs are situated in the thorax (chest), the compartment of the body between the neck and abdomen. Each lung is surrounded by a completely closed sac, the pleural sac, consisting of a thin sheet of cells called pleura. The pleural surface coating the lung known as the visceral pleura is firmly attached to the lung by connective tissue. Similarly, the outer layer, called the parietal pleura, is attached to and lines the interior thoracic wall and diaphragm. The two layers of pleura in each sac are very close but not attached to each other. Rather, they are separated by an extremely thin layer of intrapleural fluid that t surrounds the lungs and lubricates the pleural surfaces so that they can slide over each other during breathing. Changes in the hydrostatic pressure of the intrapleural fluid (the intrapleural pressure Pip) cause the lungs and thoracic wall to move in and out together during normal breathing. - The BRONCHIAL TREE is an air passageways connecting trachea with alveoli. Their main functions ar clean, warm, and moisten incoming air. They consists of right and left main BRONCHI, which subdivide within the lungs to form lobar and segmental bronchi and bronchioles. Bronchiolar walls lack cartilage but contain complete layer of smooth muscle. Constriction of this muscle impedes expiration. In lungs, they divide into successively smaller tubes: Trachea → Primary Bronchi → Secondary Bronchi → Tertiary Bronchi → Bronchioles → Terminal Bronchioles → Respiratory Bronchioles Alveolar Ducts → Alveoli - The ALVEOLI are tiny, hollow sacs with open ends that are continuous with the lumens of the airways. The total alveolar-capillary surface area is very large, and this permits the rapid exchange of large quantities of oxygen and carbon dioxide by diffusion. In some of the alveolar walls, pores permit the flow of air between alveoli. Most of the air-facing surfaces of the wall are lined by a thick continuous layer of flat sqamous epithelial cells termed type I alveolar cells. Interspersed between these cells are thicker, specialized cells termed type II alveolar cells that produce Airways beyond the larynx can be divided into two zones: - The RESPIRATORY ZONE which extends from the respiratory bronchioles down and is the region where alveoli exchange gases with the blood - The CONDUCTING ZONE from the top of the trachea to the end of the terminal bronchioles, which contains no alveoli and does not exchange gases with the blood. RESPIRATION Is defined as the physical movement of air into and out of the lungs Movement of air depends upon - Pressure differences - Boyle’s Law: Pressure and volume have an inverse relationship Volume depends on movement of diaphragm and ribs - Compliance: measure of the elasticity of the lungs Itoccurs in different steps: 1) Ventilation: Exchange of air between atmosphere and alveoli by bulk flow 2) Exchange of O2 and CO2 between alveolar air and blood in lung capillaries by diffusion 3) Transport of O2 and CO2 through pulmonary and systemic circulation by bulk flow 4) Exchange of O2 and CO2 between blood in tissue capillaries and cells in tissues by diffusion 5) Cellular utilization of O2 and production of CO2 1) VENTILATION Is described as the exchange of air between the atmosphere and alveoli. Like blood, air moves by bulk flow from a region of high pressure to one of low pressure. Bulk flow can be described by the equation F = ∆P∕R where Flow (F) is proportional to the pressure difference (ΔP) between two points and inversely proportional to the resistance (R). During ventilation, air moves into and out of the lungs because the alveolar pressure is alternately less than and greater than atmospheric pressure. In accordance with the equation above describing airflow, a negative value reflects an inward-directed pressure gradient and a positive value indicates an outward-directed gradient. Therefore, when Palv is less than Patm, airflow flows inward (inspiration), but when Palv is greater than Patm, airflow flows outward (expiration). Flow (F) is directly proportional to the pressure difference (Palv − Patm) and inversely proportional to airway resistance (R). During ventilation, a volume change leads to a pressure change, which then leads to the flow of air until the pressures are equilibrated. To understand how a change in lung dimensions causes a change in alveolar pressure, it is important to learn one more basic physical principle described by BOYLE'S LAW, which is represented by the equation P1V1 = P2V2. At constant temperature, an increase in the volume of the container decreases the pressure of the gas, whereas a decrease in the container volume increases the pressure. In other words, in a closed system, the pressure of a gas and the volume of its container are inversely proportional. During inspiration and expiration, the volume of the “container” (the lungs) is made to change, and these changes then cause, by Boyle’s law, the alveolar pressure changes that drive airflow into or out of the lungs There are no muscles attached to the lung surface to pull the lungs open or push them shut. Rather, the lungs are passive elastic structures and their volume, therefore, depends on other factors. The first of these is the difference in pressure between the inside and outside of the lung, termed the TRANSPULMUNARY PRESSURE (Ptp). The pressure inside the lungs is the air pressure inside the alveoli (Palv), and the pressure outside the lungs is the pressure of the intrapleural fluid surrounding the lungs (Pip). Thus, Ptp = Palv - Pip Transpulmonary pressure is the TRANSMURAL PRESSURE that governs the static properties of the lungs. Transmural means “across a wall” and is represented by the pressure in the inside of the structure (Pin) minus the pressure outside the structure (Pout). Inflation of the lungs requires an increase in the transmural pressure such that Pin increases relative to Pout. 2) GAS EXCHANGE BETWEEN ALVEOLI AND BLOOD (Typical alveolar gas pressures are PO2 = 105 mmHg and PCO2 = 40 mmHg) Gas exchange across respiratory membrane in the lungs is efficient due to: - Differences in partial pressure - Short diffusion distance - Soluble gases - Large surface area of all alveoli - Local coordination of blood flow and airflow (constriction/dilation) The blood that enters the pulmonary capillaries is systemic venous blood pumped by the right ventricle to the lungs through the pulmonary arteries. Having come from the tissues, it has a relatively high PCO2 (46 mmHg) and a relatively low PO2 (40 mmHg). The differences in the partial pressures of O2 and CO2 on the two sides of the alveolar-capillary membrane result in the net diffusion of oxygen from alveoli to blood and of carbon dioxide from blood to alveoli, therefore, the blood leaving the lung capillaries is rich in oxygen and low in carbon dioxide, ready to be delivered to tissues. This process relies on the principles of simple diffusion, where gases move from areas of higher concentration to areas of lower concentration across the respiratory membrane. As this diffusion occurs, the PO2 in the pulmonary capillary blood increases and the PCO2 decreases. The net diffusion of these gases ceases when the capillary partial pressures become equal to those in the alveoli. Optimal gas exchange depends on a balance between ventilation (the flow of air into and out of and perfusion (the flow of blood through the pulmonary capillaries) in what is called the VENTILATION-PERFUSION MATCHING (V/Q matching) - Low V/Q ratio: If parts of the lung are well perfused with blood but poorly ventilated (due to a blocked airway), less O2 enters the blood, and CO2 removal is impaired. This is seen in conditions like chronic obstructive pulmonary disease (COPD), pneumonia or asthma. - High V/Q ratio: When ventilation is good, but blood flow is reduced (due to a blocked blood vessel), O2 is not fully transferred to the blood, and CO2 is not effectively removed. This happens in cases like pulmonary embolism, where blood flow is obstructed. Proper V/Q matching is essential for maintaining efficient gas exchange and keeping blood oxygenated. When there are mismatches, the body makes use of different mechanisms to help correct them: - Hypoxic vasoconstriction: When parts of the lung are poorly ventilated, blood vessels in those areas constrict, redirecting blood flow to better-ventilated areas of the lung to improve oxygenation. - Bronchoconstriction: In areas of poor perfusion, the airways may constrict slightly, reducing airflow to that area and matching ventilation with the reduced blood flow. 3) TRANSPORT OF OXYGEN IN BLOOD The transport of oxygen in the blood is a vital process that ensures tissues receive the oxygen they need for cellular respiration. It is primarily carried in the blood through two mechanisms: bound to hemoglobin in red blood cells and dissolved in plasma. - Via Hemoglobin (98-99%): Hemoglobin (Hb) is a protein found in red blood cells (RBCs) that can reversibly bind oxygen. Each hemoglobin molecule has four iron-containing heme groups, and each heme can bind one oxygen molecule. Therefore, 1 hemoglobin molecule can carry up to 4 oxygen molecules. The oxygen-hemoglobin binding process is influenced by the partial pressure of oxygen (PO2). In the lungs, where PO2 is high (around 100 mmHg), oxygen readily binds to hemoglobin, forming oxyhemoglobin (HbO2). On the other hand, in tissues, where PO2 is lower (around 40 mmHg or less), oxygen is released from hemoglobin to be delivered to cells. The oxygen-hemoglobin dissociation curve is an S-shaped curve that describes the relationship between PO2 and the percentage of hemoglobin saturation. It shows that in areas of high PO2 (lungs), hemoglobin becomes almost fully saturated, while in areas of low PO2 (tissues), hemoglobin releases oxygen more readily, especially during times of increased oxygen demand, like during exercise. - Dissolved in Plasma (1-2%): A small amount of oxygen is dissolved directly in the plasma. While this amount is relatively small, it is important because it creates the partial pressure of oxygen (PO2), which drives the diffusion of oxygen from the alveoli into the blood and from the blood into the tissues. CO2 on the other hand, is transported in 3 ways: - Dissolved in plasma (7%) - Carried on carbamino compounds (23%) - As HCO3- (70%) 4/5) GAS EXCHANGE BETWEEN TISSUES AND BLOOD and CELLULAR UTILISATION Oxygen diffuses from the blood into the tissues, where it is used for cellular respiration to produce ATP, the energy currency of the cell. As oxygenated blood reaches the tissue capillaries, the partial pressure of oxygen (PO2) in the blood is higher than in the tissues. This creates a partial pressure diffusion gradient, where oxygen moves from the blood into the tissues. Once in the tissues, oxygen is used in cellular respiration to produce ATP, the energy required for cellular processes. Carbon dioxide is produced as a byproduct of cellular respiration and must be transported from tissues to the lungs for exhalation. In tissues, the partial pressure of carbon dioxide (PCO2) is higher than in the blood. This difference in partial pressure allows CO2 to diffuse from the tissues into the blood (partial pressure gradient), where is transported via three mechanisms: - Dissolved in plasma (7-10%) - Bound to hemoglobin (20-30%): CO2 binds to hemoglobin in red blood cells (forming carbaminohemoglobin) - Bicarbonate ions (60-70%): The majority of CO2 is converted into bicarbonate The exchange of gases (O2 and CO2) between blood and tissues occurs at the level of the systemic capillaries, where the walls are thin enough to allow the diffusion of gases. This coordinated exchange of O2 and CO2 between blood and tissues is essential for maintaining homeostasis and ensuring that the body’s cells receive enough oxygen for energy production while removing waste gases like carbon dioxide.  AIRWAY COMPLIANCE AND RESISTANCE They work together to determine how easily air moves into and out of the lungs. Airway Compliance: Refers to the distensibility or stretchability of the lungs and airways. It is a measure of how much the lungs expand in response to a given change in pressure. Is equal to the change in lung volume divided by the change in transpulmonary pressure High compliance means that the lungs and airways expand easily with little pressure, while lowcompliance means that more pressure is required to expand the lungs and airways. There are different factors affecting compliance: - Lung tissue elasticity: More elastic tissue in the lungs decreases compliance because it resists expansion. - Surface tension in the alveoli: The alveoli have a tendency to collapse due to surface tension, but surfactant reduces this tension and increases compliance. - Age and disease: Conditions like fibrosis reduce compliance (stiff lungs), while diseases like emphysema increase compliance (overly distended lungs but poor recoil). Airway Resistance: Also known as elastance, it refers to the opposition to airflow through the respiratory tract. It is a measure of how difficult it is to move air through the airways, particularly in the bronchi and bronchioles. High resistance means that more pressure is needed to maintain airflow. Low resistance means that air flows more easily through the airways. There are different factors affecting resistance: - Airway diameter: Bronchoconstriction (narrowing of airways) increases resistance, as seen in conditions like asthma or chronic obstructive pulmonary disease (COPD). Bronchodilation (widening of airways) decreases resistance, often mediated by the SNS - Airway length: Longer airways can increase resistance - Airflow pattern: Laminar flow (smooth, orderly flow) has less resistance. Turbulent flow (disorganized flow) increases resistance, which can occur during rapid breathing or in illnesses - Airway obstructions: Conditions like mucus buildup, tumors, or foreign bodies can increase resistance.  THE CONTROL OF BREATHING Since O2 uptake and CO2 production varies widely, breathing must be controlled so as to maintain appropriate levels of O2 and CO2 in tissues The regulation of breathing depends on two interactive control mechanisms: Neurological and Chemical, however, other factors (Hering Breuer reflex, vasomotor and voluntary control) may also be involved - Neurological control: Although it can be voluntarily controlled breathing is normally regulated via involuntary nervous mechanisms Respiratory rhythmicity centres (DRG and VRG) in the medulla oblongata contain medullary inspiratory neurones which activate the inspiratory and expiratory respiratory muscles Medullary inspiratory neurones are very sensitive (depressed response) to barbiturates and morphine In the Pons there are also apneustic and pneumotaxic centres that alter the pattern of breathing - Chemical control: The spontaneous firing pattern in the medullary neurones is regulated by chemical factors which control the rate and depth of breathing Arterial Blood Gases (ABGs): Elevated arterial pCO2, decreased arterial pH and decreased arterial pO2 stimulate ventilation Central chemoreceptors: Located close to the respiratory centre in the medulla they're particularly sensitive to changes in arterial pCO2 Peripheral chemoreceptors: Located within the carotid and aortic bodies these are very sensitive to changes in arterial pH and act as a key part of the “fail-safe” response to very low pO2 ( 60%). There are 2 types of shunt, where O2 is reduced and CO2 is normal or low: Anatomical cardiovascular system abnormality which causes mixed venous blood to bypass ventilated alveoli when passing from right to left side of the heart (Trichuspid Atresia) Intrapulmonary defect in which mixed venous blood perfuses under-ventilated alveoli arising due to pulmonary edema (fluid in the alveoli) or due to pneumonia dense consolidation  ASTHMA Asthma is a chronic inflammatory disorder of the airway characterized by airway hyper- responsiveness (AHR), mucous over-production and mucosal oedema- It's one of the most common disease worldwide with an estimated 300 million affected individuals. (increasing in many countries, especially in children) It can develop at any age (adult-onset asthma) Different are the FACTORS INFLUENCING asthma development and expression: - Host factors such as genetic, atopy, airway hyperresponsivness, gender, obesity... - Environmental factors such as allergies, occupational sensitizers, tobacco smoke, air pollution, respiratory infections, diet... Asthma is commonly associated with a TYPE I HYPERSENSITIVITY REACTION, which is an immediate allergic reaction involving IgE antibodies. In asthma, exposure to allergens (like pollen, dust mites, or pet dander) triggers the immune system to produce IgE antibodies. These antibodies bind to mast cells and basophils, leading to the release of histamine and other inflammatory mediators when the allergen is encountered again. The reaction happens quickly, usually within minutes of allergen exposure. During an asthma attack, both the bronchial wall and the lumen (airway opening) undergo several abnormal changes. The bronchial wall becomes inflamed, leading to swelling (edema) that thickens the airway walls, goblet cells in the lining overproduce mucus, which accumulates and blocks the airway and the smooth muscle layer surrounding the bronchial walls contracts excessively, narrowing the airways and reducing airflow. There is also an increase in immune cells, including eosinophils and mast cells, which release inflammatory mediators like histamines and cytokines, further worsening inflammation. Due to the thickened bronchial walls, bronchoconstriction, and excess mucus, the airway lumen is significantly narrowed, limiting airflow in and out of the lungs. Excessive mucus can also clog the lumen, leading to even greater airflow obstruction. These combined changes are what cause the classic asthma symptoms of wheezing, shortness of breath, and coughing during an attack. The overall effect is a substantial reduction in air movement, making breathing difficult and less efficient. In contrast, a TYPE IV DELAYED HYPERSENSITIVITY REACTION involves T-cells, that recognize the antigen and release cytokines, which attract macrophages to the site, causing inflammation. It's a reaction that takes 48-72 hours to develop after exposure to an antigen, therefore it is slower compared to Type I and not antibody-mediated Idependently on the type, usually, once the exposure to the allergen occurs, inflammatory mediators are released ASTHMA DIAGNOSIS can occurr in different ways: - Blood and Sputum Eosinophils: Blood eosinophilia greater than 4% or 300-400/𝝁L supports the diagnosis of asthma - Serum Immunoglobulin E: Total serum immunoglobulin E levels greater than 100 IU observed in patients experiencing allergic reactions, not specific for asthma - Arterial Blood Gas: Is more often employed to assess the severity of an asthma attack and evaluate how well the lungs are oxygenating blood and removing carbon dioxide - CXR: Chest radiographic findings are generally normal although pneumothorax needs to be considered - Measuring PEF variability: PEF is the maximum speed of exhalation after taking a deep breath. = It reflects the degree of airflow obstruction in the large airways and is measured using a peak flow meter, a portable, handheld device that helps patients monitor their lung function regularly. Measuring Variability of Peak Expiratory Flow (PEF) in Asthma is an important tool for monitoring asthma control and assessing airflow obstruction. PEF variability gives insight into the degree of airway constriction and helps track the effectiveness of asthma management strategies: Fluctuations in PEF values indicate how much the airways narrow and open over time. A peak flow variation of 10/20% is suggestive of asthma, while anything higher is strongly suggestive - Typical spirometric tracing: Is a key diagnostic tool for asthma that measures lung function, specifically how much air a person can exhale and how quickly, and it provides objective data to help diagnose, differentiate and monitor respiratory diseases. The key parameters measured in spirometry include Forced Expiratory Volume in 1 second (FEV1) which records how much air a person can forcefully exhale in 1 sec (typically lower than normal due to airway obstruction) and Forced Vital Capacity (FVC) which is the total amount of air exhaled forcefully after a deep inhalation. A reduced FEV1 and a less markedly reduced FVC are usually measured in obstruction diseases like asthma, where the FEV1/FVC ratio (below 70%) indicates airway obstruction and therefore airflow limitation, a hallmark of asthma. Additionally, spirometry tests are often repeated and the readings obtained should have a 5% gap between them. Spirometry should also carrioed out after administering a bronchodilator (a medication that opens the airways) to see if lung function improves. A significant improvement in FEV1 after using a bronchodilator suggests reversible airway obstruction Flow-Volume Loops are graphical representations of the relationship between airflow and lung volume during inhalation and exhalation - HRCT: High-Resolution Computed Tomography (HRCT) is not commonly used as the primary diagnostic tool for asthma but thickening of the bronchial walls can be observed, which indicates chronic inflammation and remodeling of the airways - Allergy SkinTesting: It is useful in atopy - Eucapnic hyperventilation: With either cold or dry air is an alternative method of bronchoprovocation testing. - Exercise testing: Exercise-induced bronchospasm consist of 6-10 minutes of strenuous exertion at 85-90% of predicted maximal heart rate After completing the exercise, spirometry (a test that measures lung function) is performed at intervals of 15-30 minutes. The defined cutoff for a positive test result is a 15% decrease in FEV1 after exercise There are different conditions that can mimic asthma: Vocal cord dysfunction, Tracheal and bronchial lesions, Foreign bodies, Congestive heart failure, Sinus disease, Gastroesophageal reflux ASTHMA CONTROL can be categorized into several levels, which help clinicians determine the most appropriate management strategies. - Well-Controlled: Patients experience minimal or no symptoms, daytime or nighttime awakenings, and have a low need for rescue medication (less than twice a week). Lung function (measured by FEV1 or peak flow) is typically at or near personal best levels. - Partially Controlled: Patients may have symptoms more than twice a week, nighttime awakenings, or a higher reliance on rescue medication. There may be some limitations on activities, and lung function might be reduced compared to the patient's best levels. - Uncontrolled: Patients experience frequent symptoms throughout the day, have nighttime awakenings at least once a week, and have a high use of rescue inhalers. Activity levels are significantly affected, and lung function is below expected levels. To evaluate asthma control, clinicians often use standardized questionnaires like the Asthma Control Test (ACT) or Asthma Control Questionnaire (ACQ), which assess various factors, including symptoms and medication use. Additionally, regular spirometry or peak flow measurements can help track lung function over time. ASTHMA MANAGEMENT focuses on: - Maintaining normal activity levels, including exercise - Maintaining pulmonary function as close to normal levels as possible - Achieving and maintaining control of symptoms - Preventing asthma exacerbations - Avoiding adverse effects from asthma medications - Preventing asthma mortality In asthma management, reliever and controller MEDICATIONS serve distinct roles in preventing and treating symptoms: - Reliever medications: Also known as rescue or quick-relief medications, they play a critical role in asthma management, primarily offering quick relief during acute symptoms such as wheezing, shortness of breath, and chest tightness. They are usually nebulised, meaning that the medicine in it is aerolized and when using the pump, the pressure will force it down the lungs SABA and SAMA: (check inhalers chapter) Systemic Glucocorticosteroids: Take longer to work compared to inhaled medications and are typically administered orally (PO) or intravenously (IV) in acute asthma attacks to reduce inflammation in the airways and prevent the worsening of symptoms. Short-Acting oral 𝝱2-Agonists and Theophylline are drugs not used frequently due to potential side effects and the availability of safer alternatives. - Controller medications: Are the backbone of long-term asthma management. They are taken daily, regardless of symptoms, to prevent asthma attacks and maintain overall control of the disease. ICS: Inhaled Corticosteroids are the cornerstone of long-term asthma control. They work by reducing inflammation in the airways, preventing asthma symptoms and reducing the frequency and severity of exacerbations. LABAs: (check inhalers chapter) Systemic Glucocorticosteroids: Are powerful anti-inflammatory medications used during severe asthma attacks or exacerbations when quick control is needed. Anti-IgE/Other Biologic Therapies: They target specific components of the immune system to treat severe asthma that does not respond to standard therapy. Anti-IgE therapy works by blocking immunoglobulin E (IgE), which plays a crucial role in allergic responses. Other biologic therapies target different pathways (like IL-5) Leukotriene Modifiers: They block the action of leukotrienes, chemicals in the immune system that contribute to inflammation, bronchoconstriction, and mucus production Theophylline, Chromones and Long-acting oral 𝝱2-agonists are drugs not used frequently due to potential side effects and the availability of safer alternatives. There are also additional tratments that can be employed in the management of asthma: - Allergen immunotherapy: Can be particularly beneficial for individuals with asthma triggered by allergic reactions. By gradually exposing patients to increasing doses of allergens, the immune system becomes desensitized, leading to fewer and less severe asthma symptoms. The therapy works by altering the immune response, by promoting a shift from an IgE-mediated response, which triggers allergic reactions, to an IgG-mediated response, which helps block the effects of IgE. This shift can reduce airway inflammation and improve overall asthma control - Bronchial thermoplasty: Is a medical procedure used to treat severe asthma that is not adequately controlled by standard medications. This innovative treatment involves the application of controlled heat to the airway walls, which reduces the amount of smooth muscle present in the bronchi. By decreasing the smooth muscle, bronchial thermoplasty aims to limit bronchoconstriction that can lead to asthma symptoms. Asthma is often accompanied by several associated problems that can complicate its management. These issues can include: - GERD: Gastroesophageal reflux disease presents itself with the production of acid reflux, that can worsen asthma symptoms by irritating the airways. - Allergic Rhinitis: It can exacerbate asthma symptoms due to increased airway inflammation and hyperreactivity. Symptoms are: Conjunctival congestion, ocular shiners, transverse crease on the nose, pale violaceous nasal mucosa and nasal polyps - Chest infections: The underlying inflammation and hyperreactivity of the airways make asthmatic patients more susceptible to respiratory infections, including bronchitis and pneumonia  CHRONIC OBSTRUCTIVE PULMUNARY DISEASE (COPD) Is a common, preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases in particular cigarette smoke and biomass fuel Estimated global prevalence of 11.7% (95% CI 8.4%–15.0%) with approximately three million deaths annually With increasing prevalence of smoking in developing countries, and aging populations in high-income countries, the prevalence of COPD is expected to rise over the next 30 years. By 2030 predicted 4.5 million COPD related deaths annually. Some factors that influence its progression are: genetic factors (alpha1 antitrypsin deficiency), age and gender (usually develops in adults, not children), lung growth and development, exposure to particles, socioeconomic status, asthma and airway hyper-reactivity, chronic bronchitis and infections The PATHOPHYSIOLOGY of COPD involves several key processes that contribute to its development and progression, primarily driven by chronic inflammation, oxidative stress, and structural changes in the lung tissue. It particularly it is a comination of 2 conditions: - Chronic bronchitis: It is characterized by the chronic inflammation of the bronchial walls, which leads to structural changes, including narrowing of the airways and fibrosis. The goblet cells and mucus glands in the airways also increase in size and number, leading to excessive mucus production which obstructs airflow and contributes to chronic cough as the body attempts to clear the airways. The excessive mucus and narrowed airways impede the flow of air, reducing ventilation and resulting in decreased oxygenation of blood and retention of carbon dioxide, causing respiratory failure in severe cases. - Emphysema: It is characterized by proteolytic enzymes, particularly neutrophil elastase, contributing to the breakdown of elastin fibers in the alveolar walls. This destruction results in the loss of surface area for gas exchange and reduced elasticity of the lungs. As alveoli are destroyed, the small airways collapse during exhalation, leading to air trapping. The loss of functional alveoli leads to a mismatch between ventilation (airflow) and perfusion (blood flow), further impairing gas exchange and causing hypoxemia Therefore, it can be said that COPD can lead to both Type 1 and Type 2 respiratory failure depending on the severity of the disease and the balance between ventilation and gas exchange disturbances. Type 1 is more common early on due to hypoxemia caused by V/Q mismatch, while Type 2 respiratory failure emerges as the disease progresses, with CO2 retention due to airway obstruction and alveolar damage. COPD significantly impacts LUNG VOLUMES, as the disease involves airway obstruction, reduced lung elasticity, and alveolar damage. Both spirometry and flow-volume loops show persistent airflow limitation, with obstructive or mixed defects shown in the graph - Decreased Forced Vital Capacity (FVC): The maximum amount of air that can be forcefully exhaled after a deep breath, is often reduced in COPD. because air is trapped in the lungs and cannot be expelled - Increased Residual Volume (RV): Is the amount of air remaining in the lungs after a full exhalation and in COPD increases significantly due to air trapping that occurs as a result of airway obstruction and loss of lung elasticity. - Increased Total Lung Capacity (TLC): The combination of air trapping and hyperinflation (the overexpansion of the lungs) leads to an increase in total lung capacity (TLC), which represents the maximum amount of air the lungs can hold. The TREATMENT of COPD focuses on managing symptoms, preventing progression, and improving quality of life. - Stop Smoking: Smoking cessation is the most critical intervention to slow down disease progression, since it damages the lungs and worsens symptoms. - Treat Acute Exacerbations: Acute exacerbations are flare-ups that worsen symptoms. Management includes: Low-dose FiO2 (Fraction of Inspired Oxygen): Controlled oxygen therapy  Nebulized SABA: Short-Acting Beta-Agonists help open airways quickly. SAMA: Short-Acting Muscarinic Antagonists are bronchodilators that can help reduce bronchospasm. Systemic corticosteroids: Help reduce inflammation, Antibiotics: Used if there is a bacterial infection contributing to the exacerbation. - Chronic Management: Long-term management focuses on maintaining stable lung function: Inhalers: Long-Acting Beta-Agonists (LABA) to keep airways open. Long-Acting Muscarinic Antagonists (LAMA) to reduce bronchoconstriction. Inhaled Corticosteroids (ICS) to reduce airway inflammation, Prophylactic Antibiotics to prevent infections. Pulmonary Rehabilitation to improve physical function. BiPAP (Bilevel Positive Airway Pressure) which provides non-invasive ventilatory support in cases of respiratory failure. Lung Volume Reduction Surgery (LVRS) to remove diseased lung tissue to improve breathing efficiency Long-Term Oxygen Therapy also knows as Oxygen supplementation  INTERSTITIAL LUNG DISEASE Encompasses more than 200 different lung conditions that cause inflammation and scarring (fibrosis) in the lung's interstitium, the tissue around the alveoli. These conditions affect the lung's ability to exchange oxygen, leading to respiratory symptoms such as shortness of breath and a persistent dry cough. PULMUNARY FIBROSIS Is a condition characterized by scarring and thickening of the lung tissue, leading to progressive respiratory decline, which would have a restrictive defect on spirometry. It presents itself with symptoms like shortness of breath and cough, and once it is established is generally irreversible and may be complicated by Pulmonary Hypertension. CLASSIFICATION is dependent on clinical, including radiological and pathological findings - Idiopathic Pulmonary Fibrosis (IPF): most common and serious progressive form - Nonspecific Interstitial Pneumonia (NSIP): associated with autoimmune diseases. - Granulomatous: characterized by the formation of granulomas, which are organized collection of immune cells that form in response to an irritant or immune trigger. - Non-granulomatous: do not involve granuloma formation but are characterized by diffuse inflammation The epidemiology of pulmonary fibrosis (PF), varies depending on the underlying CAUSE The exact cause of pulmonary fibrosis often remains unclear, but several known risk factors and etiologies have been identified: - Idiopathic: In many cases, no specific cause can be identified, it is thought to be linked to a combination of genetic predisposition and environmental factors. - Environmental and Occupational factors: Chronic inhalation of harmful substances such as silica dust, asbestos fibers, hard metal dust, coal dust, gran dust and animal droppings, can damage lung tissue, leading to fibrosis: - Autoimmune Diseases: It an occur as a result of certain autoimmune or connective tissue diseases, where the immune system mistakenly attacks lung tissue. - Medications and Radiation Therapy: Certain drugs and treatments such as chemotherapy, heart medication, some antibiotics and anti inflammatory drugs can cause lung tissue damage leading to fibrosis: - Infections: Chronic or severe lung infections such as pneumonia or tuberculosis, can cause Progressive scarring of the lung tissue has a significant impact on LUNG FUNCTION Patients with pulmonary fibrosis typically show a restrictive lung pattern on pulmonary function tests (PFTs). - Their Total Lung Capacity (TLC) is usually reduced due to lung stiffness and loss of elasticity. - Forced Vital Capacity (FVC) is also decreased because the lungs cannot fully expand. - Residual Volume (RV) is lower as well due to decreased lung compliance. - Although FEV1 is reduced, the FEV1/FVC ratio often remains normal or even increased due to a proportional reduction in both FEV1 and FVC. This distinguishes restrictive diseases like pulmonary fibrosis from obstructive diseases like COPD, where the FEV1/FVC ratio is reduced. ARTERIAL BLOOD GASSES (ABGs) analysis helps assess the efficiency of gas exchange in the lungs. - Patients with pulmonary fibrosis often experience hypoxemia (low blood oxygen levels), especially during exercise, due to impaired oxygen diffusion across the thickened alveolar membranes. As the disease progresses, hypoxemia may become more prominent, even at rest. This is because the diseased lungs cannot maintain efficient oxygen transfer under increased metabolic demands. - Initially, PaCO2 may remain normal or slightly reduced due to hyperventilation. However, as fibrosis progresses and respiratory muscle fatigue occurs, PaCO2 may rise, leading to type 1 respiratory failure (hypoxemia without hypercapnia (normal PaCO2)) TREATMENT strategies include both pharmacological and non-pharmacological approaches to manage symptoms, slow disease progression, and improve the quality of life for patients. - Non pharmacological Identify and remove potential triggers, such as environmental toxins, drugs, and allergens. For instance, quitting smoking is crucial Addressing any underlying medical issues that may contribute to ILD is essential. This can include managing autoimmune diseases or infections that exacerbate lung inflammation. For patients experiencing hypoxia, supplemental oxygen can significantly improve symptoms. Oxygen therapy may be provided on an ambulatory basis or as long-term therapy to  A structured pulmonary rehabilitation program, which includes exercise training, education, and nutritional support, can enhance the quality of life for ILD patients by improving physical endurance and respiratory function. In advanced stages of ILD, especially in patients with severe breathlessness, palliative care becomes vital. This may include palliative oxygen therapy to relieve symptoms and improve comfort In carefully selected candidates who are physically and psychologically robust, lung transplantation may be considered, particularly for patients with a diffusion capacity of the lungs for carbon monoxide (DLCO) less than 40%. - Pharmacological Non-IPF → Corticosteroids for rapidly progressive ILDs, particularly those presenting with acute respiratory failure, to reduce inflammation and stabilize lung function. → Immunosuppressants like intravenous cyclophosphamide, methotrexate, and azathioprine may be employed to manage ILD associated with connective tissue diseases or sarcoidosis. These agents help in achieving a steroid- sparing effect and can mitigate Non-IPF → Corticosteroids are not generally beneficial, instead, antifibrotic agents such as pirfenidone and nintedanib have demonstrated efficacy in slowing disease progression and preserving lung function. → Addressing comorbid conditions such as gastroesophageal reflux, which may exacerbate cough, is also an important part of the management strategy. Pulmonary Hypertension Associated with ILD → Long-term warfarin therapy may be indicated, especially if there is evidence of thromboembolic disease. This approach aims to reduce the risk of complications related to increased pulmonary artery pressures.  OXYGEN DELIVERY Oxygen delivery is a critical therapeutic intervention for managing patients with hypoxaemia (low levels of oxygen in the blood) The primary goals of oxygen therapy are to correct hypoxaemia and prevent the resulting hypoxia, a state where the supply of oxygen is insufficient to sustain normal physiological functions. Oxygen delivery methods are crucial in managing patients with respiratory conditions. They can be classified into low-flow and high-flow systems, each serving distinct purposes and patient needs. They in particular depend on age, oxygen requirenments/ therapeutic goals, patient tolarance to selected interface and humidification needs - Low-Flow Systems: They provide a variable concentration of oxygen depending on the patient's breathing pattern. These systems are best suited for patients who can initiate their own breaths and do not require high levels of supplemental oxygen. Example are the nasal cannula, the simple face mask and the face tent - High-flow systems: They provide a fixed concentration of oxygen, regardless of the patient’s breathing pattern. These systems are ideal for patients with more severe respiratory distress or those requiring precise oxygen concentrations. Examples are the Venturi mask (most useful), high-flow nasal cannula and the non-rebreather mask  OXYGEN THERAPY Oxygen therapy is a crucial intervention for managing various respiratory diseases, particularly in acute settings where immediate intervention is necessary. It encompasses several approaches tailored to specific patient needs, including Ambulatory Oxygen Therapy (AOT), Palliative Oxygen Therapy (POT), and Long-Term Oxygen Therapy (LTOT). It helps alleviate hypoxia, improves oxygenation, and enhances the quality of life for patients - In acute asthma Oxygen therapy depends on level of hypoxaemia but typically High Flow Oxygen via non-breather mask or high flow nasal cannula - In COPD Is a critical component of managing COPD, particularly for patients experiencing hypoxemia. However, giving too much oxygen can be harmful for this patient because: - They could lose the hypoxic drive In healthy individuals, low pO2 is the primary stimulus for breathing, however, if too much oxygen is administered, this hypoxic drive can be suppressed. Consequently, patients may not breathe adequately, leading to an accumulation of carbon dioxide and potential respiratory failure. - Another complication arises from ventilation-perfusion mismatch. In COPD, certain lung areas may beco